Miracle-dz/UniFAR-FTUs huggingface dataset:
Subcallosal area 25: its responsivity to the stress hormone cortisol and its opposing effects on appetitive motivation in marmosets

Aberrant activity in caudal subcallosal anterior cingulate cortex (scACC) is implicated in depression and anxiety symptomatology, with its normalisation a putative biomarker of successful treatment response. The function of scACC in emotion processing and mental health is not fully understood despite its known influence on stress-mediated processes through its rich expression of mineralocorticoid and glucocorticoid receptors. Here we examine the causal interaction between area 25 within scACC (scACC-25) and the stress hormone, cortisol, in the context of anhedonia and anxiety-like behaviour. Moreover, the overall role of scACC-25 in hedonic capacity and motivation is investigated under transient pharmacological inactivation and overactivation. The results suggest that a local increase of cortisol in scACC-25 shows a rapid induction of anticipatory anhedonia and increased responsiveness to uncertain threat. Separate inactivation and overactivation of scACC-25 increased and decreased motivation and hedonic capacity, respectively, likely through different underlying mechanisms. Together, these data show that area scACC-25 has a causal role in consummatory and motivational behaviour and produces rapid responses to the stress hormone cortisol, that mediates anhedonia and anxiety-like behaviour.
Protein-specific crowding accelerates aging in phase-separated droplets

Crowding agents, such as polyethylene glycol (PEG, are often used to mimic the cellular cytoplasm in protein assembly studies. Despite the perception that crowding agents have an inert nature, recent work has shown they are not bystanders while proteins interact. Here, we explore the diverse effects of PEG on the phase separation and maturation of proteins. We use two proteins, the FG domain of Nup98 and bovine serum albumin (BSA), which represent an intrinsically disordered protein and a protein with well-established secondary structure, respectively. PEG expedites the maturation of Nup98, enhancing denser protein packing and fortifying hydrophobic interactions which hasten beta-sheet formation and subsequent droplet gelation. In contrast for BSA, PEG appears to enhance droplet stability and limits available solvent for the protein solubilization, without inducing significant changes to the secondary structure, pointing towards a significantly different behavior of the crowding agent. Interestingly, we detect almost no presence of PEG in Nup droplets whereas PEG is detectable within BSA droplets. Our findings demonstrate a nuanced interplay between crowding agents and proteins. PEG can accelerate protein maturation in LLPS systems but its partitioning and effect on protein structure in droplets is protein specific. This suggests that crowding phenomena are specific to each protein-crowding agent pair.
STRING-ing together protein complexes: corpus and methods for extracting physical protein interactions from the biomedical literature

Understanding biological processes relies heavily on curated knowledge of physical interactions between proteins. Yet, a notable gap remains between the information stored in databases of curated knowledge and the plethora of interactions documented in the scientific literature. To bridge this gap, we introduce ComplexTome, a manually annotated corpus designed to facilitate the development of text-mining methods for the extraction of complex formation relationships among biomedical entities. This corpus comprises 1,287 documents with ∼3, 500 relationships. We train a novel relation extraction model on this corpus and find that it can highly reliably identify physical protein interactions (F1-score=82.8%). We additionally enhance the model’s capabilities through unsupervised trigger word detection and apply it to extract relations and trigger words for these relations from all open publications in the domain literature. This information has been fully integrated into the latest version of the STRING database, and all introduced resources are openly accessible via Zenodo and GitHub.
FOXA2 is essential for maintaining the urea cycle in acute liver failure

