Miracle-dz/UniFAR-FTUs huggingface dataset:
Cortical inhibitory network selects cerebellar signals for movement initiation

The onset of voluntary movements is driven by coordinated firing across a large population of motor cortical neurons. This pattern of activity is determined by both local interactions and long-range corticocortical and subcortical inputs. The way remote areas of the brain communicate to effectively drive movement is still unclear. We addressed this question by studying an important pathway through which the cerebellum communicates, via the motor thalamus, with the motor cortex. We found that similar to the sensory cortices, thalamic input to the motor cortex triggers feedforward inhibition by directly contacting inhibitory cells via particularly effective GluR2- lacking AMPA receptors blocked by NASPM. Based on these results, we constructed a classifier for SCP-responsive cortical cells to identify pyramidal and PV interneurons and study their role in controlling movements. The findings indicate that PV and pyramidal cells are co-driven by TC input in response to activation of the CTC pathway. During task performance, PV and pyramidal cells had comparable relations to movement parameters (directional tuning and movement duration). However, PV interneurons exhibited stronger movement-related activity that preceded the firing of pyramidal cells. This seemingly counterintuitive sequence of events where inhibitory cells are recruited more strongly and before excitatory cells may in fact enhance the signal-to-noise ratio of cerebellar signals by suppressing other inputs and prioritizing the excitatory synchronized volley from the TC system which occurs at the right time to overcome the inhibitory signal. In this manner, the CTC system can shape cortical activity in a way that exceeds its sheer synaptic efficacy.
Deforestation reduces the genetic structure of an epiphytic weed across space and time: an IBM approach

Deforestation has allowed the massive dispersal and reproduction of some plants that are commonly referred to as weeds. The rapid spread of many weeds into newly disturbed landscapes is often boosted by clonal growth and self-fertilization strategies, which conversely increases the spatial genetic structure (SGS) of populations and reduces the genetic diversity. Here, we use empirical and modeling approaches to evaluate the spatio-temporal SGS dynamics of Tillandsia recurvata (L.) L. , a common epiphytic weed with selfing reproduction and clonal growth widespread in dry forests and anthropically deforested landscapes in North and South America. We constructed an individual-based model (IBM) and adjusted the parameters according to empirical genetic data, to simulate the spreading of T. recurvata over time and across random landscapes with distinct tree densities. From empirical data, we observed a strong SGS among T. recurvata subpopulations hosted on neighbor trees and a contemporary spread from several population sources. Our model shows that the highest SGS appear in landscapes with more than 200 trees/ha and up to the 5th year of colonization of open landscapes (ca. 100 trees/ha) when SGS starts to reduce drastically. These results suggest that the deforestation commonly observed in anthropically transformed landscapes may reduce the dispersal limitation and genetic structure of T. recurvata subpopulations, creating suitable conditions for the rapid spread of T. recurvata from multiple surrounding sources. The combination of clonal growth and self-fertilization with the optimal conditions created by anthropogenic transformations may explain the spreading success of T. recurvata and other weeds into new landscapes. Our results indicate that the drastic reductions in tree densities induced by human-modifications in natural landscapes may lead to a partial loss of resistance for dispersal by wind and increased the conditions for T. recurvata to develop massive populations in anthropogenic landscapes.
Population and species diversity at mouse centromere satellites

Centromeres are satellite-rich chromatin domains that are essential for chromosome segregation. Centromere satellites evolve rapidly between species but little is known about population-level diversity across these loci. We developed a k-mer based method to quantify centromere copy number and sequence variation from whole genome sequencing data. We applied this method to diverse inbred and wild house mouse (genus Mus) genomes and uncover pronounced variation in centromere architecture between strains and populations. We show that patterns of centromere diversity do not mirror the known ancestry of inbred strains, revealing a remarkably rapid rate of centromere sequence evolution. We document increased satellite homogeneity and copy number in inbred compared to wild mice, suggesting that inbreeding remodels mouse centromere architecture. Our results highlight the power of k-mer based approaches for probing variation across repetitive regions and provide the first in-depth, phylogenetic portrait of centromere variation across Mus musculus.
Hierarchical Bayesian Models of Reinforcement Learning: Introduction and comparison to alternative methods

