Miracle-dz/UniFAR-FTUs huggingface dataset:
Estimating Movement Smoothness From Inertial Measurement Units

There is an increasing trend in using inertial measurement units (IMUs) to estimate movement quality and quantity, and infer the nature of motor behavior. The current literature contains several attempts to estimate movement smoothness using data from IMUs, most of which assume that the translational and rotational kinematics measured by IMUs can be directly used with existing smoothness measures - spectral arc length (SPARC) and log dimensionless jerk (LDLJ-V). However, there has been no investigation of the validity of these approaches. In this paper, we systematically evaluate the appropriateness of the using these measures on the kinematics measured by an IMU. We show that: (a) current measures (SPARC and LDLJ-V) are inappropriate for translational movements; and (b) SPARC and LDLJ-V can be used rotational kinematics measured by an IMU. For discrete translational movements, we propose a modified version of the LDLJ-V measure, which can be applied to acceleration data (LDLJ-A), while roughly maintaining the properties of the original measure. However, accuracy of LDLJ-A depends on the IMU orientation estimation error. We evaluate the performance of these measures using simulated and experimental data. We then provide recommendations for how to appropriately apply these measures in practice, and the various factors to be aware of when performing smoothness analysis using IMU data.
Mesenchymal ETV transcription factors regulate cochlear length

Mammalian cochlear development encompasses a series of morphological and molecular events that results in the formation of a highly intricate structure responsible for hearing. One remarkable event occurs during development is the cochlear lengthening that starts with cochlear outgrowth around E11 and continues throughout development. Different mechanisms contribute to this process including cochlear progenitor proliferation and convergent extension. We previously identified that FGF9 and FGF20 promote cochlear lengthening by regulating auditory sensory epithelial proliferation through FGFR1 and FGFR2 in the periotic mesenchyme. Here, we provide evidence that ETS-domain transcription factors ETV4 and ETV5 are downstream of mesenchymal FGF signaling to control cochlear lengthening. Next generation RNA sequencing identified that Etv1, Etv4 and Etv5 mRNAs are decreased in the Fgf9 and Fgf20 double mutant periotic mesenchyme. Deleting both Etv4 and Etv5 in periotic mesenchyme resulted in shortening of cochlear length but maintaining normal patterning of organ of Corti and density of hair cells and supporting cells. This recapitulates phenotype of mesenchymal-specific Fgfr1 and Fgfr2 deleted inner ear. Furthermore, analysis of Etv1/4/5 triple conditional mutants revealed that ETV1 does not contribute in this process. Our study reveals that ETV4 and ETV5 function downstream of mesenchymal FGF signaling to promote cochlear lengthening.
The influence of herbivores and neighboring plants on risk of browsing: a case study using arctic lupine (Lupinus arcticus) and arctic ground squirrels (Spermophilus parryii plesius)

We examined how herbivore distribution and density, neighboring plant density and species composition, and individual plant morphology all influence the risk that individual arctic lupines (Lupinus arcticus) will be browsed by arctic ground squirrels (Spermophilus parryii plesius). Risk of being browsed was significantly influenced by the number of resident ground squirrels but not by overall squirrel density at a site. As the leaf density of neighboring conspecifics increased, risk of browsing to an individual lupine decreased except when palatable neighbors were also present. The presence of other palatable species increased the risk of browsing. Risk was highest when both lupine and other palatable neighbors were present. The presence of unpalatable neighbors reduced the risk of browsing of individual lupines. We discuss these results in the context of three hypotheses: (1) attractant decoy, (2) resource concentration, and (3) repellent plant. No single hypothesis accounts for our observations, but an .
α-Synuclein facilitates clathrin assembly in synaptic vesicle endocytosis

