1,180 Matching Annotations
  1. Aug 2020
  2. 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. 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 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.

    2. 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 1x10(^6) 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?

    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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. Nov 2019
    1. 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 dispersion networks of O'ahu are introduced species, and that the majority of seeds being dispersed by these birds are from introduced plant species.

    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. 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.

    6. measurable, rapidly growing tumors within 7 days

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

  8. 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.

    3. control animals had progressively growing tumors by 14 days after injection, developed massive tumor burdens, and required euthanasia by day 35

      If mice were not previously exposed to the tumor cells along with a treatment, they did not fare very well.

    4. significant protection against a secondary challenge

      The mice which previously mounted an immune response with the help of anti-CTLA-4 were able to leverage a similar response toward this re-exposure. Remember that naive mice exposed to half this many tumor cells were not able to control the cancer's growth.

    5. Anti-CTLA-4 treatment had a dramatic effect on tumor growth

      The treated mice had much better outcomes than the untreated mice, which were euthanized after 35 days.

    6. completely rejected their tumors after a short period of limited growth

      The mice treated with antibodies against CTLA-4 completely recovered and were able to clear the tumors.

    7. developed progressively growing tumors and required euthanasia by 35 days after inoculation

      The mice which received these treatments could not control the growth of their tumors. They died 35 days after the tumors were injected.

    8. 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 faster, by day 17, if they developed tumors at all.

    9. All mice in the untreated and antiCD28-treated groups developed small tumors that grew progressively for 5 to 10 days and then ultimately regressed in 8 of the 10 mice by about day 23 after injection. The two small tumors that did not regress remained static for more than 90 days

      Two groups were injected with anti-CD28 or not treated. Most of the mice in these two groups cleared the tumors, but did so by day 23. Two of the mice did not completely clear the tumors but were able to keep them from growing further.

    10. raise the possibility that blockade of inhibitory signals delivered by CTLA-4-B7 interactions might augment T cell responses to tumor cells and enhance antitumor immunity

      The pieces of evidence outlined in this paragraph led the authors to conclude that blocking tumors from being able to engage CTLA-4 might result in T cells being better able to fight off tumors.

    11. resulted in immunity to a secondary exposure to tumor cells

      Administering antibodies against CTLA-4 also allows the mice to prevent establishment of tumors due to future exposure.

    12. resulted in the rejection of tumors, including preestablished tumors

      By preventing CTLA-4 from binding to its ligands, T cells can now be activated more potently. This allows them to kill cancer cells.

  9. Sep 2019
    1. reduced contact area that slide against the DLC surface, achieving an incommensurate contact

      With a combination of materials (graphene, nanodiamond particles, and DLC), the researchers were able to demonstrate the formation of nanoscrolls, which reduced the overall contact area between two sliding interfaces, leading to substantially decreased friction.

    2. We found that the presence of defects greatly facilitates the adsorption of water from the ambient atmosphere (fig. S13). Water preferentially adsorbs and stabilizes defective sites, which further prevents the formation of scrolls

      There are some limitations for the present observed near-zero friction sliding. A relatively poor tribological performance is found in humid test environments. The water molecules present at the interface is found to prevent the scrolling of graphene layers. Moreover, the defects present on graphene sheets act as catalytic sites further hampering the near-zero friction sliding in a humid environment.

    3. We saw a dramatic reduction in friction, reaching the superlubric state

      The authors have designed and executed experiments to calculate the coefficient of friction. The combination of nanomaterials they used were found to be successful in achieving super-low friction values in a dry environment.

    4. The superlubricity is thus attributed to (i) reduction in the interfacial contact area (>65%) and (ii) incommensurability between DLC and graphene scrolls.

      The mismatch of the lattices at the sliding interfaces prevents interlocking of atoms, resulting in near-zero friction. In the present case, a perfectly incommensurate surface along with reduced contact area benefited from the graphene scroll formation and contributed to superlubricity.

    5. nanodiamonds can activate, guide, and stabilize the scrolling

      The mechanism of superlubricity in the present system is explained. Authors found that nanodiamonds play a key role in the scroll formation and hence in facilitating the near-zero friction state.

    1. This is almost 100 times faster than that reported for optogenetic stimulation of the AgRP neuron soma and 500 times faster than stimulation of AgRP-PVT axon terminals (19, 20). As soon as the laser was turned off, the mice stopped eating.

      The authors wanted to compare the latency of eating onset upon stimulation of ZI projections to the PVT versus that of agRP neurons, which are known to promote food intake in response to hunger.