Hepatic encephalopathy is a lethal complication of acute liver failure (ALF), and is caused by hyperammonemia. Ammonia clearance by the liver requires an intact and complete urea cycle comprising six enzymes, including the rate-limiting enzyme carbamoyl phosphate synthetase I (CPS1). To date, the detailed regulation of CPS1 transcription in order to maintain urea cycle in physiological condition and ALF remains largely unknown. This study scrutinizes the role of pioneer factor forkhead box A 2 (FOXA2) in the regulation of CPS1 transcription, urea cycle performance and hyperammonemia. Physiologically, CPS1 transcription requires FOXA2 to maintain chromatin accessibility on its enhancers, which is essential for CCAAT enhancer-binding protein-alpha (C/EBPα) binding to activate gene transcription. In ALF, hepatic C/EBPα expression is inhibited by inflammatory mediators such as TGF-β and TNF-α. In this setting, retinoic acid receptor synergizes with FOXA2 to maintain CPS1 transcriptions. Once ALF patients suffer from massive hepatic necrosis, liver progenitor cells initiate a transcription network comprising FOXA2 and C/EBPα to perform the urea cycle and prevent hyperammonemia. In ALF, hepatic encephalopathy occurs in patients lacking hepatic FOXA2 expression. In mice with acetaminophen-induced ALF, injection of Foxa2-AAV8 maintains urea cycle and prevents hyperammonemia. Taken together, FOXA2 is essential for maintaining the urea cycle. Pharmaceutical induction of hepatic FOXA2 expression might represent a novel approach to treat hepatic encephalopathy in ALF. One Sentence Summary Pioneer factor FOXA2 synergizes with C/EBPα or RAR to maintain urea cycle in acute liver failure
Highly efficient transgenic mouse production using piggyBac and its application to rapid phenotyping at the founder generation

Pronuclear microinjection is the most popular method for producing transgenic (Tg) animals. Because the production efficiency is typically less than 20%, phenotypic characterization of Tg animals is generally performed on the next generation (F1) onwards. However, apart from in rodents, in many animal species with long generation times, it is desirable to perform phenotyping in the founder (F0) generation. In this study, we attempted to optimize a method of Tg mouse production to achieve higher Tg production efficiency using piggyBac transposon systems and established optimal conditions under which almost all individuals in the F0 generation were Tg. We also succeeded in generating bacterial artificial chromosome Tg mice with efficiency of approximately 70%. By combining this method with genome editing technology, we established a new strategy to perform phenotyping of mice with tissue-specific knockout using the F0 generation. Taking the obtained findings together, by using this method, experimental research using Tg animals can be carried out more efficiently.
Neurogenesis and neuronal migration in hypothalamic vasopressinergic magnocellular nuclei of the adult rat

In restricted mammalian brain regions, cell proliferation and migration continue postnatally and throughout adulthood. Sparse evidence has indicated that this also applies to hypothalamic regions, but the identity and nature of hypothalamic postnatal neurogenesis has remained elusive. Here, we provide evidence that neurogenesis and migration may occur in adult rat hypothalamic arginine vasopressin (AVP)-expressing nuclei and reveal tangential migration routes of AVP-ir neuronal chains and ascending axonal scaffolds. Using immunohistochemical reaction (ir) against AVP, neurophysin II, glial fibrillar acidic protein (GFAP), cell division (Ki67) and early neuronal markers (doublecortin, DCX), and neuroanatomical analysis on the rat brain in serial sections of coronal, sagittal, horizontal and septo-temporal oblique orientations from adult rats, we show that neurons from hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei are dispersed along visible tangential routes to other subcortical regions, guided by AVP-ir cell chains and axon scaffolds. Using 5′-bromo-2′-deoxyuridine (BrdU) injection in adult rats followed by BrdU-ir, we observed numerous twin-nuclei within SON and PVN, some double-labeled for AVP. Chronic water deprivation significantly increased the BrdU+ nuclei within both SON and PVN. The immunofluorescent reaction showed double labeling of AVP/DCX within SON and PVN as well as in AVP-ir cell chains. Interestingly, NeuN, a mature neuron marker, was largely absent in SON and PVN but present in neurons within adjacent hypothalamic regions. These findings provide evidence that neurogenesis and migration occur in adult rat hypothalamic vasopressinergic nuclei and reveal tangential migration routes of AVP-ir neuronal chains and ascending axonal scaffolds.
ProteinGym: Large-Scale Benchmarks for Protein Design and Fitness Prediction

