Miracle-dz/UniFAR-FTUs huggingface dataset:
Current updates and future perspectives in the evaluation of azoospermia: A systematic review

ABSTRACT Objectives: To provide a summary of the current evaluation of azoospermia and insights into future perspectives in the evaluation and counselling of men with azoospermia. Methods: A search of PubMed, Cochrane Reviews and Web of Science databases was performed for full-text English-language articles published between 1943 and 2020 focussing on ‘future perspectives’, ‘azoospermia’ and ‘evaluation’. Results: Azoospermia represents a severe form of male infertility characterised by sperm production so impaired that there are no sperm present in the ejaculate. The current evaluation of azoospermia focusses on patient history and physical examination with selected adjunctive laboratory investigations including serum hormones, a karyotype and screening for Y chromosome microdeletions. Future diagnostics are focussed on identifying the underlying genetic aetiologies for azoospermia, as well as a greater emphasis on screening for systemic illness that men with severe infertility may be predisposed to develop. Conclusion: Azoospermia represents an extreme form of male infertility, and evaluation relies heavily on history and physical examination, as genetic evaluations for these individuals remain limited. Future evaluation will focus on next-generation sequencing and more rigorous evaluation for possible co-existing and future risk of systemic disease. ABBREVIATIONS: ADGRG2, adhesion G protein-coupled receptor G2; ASRM: American Society of Reproductive Medicine; AZF: azoospermia factor; CBAVD: congenital bilateral absence of the vas deferens; CFTR: cystic fibrosis transmembrane conductance regulator; CRKL: CRK-like proto-oncogene; E2F1: E2F transcription factor 1; HAUS7: HAUS augmin-like complex subunit 7; HR: hazard ratio; KS: Klinefelter syndrome; MAZ, MYC-associated zinc finger protein; NGS: next-generation sequencing; NOA: non-obstructive azoospermia; OA: obstructive azoospermia; RHOX: reproductive homeobox on the X chromosome; SH2: SRC homology 2; TAF7L: TATA-box binding protein associated factor 7-like; TEX11: testis-expressed 11; WES: whole-exome sequencing
Winter wheat planting area extraction using SAR change detection

ABSTRACT With its all-day and all-weather imaging capability, Synthetic Aperture Radar (SAR) has shown great potential in crop identification. This letter puts forward a novel method of extracting winter wheat planting area by means of SAR change detection. Based on the phenological differences between winter wheat and other crops, the Difference Image (DI) is generated firstly by the different temporal SAR images. Then, Object Markov Random Field (OMRF) model is used to DI pre-classification. Finally, Convolutional Neural Network (CNN) is utilized to obtain the better area extraction result of winter wheat. The area extraction accuracy is proved by the field survey data, with an accuracy of 90.53%. This research can provide a new idea and method for agricultural remote sensing monitoring.
Formulation Design Development and Evaluation of Extended Release Matrix Tablets of Trimetazidine Hydrochloride.

Oral route of drug administration is oldest and safest mode of drug administration. It posses several advantages. It does not possess the sterility problem and minimal risk of damage at the site of administration. It provides accurate dosing without assistantship of administration. In conventional oral drug delivery system, there is little or no control over release of drug, and effective concentration at the target site can be achieved by administration of grossly excessive dosage form. This kind of dosing pattern result in constantly changing, unpredictable and often sub or supra therapeutic plasma concentration, leading to marked side effects in some cases. Moreover, the rate and extent of absorption from conventional formulation may vary greatly, depending on factor such as physiochemical properties of drug, presence of excipients, various physiological factors such as presence or absence of food, pH of gastrointestinal tract, G.I. motility etc. Stability study was conducted on tablets of Batch F9 stored at 300C (Room Temperature) and 400C for one month. Tablets were evaluated for hardness, friability, invitro release profile and drug content. After one month no significant changes were observed in any of the studied parameters during the study period, thus it could be concluded that formulation was stable. It was concluded that the tablets of batch F9 had considerable swelling behaviors and in vitro drug release. Percentage drug release in 8 hr is 80.77. It was observed that tablets of batch F9 followed the Huguchi release profiles. From the above results and discussion it is concluded that formulation of Extended release matrix tablet of Trimetazidine HCL containing HPMC K-15 (19.44%) and Hypermellose (19.44%), Ethyl cellulose (19.44%) batch F9 can be taken as an ideal or optimized formulation Extended release matrix tablet for 8 hour release as it fulfills the requirements for extended release matrix tablet.
An insight on established retinal injury mechanisms and prevalent retinal stem cell activation pathways in vertebrate models

