Miracle-dz/UniFAR-FTUs huggingface dataset:
Recurrent emergence and transmission of a SARS-CoV-2 spike deletion H69/V70

SARS-CoV-2 amino acid replacements in the receptor binding domain (RBD) occur relatively frequently and some have a consequence for immune recognition. Here we report recurrent emergence and significant onward transmission of a six-nucleotide out of frame deletion in the S gene, which results in loss of two amino acids: H69 and V70. We report that in human infections ΔH69/V70 often co-occurs with the receptor binding motif amino acid replacements N501Y, N439K and Y453F, and in the latter two cases has followed the RBD mutation. One of the ΔH69/V70+ N501Y lineages, now known as B.1. 1.7, has undergone rapid expansion and includes eight S gene mutations: RBD (N501Y and A570D), S1 (ΔH69/V70 and Δ144) and S2 (P681H, T716I, S982A and D1118H). In vitro, we show that ΔH69/V70 does not reduce serum neutralisation across multiple convalescent sera. However, ΔH69/V70 increases infectivity and is associated with increased incorporation of cleaved spike into virions. ΔH69/V70 is able to compensate for small infectivity defects induced by RBD mutations N501Y, N439K and Y453F. In addition, replacement of H69 and V70 residues in the B.1. 1.7 spike reduces its infectivity and spike mediated cell-cell fusion. Based on our data ΔH69/V70 likely acts as a permissive mutation that allows acquisition of otherwise deleterious immune escape mutations. Enhanced surveillance for the ΔH69/V70 deletion with and without RBD mutations should be considered as a global priority not only as a marker for the B.1. 1.7 variant, but potentially also for other emerging variants of concern. Vaccines designed to target the deleted spike protein could mitigate against its emergence as increased selective forces from immunity and vaccines increase globally. Highlights ΔH69/V70 is present in at least 28 SARS-CoV-2 lineages ΔH69/V70 does not confer escape from convalescent sera ΔH69/V70 increases spike infectivity and compensates for RBD mutations ΔH69/V70 is associated with greater spike cleavage B.1. 1.7 requires ΔH69/V70 for optimal spike cleavage and infectivity
Rrp6p/Rrp47p constitutes an independent nuclear turnover system of mature small non-coding RNAs in Saccharomyces cerevisiae

In Saccharomyces cerevisiae, the nuclear exosome/Rrp6p/TRAMP participates in the 3’-end processing of several precursor non-coding RNAs. Here we demonstrate that the depletion of nucleus-specific 3’→5’ exoribonuclease Rrp6p and its cofactor, Rrp47p led to the specific and selective enhancement of steady-state levels of mature small non-coding RNAs (sncRNAs) that include 5S and 5.8S rRNAs, snRNAs and snoRNAs, but not 18S and 25S rRNAs. Most importantly, their steady-state enhancement does not require the exosome, TRAMP, CTEXT, or Rrp6p-associated Mpp6p. Rrp6p/47p-dependent enhancement of the steady-state levels of sncRNAs is associated with the diminution of their nuclear decay-rate and requires their polyadenylation before targeting by Rrp6p, which is catalyzed by both the canonical and non-canonical poly(A) polymerases, Pap1p and Trf4p. Consistent with this finding, we also demonstrated that Rrp6p and Rrp47p exist as an exosome-independent complex. Thus, Rrp6p-Rrp47p defines a core nuclear exosome-independent novel turnover system that targets the small non-coding RNAs.
Sparse Coding in Temporal Association Cortex Improves Complex Sound Discriminability

