1,254 Matching Annotations
  1. Oct 2021
    1. These results indicate that Dmrt1functions downstream of Kdm6b to initiate the male pathway in T. scripta.

      The authors demonstrate that Dmrt1 expression relies on Kdm6b function in male gonad development, and that Kdm6b targets Dmrt1 to activate male gonad development at MPT.

    2. These data provide functional evidence that disruption of Kdm6b leads to female development at 26°C, indicating that high transcript levels of Kdm6b are critical to activate the male pathway in this temperature-dependent sex determination system.

      The knock-down of Kdm6b caused female gonad development at MPT, which shows that Kdm6b is required for proper temperature-dependent male gonad development.

    3. These expression profiles suggest that Kdm6b is an early responder to temperature or hormone treatments

      The specific abundance of Kdm6b expression in developing gonads at MPT, FPT-to-MPT temperatures, and hormone treatment show that KDM6B likely functions in temperature-dependent sex determination.

    4. implying that KDM6B functions in somatic cells to regulate the sexual development of T. scripta

      The authors only detected KDM6B in the developing cells in the gonads at MPT, so they conclude that KDM6B may function in sex development.

    5. The gene is not inherently responsive to temperature, as its male-specific expression was initiated at stage 13 in the gonad-mesonephros complexes but not in other embryonic tissues

      The authors want to know how Kdm6b expression changes based on temperature specifically in the gonads instead of all developing tissues.

    6. Although these findings suggest a reptile-wide role of Kdm6b in regulating temperature-dependent sex determination, they also suggest that both evolutionary recruitment to the pathway and the molecular mechanism of action differ across species.

      It is important to note that the Kdm6b pathway is likely used by many reptiles to regulate temperature-dependent sex determination, but that the way each species has evolved to use it might be different.

    7. These results strongly implicate KDM6B as the upstream regulator of the male pathway

      KDM6B is required for Dmrt1 activation and specifically associates with the promoter of Dmrt1.

      This shows that KDM6B orchestrates male sex development early in gonadal cells by directly removing H3K27me3 at the Dmrt1 promoter to activate Dmrt1 expression.

  2. Sep 2021
    1. After ablation, we observed a 95% reduction in time spent exploring the open arm of the EPM and a 57% increase in duration of the immobility time in the FST

      These findings validate the effectiveness of TH-IR ablation by 6-OHDA, as a decrease in time spent in the open arm of the EPM is associated with increased anxiety, and an increase in immobility time in the FST is associated with a depressed state. These results are not surprising as it is expected that a halt in the synthesis of dopamine (the feel-good transmitter) would increase anxiety and depression.

    2. Long-day exposure produced the opposite effects

      For rats, nocturnal mammals, increased photoperiod exposure is a stressor. Consequently, in both the EPM and FST, rats exhibit more depressive/anxious behaviors following long photoperiod exposure. In the EPM test, these rats spend less time in the open arm, and in the FST, they give up swimming and become almost immobile much sooner than the control group. For the short-day exposure group, the rats have more open arm activity, and in the FST persevere for longer, indicating reduced anxiety relative to the control group.

    3. Assays of CRF in the CSF and corticosterone in the plasma confirmed this to be the case (Fig. 4D).

      Panel D of Figure 4 shows that CSF levels of CRF and plasma levels of corticosterone significantly decrease following short photoperiod exposure. In panel B, short photoperiod exposure results in elevated coexpression of D2R and SST2/4R. These findings support the hypothesis that increased coexpression of D2R and SST2/4R has inhibitory effects on CRF neurons of the third ventricle.

    4. These results demonstrate that transmitter respecification is not achieved by translation from preexisting transcripts and involves de novo induction of TH or SST mRNA

      The experimenters' measurements of mRNA expression are used to determine whether transmitter respecification is resulting from new transcription or preexisting transcription. If transmitter respecification is resulting from preexisting transcripts, TH and SST mRNA would already be present in the cytosol and only following exposure to a certain photoperiod condition, translational machinery would translate that existing mRNA. Thus, if the source is preexisting mRNA, then we should not observe TH and SST mRNA counts follow numbers of TH and SST neurons, and instead mRNA levels should be unchanged. The fact that the experimenters are observing that mRNA levels follow TH and SST neuron count demonstrates that the photoperiod exposure condition is inducing de novo transcription, rather than direct translation of preexisting transcripts.

    5. Newly expressing TH-IR neurons induced through short-day photoperiod exposure coexpressed additional dopaminergic markers (3), VMAT2 (fig. S6), and the dopamine transporter, DAT (fig. S7).

      Because one role of VMAT2 is to package dopamine from the cytosol into synaptic vesicles for their release from the neuron, VMAT2 serves as a marker for the presence of dopamine. In addition to VMAT2 expression, the expression of the dopamine transporter, DAT, was also observed. Altogether, these findings serve as evidence that the newly expressed TH-IR neurons, induced by short-day photoperiod exposure, are indeed synthesizing dopamine.

    6. The number of intracellular SST-IR storage vesicles depended on photoperiod light-cycle duration

      Panel D is consistent with the findings in Panel B and Panel C, which also demonstrate an increase in SST expression following increase day exposure.

    7. The 43% increase and 96% decrease in TH-IR/SST-IR coexpression after short- and long-day exposure, in contrast to the balanced photoperiod, suggest that TH-IR and SST-IR neurons are recruited from a reserve pool of cells (23) that are switching transmitters

      In response to the photoperiod exposure condition, the circuit activity changes such that the neurons of the reserve pool are switching transmitters. The researchers believe that the TH-IR and SST-IR neurons are coming from this reserve pool of cells based on their finding that short-day exposure led to an increase in the recruitment of TH-IR neurons and diminishment of SST-IR neurons, while long-day exposure had the opposite effect.

    8. Double immunofluorescence revealed that different photoperiods changed the balance of dopamine and SST coexpression in neurons in the PaVN and PeVN

      The experimenters performed immunostaining for both dopamine and SST expression. Panel B depicts immunofluorescence of these transmitters in the PaVN. The first of the three images depicts the results from long day exposure; under this condition, there is an abundance of red representing an increase of SST expression and very little green indicating that there is a decrease in dopamine expression. Under short day exposure (third image), the opposite is true.

    9. TH expression did not differ from controls exposed to the 12L:12D photoperiod for 2 weeks

      Finding that the TH-IR neuron counts are reversible upon application of opposite photoperiod treatment is further evidence that sensory stimuli can induce neuroplastic changes in the already mature brain.

    10. No significant BrdU labeling was detected in the LPO, PaVN, or PeVN

      BrdU labeling did not result in significant amounts of active poliferating cells; this is an initial indication that inverse SST and dopamine expression is not due to neurogenesis.

    11. Week-long exposure to each of the different photoperiods failed to produce changes in numbers of TH-IR neurons in an adjacent nucleus, A13 (Fig. 1E and fig. S2B), which does not receive retinal input via the SCN

      In order for the dopamine alterations to be induced by changes in light exposure duration, the dopaminergic neurons must be able to receive retinal input, as is the case with the dopaminergic neurons in the hypothalmic nuclei, innervated by the retino-hypothalmic projection. If the neurotransmitter respecificaiton is indeed due to the photoperiod treatment, dopamine production at an adjacent dopamine source, which does not receive retinal input via the SCN, should be unaffected.

    12. Circadian fluctuations do not account for changes produced by different photoperiods.

      Within the three photoperiods, 19L:5D, 5L:19D, and 12L:12D, the number of TH-IR neurons are similar. Because there is a consensus within each photoperiod, this is indicating that circadian fluctuations are not contributing to neurotransmitter respecificaiton.

    13. FFN511 generated fluorescent signals in hypothalamic slices from brains of animals exposed to each of the three photoperiods. Fluorescence decreased upon KCl depolarization

      In panel C, before KCl depolarization, there is observable fluorescent signals from FFN511, indicating dopamine uptake. Upon KCl depolarization, the fluorescence is diminished; this is indicative of dopamine release. The results of panel C are consistent with panel A and B in that during the long day light condition (19 hours light, 5 hours darkness), the fluorescence signal is the lowest, which means less dopamine being taken up.

    14. Dopamine is colocalized with TH in the PaVN after exposure to each of the photoperiods. n = 5 animals for each photoperiod.

      Panel B: The fact that in all three photoperiod conditions, dopamine is colocalized with TH validates the use of TH as a marker of dopamine synthesis.

    15. Natural stimulation of other sensory modalities may cause changes in transmitter expression that regulate different behaviors.

      The researchers found that neurotransmitters are not actually fixed upon maturation, but are, in actuality, dynamic and can be affected by sensory stimuli such as longer or shorter photoperiods. Changes in transmitter expression result in behavioral changes as well. Thus, follow up research can explore what other sensory stimuli can change transmitter expression and also examine the corresponding behaviors that are regulated by those transmitters.

    16. Induction of newly dopaminergic neurons through exposure to the short-day photoperiod rescued the behavioral consequences of lesions.

      Shortening the length of daylight the rats are exposed to induced the formation of new dopaminergic neurons and thereby restored the rats' previous (normal) behaviors, i.e., the rats no longer displayed anxious and depressed behaviors.

    17. Pharmacological blockade or ablation of these dopaminergic neurons led to anxious and depressed behavior, phenocopying performance after exposure to the long-day photoperiod

      Using drugs to prevent dopamine production resulted in anxious and depressed behaviors by the rats; these same behaviors were also observed following extended day length exposure.

    18. Changes in postsynaptic dopamine receptor expression matched changes in presynaptic dopamine, whereas somatostatin receptor expression remained constant.

