Miracle-dz/UniFAR-FTUs huggingface dataset:
How red blood cell quality is starting to carry its weight

Red blood cell (RBC) transfusions can be a life-saving intervention for anemic or bleeding patients. However, transfusions carry both attributable and non-attributable risks, the latter exemplified by studies showing restrictive transfusion strategies lead to similar (or better) outcomes compared to liberal strategies. Although RBCs and other blood components are treated as standardized by multiple regulatory bodies, there is increasing evidence that donor characteristics and processing parameters may cause variability in these complex biologic products. This has led to a renewed interest in studying “what's in the bag” to better understand which factors could potentially harm patients. As an example, storage time has often been studied as a possible factor affecting RBC quality, but to date no randomized controlled trials have demonstrated differences in outcomes with standard age vs older RBCs. It is possible that by only considering the age of stored RBCs in these studies, other variables that might affect RBC quality related to processing or donor characteristics were not taken into account. Several groups have recently begun investigating the impact of donor factors such as sex, donor age, ethnicity, and diet on RBC quality.3,5–8 Elevated body mass index (BMI), associated with numerous metabolic changes and chronic medical conditions, has also been proposed to alter RBC biology as a relevant donor characteristic. Here, we discuss two studies reported in this issue of TRANSFUSION investigating the impact of BMI on donated RBCs: one using donor data from the Australian Red Cross Blood Service and the other by a U.S. group studying donors from Vitalant/ the REDS-III RBC-Omics project.
Cellular Management of Zinc in Group B Streptococcus Supports Bacterial Resistance against Metal Intoxication and Promotes Disseminated Infection

Streptococcus agalactiae, also known as group B streptococcus, is an opportunistic pathogen that causes various diseases in humans and animals. This bacterium has genetic systems that enable zinc detoxification in environments of metal stress, but these systems remain largely undefined. ABSTRACT Zinc is an essential trace element for normal bacterial physiology but, divergently, can intoxicate bacteria at high concentrations. Here, we define the molecular systems for Zn detoxification in Streptococcus agalactiae, also known as group B streptococcus, and examine the effects of resistance to Zn stress on virulence. We compared the growth of wild-type bacteria and mutants deleted for the Zn exporter, czcD, and the response regulator, sczA, using Zn-stress conditions in vitro. Macrophage antibiotic protection assays and a mouse model of disseminated infection were used to assess virulence. Global bacterial transcriptional responses to Zn stress were defined by RNA sequencing and quantitative reverse transcription-PCR. czcD and sczA enabled S. agalactiae to survive Zn stress, with the putative CzcD efflux system activated by SczA. Additional genes activated in response to Zn stress encompassed divalent cation transporters that contribute to regulation of Mn and Fe homeostasis. In vivo, the czcD-sczA Zn management axis supported virulence in the blood, heart, liver, and bladder. Additionally, several genes not previously linked to Zn stress in any bacterium, including, most notably, arcA for arginine deamination, also mediated resistance to Zn stress, representing a novel molecular mechanism of bacterial resistance to metal intoxication. Taken together, these findings show that S. agalactiae responds to Zn stress by sczA regulation of czcD, with additional novel mechanisms of resistance supported by arcA, encoding arginine deaminase. Cellular management of Zn stress in S. agalactiae supports virulence by facilitating bacterial survival in the host during systemic infection. IMPORTANCE Streptococcus agalactiae, also known as group B streptococcus, is an opportunistic pathogen that causes various diseases in humans and animals. This bacterium has genetic systems that enable zinc detoxification in environments of metal stress, but these systems remain largely undefined. Using a combination of genomic, genetic, and cellular assays, we show that this pathogen controls Zn export through CzcD to manage Zn stress and utilizes a system of arginine deamination never previously linked to metal stress responses in bacteria to survive metal intoxication. We show that these systems are crucial for survival of S. agalactiae in vitro during Zn stress and also enhance virulence during systemic infection in mice. These discoveries establish new molecular mechanisms of resistance to metal intoxication in bacteria; we suggest these mechanisms operate in other bacteria as a way to sustain microbial survival under conditions of metal stress, including in host environments.
Non-linear dimensionality reduction on extracellular waveforms reveals cell type diversity in premotor cortex

