Miracle-dz/UniFAR-FTUs huggingface dataset:
Disrupting short-term memory in premotor cortex affects serial dependence in visuomotor integration

Human behavior is biased by past experience. For example, when intercepting a moving target, the speed of previous targets will bias responses in future trials. Neural mechanisms underlying this so-called serial dependence are still under debate. Here, we tested the hypothesis that the previous trial leaves a neural trace in brain regions associated with encoding task-relevant information in visual and/or motor regions. We reasoned that injecting noise by means of transcranial magnetic stimulation (TMS) over premotor and visual areas would degrade such memory traces and hence reduce serial dependence. To test this hypothesis, we applied bursts of TMS pulses to right visual motion processing region hV5/MT+ and to left dorsal premotor cortex during inter-trial intervals of a coincident timing task performed by twenty healthy human participants (15 female). Without TMS, participants presented a bias towards the speed of the previous trial when intercepting moving targets. TMS over dorsal premotor cortex decreased serial dependence in comparison to the control Vertex stimulation, whereas TMS applied over hV5/MT+ did not. In addition, TMS seems to have specifically affected the memory trace that leads to serial dependence, as we found no evidence that participants’ behavior worsened after applying TMS. These results provide causal evidence that an implicit short-term memory mechanism in premotor cortex keeps information from one trial to the next, and that this information is blended with current trial information so that it biases behavior in a visuomotor integration task with moving objects. Significance Statement Human perception and action are biased by the recent past. The origin of such serial bias is still not fully understood, but a few components seem to be fundamental for its emergence: the brain needs to keep previous trial information in short-term memory and blend it with incoming information. Here, we present evidence that a premotor area has a potential role in storing previous trial information in short-term memory in a visuomotor task, and that this information is responsible for biasing ongoing behavior. These results corroborate the perspective that areas associated with processing information of a stimulus or task also participate in maintaining that information in short-term memory even when this information is no longer relevant for current behavior.
Molecular Tracking of the Leishmania Parasite

With the Visceral Leishmaniasis/Kala-azar Elimination Program in South Asia in its consolidation phase, the focus is mainly on case detection, vector control, and identifying potential sources of infection. Accordingly, emphasis is presently on curbing transmission, which is potentially achievable by identification and elimination of potential reservoirs. The strongest contenders for being the disease reservoir are cases of Post Kala-azar Dermal Leishmaniasis (PKDL) which occurs in a minor proportion of individuals apparently cured of Visceral Leishmaniasis (VL). The demonstration of parasites in tissue aspirates despite being a risky and invasive process is the gold standard for diagnosis of VL, but is now being replaced by serological tests e.g., rK39 strip test and direct agglutination test. However, these antibody based tests are limited in their ability to diagnose relapses, detect cases of PKDL, and monitor effectiveness of treatment. Accordingly, detection of antigen or nucleic acids by polymerase chain reaction has been successfully applied for monitoring of parasite kinetics. This review article provides updated information on recent developments regarding the available antibody or antigen/nucleic acid based biomarkers for longitudinal monitoring of patients with VL or PKDL and emphasizes the need for availability of studies pertaining to quantification of treatment response or relapse.
Heterogeneous catalysis in solution. Part 22.—Oxidation–reduction reactions catalysed by electron transfer through the solid: theory for partial and complete mass-transport control

Many redox reactions are so strongly catalysed at the surface of an electron-conducting solid that the catalysis becomes partly or wholly diffusion-controlled. By means of the electrochemical model (which allows one to calculate the catalytic rate vcat from the current–voltage curves of the two interacting couples) we have derived kinetic equations for cases of mixed activation and diffusion control in the Tafel region. If the experimental results have been obtained at a rotating-disc catalyst, the intercept of a plot of 1/vcat against [graphic omitted] (where ω is the angular velocity) will then lead to a value for the catalytic rate at the surface itself. We have also analysed situations in which the surface reaction is so fast as to be at equilibrium throughout. The kinetics then depend entirely upon mass transport of the reactants and products through the diffusion layer, and at a rotating disc catalyst vcat will be directly proportional to [graphic omitted]. The theoretical equations predict that the reaction orders will depend only upon the stoichiometric coefficients of the reaction, that these orders will often be fractional and that they will change dramatically if product is added to the reaction mixture at the start.
Familial prion disease-related mutation E196K displays a novel amyloid fibril structure revealed by cryo-EM