Implementing different tools and injury mechanisms in multiple animal models of retina regeneration, researchers have discovered the existence of retinal stem/progenitor cells. Although they appear to be distributed uniformly across the vertebrate lineage, the reparative potential of the retina is mainly restricted to lower vertebrates. Regenerative repair post‐injury requires the creation of a proliferative niche, vital for proper stem cell activation, propagation, and lineage differentiation. This seems to be lacking in mammals. Hence, in this review, we first discuss the many forms of retinal injuries that have been generated using animal models. Next, we discuss how they are utilized to stimulate regeneration and mimic eye disease pathologies. The key to driving stem cell activation in mammals relies on the information we can gather from these models. Lastly, we present a brief update about the genes, growth factors, and signaling pathways that have been brought to light using these models.
Resilience through diversity: Lost neuronal heterogeneity in human epilepsy renders networks vulnerable to synchronous transitions

Scott Richa,1, Homeira Moradi Chameha, Jeremie Lefebvrea,b,c,2, and Taufik A Valiantea,d,e,f,g,2 aKrembil Research Institute, University Health Network (UHN), Division of Clinical and Computational Neuroscience, Toronto, Ontario, Canada; bUniversity of Ottawa, Department of Biology, Ottawa, Ontario, Canada; cUniversity of Toronto, Department of Mathematics, Toronto, Ontario, Canada; dUniversity of Toronto, Institute of Biomedical Engineering, Toronto, ON, Canada; eUniversity of Toronto, Electrical and Computer Engineering, Toronto, ON, Canada; fUniversity of Toronto, Institute of Medical Science, Toronto, ON, Canada; gUniversity of Toronto, Division of Neurosurgery, Department of Surgery, Toronto, ON, Canada
Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis

DNA Methyltransferase 3A (DNMT3A) is an important facilitator of differentiation of both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity and excessive height. While DNMT3A is known to impact feeding behavior via the hypothalamus, here we investigated a role in adipocyte progenitors utilizing heterozygous knockout mice that recapitulate cardinal TBRS phenotypes. These mice become morbidly obese due to adipocyte enlargement and tissue expansion. Adipose tissue in these mice exhibited defects in preadipocyte maturation and precocious activation of inflammatory gene networks, including interleukin-6 signaling. Adipocyte progenitor cell lines lacking DNMT3A exhibited aberrant differentiation. Furthermore, mice in which Dnmt3a was specifically ablated in adipocyte progenitors showed enlarged fat depots and increased progenitor numbers, partly recapitulating the TBRS obesity phenotypes. Loss of DNMT3A led to constitutive DNA hypomethylation, such that the DNA methylation landscape of young adipocyte progenitors resemble that of older wild-type mice. Together, our results demonstrate that DNMT3A coordinates both the central and local control of energy storage required to maintain normal weight and prevent inflammatory obesity.
The RNA-binding protein DRBD18 regulates processing and export of the mRNA encoding Trypanosoma brucei RNA-binding protein 10

