Miracle-dz/UniFAR-FTUs huggingface dataset:
Comparative genomics suggests limited variability and similar evolutionary patterns between major clades of SARS-CoV-2

Phylogenomic analysis of SARS-CoV-2 as available from publicly available repositories suggests the presence of 3 prevalent groups of viral episomes (super-clades), which are mostly associated with outbreaks in distinct geographic locations (China, USA and Europe). While levels of genomic variability between SARS-CoV-2 isolates are limited, to our knowledge, it is not clear whether the observed patterns of variability in viral super-clades reflect ongoing adaptation of SARS-CoV-2, or merely genetic drift and founder effects. Here, we analyze more than 1100 complete, high quality SARS-CoV-2 genome sequences, and provide evidence for the absence of distinct evolutionary patterns/signatures in the genomes of the currently known major clades of SARS-CoV-2. Our analyses suggest that the presence of distinct viral episomes at different geographic locations are consistent with founder effects, coupled with the rapid spread of this novel virus. We observe that while cross species adaptation of the virus is associated with hypervariability of specific protein coding regions (including the RDB domain of the spike protein), the more variable genomic regions between extant SARS-CoV-2 episomes correspond with the 3’ and 5’ UTRs, suggesting that at present viral protein coding genes should not be subjected to different adaptive evolutionary pressures in different viral strains. Although this study can not be conclusive, we believe that the evidence presented here is strongly consistent with the notion that the biased geographic distribution of SARS-CoV-2 isolates should not be associated with adaptive evolution of this novel pathogen.
Natural image statistics at depth edges modulate perceptual stability

Binocular fusion relies on matching points in the two eyes that correspond to the same physical feature in the world. However, not all world features are binocularly visible. In particular, at depth edges parts of a scene are often visible to only one eye (so-called half occlusions). Accurate detection of these monocularly visible regions is likely to be important for stable visual perception. If monocular regions are not detected as such, the visual system may attempt to binocularly fuse non-corresponding points, which can result in unstable percepts. We investigated the hypothesis that the visual system capitalizes upon statistical regularities associated with depth edges in natural scenes to aid binocular fusion and facilitate perceptual stability. By sampling from a large set of stereoscopic natural image patches, we found evidence that monocularly visible regions near depth edges in natural scenes tend to have features more visually similar to the adjacent binocularly visible background region than to the adjacent binocularly visible foreground. The generality of these results was supported by a parametric study of three-dimensional (3D) viewing geometry in simulated environments. In two perceptual experiments, we examined if this statistical regularity may be leveraged by the visual system. The results show that perception tended to be more stable when the visual properties of the depth edge were statistically more likely. Exploiting regularities in natural environments may allow the visual system to facilitate fusion and perceptual stability of natural scenes when both binocular and monocular regions are visible. Precis We report an analysis of natural scenes and two perceptual studies aimed at understanding how the visual statistics of depth edges impact perceptual stability. Our results suggest that the visual system exploits natural scene regularities to aid binocular fusion and facilitate perceptual stability.
KMT2D links TGF‐β signaling to noncanonical activin pathway and regulates pancreatic cancer cell plasticity

Although KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development is not well understood. Here, we discovered a novel signaling axis mediated by KMT2D, which links TGF‐β to the activin A pathway. We found that TGF‐β upregulates a microRNA, miR‐147b, which in turn leads to post‐transcriptional silencing of KMT2D. Loss of KMT2D induces the expression and secretion of activin A, which activates a noncanonical p38 MAPK‐mediated pathway to modulate cancer cell plasticity, promote a mesenchymal phenotype, and enhance tumor invasion and metastasis in mice. We observed a decreased KMT2D expression in human primary and metastatic pancreatic cancer. Furthermore, inhibition or knockdown of activin A reversed the protumoral role of KMT2D loss. These findings support a tumor‐suppressive role of KMT2D in pancreatic cancer and identify miR‐147b and activin A as novel therapeutic targets.
Transcriptional regulators of the Golli/myelin basic protein locus integrate additive and stealth activities