      They found that mice start to eat much faster than mice did in previous reports where AgRP neurons were stimulated or when agRP projections to the PVT were stimulated.

    2. Stimulation of PSTh glutamatergic neuron terminals in the PVT inhibited food intake (Fig. 4L).

      PVT vGlut2 neurons decrease food intake. Therefore, stimulation of excitatory neurons upstream of them, i.e. the vGlut2 PSTh neurons, was also found to increase food intake.

    3. In spite of the light aversion, photostimulation of VGATZI-PVTterminals significantly increased the time mice spent on the illuminated side to 61% when high-fat food was available (Fig. 3D). Photostimulation increased high-fat food intake in bright light (Fig. 3E).

      Mice that received stimulation of ZI GABA terminals in the PVT spent more time in the light compartment in the presence of high-fat food even though mice usually avoid places that are brightly lit.

      This means that the stimulation of the ZI to PVT projection was able to overcome the aversive nature of the light.

    4. Although mice prefer sweet and high-fat foods when stimulation is off,

      Mice will avidly consume high-fat and sweet foods even when not hungry. This is because these foods are palatable, meaning that they are pleasurable or rewarding to eat and so will be consumed even when nutrition requirements are met.

    5. Ghrelin, a hormone that signals a reduced gut energy state (12), excited ZI GABA neurons and increased excitatory synaptic input onto these neurons (Fig. 1, K to M, and fig. S2).

      Ghrelin is produced in the stomach. Its synthesis is increased by food deprivation.

      Application of ghrelin to the brain slices containing ZI GABA neurons increases their activity in a way similar to food deprivation.

    6. Food deprivation lasting 24 hours increased ZI GABA neuron activity and excitatory neurotransmission to these neurons

      Recordings made in brain slices show that ZI GABA neurons fire more, i.e. are more active in food deprived mice. Further, inputs from other neurons that excite/activate ZI GABA neurons are increased.

      Therefore, increased ZI GABA neuron activity correlates with hunger.

      See this HHMI BioInteractive video that explains how information is transmitted between neurons: Molecular mechanism of synapse function.

    7. In control mice with tdTomato expression, consumption was only 4% of their 24-hour intake during the same period (Fig. 1E).

      Lack of food intake in a control animal that was injected with an AAV expressing only a fluorescent protein shows that the result seen in ChIEF-expressing mice was not due to non-specific effects of AAV injection or protein expression in the neurons.

  10. Aug 2019
    1. In aggregate, these results indicate that intestinal tumors can transport fructose directly from the intestinal lumen, where the fructose concentration is high after oral administration of HFCS.

      Summarizing findings from the experiments up till this point: 1) fructose often reaches the colon at high concentrations when passive transporters in the upper intestines are saturated. 2) tumors in the lower intestines and colon absorb fructose efficiently, as demonstrated by decreased fructose in the liver in tumor-bearing mice 3) colorectal tumors are able to absorb more fructose than healthy intestinal cells because they have more fructose transporters

    2. Further supporting our hypothesis, we found that GLUT5 was expressed at higher levels in APC−/−tumors as compared to IECs (fig. S5A), and in human colon tumors as compared to adjacent normal IECs

      Investigating tumor uptake of fructose further, the scientists looked at sugar uptake proteins in colorectal tumors of both mice and human tissues. They found that colorectal tumor cells expressed more of the passive fructose transporter than normal intestinal cells do.

    3. Furthermore, the amount of fructose reaching the liver and serum was reduced in tumor-bearing APC−/− mice compared to WT mice (Fig. 2A), implying that fructose is trapped by the tumors instead of being transported to the liver and blood

      The scientists also looked at how much fructose and was reaching the liver and blood to test metabolism of the sugar. They found that in tumor-bearing mice there was less fructose metabolized in the liver and less reached the blood. This suggests that the tumors consumed more of the fructose.

    4. we confirmed that APC−/− tumors efficiently transported both fructose and glucose following a bolus of HFCS (fig. S4B).

      After administering high fructose corn syrup with the labeled carbons on glucose and fructose to a mouse with colorectal tumors the scientists found that the tumor took up and metabolized both glucose and fructose.

    5. These results suggest that the chronic intake of modest amounts of HFCS in liquid form facilitates tumor growth in the setting of APC deficiency independent of obesity and the metabolic syndrome.

      Summarizing their results: In APC deficient mice (where colorectal tumors readily develop) consumption of even small amounts of high fructose corn syrup increases tumor growth.