The parasite Trypanosoma brucei grows as bloodstream forms in mammalian hosts, and as procyclic forms in tsetse flies. Trypanosome protein coding genes are arranged in polycistronic transcription units, so gene expression regulation depends heavily on post-transcriptional mechanisms. The essential RNA-binding protein RBP10 is expressed only in mammalian-infective forms, where it targets procyclic-specific mRNAs for destruction. We show that developmental regulation of RBP10 expression is mediated by the exceptionally long 7.3 Kb 3’-UTR of its mRNA. Different regulatory sequences that can independently enhance mRNA stability and translation in bloodstream forms, or destabilize and repress translation in procyclic forms, are scattered throughout the 3’-UTR. The RNA-binding protein DRBD18 is implicated in the export of a subset of mRNAs from the nucleus in procyclic forms. We confirmed that in bloodstream forms, DRBD18 copurifies the outer ring of the nuclear pore, mRNA export proteins and exon junction complex proteins. Loss of DRBD18 in bloodstream forms caused accumulation of several shortened RBP10 mRNA isoforms, with loss of longer species, but RNAi targeting the essential export factor MEX67 did not cause such changes, demonstrating specificity. Long RBP10 mRNAs accumulated in the nucleus, while shorter ones reached the cytoplasm. We suggest that DRBD18 binds to processing signals in the RBP10 3’-UTR, simultaneously preventing their use and recruiting mRNA export factors. DRBD18 depletion caused truncation of the 3’-UTRs of more than 100 other mRNAs, suggesting that it has an important role in regulating use of alternative processing sites.
Physiological noise optimizes multiplexed coding of vibrotactile-like signals in somatosensory cortex

Neurons can use different aspects of their spiking to simultaneously represent (multiplex) different features of a stimulus. For example, some pyramidal neurons in primary somatosensory cortex (S1) use the rate and timing of their spikes to respectively encode the intensity and frequency of vibrotactile stimuli. Doing so has several requirements. Because they fire at low rates, pyramidal neurons cannot entrain 1:1 with high-frequency (100-600 Hz) inputs and instead must skip (i.e. not respond to) some stimulus cycles. The proportion of skipped cycles must vary inversely with stimulus intensity for firing rate to encode stimulus intensity. Spikes must phase lock to the stimulus for spike times (intervals) to encode stimulus frequency but, in addition, skipping must occur irregularly to avoid aliasing. Using simulations and in vitro experiments in which S1 pyramidal neurons were stimulated with inputs emulating those induced by vibrotactile stimuli, we show that fewer cycles are skipped as stimulus intensity increases, as required for rate coding, and that physiological noise induces irregular skipping without disrupting phase locking, as required for temporal coding. This occurs because the reliability and precision of spikes evoked by small- amplitude, fast-onset signals are differentially sensitive to noise. Simulations confirmed that differences in stimulus intensity and frequency can be well discriminated based on differences in spike rate or timing, respectively, but only in the presence of noise. Our results show that multiplexed coding by S1 pyramidal neurons is facilitated rather than degraded by physiological levels of noise. In fact, multiplexing is optimal under physiologically noisy conditions.
Enhanced specificity mutations perturb allosteric signaling in CRISPR-Cas9

CRISPR-Cas9 is a molecular tool with transformative genome editing capabilities. At the molecular level, an intricate allosteric signaling is critical for DNA cleavage, but its role in the specificity enhancement of the Cas9 endonuclease is poorly understood. Here, solution NMR is combined with multi-microsecond molecular dynamics and graph theory-derived models to probe the allosteric role of key enhancement specificity mutations. We show that the mutations responsible for increasing the specificity of Cas9 alter the allosteric structure of the catalytic HNH domain, impacting the signal transmission from the DNA recognition region to the catalytic sites for cleavage. Specifically, the K855A mutation strongly disrupts the HNH domain allosteric structure, exerting the highest perturbation on the signaling transfer, while K810A and K848A result in more moderate effects on the allosteric intercommunication. This differential perturbation of the allosteric signaling reflects the different capabilities of the single mutants to increase Cas9 specificity, with the mutation achieving the highest specificity also strongly perturbing the signaling transfer. These outcomes reveal that the allosteric regulation is critical for the specificity enhancement of the Cas9 enzyme, and are valuable to harness the signaling network to improve the system’s specificity.
Brain stimulation boosts perceptual learning by altering sensory GABAergic plasticity and functional connectivity