      When more of the neurotransmitter dopamine is produced, there is also an increase in the postsynaptic dopamine receptor. Likewise, when less dopamine is produced, it follows that there is a decreased expression of dopamine receptors. However, for somatostatin, this was not the case. Regardless of whether somatostatin production is increased or decreased, the somatostatin receptor expression is unchanged.

    1. We found that specialization, modularity, nestedness, and the simulated robustness in all scenarios to species loss of the O‘ahu networks overlapped with the range of values observed in other networks.

      The results from the simulated extinction, along with the measurement of network interaction patterns (modularity, nestedness, and specialization), were all similar between O'hau and other tropical or non-tropical locations.

    2. Thus, plant-animal networks appear to have distinct links (high interaction rewiring) even when the same species are present in both sites, irrespective of whether networks are dominated by native or introduced species

      The authors conclude that plants and animals at different sites across the island develop their own unique pattern of interactions, whether the sites are populated by mostly native or novel species.

    3. Surprisingly, only 53% of the interaction dissimilarity was due to differences in species composition among sites (βST = 0.30 ± 0.09), whereas 47% was because pairs of species that interacted in one site did not interact in another site where they co-occurred (βOS = 0.27 ± 0.07; fig. S4

      Referring to figure 3, the majority of dissimilarity across sites was due to linkage turnover, represented as the gray bars. This means that even though the sites shared similar species, the interactions were different.

    4. [interaction dissimilarity (βWN) = 0.57 ± 0.11, mean ± SE; n = 21 pairwise sites; Fig. 3 and table S5], indicating that, on average, only 43% of interactions were shared between sites despite the most common bird and plant species occurring at all sites (tables S2 and S3)

      The authors found that the majority of the sites in O'ahu had different sets of interactions between plant and bird species.

    5. Here we show that the interaction patterns recurrently identified in native-dominated networks also emerge in novel mutualistic networks composed of species with little or no shared evolutionary history. This result indicates that prolonged shared evolutionary history is not necessary for the emergence of complex network structure

      The authors concluded that introduced species do not necessarily have to be evolutionarily related to native species to form similar interaction networks. This conclusion was based on their results demonstrating that introduced species on the island successfully formed modular networks comparable to the networks that were formed between native species. 

    6. Furthermore, partner sharing (how distinct species share resources) in SDNs on Oʻahu is structured in a complementary way among bird and plant species, giving rise to distinct modules in which certain birds and plants interact preferentially. The emergence of such structures indicates that these novel SDNs largely reproduce the well-known patterns exhibited in mutualistic networks (18) and that SDN structure is highly conserved, regardless of variation in plant and bird communities.

      The introduced birds and plants integrate successfully into the ecosystem of O'ahu because they follow the same strategies used by the native plants and birds: creating beneficial relationships with specific species and carefully sharing the resources of the island with other organisms. 

    7. We found that despite all interactions being novel and primarily involving introduced species, networks were structurally complex and notably similar between scales (local versus regional) and across sites.

      The authors concluded that overall, the complex network structures of the island's ecosystem on both the local and regional scale remained the same, even though these networks were now infiltrated with invading plant and animal species.

    8. At the local scale, networks had low to intermediate connectance and, unlike the regional network, were not nested. Similar to the regional network, six of seven local networks were specialized and modular, presenting three or four modules (Fig. 2, fig. S3, and table S4)

      At individual sites, the authors again saw species mostly interact with only a subset of the total partners available. 

    9. Thus, although introduced birds are critical for seed dispersal in the ecosystem, they are primarily dispersing introduced plants (only 6.7% of interactions involved native plants).

      The authors concluded that the majority of plants and animals involved in the seed dispersal networks of O'ahu are introduced species, and that the majority of seeds being dispersed by these birds are from introduced plant species.

    10. Oʻahu’s SDN included 15 bird and 44 plant species connected by 112 distinct links (Fig. 1)

      The authors identified 44 different plant species and 15 different birds in O'ahu. Figure 1 depicts each bird (left column) and each plant (right column) as rectangles. The lines connecting a bird to a plant represent a seed dispersal event.

    1. Cities that implemented a Level 1 response (any combination of control measures) (figs. S2 and S4) pre-emptively, before discovering any COVID-19 cases, reported 33.3% (95%CI: 11.1-44.4%) fewer laboratory-confirmed cases

      The result shows that early intervention can decelerate the spread of COVID-19.

      To calculate the percentage used here, the authors first calculated the difference in the average numbers of laboratory-confirmed cases for two groups of cities. The difference was then divided by the number of cases for cities that introduced controls later.

    2. The dispersal of COVID-19 from Wuhan was rapid

      By referring to the cumulative number of cities that reported COVID-19 cases and comparing the spreading trend to that of the H1N1 pandemic, the authors concluded that the spread of COVID-19 was rapid.

    1. Our results underscore the combined value of balloon and satellite ozone data, volcanic aerosol measurements, and chemistry-climate models

      This paper shows that in order to draw a conclusion about the healing of the Antarctic ozone hole, the following is required:

      1. Gathering data on the amount of atmospheric ozone over time using balloons and satellites.

      2. Since aerosols released by volcanic eruptions can deplete ozone, volcanic aerosols must be measured.

      3. Ozone depletion models which account for climate and chemistry must be used to interpret ozone abundance data.

    2. ozone holes in 2011 and 2015 are estimated to have been, respectively, about 1.0 million and 4.4 million km2 larger because of volcanic eruptions (especially Puyehue-Cordón Caulle in 2011 and Calbuco in 2015) than they would otherwise have been, substantially offsetting the chemical healing in those years.

      If the effects of the volcanic eruptions in 2011 and 2015 are removed, the chemically-induced Antarctic ozone hole shows signs of healing.

    3. Because the model reproduces much of the observed year-to-year variability in September total ozone from both the South Pole station and SBUV observations, confidence is increased that there is a significant chemical contribution to the trends

      The model is accurately simulating the ozone trends, and it shows that the decline in ozone depleting chemicals is driving the healing.

    4. along with strong chemical recovery, make September the month when the Antarctic ozone layer has undergone the largest amount of healing since 2000

      While October is the month when the Antarctic ozone hole was originally discovered, the smaller variations from non-chemical factors makes it easier to observe healing in September.

    5. Further, the conclusion that the volcanic aerosols were the dominant cause of the record size of the October 2015 ozone hole

      Since the ozone depleting substances released by humans were not increasing, it was important to understand why the Antarctic ozone hole was so large in the year 2015.

      The paper concludes that the unusually large hole was due to a volcanic eruption in Calbuco, Chile.

      The sulfur based aerosols released from volcanoes can also deplete the ozone layer, so they must be accounted for when tracking the hole over time.

    6. recovery of the ozone layer since the Montreal Protocol.

      The Montreal Protocol was established to heal the hole in the ozone layer by phasing-out the release of ozone depleting substances. This paper concludes that the hole in the Antarctic ozone layer is starting to heal as a result of the reduction in ozone depleting substances.

    1. Conclusions

      when finishing a paper make sure to add transition phrases such as " finally" , " so", " in conclusion".

  3. Aug 2021
    1. Indeed, when the same reactants were subjected to rhodium catalysis [1 mol % Rh2(OAc)4], O–H and N–H insertions were the predominant reaction pathways, and copper catalysis [10 mol % Cu(OTf)2] gave complex mixtures of products (table S7).

      Reactions catalyzed by Rma cyt c have distinct advantages such as high chemoselectivity and enantiospecificity over reactions catalyzed by organometallic catalysts.

    2. free alcohols and primary amines

      Free alcohols and primary amines are reactive functional groups that do not interfere with this enzymatic carbene-transfer reaction.

    3. chemoselectivity

      Rma cyt c exhibits preference for carbon-silicon bond formation over other competing side reactions.

    4. We thus chose Rmacyt c as the platform for evolving a carbon–silicon bond-forming enzyme.

      The wild-type protein chosen must exhibit some degree of activity for the desired reaction. When compared to hemin, hemin with bovine serum, a range of cytochrome P450 and myoglobin variants, it was found that Rma cyt c showed 97% ee. This was chosen as the enzyme that would form the starting point for directed evolution.

    1. We found that populations of interneurons in the adult rat hypothalamus switched between dopamine and somatostatin expression in response to exposure to short- and long-day photoperiods.

      Altering the amount of time that a rat is exposed to light in a day leads to changes in the type of neurotransmitters being expressed by a set interneurons located in the hypothalamus. When the rat's daily light exposure is restricted to a shorter time frame, those interneurons favor dopamine expression. In contrast, longer daily periods of light exposure results in those same interneurons favoring somatostatin expression.

    1. In summary, this analysis shows that

      The authors summarized all major findings in this paragraph.

    2. But together and interactively, these control measures offer an explanation of why the rise in incidence was halted and reversed

      The simulated result agrees with the actual data, revealing that simultaneously taking both measures may be the reason for the reduction in the total case number.

    3. Thus, neither of these interventions would, on their own, have reversed the rise in incidence by 19 February

      The simulated patterns of transmission with single or no intervention taken are different from the actual scenario shown in Fig. 4A. The discrepancy means that neither of these interventions could overturn the spreading and growth of COVID-19 in China when implemented individually.

    4. the case reproduction number declined to 0.97, 2.01 and 3.05 (estimated as C1R0) in three groups of provinces, depending on the rate of implementation in each group (Table 3 and table S4). Once the implementation of interventions was 95% complete everywhere (stage 2), the case reproduction number had fallen to 0.04 on average (C2R0)

      The significant reductions in the case reproduction number due to the regional (stage 1) and massive (stage 2) implementation of transmission control measures point to the importance of intervention in stopping the epidemic.

    5. suggest that transmission control measures were not only associated with a delay in the growth of the epidemic, but also with a marked reduction in the number of cases

      The transmission control measures were also found effective in reducing the total number of cases.