Reinforcement learning models have been used extensively and with great success to capture learning and decision-making processes in humans and other organisms. One essential goal of these computational models is generalization to new sets of observations. Extracting parameters that can reliably predict out-of-sample data can be difficult, however: reinforcement learning models often face problems of non-identifiability, which can lead to poor predictive accuracy. The use of prior distributions to regularize parameter estimates can be an effective way to remedy this issue. While previous research has suggested that empirical priors estimated from a separate dataset improve identifiability and predictive accuracy, this paper outlines an alternate method for the derivation of empirical priors: hierarchical Bayesian modeling. We provide a detailed introduction to this method, and show that using hierarchical models to simultaneously extract and impose empirical priors leads to better out-of-sample prediction while being more data efficient.
Neighborhood environment, social cohesion, and epigenetic aging

Living in adverse neighborhood environments have been linked to increased risk of aging-related diseases and mortality; however, the biological mechanisms explaining this observation remain poorly understood. DNA methylation (DNAm), a proposed biomarker of biological aging responsive to environmental stressors, offers promising insight into molecular pathways. We examined associations of three measures of neighborhood conditions (poverty, quality, and social cohesion) with three different epigenetic clocks (Horvath, Hannum, and Levine) using data from the Detroit Neighborhood Health Study (n=158). Using linear regression models, we evaluated associations in the total sample and stratified by gender and social cohesion. Differential effects by gender were found between men and women. Neighborhood poverty was associated with PhenoAge acceleration among women, but not among men (women: β = 1.4; 95% CI: −0.4, 3.3 vs. men: β = −0.3; 95% CI: −2.2, 1.5) in fully adjusted models. In models stratified on social cohesion, association of neighborhood poverty and quality with accelerated DNAm aging remained elevated for residents living in neighborhoods with lower social cohesion, but were null for those living in neighborhoods with higher social cohesion. Our study suggests that living in adverse neighborhood conditions can speed up epigenetic aging, while positive neighborhood characteristics may buffer effects.
Septate junction proteins are required for egg elongation and border cell migration during oogenesis in Drosophila

Protein components of the invertebrate occluding junction - known as the septate junction (SJ) - are required for morphogenetic developmental events during embryogenesis in Drosophila melanogaster. In order to determine whether SJ proteins are similarly required for morphogenesis during other developmental stages, we investigated the localization and requirement of four representative SJ proteins during oogenesis: Contactin, Macroglobulin complement-related, Neurexin IV, and Coracle. A number of morphogenetic processes occur during oogenesis, including egg elongation, formation of dorsal appendages, and border cell migration. We found that all four SJ proteins are expressed in the egg throughout oogenesis, with the highest and most sustained levels in the follicular epithelium (FE). In the FE, SJ proteins localize along the lateral membrane during early and mid-oogenesis, but become enriched in an apical-lateral domain (the presumptive SJ) by stage 10b. SJ protein relocalization requires the expression of other SJ proteins, as well as rab5 and rab11 in a manner similar to SJ biogenesis in the embryo. Knocking down the expression of these SJ proteins in follicle cells throughout oogenesis results in egg elongation defects and abnormal dorsal appendages. Similarly, reducing the expression of SJ genes in the border cell cluster results in border cell migration defects. Together, these results demonstrate an essential requirement for SJ genes in morphogenesis during oogenesis, and suggests that SJ proteins may have conserved functions in epithelial morphogenesis across developmental stages. Article Summary Septate junction (SJ) proteins are essential for forming an occluding junction in epithelial tissues of Drosophila melanogaster. SJ proteins are also required for morphogenetic events during embryogenesis prior to the formation of an occluding junction. To determine if SJ proteins function in morphogenesis at other developmental stages, we examined their function during oogenesis, and found that SJ proteins are expressed in the follicular epithelium of the egg chamber and are required for egg elongation, dorsal appendages formation, and border cell migration. Additionally, we found that the formation of SJs in oogenesis is similar to that in embryonic epithelia.
The cowboy effect: robot gaze influences human decisions