The mouse auditory cortex is comprised of several auditory fields spanning the dorsoventral axis of the temporal lobe. The ventral most auditory field is the temporal association cortex (TeA), which remains largely unstudied. Using Neuropixels probes, we simultaneously recorded from primary auditory cortex (AUDp), secondary auditory cortex (AUDv), and TeA, characterizing neuronal responses to pure tones and frequency modulated (FM) sweeps in awake head-restrained female mice. As compared with AUDp and AUDv, single-unit (SU) responses to pure tones in TeA were sparser, delayed, and prolonged. Responses to FMs were also sparser. Population analysis showed that the sparser responses in TeA render it less sensitive to pure tones, yet more sensitive to FMs. When characterizing responses to pure tones under anesthesia, the distinct signature of TeA was changed considerably as compared with that in awake mice, implying that responses in TeA are strongly modulated by non-feedforward connections. Together, these findings provide a basic electrophysiological description of TeA as an integral part of sound processing along the cortical hierarchy. SIGNIFICANCE STATEMENT This is the first comprehensive characterization of the auditory responses in the awake mouse auditory temporal association cortex (TeA). The study provides the foundations for further investigation of TeA and its involvement in auditory learning, plasticity, auditory driven behaviors etc. The study was conducted using state of the art data collection tools, allowing for simultaneous recording from multiple cortical regions and numerous neurons.
Robust representation of natural images by sparse and variable population of active neurons in visual cortex

Natural scenes sparsely activate neurons in the primary visual cortex (V1). However, whether and how sparsely active neurons sufficiently and robustly represent natural image contents has not been revealed. We reconstructed the natural images from neuronal activities of mouse V1. Single natural images were linearly decodable from surprisingly small number (~20) of highly responsive neurons. This was achieved by diverse receptive fields (RFs) of the small number of responsive neurons. Furthermore, these neurons robustly represented the image against trial-to-trial response variability. Synchronous neurons with partially overlapping RFs formed functional clusters and were active at the same trials. Importantly, multiple clusters represented similar patterns of local images but were active at different trials. Thus, integration of activities among the clusters led to robust representation against the variability. Our results suggest that the diverse, partially overlapping RFs ensure the sparse and robust representation, and propose a new representation scheme in which information is reliably represented, while representing neuronal patterns change across trials.
Deterring Property Tax Delinquency in Philadelphia: An Experimental Evaluation of Nudge Strategies

Municipal governments commonly confront the problem of tardy or delinquent property tax payments. We implement an experiment in property tax collection for tardy taxpayers in the City of Philadelphia for the calendar year, 2015. The experiment sent one of seven reminder letters to the tardy taxpayers, testing the efficacy of a simple reminder, two alternative reminders stressing economic sanctions, and four alternative reminders emphasizing either that taxpayers receive neighborhood services or city-wide services for their tax payments, that most of their neighbors pay their taxes on time, or that as a citizen in a democracy it is a civic duty to pay taxes on time. Compliance behaviors were compared to a holdout sample that received no reminder letter. The most effective letters were those that threatened an economic sanction for continued non-compliance. These letters were particularly cost-effective in raising additional city revenues. There was no evidence that those receiving a reminder for the calendar year 2015 improved their tax compliance behavior in the calendar year 2016.
1 Capacity sharing between concurrent 2 movement plans in the frontal eye field during the 3 planning of sequential saccades 4 5

Capacity sharing between concurrent 2 movement plans in the frontal eye field during the 3 planning of sequential saccades 4 5 Debaleena Basu, Naveen Sendhilnathan, Aditya Murthy 6 Centre for Neuroscience, Indian Institute of Science, Bangalore, Karnataka 560012, India 7 Department of Neuroscience, Columbia University in the City of New York, NY 10027, USA 8 *Corresponding author: Dr. Debaleena Basu; e-mail: basu.debaleena@gmail.com 9 10 11 Number of pages: 35 12 Figures: 7 13 Supplementary figures: 5 14 15
Life-history dynamics: damping time, demographic dispersion and generation time

Transient dynamics are crucial for understanding ecological and life-history dynamics. In this study, we analyze damping time, the time taken by a population to converge to a stable (st)age structure following a perturbation, for over 600 species of animals and plants. We expected damping time to be associated with both generation time Tc and demographic dispersion σ based on previous theoretical work. Surprisingly, we find that damping time (calculated from the population projection matrix) is approximately proportional to Tc across taxa on the log-log scale, regardless of σ. The result suggests that species at the slow end of fast-slow continuum (characterized with long generation time, late maturity, low fecundity) are more vulnerable to external disturbances as they take more time to recover compared to species with fast life-histories. The finding on damping time led us to next examine the relationship between generation time and demographic dispersion. Our result reveals that the two life-history variables are positively correlated on a log-log scale across taxa, implying long generation time promotes demographic dispersion in reproductive events. Finally, we discuss our results in the context of metabolic theory and contribute to existing allometric scaling relationships.
Genotyping common, large structural variations in 5,202 genomes using pangenomes, the Giraffe mapper, and the vg toolkit

