Miracle-dz/UniFAR-FTUs huggingface dataset:
A cortical circuit mechanism for coding and updating task structural knowledge in inference-based decision-making

Making decisions based on knowledge about causal environmental structures is a hallmark of higher cognition in mammalian brains. Despite mounting work in psychological and cognitive sciences, how the brain implements knowledge-based decision-making at neuronal circuit level remains a terra incognita. Here we established an inference-based auditory categorization task, where mice performed within-session re-categorization of stimuli by inferring the changing task rules. Using a belief-state reinforcement learning (BS-RL) model, we quantified the hidden variable associated with task knowledge. Using simultaneous two-photon population imaging and projection-specific optogenetics, we found that a subpopulation of auditory cortex (ACx) neurons encoded the hidden task-rule variable, which depended on the feedback input from orbitofrontal cortex (OFC). Chemogenetic silencing of the OFC-ACx projection specifically disrupted re-categorization performance. Finally, imaging from OFC axons within ACx revealed task state-related value signals in line with the modeled updating mechanism. Our results provide a cortical circuit mechanism underlying inference-based decision-making.
Tracking strains predicts personal microbiomes and reveals recent adaptive evolution

An individual’s microbiome consists of a diverse set of bacterial strains that encode rich information on its colonization and evolutionary history. Here, we introduce a versatile and straightforward reference-based strain tracking approach (StrainTrack) that determines whether distinct metagenomes carry closely-related strains based on gene presence and absence profiles. We show that StrainTrack can predict whether two metagenomes originate from the same donor via counting the number of species sharing closely-related strains, achieving >96% specificity, and ∼100% sensitivity. When applied to the metagenomes of adult twins in the TwinsUK registry, we identify six cases of closely-related strains carried by both twins, potentially over decades of colonization.
Fractional diffusion theory of balanced heterogeneous neural networks

Interactions of large numbers of spiking neurons give rise to complex neural dynamics with fluctuations occurring at multiple scales. Understanding the dynamical mechanisms underlying such complex neural dynamics is a long-standing topic of interest in neuroscience, statistical physics and nonlinear dynamics. Conventionally, fluctuating neural dynamics are formulated as balanced, uncorrelated excitatory and inhibitory inputs with Gaussian properties. However, heterogeneous, non-Gaussian properties have been widely observed in both neural connections and neural dynamics. Here, based on balanced neural networks with heterogeneous, non-Gaussian features, our analysis reveals that in the limit of large network size, synaptic inputs possess power-law fluctuations, leading to a remarkable relation of complex neural dynamics to the fractional diffusion formalisms of non-equilibrium physical systems. By uniquely accounting for the leapovers caused by the fluctuations of spiking activity, we further develop a fractional Fokker-Planck equation with absorbing boundary conditions. This body of formalisms represents a novel fractional diffusion theory of heterogeneous neural networks and results in an exact description of the network activity states. This theory is further implemented in a biologically plausible, balanced neural network and identifies a novel type of network state with rich, nonlinear response properties, providing a unified account of a variety of experimental findings on neural dynamics at the individual neuron and the network levels, including fluctuations of membrane potentials and population firing rates. We illustrate that this novel state endows neural networks with a fundamental computational advantage; that is, the neural response is maximised as a function of structural connectivity. Our theory and its network implementations provide a framework for investigating complex neural dynamics emerging from large networks of spiking neurons and their functional roles in neural processing.
Local circuits of layer Vb-to-Va neurons mediate hippocampal-cortical outputs in lateral but not in medial entorhinal cortex

The entorhinal cortex, in particular neurons in layer V, allegedly mediate transfer of information between the hippocampus and the neocortex, underlying long-term memory. Recently, this circuit has been shown to comprise a hippocampal output recipient layer Vb and a cortical projecting layer Va. With the use of in vitro electrophysiology in transgenic mice specific for layer Vb, we assessed the presence of the thus necessary connection between layer Vb and layer Va in the two functionally distinct medial (MEC) and lateral (LEC) subdivisions; MEC processes allocentric spatial information, whereas LEC represents the content of episodes. Using identical experimental approaches, we show that in LEC, but not in MEC, layer Vb neurons provide substantial direct input to layer Va neurons. This indicates that the hippocampal-cortex output circuit is present only in LEC, suggesting that episodic systems consolidation predominantly uses LEC-derived information and not allocentric spatial information from MEC.
Sequences of the genomic DNAs encoding the S2, S9, S10, and S23 alleles from almond, Prunus dulcis

