Finally, we found that tau-dependent Aβ toxicity was modulated by site-specific tau phosphorylation, which inhibited postsynaptic PSD-95/tau/Fyn complexes, revealing an Aβ toxicity–limiting role of p38γ in AD that is distinct and opposite to the effects of p38α and p38β (11, 13, 14).

PTZ-induced seizures are reduced in tau−/− mice (8, 9). Adeno-associated virus (AAV)–mediated expression of WT and T205A neurons, but not T205E tau or green fluorescent protein (GFP), in the forebrains of tau−/− mice enhanced PTZ-induced seizures (Fig. 4D and fig. S25).

Hence, phosphorylation of tau at T205 should similarly mitigate neurotoxicity. Aβ caused cell death in WT and T205A neurons but significantly less in T205E tau-expressing neurons (fig. S23). Similarly, neurons expressing p38γ and, more so, p38γCA were significantly more resistant to Aβ-induced cell death than controls (fig. S24).

Pan-p38 inhibition stopped p38γ/p38γCA-induced disruption of PSD-95/tau/Fyn complexes

Hence, p38γ regulated PSD-95/tau/Fyn complexes via phosphorylating tau at T205.

Increasing p38γ levels compromised PSD-95/tau/Fyn interaction in cells, and expression of a constitutively active p38γ variant (p38γCA) completely abolished this interaction

Similarly, pT205 was markedly reduced in APP23.p38γ−/− animals compared with APP23.p38γ+/+ mice (Fig. 4B)

no PSD-95/tau/Fyn complexes were isolated from tau−/− and tau−/−.p38γ−/− brains

In summary, the levels of active p38γ kinase and tau phosphorylation at T205 determined susceptibility to excitotoxicity and Aβ toxicity.

the effects of p38γ on excitotoxicity and Aβ toxicity were tau-dependent.

increasing tau levels in p38γ−/− mice [brought about by crossing with nonmutant tau-expressing Alz17 mice (23)] significantly enhanced PTZ-induced seizures in Alz17.p38γ−/− mice

In summary, p38γ depletion exacerbated excitotoxicity, neuronal circuit synchronicity, mortality, and memory deficits in APP23 mice, without changes in Aβ pathology.

Electroencephalography showed enhanced spontaneous epileptiform activity and interictal hypersynchronous discharges in APP23.p38γ−/− compared with APP23.p38γ+/+ mice

Compared with APP23.p38γ+/+ mice, APP23.p38γ−/− animals had increased sensitivity to PTZ-induced seizures

only p38γ localized to postsynapses and limited excitotoxicity.

mimicking site-specific tau phosphorylation alleviated Aβ-induced neuronal death and offered protection from excitotoxicity.

depletion of p38γ exacerbated neuronal circuit aberrations, cognitive deficits, and premature lethality in a mouse model of AD, whereas increasing the activity of p38γ abolished these deficits

first, the sex-determining proteins studied in the present work evolve at constant rates, as suggested by global molecular clock tests (Table 1).

The high levels of genetic differentiation detected within C. jimenezii raise questions whether these two populations can be treated as different varieties/subspecies within this taxon or if indeed they may represent two different species.

Therefore we recommend not translocating material between these two populations for genetic conservation or ecological restoration programs until the taxonomy of this species within Coccothrinax is further studied.

The taxonomic uncertainties between the two populations of C. jimenezii have important implications for reintroduction programs. These two sites of C. jimenezii represent two clear management units for conservation, and the population genetic data suggest that we cannot rule out that they are two distinct taxa.

We have not been able to find data regarding the environmental history in these two populations since the 15th century. However, there is agreement among conservation biologists that since the arrival of the Europeans to this island there has been habitat fragmentation and deforestation linked to rapid expansion of urban and rural activities (Sambrook et al., 1999; Alscher, 2011; Foxx, 2012). Palms have long-life cycles; therefore, the detrimental consequences of genetic drift on genetic diversity can take a long period of time to manifest because of their long generation time and the presence of overlapping cohorts (Duminil et al., 2009).