Myelin is composed of plasma membrane spirally wrapped around axons and compacted into dense sheaths by myelin associated proteins. In the central nervous system (CNS), myelin is elaborated by neuroepithelial derived oligodendrocytes and in the peripheral nervous system (PNS) by neural crest derived Schwann cells. While some myelin proteins are unique to only one lineage, myelin basic protein (Mbp) is expressed in both. Overlapping the Mbp gene is Golli, a transcriptional unit that is expressed widely both within and beyond the nervous system. A super-enhancer domain within the Golli/Mbp locus contains multiple enhancers shown previously to drive reporter construct expression specifically in oligodendrocytes or Schwann cells. In order to determine the contribution of each enhancer to the Golli/Mbp expression program and examine if interactions among these enhancers occur, we derived mouse lines in which enhancers were deleted, either singly or in different combinations, and relative mRNA accumulation was measured at key stages of development. Although super-enhancers have been shown to facilitate interaction among their component enhancers, the enhancers investigated here demonstrated functions that were largely additive. However, enhancers demonstrating autonomous activity strictly in one cell lineage, when missing, were found to significantly reduce output in the other thus revealing cryptic “stealth” activity. Further, Golli accumulation in all cell types investigated was markedly and uniformly attenuated by the absence of a key oligodendrocyte enhancer. Our observations expose a novel level of enhancer interaction and are consistent with a model in which enhancer-mediated DNA looping underlies higher-order Golli/Mbp regulatory organization. AUTHOR SUMMARY The control of transcription is mediated through regulatory sequences that engage in a lineage and developmentally contextual manner. The Golli/Mbp locus gives rise to several mRNAs and while Mbp mRNAs accumulate exclusively in the two glial cell types that elaborate myelin, Golli mRNAs accumulate in diverse cell types both within and beyond the nervous system. To determine how the different Golli/Mbp enhancers distribute their activities and to reveal if they operate as autonomous agents or have functionally significant interactions with each other we derived multiple enhancer knock-out lines. Comparing the developmental accumulation of Mbp and Golli mRNAs revealed that the autonomous targeting capacity of multiple enhancers accurately predicted their in-situ contributions. Also, they acted in a largely additive manner indicating significant individual autonomy that can be accounted for by a simple chromatin looping model. Unexpectedly, we also uncovered cryptic “stealth” activity emanating from these same enhancers in lineages where they show no autonomous targeting capacity thus providing new insight into the control of lineage specific gene expression.
Adipose depot-specific upregulation of Ucp1 or mitochondrial oxidative complex proteins are early consequences of genetic insulin reduction in mice

Hyperinsulinemia plays a causal role in adipose tissue expansion. Mice with reduced insulin have increased energy expenditure, but the mechanisms remained unclear. Here we investigated the effects of genetically reducing insulin production on uncoupling and oxidative mitochondrial proteins in liver, skeletal muscle, white adipose tissue (WAT), and brown adipose tissue (BAT). Male Ins1+/+ or Ins1+/- littermates were fed either a low-fat diet (LFD) or a high-fat diet (HFD) for 4 weeks, starting at 8 weeks of age. Replicating our previous observations, HFD increased fasting hyperinsulinemia, and Ins1+/- mice had significantly lower circulating insulin compared with Ins1+/+ littermates. Fasting glucose and body weight were not different between genotypes. We did not observe significant differences in liver in skeletal muscle. In mesenteric WAT, Ins1+/- mice had reduced Ndufb8 and Sdhb. Ucp1 was increased in the context of the HFD, and HFD alone had a dramatic inhibitory effect on Pparg abundance. In inguinal WAT, Ins1+/- mice exhibited significant increases in oxidative complex proteins, independent of diet, without affecting Ucp1, Pparg, or Prdm16:Pparg association. In BAT, lowered insulin increased Sdhb protein levels that had been reduced by HFD. Ucp1 protein, Prdm16:Pparg association, and Sirt3 abundance were all increased in the absence of diet-induced hyperinsulinemia. Our data show that reducing insulin upregulates oxidative proteins in inguinal WAT without affecting Ucp1, while in mesenteric WAT and BAT, reducing insulin upregulates Ucp1 in the context of HFD. Preventing hyperinsulinemia has early depot-specific effects on adipose tissue metabolism and help explain the increased energy expenditure previously reported in Ins1+/- mice.
Ratcheting quasi-ballistic electrons in silicon geometric diodes at room temperature

Room-temperature electron ratchets Conventional diodes rectify current flow by forming a junction between dissimilar conductors; a metal-semiconductor diode that forms a Schottky barrier is one example. In these devices, capacitance limits operating frequency. Custer et al. describe a diode made entirely of silicon that can rectify currents up to 40 gigahertz at room temperature. They fabricated silicon nanowires with a cylindrical sawtooth profile that act as ratchets, funneling current preferentially in one direction through specular reflection of quasi-ballistic electrons. Science, this issue p. 177 A silicon nanowire with an asymmetric shape preferentially directs charge carriers to produce a high-frequency geometric diode. Ratcheting effects play an important role in systems ranging from mechanical socket wrenches to biological motor proteins. The underlying principle is to convert a fluctuating, unbiased force into unidirectional motion. Here, we report the ratcheting of electrons at room temperature using a semiconductor nanowire with precisely engineered asymmetry. Modulation of the nanowire diameter creates a cylindrical sawtooth geometry with broken inversion symmetry on a nanometer-length scale. In a two-terminal device, this structure responded as a three-dimensional geometric diode that funnels electrons preferentially in one direction through specular reflection of quasi-ballistic electrons at the nanowire surface. The ratcheting effect causes charge rectification at frequencies exceeding 40 gigahertz, demonstrating the potential for applications such as high-speed data processing and long-wavelength energy harvesting.
Mental geometry of perceiving 3D size in pictures