    6. Although the total number of tumors was similar (fig. S3, A and B), HFCS treatment significantly increased the number of large adenomas (>3 mm in diameter) and high-grade tumors in the HFCS group compared to the Con group (Fig. 1, C to F, and fig. S3C).

      Results from experiment Part 2: Comparing mice fed with different amounts of high fructose corn syrup did not change the number of tumors formed. However, the size of the tumors, and the aggressiveness of the cancer differed between the mice fed a small amount of high fructose corn syrup and the control group with no high fructose corn syrup. This demonstrates that even a small amount of high fructose corn syrup is increasing tumor growth.

    7. Chronic treatment of HFCS using this strategy did not induce obesity or metabolic dysfunction in APC−/− mice (Fig. 1, A and B, and fig S2).

      Result from experiment Part 1: Mice given a small amount of high fructose corn syrup did not become obese (as intended) and they did not develop metabolic syndrome. This suggests that high fructose corn syrup itself is not causing metabolic syndrome, but rather obesity is causing these health complications.

    8. The consumption of HFCS in this manner led to obesity in both WT and APC−/− mice (fig. S1), and to metabolic dysfunction in WT mice (fig. S2) over an 8-week period.

      In response to consumption of high fructose corn syrup mice in both groups gained a lot of weight and began displaying symptoms of metabolic dysfunction (high blood pressure, abnormal cholesterol etc.). It was unclear as to whether high fructose corn syrup consumption or obesity led to the development of metabolic dysfunction so the authors went on to test this next.

    9. Notably, there was almost no labeling of downstream metabolites of F1P from 13C-fructose when unlabeled glucose was added to the medium (Fig. 2D and fig. S6A), suggesting that the presence of glucose saturates aldolase and prevents fructose from being cleaved into three carbon units in this time frame. Because KHK produces F1P much faster than aldolase cleaves it, F1P accumulates (fig. S6B). This results in an acute drop in cytosolic ATP in tumors from APC−/− mice that had received HFCS as compared to Con tumors following a bolus (and Fig. 2E).

      ADDING EMPHASIS

    10. As expected, F1P was predominantly 13C-labeled at all six positions (M+6) in tumors treated with 13C-fructose or 13C-fructose + unlabeled glucose (47.1 and 67.1%, respectively), as assessed by the percentage of labeling (Fig. 2C); these findings confirm the activity and presence of KHK in the tumors.
    1. veratridine did not significantly alter TH-positive cell number, suggesting that depolarization increased TH per neuron rather than increasing the number of neurons.

      What could have been the cause of the increase in TH activity? The answers could be one of the two options: An increase in the number of TH-positive neurons in the sample or an increase in the amount of TH per neuron.

      In other words, is it an individual neuron's effect or a collective effort of all neurons in the sample? To address this, the authors decided to measure the number of TH-positive cells in the control and veratridine-treated cultures.

      The results show that the there is no difference in the number of neurons between both groups. Based on that, they concluded there is an increase in the amount of TH per neuron individually but not in the total number of TH-positive neurons.

    2. depolarizing concentrations of K+ reproduced the effect of veratridine, suggesting that depolarization per se increased TH activity

      Potassium (K+) is used as a depolarizing agent in this study. The depolarization using potassium is expected to behave similarly to the effects observed with veratridine as both the chemicals increase the influx of sodium channels.

      The authors show that, in the presence of potassium, there is approximately a 35% increase in TH activity as compared to their controls.

    3. this effect was blocked by tetrodotoxin

      Tetrodotoxin is a sodium channel blocker while veratridine does the opposite, it activates these channels causing an influx of sodium. Since these two drugs act in opposition to each other, we expect them to have no net effect in the cultures. And that’s what was observed in the cultures exposed to veratridine in the presence of tetrodotoxin (see TTX+Ver in Figure 4). There is no further effect in the TH activity as compared to their controls.

    4. Veratridine exposure significantly increased TH activity over cultures of the contralateral control locus

      Veratridine binds to the sodium channel binding site thereby increasing the flow of sodium ions into the cell. The authors have shown that, when the cultures are exposed to veratridine, there is approximately a 40% increase in the activity of tyrosine hydrolase (TH) compared to their controls. Controls are cultures that are not exposed to any drugs.

    5. In culture, the (now denervated) adult ganglia exhibited a tenfold rise in substance P, mimicking the increase in neonatal ganglia

      Explants from the superior cervical ganglia were obtained to address the question: Is there transmitter plasticity in mature neurons?

