Miracle-dz/UniFAR-FTUs huggingface dataset:
Maladaptive cue-controlled cocaine-seeking habits promote increased relapse severity in rats

The inflexible pursuit of drug-seeking and great tendency to relapse that characterize addiction has been associated with the recruitment of the dorsolateral striatum-dependent habit system. However, the mechanisms by which maladaptive drug-seeking habits influence subsequent relapse are obscure. Here, we show that rats with a long history of cocaine-seeking, controlled by drug-paired cues and mediated by the habit system, show highly exacerbated drug-seeking at relapse that is not mediated by cocaine withdrawal. This heightened tendency to relapse is underpinned by transient engagement of the dorsomedial striatum goal-directed system and reflects emergent negative urgency resulting from the prevention of enacting the seeking habit during abstinence. These results reveal a novel mechanism underlying the pressure to relapse and indicate a target for preventing it. One Sentence Summary Instrumental deprivation triggers flexibility in the well-established cue-controlled cocaine-seeking behaviour.
Clearing spheroids for 3D fluorescent microscopy: combining safe and soft chemicals with deep convolutional neural network

In life sciences, there are increasing interest in 3D culture models to better reproduce the 3D environment encountered in-vivo. Imaging of such 3D culture models is instrumental for drug discovery, but face several issues before its use becomes widespread. Extensive microscopic investigation of these 3D cell models faces the challenge of light penetration in depth in opaque biological tissues. To overcome this limit, diverse clearing techniques have emerged over the past decades. However, it is not straightforward to choose the best clearing protocols, and assess quantitatively their clearing efficiency. Focusing on spheroids, we propose a combination of fast and cost-effective clearing procedure for such medium-sized samples. A generic method with local contrast metrics and deep convolutional neural network-based segmentation of nuclei is proposed to quantify the efficiency of clearing. We challenged this method by testing the possibility to transfer segmentation knowledge from a clearing protocol to another. The later results support the pertinence of training deep learning algorithms on cleared samples to further use the segmentation pipeline on non-cleared ones. This second step of the protocol gives access to digital clearing possibilities applicable to live and high-throughput optical imaging.
Nutrients and Ruminal Digestibility of Baby Corn By-product Silages under Different Harvesting Methods

Abstract The objective of this study was to determine nutrients and ruminal digestibility of silages from baby corn by-products. The experiment was assigned in Completely Randomized Design with 5 treatments and 4 replications. The treatments were silages under different harvesting method including baby corn stalks cut at 10, 40 and 70 cm height above ground, baby corn husk with and without silk. After 30 d ensiling, the silage samples were collected and analyzed for nutrients while ruminal digestibility was determined using Batch culture for 24 h incubation. Ruminal gas production was estimated in glass syringe for 24 h. The results showed that increasing in cutting height from 10 to 70 cm improved nutrients of silage by decreasing (P 0.05) NDF (72.38 and 71.93%DM), dry matter digestibility (44.79 and 45.25%DM), organic matter digestibility (42.26 and 43.36%). The methane gas production was the highest in the husk without silk silage whereas silages from different cutting stalks and silage from husk with silk produced a similar amount of the methane gas (7.25-8.0 ml/200mg; P>0.05). In conclusion, increase the stalk cutting height to 70 cm improved the silage quality by increasing nutrients and ruminal digestibility. Silage from baby corn husk with silk had higher nutrients and ruminal digestibility than baby corn stalk silages. Lowering dry matter loss of silage from baby corn husk with silk by reducing moisture prior to ensiling requires further investigation. Keywords : Baby corn stalk; Baby corn husk; Cutting height; Silage; Nutrient; Ruminal digestibility; Batch culture.
Improving sequence-based modeling of protein families using secondary-structure quality assessment