In most everyday life situations, the brain needs to engage not only in making decisions, but also in anticipating and predicting the behavior of others. In such contexts, gaze can be highly informative about others’ intentions, goals and upcoming decisions. Here, we investigated whether a humanoid robot’s gaze (mutual or averted) influences the way people strategically reason in a social decisionmaking context. Specifically, participants played a strategic game with the robot iCub while we measured their behavior and neural (EEG) activity. Participants were slower to respond when iCub established mutual gaze prior to their decision, relative to averted gaze. This was associated with a higher decision threshold in the drift diffusion model and accompanied by more synchronized EEG alpha activity. In addition, we found that participants reasoned about the robot’s actions in both conditions. However, those who mostly experienced the averted gaze were more likely to adopt a self-oriented strategy and their neural activity showed higher sensitivity to outcome. Altogether, these findings suggest that robot gaze acts as a strong social signal for humans, modulating response times, decision threshold, neural synchronization, as well as choice strategies and sensitivity outcomes. This has strong implications for all contexts involving human-robot interaction, from robotics to clinical applications.
Hairy cell leukemia: A clinicopathological study of 18 cases

Introduction: Hairy cell leukemia (HCL) is an uncommon chronic B-cell lymphoproliferative disorder. It affects primarily elderly men and presents with splenomegaly, pancytopenia and monocytopenia. It has to be differentiated from various chronic lymphoproliferative disorders (CLPDs) because of different protocol of treatment and clinical course. Methods: This study included 18 cases of HCL out of 300casesof CLPDs diagnosed over a period of 4 years (2009-2012) at tertiary cancer centre. All 18 cases were evaluated for clinical history, signs and symptoms, laboratory data, all initial and follow up peripheral blood smear (PBS) examinations, bone marrow aspirate (BMA) with imprint smear, bone marrow biopsy, immunophenotyping data, treatment details and response to treatment from medical records. Results: This study included 18 cases, age group of 35-69 years, with a median age of 40years and male predominance. M:F ratio was 6:1. HCL was 6% out of allCLPDs. Patients were presented with common complaints of weakness, fever and abdominal pain. On clinical examination, commonest findings were pallor, splenomegaly, hepatomegaly and abdominal lump. On laboratory investigations, 17 cases had anemia, 4 cases had leucocytosis, 11 cases had leucopenia and 11 cases had pancytopenia. On bone marrow biopsy,findings were diffuse infiltration of the marrow by atypical lymphoid cells having abundant cytoplasm. For immunophenotyping all patients` blood samples were CD19 gated on lymphocytes. It showed co expression of CD103, CD11c and CD25. Thirteen patients were treated with cladribine based chemotherapy with excellent responses. Conclusion: HCL clinically presents with pancytopenia and splenomegaly in middle aged male but few patient can present with unusual clinical features like absence of a palpable spleen, generalized lymphadenopathy and leucocytosis.
Genetic characterization of a mild isolate of papaya ringspot virus type-P (PRSV-P) and assessment of its cross-protection potential under greenhouse and field conditions