Predicting the effects of mutations in proteins is critical to many applications, from understanding genetic disease to designing novel proteins that can address our most pressing challenges in climate, agriculture and healthcare. Despite a surge in machine learning-based protein models to tackle these questions, an assessment of their respective benefits is challenging due to the use of distinct, often contrived, experimental datasets, and the variable performance of models across different protein families. Addressing these challenges requires scale. To that end we introduce ProteinGym, a large-scale and holistic set of benchmarks specifically designed for protein fitness prediction and design. It encompasses both a broad collection of over 250 standardized deep mutational scanning assays, spanning millions of mutated sequences, as well as curated clinical datasets providing high-quality expert annotations about mutation effects. We devise a robust evaluation framework that combines metrics for both fitness prediction and design, factors in known limitations of the underlying experimental methods, and covers both zero-shot and supervised settings. We report the performance of a diverse set of over 70 high-performing models from various subfields (eg., alignment-based, inverse folding) into a unified benchmark suite. We open source the corresponding codebase, datasets, MSAs, structures, model predictions and develop a user-friendly website that facilitates data access and analysis.
When to attend? Temporal attention interacts with expectation

Temporal attention is voluntarily deployed at specific moments, whereas temporal expectation is deployed according to timing probabilities. When the target appears at an expected moment in a sequence, temporal attention improves performance at the attended moments, but the timing and the precision of the attentional window remain unknown. Here we independently and concurrently manipulated temporal attention–via behavioral relevance–and temporal expectation–via session-wise precision and trial-wise hazard rate–to investigate whether and how these mechanisms interact to improve perception. Our results reveal that temporal attention interacts with temporal expectation–the higher the precision, the stronger the attention benefit, but surprisingly this benefit decreased with delayed onset despite the increasing probability of stimulus appearance. When attention was suboptimally deployed to earlier than expected moments, it could not be reoriented to a later time point. These findings provide evidence that temporal attention and temporal expectation are different mechanisms, and highlight their interplay in optimizing visual performance. Relevance Our ability to process visual information is limited both across space and time. Here we disentangle how two mechanisms–attention and expectation–help us overcome temporal limitations. We concurrently manipulated attention and expectation independently to investigate whether and how they interact. We found that temporal attention interacts with two distinct forms of expectation. Temporal expectation strengthens the benefits of temporal attention on performance for the attended time points, depending on how precise the expectations are. Surprisingly, the advantages of attention decrease when stimuli occur later than expected, suggesting a limitation of attention to reorient from earlier to later time points. This study provides further evidence that humans cannot sustain temporal attention even over short periods, reveals that although temporal attention and expectation interact to improve visual performance, expectation suboptimally guides attention, and highlights that attention and expectation are different temporal mechanisms.
Brain-wide activity-identity mapping of neural networks associated with prosocial motivation in rats

A prosocial response to others in distress is an important driver of behavior across social species. To investigate the neurobiological mechanism leading to prosocial behavior, we use a helping behavior test wherein rats may release a trapped conspecific by opening a restrainer door. To ensure rats were not acting for social interaction, a separation divider prevented post-release contact (“separated” test). Despite the divider, most rats consistently opened the restrainer, demonstrating prosocial motivation. Brain-wide c-Fos analysis conducted via our opensource software "Brainways", revealed activity in empathy-related regions, including the anterior cingulate and insular cortices. Nucleus accumbens activity, previously recorded during helping, was not significant in the “separated” test. Chemogenetic manipulations of the accumbens did not prevent helping, suggesting that its activity reflects contact seeking. Mapping of oxytocin and dopamine receptors on active cells revealed region-specific recruitment of these subpopulations, depending on the social context. Network connectivity analysis highlights context-dependent functional subcircuits.
Managing older people with atrial fibrillation and preventing stroke: a review of anticoagulation approaches