Motivation Modeling of protein family sequence distribution from homologous sequence data recently received considerable attention, in particular for structure and function predictions, as well as for protein design. In particular, Direct Coupling Analysis, a method to infer effective pairwise interactions between residues, was shown to capture important structural constraints and to successfully generate functional protein sequences. Building on this and other graphical models, we introduce a new framework to assess the quality of the secondary structures of the generated sequences with respect to reference structures for the family. Results We introduce two scoring functions characterizing the likeliness of the secondary structure of a protein sequence to match a reference structure, called Dot Product and Pattern Matching. We test these scores on published experimental protein mutagenesis and design dataset, and show improvement in the detection of non-functional sequences. We also show that use of these scores help rejecting non-functional sequences generated by graphical models (Restricted Boltzmann Machines) learned from homologous sequence alignments. Availability Supplementary Materials, Data and Code available at https://github.com/CyrilMa/ssqa. Contact cyril.malbranke@ens.fr
Cardiac fibroblast GSK-3α mediates adverse myocardial fibrosis via IL-11 and ERK pathway

Background Heart failure is the leading cause of mortality, morbidity, and healthcare expenditures worldwide. Numerous studies have implicated Glycogen Synthase Kinase-3 (GSK-3) as a promising therapeutic target for cardiovascular diseases. GSK-3 isoforms appear to play overlapping, unique, and even opposing functions in the heart. Recently our group has identified cardiac fibroblast (CF) GSK-3β as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of CF-GSK-3α in myocardial fibrosis is unknown. Methods and Results Herein, we employed two entirely novel conditional fibroblast-specific and tamoxifen-inducible mouse models to define the role of CF-GSK-3α in fibroblast activation and myocardial fibrosis. Specifically, GSK-3α was deleted from cardiac fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or periostin-promoter-driven Cre recombinase. At 2 months of age, WT and KO mice were subjected to cardiac injury, and heart functions were monitored by serial echocardiography. Histological analysis and morphometric studies were performed at 8 weeks post-injury. In both settings, GSK-3α deletion restricted fibrotic remodeling and improved cardiac function. To investigate underlying mechanisms, we examined the effect of GSK-3α deletion on myofibroblast transformation and pro-fibrotic TGFβ1-SMAD3 signaling in vitro. A significant reduction in cell migration, collagen gel contraction, and α-SMA expression in TGFβ1 treated GSK-3α KO MEFs confirmed that GSK-3α is required for myofibroblast transformation. Surprisingly, GSK-3α deletion did not affect SMAD3 activation, indicating the pro-fibrotic role of GSK-3α is SMAD3 independent. To further delineate the underlying mechanism, total proteins were isolated from CFs of WT and KO animals at 4 weeks post-injury, and kinome profiling was performed by utilizing PamStation®12 high throughput microarray platform. The kinome analysis identified the downregulation of RAF family kinase activity in GSK3α-KO-CFs. Moreover, mapping of significantly altered kinases against literature annotated interactions generated ERK-centric networks. Importantly, flow cytometric analysis of CFs confirmed a significant decrease in pERK levels in KO mice. Additionally, our in vitro studies demonstrated that GSK-3α deletion prevented TGFβ1 induced ERK activation thereby validating our findings from kinome analysis. Interestingly, IL-11, a fibroblast specific downstream effector of TGFβ1, was very low in GSK-3α KO MEFs as compared to WT and ERK inhibition further reduced IL-11 expression in them. All these results indicate that GSK-3α mediates pro-fibrotic response in the injured heart through IL-11 and ERK pathway. Conclusion CF-GSK-3α plays a causal role in myocardial fibrosis that could be therapeutically targeted for future clinical applications.
Superscatterer Illusions Without Using Complementary Media

Research has suggested that it is possible to create a superscatterer using complementary media, which is however very difficult to realize, and hence such a superscatterer has not been verified by experiments. An easier way to realize superscatterer illusions with abundant functionality based on transformation optics is proposed here, in which only anisotropic and inhomogeneous media with positive components are required. By enclosing a metallic object within the superscatterer illusion device, the scattering signature of the object equals that of an enlarged metallic object with a pre‐controlled scaling factor and multiple dielectric objects with pre‐designed material properties. The proposal is demonstrated by numerical simulations and finally verified by experiments of an elaborately designed proof‐of‐concept sample made of 6408 gradually varying meta‐atoms. A new strategy, combining compact electric‐ and magnetic‐resonance particles, is proposed to fulfill the complicated inhomogeneous and anisotropic material properties.
Isolation and Determination of Polymeric Polyphenols Using Sephadex LH-20 and Analysis of Grape Tissue Extracts