Interpreting cluttered scenes —a key skill for successfully interacting with our environment— relies on our ability to select relevant sensory signals while filtering out noise. Training is known to improve our ability to make these perceptual judgements by altering local processing in sensory brain areas. Yet, the brain-wide network mechanisms that mediate our ability for perceptual learning remain largely unknown. Here, we combine transcranial direct current stimulation (tDCS) with multi-modal brain measures to modulate cortical excitability during training on a signal-in-noise task (i.e. detection of visual patterns in noise) and test directly the link between processing in visual cortex and its interactions with decision-related areas (i.e. posterior parietal cortex). We test whether brain stimulation alters inhibitory processing in visual cortex, as measured by magnetic resonance spectroscopy (MRS) of GABA and functional connectivity between visual and posterior parietal cortex, as measured by resting state functional magnetic resonance imaging (rs-fMRI). We show that anodal tDCS during training results in faster learning and decreased GABA+ during training, before these changes occur for training without stimulation (i.e. sham). Further, anodal tDCS decreases occipito-parietal interactions and time-varying connectivity across the visual cortex. Our findings demonstrate that tDCS boosts learning by accelerating visual GABAergic plasticity and altering interactions between visual and decision-related areas, suggesting that training optimises gain control mechanisms (i.e. GABAergic inhibition) and functional inter-areal interactions to support perceptual learning.
Proteome signatures of reductive stress cardiomyopathy

Nuclear factor erythroid 2-related factor 2 (NRF2), a redox sensor, is vital for cellular redox homeostasis. We reported that transgenic mice expressing constitutively active Nrf2 (CaNrf2-TG) exhibit reductive stress (RS). In this study, we identified novel protein biomarkers for RS-induced cardiomyopathy using Tandem Mass Tag (TMT) proteomic analysis in heart tissues of TG (CaNrf2-TG) and non-transgenic (NTg) mice at 6-7 months of age (N= 4/group). A total of 1105 proteins were extracted from 22544 spectra. Of note, about 560 proteins were differentially expressed in TG vs. NTg hearts, indicating a global impact of RS on myocardial proteome. From a closer analysis of the proteome datasets, we identified over 32 proteins that were significantly altered in response to RS. Among these, 20 were upregulated and 12 were downregulated in the hearts of TG vs. NTg mice, suggesting that these proteins could be putative signatures of RS. Scaffold analysis revealed a clear distinction between TG vs NTg hearts. Of note, we observed several proteins with redox (#185; cysteine residues), NEM-adducts (#81), methionine-loss (#21) and acetylation (#1) modifications in TG vs. NTg hearts due to chronic RS. The majority of the differentially expressed proteins (DEPs) that are significantly altered in RS mice were found to be involved in stress related pathways such as antioxidants, NADPH, protein quality control (PQC), etc. Interestingly, proteins that were involved in mitochondrial respiration, lipophagy and cardiac rhythm were dramatically decreased in TG hearts. Of note, we identified the glutathione family of proteins as the significantly changed subset of the proteome in TG heart. Surprisingly, our comparative analysis of NGS based transcriptome and TMT-proteome indicated ∼50% of the altered proteins in TG myocardium was found to be negatively correlated with their transcript levels. Modifications at cysteine/NEM-adducts (redox), methionine or lysine residues in multiple proteins in response to chronic RS might be associated with impaired PQC mechanisms, thus causing pathological cardiac remodeling. Graphical Abstract
Molecular and Cellular Adaptations in Hippocampal Parvalbumin Neurons Mediate Behavioral Responses to Chronic Social Stress

Parvalbumin-expressing interneurons (PV neurons) maintain inhibitory control of local circuits implicated in behavioral responses to environmental stressors. However, the roles of molecular and cellular adaptations in PV neurons in stress susceptibility or resilience have not been clearly established. Here, we show behavioral outcomes of chronic social defeat stress (CSDS) are mediated by differential neuronal activity and gene expression in hippocampal PV neurons in mice. Using in vivo electrophysiology and chemogenetics, we find increased PV neuronal activity in the ventral dentate gyrus is required and sufficient for behavioral susceptibility to CSDS. PV neuron-selective translational profiling indicates mitochondrial oxidative phosphorylation is the most significantly altered pathway in stress-susceptible versus resilient mice. Among differentially expressed genes associated with stress-susceptibility and resilience, we find Ahnak, an endogenous regulator of L-type calcium channels which are implicated in the regulation of mitochondrial function and gene expression. Notably, Ahnak deletion in PV neurons impedes behavioral susceptibility to CSDS. Altogether, these findings indicate behavioral effects of chronic stress can be controlled by selective modulation of PV neuronal activity or a regulator of L-type calcium signaling in PV neurons.
NeuroML-DB: Sharing and characterizing data-driven neuroscience models described in NeuroML