We show that the classical problem of 3D size perception in obliquely viewed pictures can be understood by comparing human performance to the optimal geometric solution. A photograph seen from the camera position, forms the same retinal projection as the physical 3D scene, but retinal projections of sizes and shapes are distorted in oblique viewing. For real scenes, we previously showed that size and shape inconstancy result despite observers using the correct geometric back-transform, because some retinal images evoke misestimates of viewing elevation. Now, we examine how observers estimate 3D sizes in oblique views of pictures of objects in different poses on the ground. Compared to the camera position estimates, sizes in oblique views were seriously underestimated for objects at fronto-parallel poses, but there was almost no change for objects perceived as pointing towards the viewer. The inverse of the function relating projected length to pose, camera elevation and viewing azimuth, gives the optimal correction factor for inferring correct 3D lengths if the elevation and azimuth are estimated accurately. Empirical correction functions had similar shapes to optimal, but lower amplitude. Measurements revealed that observers systematically underestimated viewing azimuth, similar to the fronto-parallel bias for object pose perception. A model that adds underestimation of viewing azimuth to the geometrical back-transform, provided good fits to estimated 3D lengths from oblique views. These results add to accumulating evidence that observers use internalized projective geometry to perceive sizes, shapes and poses in 3D scenes and their pictures.
Comprehensive single cell analysis of pandemic influenza A virus infection in the human airways uncovers cell-type specific host transcriptional signatures relevant for disease progression and pathogenesis

Respiratory viruses, such as the 2009 pandemic strain of influenza A virus (IAV, H1N1pdm09), target cells found in the human respiratory epithelium. These cells, which form a pseudostratified epithelial layer along the airways, constitute the first line of defence against respiratory pathogens and play a crucial role in the host antiviral response. However, despite their key role in host defence, it remains unknown how distinct cell types in the respiratory epithelium respond to IAV infection and how these responses may contribute to IAV-induced pathogenesis and overall disease outcome. Here, we used single cell RNA-sequencing (scRNA-seq) to dissect the host response to IAV infection in its natural target cells. scRNA-seq was performed on human airway epithelial cell (hAEC) cultures infected with either wild-type pandemic IAV (WT) or with a mutant version of IAV (NS1R38A) that induced a robust innate immune response. We then characterized both the host and viral transcriptomes of more than 19,000 single cells across the 5 major cell types populating the human respiratory epithelium. For all cell types, we observed a wide spectrum of viral burden among single infected cells and a disparate host response between infected and bystander populations. Interestingly, we also identified multiple key differences in the host response to IAV among individual cell types, including high levels of pro-inflammatory cytokines and chemokines in secretory and basal cells and an important role for luminal cells in sensing and restricting incoming virus. Multiple infected cell types were shown to upregulate interferons (IFN), with type III IFNs clearly dominating the antiviral response. Transcriptional changes in genes related to cell differentiation, cell migration, and tissue repair were also identified. Strikingly, we also detected a shift in viral host cell tropism from non-ciliated cells to ciliated cells at later stages of infection and observed major changes in the cellular composition. Microscopic analysis of both WT and NS1R38A virus-infected hAECs at various stages of IAV infection revealed that the transcriptional changes we observed at 18 hpi were likely driving the downstream histopathological alterations in the airway epithelium. To our knowledge, this is the first study to provide a comprehensive analysis of the cell type-specific host antiviral response to a respiratory virus infection in its natural target cells – namely, the human respiratory epithelium.
Detecting genetic variation and base modifications together in the same single molecules of DNA and RNA at base pair resolution using a magnetic tweezer platform

Accurate decoding of nucleic acid variation is important to understand the complexity and regulation of genome function. Here we introduce a single-molecule platform based on magnetic tweezer (MT) technology that can identify and map the positions of sequence variation and multiple base modifications together in the same single molecules of DNA or RNA at single base resolution. Using synthetic templates, we demonstrate that our method can distinguish the most common epigenetic marks on DNA and RNA with high sensitivity, specificity and precision. We also developed a highly specific CRISPR-Cas enrichment strategy to target genomic regions in native DNA without amplification. We then used this method to enrich native DNA from E. coli and characterized the differential levels of adenine and cytosine base modifications together in molecules of up to 5 kb in length. Finally, we enriched the 5‘UTR of FMR1 from cells derived from a Fragile X carrier and precisely measured the repeat expansion length and methylation status of each molecule. These results demonstrate that our platform can detect a variety of genetic, epigenetic and base modification changes concomitantly within the same single molecules.
Prey choice of the common vampire bat on introduced species in an Atlantic forest land-bridge island

