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TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions in cis or through competition of shared ligands. Whether TIGIT directly delivers cell-intrinsic inhibitory signals in T cells remains unclear. Here we show, by analysing lymphocytes from matched human tumour and peripheral blood samples, that TIGIT and CD226 co-expression is rare on tumour-infiltrating lymphocytes. Using super-resolution microscopy and other techniques, we demonstrate that ligation with CD155 causes TIGIT to reorganise into dense nanoclusters, which coalesce with T cell receptor (TCR)-rich clusters at immune synapses. Functionally, this reduces cytokine secretion in a manner dependent on TIGIT’s intracellular ITT-like signalling motif. Thus, we provide evidence that TIGIT directly inhibits lymphocyte activation, acting independently of CD226, requiring intracellular signalling that is proximal to the TCR. Within the subset of tumours where TIGIT-expressing cells do not commonly co-express CD226, this will likely be the dominant mechanism of action. CD226 provides a co-stimulatory signal to the T cell receptor during activation, and TIGIT is believed to inhibit this process by competing for the CD226 ligand CD155. Here authors show that ligand binding induces dense nanocluster formation by TIGIT which initiates intrinsic, CD226 independent inhibitory signals, proximal to T cell receptor signalling.

Ecosystem restoration is a common tool for re-establishing ecosystem processes, structures, and functions to improve biodiversity and services in coastal and estuarine ecosystems. In the Salish Sea, salmon habitats have been fragmented, reduced in size, and diminished in quality, and the ecosystem processes that form and sustain these habitats have been degraded and disrupted as well. This loss is especially prevalent in estuaries, where up to 90% of former salmon habitat has been lost or compromised. Salmon species are integral to the identities and cultures of people in the Pacific Northwest, yet salmon abundances remain at historic lows, especially in urbanized areas. Recent investments in restoration are creating rearing habitat and repairing lost ecosystem function. However, restoration efforts in this region have largely proceeded at the site scale, with less attention to big-picture thinking regarding how restoration will effectively recover degraded or lost habitats for target species. As a result, no landscape-scale evaluation program exists, and the cumulative benefits of multiple interventions are unknown. We describe innovative methods for science synthesis related to the evaluation of cumulative effects of ecosystem restoration for Pacific salmon, using years of existing, but disparate data. Building from previous work on cumulative effects evaluation and incorporating a hierarchy of hypotheses approach, we propose using causal inference across numerous hypotheses in a framework to assess the cumulative benefits to Pacific salmon from multiple estuarine restoration projects. We present the framework as a method that can be used to address many complex questions and provide examples from the Salish Sea where the approach is being implemented. The framework draws on science synthesis from numerous fields and uses a hierarchy of hypotheses, causal analysis at multiple scales, and a new hierarchy of synthesis for assessing multiple lines of evidence documenting restoration effects on Pacific salmon. We propose causal inference to synthesize dissimilar data streams, in our case, to identify various manifestations of cumulative effects of restoration and benefits to salmon, and to further inform restoration and recovery planning. A unifying framework would allow for the detection of thresholds at which restoration provides measurable improvement and would greatly advance understanding of the effects of restoration on ecosystems.

Across many different contexts, randomized evaluations find that school participation is sensitive to costs: Reducing out-of-pocket costs, merit scholarships, and conditional cash transfers all increase schooling. Addressing child health and providing information on how earnings rise with education can increase schooling even more cost-effectively. However, among those in school, test scores are remarkably low and unresponsive to more-of-the-same inputs, such as hiring additional teachers, buying more textbooks, or providing flexible grants. In contrast, pedagogical reforms that match teaching to students' learning levels are highly cost effective at increasing learning, as are reforms that improve accountability and incentives, such as local hiring of teachers on short-term contracts. Technology could potentially improve pedagogy and accountability. Improving pre-and postprimary education are major future challenges.