      Explants were obtained from rats of age six months and one year. A ten-fold increase was observed in the activity of substance P.

    1. The geographical annual and diurnal ranges of temperature would be partly smoothed away, if the quantity of carbonic acid was augmented. The reverse would be the case (at least to a latitude of 50° from the equator), if the carbonic acid diminished in amount.

      The model predicted that atmospheric CO2 levels influence the temperature contrast between the seasons and between night and day. Lower CO2 levels increase the temperature contrast. Higher CO2 levels decrease the contrast.

    2. the temperature in the arctic regions would rise about 8° to 9° C., if the carbonic acid increased to 2.5 or 3 times its present value.

      Based on observations of the geological record, scientists estimated that the temperature in arctic regions during the warm Tertiary Period was 8 to 9 C higher than now.

      Using the data generated by his model and summarized in Table VII, Arrhenius concluded that this temperature increase could have been caused by an atmospheric CO2 increase of 2.5 to 3 times current levels.

  11. Jul 2019
    1. 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."

    2. free alcohols and primary amines

      Free alcohols and primary amines are very reactive functional groups that are inert during this carbene transfer reaction.

    3. 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.

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

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

    5. Chemoselectivity

      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.

    6. the triple mutant catalyzed the formation of 20 silicon-containing products,

      A generally applicable protocol, as a result of directed evolution, over a variety of substrates illustrates the synthetic utility of the mutant.

    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 factors (modularity, nestedness, and specialization) were all similar between Ohau and other tropical or non-tropical locations.

  12. Jun 2019
    1. 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 plant and animals at different sites across the island develop their own unique pattern of interactions, even if the sites populated mostly of native or novel species.

    2. 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 species do not necessarily have to be evolutionary related to form a mutual relationship. This conclusion was based on their results demonstrating that introduced species on the island successfully formed beneficial interactions with native and other species that shared little phylogenetic similarities.

    3. 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 reason the introduced birds and plants integrate successfully into the ecosystem of O'ahu is because they follow the same strategies that the native plants and birds developed: creating beneficial relationships with specific species, and carefully sharing the resources of the island with other organisms.

    4. This high degree of similarity between novel and native-dominated networks suggests that the processes that structure interactions in such communities are largely independent of species identity and that ecological filtering occurs over relatively short (ecological) time, leading to functionally similar sets of players as compared with systems that have long evolutionary histories

      The authors concluded that novel species' interactions, developed over a relatively short period of time, still resemble much older interactions between native species.

    5. However, the lack of association between rewiring and examined factors indicates that birds and plants in the system are highly flexible and can switch partners, irrespective of abiotic conditions and the identity of species in the community.

      The authors found that neither abiotic (rainfall and elevation) nor biotic (invasive species) factors influenced the variations in plant and animal interactions measured from different sites with similar species populations.

    6. pecifically, interaction dissimilarity and the dissimilarity caused by species turnover were influenced by elevation and rainfall, but not by percent of introduced plant species (tables S6 to S9). This suggests that the environment indirectly influences interactions via effects on species distributions, including the distribution of introduced species.

      Results in the supplement section show that abiotic factors (rainfall and elevation) affected the composition of species found at a site, thereby creating different network interactions between sites.

    7. 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 grey bars. This means that even though the sites shared similar species, the interactions were different.

    8. [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 measured high levels of dissimilarity across various sites of the island, depicted as the black/gray bars in the graph of Figure 3

    1. Axotomy of the petrosal neurons, separating the cell bodies from peripheral targets, resulted in a precipitous decline in TH catalytic activity and disappearance of TH immunoreactivity

      Cutting down the axons in the petrosal neurons causes a decrease in TH activity and immunoreactivity. However, there is a certain level of TH recovery after four weeks, which could be due to the regeneration or recovery of the severed axon.

    2. nicotinic receptor stimulation, with consequent depolarization or attendant transmembrane Na+ influx, or both, decrease substance P in mature sympathetic neurons, as in neonatal neurons

      With nicotinic receptor stimulation, the depolarization or the influx of sodium ions across the membrane causes a decrease in substance P in both mature and developing neurons.

    3. These observations suggest that membrane depolarization and associated transmembrane Na+ influx decrease [Leu]enkephalin in adult medulla

      Decrease in [leu]enkephalin in adrenal medulla is dependent on two related factors: Membrane depolarization and the sodium influx through the membranes.

