Miracle-dz/UniFAR-FTUs huggingface dataset:
Object recognition under occlusion revisited: elucidating algorithmic advantages of recurrent computation

Recurrent connections are ubiquitous in the visual system, yet their role is less understood compared to that of feedforward visual processing. Occluded object recognition, an ethologically critical cognitive capacity, is thought to rely crucially on recurrent processing of visual information. Understanding how occluded object recognition depends on recurrent connections is thus of great importance. Here, using deep neural networks as our main tool, we performed comprehensive, controlled computational experiments to elucidate the potential role and necessity of recurrent computation in this task. While our comparison of neural network architectures revealed that sufficiently deep feedforward networks could easily outperform recurrent ones, contrary to previous studies, at the same time we found evidence that recurrent networks learn to “explain away” occlusion by leveraging information about the occluder, without being explicitly trained to do so. Furthermore, inspired by recent experimental studies, we demonstrated that a deep network model incorporating biologically inspired features was capable of faithfully reconstituting corrupted representations, even for heavily occluded objects, by taking global contexts into account through recurrent iterations. Lastly, we examined how occlusion shapes internal representations of neural networks optimized for object recognition. Although representations of occlusion-trained and non-occlusion-trained networks were nearly indistinguishable for unoccluded images, they exhibited highly divergent representations for occluded images. Our work sheds new light on computational roles of recurrent connections, a pervasive component of biological circuits, and how ethologically relevant conditions may strongly reshape neural representations supporting key cognitive functions.
Furin cleaves SARS-CoV-2 spike-glycoprotein at S1/S2 and S2'for viral fusion/entry: indirect role for TMPRSS2

The Spike (S)-protein of SARS-CoV-2 binds host-cell receptor ACE2 and requires proteolytic "priming" (S1/S2) and "fusion-activation" (S2) for viral entry. The S-protein furin-like motifs PRRAR685{downarrow} and KPSKR815{downarrow} indicated that proprotein convertases promote virus entry. We demonstrate that furin and PC5A induce cleavage at both sites, ACE2 enhances S2 processing, and their pharmacological inhibition (BOS-inhibitors) block endogenous cleavages. S1/S2-mutations (S1/S2) limit S-protein-mediated cell-to-cell fusion, similarly to BOS-inhibitors. Unexpectedly, TMPRSS2 does not cleave at S1/S2 or S2, but it can: (i) cleave/inactivate S-protein into S2a/S2b; (ii) shed ACE2; (iii) cleave S1-subunit into secreted S1, activities inhibited by Camostat. In lung-derived Calu-3 cells, BOS-inhibitors and {micro}S1/S2 severely curtail "pH-independent" viral entry, and BOS-inhibitors alone/with Camostat potently reduce infectious viral titer and cytopathic effects. Overall, our results show that: furin plays a critical role in generating fusion-competent S-protein, and indirectly, TMPRSS2 promotes viral entry, supporting furin and TMPRSS2 inhibitors as potential antivirals against SARS-CoV-2.
Activation of MrgprA3 and MrgprC11 on Bladder-Innervating Afferents Induces Peripheral and Central Hypersensitivity to Bladder Distension