The answers to fundamental questions about the origins of animal life and the evolution of their diverse phenotypes may be held in the genomes of distinct invertebrate phyla.

Likewise, there is no evidence for differences among the pairs in historical effective population sizes or generation times that can be related to divergence (20).

Our data can also be used to estimate rates of divergence in reproductive compatibility.

Pacific members of the most divergent pairs are found deeper in the intertidal or are rare in habitats with heavy sedimentation (25) (Fig. 2). Thus, larval avoidance (26) of shoaling waters over the rising isthmus (6, 7) may have accelerated genetic isolation of these pairs.

However, they do show some distributional differences that could affect sensitivity to changing conditions associated with gradual rise of the isthmus.

The null hypothesis, that isolation was simultaneous but rates of divergence are highly variable, is incompatible with the observed pattern because metabolic enzymes, mtDNA, and mate recognition share no mechanistic basis that would cause their divergence rates to be automatically associated.

Geographic isolation is thought to permit divergence and speciation by disruption of gene flow

Even the least divergent pairs show substantial reproductive isolation

4.4 to 6.1 (P5-CS), 4.0 to 6.3 (P6-C6), and 6.8 to 9.1 (P7-C7) Ma

All the shrimps we studied are shallow water, fully marine forms with planktonic larvae.

Fig. 2

Table 1

Energy intake and thermal excess were positively correlated with body size as measured by the curved fork length (CFL) of tagged tunas

Lower energy intake was observed during late summer (August and September), when bluefin tuna are moving up through the Southern California Bight (28° to 32°N).

The largest size-based differences in energy intake were also observed in October (Fig. 6 and table S3), indicating that thermal niche expansion in this endothermic species results in high energetic reward

Management of nutrient effects on both of these pathways would positively affect riverine health.

Litter quantity in the streambed was predicted to be 2.8 times and 7.7 times higher in reference versus nutrient-enriched streams after 6 and 12 months,

Reach-scale outputs of C increased as fine POC export, as well as respiration (15).

They may limit terrestrial C loss as CO2 and maintain downstream C export, but contribute to depletion of local C resources (22, 23).

However, roughly similar-sized effects of N and P on loss rates are strong evidence of co-limitation (Fig. 2 and table S3).

Another study in which mouse NC cultures were treated with Edn3, Edn1, or Kitl showed an increase in the number of melanocyte progenitors; however, Kitl alone was not sufficient to induce the differentiation of melanocyte progenitors into mature melanocytes. Mature melanocytes were however observed, when treatment with Kitl was followed by Edn3 or Edn1 (Reid et al., 1996). As previously noted, although in the absence of Edn3, Kit-positive and DOPA-positive cells arose in mouse NC cultures, Ednrb signaling was required for the generation of fully pigmented melanocytes (Ono et al., 1998). These findings hint to a specific requirement for Ednrb signaling, independent of Kit signaling, in melanocyte differentiation. This requirement for Ednrb in the final phase of melanocyte differentiation may occur cell-autonomously, as suggested by the inability of Ednrb null cells to generate pigment even in the presence of Kitl (Hou et al., 2004). Together these findings point at a cooperative interaction between Kit and Ednrb signaling in melanocyte development, with Ednrb signaling being specifically required in the final differentiation step

Table 2

Fig. 1 Single most parsimonious phylogenetic tree constructed on the basis of mtDNA sequences with PAUP (18). Transitions were given one-quarter the weight of transversions (based on the fourfold greater abundance of transitions than transversions in our data), and trees were rooted by the P7-P7'-C7 clade. Taxon codes are as in Table 1.

our findings suggest that the overexploitation of spawning aggregations can fundamentally alter the natural predator-prey equilibrium, limiting foraging options for reef sharks within aggregation sites.

These observations confirmed that hundreds of sharks actively feed on a large variety of prey (at least 14 fish species; Figures 4 and S3). In particular, sharks feed aggressively on the large number of groupers present during spawning aggregations in June and July [13]. Shark abundance and residency times both increase when camouflage groupers (Epinephelus polyphekadion) arrive from the surrounding reef area to spawn

Overall, sharks showed different degree of residency (mean ± SEM = 42.21% ± 7.75% of days present in the pass; range = 2.1%–95.9%; Table S3), with three transient (<20% residency), six semi-resident (20%–70% residency), and four highly resident (>70% residency) sharks (Figure S2).