    4. In contrast, 4-day adult explants revealed a marked increase in proenkephalin mRNA, which paralleled the rise in [Leu]enkephalin

      At four days, mRNA of proenkephalin showed a greater increase similar to the increase observed in [leu]enkephalin in medullary explants.

    5. Our observations suggested, consequently, that opiate peptidergic and catecholaminergic traits may be differentially regulated in the adult medulla.

      The results described in the previous two sentences suggest that each class of transmitters are regulated differently in the adult medulla.

    1. among women with higher levels of stereotype endorsement, the end-of-semester FMCE scores were higher in the affirmation condition than in the control condition

      Values affirmation improved performance for women, especially those who endorsed the gender stereotype.

    2. men's exam scores were little affected by stereotype endorsement, regardless of condition

      Men's performance on exams was not affected by the degree to which they endorsed the gender stereotype.

    3. the values affirmation was particularly beneficial for women who tended to endorse the gender stereotype

      Values affirmation was more effective for women who believed more strongly that the gender stereotype (i.e., that men are better at physics than women) was true.

    4. suggesting that the reduced gender gap observed in this study is based more robustly on the affirmation’s positive impact on women than on its negative impact on men.

      Because women did better on all measures when they performed values affirmation, and men only performed worse according to one measure, it is likely that the reduction in the gender gap observed after the values affirmation intervention is due to women's scores improving rather than men's scores becoming worse. 

    5. affirmation negatively affected men’s exam scores

      Men who performed values affirmation did, on average, slightly worse on course exams than men who didn't perform values affirmation. However, this was not seen on all measures of success (for example, the effect was not seen on the FMCE score).

    6. more women earned B’s in the affirmation group than in the control group, whereas more women earned C’s in the control group than in the affirmation group

      Values affirmation resulted in a shift in the distribution of overall grades for women (but not men). In the values affirmation group, more women earned Bs (relative to Cs) than in the control group.

    7. The reduction in the gender gap remained evident on the final

      Values affirmation reduced the gender gap in final exam scores even though the intervention occurred several weeks before the final exam. This suggests that the effects may be relatively long-lasting.

    8. Course grades, based substantially (75%) on the exam scores, showed a similar pattern

      Values affirmation reduced the gender gap in overall course grades between men and women.

    9. the gender gap was significantly smaller in the affirmation condition than in the control condition

      The authors found that the values affirmation intervention reduced the gender gap between men and women on average exam score.

      In the control condition, men scored higher than women. However, in the values affirmation condition, there was no significant difference in scores between men and women.

    1. Similarly, the expression of FosB after cocaine administration was the same in mice exposed to nicotine 14 days earlier and in mice without previous nicotine exposure

      In contrast to the results we obtained with 7 days of nicotine treatment paired with cocaine, these animals did not show any change in the magnitude of LTP, no increase in locomotor activity of in FosB gene expression.

      This indicates that the priming effect of nicotine can occur only when the drugs are given in a close window and not otherwise.

    2. Theophylline-treated mice also showed a reduction in levels of acetylated histone H4

      A reduction in acetylated levels of histone H4 was observed

    3. The acetylated chromatin induced by nicotine exposure would then allow greater FosB gene expression in response to cocaine injection than FosB gene expression after cocaine alone.

      Figures 5 and 6 suggest that the nicotine inhibits HDAC activity, thereby causing global acetylation in the striatum and affecting gene expression.

      In response to cocaine, this acetylation is further enhanced, thus allowing a more significant response in gene expression.

    4. exhibited no increase in FosB mRNA expression in response to cocaine, although cocaine alone increased FosB expression by 176%

      FosB gene expression is also reduced in mice treated with theophylline and cocaine compared to theophylline alone.

    5. Both groups showed a comparable increase in LTP. However, the theophylline-treated mice exhibited an attenuated LTP reduction in response to cocaine treatment

      As expected, in LTP experiments, the mice treated with theophylline and cocaine injections showed a decrease in the magnitude of LTP compared to mice treated with theophylline alone.

    6. Similar to nicotine alone, SAHA alone did not cause a depression in LTP

      SAHA alone did not impair LTP just like nicotine did not impair LTP.

    7. SAHA pretreatment fully simulated nicotine pretreatment and induced a greater reduction in LTP in the core of the NAc than did cocaine alone

      Pretreatment with SAHA followed by cocaine caused a dramatic decrease in the magnitude of LTP response at 180 mins. These results suggest that nicotine does inhibit HDAC activity.