Understanding the sensory mechanisms innervating the bladder is paramount to developing efficacious treatments for chronic bladder hypersensitivity conditions. The contribution of Mas-gene-related G protein-coupled receptors (Mrgpr) to bladder signaling is currently unknown. Using male and female mice, we show with single-cell RT-PCR that subpopulations of DRG neurons innervating the mouse bladder express MrgprA3 (14%) and MrgprC11 (38%), either individually or in combination, with high levels of coexpression with Trpv1 (81%-89%). Calcium imaging studies demonstrated MrgprA3 and MrgprC11 agonists (chloroquine, BAM8-22, and neuropeptide FF) activated subpopulations of bladder-innervating DRG neurons, showing functional evidence of coexpression between MrgprA3, MrgprC11, and TRPV1. In ex vivo bladder-nerve preparations, chloroquine, BAM8-22, and neuropeptide FF all evoked mechanical hypersensitivity in subpopulations (20%-41%) of bladder afferents. These effects were absent in recordings from Mrgpr-clusterΔ−/− mice. In vitro whole-cell patch-clamp recordings showed that application of an MrgprA3/C11 agonist mixture induced neuronal hyperexcitability in 44% of bladder-innervating DRG neurons. Finally, in vivo instillation of an MrgprA3/C11 agonist mixture into the bladder of WT mice induced a significant activation of dorsal horn neurons within the lumbosacral spinal cord, as quantified by pERK immunoreactivity. This MrgprA3/C11 agonist-induced activation was particularly apparent within the superficial dorsal horn and the sacral parasympathetic nuclei of WT, but not Mrgpr-clusterΔ−/− mice. This study demonstrates, for the first time, functional expression of MrgprA3 and MrgprC11 in bladder afferents. Activation of these receptors triggers hypersensitivity to distension, a critically valuable factor for therapeutic target development. SIGNIFICANCE STATEMENT Determining how bladder afferents become sensitized is the first step in finding effective treatments for common urological disorders such as overactive bladder and interstitial cystitis/bladder pain syndrome. Here we show that two of the key receptors, MrgprA3 and MrgprC11, that mediate itch from the skin are also expressed on afferents innervating the bladder. Activation of these receptors results in sensitization of bladder afferents, resulting in sensory signals being sent into the spinal cord that prematurely indicate bladder fullness. Targeting bladder afferents expressing MrgprA3 or MrgprC11 and preventing their sensitization may provide a novel approach for treating overactive bladder and interstitial cystitis/bladder pain syndrome.
Chromosome dynamics and spatial organization during the non-binary cell cycle of a predatory bacterium

In bacteria, the dynamics of chromosome replication and segregation are tightly coordinated with cell cycle progression, and largely rely on specific spatiotemporal arrangement of the chromosome. Whereas these key processes are mostly investigated in species that divide by binary fission, they remain mysterious in bacteria producing larger number of descendants. Here, we establish the predatory bacterium Bdellovibrio bacteriovorus as a model to investigate the non-binary processing of a circular chromosome. Our data reveal its extreme compaction in a dense polarized nucleoid. We also show that a first binary-like cycle of replication and asymmetric segregation is followed by multiple asynchronous rounds of replication and progressive ParABS-dependent partitioning, uncoupled from cell division. Surprisingly, ParB localization at the centromere is cell-cycle regulated. Altogether, our findings support a model of complex chromosome choreography, leading to the generation of variable numbers of offspring, highlighting the adaptation of conserved mechanisms to achieve non-binary reproduction in bacteria.
Learning to use episodic memory for event prediction

When should episodic memories be stored and retrieved to support event understanding? Traditional list-learning memory experiments make it obvious when to store and retrieve memories, but it is less obvious when to do this in naturalistic settings. To address this question, we trained a memory-augmented neural network to predict upcoming events, in an environment where situations (sets of parameters governing transitions between events) sometimes reoccurred. The model was allowed to learn a policy for when to consult episodic memory, and we explored how this learned policy varied as a function of the task environment. We found that the learned retrieval policy is shaped by internal uncertainty about upcoming events, the level of penalty associated with incorrect predictions, the confusability of stored memories, the presence of a “familiarity signal” indicating the availability of relevant memories, and the presence of statistical regularities (prototypical events). With regard to encoding policy, we found that selectively storing episodic memories at the end of an event (but not mid-event) leads to better subsequent event prediction performance and less incorrect recall. Additionally, we found that the model can integrate information over long timescales even without the hippocampus; it can link information over many event segments via episodic memory; and it shows classic schema-consistent memory effects when the upcoming time point has a prototypical event. Overall, these modeling results provide a normative explanation of several existing behavioral and neuroimaging findings regarding the use of episodic memory in naturalistic settings, and lead to a wide range of testable predictions.
Gene expression profiling of malaria parasites reveals common virulence gene expression in adult first-time infected patients and severe cases

