Miracle-dz/UniFAR-FTUs huggingface dataset:
Giant GAL gene clusters for the melibiose-galactose pathway in Torulaspora

In many yeast species the three genes at the center of the galactose catabolism pathway, GAL1, GAL10 and GAL7, are neighbors in the genome and form a metabolic gene cluster. We report here that some yeast strains in the genus Torulaspora have much larger GAL clusters that include genes for melibiase (MEL1), galactose permease (GAL2), glucose transporter (HGT1), phosphoglucomutase (PGM1), and the transcription factor GAL4, in addition to GAL1, GAL10, and GAL7. Together, these 8 genes encode almost all the steps in the pathway for catabolism of extracellular melibiose (a disaccharide of galactose and glucose). We show that a progenitor 5-gene cluster containing GAL 7-1-10-4-2 was present in the common ancestor of Torulaspora and Zygotorulaspora. It added PGM1 and MEL1 in the ancestor of Torulaspora. It underwent further expansion in the T. pretoriensis clade, involving the fusion of three progenitor clusters in tandem and the gain of HGT1. These giant GAL clusters are highly polymorphic in structure, and subject to horizontal transfers, pseudogenization and gene losses. We identify recent horizontal transfers of complete GAL clusters from T. franciscae into one strain of T. delbrueckii, and from a relative of T. maleeae into one strain of T. globosa. The variability and dynamic evolution of GAL clusters in Torulaspora indicates that there is strong natural selection on the GAL pathway in this genus.
Augmin prevents merotelic attachments by promoting proper arrangement of bridging and kinetochore fibers

The human mitotic spindle is made of microtubules nucleated at centrosomes, at kinetochores, and from pre-existing microtubules by the augmin complex. However, it is unknown how the augmin-mediated nucleation affects distinct microtubule bundles and thereby mitotic fidelity. Here we use superresolution microscopy to analyze the previously indistinguishable microtubule arrangements within the crowded metaphase plate area and demonstrate that augmin is vital for the formation of uniformly arranged parallel units consisting of sister kinetochore fibers connected by a bridging fiber. This ordered geometry helps both prevent and resolve merotelic attachments through joint action of bridging and kinetochore fibers. Augmin depletion resulted in thinning of both kinetochore and bridging fibers, with bridging fibers often absent from kinetochore pairs with a reduced interkinetochore distance. We propose a model where augmin promotes mitotic fidelity and tension on kinetochores by generating assemblies consisting of bridging and kinetochore fibers that align sister kinetochores parallel to the spindle axis to face opposite poles, thereby preventing erroneous attachments. SUMMARY Štimac, Koprivec et al. show that augmin promotes mitotic fidelity and tension on kinetochores by generating parallel assemblies consisting of bridging fibers that connect sister kinetochore fibers, precise organization of which prevents erroneous attachments.
Palm-to-finger cortical functional interactions in primary somatosensory cortex: a 7T fMRI study

Many studies focused on the cortical representations of fingers, while the palm is relatively neglected despite its importance for hand function. Here, we investigated palm representation (PR) and its interactions with finger representations (FRs) in primary somatosensory cortex (S1). Few studies in humans suggested that PR is located medially with respect to FRs in S1, yet to date, no study directly quantified the somatotopic organization of PR and the five FRs. Importantly, the relationship between the somatotopic organization and the cortical functional interactions between PR and FRs remains largely unexplored. Using 7T fMRI, we mapped PR and the five FRs at the single subject level. First, we analyzed the cortical distance between PR and FRs to determine their somatotopic organization. Results show that the PR was located medially with respect to D5. Second, we tested whether the observed cortical distances would predict palm-finger functional interactions. Using three complementary measures of functional interactions (co-activations, pattern similarity and resting-state connectivity), we show that palm-finger functional interactions were not determined by their somatotopic organization, that is, there was no gradient moving from D5 to D1, except for resting-state connectivity, which was predicted by the somatotopy. Instead, we show that the representational geometry of palm-finger functional interactions reflected the physical structure of the hand. Collectively, our findings suggest that the spatial proximity between topographically organized neuronal populations do not necessarily predicts their functional interactions, rather the structure of the sensory space (e.g. the hand shape) better predicts the observed functional interactions.
The fronto-parietal network connects more strongly to central than peripheral V1