A simple chromatographic method using Sephadex LH-20 was developed to separate non-polymeric and polymeric phenols. Non-polymeric phenols are eluted from the gel by 60% methanol. A subsequent elution with 50% acetone enables quantitative recovery of polymeric phenols. The phenolic concentration in each fraction is then measured using the Folin Ciocalteu procedure. The method was used to measure concentrations of polymeric phenols in grape seed, skin, stem, and leaf tissue extracts. Seeds were found to contain the highest and most uniform concentrations of polymeric phenols. Stems and leaves contained similar concentrations of polymeric phenols. Skins contained the lowest and most variable concentrations of polymeric phenols. The Sephadex LH-20 method and HPLC peak area ratios gave very similar estimates of the percentage of polymeric phenols in tissue extracts. However, the former method enables isolation and quantitative analysis of polymeric phenols. Thus, the Sephadex procedure provides results that can be used in efforts to produce a "balance sheet" summary of all phenols present in grape extracts or wines.
Metabolic flux partitioning between the TCA cycle and glyoxylate shunt combined with a reversible methyl citrate cycle provide nutritional flexibility for Mycobacterium tuberculosis

The utilisation of multiple host-derived carbon substrates is required by Mycobacterium tuberculosis (Mtb) to successfully sustain a tuberculosis infection thereby identifying the Mtb specific metabolic pathways and enzymes required for carbon co-metabolism as potential drug targets. Metabolic flux represents the final integrative outcome of many different levels of cellular regulation that contribute to the flow of metabolites through the metabolic network. It is therefore critical that we have an in-depth understanding of the rewiring of metabolic fluxes in different conditions. Here, we employed 13C-metabolic flux analysis using stable isotope tracers (13C and 2H) and lipid fingerprinting to investigate the metabolic network of Mtb growing slowly on physiologically relevant carbon sources in a steady state chemostat. We demonstrate that Mtb is able to efficiently co-metabolise combinations of either cholesterol or glycerol along with C2 generating carbon substrates. The uniform assimilation of the carbon sources by Mtb throughout the network indicated no compartmentalization of metabolism in these conditions however there were substrate specific differences in metabolic fluxes. This work identified that partitioning of flux between the TCA cycle and the glyoxylate shunt combined with a reversible methyl citrate cycle as the critical metabolic nodes which underlie the nutritional flexibility of Mtb. These findings provide new insights into the metabolic architecture that affords adaptability of Mtb to divergent carbon substrates. Importance Each year more than 1 million people die of tuberculosis (TB). Many more are infected but successfully diagnosed and treated with antibiotics, however antibiotic-resistant TB isolates are becoming ever more prevalent and so novel therapies are urgently needed that can effectively kill the causative agent. Mtb specific metabolic pathways have been identified as an important drug target in TB. However the apparent metabolic plasticity of this pathogen presents a major obstacle to efficient targeting of Mtb specific vulnerabilities and therefore it is critical to define the metabolic fluxes that Mtb utilises in different conditions. Here, we used 13C-metabolic flux analysis to measure the metabolic fluxes that Mtb uses whilst growing on potential in vivo nutrients. Our analysis identified selective use of the metabolic network that included the TCA cycle, glyoxylate shunt and methyl citrate cycle. The metabolic flux phenotypes determined in this study improves our understanding about the co-metabolism of multiple carbon substrates by Mtb identifying a reversible methyl citrate cycle and the glyoxylate shunt as the critical metabolic nodes which underlie the nutritional flexibility of Mtb.
Gypenosides modulate NCX calcium flux, insulin secretion and cytoprotection in BRIN-BD11 pancreatic β-cells