Sequestration of Plasmodium falciparum-infected erythrocytes to host endothelium through the parasite-derived PfEMP1 adhesion proteins is central to the development of malaria pathogenesis. PfEMP1 proteins have diversified and expanded to encompass many sequence variants conferring each parasite a similar array of human endothelial receptor binding phenotypes. Here, we analyzed RNA-seq profiles of parasites isolated from 32 P. falciparum infected adult travelers returning to Germany. Patients were categorized into either malaria naïve (n=15) or pre-exposed (n=17), and into severe (n=8) or non-severe (n=24) cases. For differential expression analysis of PfEMP1-encoding var gene transcripts were de novo assembled from RNA-seq data and, in parallel, var expressed sequence tags were analyzed and used to predict the encoded domain composition of the transcripts. Both approaches showed in concordance that severe malaria was associated with PfEMP1 containing the endothelial protein C receptor (EPCR)-binding CIDRα1 domain, whereas CD36-binding PfEMP1 was linked to non-severe malaria outcomes. First-time infected adults were more likely to develop severe symptoms and tended to be infected for a longer period. Thus, parasites with more pathogenic PfEMP1 variants are more common in patients with a naïve immune status and/or adverse inflammatory host responses to first infections favors growth of EPCR-binding parasites.
LISA: Learned Indexes for Sequence Analysis

Background: Next-generationsequencing(NGS)technologieshave enabled affordable sequencing of billions of short DNA fragments at high throughput, paving the way for population-scale genomics. Genomics data analytics at this scale requires overcoming performance bottlenecks, such as searching for short DNA sequences over long reference sequences. Results: In this paper, we introduce LISA (Learned Indexes for Sequence Analysis), a novel learning-based approach to DNA sequence search. We focus on accelerating two of the most essential flavors of DNA sequence search— exact search and super-maximal exact match (SMEM) search . LISA builds on and extends FM-index, which is the state-of-the-art technique widely deployed in genomics tools. Experiments with human, animal, and plant genome datasets indicate that LISA achieves up to 2 . 2 × and 10 . 8 × speedups over the state-of-the-art FM-index based implementations for exact search and super-maximal exact match (SMEM) search , respectively.
Definition of germ layer cell lineage alternative splicing programs reveals a critical role for Quaking in specifying cardiac cell fate

Alternative splicing is critical for development; however, its role in the specification of the three embryonic germ layers is poorly understood. By performing RNA-Seq on human embryonic stem cells (hESCs) and derived definitive endoderm, cardiac mesoderm, and ectoderm cell lineages, we detect distinct alternative splicing programs associated with each lineage. The most prominent splicing program differences are observed between definitive endoderm and cardiac mesoderm. Integrative multi-omics analyses link each program with lineage-enriched RNA binding protein regulators, and further suggest a widespread role for Quaking (QKI) in the specification of cardiac mesoderm. Remarkably, knockout of QKI disrupts the cardiac mesoderm-associated alternative splicing program and formation of myocytes. These changes arise in part through reduced expression of BIN1 splice variants linked to cardiac development. Mechanistically, we find that QKI represses inclusion of exon 7 in BIN1 pre-mRNA via an exonic ACUAA motif, and this is concomitant with intron removal and cleavage from chromatin. Collectively, our results uncover alternative splicing programs associated with the three germ lineages and demonstrate an important role for QKI in the formation of cardiac mesoderm.
uPTI: uniaxial permittivity tensor imaging of intrinsic density and anisotropy