Central and peripheral vision are important for distinct aspects of everyday life. We use central vision to read and peripheral vision to get the gist of a scene. To understand how these differences are reflected in connectivity between V1 and higher-order cognitive areas, we examined the differential connectivity of V1 that represent central and peripheral vision. We used diffusion-weighted-imaging and resting-state blood-oxygen-level-dependent data to examine structural and functional connectivity. The present results demonstrate strong evidence that centrally-representing portions of V1 are more strongly functionally and structurally connected to the fronto-parietal network than are peripherally representing portions of V1. This suggests that these patterns of connections between central V1 and the fronto-parietal network are direct and support attention-demanding visual tasks. Overall, our findings contribute to understanding how the human brain processes visual information and forms a baseline for any modifications in processing that might occur with training or experience.
Topological Assembly of a Deployable Hoberman Flight Ring from DNA

Deployable geometries are finite auxetic structures that preserve their overall shapes during expansion and contraction. The topological behaviors emerge from intricately arranged elements and their connections. Despite considerable utility of such configurations in nature and in engineering, deployable nanostructures have never been demonstrated. Here we show a deployable flight ring, a simplified planar structure of Hoberman sphere, using DNA origami. The DNA flight ring consists of topologically assembled six triangles in two layers that can slide against each other, thereby switching between two distinct (open and closed) states. The origami topology is a trefoil knot, and its auxetic reconfiguration results in negative Poisson’s ratios. This work shows the feasibility of deployable nanoarchitectures, providing a versatile platform for topological studies and opening new opportunities for bioengineering.
A Hybrid of Light-Field and Light-Sheet Imaging to Decouple Myocardial Biomechanics from Intracardiac Flow Dynamics

Biomechanical forces intimately contribute to cardiac morphogenesis. However, 4-D (3-D space + time) imaging is needed to investigate the developmental cardiac mechanics with high temporal and spatial resolution. We hereby integrated light-sheet fluorescence microscopy (LSFM) with light-field microscopy (LFM), to simultaneously visualize myocardial contractility and intracardiac blood flow in three dimensions at 200 volumes per second (vps). LSFM allows for reconstruction of the myocardial contraction in zebrafish embryo; and LFM enables simultaneous tracking of the blood cells entering and leaving the contracting heart. We herein established particle tracking velocimetry to interrogate the trajectories of intracardiac blood cells, and we demonstrated deformable image registration to reveal a decrease in the myocardial contractility from atrioventricular (AV) canal to the outflow tract (OFT). We imaged myocardium undergoing torsional contraction and blood flow undergoing regurgitation. Taken together, the integration of light-field and light-sheet microscopy, followed by an image-based analysis pipeline, provides the biomechanical insights into coupling myocardial kinetics with rotational contraction along with intracardiac flow dynamics during development.
Inhibition of guanosine monophosphate synthetase (GMPS) blocks glutamine metabolism and prostate cancer growth in vitro and in vivo

Cancer cells increase their uptake of nutrients and metabolize them to provide the necessary building blocks for new cancer cells. Glutamine is a critical nutrient in cancer, however its contribution to purine metabolism in prostate cancer has not previously been determined. Guanosine monophosphate synthetase (GMPS) acts in the de novo purine biosynthesis pathway, utilizing a glutamine amide to synthesize the guanine nucleotide and replenish the purine pool in proliferative cancer cells. This study demonstrates that GMPS mRNA expression correlates with Gleason score in prostate cancer samples, while high GMPS expression was associated with decreased rates of overall and disease/progression-free survival. Pharmacological inhibition or knockdown of GMPS significantly decreased cell growth in both LNCaP and PC-3 prostate cancer cells. GMPS knockdown was rescued by addition of extracellular guanosine to the media, suggesting a direct effect on nucleotide synthesis. We utilized 15N-(amide)-glutamine and U-13C5-glutamine metabolomics to dissect the pathways involved, and intriguingly, despite similar growth inhibition by GMPS knockdown, we show unique metabolic effects across each cell line. PC-3 cells showed a build-up of purine precursors, as well as activation of purine salvage pathways highlighted by significant increases in guanine, adenosine, inosine and cytosine. Both cell lines exhibited increased levels of pyrimidines and prioritized TCA cycle in distinct ways to produce increased aspartate, another important purine precursor. Using a PC-3 xenograft mouse model, tumor growth was also significantly decreased after GMPS knockdown. These data further highlight the importance of glutamine metabolism for prostate cancer cell growth and provide support for GMPS as a new therapeutic target in prostate cancer.
Integrative approaches to improve the informativeness of deep learning models for human complex diseases