α-Synuclein and family members β-, and γ-synuclein, are presynaptic proteins that sense and generate membrane curvature, properties important for synaptic vesicle (SV) cycling. αβγ-synuclein triple knockout (KO) neurons exhibit SV endocytosis (SVE) deficits. Here, we investigate how SVE is regulated by α-synuclein. Immuno-electron microscopy (EM) of synaptosomes reveals that α-synuclein relocalizes from SVs to the synaptic membrane upon stimulation, allowing α-synuclein to function on presynaptic membranes during or after stimulation. On cell membranes, we observe that α-synuclein is colocalized with clathrin and its adaptor AP180. Clathrin patches that contain both α-synuclein and AP180 were significantly larger than clathrin patches containing either protein alone. We also find that recruitment of clathrin and AP180 recruitment to membranes are altered in the absence of synucleins. Visualizing clathrin assembly on membranes using an in vitro endocytosis reconstitution system reveals that α-synuclein increases clathrin patch size and enhances clathrin lattice curvature, facilitating normal clathrin coated pit maturation. Thus, α-synuclein is an endocytic accessory protein that acts at early stages of SVE to controls the size and curvature of clathrin structures on the membrane.
The RNA Polymerase II core subunit RPB-9 directs transcriptional elongation at piRNA loci in Caenorhabditis elegans

PIWI-interacting RNAs (piRNAs) are genome-encoded small RNAs that regulate germ cell development and maintain germline integrity in many animals. Mature piRNAs engage Piwi Argonaute proteins to silence complementary transcripts, including transposable elements and endogenous genes. piRNA biogenesis mechanisms are diverse and remain poorly understood. Here, we identify the RNA Polymerase II (RNA Pol II) core subunit RPB-9 as required for piRNA-mediated silencing in the nematode Caenorhabditis elegans. rpb-9 mutants fail to initiate heritable piRNA-mediated gene silencing. Furthermore, we show that RPB-9 is required to repress two DNA transposon families and a subset of somatic genes in the C. elegans germline. We provide genetic and biochemical evidence that RPB-9 is required for piRNA biogenesis. We demonstrate that RPB-9 acts to promote transcriptional elongation/termination at endogenous piRNA loci. We conclude that as a part of its rapid evolution the piRNA pathway has co-opted another ancient machinery, this time for high-fidelity transcription.
An Arf/Rab cascade controls the growth and invasiveness of glioblastoma

Glioblastoma is the most common and deadly malignant brain cancer. We now demonstrate that loss of function of the endosomal GTPase Rab35 in human brain tumor initiating cells (BTICs) increases glioblastoma growth and decreases animal survival following BTIC implantation in mouse brain. Mechanistically, we identify that the GTPase Arf5 interacts with the guanine nucleotide exchange factor (GEF) for Rab35, DENND1/connecdenn and allosterically enhances its GEF activity towards Rab35. Knockdown of either Rab35 or Arf5 increases cell migration, invasiveness and self-renewal in culture and enhances the growth and invasiveness of BTIC-initiated brain tumors in mice. RNAseq of the tumors reveals upregulation of the tumor-promoting transcription factor SPOCD1, and disruption of the Arf5/Rab35 axis in glioblastoma cells leads to strong activation of the epidermal growth factor receptor with resulting enhancement of SPOCD1 levels. These discoveries reveal an unexpected cascade between an Arf and a Rab and indicate a role for the cascade, and thus endosomal trafficking, in brain tumors.
Histone deacetylase inhibitors butyrate and bufexamac inhibit de novo HIV-1 infection in CD4 T-cells

While current combined antiretroviral therapy (cART) allows control of HIV replication in patients and effectively suppresses plasma viral loads, it is unable to target latent reservoirs, which are responsible for virus rebound after discontinuation of therapy. Several histone deacetylase inhibitors (HDACIs) have been shown to target reservoirs and to reactivate latent HIV. While this effect is highly desired, it carries the risk that HIV-1 may be reactivated in tissue compartments were cART concentrations are insufficient and thus leading to de novo infections in this sites. To address this concern, we evaluated the effect of different HDACIs for their ability to reverse HIV latency and to modulate de novo infections. Two of the inhibitors, sodium butyrate and bufexamac, significantly inhibited de novo HIV-1 infection in activated CD4+ T-cells. Transcriptome and proteome analysis indicated global changes of protein abundancies, exhibited reduced proliferation of CD4+ T-cells, and revealed butyrate-based proteasomal degradation of EP300, an important factor for HIV-1 replication. Our results disclose new potential treatment strategies and minimizes the concern of potential reservoir reseeding by HDACIs.
Structural and functional analysis of pyocin S8 from Pseudomonas aeruginosa : requirement of a glutamate in the H-N-H motif for the DNase activity