We introduce Giraffe, a pangenome short read mapper that can efficiently map to a collection of haplotypes threaded through a sequence graph. Giraffe, part of the variation graph toolkit (vg)1, maps reads to thousands of human genomes at around the same speed BWA-MEM2 maps reads to a single reference genome, while maintaining comparable accuracy to VG-MAP, vg’s original mapper. We have developed efficient genotyping pipelines using Giraffe. We demonstrate improvements in genotyping for single-nucleotide variants (SNVs), small insertions and deletions (indels) and structural variations (SVs) genome-wide. We use Giraffe to genotype about 167 thousand structural variants ascertained from long read studies in 5,202 human genomes sequenced with short reads, including the complete 1000 Genomes Project dataset, at an average cost of $1.50 per sample. We determine the frequency of these variations in diverse human populations, characterize their complex allelic variations and identify thousands of expression quantitative trait loci (eQTLs) driven by these variations.
Poxviruses package viral redox proteins in lateral bodies and modulate the host oxidative response

All poxviruses contain a set of proteinaceous structures termed lateral bodies (LB) that deliver viral effector proteins into the host cytosol during virus entry. To date, the spatial proteotype of LBs remains unknown. Using the prototypic poxvirus, vaccinia virus (VACV), we employed a quantitative comparative mass spectrometry strategy to determine the poxvirus LB proteome. We identified a large population of cellular proteins, the majority being mitochondrial, and 15 viral LB proteins. Strikingly, one-third of these comprise the full set of VACV redox proteins whose LB residency could be confirmed using super-resolution microscopy. We further show that VACV infection exerts an anti-oxidative effect on host cells and that artificial induction of oxidative stress impacts early gene expression and virion production. In addition to defining the spatial proteotype of these enigmatic viral structures, these findings implicate poxvirus redox proteins as modulators of host oxidative anti-viral responses and provide a solid starting point for future investigations into the role of LB resident proteins in host immunomodulation.
Defective myelination in an RNA polymerase III mutant leukodystrophic mouse

Significance Pathogenic mutations in subunits of RNA polymerase (Pol) III cause a prevalent autosomal recessive form of leukodystrophy. However, understanding of the mechanisms of pathogenesis, including how ubiquitously expressed Pol III mutations affect primarily the central nervous system, has been limited by the absence of an animal model of the disease. We show that conditional knockin of pathogenic Polr3a mutations in the Olig2 lineage in mice results in growth, neurobehavioral, and hypomyelination phenotypes, reflecting a subset of clinical features of Pol III-related leukodystrophy patients. Myelination defects in the mice identify neural-specific roles for Pol III transcription. The phenotypes of Pol III-related leukodystrophic mice enable genetic and pharmacological approaches aimed at mitigating the consequences of this disease in humans. RNA polymerase (Pol) III synthesizes abundant short noncoding RNAs that have essential functions in protein synthesis, secretion, and other processes. Despite the ubiquitous functions of these RNAs, mutations in Pol III subunits cause Pol III-related leukodystrophy, an early-onset neurodegenerative disease. The basis of this neural sensitivity and the mechanisms of disease pathogenesis are unknown. Here we show that mice expressing pathogenic mutations in the largest Pol III subunit, Polr3a, specifically in Olig2-expressing cells, have impaired growth and developmental delay, deficits in cognitive, sensory, and fine sensorimotor function, and hypomyelination in multiple regions of the cerebrum and spinal cord. These phenotypes reflect a subset of clinical features seen in patients. In contrast, the gross motor defects and cerebellar hypomyelination that are common features of severely affected patients are absent in the mice, suggesting a relatively mild form of the disease in this conditional model. Our results show that disease pathogenesis in the mice involves defects that reduce both the number of mature myelinating oligodendrocytes and the ability of these cells to produce a myelin sheath of normal thickness. The findings suggest unique sensitivities of oligodendrogenesis and myelination to perturbations of Pol III transcription.
NGLY1 knockdown or pharmacological inhibition induces cellular autophagy