A mild isolate of Papaya ringspot virus type-P, abbreviated as PRSV-mild, from Ecuador was sequenced and characterized. The most distinguishing symptom induced by PRSV-mild was gray powder-like leaf spots radiating from secondary veins. In greenhouse experiments, PRSV-mild did not confer durable protection against a severe isolate of the virus (PRSV-sev), obtained from the same field. Furthermore, isolate specific detection in cross-protected plants showed that PRSV-sev becomes dominant in infections, rendering PRSV-mild undetectable at 90 - 120 days post superinfection. Virus testing using isolate-specific primers detected PRSV-mild in two out of five surveyed provinces, with 10% and 48% of incidence in Santo Domingo and Los Ríos, respectively. Comparative genomics showed that PRSV-mild lacks two amino acids from the coat protein region, whereas amino acid determinants for asymptomatic phenotypes were not identified. Recombination events were not predicted in the genomes of the Ecuadorean isolates. Phylogenetic analyses placed both PRSV-mild and PRSV-sev in a clade that includes an additional PRSV isolate from Ecuador and others from South America.
Multi-omic Single-cell Atlas Reveals Broad Ex Vivo Effects on Human Immunobiology

Multi-omic profiling of human peripheral blood is increasingly utilized to identify biomarkers and pathophysiologic mechanisms of disease. The importance of these platforms in clinical and translational studies led us to investigate the impact of delayed blood processing on the numbers and state of peripheral blood mononuclear cells (PBMC) and on the plasma proteome. Similar to previous studies, we show minimal effects of delayed processing on the numbers and general phenotype of PBMCs up to 18 hours. In contrast, profound changes in the single-cell transcriptome and composition of the plasma proteome become evident as early as 6 hours after blood draw. These reflect patterns of cellular activation across diverse cell types that lead to progressive distancing of the gene expression state and plasma proteome from native in vivo biology. Differences accumulating during an overnight rest (18 hours) could confound relevant biologic variance related to many underlying disease states.
Deletion of Histone Methyltransferase G9a Suppresses Mutant Kras-driven Pancreatic Carcinogenesis

Background/Aim: The entire mechanisms by which epigenetic modifiers contribute to the development of pancreatic cancer remain unknown. Although the histone methyltransferase G9a is a promising target in human cancers, its role in pancreatic carcinogenesis has been under-studied. The aim of the study was to examine the role of G9a in pancreatic carcinogenesis by a gene-targeting mouse model. Materials and Methods: We established pancreas-specific G9aflox/flox mice and crossed them with Ptf1aCre/; KrasG12D/+ (KC) mice, which spontaneously develop pancreatic cancer. The phenotypes of the resulting KC mice with G9a deletion were examined. We analyzed transcriptomic data by microarray and genome-wide chromatin accessibility by transposase-accessible chromatin using sequencing. We established pancreatic organoids from KC mice. Results: G9a deficiency impaired the progression of pancreatic intraepithelial neoplasia (PanIN) and prolonged the survival of KC mice. The number of phosphorylated Erk-positive cells and Dclk1-positive cells, which are reported to be essential for the progression of PanIN, were decreased by G9a deletion. UNC0638, an inhibitor of G9a, suppressed the growth of organoids and increased global chromatin accessibility, especially around the regions including the protein phosphatase 2A genes. Conclusion: Thus, our study suggested the functional interaction of G9a, Dclk1 and Mapk pathway in the Kras-driven pancreatic carcinogenesis. The inhibition of G9a may suppress the initiation of oncogenic Kras-driven pancreatic carcinogenesis.
Nile Red and 2-NBDG Are Incompatible for the Simultaneous Detection of Lipid and Glucose Accumulation