ABSTRACT Introduction Oral anticoagulants (OACs) are the cornerstone of stroke prevention in atrial fibrillation (AF), but prescribing decisions in older people are complicated. Clinicians must assess the net clinical benefit of OAC in the context of multiple chronic conditions, polypharmacy, frailty and life expectancy. The under-representation of high-risk, older adult sub-populations in clinical trials presents the challenge of choosing the right OAC, where a ‘one-size-fits-all’ approach cannot be taken. Areas covered This review discusses OAC approaches for stroke prevention in older people with AF and presents a prescribing aid to support clinicians’ decision-making. High-risk older adults with multiple chronic conditions, specifically chronic kidney disease, dementia/cognitive impairment, previous stroke/transient ischemic attack or intracranial hemorrhage, polypharmacy, frailty, low body weight, high falls risk, and those aged ≥75 years are considered. Expert opinion Non-vitamin K antagonist OACs are the preferred first-line OAC in older adults with AF, including high-risk subpopulations, after individual assessment of stroke and bleeding risk, except those with mechanical heart valves and moderate-to-severe mitral stenosis. Head-to-head comparisons of NOACs are not available, therefore the choice of drug (and dose) should be based on an individual’s risk (stroke and bleeding) and incorporate their treatment preferences. Treatment decisions must be person-centered and principles of shared decision-making applied.
Recovery of fibroblasts from membrane attack by S. aureus α-toxin does not depend on acid sphingomyelinase but involves macropinocytosis

Damage of the plasma membrane by mechanical stress or pore forming proteins, like streptolysin O, may trigger Ca2+ influx-dependent repair mechanisms. Ca2+ influx-dependent lysosomal exocytosis, leading to release of acid sphingomyelinase, remodeling of the plasma membrane and caveolar endocytosis of membrane lesions, is reportedly involved in membrane repair after both mechanical damage or perforation by streptolysin O. Although the small β-barrel pore forming S. aureus α-toxin may also increase cytosolic Ca2+ concentration in certain cell types, and reportedly lead to release of acid sphingomyelinase from endothelial cells, evidence for a role of this response for membrane repair after attack by α-toxin is lacking. We exploited fibroblasts expressing dysfunctional acid sphingomyelinase to investigate whether this enzyme is required for membrane repair after S. aureus α-toxin attack. Because α-toxin-dependent loss of cellular ATP and externalization of phosphatidylserine were reversible, membrane damage by this pore former triggered an effective repair response in these cells. Although α-toxin depolarized the plasma membrane, it did not cause a simultaneous increase of [Ca2+]i. Consistently, there was no release of β-hexosaminidase, a marker of lysosomal exocytosis. Acid sphingomyelinase-deficient fibroblasts internalized α-toxin, which however did not co-localize with caveolin-1, but with FITC-dextran 70kDa, a cargo of macropinosomes. Inhibition of actin polymerization or sterol synthesis prevented recovery from α-toxin-dependent membrane damage. Therefore, we conclude that defense of fibroblasts against α-toxin does not depend on rapid calcium-influx, lysosomal exocytosis, and functional acid sphingomyelinase, but involves ongoing cholesterol synthesis and macropinocytosis.
Reassessing the association of VDR and its polymorphisms with tuberculosis in global populations

Background Vitamin D is a hormone that regulates the calcium homeostasis of the body. Besides this classical function, it is also regarded as an important immunomodulator. Most active Vitamin D actions are mediated through the Vitamin D receptor (VDR), a transcription factor and also a member of the nuclear receptor superfamily. In this study, we explored the phylogeographic attributes of the four most well-known polymorphisms of the VDR gene namely rs7975232 (ApaI), rs731235 (TaqI), rs1544410 (BsmI), rs2228570 (FokI) and also evaluated their association with the incidence of tuberculosis in global populations. This study integrated several in-silico approaches on population databases to evaluate the pattern of distribution, linkage and selection patterns of these SNPs. Results The ancestral alleles of rs7975232, rs731235, and rs1544410 are still present in over 50% frequency in modern human populations. These SNPs also have a very strong linkage disequilibrium among themselves in all population groups but no haplotype blocks are seen in South Asian populations constituting these polymorphisms. The selection results reveal a negative Tajima’s D value in West and East Eurasian populations suggesting positive selection in these regions… In correlation studies, we found no association between the incidence of tuberculosis and the allele or genotype frequency of these four SNPs. Conclusion The four SNPs of VDR behave differently in South Asian populations as compared to West and East Eurasian populations but no significant association was found with the incidence of tuberculosis in global populations.
A cross-attention transformer encoder for paired sequence data