Gypenosides are saponins extracted from the plant Gynostemma pentaphyllum, suggested to have antidiabetic and anti-obesity potential. However, its mechanism of action is not fully understood. The present study aimed to investigate the cytoprotective and insulin stimulatory effects of gypenosides using the rat BRIN-BD11 β-cell line. Gypenosides provided a significant cytoprotective effect against palmitate-, peroxide- and cytokine-induced cytotoxicity, with upregulation of antioxidant genes Nrf2, Cat, Sod1, and Gpx1. Acutely, gypenosides enhanced intracellular calcium ([Ca2+]i) and insulin secretion in a dose-dependent manner. The presence of the sodium/calcium exchanger (NCX) reverse mode inhibitor SN-6 blocked the gypenosides mediated increase in [Ca2+]I but not the insulin secretion. These findings indicate that gypenosides may enhance [Ca2+]i by activating the reverse mode of NCX channels and a possible calcium-independent mechanism involved in their insulin secretion. Gypenosides also upregulate the antioxidant gene expression and protect against oxidative stress and lipotoxicity, providing the rationale for their observed antidiabetic actions.
ChIPflow: from raw data to epigenomic dynamics

We present ChIPflow, a Snakemake-based pipeline for epigenomic data from the raw fastq files to the differential analysis. It can be applied to any chromatin factor, e.g. histone modification or transcription factor, which can be profiled with ChIP-seq. ChIPflow streamlines critical steps like the quality assessment of the immunoprecipitation using cross-correlation and the replicate comparison for both narrow and broad peaks. For the differential analysis ChIPflow provides linear and nonlinear methods for normalisation between samples as well as conservative and stringent models for estimating the variance and testing the significance of the observed binding/marking differences. ChIPflow can process in parallel multiple chromatin factors with different experimental designs, number of biological replicates and/or conditions. It also facilitates the specific parametrisation of each dataset allowing both narrow or broad peak calling, as well as comparisons between the conditions using multiple statistical settings. Finally, complete reports are produced at the end of the bioinformatic and the statistical part of the analysis, which facilitate the data quality control and the interpretation of the results. We explored the discriminative power of the statistical settings for the differential analysis, using a published dataset of three histone marks (H3K4me3, H3K27ac and H3K4me1) and two transcription factors (Oct4 and Klf4) profiled with ChIP-seq in two biological conditions (shControl and shUbc9). We show that distinct results are obtained depending on the sources of ChIP-seq variability and the dynamics of the chromatin factor under study. We propose that ChIPflow can be used to measure the richness of the epigenomic landscape underlying a biological process by identifying diverse regulatory regimes and the associated genes sets.
Input-Independent Homeostasis of Developing Thalamocortical Activity

Abstract The isocortex of all mammals studied to date shows a progressive increase in the amount and continuity of background activity during early development. In humans the transition from a discontinuous (mostly silent, intermittently bursting) cortex to one that is continuously active is complete soon after birth and is a critical prognostic indicator. In the visual cortex of rodents this switch from discontinuous to continuous background activity occurs during the 2 d before eye-opening, driven by activity changes in relay thalamus. The factors that regulate the timing of continuity development, which enables mature visual processing, are unknown. Here, we test the role of the retina, the primary input, in the development of continuous spontaneous activity in the visual cortex of mice using depth electrode recordings from enucleated mice in vivo. Bilateral enucleation at postnatal day (P)6, one week before the onset of continuous activity, acutely silences cortex, yet firing rates and early oscillations return to normal within 2 d and show a normal developmental trajectory through P12. Enucleated animals showed differences in silent period duration and continuity on P13 that resolved on P16, and an increase in low frequency power that did not. Our results show that the timing of cortical activity development is not determined by the major driving input to the system. Rather, even during a period of rapid increase in firing rates and continuity, neural activity in the visual cortex is under homeostatic control that is largely robust to the loss of the primary input.
A Model Study of the Enzyme-Catalyzed Cytosine Methylation Using ab Initio Quantum Mechanical and Density Functional Theory Calculations: pKa of the Cytosine N3 in the Intermediates and Transition States of the Reaction