      Reaching the peak of the number of confirmed cases means that an epidemic stops growing and turns to an end. Thus, reaching the peak sooner is desired in this case.

    6. cities that suspended intra-city public transport and/or closed entertainment venues and banned public gatherings, and did so sooner, had fewer cases during the first week of their outbreaks

      The coefficients in Table 2 are statistically significant. This means that each coefficient is significantly different from the value under the null hypothesis of no correlation, indicated by the probability for the null hypothesis to be true, P, smaller than 0.01.

      These results indicate correlations between the factors shown in the table and the number of laboratory-confirmed cases.

    7. see also figs. S2 and S4

      The authors summarized measures taken by different cities and the timing of responses.

      The differences in the types of measures and the timings of their implementations offer directions for the correlational studies present in the later sections of this paper.

    8. a delayed arrival time of COVID-19 in other cities by an estimated 2.91 days (95%CI: 2.54 to 3.29 days)

      The Wuhan lockdown was found to effectively delay the spread of COVID-19 to other cities in China.

    9. COVID-19 arrived sooner in those cities that had larger populations and had more travellers from Wuhan

      Based on the statistically significant correlation shown in Figure 2C, the authors concluded that the outflow of people from Wuhan before the shutdown is positively associated with the spread of COVID-19.

      This finding lays a foundation for the later examination of the effectiveness of the Wuhan shutdown in slowing the dispersal of COVID-19.

    10. In 2020, the travel ban prevented almost all of that movement and markedly reduced the number of exportations of COVID-19 from Wuhan

      A sharp drop in the number of movements from Wuhan confirmed the effectiveness of the travel ban.

    1. During the following centuries, introduction of MeV into naive human populations and/or flare-ups of the disease might have caused some ancient epidemics whose etiology remains uncertain.

      Because we do not have sequence data on all outbreaks occurring after measles emerged as a human virus, we cannot say if all outbreaks of similar diseases were caused by measles or a similar related virus that then died out.

    2. Then, almost as soon as contiguous settlements reached sufficient sizes to maintain the virus’ continuous transmission (Fig. 3), it emerged as a human pathogen, the progenitor of modern-day MeV.

      When human populations were large enough, this virus mutated again and kept spreading throughout human populations. This virus eventually became modern-day measles.

    3. As a fast-evolving RNA virus, it may have produced variants that were able to cross the species barrier on several occasions, but small human populations could only serve as dead-end hosts.

      Bovine virus mutates quickly because it is an RNA virus. It may have mutated so that it was able to infect humans on multiple occasions. However, human populations were not yet at the critical community size, so the virus died out.

    4. Under this scenario, a bovine virus, the common ancestor of modern strains of RPV and MeV, circulated in large populations of cattle (and possibly wild ungulates) since its divergence from PPRV around the fourth millennium BCE [3199 BCE (95% HPD interval, 4632 to 1900 BCE)]

      Before measles became a disease of humans, its predecessor, bovine virus, was common in cattle and possibly other hoofed mammals. This bovine virus was already distinct from peste des petits ruminants virus which is the virus most closely related to it.

    5. We found a significantly negative coefficient for the time-dependent nonsynonymous/synonymous substitution rate ratio (ω) (11), indicating strong long-term purifying selection;

      Nonsynonymous mutations change the sequence of a protein and are more likely to cause changes in function, while synonymous mutations don't change the protein and are silent in terms of function.

    6. significant additional unexplained variation, as modeled by the random effects
    7. a significantly positive coefficient for the fixed effect on the PPRV rate, indicating a faster evolutionary rate in this clade
    8. The relatedness of the 1912 and 1960 genomes to now extinct MeV lineages is in line with a marked reduction of MeV genetic diversity during the 20th century as a product of massive vaccination efforts.

      When vaccines for measles were introduced the number of people infected declined significantly this caused many strains to die out.

  4. Jul 2021
    1. streamlined alternative to transition-metal catalysis

      Although transition metal catalysis offers several advantages, the metals typically used are toxic. Removal of these metals after the synthetic process is time consuming and expensive. The process described in the research ensures sustainability and reduces cost.

    2. functional-group protection and/or manipulation

      Functional group protection and deprotection increases the number of steps and auxiliary agents during synthesis and is not considered green. The methodology described in this research obeys one of the principles of green chemistry: "Unnecessary derivatization (use of blocking groups, protection/deprotection, temporary modification of physical/chemical processes) should be minimized or avoided if possible, because such steps require additional reagents and can generate waste."

    3. “Active site” structure of wild-type Rma cyt c showing a covalently bound heme cofactor ligated by axial ligands H49 and M100. Amino acid residues M100, V75, and M103 residing close to the heme iron were subjected to site-saturation mutagenesis.

      Axial methionine in cyt c is known to be labile. The proposed model for the binding for the iron-silane complex is one where the complex forms such that the silane molecule takes the place of the axial methionine. The silane may approach from the more exposed side in the protein. This further explains the observed stereochemistry of the organosilicon product. The V75T, M100D, and M103E mutations are thought to improve reactivity by providing better access of the substrate to the iron center.

    4. Synthetic methodologies such as carbene insertion into silanes can be rendered enantioselective using chiral transition metal complexes based on rhodium (11, 12), iridium (13), and copper (14, 15).

      Certain iridium catalytic systems show 97% ee, while copper catalysts show 35% ee and rhodium has been shown to exhibit 77% ee.

  5. Jun 2021
    1. The regional network had low connectance, moderate specialization, and nested and modular topologies, with three distinct modules (Fig. 1, fig. S2, and table S4).

      When studying larger areas of the island, the authors observed that species engaged in only a small portion of the possible interactions available, with groups of species specifically interacting amongst each other.

    2. Our findings suggest that shared evolutionary history is not a necessary process for the emergence of complex network structure, and interaction patterns may be highly conserved, regardless of species identity and environment.

      Invasive species can maintain interactions and behaviors with their surroundings similar to the native species they replaced, even if both species are not related.

    1. These in vitro and in vivo examples of carbon–silicon bond formation using an enzyme and Earth-abundant iron affirm the notion that nature’s protein repertoire is highly evolvable and poised for adaptation:

      Rma cyt c V75T M100D M103E variant is not the most evolved protein. This is considered only as a starting point to future enzymes that will show greater selectivity.

    2. Chemoselectivity and in vivo activity of evolved Rma cyt c.

      With each mutation, the chemoselectivity of the enzyme is greatly enhanced. V75T M100D M103E favors the carbon-silicon bond 29 times more than the wild type. This is attributed to the improved binding and orientation of the silicon donor in the enzyme's active site.

    3. No product formation was observed in the absence of heme,

      Heme proteins are required for the reaction to occur.

  6. Apr 2021
    1. only two mice treated with anti-CTLA-4 had tumors by day 30, and one additional mouse developed a tumor around day 40

      By treating the mice with anti-CTLA-4, the authors were able to prevent tumor growth in two mice and delay it considerably in the other three.

    2. These results demonstrate that tumor rejection mediated by CTLA-4 blockade results in immunologic memory

      The mice described in this section rejected the tumors twice: the first time, they were being treated with anti-CTLA-4, and the second time, they were not. This means that their immune system was able to fight off the second tumor on its own, and much faster than the immune systems of mice which had not previously survived exposure to the tumor. These are hallmarks of immunologic memory, the same phenomenon that ensures you only get chicken pox once in your life.

    3. Anti-CTLA-4 appeared to be less effective at a tumor dose of 1×1061×106<math xmlns="http://www.w3.org/1998/Math/MathML"><mn>1</mn><mo>×</mo><msup><mn>10</mn><mn>6</mn></msup></math> cells, where treatment resulted in significantly reduced tumor growth rates, but four of five mice developed progressively growing tumors

      The authors repeated the experiment with an even lower tumor burden of 1x106 cells and found that the effectiveness of treatment was reduced at this dose. They do not propose a reason for this; perhaps you can think of one?

    4. three of five mice treated with anti-CTLA-4 developed very small tumors, all of which regressed completely by day 17

      The third group of mice was treated with antibodies targeting CTLA-4. Those mice were able to clear the tumors more quickly, by day 17, if they developed tumors at all.

  7. Mar 2021
    1. We believe that the simple design, fabrication, and operation of these color-changing soft machines make these systems accessible and potentially useful to many different scientific fields.

      The authors suggest that their devices can be used by other scientists to observe things such as how camouflage can affect predator/prey relationships. Because these devices are non-living things but have the same camouflaging capabilities of some living things, they can avoid using animals for testing and experiments; something that is unavoidable otherwise.

    2. The ability of color layers simultaneously to change color in the visible and the IR is a capability not used by organisms and not easily replicated by using other technologies: Animals are limited in their ability to control their temperature; soft machines fabricated in silicone elastomers are not.

      The authors show us here that their devices can camouflage in the visible light spectrum as well as the IR spectrum. This is something animals cannot do, and this shows that animals are limited in their camouflaging capabilities while their devices are not limited.

    3. Both designs created large, disjointed patches of contrasting brightness similar to the environment but not to the shape of the robot; this disjuncture in shape [disruptive coloration (3)] helped conceal the robot.

      This result sentence tells us that the robots have successfully camouflaged themselves because they have differences in brightness that mimicked the environment. Since the brightness patches did not outline the device structure, it blended right in.

    4. The weight and flexibility of the color layer did not substantially slow the robot’s locomotion (the velocity was 0.6 times the velocity of the same robot without the color layer)

      This results sentence shows that the robot's dexterity, or ability to move easily/freely, was not heavily affected by the addition of the color layer. To elaborate on their point, they show that the robot with the color layer was 0.6 times the robot without a color layer. In short, the robot with the color layer is only a bit slower than the robot without one.