AbstractObjectivesTo determine the extent and content of academic publishers’ and scientific journals’ guidance for authors on the use of generative artificial intelligence (GAI).DesignCross sectional, bibliometric study.SettingWebsites of academic publishers and scientific journals, screened on 19-20 May 2023, with the search updated on 8-9 October 2023.ParticipantsTop 100 largest academic publishers and top 100 highly ranked scientific journals, regardless of subject, language, or country of origin. Publishers were identified by the total number of journals in their portfolio, and journals were identified through the Scimago journal rank using the Hirsch index (H index) as an indicator of journal productivity and impact.Main outcome measuresThe primary outcomes were the content of GAI guidelines listed on the websites of the top 100 academic publishers and scientific journals, and the consistency of guidance between the publishers and their affiliated journals.ResultsAmong the top 100 largest publishers, 24% provided guidance on the use of GAI, of which 15 (63%) were among the top 25 publishers. Among the top 100 highly ranked journals, 87% provided guidance on GAI. Of the publishers and journals with guidelines, the inclusion of GAI as an author was prohibited in 96% and 98%, respectively. Only one journal (1%) explicitly prohibited the use of GAI in the generation of a manuscript, and two (8%) publishers and 19 (22%) journals indicated that their guidelines exclusively applied to the writing process. When disclosing the use of GAI, 75% of publishers and 43% of journals included specific disclosure criteria. Where to disclose the use of GAI varied, including in the methods or acknowledgments, in the cover letter, or in a new section. Variability was also found in how to access GAI guidelines shared between journals and publishers. GAI guidelines in 12 journals directly conflicted with those developed by the publishers. The guidelines developed by top medical journals were broadly similar to those of academic journals.ConclusionsGuidelines by some top publishers and journals on the use of GAI by authors are lacking. Among those that provided guidelines, the allowable uses of GAI and how it should be disclosed varied substantially, with this heterogeneity persisting in some instances among affiliated publishers and journals. Lack of standardization places a burden on authors and could limit the effectiveness of the regulations. As GAI continues to grow in popularity, standardized guidelines to protect the integrity of scientific output are needed.

There is growing interest in the use of biofeedback-augmented gait training in cerebral palsy (CP). Audiovisual, sensorimotor, and immersive biofeedback paradigms are commonly used to elicit short-term gait improvements; however, outcomes remain variable. Because biofeedback training requires that individuals have the capacity to both adapt their gait in response to feedback and retain improvements across sessions, changes in either capacity may affect outcomes. Yet, neither has been explored extensively in CP. In this study, we evaluated the extent to which adolescents with CP (7M/1F; 14 years (12.5,15.26)) could adapt gait and retain improvements across four, 20-minute sessions using combined audiovisual and sensorimotor biofeedback. Both systems were designed to target plantarflexor activity. Audiovisual biofeedback displayed real-time soleus activity and sensorimotor biofeedback was provided using a bilateral resistive ankle exoskeleton. We quantified the time-course of change in muscle activity within and across sessions and overground walking function before and after the four sessions. All individuals were able to significantly increase soleus activity from baseline using multimodal biofeedback (p < 0.031) but demonstrated heterogeneous adaptation strategies. In-session soleus adaptation had a moderate positive correlation with short-term retention of the adapted gait patterns (0.40 ≤ ρ ≤ 0.81), but generally weak correlations with baseline walking function (GMFCS Level) and motor control complexity (ρ ≤ 0.43). The latter indicates that adaptation capacity may be a critical and unique metric underlying response to biofeedback. Notably, in-session gains did not correspond to significant improvements in overground walking function (p > 0.11). This work suggests that individuals with CP have the capacity to adapt their gait using biofeedback, but responses are highly variable. Characterizing the factors driving adaptation to biofeedback may be a promising avenue to understand the heterogeneity of existing biofeedback training outcomes and inform future system optimization for integration into clinical care.