Pan-caspase inhibitor Z-VAD-fmk acts as an inhibitor of peptide:N-glycanase (NGLY1); an endoglycosidase which cleaves N-linked glycans from glycoproteins exported from the endoplasmic reticulum during ER-associated degradation (ERAD). Pharmacological N-glycanase inhibition by Z-VAD-fmk or siRNA knockdown (KD) induces GFP-LC3 positive puncta in HEK 293 cells. Activation of ER stress markers or reactive oxygen species (ROS) induction are not observed. In NGLY1 inhibition or KD, upregulation of autophagosome formation without impairment of autophagic flux are observed. Enrichment and proteomics analysis of autophagosomes after Z-VAD-fmk treatment or NGLY1 KD reveals comparable autophagosomal protein content. Upregulation of autophagy represents a cellular adaptation to NGLY1 inhibition or KD, and ATG13-deficient mouse embryonic fibroblasts (MEFs) show reduced viability under these conditions. In contrast, treatment with pan-caspase inhibitor, Q-VD-OPh does not induce cellular autophagy. Therefore, experiments with Z-VAD-fmk are complicated by the effects of NGLY1 inhibition and Q-VD-OPh represents an alternative caspase inhibitor free from this limitation.
No behavioural evidence for rhythmic facilitation of perceptual discrimination

It has been hypothesized that internal oscillations can synchronize (i.e., entrain) to external environmental rhythms, thereby facilitating perception and behavior. To date, evidence for the link between the phase of neural oscillations and behavior has been scarce and contradictory; moreover, it remains an open question whether the brain can use this tentative mechanism for active temporal prediction. In our present study, we conducted a series of auditory pitch discrimination tasks with 181 healthy participants in an effort to shed light on the proposed behavioral benefits of rhythmic cueing and entrainment. In the three versions of our task, we observed no perceptual benefit of purported entrainment: targets occurring in-phase with a rhythmic cue provided no perceptual benefits in terms of discrimination accuracy or reaction time when compared with targets occurring out-of-phase or targets occurring randomly, nor did we find performance differences for targets preceded by rhythmic vs. random cues. However, we found a surprising effect of cueing frequency on reaction time, in which participants showed faster responses to cue rhythms presented at higher frequencies. We therefore provide no evidence of entrainment, but instead a tentative effect of covert active sensing in which a faster external rhythm leads to a faster communication rate between motor and sensory cortices, allowing for sensory inputs to be sampled earlier in time.
16p12.1 Deletion Orthologs are Expressed in Motile Neural Crest Cells and are Important for Regulating Craniofacial Development in Xenopus laevis

Copy number variants (CNVs) associated with neurodevelopmental disorders are characterized by extensive phenotypic heterogeneity. In particular, one CNV was identified in a subset of children clinically diagnosed with intellectual disabilities (ID) that results in a hemizygous deletion of multiple genes at chromosome 16p12.1. In addition to ID, individuals with this deletion display a variety of symptoms including microcephaly, seizures, cardiac defects, and growth retardation. Moreover, patients also manifest severe craniofacial abnormalities, such as micrognathia, cartilage malformation of the ears and nose, and facial asymmetries; however, the function of the genes within the 16p12.1 region have not been studied in the context of vertebrate craniofacial development. The craniofacial tissues affected in patients with this deletion all derive from the same embryonic precursor, the cranial neural crest, leading to the hypothesis that one or more of the 16p12.1 genes may be involved in regulating neural crest cell (NCC)-related processes. To examine this, we characterized the developmental role of the 16p12.1-affected gene orthologs, polr3e, mosmo, uqcrc2, and cdr2, during craniofacial morphogenesis in the vertebrate model system, Xenopus laevis. While the currently-known cellular functions of these genes are diverse, we find that they share similar expression patterns along the neural tube, pharyngeal arches, and later craniofacial structures. As these genes show co-expression in the pharyngeal arches where NCCs reside, we sought to elucidate the effect of individual gene depletion on craniofacial development and NCC migration. We find that reduction of several 16p12.1 genes significantly disrupts craniofacial and cartilage formation, pharyngeal arch migration, as well as NCC specification and motility. Thus, we have determined that some of these genes play an essential role during vertebrate craniofacial patterning by regulating specific processes during NCC development, which may be an underlying mechanism contributing to the craniofacial defects associated with the 16p12.1 deletion.
The ascending arousal system promotes optimal performance through mesoscale network integration in a visuospatial attentional task