Prion diseases are caused by the conformational conversion of prion protein (PrP) from its cellular form (PrPC) into a protease-resistant, aggregated form (PrPSc). 42 different familial mutations were identified in human PrP, which lead to genetic prion diseases with distinct clinical syndromes. Here we report cryo-EM structure of an amyloid fibril formed by full-length human PrP with E196K mutation, a familial Creutzfeldt-Jakob disease-related mutation. This mutation disrupts key interactions in wild-type PrP fibril and results in a rearrangement of the overall structure, forming an amyloid fibril with a conformation distinct from wild-type PrP fibril. The E196K fibril consists of two protofibrils intertwined into a left-handed helix. Each subunit forms five β-strands stabilized by a disulfide bond and an unusual hydrophilic cavity. Two pairs of amino acids (Lys194 and Glu207; Lys196 and Glu200) from opposing subunits form four salt bridges to stabilize the zigzag interface of the two protofibrils. Furthermore, the E196K fibril exhibits a significantly lower conformational stability and protease resistance activity than the wild-type fibril. Our results provide direct structural evidences of the diverse mammalian prion strains and fibril polymorphism of PrP, and highlight the importance of familial mutations in determining the different prion strains.
The Wild Worm Codon Adapter: a web tool for automated codon adaptation of transgenes for expression in non-Caenorhabditis nematodes

Advances in genomics techniques are expanding the range of nematode species that are amenable to transgenesis. Due to divergent codon usage biases across species, codon optimization is often a critical step for the successful expression of exogenous transgenes in nematodes. Platforms for generating DNA sequences codon optimized for the free-living model nematode Caenorhabditis elegans are broadly available. However, until now such tools did not exist for non-Caenorhabditis nematodes. We therefore developed the Wild Worm Codon Adapter, a tool for rapid transgene codon optimization for expression in non-Caenorhabditis nematodes. The app includes built-in optimization for parasitic nematodes in the Strongyloides, Nippostrongylus and Brugia genera as well as the predatory nematode Pristionchus pacificus. The app also supports custom optimization for any species using user-provided optimization rules. In addition, the app supports automated insertion of synthetic or native introns, as well as the analysis of codon bias in transgene and native sequences. Here, we describe this web-based tool and demonstrate how it may be used to analyze genome-wide codon bias in Strongyloides species.
Improving Generalizability of Protein Sequence Models with Data Augmentations

While protein sequence data is an emerging application domain for machine learning methods, small modifications to protein sequences can result in difficult-to-predict changes to the protein’s function. Consequently, protein machine learning models typically do not use randomized data augmentation procedures analogous to those used in computer vision or natural language, e.g., cropping or synonym substitution. In this paper, we empirically explore a set of simple string manipulations, which we use to augment protein sequence data when fine-tuning semi-supervised protein models. We provide 276 different comparisons to the Tasks Assessing Protein Embeddings (TAPE) baseline models, with Transformer-based models and training datasets that vary from the baseline methods only in the data augmentations and representation learning procedure. For each TAPE validation task, we demonstrate improvements to the baseline scores when the learned protein representation is fixed between tasks. We also show that contrastive learning fine-tuning methods typically outperform masked-token prediction in these models, with increasing amounts of data augmentation generally improving performance for contrastive learning protein methods. We find the most consistent results across TAPE tasks when using domain-motivated transformations, such as amino acid replacement, as well as restricting the Transformer attention to randomly sampled sub-regions of the protein sequence. In rarer cases, we even find that information-destroying augmentations, such as randomly shuffling entire protein sequences, can improve downstream performance.
Evidences for functional trans-acting eRNA-promoter R-loops at Alu sequences

Enhancers modulate gene expression by interacting with promoters. Models of enhancer-promoter interactions (EPIs) in the literature involve the activity of many components, including transcription factors and nucleic acid. However, the role that sequence similarity plays in EPIs, remains largely unexplored. Herein, we report that Alu-derived sequences dominate sequence similarity between enhancers and promoters. After rejecting the alternative DNA:DNA and DNA:RNA triplex models, we proposed that enhancer-associated RNAs, or eRNAs, may directly contact their targeted promoters by forming trans-acting R-loops at those Alu sequences. We showed how the characteristic distribution of functional genomic data, such as RNA-DNA proximate ligation reads, binding of transcription factors, and RNA-binding proteins, align with the Alu sequences of EPIs. We also showed that these aligned Alu sequences may be subject to the constraint of coevolution, further implying the functional significance of these R-loop hybrids. Finally, our results showed that eRNA and Alu elements associate in a manner previously unrecognized in the EPIs and the evolution of gene regulation networks in mammals.
Synthesizing VERDICT maps from standard DWI data using GANs