Multi-drug resistance (MDR) is a serious threat to global public health, making the development of new antimicrobials an urgent necessity. Pyocins are protein antibiotics produced by Pseudomonas aeruginosa strains to kill closely related cells during intraspecific competition. Here, we report an in depth biochemical, microbicidal and structural characterization of a new S-type pyocin, named S8. Initially, we described the domain organization and secondary structure of S8. Subsequently, we observed that a recombinant S8 composed of the killing subunit in complex with the immunity (Im) protein killed the strain PAO1. Furthermore, mutation of a highly conserved glutamic acid to alanine (Glu100Ala) completely inhibited this antimicrobial activity. Probably the integrity of the H-N-H motif is essential in the killing activity of S8, as Glu100 is a highly conserved component of this structure. Next, we observed that S8 is a metal-dependent endonuclease, as EDTA treatment abolished its ability to cleave supercoiled pUC18 plasmid. Supplementation of apo S8 with Ni2+ strongly induced this DNase activity, whereas Mn2+ and Mg2+ exhibited moderate effects and Zn2+ was inhibitory. Additionally, S8 bound Zn2+ with a higher affinity than Ni2+ and the Glu100Ala mutation decreased the affinity of S8 for these metals as shown by isothermal titration calorimetry (ITC). Finally, we describe the crystal structure of the Glu100Ala pyocin-S8DNase-Im complex at 1.38 Å, which gave us new insights into the endonuclease activity of S8. Our results reinforce the possible use of S8 as an alternative antibiotic for MDR Pseudomonas aeruginosa strains, while leaving commensal human microbiota intact.
Reproductive biology of wild and domesticated Ensete ventricosum: Further evidence for maintenance of sexual reproductive capacity in a vegetatively propagated perennial crop

Loss of sexual reproductive capacity has been proposed as a syndrome of domestication in vegetatively propagated crops, but there are relatively few examples from agricultural systems. In this study we compare sexual reproductive capacity in wild (sexual) and domesticated (vegetative) populations of enset (Ensete ventricosum (Welw.) Cheesman), a tropical banana relative and Ethiopian food security crop. We examined floral and seed morphology and germination ecology across 35 wild and domesticated enset. We surveyed variation in floral and seed traits, including seed weight, viability and internal morphology, and germinated seeds across a range of constant and alternating temperature regimes to characterise optimum germination requirements. We report highly consistent floral allometry, seed viability, internal morphology and days to germination in wild and domesticated enset. However, seeds from domesticated plants responded to cooler temperatures with greater diurnal range. Shifts in germination behaviour appear concordant with a climatic envelope shift in the domesticated distribution. Our findings provide evidence that sexual reproductive capacity has been maintained despite long-term near-exclusive vegetative propagation in domesticated enset. Furthermore, certain traits such as germination behaviour and floral morphology, may be under continued selection, presumably through rare sexually reproductive events. Compared to sexually propagated crops banked as seeds, vegetative crop diversity is typically conserved in living collections that are more costly and insecure. Improved understanding of sexual propagation in vegetative crops may have applications in germplasm conservation and plant breeding.
Molecular Basis for ADP-ribose Binding to the Macro-X Domain of SARS-CoV-2 Nsp3

The virus that causes COVID-19, SARS-CoV-2, has a large RNA genome that encodes numerous proteins that might be targets for antiviral drugs. Some of these proteins, such as the RNA-dependent RNA polymers, helicase and main protease, are well conserved between SARS-CoV-2 and the original SARS virus, but several others are not. This study examines one of the proteins encoded by SARS-CoV-2 that is most different, a macrodomain of nonstructural protein 3 (nsp3). Although 26% of the amino acids in this SARS-CoV-2 macrodomain differ from those seen in other coronaviruses, biochemical and structural data reveal that the protein retains the ability to bind ADP-ribose, which is an important characteristic of beta coronaviruses, and potential therapeutic target.
Social Isolation Stress in Adolescence, but not Adulthood, Produces Hypersocial Behavior in Adult Male and Female C57BL/6J Mice