Transformer-based sequence encoding architectures are often limited to a single-sequence input while some tasks require a multi-sequence input. For example, the peptide–MHCII binding prediction task where the input consists of two protein sequences. Current workarounds to solve this input-type mismatch lack resemblance with the biological mechanisms behind the task. As a solution, we propose a novel cross-attention transformer encoder that creates a cross-attended embedding of both input sequences. We compare its classification performance on the peptide–MHCII binding prediction task to a baseline logistic regression model and a default transformer encoder. Finally, we make visualizations of the attention layers to show how the different models learn different patterns.
Cognitive Phenotype Shifts in Risk-Taking: Interplay of Non-Suicidal Self-Injury Behaviors and Intensified Depression

Background Non-suicidal self-injury (NSSI) behavior is significantly prevalent in both adolescents and psychiatric populations, with the highest risk observed in individuals with major depressive disorder (MDD). NSSI can be considered a result of risky decision-making in response to negative emotions, where individuals choose self-harm over other harmless alternatives, suggesting a potential decision-making deficit in NSSI individuals. This study delves into the complex relationship between NSSI and depression severity in decision-making and its cognitive underpinnings. Method We assessed decision behaviors in MDD patients with and without NSSI and healthy controls using the Balloon Analogue Risk Task, which involves risk-taking, learning, and exploration in uncertain scenarios. Using computational modeling, we dissected the nuanced cognitive dimensions influencing decision behaviors. A novel statistical method was developed to elucidate the interaction effects between NSSI and depression severity. Result Contrary to common perceptions, we found that individuals with NSSI behaviors were typically more risk-averse, but as depressive symptoms intensified, they began to perceive less risk and meanwhile behave more randomly. Conclusions This research offers new insights into the cognitive aspects of NSSI and depression, underscoring the importance of recognizing the influence of comorbid mental disorders in deciphering the cognitive underpinnings of such behaviors, especially in the context of prevalent cross-diagnostic phenomena like NSSI behaviors.
Approximate Maximum Rank Aggregation: Beyond the Worst-Case

The fundamental task of rank aggregation is to combine multiple rankings on a group of candidates into a single ranking to mitigate biases inherent in individual input rankings. This task has a myriad of applications, such as in social choice theory, collaborative filtering, web search, statistics, databases, sports, and admission systems. One popular version of this task, maximum rank aggregation (or the center ranking problem), aims to find a ranking (not necessarily from the input set) that minimizes the maximum distance to the input rankings. However, even for four input rankings, this problem is NP-hard (Dwork et al., WWW’01, and Biedl et al., Discrete Math.’09), and only a (folklore) polynomial-time 2-approximation algorithm is known for finding an optimal aggregate ranking under the commonly used Kendall-tau distance metric. Achieving a better approximation factor in polynomial time, ideally, a polynomial time approximation scheme (PTAS), is one of the major challenges. This paper presents significant progress in solving this problem by considering the Mallows model , a classical probabilistic model. Our proposed algorithm outputs an (1 + ε )-approximate aggregate ranking for any ε > 0, with high probability, as long as the input rankings come from a Mallows model, even in a streaming fashion. Furthermore, the same approximation guarantee is achieved even in the presence of outliers , presumably a more challenging task. 2012 ACM Subject Classification Theory of computation → Probabilistic computation; Theory of computation → Facility location and clustering; Theory of computation → Theory and algorithms for application domains