The reaction mechanism of the DNA (cytosine-5)-methyltransferase-catalyzed cytosine methylation was investigated using ab initio quantum mechanical (at the MP2/6-31+G*//HF/6-31+G* and MP2/6-31+G*//HF/3-21+G* levels) and density functional theory calculations (Becke3LYP/6-31+G*) in the gas phase and in solution. The effects of aqueous solvation on the reaction energies were included by using an isodensity surface-polarized continuum model. The quantum mechanical model consisted of 1-methylcytosine (the model of the target cytosine), methylthiolate (the model of the side chain of the catalytic cysteine), and trimethylsulfonium (the model of the methyl-donating AdoMet). In addition, an approach is presented to estimate the pKa of the cytosine N3 in the reaction intermediates and transition states and on the calculated reaction profiles. The approach involves calculation of the gas-phase proton affinities and solvation energies of the neutral and protonated forms of the molecules using ab initio quantum mecha.
Twitter Sentimental Analysis & Algorithm Comparison for Uber & Ola Using ‘R’

Twitter is a social networking site where a large number of users are actively present. Data with hashtags are popular widely on twitter, hence twitter has large amounts of datasets where user tweet their reviews. These sentiments are used to understand what opinion do people have about a product or service through their tweets. The datasets used in this system for extracting tweets are ‘UBER & OLA’. We understand reviews of people towards different products or services which in turn gives business insights as to what changes can be done or incorporated. It also helps us in the analysis of market trends and monetization. In this paper, we propose two models for sentiment analysis based on Naïve Bayes and Support Vector Machine (SVM). Its purpose is to analyze sentiments more effectively. This system uses R-statistical programming language to generate outputs. Further, this paper represents the outputs in Word Cloud. The two classifier algorithms are machine learning algorithms in which we compare their overall accuracy, precision and recall values.
Comparative guest, thermal, and mechanical breathing of the porous metal organic framework MIL-53(Cr): A computational exploration supported by experiments

The breathing of the flexible metal organic framework MIL-53(Cr) has been widely explored by both experimental and modeling approaches upon the inclusion of different guest molecules within its porosity. This spectacular phenomenon has been only partially tackled by force field based simulations mainly due to the complexity of deriving a set of accurate potential parameters able to capture the associated structural transition implying a unit cell volume change up to 40%. Here, a new parametrization of a flexible force field for the MIL-53(Cr) framework is realized from an iterative procedure starting with the experimental structural data collected in the presence of CO2 as the guest molecule. Hybrid osmotic Monte Carlo simulations based on this refined force field are then successfully conducted to reproduce for the first time the complex shape of the CO2 adsorption isotherm in the whole range of pressures. The structural behavior of the MIL-53(Cr) under a wide range of applied temperature and pressure is.
SL2 quantum trace in quantum Teichmüller
theory via writhe

Quantization of Teichmuller space of a punctured Riemann surface $S$ is an approach to three dimensional quantum gravity, and is a prototypical example of quantization of cluster varieties. Any simple loop $\gamma$ in $S$ gives rise to a natural function $\mathbb{I}(\gamma)$ on the Teichmuller space, namely the trace of monodromy along $\gamma$. Per any choice of an ideal triangulation $\Delta$ of $S$, this function $\mathbb{I}(\gamma)$ is a Laurent polynomial in the square-roots of the exponentiated shear coordinates for the edges of $\Delta$. An important problem was to construct a quantization of this function $\mathbb{I}(\gamma)$, namely to replace it by a non-commutative Laurent polynomial in the quantum variables, so that the result does not depend on the choice of triangulation $\Delta$. This problem, which is closely related to the framed protected spin characters in physics, has been solved algebraically by Allegretti and Kim using Bonahon-Wong's ${\rm SL}_2$ quantum trace for skein algebras, and geometrically by Gabella using Gaiotto-Moore-Neitzke's Seiberg-Witten curves, spectral networks, and writhe of links. We show that these two solutions to the quantization problem coincide, while enhancing and modifying the latter one by Gabella.