Chronic stress during the developmental period of adolescence increases susceptibility to many neuropsychiatric diseases in adulthood, including anxiety, affective, and alcohol/substance use disorders. Preclinical rodent models of adolescent stress have produced varying results that are species, strain, sex, and laboratory-dependent. However, adolescent social isolation is a potent stressor in humans that has been reliably modeled in male rats, increasing adult anxiety-like and alcohol drinking behaviors, among others. In this study, we examined the generalizability and sex-dependence of this model in C57BL/6J mice, the most commonly used rodent strain in neuroscience research. We also performed a parallel study using social isolation in adulthood to understand the impact of adult social isolation on basal behavioral phenotypes. We found that six weeks of social isolation in adolescence beginning at postnatal day (PD) 28 produced a hypersocial phenotype in both male and female adults in multiple assays and a female-specific anxiolytic phenotype in the elevated plus maze, but it had no effects in other assays for avoidance behavior, fear conditioning, alcohol drinking, reward or aversion sensitivity, novel object exploration, or forced swim behavior in either sex. In contrast, social isolation in adulthood beginning at PD77 produced an anxiogenic phenotype in the light/dark box but had no effects on any other assays. Altogether, our results suggest that 1) adolescence is a critical period for social stress in C57BL/6J mice, producing aberrant social behavior in a sex-independent manner and 2) chronic individual housing in adulthood does not alter basal behavioral phenotypes that may confound interpretation of behavior following other laboratory manipulations.
Does hippocampal volume explain performance differences on hippocampal-dependent tasks?

Marked disparities exist across healthy individuals in their ability to imagine scenes, recall autobiographical memories, think about the future and navigate in the world. The importance of the hippocampus in supporting these critical cognitive functions has prompted the question of whether differences in hippocampal grey matter volume could be one source of performance variability. Evidence to date has been somewhat mixed. In this study we sought to mitigate issues that commonly affect these types of studies. Data were collected from a large sample of 217 young, healthy adult participants, including whole brain structural MRI data (0.8mm isotropic voxels) and widely-varying performance on scene imagination, autobiographical memory, future thinking and navigation tasks. We found little evidence that hippocampal grey matter volume was related to task performance in this healthy sample. This was the case using different analysis methods (voxel-based morphometry, partial correlations), when whole brain or hippocampal regions of interest were examined, when comparing different sub-groups (divided by gender, task performance, self-reported ability), and when using latent variables derived from across the cognitive tasks. Hippocampal grey matter volume may not, therefore, significantly influence performance on tasks known to require the hippocampus in healthy people. Perhaps only in extreme situations, as in the case of licensed London taxi drivers, are measurable ability-related hippocampus volume changes consistently exhibited. Highlights Evidence is mixed about whether hippocampal volume affects cognitive task performance This is particularly the case concerning individual differences in healthy people We collected structural MRI data from 217 healthy people They also had widely-varying performance on cognitive tasks linked to the hippocampus In-depth analyses showed little evidence hippocampal volume affected task performance
Structural and Functional Implications of Non-synonymous Mutations in the Spike protein of 2,954 SARS-CoV-2 Genomes

SARS-CoV-2, the causative agent of COVID-2019 pandemic is an RNA virus prone to mutations. Information on mutations within the circulating strains of the virus is pivotal to understand disease spread and dynamics. Here, we analyse the mutations associated with 2,954 globally reported high quality genomes of SARS-CoV-2 with special emphasis on genomes of viral strains from India. Molecular phylogenetic analysis suggests that SARS-CoV-2 strains circulating in India form five distinct phyletic clades designated R1-R5. These clades categorize into the previously reported S, G as well as a new unclassified subtype. A detailed analysis of gene encoding the Spike (S) protein in the strains across the globe shows non-synonymous mutations on 54 amino acid residues. Among these, we pinpoint 4 novel mutations in the region that interacts with human ACE2 receptor (RBD). Further in silico molecular docking analyses suggest that these RBD mutations could alter the binding affinity of S-protein with ACE2 that may lead to changes in SARS-CoV-2 infectivity. Strikingly, one of these RBD mutations (S438F) is unique to a subset within the R4 clade suggesting intrinsic S-protein variations in strains currently circulating in India. Together, our findings reveal a unique pattern of SARS-CoV-2 evolution that may alert vaccine and therapeutic development.
Predicting the activation of the androgen receptor by mixtures of ligands using Generalized Concentration Addition