    1. This article demonstrates how Monte Carlo simulation can be used to solve a real-world, every day problem: Of these three games, which one will provide entertainment for my four-year-old yet let me retain my sanity? If your child is inflexible regarding changing the rules, choose Cootie or Chutes and Ladders which have similar average game lengths. Of the two, Chutes and Ladders is probably the more interesting because of the possibility of moving both forward and backward. If your child insists on Candyland, consider changing the rules as suggested above. An alternative strategy, of course, is simply to let your child cheat. This not only shortens the games, but has the additional incentive that it usually causes the child to win and puts them in a better mood (though it certainly doesn't teach much about ethics). On the bright side, in the few weeks it has taken to complete this study, we have progressed from board games to card games, specifically Uno, which are much more interesting for adults and children. Perhaps there is a God after all.

      The most awesome set of conclusions I've read in a paper in years!

    1. Still, the SOMA represents a platform with the potential to deliver a broad range of biologic drugs, including but not limited to other protein- and nucleic acid–based therapies. The drug delivery efficacy achieved with this technology suggests that this method could supplant subcutaneous injections for insulin and justifies further evaluation for other biomacromolecules.

      This device could not only be used for pharmaceutical drugs, but since the enzyme activity was unaltered after compression, that suggests that protein-based and nucleic acid-based therapies, such as gene silencing, could be performed by this device. If further testing suggests that there are no long term effects, SOMAs could potentially replace the current insulin delivery methods, improving diabetic patients' quality of life.

    2. For example, milliposts fabricated with lysozyme and glucose-6-phosphate dehydrogenase demonstrated full enzymatic activity after undergoing the high-pressure manufacturing process (fig. S13).

      This is very important for using other medicines in the future. Other enzymes and medications such as lysozyme and glucose-6-dehygrogenase, worked in the fabricated milliposts. If the medicine you are treating a patient with requires a large dose, this SOMA may not be a good option because it can only hold so much medicine in the given space. It is also important to make the millipost stable enough to push through the gastric tissue.

    3. Increasing the depth and width of millipost penetration will increase drug loading but may compromise the gastric mucosa and increase perforation risk.

      Making the millipost longer or wider could make this SOMA more dangerous. The gastric mucosa, or stomach tissue is only 16 mm thick, so making a longer needle could allow for more drug to be stored, but it could cause damage to the stomach and could even lead the stomach to become perforated, which can lead to a deadly infection.

    4. The SOMA provides a way to deliver insulin orally and could potentially be used to administer other APIs.

      Since the delivery is oral and automatic, this device could improve the quality of life for people with diabetes. Since it worked with insulin, this device could potentially be used to inject medicines other than insulin directly into the bloodstream. This idea opens up new treatment options for people with daily injection treatments.

  8. Feb 2021
    1. The color of these microfluidic networks can be changed simultaneously in the visible and infrared—a capability that organisms do not have.

      The authors refer to the microfluidic networks they made within soft machines. They mention that these networks can be changed within both visible and infrared light at the same time, and that living organisms cannot do this.

    1. Further research will be required to determine chronic effects caused by daily gastric injections, foreign body response, and local therapeutic agent exposure.

      To ensure the safety of patients, further testing will be required. There is much more work to be done to ensure that this device is safe and does not cause any long term effects. It is possible that injecting the stomach lining repeatedly over time could have some unknown effects or there could be an immune response to this device in some people. Since the authors do not know the long term effects of this device, it will not be available on the market for some time.

    2. Of note, the deliverable dose is constrained by the volume, formulation, and stability of the millipost.

      This is very important for using other medicines in the future. If the medicine you are treating a patient with requires a large dose, this SOMA may not be a good option because it can only hold so much medicine in the given space. It is also important to make the millipost stable enough to push through the gastric tissue.

  9. Aug 2020
  10. Jul 2020
    1. Our results provide evidence of two loci with major effects on beak morphology across Darwin’s finches. ALX1, a transcription factor gene, has been associated with beak shape (15), and here we find that HMGA2 is associated with beak size.

      Coupled with the team's previous study that showed the ALX1 gene controlled beak shape, this study shows evidence that HMGA2 is associated with beak size.

      These findings show how scientific research builds upon itself to continue to not only answer questions, but to continue to ask questions.

    2. Segregation is mainly observed in species with intermediate size (medium ground and tree finches).

      In contrast to haplotypes present in large and small finches, the medium-sized finches tended to inherit the particular genes from both parents.

      This is what we may call a heterozygous condition.

    3. Genotypes associated with large beak size were at a strong selective disadvantage in medium ground finches (selection coefficient s = 0.59).

      After the drought, medium ground finches with larger beaks were at a severe disadvantage because they could not compete for food with the large ground finches.

      When a genotype is shown to be disadvantaged, what happens to the genes in that gene pool? What happens to those disadvantaged individuals? What happens to the population as a whole?

    1. the remaining trunk formed one anterior and one posterior blastema, which then differentiated to replace the missing structures

      After amputation, the trunk of the control worms that remained developed a blastema. A blastema is a mass of cells that tell other cells to differentiate (become different cell types) and sends them to the correct location in the body. In injured animals, blastemas help direct tissue regeneration. You can find out more about blastemas and regeneration through this link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753424/

    2. Our results indicate that β-catenin activity is a key target of polarity specification in planarians, providing mechanistic insight into the old, unanswered question of how blastema fate is controlled. We propose that the evolutionarily ancient β-catenin protein, in a manner reminiscent of its role during metazoan embryogenesis (6, 8), acts as a molecular switch in adult planarians and that it may play a similar role in the adult tissues of other animals.

      This research using planaria as a model organism, suggests that β-catenin is an important molecule that has been retained over evolutionary time. It acts as as switch to determine cell fate during embyrogenesis and in adult tissue. It is suggested that this hypothesis may be the same for other species and provides important insights in organ regeneration.

    3. Both blastemas of Smed-βcatenin-1(RNAi) worms adopted an anterior fate, resulting in animals with two heads of opposite orientation (penetrance = 100%, n = 39).

      All of the planaria with the β-catenin silenced developed two heads, with the second head in the location where the tail should be.

    4. Under these conditions, anterior blastemas were properly fated, indicating that the misspecification phenotype of Smed-APC-1(RNAi) depends on Smed-βcatenin-1 (Fig. 2C). Additionally, posterior blastemas adopted an anterior fate, indicating that the Smed-βcatenin-1(RNAi) phenotype does not depend on APC activity. The combined data show that signaling through β-catenin occurs at posterior amputations and is necessary and sufficient to specify tail fate. In contrast, signaling through β-catenin is blocked or never occurs at anterior amputations, and this is necessary and sufficient to specify head fate. The premature expression of the anterior marker in Smed-βcatenin-1(RNAi) worms may indicate that in wild-type planarians, β-catenin inhibition does not immediately follow amputation (Fig. 2A). We suggest that β-catenin activity acts as a molecular switch to specify head versus tail fate in planarians.

      These data suggest that the presence or absence of β-catenin is necessary during early development of the blastema so that the cells differentiate into either a head or a tail. The presence of β-catenin in the anterior end after amputation directs cells to become the head, while its absence in the posterior blastema is necessary for the cells to differentiate into the tail.

    1. the direct activation of local glial cells appeared not to be sufficient to treat parkinsonian symptoms, pointing to consideration of other circuit mechanisms.

      When blue light passed through the optrode to the STN, neuronal firing was inhibited by activating ChR2-expressing astrocytes. ChR2 allowed for the influx of calcium into astrocytes, causing a release of glutamate and adenosine into the cellular environment. Adenosine would then bind to adenosine A1 receptors and inhibit neuronal firing. Even though they were able to inhibit firing, motor pathology was still unaffected by this intervention, alluding to other circuit mechanisms.

    2. However, for PD as well as for other neurological and psychiatric diseases, maintaining high temporal precision of the circuit interrogation technology will be crucial, because as illustrated here, fundamentally different effects are seen when driving the same cell type at different temporal frequencies.

      It is clear from these results that a beneficial effect is seen in ameliorating pathological motor deficits in a frequency-dependent manner, similar to that of DBS. Optogenetics offers temporal precision and cell-type specific targeting which are necessary parameters in high-frequency stimulation of a selective cell population.

    3. Both the disease and treatment are extraordinarily complex; the fact that DBS can improve many PD symptoms, including tremor, rigidity, and bradykinesia—but not others, such as speech impairment, depression, and dementia—points to the need for ongoing work to map and functionally interrogate disease circuitry beyond the brain regions investigated here.

      Though DBS is a potent treatment for Parkinson's disease, the actual mechanism through which it can regulate motor deficits is still complex due to the multitude of neural circuitry involved as well as other glial modulators that could play a role.

    4. M1 stimulation of this kind potently influenced neural activity in the STN

      By doing a separated-optrode experiment where an optrode was placed over M1 and a recording electrode placed in the STN, the researchers were able to see a frequency-dependent resolution of parkinsonian motor deficits.

    5. Our data, in implicating deep layer V neurons as sufficient targets in primary motor cortex, may help address these issues by informing the design of cortical interventions with regard to subdural rather than superficial extradural stimulation.

      Based upon the investigators' results, they can extrapolate how their findings will impact future treatment of Parkinson's disease—not by implementing an optogenetic approach, but by targeting a different area in the pathological neural circuit that could prove more effective.

    6. HFS delivered locally to the STN area failed to affect PD behavioral symptoms

      Though they showed an increase in electrical activity upon blue light ChR2 activation, the high-frequency stimulation did not alter motor symptoms, and the increase in electrical activity does not sufficiently account for high-frequency stimulation's therapeutic effects in Parkinson's disease.