Summary Partial genomic sequences of the S–alleles S2, S9, and S10, identified in genomic DNA selected from Prunus dulcis ‘Cristomorto’ (S1S2), ‘Anxaneta’ (S2S9), ‘Primorskiy’ (S5S9), and ‘Gabaix’ (S5S10), were found to contain introns of 562, 1, 343, and ~705 bp, and partial exons of 537, 486, and 495 bp respectively. In addition, another allele, characterized as S23, was identified in the two Australian cultivars Johnston’s Prolific and Pierce. This allele had an intron size of 662 bp and a partial exon size of 489 bp, and may have been introduced into Australia in the Spanish cultivar Ramillete (S6S23). The exon/intron splice junction sites of all alleles followed the GT/AG consensus sequence rule, and the sequences were found to be highly conserved.
Positive selection within the genomes of SARS-CoV-2 and other Coronaviruses independent of impact on protein function

Background The emergence of a novel coronavirus (SARS-CoV-2) associated with severe acute respiratory disease (COVID-19) has prompted efforts to understand the genetic basis for its unique characteristics and its jump from non-primate hosts to humans. Tests for positive selection can identify apparently nonrandom patterns of mutation accumulation within genomes, highlighting regions where molecular function may have changed during the origin of a species. Several recent studies of the SARS-CoV-2 genome have identified signals of conservation and positive selection within the gene encoding Spike protein based on the ratio of synonymous to nonsynonymous substitution. Such tests cannot, however, detect changes in the function of RNA molecules. Methods Here we apply a test for branch-specific oversubstitution of mutations within narrow windows of the genome without reference to the genetic code. Results We recapitulate the finding that the gene encoding Spike protein has been a target of both purifying and positive selection. In addition, we find other likely targets of positive selection within the genome of SARS-CoV-2, specifically within the genes encoding Nsp4 and Nsp16. Homology-directed modeling indicates no change in either Nsp4 or Nsp16 protein structure relative to the most recent common ancestor. Thermodynamic modeling of RNA stability and structure, however, indicates that RNA secondary structure within both genes in the SARS-CoV-2 genome differs from those of RaTG13, the reconstructed common ancestor, and Pan-CoV-GD (Guangdong). These SARS-CoV-2-specific mutations may affect molecular processes mediated by the positive or negative RNA molecules, including transcription, translation, RNA stability, and evasion of the host innate immune system. Our results highlight the importance of considering mutations in viral genomes not only from the perspective of their impact on protein structure, but also how they may impact other molecular processes critical to the viral life cycle.
Tuning of self-renewing capacity in the Arabidopsis stomatal lineage by hormonal and nutrition regulation of asymmetric cell divisions

Asymmetric and self-renewing divisions build and pattern tissues. In the Arabidopsis thaliana stomatal lineage, asymmetric cell divisions, guided by polarly localized cortical proteins, generate the majority of cells on the leaf surface. These divisions can be fine-tuned by systemic and environmental signals to modify tissue development, but the molecular mechanisms by which plants incorporate such cues to regulate asymmetric divisions are largely unknown. In a screen for modulators of cell polarity and asymmetric divisions, we identified a mutation in CONSTITIUTIVE TRIPLE RESPONSE 1, a negative regulator of ethylene signaling. We subsequently revealed antagonistic impacts of ethylene and glucose signaling on the self-renewing capacity of stomatal lineage stem cells. Quantitative analysis of the impacts of these signaling systems on cell polarity and fate dynamics showed that developmental information may be encoded in both the spatial and temporal asymmetries of polarity proteins. Taken together, our results provide a framework for a mechanistic understanding of how systemic information such as nutritional status and environmental factors tune stem cell behavior in the stomatal lineage, ultimately enabling optimization of leaf size and cell-type composition.
Brain-Environment Alignment during Movie Watching Predicts Cognitive-Affective Function in Adulthood