Previous research has shown that the autonomic nervous system provides essential constraints over ongoing cognitive function. However, there is currently a relative lack of direct empirical evidence for how this interaction manifests in the brain at the macro-scale level. Here, we examine the role of ascending arousal and attentional load on large-scale network dynamics by combining pupillometry, functional MRI and graph theoretical analysis to analyze data from a visual motion-tracking task with a parametric load manipulation. We found that attentional load effects were observable in measures of pupil diameter and in a set of brain regions that parametrically modulated their BOLD activity and meso-scale network-level integration. In addition, the regional patterns of network reconfiguration were correlated with the spatial distribution of the α2a adrenergic receptor. Our results further solidify the relationship between ascending noradrenergic activity, large-scale network integration, and cognitive task performance. Author Summary In our daily lives, it is usual to encounter highly demanding cognitive tasks. They have been traditionally regarded as challenges that are solved mainly through cerebral activity, specifically via information-processing steps carried by neurons in the cerebral cortex. Activity in cortical networks thus constitutes a key factor for improving our understanding cognitive processes. However, recent evidence has shown that evolutionary older players in the central nervous system, such as brainstem’s ascending modulatory systems, might play an equally important role in diverse cognitive mechanisms. Our article examines the role of the ascending arousal system on large-scale network dynamics by combining pupillometry, functional MRI and graph theoretical analysis.
Consequences of producing DNA gyrase from a synthetic gyrBA operon in Salmonella enterica serovar Typhimurium

DNA gyrase is an essential type II topoisomerase that is composed of two subunits, GyrA and GyrB and has an A2B2 structure. Although both subunits are required in equal proportions to form DNA gyrase, the gyrA and gyrB genes that encode them in Salmonella (and in many other bacteria) are at widely separated locations on the chromosome, are under separate transcriptional control and are present in different copy numbers in rapidly growing bacteria (gyrA is near the terminus of chromosome replication while gyrB is near the origin). We generated a synthetic gyrBA operon at the oriC-proximal location of gyrB to test the significance of the gyrase gene position for Salmonella physiology. Producing gyrase from an operon did not alter growth kinetics, cell morphology, competitive fitness index, or sensitivity to some gyrase-inhibiting antibiotics. However, the operon strain had altered DNA supercoiling set points, its SPI-2 virulence genes were expressed at a reduced level and its survival was reduced in macrophage. The gyrB gene could not be deleted from its oriC-proximal location, even in a gyrB merodiploid strain. We discuss the physiological significance of the different gyrA and gyrB gene arrangements found naturally in Salmonella and other bacteria.
The Relative Roles of Voice and Gesture in Early Communication Development

Both vocalization and gesture are universal modes of communication and fundamental features of language development. Many believe that language evolved out of early gestural use; however, evidence reported here suggests vocalization precedes gesture in human communication and forms the predominant foundation for language. To our knowledge no prior research has investigated the rates of emergence of both gesture and vocalization in human infants to evaluate this question. We evaluated the rates of gesture and speech-like vocalizations (protophones) of 10 infants at 4, 7, and 11 months of age using parent-infant laboratory recordings. We found that infant protophones outnumbered gestures substantially at all three ages, ranging from >30 times more protophones than gestures at 3 months, to more than twice as many protophones as gestures at 11 months. The results suggest that vocalization is the predominant mode of communication in human infants from the beginning of life.