    7. HFS of afferent fibers to the STN potently reduced STN spiking across all frequency bands

      In accordance with high-frequency stimulation's therapeutic effects in Parkinson's disease patients via deep brain stimulation, the authors observed that HFS of the afferent fibers via ChR2 blue light activation reduced STN spiking.

    8. driving STN afferent fibers with HFS and LFS differentially modulated PD symptoms in a manner corresponding to frequencies of stimulation linked clinically to ameliorated or exacerbated PD symptoms

      As proof of principle, the authors were able to selectively target projection neurons and express ChR2 using the promoter Thy1. Upon high-frequency stimulation, the hemiparkinsonian rats showed a significant therapeutic decrease in rotation behavior, while low-frequency stimulation exacerbated the motion deficits.

    1. This indicates that a less degassed, high-3He/4He deep mantle source infiltrates the transition zone, where it interacts with recycled material, creating the diverse compositions recorded in ocean island basalts

      The composition of ocean island basalts provides vital information about how and when the different reservoirs are formed in the mantle. The high <sup>3</sup>He/<sup>4</sup>He ratio and degassed nature of the mantle source are clues which tell us the real age of the ocean island basalts. High <sup>3</sup>He/<sup>4</sup>He ratios means it comes from a deep mantle source. The extreme in He-C-Pb-Sr is due to the recycling of material within the transition zone. The interaction of the deep mantle with the transition zone is what creates the variability in ocean island basalts.

    2. Although unexpected, a high-3He/4He source dominating the isotope ratio could explain why the R/Ra values are higher than those found for MORBs. This would be most visible in rocks that have low helium concentrations and low U-Th-Sm contents, such as recycled pelagic sediments strongly depleted in almost all their helium and U-Th during subduction

      A "high- <sup>3</sup>He/<sup>4</sup>He" ratio indicates the predominance of helium obtained from undisturbed regions of the Earth. This ratio also indicates that chances of finding radioactive helium (helium-4) is low. Hence, it is not a surprise to see these kind of helium ratios in rocks with low concentrations of radioactive trace elements, such as, U and Th. As U and Th are the parent isotopes to helium-4, if there is no parent isotope at the start of the radioactive decay, there will be little daughter isotope produced.

    1. The gender gap in the learning of physics concepts was substantial in the control condition (d = 0.46) (F1,304 = 6.23, P = 0.01), indicating that men improved their FMCE scores more than women over the semester. In the affirmation condition, however, this gender learning gap entirely disappeared

      Values affirmation erased the gender gap in the Force and Motion Conceptual Evaluation (FMCE).

      Women who did not affirm values did not increase their scores on the FMCE from the first test to the second test as much as men did. However, women who did values affirmations had score increases similar to men.

  11. Jun 2020
    1. caused striking alterations in the anteroposterior (A/P) identity of regenerating tissues

      Silencing of β-catenin, both dishevelled homologs (Smed-dvl-1;Smed-dvl-2), or APC (Smed-APC-1) disrupted the ability of the cells to determine whether they belonged in the front or back of the animal during regeneration.

    2. Smed-dvl-1(RNAi);Smed-dvl-2(RNAi) worms also regenerated heads from both blastemas but displayed additional phenotypes, including ectopic and supernumerary photoreceptors in the anterior region.

      Smed-dvl-1(RNAi);Smed-dvl-2(RNAi) planarian groups also developed two heads, as well as extra photoreceptor cells in locations where are they are not typically found on the anterior portion of the body.

    3. In control animals at 12 hours after amputation, the anterior marker was virtually undetectable, whereas the posterior marker was clearly evident in the posterior blastema; 24 hours after amputation, the two markers recapitulated the A/P specificity seen later during regeneration and in adult animals (Fig. 1, O and S; Fig. 2, A and B). However, in Smed-βcatenin-1(RNAi) trunks, the anterior marker was expressed at both ends by 12 hours and maintained throughout the experiment, whereas the posterior marker remained markedly reduced (Fig. 2, A and B). The reverse was observed in Smed-APC-1(RNAi) trunks (Fig. 2, A and B). Consistent with the inferred time window for β-catenin signaling, Smed-βcatenin-1 and Smed-APC-1 were expressed at both ends in wild-type animals by 12 hours (fig. S7). These results indicate that β-catenin and APC act very early to determine blastema identity.

      Alvarado and colleagues surmised from the results of the previous experiment that β-catenin was regulated early in the blastema identify development. In comparing the migration and differentiation timing between both β-catenin and APC-1 with the control animals, they were able to confirm that indeed it occurred that blastema cell identity occurred very early.

    4. Our data indicate that β-catenin activity is regulated during lateral regeneration and that the β-catenin switch can dominantly misspecify regenerating tissues regardless of A/P position or amputation angle.

      The results form the fourth set of amputation experiments suggests that β-catenin is regulated at locations of amputation.

    5. Ectopic photoreceptors were visible in the tail of all (n = 20) Smed-βcatenin-1(RNAi) animals and none of the control animals (Fig. 4, G, H, M, and N). Intact RNAi-treated animals also exhibited ectopic lateral protrusions, formed a brain in the tail region, and expressed the anterior marker posteriorly (Fig. 4, I to L and O to R, and movie S6). The molecular basis for such a change of A/P polarity in an adult organism was previously unknown.

      The results of the observations of the unamputated animals with silenced genes allowed the researchers to identify that β-catenin plays a role in the anterior/posterior identity of cells in adult animals. This mechanism was not previously known.

    6. Together, our data demonstrate the fundamental importance of β-catenin in the maintenance of polarity and cell fate during tissue regeneration and homeostasis in planarians (fig. S8). Our findings reveal a dynamic control of β-catenin in adult animals that is not readily apparent during the progression of embryogenesis: The precise quantity and location of regenerating tissue is different for each individual and for each regeneration event, newly regenerated tissues must integrate with the old, and ongoing homeostatic cell turnover may require sustained instructive cues.

      This research identified previously unknown roles of β-catenin. Previous research identified the role it plays in embryogenesis with regard to cell fate and migration. However, identification of its multiple roles in adult tissue regeneration and homeostasis was not previously identified.

    7. We noted that misspecified heads and tails in RNAi-treated worms moved independently from the rest of the animal, hence this tissue was functioning autonomously (movies S1 to S3). We conclude that silencing Smed-βcatenin-1, Smed-dvl-1(RNAi);Smed-dvl-2(RNAi), or Smed-APC-1 is sufficient to misspecify blastema identity.

      Both heads and tails that developed in the wrong locations functioned separate from the the movements of the rest of the animal. The RNAi silencing changed the cellular identity of the stem cells so that they migrated to the wrong location and incorrect cell differentiation.

    8. The “posterior” head of Smed-βcatenin-1(RNAi) and Smed-dvl-1(RNAi);Smed-dvl-2(RNAi) animals contained a characteristically anterior nervous system and gut, as did the “anterior” head

      The results of the anatomical analysis indicate that the head located in the posterior region in the experimental animals resembled cells usually found in the anterior region as part of the nervous system. This indicates that stem cells did not locate to the correct position for a head when these genes were silenced.

    9. In contrast, the “anterior” tail of Smed-APC-1(RNAi) animals was devoid of discernible brain tissue and exhibited posterior structures, as did the “posterior” tail (Fig. 1, J and N)

      By silencing this protein, stem cells were directed to both anterior and posterior regions of the body, but were directed to become anatomical tails, with not formation of brain tissue present in either end.

    10. On the other hand, Smed-APC-1(RNAi) animals regenerated tails from both amputation planes

      Silencing fo the Smed-APC-1 resulted in each end of the animal developing a tail.

    1. At ~300 ka post-KPgE we see several additional signs of ecosystem “recovery”, including i) the increase and then plateau of megafloral standing richness; ii) LMA exceeding pre-KPgE levels; iii) diversification of Juglandaceae, a potentially energy-rich food source for mammals; and iv) the first significant taxonomic diversification, dietary specialization (e.g., increased herbivory), and increase in maximum body mass of mammals (Pu1/Pu2).

      The authors discovered that at around 300,000 years after the asteroid impact that (a) the increase in large, flowering plant species leveled off, (b) the average leaf mass area had increased, indicating a greater level of energy capture through photosynthesis, and (c) there was a continuing increase in the diversity of woody plants, resulting in more energy-rich food. Additional evidence indicates that there was an increase in the number of mammal species that fed on these plants. The authors concluded that these events culminated in the observed increase in the body mass of mammals.

    2. The timing of these warming intervals corresponds with changes in plant richness and taxonomic composition and, likely due to additional food sources, coincident shifts in mammalian taxonomic composition, ecologic diversification, and expansion in the range of maximum mammalian body mass

      The fossil record shows that the latest of the Cretaceous mammals exhibited a great diversity of adaptations to the environment based on their role in the ecosystem. Some were strict carnivores, others were omnivores that fed primarily on plants, and others strict herbivores. Across the K-Pg boundary, there is a pattern of extinction that selected against larger bodied mammals with specialized diets, especially strict carnivores and species with plant-based diets. This suggests that many of the extinctions were due to a decrease in photosynthesis and plant production rather than these species being instantaneously killed.

    3. For the first time, we corroborate (31) a warm interval immediately post-K–Pg in a terrestrial section.

      Terrestrial climates near the time of the Cretaceous mass extinction are not well known. Temperature estimates from deep-sea sites are more reliable. Through an analysis of fossil pollen and spore samples found in North Dakota sediments and their correlation with foraminifera fossils from deep marine sediments, it has been possible to accurately determine Earth's warming and cooling trends. These trends influence biodiversity.

    4. Our discovery supports (i) a nearly synchronous first appearance of legumes in North America and southern South America;

      Legumes appeared in the fossil record at the same time as the size of mammals was increasing. The authors concluded that legumes provided a food resource rich in proteins and carbohydrates to support larger mammals.