The brain’s functional architecture changes considerably across multiple timescales. While the role of variations over long timescales (e.g., years) is widely documented, the functional relevance of microtemporal (i.e., second-level) fluctuations is still debated. Using fMRI data collected during movie watching from two independent samples, we demonstrate that the adaptiveness of variability in functional brain architecture fluctuates across the adult lifespan (18-88 years) due to age-related differences in the associated profiles of network communication. Greater coupling between changes in brain architecture and concrete environmental features is stronger at younger ages and linked to poorer cognitive-affective outcomes. Whole-brain communication pathways anchored in regions key to episodic and semantic context creation contribute to greater brain reconfiguration in response to abstract contextual changes and stronger coupling between changes in brain architecture and concrete environmental features. Our results provide new insights into age-related differences in brain-environment alignment and their relevance to cognitive adaptability and psychopathology.
Divergent Resistance Mechanisms to Immunotherapy Explain Responses in Different Skin Cancers

The advent of immune checkpoint therapy for metastatic skin cancer has greatly improved patient survival. However, most skin cancer patients are refractory to checkpoint therapy, and furthermore the differential intra-immune signaling between cancers driving the response to checkpoint therapy remains uncharacterized. When comparing the immune transcriptome in the tumor microenvironment of melanoma and basal cell carcinoma (BCC), we found that the presence of memory B cells and macrophages negatively correlate when stratifying patients by response, with memory B cells more present in responders. Inhibitory immune signaling is reduced in melanoma responders and is increased in BCC responders. We further explored the relationships between macrophages, B cells and response to checkpoint therapy by developing a stochastic differential equation model which qualitatively agrees with the data analysis. Our model predicts BCC to be more refractory to checkpoint therapy than melanoma. We show differences in tumor progression and regression that could serve as a diagnostic and predict the optimal ratio of macrophages and memory B cells for successful treatment.
Behavioral elements and neural circuits underlying exploratory decisions in normative anxiety

Exploration reduces uncertainty about the environment and improves the quality of future decisions, but at the cost of uncertain and suboptimal outcomes. Although anxiety increases intolerance to uncertainty, it remains unclear whether and how anxiety modulates exploratory decision-making. We use a three-armed-bandit task in both loss and gain domains and find that higher trait-anxiety increases exploration, which in turn underlies an inverse-U-shaped relationship between anxiety and overall performance. We identify two distinct sources: first, decisions made by anxious individuals were guided towards reduction of uncertainty, and second, decisions were less guided by immediate value gains. Imaging (fMRI) revealed that anxiety correlated negatively with the representation of expected-value in the dorsal-anterior-cingulate-cortex, and in contrast positively with the representation of uncertainty in the anterior-insula. We conclude that a shift in balance towards representation of uncertainty in the insula prevails over value representation in the dACC, and entails maladaptive decision-making in individuals with higher normal-range anxiety.
LIFE HISTORY PARAMETERS IN MELANOPLUS SANGUINIPES (F.) IN TWO CRESTED WHEATGRASS PASTURES