Cortical circuits are thought to contain a large number of cell types that coordinate to produce behavior. Current in vivo methods rely on clustering of specified features of extracellular waveforms to identify putative cell types, but these capture only a small amount of variation. Here, we develop a new method (WaveMAP) that combines non-linear dimensionality reduction with graph clustering to identify putative cell types. We apply WaveMAP to extracellular waveforms recorded from dorsal premotor cortex of macaque monkeys performing a decision-making task. Using WaveMAP, we robustly establish eight waveform clusters and show that these clusters recapitulate previously identified narrow- and broad-spiking types while revealing previously unknown diversity within these subtypes. The eight clusters exhibited distinct laminar distributions, characteristic firing rate patterns, and decision-related dynamics. Such insights were weaker when using feature-based approaches. WaveMAP therefore provides a more nuanced understanding of the dynamics of cell types in cortical circuits. Significance How different cell types sculpt activity patterns in brain areas associated with decision-making is a fundamentally unresolved problem in neuroscience. In monkeys, and other species where transgenic access is not yet possible, identifying physiological types in vivo relies on only a few discrete user-specified features of extracellular waveforms to identify cell types. Here, we show that non-linear dimensionality reduction with graph clustering applied to the entire extracellular waveform can delineate many different putative cell types and does so in an interpretable manner. We show that this method reveals previously undocumented physiological, functional, and laminar diversity in the dorsal premotor cortex of monkeys, a key brain area implicated in decision-making.
Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2

Apart from the canonical fingers, palm and thumb domains, the RNA dependent RNA polymerases (RdRp) from the viral order Nidovirales possess two additional domains. Of these, the function of the Nidovirus RdRp associated nucleotidyl transferase domain (NiRAN) remains unanswered. The elucidation of the 3D structure of RdRp from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), provided the first ever insights into the domain organisation and possible functional characteristics of the NiRAN domain. Using in silico tools, we predict that the NiRAN domain assumes a kinase or phosphotransferase like fold and binds nucleoside triphosphates at its proposed active site. Additionally, using molecular docking we have predicted the binding of three widely used kinase inhibitors and five well characterized anti-microbial compounds at the NiRAN domain active site along with their drug-likeliness as well as DFT properties. For the first time ever, using basic biochemical tools, this study shows the presence of a kinase like activity exhibited by the SARS-CoV-2 RdRp. Interestingly, the proposed kinase inhibitors and a few of the predicted nucleotidyl transferase inhibitors significantly inhibited the aforementioned enzymatic activity. In line with the current global COVID-19 pandemic urgency and the emergence of newer strains with significantly higher infectivity, this study provides a new anti-SARS-CoV-2 drug target and potential lead compounds for drug repurposing against SARS-CoV-2.
Exploring the dynamic mechanisms of steady-state visual evoked 1 potentials at the whole-brain level: evidence from a computational 2 study

18 Periodic visual stimulation can induce stable steady-state visual evoked potentials (SSVEPs) 19 distributed in multiple brain regions and has potential applications in both neural engineering 20 and cognitive neuroscience. However, the underlying dynamic mechanisms of SSVEPs at the 21 whole-brain level are still not completely understood. Here, we addressed this issue by 22 simulating the rich dynamics of SSVEPs with a large-scale brain model designed with 23 constraints of neuroimaging data acquired from the human brain. By eliciting activity of the 24 occipital areas using an external periodic stimulus, our model was capable of replicating both 25 the spatial distributions and response features of SSVEPs that were observed in experiments. 26 In particular, we confirmed that alpha-band (8-12 Hz) stimulation could evoke stronger SSVEP 27 responses; this frequency sensitivity was due to nonlinear resonance and could be modulated 28 by endogenous factors in the brain. Interestingly, the stimulus-evoked brain networks also 29 exhibited significant superiority in topological properties near this frequency-sensitivity range, 30 and stronger SSVEP responses were demonstrated to be supported by more efficient functional 31 connectivity at the neural activity level. These findings not only provide insights into the 32 mechanistic understanding of SSVEPs at the whole-brain level but also indicate a bright future 33 for large-scale brain modeling in characterizing the complicated dynamics and functions of the 34 brain.
A theory of evolutionary dynamics on any complex spatial structure

Understanding how the spatial arrangement of a population shapes its evolutionary dynamics has been of long-standing interest in population genetics. Most previous studies assume a small number of demes connected by migration corridors, symmetrical structures that most often act as well-mixed populations. Other studies use networks to model the more complex topologies of natural populations and to study the structures that suppress or amplify selection. However, they usually assume very small, regular networks, with strong constraints on the strength of selection considered. Here we build network generation algorithms, evolutionary simulations and derive general analytic approximations for probabilities of fixation in populations with complex spatial structure. By tuning network parameters and properties independent of each other, we systematically span across network families and show that both a network’s degree distribution, as well as its node mixing pattern shape the evolutionary dynamics of new mutations. We analytically write the relevant selective parameter, predictive of evolutionary dynamics, as a combination of network statistics. As one application, we use recent imaging datasets and build the cellular spatial networks of the stem cell niches of the bone marrow. Across a wide variety of parameters and regardless of the birth-death process used, we find these networks to be strong suppressors of selection, delaying mutation accumulation in this tissue. We also find that decreases in stem cell population size decrease the suppression strength of the tissue spatial structure, hinting at a potential diminishing spatial suppression in the bone marrow tissue as individuals age.
High similarity among ChEC-seq datasets