Comparisons involving the static control law suggest three separate contributions to the success of this approach: discovering a good generic assistance pattern, customizing it to individual users, and facilitating motor learning.

Results from a prior experiment using the same hardware (17), comparing the zero-torque condition with walking in normal shoes (no exoskeleton) or with static assistance.

Metabolic energy cost of walking for each condition, tested in validation trials. Optimized assistance resulted in the lowest metabolic rate and a large reduction compared to the zero-torque condition. Variability is primarily due to differences between participants. Bars are means, error bars are standard deviations, and asterisks denote statistical significance (P < 0.05)

The primary outcome was the energy cost of walking, defined as gross metabolic rate during walking minus the rate measured while standing still

Static assistance resulted in a 19.3 ± 8.6% reduction in energy cost compared to zero torque (t test, P = 4 × 10−5, n= 11), a larger improvement than in our

The static pattern, based on (17), is similar to the optimized patterns but resulted in higher metabolic rate. Torque was negligible in the zero-torque mode.

These tests hint at the potential for a new type of biomechanics study, in which human-in-the-loop optimization can be leveraged to compare the best possible outcomes for different devices or gait conditions or to test how various features of gait change with optimized performance.

activity in the optimized condition was reduced by 41% compared to the zero-torque mode and 36% compared to walking in normal shoes

The evolutionary strategy that we used was more effective than other methods that we tried, but it seems likely that improved techniques could be developed.

These approaches have scope to improve mobility for people with a wide range of distinct physiological needs, from individuals with chronic stroke to athletes.

A scaling argument predicts a maximum volume when the disk height reaches ZMaxVol/H ~ Fr* (16), in excellent agreement with observations

the domestic cat’s inertia- and gravity-controlled lapping mechanism is conserved among felines

Gravity-driven drainage then reduces the rate of volume increase, and V is at a maximum when gravity and inertia balance (Fig. 4B).

to defeat gravity and pull liquid into the mouth

When the disk is close to the bath (Z << H), the column is cylindrical and V increases as V/R3 = πZ/R (Fig. 4B inset).

we find that Fr* is indeed of order unity (0.4), using the experimentally measured values UMAX =78 cm s−1 and H = 3 cm (Fig. 2B) and a tongue size of R ≈ 5 mm (Fig. 1G).

For small disks (R = 2.5 and 5 mm), ZP/H increased linearly with Fr*, whereas large disks (R = 10 and 12.7 mm) reached the final height before pinch-off (ZP/H = 1). Theory also successfully predicts that pinch-off occurs close to the disk (Fig. 3).

Estimation of the forces involved suggests that the fluid dynamics of lapping are governed by inertia and gravity, whereas viscous and capillary forces are negligible (16).

The tongue accelerates as it leaves the water surface, attains a remarkable maximum speed of UMAX = 78 ± 2 cm s−1, then decelerates as it enters the mouth. Recordings of 10 adult individuals (16) yielded a lapping frequency f = 3.5 ± 0.4 s−1 and an ingested volume per lap V = 0.14 ± 0.04 ml.

and yields a prediction for the dependence of frequency on animal mass

We find (16) that ZP/H ~ Fr* for Fr* < 1 and ZP/H ~ 1 otherwise.

Sharks in the pass are using fish spawning aggregations as energetic subsidies to reduce the need for costly foraging excursions outside the pass boundaries, enabling this energy to be directed to other physiological functions.

However, our results also suggest that when the spawning aggregation subsidies become scarcer during summer and metabolic rate increases due to warmer waters, sharks shift to investing in foraging excursions to escape low energy availability in the pass.