VERDICT maps have shown promising results in clinical settings discriminating normal from malignant tissue and identifying specific Gleason grades non-invasively. However, the quantitative estimation of VERDICT maps requires a specific diffusion-weighed imaging (DWI) acquisition. In this study we investigate the feasibility of synthesizing VERDICT maps from standard DWI data from multi-parametric (mp)- MRI by employing conditional generative adversarial networks (GANs). We use data from 67 patients who underwent both standard DWI-MRI and VERDICT MRI and rely on correlation analysis and mean squared error to quantitatively evaluate the quality of the synthetic VERDICT maps. Quantitative results show that the mean values of tumour areas in the synthetic and the real VERDICT maps were strongly correlated while qualitative results indicate that our method can generate realistic VERDICT maps that could supplement mp-MRI assessment for better diagnosis.
Complement Decay-Accelerating Factor is a modulator of influenza A virus lung immunopathology

Clearance of viral infections, such as SARS-CoV-2 and influenza A virus (IAV), must be fine-tuned to eliminate the pathogen without causing immunopathology. As such, an aggressive initial innate immune response favors the host in contrast to a detrimental prolonged inflammation. The complement pathway bridges innate and adaptive immune system and contributes to the response by directly clearing pathogens or infected cells, as well as recruiting proinflammatory immune cells and regulating inflammation. However, the impact of modulating complement activation in viral infections is still unclear. In this work, we targeted the complement decay-accelerating factor (DAF/CD55), a surface protein that protects cells from non-specific complement attack, and analyzed its role in IAV infections. We found that DAF modulates IAV infection in vivo, via an interplay with the antigenic viral proteins hemagglutinin (HA) and neuraminidase (NA), in a strain specific manner. Our results reveal that, contrary to what could be expected, DAF potentiates complement activation, increasing the recruitment of neutrophils, monocytes and T cells. We also show that viral NA acts on the heavily sialylated DAF and propose that it exacerbates complement activation, leading to lung immunopathology. Remarkably, this mechanism has no impact on viral loads but rather on the host resilience to infection and may have direct implications in zoonotic influenza transmissions. Author summary Exacerbated complement activation and immune deregulation are at the basis of several pathologies induced by respiratory viruses. Here, we report that complement decay-accelerating factor (DAF), which inhibits complement activation in healthy cells, increases disease severity upon Influenza A virus (IAV) infection. Remarkably, DAF interaction with IAV proteins, hemagglutinin (HA) and neuraminidase (NA), resulted in excessive complement activation and recruitment of innate and adaptive immune cells, without affecting viral loads. Furthermore, we observed that viral NA directly cleaves DAF and promotes complement activation, providing a possible link between IAV-DAF interaction and pathology. Therefore, our results unveil a novel pathway that could modulate disease severity, which may help to understand the increased pathogenicity of zoonotic and pandemic IAV infections.
Dorsal CA1 hippocampal place cells form a multi-scale representation of megaspace

Spatially firing “place cells” within the hippocampal CA1 region form internal maps of the environment necessary for navigation and memory. In rodents, these neurons have been almost exclusively studied in small environments (<4 m2). It remains unclear how place cells encode a very large open 2D environment, which is more analogous to the natural environments experienced by rodents and other mammals. Such an ethologically realistic environment would require a more complex spatial representation, capable of simultaneously representing space at overlapping multiple fine to coarse informational scales. Here we show that in a ‘megaspace’ (18.6 m2), the majority of dorsal CA1 place cells exhibited multiple place subfields of different sizes, akin to those observed along the septo-temporal axis. Furthermore, the total area covered by the subfields of each cell was not correlated with the number of subfields, and this total area increased with the scale of the environment. The multiple different-sized subfields exhibited by place cells in the megaspace suggest that the ensemble population of subfields form a multi-scale representation of space within the dorsal hippocampus. Our findings point to a new dorsal hippocampus ensemble coding scheme that simultaneously supports navigational processes at both fine- and coarse-grained resolutions.
Genome-wide CRISPRi screening identifies OCIAD1 as a prohibitin client and regulatory determinant of mitochondrial Complex III assembly in human cells

Dysfunction of the mitochondrial electron transport chain (mETC) is a major cause of human mitochondrial diseases. To identify determinants of mETC function, we screened a genome-wide human CRISPRi library under oxidative metabolic conditions with selective inhibition of mitochondrial Complex III and identified OCIA domain-containing protein 1 (OCIAD1) as a Complex III assembly factor. We find that OCIAD1 is an inner mitochondrial membrane protein that forms a complex with supramolecular prohibitin assemblies. Our data indicate that OCIAD1 is required for maintenance of normal steady state levels of Complex III and the proteolytic processing of the catalytic subunit cytochrome c1 (CYC1). In OCIAD1 depleted mitochondria, unprocessed CYC1 is hemylated and incorporated into Complex III. We propose that OCIAD1 acts as an adaptor within prohibitin assemblies to stabilize and/or chaperone CYC1 and to facilitate its proteolytic processing by the IMMP2L protease.
Close to Optimal Cell Sensing Ensures the Robustness of Tissue Differentiation Process: The Avian Photoreceptor Mosaic Case