Glucose is the universal energy source and a critical substrate for lipid synthesis in mammalian cells. Analysis of both glucose and lipid in cells is important for the understanding of the regulation of lipid synthesis in many cell types, but especially adipocytes, the major storage cell for fat in mammals. The fluorescent 7-nitrobenz-2-oxa-1,3-diazole (NBD) derivative of glucose, 2-NBDG, is used to monitor glucose uptake and the lipid-selective fluorophore Nile red is used to monitor lipid accumulation. Previous reports have used NBD-based fluorophores and Nile red simultaneously despite the possibility of spectral overlap. In this study, we determined if these fluorophores were experimentally compatible in preadipocytes and adipocytes stained with 2-NBDG and Nile red separately or costained. We found that Nile red is detectable in the wavelengths necessary to excite and detect 2-NBDG. This interference was further increased by the solvatochromic effect of lipid-localized Nile red. In addition, we found a synergistic increase in fluorescent intensity when both fluorophores were present. Unfortunately, even fine control of the excitation or emission wavelengths did not identify wavelengths suitable for selective detection when cells were costained. Therefore, 2-NBDG and Nile red cannot be used simultaneously—but can likely be used sequentially—to assess glucose uptake and lipid accumulation in lipid-laden cells.
Change in home language environment and English literacy achievement over time: A multi-group latent growth curve modeling investigation

In most studies investigating the educational outcomes of linguistically diverse students, variables that identify this population have been considered as static. In reality, owing to the dynamic nature of students and their families, students’ home language environments change over time. This study aims to understand how elementary school students’ home language environments change over time, and how longitudinal patterns of English literacy achievement across grades 3, 6, and 10 differ among students with various home language shift patterns in Ontario, Canada. The longitudinal cohort data of 89,609 students between grades 3 and 10 from the provincial assessments were analyzed for changes in their home language environment. A subsample of 18,000 students was used to examine different patterns of relative literacy performance over time and their associations with immigration background and early intervention programming using multi-group latent growth curve modeling. Our findings suggest a strong movement toward an English-dominant home language environment among multilingual students; yet, students whose homes remained as multilingual demonstrated the highest literacy achievement in the early grade as well as the highest improvement in relative performance over time. The paper draws implications for promoting students’ home language, instilling a positive view of multilingual competence.
Mice alternate between discrete strategies during perceptual decision-making

Classical models of perceptual decision-making assume that subjects use a single, consistent strategy to form decisions, or that strategies evolve slowly over time. Here we present new analyses suggesting that this common view is incorrect. We analyzed data from mouse and human decision-making experiments and found that choice behavior relies on an interplay between multiple interleaved strategies. These strategies, characterized by states in a hidden Markov model, persist for tens to hundreds of trials before switching, and may alternate multiple times within a session. The identified mouse decision-making strategies were highly consistent across individuals and comprised a single “engaged” state, in which decisions relied heavily on the sensory stimulus, and several biased states in which errors frequently occurred. These results provide a powerful alternate explanation for “lapses” often observed in rodent psychophysical experiments, and suggest that standard measures of performance mask the presence of dramatic changes in strategy across trials.
Unraveling the transcriptional networks that drive oligodendrocyte fate specification in Sonic hedgehog-responsive neocortical progenitors

In the developing nervous system, progenitors first generate neurons before making astrocytes and oligodendrocytes. We previously showed that increased Sonic hedgehog (Shh) signaling in dorsal forebrain progenitors is important for their production of oligodendrocytes as neurogenesis winds down. Here, we analyzed single-cell RNA sequencing datasets to better understand how Shh controls this neuron-to-oligodendrocyte switch in the neocortex. We first identified Shh-responding progenitors using a dataset in which Shh was overexpressed in the mouse dorsal forebrain. Pseudotime trajectory inferences revealed a subpopulation committed to the oligodendrocyte precursor cell (OPC) lineage. Genes upregulated along this lineage defined a pre-OPC state, as cells transitioned from progenitors to OPCs. Using several datasets from wild-type mouse and human embryos at different ages, we confirmed a pre-OPC state preceding OPC emergence during normal development. Finally, we show that pre-OPCs are enriched for a gene regulatory network involving the transcription factor Ascl1. Genetic lineage-tracing demonstrated Ascl1+ dorsal progenitors primarily make oligodendrocytes. We propose a model in which Shh shifts the balance between opposing transcriptional networks toward an Ascl1 lineage, thereby facilitating the switch between neurogenesis and oligodendrogenesis.