Biological architecture is intrinsically tensorial. The permittivity tensor (PT) of biological material reports the density, angular anisotropy, symmetry, and 3D orientation of biomolecules. High-resolution measurement of PT can enable quantitative and label-free analysis of organelle, cell, and tissue architecture, but remains challenging. We report uniaxial permittivity tensor imaging (uPTI), a label-free computational imaging method for volumetric measurement of PT with diffraction-limited resolution. uPTI encodes the components of PT into intensity modulations using oblique illumination and polarization-resolved imaging. The high-dimensional data is decoded with a vectorial image formation model and a multi-channel convex optimization, assuming that the molecular distribution in each voxel has uniaxial symmetry. We describe a modular implementation of uPTI that can be multiplexed with complementary imaging modalities. We report volumes of uPT in mouse brain tissue, SARS-CoV-2 infected cardiomyocytes, RSV infected A549 cells, H&E stained tissue sections, isotropic beads, and anisotropic glass targets. uPTI enabled volumetric imaging of the 3D orientation and symmetry of organelles, cells, and tissue components with higher spatio-angular resolution than current vectorial tomography, ptychography, and light-field microscopy methods. We provide an open source implementation of the image formation model and reconstruction algorithms.
Connexin-36-expressing Gap Junctions in VTA GABA Neurons Sustain Opiate Dependence

Drug dependence is characterized by a switch in motivation wherein a positively reinforcing substance becomes negatively reinforcing. Ventral tegmental area (VTA) GABA neurons form a point of divergence between two double dissociable pathways responsible for these respective motivational states. Here we show that this switch from drug-naïve to opiate-dependent and withdrawn (ODW) motivation is contingent upon the gap junction-forming protein, connexin-36 (Cx36), in VTA GABA neurons. Intra-VTA infusions of the Cx36 blocker, mefloquine, in ODW rats resulted in a reversion to a drug-naïve motivational state and a loss of opiate withdrawal aversions. Consistent with these data, conditional knockout mice lacking Cx36 in GABA neurons (GAD65-Cre;Cx36fl(CFP)/fl(CFP)) were perpetually drug-naïve and never experienced opiate withdrawal aversions. Further, viral-mediated rescue of Cx36 in VTA GABA neurons was sufficient to restore their susceptibility to ODW motivation. Our findings reveal a functional role for VTA gap junctions that has eluded prevailing circuit models of addiction. Significance The motivation to seek drugs can vary depending on prior exposure. For instance, recreational and habitual drug use can stem from a desire to experience the pleasurable or relieving properties of the substance, respectively. Here we identify a subpopulation of midbrain neurons that dictate opiate-seeking motivation via expression of the gap junction protein, connexin-36. We show that connexin-36 expression increases upon opiate dependence and withdrawal. We then demonstrate that this is not merely a correlation, as pharmacological or genetic manipulations that interfere with connexin-36 function prevent the development of opiate dependence in rats and mice. Our results identify gap junctions as a critical node in the pathogenesis of opiate addiction, and a potential new target for substance use disorder pharmacotherapies.
The evolution of anisogamy does not always lead to male competition

Anisogamy has evolved in a large proportion of sexually reproducing multicellular organisms allowing the definition of the female and male sexes, producing large and small gametes, respectively. Anisogamy is the initial sexual dimorphism: it has lead the sexes to experience selection differently, which makes it a good starting point to understand the evolution of further sexual dimorphisms. For instance, it is generally accepted that anisogamy sets the stage for more intense intrasexual competition in the male sex than in the female sex. However, we argue that this idea may rely on assumptions on the conditions under which anisogamy has evolved in the first place. We consider here two widely accepted scenarios for the evolution of anisogamy: gamete competition or gamete limitation. We present a mechanistic mathematical model in which both gamete size and an intrasexual competition trait for fertilisation can coevolve in a population starting without dimorphism between its two mating types. Two different intrasexual competition traits are investigated, gamete motility and the ability of gametes to capture gametes of the opposite mating type. We show that gamete competition and gamete limitation can lead to greatly different outcomes in terms of which sex competes most for fertilisation. Our results suggest that gamete competition is most likely to lead to stronger competition in males. On the other hand, under gamete limitation, competition in form of motility can evolve in either sex while gamete capture mainly evolves in females. This study suggests that anisogamy does not per se lead to more intense male competition. The conditions under which anisogamy evolves matter, as well as the competition trait considered.
Human Erbb2-induced Erk activity robustly stimulates cycling and functional remodeling of rat and human cardiomyocytes