The way that progenitor cell fate decisions and the associated environmental sensing are regulated to ensure the robustness of the spatial and temporal order in which cells are generated towards a fully differentiating tissue still remains elusive. Here, we investigate how cells regulate their sensing intensity and radius to guarantee the required thermodynamic robustness of a differentiated tissue. In particular, we are interested in finding the conditions where dedifferentiation at cell level is possible (microscopic reversibility) but tissue maintains its spatial order and differentiation integrity (macroscopic irreversibility). In order to tackle this, we exploit the recently postulated Least microEnvironmental Uncertainty Principle (LEUP) to develop a theory of stochastic thermodynamics for cell differentiation. To assess the predictive and explanatory power of our theory, we challenge it against the avian photoreceptor mosaic data. By calibrating a single parameter, the LEUP can predict the cone color spatial distribution in the avian retina and, at the same time, suggest that such a spatial pattern is associated with quasi-optimal cell sensing. By means of the stochastic thermodynamics formalism, we find out that thermodynamic robustness of differentiated tissues depends on cell metabolism and cell sensing properties. In turn, we calculate the limits of the cell sensing radius that ensure the robustness of differentiated tissue spatial order. Finally, we further constrain our model predictions to the avian photoreceptor mosaic.
The hippocampus shows an own-age bias during unfamiliar face viewing

The present study investigated the neural correlates of the own-age bias for face recognition in a repetition suppression paradigm. Healthy young and older adults viewed upright and inverted unfamiliar faces. Some of the upright faces were repeated following one of two delays (lag 0 or lag 11). Repetition suppression effects were observed in bilateral fusiform cortex. However, there were no significant effects indicating an own-age bias in repetition suppression. The absence of these effects is arguably inconsistent with perceptual expertise accounts of own-age biases in face processing. By contrast, the right anterior hippocampus showed an own-age bias (greater activity for own-than other-age faces) when viewing an unfamiliar face for the first time. Given the importance of the hippocampus for episodic memory encoding, we conjecture that the increased hippocampal activity for own-age relative to other-age faces reflects differential engagement of neural processes supporting the episodic encoding of faces and might provide insight into the neural underpinnings of own-age biases in face recognition memory.
Pak1 kinase regulates ribonucleoprotein granules through Sts5 for polarized growth and the glucose starvation response

Fission yeast cells maintain a rod shape due to conserved signaling pathways that organize the cytoskeleton for polarized growth. We discovered a mechanism linking the conserved protein kinase Pak1 with cell shape through the RNA-binding protein Sts5. Pak1 prevents Sts5 association with P bodies by directly phosphorylating its intrinsically disordered region (IDR). Pak1 and the cell polarity kinase Orb6 both phosphorylate the Sts5 IDR but at distinct residues. Mutations preventing phosphorylation in the Sts5 IDR cause increase P body formation and defects in cell shape and polarity. Unexpectedly, when cells encounter glucose starvation, PKA signaling triggers Pak1 recruitment to P bodies with Sts5. Through retargeting experiments, we reveal that Pak1 localizes to these ribonucleoprotein (RNP) granules to promote rapid dissolution of Sts5 upon glucose addition. Our work reveals a new role for Pak1 in regulating cell shape through RNPs during normal and stressed growth conditions.
Correlation between structure and function in phosphatidylinositol lipid-dependent Kir2.2 gating

Inward rectifier K+(Kir) channels regulate cell membrane potential. Different Kir channels respond to unique ligands, but all are regulated by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). Using planar lipid bilayers we show that Kir2.2 exhibits bursts of openings separated by long quiescent inter-burst periods. Increasing PI(4,5)P2 concentration shortens the Kir2.2 inter-burst duration and lengthens the burst duration without affecting dwell times within a burst. From this, we propose that burst and inter-burst durations correspond to the CTD-docked and CTD-undocked conformations observed in the presence and absence of PI(4,5)P2 in atomic structures. We also studied the effect of different phosphatidylinositol lipids on Kir2.2 activation and conclude that the 5’ phosphate is essential to Kir2.2 pore opening. Other phosphatidylinositol lipids can compete with PI(4,5)P2 but cannot activate Kir2.2 without the 5’ phosphate. PI(4)P, which is directly interconvertible to and from PI(4,5)P2, might thus be a regulator of Kir channels in the plasma membrane.