ChEC-seq is a method used to identify protein-DNA interactions across a genome. It involves fusing micrococcal nuclease (MNase) to a protein of interest. In principle, specific genome-wide interactions of the fusion protein with chromatin result in local DNA cleavages that can be mapped by DNA sequencing. ChEC-seq has been used to draw conclusions about broad gene-specificities of certain protein-DNA interactions. In particular, the transcriptional regulators SAGA, TFIID, and Mediator are reported to generally occupy the promoter/UAS of genes transcribed by RNA polymerase II in yeast. Here we compare published yeast ChEC-seq data performed with a variety of protein fusions across essentially all genes, and find high similarities with negative controls. We conclude that ChEC-seq patterning for SAGA, TFIID, and Mediator differ little from background at most promoter regions, and thus cannot be used to draw conclusions about broad gene specificity of these factors.
Investigation of layer specific BOLD in the human visual cortex during visual attention

Directing spatial attention towards a particular stimulus location enhances cortical responses at corresponding regions in cortex. How attention modulates the laminar response profile within the attended region, however, remains unclear. In this paper, we use high field (7T) fMRI to investigate the effects of attention on laminar activity profiles in areas V1-V3; both when a stimulus was presented to the observer, and in the absence of visual stimulation. Replicating previous findings, we find robust increases in the overall BOLD response for attended regions in cortex, both with and without visual stimulation. When analyzing the BOLD response across the individual layers in visual cortex, we observed no evidence for laminar-specific differentiation with attention. We offer several potential explanations for these results, including theoretical, methodological and technical reasons. Additionally, we provide all data and pipelines openly, in order to promote analytic consistency across layer-specific studies, improve reproducibility, and decrease the false positive rate as a result of analytical flexibility.
Molecular diagnosis and prognosis of cancers of unknown-primary (CUPs): progress from a microRNA-based droplet digital PCR assay

Metastasis is responsible for the majority of cancer-related deaths. Particularly challenging is the management of metastatic cancer of unknown primary site (CUP), whose tissue-of-origin (TOO) remains undetermined even after expensive investigations. CUP therapy is rather unspecific and poorly effective. Molecular approaches developed to identify CUPs’ potential tissue-of-origin, can overcome some of these issues. In this study, we applied a pre-determined set of microRNAs (miRNAs) to infer the TOO of 53 metastatic cancers of unknown or uncertain origin. We designed a molecular assay to quantify 89 miRNAs at the copy number level, using EvaGreen-based Droplet Digital PCR. We assessed miRNA expression in 159 samples including primary tumors from 17 tumor classes (reference set), metastases of known and unknown origin. We applied two different statistical models for class prediction to obtain CUP’s most probable TOOs. Specifically, we used the shrunken centroids using PAMR (Prediction Analysis of Microarrays for R) and the least absolute shrinkage and selection operator (LASSO) models. The molecular test was successfully applied to FFPE samples and provided a site-of-origin identification within one-week from the biopsy procedure. The most frequently predicted origins were gastrointestinal, pancreas, breast and lung. The assay was applied to multiple metastases from the same CUP, collected from different metastatic sites: the molecular prediction revealed an impressive agreement in site-of-origin prediction, intrinsically validating our assay. The final prediction was compared with the clinico-pathological hypothesis of primary site. Moreover, a panel of 14 miRNAs proved to have prognostic value and being associated with overall survival. Our study demonstrated that miRNA expression profiling in CUP samples could be employed as diagnostic and prognostic test. Our molecular analysis can be performed on-request, concomitantly with standard diagnostic workup and in association with genetic profiling, to offer valuable indication about the possible primary site, thereby supporting treatment decisions.
Akaike model selections of the vegetation structures and aerosphere factors in supporting lesser short nosed fruit bat (Cynopterus brachyotis Muller, 1838) populations in Asia mountainous paddy fields