Multiple mitogenic pathways capable of promoting mammalian cardiomyocyte (CM) proliferation have been identified as potential candidates for functional heart repair following myocardial infarction. However, it is unclear whether the effects of these mitogens are species-specific and how they directly compare in the same cardiac setting. Here, we examined how CM-specific lentiviral expression of various candidate mitogens affects human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and neonatal rat ventricular myocytes (NRVMs) in vitro. In 2D-cultured CMs from both species, and in highly mature 3D-engineered cardiac tissues generated from NRVMs, a constitutively-active mutant form of the human gene Erbb2 (cahErbb2) was the most potent tested mitogen. Persistent expression of cahErbb2 induced CM proliferation, sarcomere loss, and remodeling of tissue structure and function, which were attenuated by small molecule inhibitors of Erk signaling. These results suggest transient activation of Erbb2/Erk axis in cardiomyocytes as a potential strategy for regenerative heart repair.
Statistics of Flow and the Scaling of Ceramic Water Filters

AbstractAccording to the World Health Organization (WHO), there was an increase in the number of people that have access to safe drinking water between 2006 and 2010. Such trends can be accounted for partly by the increasing usage of ceramic water filters that can remove microbial pathogens from water. However, the initial flow rates in such filters are often limited to ranges between 1 and 3 L/h. In this paper, six frustum-shaped ceramic water filters of the same clay:sawdust composition were tested. Each ceramic water filter was filled with water and allowed to filter 20 times. Each time, the flow rate and water level were measured for a consecutive 12 h. Permeability values were estimated for each run of the ceramic water filters. Statistical analysis was performed on flow rates (in the first hour), mean flow rates, and estimated permeability values. The flow rate values (in the first hour) for the six ceramic water filters were found to be between 1.4 and 3.0 L/h. An effective permeability was obtai.
The secreted hypersensitive response inducing protein 1 from Botrytis cinerea displays non-canonical PAMP-activity

According to their lifestyle, plant pathogens are divided into biotrophic and necrotrophic organisms. While biotrophic pathogens establish a relationship with living host cells, necrotrophic pathogens rapidly kill host cells and feed on the cell debris. To this end, the necrotrophic ascomycete fungus Botrytis cinerea secretes large amounts of phytotoxic proteins and cell wall degrading enzymes. However, the precise role of these proteins during the infection process is unknown. Here we report on the identification and characterization of the previously unknown toxic protein hypersensitive response inducing protein 1 (Hip1), which induces plant cell death. We found the adoption of a folded protein structure to be a prerequisite for Hip1 to exert its necrosis-inducing activity in Nicotiana benthamiana. Localization and the induction of specific plant responses by Hip1 indicate recognition as pathogen-associated molecular pattern at the plant plasma membrane. Our results demonstrate that recognition of Hip1, even in the absence of obvious enzymatic or poreforming activity, induces strong plant defense reactions eventually leading to plant cell death.
Minor pilin genes are involved in motility and natural competence in Synechocystis sp. PCC 6803

Cyanobacteria synthesize type IV pili, which are known to be essential for motility, adhesion and natural competence. They consist of long flexible fibres that are primarily composed of the major pilin PilA1 in Synechocystis sp. PCC 6803. In addition, Synechocystis encodes less abundant pilin-like proteins, which are known as minor pilins. The transcription of the minor pilin genes pilA5, pilA6 and pilA9-pilA11 is inversely regulated in response to different conditions. In this study, we show that the minor pilin PilA5 is essential for natural transformation but is dispensable for motility and flocculation. In contrast, a set of minor pilins encoded by the pilA9-slr2019 transcriptional unit are necessary for motility but are dispensable for natural transformation. Neither pilA5-pilA6 nor pilA9-slr2019 are essential for pilus assembly as mutant strains showed type IV pili on the cell surface. Microarray analysis demonstrated that the transcription levels of known and newly predicted minor pilin genes change in response to surface contact. A total of 120 genes were determined to have altered transcription between planktonic and surface growth. Among these genes, 13 are located on the pSYSM plasmid. The results of our study indicate that different minor pilins facilitate distinct pilus functions.