Abstract A combination of published techniques provided point estimates of life history parameters for two natural field populations of Melanoplus sanguinipes (F.) in crested wheatgrass pastures. Stage-specific survival rates averaged 0.4798, 0.2261, 0.7628, and 0.6903 for egg, instars I–III combined, instar IV, and instar V, respectively. Daily survival rates of adults averaged 0.9702, but were slightly lower for females than for males. Estimated duration of nymphal instars averaged 8.4 days, the adult preoviposition period averaged 13.3 days, and adult longevity averaged 26.7 and 36.3 days in the two populations. Oviposition rates were estimated for up to four successive ovipositions, and net replacement rates of populations also were estimated. Neither population replaced itself, indicating that potential capacities for increase were not approached under conditions of these studies. Résumé Un ensemble de techniques publiées a permis d’obtenir des estimés ponctuels des paramètres du cycle évolutif de deux populations naturelles de Melanoplus sanguinipes (F.) dans les pâturages à agropyre à crête. Les taux de survie spécifique du stade étaient en moyenne de 0,4798, 0,2261, 0,7628 et 0,6903 pour les oeufs, les stades I à II combinés, le stade IV et le stade V. Les taux de survie journaliers des adultes étaient en moyenne de 0,9702, mais étaient légèrement plus faibles chez les femelles que les mâles. La durée moyenne des stades larvaires étaient de 8,4 jours, la période de préoviposition moyenne de 13,3 jours et la longévité moyenne de 26,7 et 36,3 jours chez les deux populations. Les taux de ponte ont été estimés pour un maximum de quatre pontes successives, et on a aussi estimé les taux nets de remplacement des populations. Aucune des populations ne s’est remplacée elle-même, indiquant que les capacités d’accroissement n’étaient pas atteintes dans les conditions de ces études.
Nuptial Vocalizations of Male Least Seedsnipe: Structure and Evolutionary Significance

Acoustic displays of non-passerines hold promise for understanding how communication is adapted to the physical environment and for resolving systematic relationships. The potential of acoustic characteristics for systematics can be illustrated with shorebirds. Some shorebird displays (e.g., snipe drumming) differ greatly between closely related species, so should be informative about low-level relationships. Other displays (e.g., duetting in stone-curlews, avocets, and oystercatchers; Stepanjan 1970, 1979) are evolutionarily conservative and extremely similar even between shorebird species that diverged from one another millions of years ago; such conservative displays may help to resolve high-order relationships. A shorebird group whose systematic position may be clarified by acoustic information is the seedsnipe (Thinocoridae). The relationships of the four species of seedsnipe to other shorebirds remain enigmatic despite a wealth of systematic and phylogenetic studies over many years (Strauch 1978, Sibley and Ahlquist
Functional dynamics of de-afferented early visual cortex in glaucoma

fMRI studies in macular degeneration (MD) and retinitis pigmentosa (RP) demonstrated that responses in the lesion projection zones (LPZ) of V1 are task related, indicating significant limits of bottom-up visual system plasticity in MD and RP. In advanced glaucoma (GL), a prevalent eye disease and leading cause of blindness, the scope of visual system plasticity is currently unknown. We performed 3T fMRI in patients with extensive visual field defects due to GL (n=5), RP (n=2) and healthy controls (n=7; with simulated defects). Participants viewed contrast patterns drifting in 8 directions alternating with uniform gray and performed 3 tasks: (1) passive viewing (PV), (2) one-back task (OBT) and (3) fixation-dot task (FDT). During PV, they passively viewed the stimulus with central fixation, during OBT they reported the succession of the same two motion directions, and during FDT a change in the fixation color. In GL, LPZ responses of the early visual cortex (V1, V2 and V3) shifted from negative during PV to positive for OBT [p (corrected): V1(0.006); V2(0.04); V3(0.008)], while they were negative in the controls’ simulated LPZ for all stimulation conditions. For RP a similar pattern as for GL was observed. Consequently, activity in the de-afferented visual cortex in glaucoma is, similar to MD and RP, task-related. In conclusion, the lack of bottom-up plasticity appears to be a general feature of the human visual system. These insights are of importance for the development of treatment and rehabilitation schemes in glaucoma. Highlights Functional dynamics of early visual cortex LPZ depend on task demands in glaucoma Brain activity in deprived visual cortex suggests absence of large-scale remapping Limited scope of bottom-up plasticity is a general feature of human visual system Visual system stability and plasticity is of relevance for therapeutic advances
Rational design of a new class of protease inhibitors for the potential treatment of coronavirus diseases