As an aerial and arboreal fauna, the abundances and populations of fruit bat Cynopterus brachyotis were influenced by the vegetation structures and aerosphere condition variables of fruit bat ecosystems. While mountaineous paddy field is an unique habitat since the trees are scarce and has exposure to the aerosphere variables including air temperature and humidity. Here this paper aims to select the best vegetation structures and aerosphere factors that support the abundance of C. brachyotis in mountainous paddy field landscape in West Java. The model selection was using AIC methodology by testing 15 models including 5 single models and 10 combination models of explanatory variables. Based on the model, tree height and combinations of tree height and elevation produced the best prediction for the bat abundances, as described by low values of AIC and the highest values of R2 and adjusted R2. For the best models, the AIC values ranged from 16.674 to 17.603, from 0.3404 to 0.4144 (R2), and 0.2461 to 0.2192 for adjusted R2. Regarding conservation of C. brachyotis and learning from the model, the conservation approaches mainly in mountainous paddy fields are encouraged to protect and conserve high altitude landscapes and trees with height > 10 m. Whereas the AIC results show lack of aerosphere variable effects on C. brachyotis (AIC: 19.346-20.406, R2: 0.1124-0.001353, and adjusted R2: −0.01444 − −0.1413).
Sensory experience modulates the reorganisation of temporal auditory regions for executive processing

Crossmodal plasticity refers to the reorganisation of sensory cortices in the absence of their main sensory input. Understanding this phenomenon provides insights into brain function and its potential for change and enhancement. Using fMRI, we investigated how early deafness influences crossmodal plasticity and the organisation of executive functions in the adult human brain. Results from a range of visual executive function tasks (working memory, task switching, planning, inhibition) show that deaf individuals specifically recruit “auditory” regions during task switching. Neural activity in superior temporal regions, most significantly in the right hemisphere, are good predictors of behavioural performance during task switching in the deaf group, highlighting the functional relevance of the observed cortical reorganisation. Our results show executive processing in typically sensory regions, suggesting that the development and ultimate role of brain regions are influenced by perceptual environmental experience.
Spatial transcriptomics reveals unique molecular fingerprints of human nociceptors

Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root (DRG) and trigeminal ganglia. These neurons are critical for the generation of neuronal signals that ultimately create the perception of pain. These neurons are also primary targets for acute and chronic pain therapeutics. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and elucidating new drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single dorsal root ganglion (DRG) neurons from 8 organ donors. We identified 12 clusters of human sensory neurons, 5 of which are C nociceptors; as well as 1 Aβ nociceptor, 2 Aδ, 2 Aβ and 1 proprioceptor subtypes. By focusing on expression profiles for ion channels, G-protein coupled receptors (GPCRs) and other pharmacological targets, we provide a rich map of drug targets in the human DRG with direct comparison to mouse sensory neuron transcriptomes. We also compare human DRG neuronal subtypes to non-human primates showing conserved patterns of gene expression among many cell types, but divergence among specific nociceptor subsets. Finally, we identify sex differences in human DRG subpopulation transcriptomes, including a marked increase in CALCA expression in female pruritogen receptor enriched nociceptors. Our data open the door to development of drug discovery programs for new pain targets and unparalleled molecular characterization of clinical sensory disorders. One Sentence Summary We used spatial transcriptomics to molecularly characterize human sensory neurons, comparing them to mouse and non-human primate finding similarities but also divergence, in particular among drug targets.
Decoding nucleosome positions with ATAC-seq data at single-cell level

As the basal bricks, the dynamics and arrangement of nucleosomes orchestrate the higher architecture of chromatin in a fundamental way, thereby affecting almost all nuclear biology processes. Thanks to its rather simple protocol, ATAC-seq has been rapidly adopted as a major tool for chromatin-accessible profiling at both bulk and single-cell level. However, to picture the arrangement of nucleosomes per se remains a challenge with ATAC-seq. In the present work, we introduce a novel ATAC-seq analysis toolkit, named deNOPA, to predict nucleosome positions. Assessments showed that deNOPA not only outperformed state-of-the-art tools, but it is the only tool able to predict nucleosome position precisely with ultrasparse ATAC-seq data. The remarkable performance of deNOPA was fueled by the reads from short fragments, which compose nearly half of sequenced reads and are normally discarded from nucleosome position detection. However, we found that the short fragment reads enrich information on nucleosome positions and that the linker regions were predicted by reads from both short and long fragments using Gaussian smoothing. We applied deNOPA to a single-cell ATAC-seq dataset and deciphered the intrapopulation heterogeneity of the human erythroleukemic cell line (K562). Last, using deNOPA, we showed that the dynamics of nucleosome organization may not directly couple with chromatin accessibility in the cis-regulatory regions when human cells respond to heat shock stimulation. Our deNOPA provides a powerful tool with which to analyze the dynamics of chromatin at nucleosome position level in the single-cell ATAC-seq age.