    5. Loxolophus sp. [(E) and (F)

      Loxolophus is the oldest placental mammal to be discovered. It has teeth for eating both meat and plants, thus adapting it to a recovering ecosystem.

  12. Apr 2020
    1. all Big Birds were homozygous

      The constant frequency of L alleles for HMGA2 and B alleles for ALX1 indicate that at these loci, the allele frequencies have reached an equilibrium.

    2. it can be established in only three generations

      The authors summarize all their evidence that homoploid hybrid speciation has occurred in the Big Bird lineage. They note how unusual this example is because it occurs faster than expected.

    3. it is likely that the founder population has already become reproductively isolated from G. conirostris

      The authors suggest in this paragraph that the Big Bird lineage is likely to be reproductively isolated from both parental species, providing further support that the lineage is on its way to becoming a new species.

    4. transgressive segregation produced genotype combinations

      Because the bill depth trait changed without changes in body size or bill length, the authors suggest that the unique combinations produced by transgressive segregation were an adaptation that allowed these birds to survive and reproduce.

    5. more indicative of selection than of drift.

      The authors combine the knowledge of genotype frequencies with the changes in bill shape and conclude that the likely reason for this is natural selection, further support for their argument that speciation is occurring.

    6. they are consistent with the hypothesis

      The different effects of the B alleles, and the fact that they segregate, support the idea that at the ALX1 gene locus, there are more than two alleles, all of which affect bill size differently. However, more data are needed to further support this hypothesis.

    7. The low values probably represent low additive genetic variation because the traits are highly heritable in Geospizaspecies

      The authors conclude that their measurements, both genetic (inbreeding coefficient, admixture, average nucleotide diversity) and bill shape (length and depth), do show low levels of variation in the Big Bird population.

      They conclude that this is expected because the bill shape traits are highly determined by genes, and so low genetic diversity would lead to low physical diversity of certain traits, such as bill shape.

    8. possibly caused by natural selection

      Based on their detailed analysis of the body size and bill shape of these Big Birds, the authors conclude that a change in the characteristics of the population is occurring such that it is becoming different than the parent populations. They suggest that it is possible that natural selection is the method by which this change is occurring, which supports their argument that a new species is forming.

    1. printed collagen had extensive cell infiltration and collagen remodeling

      FRESH-printed collagen disks had more cells and much deeper cell penetration in comparison to cast collagen disks. These results shows that FRESH-printed implants provide a better platform for host cells to move into and grow.

    2. Mechanical function was demonstrated by mounting the valve in a flow system with a pulsatile pump to simulate physiologic pressures, and we observed cyclical opening and closing of the valve leaflets

      Authors reached the following conclusions with their FRESH-printed functional tri-leaflet heart valves:

      First, the valve had well-separated leaflets, and was structurally robust enough.

      Second, the leaflets (flaps) functioned properly, repeatedly opening and closing when mounted to a pump system which generates a pulsating flow, mimicking the heart pumping blood.

      Third, less than 15% regurgitation was observed, meaning less than 15% of the fluid went backwards through the valve as the leaflets closed. Regurgitation is an indication of a leaky heart valve.

      Fourth, maximum fluid pressures measured across the printed valve were within the physiological range observed in human heart.

      Finally, authors were able to culture cells on the leaflets which demonstrates their biocompatibility and potential for developing artificial implants.

    3. We confirmed the patency of vessels ~100 μm in diameter by optically clearing and reperfusing the multiscale vasculature

      This result confirmed that the authors were able to print open vessels at small scales (100 microns). This is significant because engineering small-scale vasculature has historically been a major challenge in bioprinting.

    4. A pH 7.4 support bath with 50 mM HEPES was the optimal balance between individual strand resolution and strand-to-strand adhesion and was versatile, enabling FRESH printing of multiple bio-inks with orthogonal gelation mechanisms including collagen-based inks, alginate, fibrinogen, and methacrylated hyaluronic acid in the same print by adding CaCl2, thrombin, and UV light exposure

      The pH of support bath was set to 7.4 using a buffer agent (50 mM HEPES), which produced the best results for 3D printing.

      Additionally, this 3D printing mechanism is compatible with other 3D printing methods based on alternative gelation methods. FRESH v2.0 enables orthogonal printing, which means you can use it in combination with other 3D printing methods to create hybrid structures on the same scaffold.

    5. printed collagen had extensive cell infiltration and collagen remodeling

      FRESH-printed collagen disks had more cells and much deeper cell penetration in comparison to cast collagen disks. These results shows that FRESH-printed implants provide a better platform for host cells to move into and grow.

    1. Diamonds recovered from kimberlite pipes are less likely to have been exposed to cosmic rays,

      An elevated R/Ra ratio indicates that there has been exposure to cosmic rays in the past. This means some meteorites may have crashed onto ancient Earth and the He concentration in the rock has remained relatively undisturbed since then.

    2. The He isotopic signatures released from the sparse fluid inclusions vary from 0.7 to 49.9 R/Ra (Figs. 1 and 2).

      This observation indicates that the R/Ra ratio measured from the sparse fluid inclusions cover a very wide range of values. Higher values indicate that the relative abundance of helium-3 to helium-4 to that in air is very high (almost 50 times). When the values are this high, the elevated levels of helium-3 isotope indicates that these fluid inclusions are coming from a very ancient reservoir located deep inside the Earth.

    3. Thus, our studied diamonds provide the most direct and undegassed evidence of the variation in helium isotope compositions in Earth’s transition zone.

      In the diamond fluid inclusions richest in helium-3, the <sup>3</sup>He/<sup>4</sup>He ratio is about 50 times to that of air. This considerably high isotope ratio suggests that the real age of these fluid inclusions date back to the early days of Earth's formation.

    1. The stacked actuators readily showed large actuation response up to a frequency of 20 Hz (movie S3).

      Watch this video to view a stack of five donut HASEL actuators with an electrode diameter of 2.5 cm actuated with a 15 kV reversing square wave at 0.5, 5, 10, 15, and 20 Hz.

      The HASEL actuators can be actuated (expand and contract) up to 20 times per second.

    2. Thermally activated coiled polymer fiber actuators (49.9 kW/kg) (11) and shape-memory alloys (50 kW/kg) (11, 26) have higher peak specific power; however, their efficiency is low (<2%) (11, 26) and thermomechanical actuators are more difficult to control than electromechanical actuators.

      HASEL has a peak specific power 10 times lower than thermomechanical muscles. However, thermomechanical muscles are much less efficient (<2%) compared to HASEL (21%). HASEL is driven through electrostatic attraction with relatively less energy loss. Thermomechanical muscles expand or contract in the presence of heat to generate force. However, this also means a large portion of the energy used to power them is lost through heat.

    3. during contraction of the two-unit actuator was 614 W/kg; specific work during contraction was 70 J/kg

      Power and work of the actuators were measured for their ability to lift a hanging mass.

    4. However, the thick elastomer shells (>1 mm) used in this work required high voltages to reach electric fields large enough for actuation.

      HASEL actuators are made from inexpensive, readily available materials that only require basic fabrication techniques. However, because the elastomer shells are quite thick, they require high voltages to reach the electric fields required for actuation. As a result, authors hope to make new versions of the HASEL actuators with thinner elastomeric shells and using dielectric layers with higher permittivity, so that less voltage is required for actuation.

    5. The use of hydraulic principles in HASEL actuators results in the capability to scale actuation force and strain

      HASEL actuators combine the strengths of soft fluidic actuators and electrostatic actuators. They rely on soft matter hydraulic architectures and local hydraulic pressure generated by electrostatic forces. As a result, actuation force and strain can be scaled up.

    6. relative to donut HASEL actuators, gas bubbles were more easily trapped between the electrodes (fig. S14)

      While performing experiments with planar and donut HASEL actuators, authors observed that gas bubbles formed after dielectric breakdown occurred. Gas bubbles negatively impact the performance of the actuators. The bubbles reduce the dielectric breakdown voltages and lead to subsequent breakdowns at the same locations.

      Gas bubbles were found to be more easily trapped between electrodes in the planar HASEL actuators compared to the donut HASEL actuators, indicating that shape plays a role in the overall success of the actuator.

    7. A single unit actuator was able to operate under a large applied load of 1.5 kg [corresponding to a stress of 0.3 MPa, near the maximum value for mammalian skeletal muscle (26)] and still achieved 16% strain (fig. S13)

      The operation of a planar HASEL actuator was tested under a large load and high stress to assess if it is comparable to mammalian skeletal muscle. The load and stress applied were near the maximum values of mammalian skeletal muscle, and a 16% strain was achieved. This result depicts that the single-unit actuator is very successful and shows promise to be used in a variety of applications because multiple actuators can be combined to achieve greater results.

    8. Cycle life at high mechanical output power was demonstrated with a single-unit HASEL actuator, which provided 358 W/kg average (586 W/kg peak) specific power during contraction

      Power of the single-unit actuator was measured in the same way as the two-unit actuator. Similar to the two-unit actuator, the single-unit demonstrated 586 W/kg of peak power and an average power of 358 W/kg while lifting a 1 kg mass. The actuator is able to operate efficiently under large loads for an extended period of time.

    9. a single-unit actuator achieved 107% linear strain under a load of 250 g (actuation stress ~32 kPa) and a two-unit actuator achieved 124% linear strain under a load of 700 g (actuation stress ~114 kPa)

      The planar HASEL actuators were more effective when they are operated near their resonant frequencies. A single actuator stretched 107% of its original length when a 250 gram weight is attached. A double-unit actuator stretched 124% of its original length when a 700 gram weight is attached.