    8. we found that a single cocaine injection after local pretreatment with SAHA for 7 days resulted in 142% more FosB mRNA expression than without pretreatment with SAHA

      Further, when SAHA was infused into nuclear accumbens for 7 days followed by cocaine injection, the FosB expression levels and acetylation of histone residues in striatum increased than the pretreatment with SAHA.

    9. observed a 71% increase in FosB expression in the pretreated mice compared to mice treated with cocaine alone

      Similar to nicotine, SAHA increased the FosB expression levels by 71% and caused acetylation of histone residues in the striatum.

    10. there was a 28% reduction in HDAC of mice treated for 7 to 10 days with nicotine

      28% reduction in HDAC activity was measured in animals treated with nicotine, suggesting that the nicotine inhibits the HDAC activity, thereby decreasing deacetylase activity.

    11. 7 days of nicotine treatment (10 μg/ml) increased histone H3 and H4 acetylation by 32 and 61% in the whole striatum, compared with controls treated with water, much as it did at the FosB promoter

      Again, there was an increase in acetylation levels of H3 and H4 in the striatum.

      These results suggest that the nicotine increases the effect of cocaine on FosB expression by increasing the acetylated residues in FosB, thereby enhancing chromatin reorganization.

    12. We found that, after 7 days of nicotine treatment (10 μg/ml), acetylation of both histone H3 and histone H4 was increased by 34 and 39%, respectively

      Authors observed the acetylation of histone H3 and H4. It is shown that both H3 and H4 got acetylated after a single dose of cocaine injection and after nicotine pretreatment.

    13. The effects on FosB expression are unidirectional; nicotine primes the cocaine response, but cocaine does not prime the nicotine response

      This suggests that the nicotine precedes cocaine and not in the reverse order.

    14. We found that 7 days of cocaine treatment blunted rather than amplified the effect of nicotine on FosB expression in the striatum when compared to the response to nicotine alone.

      On the contrary, the increase in FosB expression we observed in nicotine pretreatment is entirely absent with the cocaine pretreated animals.

    15. Chronic nicotine administration produces changes in gene expression in the brain so that, after nicotine, the brain responds differently to cocaine with respect to long-term synaptic changes

      It could be that the nicotine causes a gene expression in animals. This primed response serves as a precursor for the brain to respond differently to cocaine to produce long term plasticity changes.

    16. As in the behavioral and physiological experiments, 24 hours of nicotine pretreatment produced quite different results from the 7-day treatment and did not lead to an increased FosB response to cocaine

      On the contrary, FosB expression was increased only in animals that received a cocaine injection after 7 days of nicotine treatment and not in 24 hours of treatment.

      This suggests that the long term nicotine effect is responsible for the changes in gene expression.

    17. we found that both 24 hours and 7 days of administration of nicotine (10 μg/mg) in the drinking water caused 50 and 61% increases in FosB expression

      Both 24 hours and 7 days of nicotine administration caused an increase in FosB expression by 50% and 61%.

    18. Treatment with cocaine alone for 7 days or cocaine treatment for 7 days followed by 24 hours of nicotine treatment did not alter LTP

      However, mice treated with cocaine show a 17% decrease in the observed LTP.

    19. The reduction started immediately after the high-frequency stimulation (HFS) and persisted for up to 180 min compared with cocaine alone

      In this experiment, the authors wanted to determine if the sequential drug use of cocaine can alter the cocaine-induced synaptic plasticity.

      After high-frequency stimulation (HFS), mice treated with nicotine alone or water exhibit LTP that lasts for 180 mins. Mice pretreated with nicotine combined with cocaine injection show a dramatic reduction (~40%) in the observed LTP.

      This suggests that the changes in LTP in nucleus accumbens is caused by pre-exposure of nicotine to the mouse.

    20. We found that the rate of cocaine dependence was the highest among cocaine users who initiated cocaine after having smoked cigarettes

      Similar to the results obtained from animals, the individuals who started using cocaine were also active smokers, i.e., they initiated cocaine after smoking.

    21. mice pretreated with nicotine showed a 78% further increase in preference for the cocaine-coupled chamber compared with mice treated only with cocaine, with no previous exposure to nicotine

      Mice pretreated with nicotine coupled with cocaine injections showed a further 78% increase in preference to cocaine-coupled chamber than cocaine-treated animals.

      This suggests that persistent treatment of nicotine for 7 days increases the locomotor activity and behavioral responses of the animals