The consequence is sharks being forced to undertake energetically costly wider-range foraging as the only option to meet energy requirements

alleles associated with high fitness within sites tend to be local alleles linked to particular climatic factors, providing evidence of local adaptation in A. thaliana at the scale of the European continent

the alleles associated with high fitness exhibited greater climate specificity

three most interesting candidate genes

no molecular function was significantly over- or underrepresented in all sets of candidate genes

Overall, among the 797 top SNPs, only 12 SNPs were associated with fitness in more than one environment; loci with major genetic effects were largely independent across sites

no recent selective sweeps have occurred at these loci

alleles improving survival were high-frequency alleles

Alleles associated with increased silique number were significantly rarer than genomic controls

more often alleles associated with low fitness exhibited greater climate specialization

we found no evidence that the alleles conferring high fitness in Finland were locally abundant.

associated with higher survival in England and Spain and silique number in Germany, England, and Spain were significantly closer to the planting sites in Germany, England, and Spain, respectively, relative to genomic controls

New candidate algorithms should tolerate high measurement noise, facilitate human adaptation, and require very few evaluations before converging.

we found only small changes in optimized parameters (table S3) and no further reduction in metabolic rate (fig. S9).

Successfully reducing both metabolic rate and muscle activity suggests that alternate objective functions with similar properties could be optimized—for example, related to speed (40), endurance (41), balance, or overall satisfaction

Optimizing a similar number of parameters in a feedback control structure, such as a neuromuscular model (38), or switching between optimized modes (39) could enhance performance under changing locomotor conditions.

Optimized ankle exoskeleton torque pattern for each participant. Patterns varied widely and spanned a large portion of the allowable range. Lines are measured torque, normalized to stride time and body mass, averaged across strides.

We also applied the approach to running with exoskeletons on both ankles (subject 2; table S1) and found a 27% improvement in energy cost compared to the zero-torque mode and 13% energy savings compared to normal running shoes (Fig. 4F).

At a slow walking speed (0.75 m s−1), the algorithm drove torque to its lower limit, resulting in a small reduction in energy cost compared to zero torque (Fig. 4A) and a 19% reduction compared to the initial control law (fig. S6).

Optimized assistance reduced the metabolic cost of walking at a typical speed (1.25 m s−1; 33% reduction versus zero torque, 25% versus normal shoes; Fig. 4B)

These wide-ranging control laws, some of which participants noted were initially uncomfortable, may have forced them to explore new motor control strategies, which has been shown to be a necessary part of skill acquisition in some interventions

Participants had a similar duration of exposure to the exoskeleton in both studies, but in the prior study, participants were trained with a narrow range of eight static control laws, whereas during optimization, they experienced 32 diverse control laws.

The primary differences between these studies relate to the conditions during adaptation

Eight of 11 participants had a lower metabolic rate with optimized assistance, with the difference in rate ranging from a 3.3% increase to a 16.5% reduction

Individually optimized assistance resulted in 5.8 ± 6.2% lower metabolic rate than with the static control law (t test, P = 0.01, n = 11)

Static assistance (Fig. 3E) was similar to the average of the optimized control laws, and in our prior study (17), it delivered a 6% reduction in energy cost.

Human-in-the-loop optimization accommodates this complexity.

Optimized torque patterns (Fig. 3D) did share some qualitative features with each other, such as a peak torque that occurred at about 50% of stride, suggesting qualities that may be beneficial for most people and useful initial parameters for future optimizations.

For example, the timing of optimized torque onset ranged from onset at 17% to onset at 37% of the stride period (Fig. 3D), or about half the testable range in this and prior studies (3)

suggesting about a 14% net improvement with optimized assistance compared to normal shoes

Wearing the exoskeleton in zero-torque mode is about 10% more costly than walking in normal shoes without the exoskeleton (Fig. 3B)

Optimized parameters were identified after four generations

Optimized assistance substantially improved energy economy for all participants, confirming the effectiveness of the method.

Static assistance approximated the best hand-tuned torque pattern for this device, which had previously resulted in a 6% reduction in energy cost compared to zero torque (17)

(A) Slow walking (0.75 m s−1). (B) Normal walking (1.25 m s−1). (C) Fast walking (1.75 m s−1). (D) Uphill walking (10% grade). (E) Loaded walking (load equal to 20% of body mass).