    10. Conversion efficiency was 21%,

      The percentage of the electrostatic energy fed into the actuator that is converted into mechanical energy is 21%.

    1. The dosage forms were retained in the stomach for the entirety of the experiment.

      Both smart pills with long-acting formulation 1 and 2 were able to stay in the stomach for over 20 days and provided sustained drug release during this period, demonstrating their potential as once-a-month birth control pill.

    2. To overcome the economic and cultural barriers in low-income countries, a long-acting contraceptive should have several key features. We believe that the orally administered long-acting contraceptive described here satisfies several of these considerations. These include (i) opportunity for self-administration, (ii) drug administration by the oral route, (iii) circumvention of the need for clinical procedures for dosage form removal, and (iv) maintenance of privacy. Hence, our technology stands to benefit a large patient population that prefers oral medication or is in regions of the world where self-medication is the only means to chronic therapy.

      This long-acting smart birth control pill can help overcome cultural and economic barriers in low-income countries. This once-monthly smart pill would benefit a large patient population that cannot afford high-cost birth control methods such as implants.

    3. Future successful human translation will require further development in dogs and humans with a focus on further optimal material selection for retention of the dosage form for the desired period and complete drug release in the prescribed period. Additional studies will be needed to test the contraceptive efficacy of this dosage form, which was not evaluated in these studies.

      The authors concluded that they will need to do further testing in humans and animals to test different materials that will help keep the smart pill in the stomach for a desired period and release its drug content over this period. In addition, further testing is needed to verify the efficiency of this smart pill in preventing pregnancy.

    4. Programmed exit of the dosage form from the stomach may be achieved by inclusion of tough materials that disintegrate in the presence of chemical or thermal stimuli (23, 28, 29) and pH-sensitive linkers to maximize safety in the setting of inadvertent transit across the pylorus (23, 25).

      Here, the authors describe a possible improvement to their oral contraceptive. The authors suggest that by integrating chemically or thermally responsive materials, it might be possible to program the exit time of the smart pill. For instance, the arms can disintegrate after 21 days, allowing the dosage form to leave the stomach.

    5. The first formulation (long-acting formulation–1) contained half the drug loaded into a PDMS matrix and the other half loaded into a poly(sebacic anhydride) matrix. The second formulation (long-acting formulation–2) had the entirety of the drug loaded into a PDMS matrix. Formulation-2 produced a peak concentration on day 2, after which concentrations slowly declined throughout the study. In contrast, formulation-1 produced comparable concentrations on days 3, 11, and 17, and changes in serum concentration were not unidirectional. Moreover, formulation-1 produced lower (undetectable at some time points) concentrations than formulation-2.

      In the first formulation, the drug was loaded into two different polymer matrices (half into PDMS and half into polysebacic anhydride). In the second formulation, the entire drug was loaded in one polymer matrix (PDMS).

      The first formulation resulted in continuous drug release over 20 days, however, the drug concentration in the serum was fluctuating quite a bit. In the second formulation, the drug concentration in the serum was initially high (similar to the tablet case), and steadily decreased over a 30-day period, however not as fast as the tablet form.

    6. To enable protection of drug from the gastric environment and sustained release, we encapsulated the drug in polymer matrices.

      The authors used a polymer to coat the device so that the gastric environment doesn't degrade the drug too quickly and makes sure the drug releases evenly and consistently. This explains how authors developed a solution for the second problem listed above.

    7. To address the issue of gastric residence, we chose materials and geometries that were highly durable and evaluated their performance using a series of mechanical tests.

      The movements of the stomach can break the arms of the smart pill, causing its early unintended exit. To prevent this, authors chose geometries and materials and tested their mechanical properties to make sure that the smart pill would resist the harsh acidic environment in the stomach.

    8. We detected drug in serum up to 29 days after administration of long-acting formulation–2, when the average serum concentration was 13 ± 2 pg/ml (n = 3).

      Using long-acting formulation 2, the authors detected drug in the serum for 29 days where the serum concentration remained above 10pg/ml. long-lasting formulation 1 resulted in drug concentrations which fluctuated over the 30-day period whereas long-lasting formulation 2 lead to steady decrease in drug concentration over the same period.

    9. Twenty-four hours after dosing, the average concentration fell to 16% of the maximum concentration (32 ± 6 pg/ml, n = 5), and by 48 hours, the average concentration was reduced to 5 ± 4 pg/ml (n = 5).

      After 24 hours, the average drug concentration dropped to 16% of the maximum concentration. After 48 hours, it dropped to 2.5% of the maximum concentration. Therefore, the Levora tablets provide pregnancy protection for only a day.

    10. This dosage form fits in a 000 capsule to enable oral administration and recoils in the stomach to assume a size larger than the pylorus. This latter property enables the dosage form to reside in the stomach, where it releases levonorgestrel.

      Smart pill is introduced as a capsule so that it is easy for the patient to swallow and get to the stomach. In the stomach, the capsule dissolves allowing the 6 arms to unfold such that the device is large enough to stay in the stomach for a month and release the drug over time.

    11. We then synthesized poly(sebacic anhydride) and PDMS matrices loaded with increasing amounts of levonorgestrel and analyzed drug release in vitro (Fig. 1, F and G). Drug release occurred at a near-constant rate from both matrices, and it was affected by the type of polymer matrix and amount of drug loaded.

      The authors tested the release of the contraceptive drug (levonorgestrel) loaded within a biodegradable polymer matrix (polysebacic anhydride) and another biocompatible polymer matrix (PDMS) at different concentrations (12.5, 25, 40, 50%). The authors monitored the percentage of drug released over 30 days while in the simulated gastric fluid. Drug release occurred at a near constant rate. The lower the drug concentration the faster the drug release. Drug release from PDMS matrices was slower than that from polysebacic anhydride matrices. The author concluded that by changing the matrix, the rate of drug release could be altered.

    12. Because of the higher surface area afforded by the slotted holes, we pursued this design further.

      The caged slotted holes were better than the v-shaped and caged circular holes. It allowed for optimal, sustained release of the drug over a month. This geometry provided enough surface area for effective release of the drug, while also limiting the exposure so the medicine did not run out before the month was over.

    13. 2 of the 18 arms detached from the dosage form body within 30 days after ingestion. It is likely that the amount of drug delivered and gastric retention would be adversely affected if more arms were lost or if arms were lost early. Loss of arms at later times during the dosing period, when most of the drug is released, will not affect the efficacy of the system.

      Since the arms contain the drug, losing arms would reduce the total amount of drug to be released. In addition, if arms are lost, the dosage form can pass through pylorus, and move into small intestine, and the birth control drug will no longer be effective. Therefore, the stability of the arms ensure that the smart pill is retained in the stomach and provides sustained drug release over extended periods.

  13. Mar 2020
    1. We analyzed the stability of levonorgestrel in SGF for 24 hours and observed no significant degradation (96.3 ± 4.3 μg/ml, n = 5 versus 90.4 ± 9.6 μg/ml, n = 5; P = 0.122, Student’s t test) (Fig. 1E).

      The authors tested the stability of the birth control drug (levonorgestrel) in a highly acidic environment (simulated gastric fluid) at body temperature over 24 hours mimicking the conditions in the stomach. The authors did not observe any significant degradation. The drug concentration stayed around 90 μg/mL over the 24 hours. This essentially shows that the smart pill residing in the stomach can successfully deliver the birth control drug over an extended period.

    2. To address this issue, we have developed a gastric resident dosage form that can be placed in a gelatin capsule to enable oral administration.

      The author's created a pill that can be swallowed and could stay in the digestive tract for about a month. The drug is slowly administered over the month instead of being absorbed right away.

    1. Although the 3D bioprinting of a fully functional organ is yet to be achieved, we now have the ability to build constructs that start to recapitulate the structural, mechanical, and biological properties of native tissues.

      The authors aren't quite ready to develop full organs yet, but the work done in this paper has demonstrated several leaps towards this goal: a model of a live coronary artery, collagen disks that promoted vascularization, printed ventricles and heart valves that showed typical physiological function, and a precise recreation of a full-scale heart structure.

    2. We used μCT imaging to confirm reproduction of all the anatomical structures contained within the 3D model of the heart, including the atrial and ventricular chambers, trabeculae, and pulmonary and aortic valves

      The collagen 3D printing method was able to completely and accurately reproduce all the components and features of the heart from their computer model.

    3. The decrease in cross-sectional area of the interior chamber during peak systole showed a maximum of ~5% at 1-Hz pacing (N = 4)

      During peak systole, the highest pressure generated as the ventricle contracts, the inner void of the ventricle decreased in area by about 5%. This means the walls of the printed ventricle thickened while the ventricle contracted at 60 bpm.

    4. The ventricles had a baseline spontaneous beat rate of ~0.5 Hz and could be captured and paced at 1 and 2 Hz by means of field stimulation (Fig. 3J).

      On its own, the ventricle could beat about once per 2 seconds (30 bpm). By using additional stimulation, the authors could get the ventricle to beat from 60-120 bpm.

    5. Calcium imaging revealed contracting hESC-CMs throughout the entire printed ventricles, with directional wave propagation in the direction of the printed hESC-CMs observed from the side (Fig. 3, D and E) and top (Fig. 3, F and G) during spontaneous contractions in multiple ventricles (N = 3) (movie S6).

      Electrical activity causes contraction of the cardiomyocytes, and the calcium imaging shows presence of this electrical activity. Additionally, the calcium was observed to propagate (move) through the ventricle at a velocity of 2 centimeters per second

    6. A test print design (fig. S11A) verified that the collagen pH was neutralized quickly enough to maintain ~96% post-printing viability by LIVE/DEAD staining

      The test print verified that 96% of the cardiomyocytes printed using the bio-ink were able to to survive in the printed collagen.