Some tick populations have increased dramatically in the past several decades leading to an increase in the incidence and emergence of tick-borne diseases. Management strategies that can effectively reduce tick populations while better understanding regional tick phenology is needed. One promising management strategy is prescribed burning. However, the efficacy of prescribed burning as a mechanism for tick control is unclear because past studies have provided conflicting data, likely due to a failure of some studies to simulate operational management scenarios and/or account for other predictors of tick abundance. Therefore, our study was conducted to increase knowledge of tick population dynamics relative to long-term prescribed fire management. Furthermore, we targeted a region, southwestern Georgia and northwestern Florida (USA), in which little is known regarding tick dynamics so that basic phenology could be determined. Twenty-one plots with varying burn regimes (burned surrounded by burned [BB], burned surrounded by unburned [BUB], unburned surrounded by burned [UBB], and unburned surrounded by unburned [UBUB]) were sampled monthly for two years while simultaneously collecting data on variables that can affect tick abundance (e.g., host abundance, vegetation structure, and micro- and macro-climatic conditions). In total, 47,185 ticks were collected, of which, 99% were Amblyomma americanum, 0.7% were Ixodes scapularis, and fewer numbers of Amblyomma maculatum, Ixodes brunneus, and Dermacentor variabilis. Monthly seasonality trends were similar between 2010 and 2011. Long-term prescribed burning consistently and significantly reduced tick counts (overall and specifically for A. americanum and I. scapularis) regardless of the burn regimes and variables evaluated. Tick species composition varied according to burn regime with A. americanum dominating at UBUB, A. maculatum at BB, I. scapularis at UBB, and a more even composition at BUB. These data indicate that regular prescribed burning is an effective tool for reducing tick populations and ultimately may reduce risk of tick-borne disease.

Copper-based catalyst is uniquely positioned to catalyze the hydrocarbon formations through electrochemical CO 2 reduction. The catalyst design freedom is limited for alloying copper with H-affinitive elements represented by platinum group metals because the latter would easily drive the hydrogen evolution reaction to override CO 2 reduction. We report an adept design of anchoring atomically dispersed platinum group metal species on both polycrystalline and shape-controlled Cu catalysts, which now promote targeted CO 2 reduction reaction while frustrating the undesired hydrogen evolution reaction. Notably, alloys with similar metal formulations but comprising small platinum or palladium clusters would fail this objective. With an appreciable amount of CO-Pd 1 moieties on copper surfaces, facile CO * hydrogenation to CHO * or CO-CHO * coupling is now viable as one of the main pathways on Cu(111) or Cu(100) to selectively produce CH 4 or C 2 H 4 through Pd-Cu dual-site pathways. The work broadens copper alloying choices for CO 2 reduction in aqueous phases. The inclusion of platinum-group metals for CO2 reduction electrocatalyst design may trigger the unwanted hydrogen evolution reaction. However, here the authors show that single-atom Pd and Pt on facet-selective Cu can selectively boost CO2 to CH4 or C2H4 conversion through dual-site pathways.

The Order Pelagibacterales (SAR11) is the most abundant group of heterotrophic bacterioplankton in global oceans and comprises multiple subclades with unique spatiotemporal distributions. Subclade IIIa is the primary SAR11 group in brackish waters and shares a common ancestor with the dominant freshwater IIIb (LD12) subclade. Despite its dominance in brackish environments, subclade IIIa lacks systematic genomic or ecological studies. Here, we combine closed genomes from new IIIa isolates, new IIIa MAGS from San Francisco Bay (SFB), and 460 highly complete publicly available SAR11 genomes for the most comprehensive pangenomic study of subclade IIIa to date. Subclade IIIa represents a taxonomic family containing three genera (denoted as subgroups IIIa.1, IIIa.2, and IIIa.3) that had distinct ecological distributions related to salinity. The expansion of taxon selection within subclade IIIa also established previously noted metabolic differentiation in subclade IIIa compared to other SAR11 subclades such as glycine/serine prototrophy, mosaic glyoxylate shunt presence, and polyhydroxyalkanoate synthesis potential. Our analysis further shows metabolic flexibility among subgroups within IIIa. Additionally, we find that subclade IIIa.3 bridges the marine and freshwater clades based on its potential for compatible solute transport, iron utilization, and bicarbonate management potential. Pure culture experimentation validated differential salinity ranges in IIIa.1 and IIIa.3 and provided detailed IIIa cell size and volume data. This study is an important step forward for understanding the genomic, ecological, and physiological differentiation of subclade IIIa and the overall evolutionary history of SAR11.