The proliferation of native, alien, invasive and domestic species provide novel and abundant food resources for the common vampire bat (Desmodus rotundus) that could alter its prey preference. Based on the analysis of carbon and nitrogen stable isotopes, we report the prey choice of D. rotundus on introduced mammals in an tropical land-bridge island where the domestic animals were removed and 100 individuals of 15 mammal species were intentionally introduced. Our analysis shows that, D. rotundus on Anchieta Island were more likely to prey upon species from open habitats (mean value of −14.8‰), i.e., animals with high δ13C values characterized by the consumption of C4 resources. As expected for a top predator species, δ15N values for D. rotundus were higher (mean value of 8.2‰) and overlapped the niche of the capybaras (Hydrochoerus hydrochaeris) from the Anchieta Island, while it was distant from coatis, and also from those potential prey from the preserved area in the mainland, including the capybaras, indicating that among all potential mammalian prey species, they fed exclusively on capybaras, the highest mammalian biomass on island. Based on previous information on human occupation, the domestic animals present on Anchieta island might be the main prey of D. rotundus and responsible for maintaining a viable population. As the capybaras were introduced only 36 years ago, this suggests a rapid prey shift due to anthropogenic disturbances, which has allowed common vampire bats to successfully exploit them. Literature records also show that common vampire bats were not captured in preserved areas of the mainland which are near Anchieta Island indicating that the percentage of capture of D. rotundus is usually low in natural forested habitats where potential prey are scattered. As three individuals of introduced capybaras were confirmed died from bat rabies viruses (RABV) in 2020, we suggest periodic monitoring of bat rabies viruses in common vampire bat populations on Anchieta Island and areas nearby, in order to quantify the magnitude of the outbreak area and develop strategies for controlling, especially considering that the island and areas nearby is frequently visited by tourists. We highlighted that this prey choice is context-dependent, and possibly influenced by the removal of domestic animals, the explosive population growth of introduced capybaras combined with their predictable foraging behavior.
Modeling the Short-Term Dynamics of in Vivo Excitatory Spike Transmission

Information transmission in neural networks is influenced by both short-term synaptic plasticity (STP) as well as nonsynaptic factors, such as after-hyperpolarization currents and changes in excitability. Although these effects have been widely characterized in vitro using intracellular recordings, how they interact in vivo is unclear. Here, we develop a statistical model of the short-term dynamics of spike transmission that aims to disentangle the contributions of synaptic and nonsynaptic effects based only on observed presynaptic and postsynaptic spiking. The model includes a dynamic functional connection with short-term plasticity as well as effects due to the recent history of postsynaptic spiking and slow changes in postsynaptic excitability. Using paired spike recordings, we find that the model accurately describes the short-term dynamics of in vivo spike transmission at a diverse set of identified and putative excitatory synapses, including a pair of connected neurons within thalamus in mouse, a thalamocortical connection in a female rabbit, and an auditory brainstem synapse in a female gerbil. We illustrate the utility of this modeling approach by showing how the spike transmission patterns captured by the model may be sufficient to account for stimulus-dependent differences in spike transmission in the auditory brainstem (endbulb of Held). Finally, we apply this model to large-scale multielectrode recordings to illustrate how such an approach has the potential to reveal cell type-specific differences in spike transmission in vivo. Although STP parameters estimated from ongoing presynaptic and postsynaptic spiking are highly uncertain, our results are partially consistent with previous intracellular observations in these synapses. SIGNIFICANCE STATEMENT Although synaptic dynamics have been extensively studied and modeled using intracellular recordings of postsynaptic currents and potentials, inferring synaptic effects from extracellular spiking is challenging. Whether or not a synaptic current contributes to postsynaptic spiking depends not only on the amplitude of the current, but also on many other factors, including the activity of other, typically unobserved, synapses, the overall excitability of the postsynaptic neuron, and how recently the postsynaptic neuron has spiked. Here, we developed a model that, using only observations of presynaptic and postsynaptic spiking, aims to describe the dynamics of in vivo spike transmission by modeling both short-term synaptic plasticity (STP) and nonsynaptic effects. This approach may provide a novel description of fast, structured changes in spike transmission.