Optimized control law parameter values. Optimized values varied widely across participants. Values are normalized to their allowable range (26). Lines are medians, boxes cover the 25th to 75th percentiles, and whiskers show the range.

Energy cost reductions ranged from 14.2 to 37.9% (fig. S4 and table S3), with an average reduction of 24.2 ± 7.4% (t test, P = 1 × 10−6, n = 11; Fig. 3A).

Optimized assistance reduced the metabolic cost of walking to 2.16 ± 0.38 W kg−1, down from 2.84 ± 0.40 W kg−1 with zero torque (mean ± standard deviation).

We optimized assistance for 11 participants (subjects 1 to 11; table S1) as they walked on a treadmill at a normal speed (1.25 m s−1).

Ankle torque was determined by four parameters: peak torque, timing of peak torque, and rise and fall times (Fig. 2A) (26)

Ankle exoskeleton. Drive rope tension caused the device to push on the shank, heel, and toe contact, generating an ankle torque.

Exoskeleton emulator system. Off-board motor and control hardware actuated a tethered exoskeleton worn on one ankle while participants walked on a treadmill.

Examples of possible torque patterns.

Parameterization of ankle torque. Each control law determined applied torque as a function of time, normalized to stride period, as a cubic spline defined by peak time, rise time, fall time, and peak torque.

A method for minimizing the energy cost of human walking, in which various control laws are applied, metabolic (met.) rate is quickly estimated (est.) for each, costs are compared, and an evolution strategy is used to generate a new set of control laws to be tested, all during walking.

Measurements of human performance are used to update device control so as to improve performance in the human portion of the system.

The balance of inertia and gravity yields a prediction for the lapping frequency

The tongue’s vertical position during upward motion is well described by an error-function

This competition between inertia and gravity sets the lapping frequency

Consequently, the balance between inertia and gravity dictates the lapping frequency, f, by controlling the time of pinch-off

Western assay of induced SX4 cells showed the presence of Venus only in the membrane fraction and not in the cytoplasmic fraction, suggesting efficient membrane localization of Tsr-Venus.

There are a number of possible explanations for this unanticipated result. First, union members may have a higher level of dissatisfaction with the organisation and management processes (Freeman and Medoff, 1984: 21; Bryson et al., 2004), including communications and participative arrangements, and therefore perceive less favourably their degree of influence within the organisation (Kleinman, 2000: 403–404) or the degree of managerial responsiveness (Bryson et al., 2006). Bryson (2004) found that union members had a higher level of job dissatisfaction than non-union workers but that after an extensive array of control variables were included, no significant negative relationship was found. This finding, they suggested, may well be due to a selection bias on the part of employees. Employees who had higher aspirations for their working life may be more likely to join a union. This proposition resonates well in the case of PSR, where some 63.8 per cent of unionised employees indicated that a major reason for joining the union was because they wanted to have a say in matters affecting their working life. Unions themselves may also contribute to this dissatisfaction by raising employee expectations that they are unable to meet (see also discussion on ‘consciousness raising’ in Guest and Conway, 2004: 115–116) and by providing their members with considerable information about problems within the organisation and the problems they are encountering with management. This is likely to be part of the explanation for the findings of this research as at the time of the survey, PSR management were keen to introduce a performance-related pay scheme which had led to an active campaign of opposition by the union.A second explanation is that union members may have higher expectations of voice. Employees join unions for a variety of reasons (Peetz, 1998), but overall, they expect unions to make a difference to their working lives. As Bryson and Freeman (2007: 84) found, ‘unionised workers reported more problems with management’ than non-union workers. In the case of PSR, the major reasons for employees joining the union were a belief in unions, wanting to have a say in things that affect their working life and a belief that unions generate better wages and conditions. Clearly, these union members had high expectations concerning voice. Yet, it was also the case that these expectations were not being met. Improved wages and working conditions were becoming harder to achieve as the enterprise bargaining system, with its emphasis on productivity improvements, had led to trade-offs involving redundancies, a decline in wage relativities with the private sector, and the possibility of a new performance-based pay scheme being introduced.A third explanation is that the overall focus within PSR at the time of the research had shifted from curiosity-led to commercially-driven research with an emphasis on productivity and efficiency. For employees of PSR, most of who were accustomed to the more protected working environment of the public sector, this meant that external factors were now driving research, and the scientific arguments used in the past for justifying research projects were becoming less important. In this environment, the value of union membership was becoming more marginal as union members had less protection than that of the past in the case of redundancies and adverse performance appraisals. In addition, other benefits of union membership such as access to grievance procedures were available to all employees regardless of their union status. It may also have been the case that management's approach to reform, for example the introduction of a performance-based pay scheme that ran counter to the wishes of union members and past practices, may have led many unionists to believe they were being targeted. In this context, the tense state of the relationship between management and the union may have created a negative perception of collective union voice (Freeman and Medoff, 1984).