The coronavirus main protease, Mpro, is a key protein in the virus life cycle and a major drug target. Based on crystal structures of SARSCoV2 Mpro complexed with peptidomimetic inhibitors, we recognized a binding characteristic shared with proline-containing inhibitors of hepatitis C virus protease. Initial tests showed that this subclass of HCV protease inhibitors indeed exhibited activity against Mpro. Postulating a benefit for a preorganized backbone conformation, we designed new ketoamide-based Mpro inhibitors based on central proline rings. One of the designed compounds, ML1000, inhibits Mpro with low-nanomolar affinity and suppresses SARSCoV2 viral replication in human cells at sub-micromolar concentrations. Our findings identify ML1000 as a promising new pre-organized scaffold for the development of anti-coronavirus drugs.
Dependency Parse Reranking Based on Subtree Extraction

We present a new reranking approach for dependency parsing that can utilize complex subtree representation by applying efficient subtree selection heuristics. We demonstrate the effectiveness of the approach in experiments conducted on the Penn Treebank and the Chinese Treebank. Our system improves the baseline accuracy from 91.88% to 93.37% for English, and in the case of Chinese from 87.39% to 89.16%.
Influence of Environmental Po2 on Embryonic Oxygen Consumption, Rate of Development, and Hatching in the Frog Pseudophryne bibroni

Embryos of the frog Pseudophryne bibroni develop on land in depressions underneath objects or vegetation. They hatch only after they have reached Gosner stage 26-27 and are flooded with water. Flooding of the nest reduces Po2 outside the eggs owing to O2 consumption by the embryos. Low Po2 limits the rate of O2 consumption (V̇o2), retards embryonic development, and triggers hatching. In terrestrial embryos at the hatching stage at 12 C, V̇o2 becomes severely limited at Po2 below 14.7 kPa (111 mmHg). In embryos raised in water, rate of development decreases with decreasing Po2 below 38.0 kPa (285 mmHg). In embryos raised on land and then flooded, hatching occurs in less than 12 h when Po2 of the gas above the water is less than 29.9 kPa (224 mmHg). In contrast, hatching of nonflooded embryos on either wet or dry substrate occurs within this time interval only when Po2 is below 5.2 kPa (39 mmHg). This difference in hatching response is apparently due to O2 depletion in the water surrounding the aquatic eggs rather than to differences in water potential of the environment. Thus, hatching is not immediately stimulated within a range of Po2 that limits V̇o2 (5.2-14.7 kPa). Hatching occurs only after protracted flooding, which may help ensure that the hatchling emerges into enough standing water to complete metamorphosis.
Contrasting Variable and Stable Subsurface Microbial Populations: an ecological time series analysis from the Deep Mine Microbial Observatory, South Dakota, USA

The deep subsurface contains a vast reservoir of microbial life. While recent studies have revealed critical details about this biosphere including the sheer diversity of microbial taxa and their metabolic potential, long-term monitoring of deep subsurface microbial populations is rare, thus limiting our understanding of subsurface microbial population dynamics. Here we present a four-year time series analysis of subsurface microbial life from the Deep Mine Microbial Observatory (DeMMO), Lead, SD, USA. We find distinct and diverse populations inhabiting each of 6 sites over this ~1.5 km deep slice of terrestrial crust, corresponding to distinct geochemical habitats. Alpha diversity decreases with depth and beta diversity measures clearly differentiate samples by site over time, even during substantial perturbations. Population dynamics are driven by a subset of variable (and often relatively abundant) OTUs, but the vast majority of detected OTUs are stable through time, constituting a core microbial community. The phylogenetic affiliations of both stable and variable taxa, including putative sulfate reducers, methanogens, spore formers, and many uncultivated lineages, are similar to those found previously in subsurface environments. This work reveals the dynamic nature of the terrestrial subsurface, contributing to a more holistic understanding than can be achieved when viewing shorter timeframes. Originality-Significance Statement This four-year record of deep mine microbial diversity and geochemistry is the first of its kind and allows for direct investigation of temporal trends in deep subsurface biogeochemistry. We identify disparate populations of variable and stable taxa, suggesting the presence of a core deep subsurface microbiome with unique niche partitioning.