As researchers develop computational models of neural systems with increasing sophistication and scale, it is often the case that fully de novo model development is impractical and inefficient. Thus arises a critical need to quickly find, evaluate, re-use, and build upon models and model components developed by other researchers. We introduce the NeuroML Database (NeuroML-DB.org), which has been developed to address this need and to complement other model sharing resources. NeuroML-DB stores over 1,500 previously published models of ion channels, cells, and networks that have been translated to the modular NeuroML model description language. The database also provides reciprocal links to other neuroscience model databases (ModelDB, Open Source Brain) as well as access to the original model publications (PubMed). These links along with Neuroscience Information Framework (NIF) search functionality provide deep integration with other neuroscience community modeling resources and greatly facilitate the task of finding suitable models for reuse. Serving as an intermediate language, NeuroML and its tooling ecosystem enable efficient translation of models to other popular simulator formats. The modular nature also enables efficient analysis of a large number of models and inspection of their properties. Search capabilities of the database, together with web-based, programmable online interfaces, allow the community of researchers to rapidly assess stored model electrophysiology, morphology, and computational complexity properties. We use these capabilities to perform a database-scale analysis of neuron and ion channel models and describe a novel tetrahedral structure formed by cell model clusters in the space of model properties and features. Author Summary Computational models of neurons and their circuits are increasingly used by neuroscience researchers as a tool to probe fundamental aspects of brain function. Here we describe a database of computational models of neurons and networks that makes it easier to evaluate and reuse these models. The models in the database are available in a standard format, called NeuroML, that makes it easier to extend and reuse the models in simulation studies using a wide range of simulation software platforms. The use of this standard format also makes it easier to characterize models in an automated way and analyze relationships across the features of simulated data from model simulations. Striking Image
A natural genetic variation screen identifies insulin signaling, neuronal communication, and innate immunity as modifiers of hyperglycemia in the absence of Sirt1

Variation in the onset, progression, and severity of symptoms associated with metabolic disorders such as diabetes impairs the diagnosis and treatment of at-risk patients. Diabetes symptoms, and patient variation in these symptoms, is attributed to a combination of genetic and environmental factors, but identifying the genes and pathways that modify diabetes in humans has proven difficult. A greater understanding of genetic modifiers and the ways in which they interact with metabolic pathways could improve the ability to predict a patient’s risk for severe symptoms, as well as enhance the development of individualized therapeutic approaches. In this study we use the Drosophila Genetic Reference Panel (DGRP) to identify genetic variation influencing hyperglycemia associated with loss of Sirt1 function. Through analysis of individual candidate functions, physical interaction networks, and Gene Set Enrichment Analysis (GSEA) we identify not only modifiers involved in canonical glucose metabolism and insulin signaling, but also genes important for neuronal signaling and the innate immune response. Furthermore, reducing the expression of several of these candidates suppressed hyperglycemia, making them ideal candidate therapeutic targets. These analyses showcase the diverse processes contributing to glucose homeostasis and open up several avenues of future investigation.
Ultrafast charge dynamics in dispersions of monolayer MoS2 nanosheets

Ultrafast charge dynamics in dispersions of MoS2 nanosheets in N-methyl-2-pyrrolidone are reported. Samples were prepared by the ultrasonication-assisted exfoliation of MoS2 powder, resulting in nanosheets that were predominantly monolayer and had an average sheet size of 32.4 ± 0.1 nm. These dispersions were characterized using absorption and photoluminescence spectroscopy, transient photoluminescence measurements, and atomic force microscopy before the ultrafast charge dynamics were studied via transient absorption spectroscopy. The transient absorption spectra exhibited bleach peaks and photoinduced absorption peaks in spectral regions corresponding to both the A and B excitons of MoS2. The growth and decay of the features in the B exciton region were determined largely by the dynamics of the exciton population, while the features in the A exciton region depend on the dynamics of both excitons and trions.