Concentration/dose addition (CA) is widely used for compounds that act by similar mechanisms. But, CA cannot make predictions for mixtures of full and partial agonists for effect levels above that of the least efficacious component. As partial agonists are common, we developed Generalized Concentration Addition (GCA), which has been successfully applied to systems in which ligands compete for a single binding site. Here, we applied a pharmacodynamic model for a system with two binding sites, the androgen receptor (AR). AR acts according to the classic homodimer activation model: each cytoplasmic AR protein binds ligand, undergoes a conformational change that relieves inhibition of dimerization, and binds to DNA response elements as a dimer. We generated individual dose-response data for full (dihydroxytestosterone, BMS564929) and partial (TFM-4AS-1) agonists and a competitive antagonist (MDV3100) using reporter data generated in the MDA-kb2 cell line. We used the Schild method to estimate the binding affinity of AR for MDV3100. Data for individual compounds fit the AR pharmacodynamic model well. The partial agonist had agonistic effects at low effect levels and antagonistic effects at high levels, as predicted by pharmacological theory. The GCA model fit the empirical mixtures data—full/full agonist, full/partial agonist and full agonist/antagonist—as well or better than relative potency factors (a special case of CA) or effect summation. The ability of generalized concentration addition to predict the activity of mixtures of different types of androgen receptor ligands is important as a number of environmental compounds act as partial AR agonists or antagonists.
Programmatic access to bacterial regulatory networks with regutools

Summary RegulonDB has collected, harmonized and centralized data from hundreds of experiments for nearly two decades and is considered a point of reference for transcriptional regulation in Escherichia coli K12. Here, we present the regutools R package to facilitate programmatic access to RegulonDB data in computational biology. regutools gives researchers the possibility of writing reproducible workflows with automated queries to RegulonDB. The regutools package serves as a bridge between RegulonDB data and the Bioconductor ecosystem by reusing the data structures and statistical methods powered by other Bioconductor packages. We demonstrate the integration of regutools with Bioconductor by analyzing transcription factor DNA binding sites and transcriptional regulatory networks from RegulonDB. We anticipate that regutools will serve as a useful building block in our progress to further our understanding of gene regulatory networks. Availability and Implementation regutools is an R package available through Bioconductor at bioconductor.org/packages/regutools. Contact github.com/ComunidadBioInfo/regutools, lcolladotor@gmail.com, alejandro.reyes. ds@gmail.com.
Polyamine-controlled proliferation and protein biosynthesis are independent determinants of hair follicle stem cell fate

Stem cell differentiation is accompanied by an increase in mRNA translation. The rate of protein biosynthesis is influenced by the polyamines putrescine, spermidine, and spermine that are essential for cell growth and stem cell maintenance. However, the role of polyamines as endogenous effectors of stem cell fate and whether they act through translational control remains obscure. Here, we investigated the function of polyamines in stem cell fate decisions using hair follicle stem cell (HFSC) organoids. HFSCs showed lower translation rates than progenitor cells, and a forced suppression of translation by direct targeting of the ribosome or through specific depletion of natural polyamines elevated stemness. In addition, we identified N1-acetylspermidine as a novel parallel regulator of cell fate decisions, increasing proliferation without reducing translation. Overall, this study delineates the diverse routes of polyamine metabolism-mediated regulation of stem cell fate decisions. Key Points Low mRNA translation rates characterize hair follicle stem cell (HFSC) state Depletion of natural polyamines enriches HFSCs via reduced translation N1-acetylspermidine promotes HFSC state without reducing translation N1-acetylspermidine expands the stem cell pool through elevated proliferation