Both the pre-supplementary motor area (preSMA) and the right inferior frontal gyrus (rIFG) are important for stopping action outright. These regions are also engaged when preparing to stop. We aimed to elucidate the roles of these regions by harnessing the high spatio-temporal resolution of electrocorticography (ECoG), and by using a task that engages both preparing to stop and stopping outright. First, we validated the task using fMRI in 16 healthy control participants to confirm that both the preSMA and the rIFG were active. Next, we studied a rare patient with intracranial grid coverage of both these regions, using macrostimulation, diffusion tractography, cortico-cortical evoked potentials (CCEPs) and task-based ECoG. Macrostimulation of the preSMA induced behavioral motor arrest. Diffusion tractography revealed a structural connection between the preSMA and rIFG. CCEP analysis showed that stimulation of the preSMA evoked strong local field potentials within 30ms in rIFG. During the task, when preparing to stop, there was increased high gamma amplitude (~70–250Hz) in both regions, with preSMA preceding rIFG by ~750ms. For outright stopping there was also a high gamma amplitude increase in both regions, again with preSMA preceding rIFG. Further, at the time of stopping, there was an increase in beta band activity (~16Hz) in both regions, with significantly stronger inter-regional coherence for successful vs. unsuccessful stop trials. The results complement earlier reports of a structural/functional action control network between the preSMA and rIFG. They go further by revealing between-region timing differences in the high gamma band when preparing to stop and stopping outright. They also reveal strong between-region coherence in the beta band when stopping is successful. Implications for theories of action control are discussed. ► We used fMRI in healthy adults and multiple methods in a single epilepsy patient. ► We studied the presupplementary motor area and right inferior frontal gyrus. ► The preSMA and rIFG are structurally and functionally connected. ► Gamma activity in preSMA occurs before rIFG in anticipation of action control. ► Beta-band coherence between preSMA and rIFG occurs during action control.

Understanding habitat selection of gray foxes (Urocyon cinereoargenteus) is essential to evaluate their potential response to changes in land use and predator communities. Few studies have evaluated temporal habitat selection or explicitly identified habitats used by gray foxes for diurnal refugia. We used GPS collars to obtain location data for 34 gray foxes (20 males and 14 females) from February 2014 to December 2015 to evaluate temporal (seasonal and diel) habitat selection and selection of diurnal refugia in southwestern Georgia, USA. We analyzed habitat selection at 2 levels, selection of a core area within the home range and selection of locations within the home range. Habitat selection was non-random (P < 0.001) but consistent among seasons, between day and night, and between sexes (P > 0.05). Hardwoods, human use (i.e., areas associated with regular human activity such as buildings, lawns, parking areas, etc.), and roads were selected (P < 0.05), whereas pine dominated stands were used randomly (P > 0.05). Selection of habitats for diurnal refugia did not vary seasonally or by sex (P > 0.05), with foxes selecting (P < 0.05) areas near hardwood forests, roads, agriculture, human use, pastures/food plots, and shrub scrub habitats. Gray foxes were observed on the ground while resting, and we found no evidence of gray foxes diurnally resting in trees. Our results suggest that on our study area, gray foxes are an edge species that prefer forests with a hardwood component in areas near human use and roads.