However, the specific benefit drongos gain from producing such a large array of mimetic alarm calls is unclear.

No significant effects were observed for the striatal volumes, with only a marginal effect observed for putamen (P = 0.062) when congruent reaction time was included as covariate.

ID: 020
Variable: Flanker performance, striatal vol
Interpretation: no relationship found

ID: 021
Variable: Flanker performance, putamen vol
Model: ? (includes congruent RT)
P: 0.062
Interpretation: slight cognitive control effect observed for putamen volume

But there’s, I think there is a question of how you interpret the data, even ... ifthe experiments are very well designed. And, in terms of advice—not that I’mgoing to say that it’s shocking—but one of my mentors, whom I very muchrespect as a scientist—I think he’s extraordinarily good—advised me to alwaysput the most positive spin you can on your data. And if you try to present, like,present your data objectively, like in a job seminar, you’re guaranteed tonotgetthe job

Quality (DRG) 1.2675 0.61

“Unfortunately, I couldn’t find the effect,” he said. “But the worst part was that when I submitted these null results I had difficulty getting them published.

Why sully a CV with papers from the ‘Journal of Failed Experiments’? Don’t we want our colleagues (and especially our competitors) to believe that we succeed at every undertaking?

Thus, although the arguments in favor of small-unit publishing all seem to revolve around benefits to the community, the costs of generating these small units would fall on individual authors. If the community is to reap the benefits, then the costs to the individual authors must be driven to zero – or associated with some reward.

Time spent publishing small papers is time not spent developing big ones

but because journal editors are obsessively vigilant about rejecting papers that fall below a threshold of ‘novelty’, these papers become unpublishable in practical terms

Reasons for not making data electronically available. Regarding their attitudes towards data sharing, most of the respondents (85%) are interested in using other researchers' datasets, if those datasets are easily accessible. Of course, since only half of the respondents report that they make some of their data available to others and only about a third of them (36%) report their data is easily accessible, there is a major gap evident between desire and current possibility. Seventy-eight percent of the respondents said they are willing to place at least some their data into a central data repository with no restrictions. Data repositories need to make accommodations for varying levels of security or access restrictions. When asked whether they were willing to place all of their data into a central data repository with no restrictions, 41% of the respondents were not willing to place all of their data. Nearly two thirds of the respondents (65%) reported that they would be more likely to make their data available if they could place conditions on access. Less than half (45%) of the respondents are satisfied with their ability to integrate data from disparate sources to address research questions, yet 81% of them are willing to share data across a broad group of researchers who use data in different ways. Along with the ability to place some restrictions on sharing for some of their data, the most important condition for sharing their data is to receive proper citation credit when others use their data. For 92% of the respondents, it is important that their data are cited when used by other researchers. Eighty-six percent of survey respondents also noted that it is appropriate to create new datasets from shared data. Most likely, this response relates directly to the overwhelming response for citing other researchers' data. The breakdown of this section is presented in Table 13.

HR people can’t believe that a company the size of Netflix doesn’t hold annual reviews. “Are you making this up just to upset us?” they ask. I’m not. If you talk simply and honestly about performance on a regular basis, you can get good results—probably better ones than a company that grades everyone on a five-point scale.