    7. Cardiac ventricles printed with human cardiomyocytes showed synchronized contractions, directional action potential propagation, and wall thickening up to 14% during peak systole.

      The authors FRESH printed a heart ventricle (two large chambers at the bottom of the heart that collect and expel blood) using collagen support material and cardiomyocytes (functional cells that generate contractile force in the heart). The printed ventricle mimicked several key features of a typical human heart: electrical activity, contractions, and wall thickening during the peak systole (maximum pressure reached while the ventricle contracts to pump blood out to the body).

      These results are of great significance in the field of tissue engineering. 3D printed tissues and organs can greatly improve treatment methods such as organ transplants. The authors’ ability to print a ventricle that mimics the human heart is a giant leap towards this goal.

    8. Collagen disks that were FRESH-printed with VEGF and extracted after 10 days in vivo showed enhanced vascularization relative to cast controls

      After leaving the two disks underneath the rodent skin for 10 days, the authors observed that the collagen disks containing VEGF showed much more vessel formation than the control disks.

      Vascularization shows that the body has "accepted" the collagen disks, which is a significant result.

    9. the number of cells in the constructs was significantly greater for the printed collagen at 3 and 7 days compared to cast control

      Cells filled the printed, porous collagen disks within 3 days which restructured the collagen, indicating healthy tissue formation. Very few cells filled the solid disks which indicates tissue formation was unsuccessful.

    10. demonstrating viability and active remodeling of the gel through cell-driven compaction.

      Around the static tube (no perfusion), only one layer of C2Cl2 cells remained alive after five days. In contrast, in the tube which the cells were fed (perfusion), almost all of the cells were alive after 5 days. The cells formed a tight tissue surrounding the tube that leads to compaction of the collagen.

      This result proved that the authors were able to 3D print an artificial tube with living cells mimicking a live coronary artery.

    11. the addition of VEGF to the printed collagen resulted in widespread vascularization,

      FRESH printed collagen disks (containing fibrinogen and VEGF) promoted movement of C2C12 cells (cell infiltration) into the porous structure of the collagen. They also promoted formation of blood vessel-like structures (vascularization). Overall these findings indicate that this 3D printing technique produces tissue-like structures closely mimicking physiological blood vessel formation.

    12. We present a method to 3D-bioprint collagen using freeform reversible embedding of suspended hydrogels (FRESH) to engineer components of the human heart at various scales, from capillaries to the full organ.

      This is the key result from the authors’ work. Their modified 3D printing method (FRESH) allowed them to reliably print collagen, an important protein in the extracellular matrix. This breakthrough introduces the possibility of constructing various tissues and organ components with high resolution.

      In short, the printing method dispenses a gel within another gel. Both gels contain tiny particles. The gel that is printed contains collagen which forms the scaffold for the artificial tissues and organs. The second gel mainly serves as a support structure and is melted away after printing.

    13. Tail vein injection of fluorescent lectin confirmed an extensive host-derived vascular network with vessels ranging from 8 to 50 μm in diameter throughout the printed collagen disk

      By injecting a fluorescent protein (lectin) into the rodent's vein, the authors were able to demonstrate the formation of different sized blood vessels into a network in the collagen disks. This proves the success of using VEGF

    14. Multiphoton microscopy enabled deeper imaging into the printed constructs and showed vessels containing red blood cells at depths of at least 200 μm

      Here, the authors showed that the formed vessels also contained red blood cells. To do this, they used multiphoton microscopy. This method uses photon absorption and infrared light to suppress image background and reduce light scattering. These two effects allow for a deeper tissue penetration.

    15. FRESH v2.0 improves the resolution

      FRESH v2.0 allowed authors to print collagen filaments 10 times finer than v1.0, resulting in ability to print features as small as 20 microns.

    1. The higher actuation strain is attributed to the layer of liquid dielectric, which effectively reduces the modulus of the HASEL actuator

      The soft nature of the liquid dielectric material helps HASEL actuators to move more (higher actuation strain) under the same actuation voltage.

    2. A stack of five donut HASEL actuators achieved 37% linear strain, which is comparable to linear strain achieved by biological muscle (26) and corresponds to an actuation stroke of 7 mm (Fig. 2B).

      With 5 HASEL actuators stacked on top of each other, the authors found that the strain achieved is 37%, which is the similar to the strain of actual muscle.

    1. Many practicing ecologists still view large animals in general, and apex consumers in particular, as ecological passengers riding atop the trophic pyramid but having little impact on the structure below.

      In the past, the role that top-down forces can have within a system has not been appreciated. The role that apex predators play within a complex ecosystem is not often recognized until after those organisms are removed.

      The authors are calling for a change in the lens through which ecosystem ecologists view the role of these species, specifically, that the working hypothesis of ecosystem ecologists should be that apex consumers play a fundamental role in any particular ecosystem's structure and stability until empirical research indicates otherwise.

  14. Feb 2020
    1. Hence, predator behaviour may aim to maximize foraging success based on both prey behaviour and the physiological processes that can influence behaviour of prey (i.e. metabolic rates).

      The original hypothesis that shark behavior would be solely tied to their own temperature (most active when warm and resting when cool, or some other binary relationship) is revised in light of the more nuanced pattern that the researchers observed in the data.

      Here, the authors present a new hypothesis that also includes the temperature and behavior of prey, pointing out that the sharks may be most active when the temperature gap between predator and prey is the largest due to their differences in thermal inertia. When the shark is cooling, the fish upon which it preys will have cooled down even more, reducing their ability to escape from the still relatively warm shark.

    1. engineer tissue components of the human heart

      The authors were successful in designing and fabricating human heart components with 3D printed collagen.

    1. This hypothesis is supported by the close correlation between diversification reflected in fossil juglandaceous pollen and the appearance of several large herbivorous periptychid mammals whose specialized and enlarged premolars are thought to be for hard-object feeding (37, 38).

      The fossil record shows that as woody plants increased in number and became more diverse, the diet of many mammal species shifted from being primarily omnivorous or insectivorous to herbivorous. The authors determined that this dietary shift correlated with an increase in the body mass of placental mammals as indicated through an analysis of the size and structure of the fossil mammals’ molars.

    2. We recognize sixteen mammalian taxa

      Based on skulls, teeth, and other cranial parts, the authors could conclude they had found representatives of sixteen mammalian taxa. This was supported by the work of S. Chester.

    1. The He isotopic data for fluid inclusions in superdeep diamonds presented here resolve this issue by showing direct evidence that the high-3He/4He source must be present in the deep mantle, beneath a depth of 410 km.

      This is the main conclusion of this research work. The authors have presented evidence that the diamond fluid inclusions analyzed originate from the deep mantle region of the Earth, which is at least 410 kilometers underneath Earth's surface.

    2. Our diamonds have physical features and properties that are consistent with other diamonds from Earth’s transition zone (410 to 660 km depth), including dislocations or diffuse growth zones (database S1) and no detectable nitrogen (N) or fully aggregated N defects (database S2) (24).

      There has been an ongoing debate about the exact location of the chemical reservoirs that lie deep within the planet Earth. Timmerman and colleagues have successfully narrowed down this location to Earth's transition zone, i.e., 410 to 660 kilometers underneath Earth's surface. These conclusions are based on not only the relative abundance of helium-3 to helium-4 isotopes, but also on the physical similarities between the studied diamonds with already identified ones.

    3. This observation requires that the high-3He/4He source has higher He abundances than reservoirs with low 3He/4He ratios and thus supports the presence of a primordial 3He plume.

      Any increase in the helium-3 isotope abundance provides strong evidence of the location and age of the chemical reservoirs explored in this study. Helium-3 isotope formation dates back to the beginning of Earth and any recent formation of the isotope on Earth's surface has been ruled out due to its tendency to get lost in the space. Thus the the authors are confident that this spike in helium-3 is coming from very ancient reservoir deep inside the Earth.

  15. Nov 2019
    1. we have observed these effects against unmanipulated, wild-type tumors

      Anti-CTLA-4 treatment can be used for the normal tumors that a patient's immune system may get exposed to. It is not necessary to first extract tumor cells and modify them for the immune system to be able to recognize them. This makes it a very powerful treatment.

    2. CTLA-4 blockade might sustain proliferation of activated T cells by removing inhibitory signals that would normally terminate the response

      Another proposed mechanism of the effectiveness of CTLA-4 blockade is given. This mechanism could work in tandem with the previous one. Anti-CTLA-4 treatment may be allowing activated T cells to divide and grow for a longer period of time, so that there is a larger number of them circulating in the body and available to respond to the cancerous cells.

    3. removal of inhibitory signals may lower the overall threshold of T cell activation and allow normally unreactive T cells to become activated

      The authors propose that the effectiveness of CTLA-4 blockade may arise from lowering the number or concentration of antigens that T cells expect to be exposed to before they become fully activated. That is, anti-CTLA-4 may be allowing T cells to become more sensitive.

    4. rapidly growing tumors, whereas 7 of 10 mice treated with anti-CTLA-4 were tumor-free by day 25 after injection

      Similar trends were observed in this experiment. Mice left untreated grew tumors rapidly, while the majority of those treated with anti-CTLA-4 remained tumor-free.

    5. measurable, rapidly growing tumors within 7 days

      Those mice that were not treated grew tumors in the first week of the experiment.

  16. Oct 2019
    1. delaying treatment appeared to be more effective

      Not only was delaying treatment effective, it was more effective than treating the mice on the same day that tumors are introduced.

    2. Only one of the previously immunized mice had a detectable tumor by day 14

      Most of the previously immunized mice did not develop tumors of detectable size; that is, their immune system was able to kill all the tumor cells almost as soon as they were introduced. Only one of the mice developed a detectable tumor, but the growth was very slow.