Deep learning models have achieved great success in predicting genome-wide regulatory effects from DNA sequence, but recent work has reported that SNP annotations derived from these predictions contribute limited unique information for human complex disease. Here, we explore three integrative approaches to improve the disease informativeness of allelic-effect annotations (predicted difference between reference and variant alleles) constructed using two previously trained deep learning models, DeepSEA and Basenji. First, we employ gradient boosting to learn optimal combinations of deep learning annotations, using (off-chromosome) fine-mapped SNPs and matched control SNPs for training. Second, we improve the specificity of these annotations by restricting them to SNPs implicated by (proximal and distal) SNP-to-gene (S2G) linking strategies, e.g. prioritizing SNPs involved in gene regulation. Third, we predict gene expression (and derive allelic-effect annotations) from deep learning annotations at SNPs implicated by S2G linking strategies — generalizing the previously proposed ExPecto approach, which incorporates deep learning annotations based on distance to TSS. We evaluated these approaches using stratified LD score regression, using functional data in blood and focusing on 11 autoimmune diseases and blood-related traits (average N=306K). We determined that the three approaches produced SNP annotations that were uniquely informative for these diseases/traits, despite the fact that linear combinations of the underlying DeepSEA and Basenji blood annotations were not uniquely informative for these diseases/traits. Our results highlight the benefits of integrating SNP annotations produced by deep learning models with other types of data, including data linking SNPs to genes.
Diagnosing Community-Acquired Pneumonia: diagnostic accuracy study of a cough-centred algorithm for use in primary and acute-care consultations.

ABSTRACT Background Community-acquired pneumonia (CAP) is an essential consideration in patients presenting to primary care with respiratory symptoms; however, accurate diagnosis is difficult when clinical and radiologic examinations are not possible, such as during telehealth consultations. Aim To develop and test a smartphone-based algorithm for diagnosing CAP without need for clinical examination or radiology inputs. Design and Setting A prospective cohort study using data from subjects aged over 12 years presenting with acute respiratory symptoms to a hospital in Western Australia. Method Five cough audio-segments were recorded and four patient-reported symptoms (fever, acute cough, productive cough, age) were analysed by the smartphone-based algorithm to generate an immediate diagnostic output for CAP. We recruited independent cohorts to train and test the accuracy of the algorithm. Diagnostic agreement was calculated against the confirmed discharge diagnosis of CAP by specialist physicians. Specialist radiologists reported medical imaging. Results The algorithm had high percent agreement (PA) with the clinical diagnosis of CAP in the total cohort (n=322, Positive PA=86%, Negative PA=86%, AUC=0.95); in subjects 22-65 years (n=192, PPA=86%, NPA=87%, AUC=0.94) and in subjects >65 years (n=86, PPA=86%, NPA=87.5%, AUC=0.94). Agreement was preserved across CAP severity: 85% (80/94) of subjects with CRB-65 scores 1-2, and 87% (57/65) with a score of 0, were correctly diagnosed by the algorithm. Conclusion The algorithm provides rapid and accurate diagnosis of CAP. It offers improved accuracy over current protocols when clinical evaluation is difficult. It provides increased capabilities for primary and acute care, including telehealth services, required during the COVID-19 pandemic.
Immunohistochemical expression of p27 in ductal carcinoma of breast and its correlation with HER2/neu expression and hormonal status

Introduction Breast cancer is the most common malignancy that affects women, with a prevalence of 23% of all cancers in women worldwide. In Egypt, carcinoma of the breast is the most prevalent cancer among Egyptian women. Despite improvements in early diagnostic methods and advances in treatment, mortality because of breast cancer remains high. The cyclin-dependent kinase inhibitor p27 (also known as Kip1) is a key regulator of progression from the G1 to the S-phase. This work aimed at studying the expression of p27 in breast duct carcinoma in comparison with well-established prognostic factors in breast cancer including estrogen receptor and progesterone receptor status, and HER2/neu expression. Materials and methods This immunohistochemical study was carried out by retrieval of formalin-fixed, paraffin-embedded tissue sections from archival blocks prepared from 58 modified radical mastectomy and lumpectomy specimens diagnosed as breast duct carcinoma. The specimens were collected from the Department of Pathology at the National Cancer Institute, Cairo University, from January 2006 to July 2009. Each case was tested for immunohistochemical expression of estrogen receptors, progesterone receptors, HER2, and p27. Results p27 expression was correlated significantly with the expression of estrogen and progesterone receptors; moreover, loss of p27 was associated with positivity to HER2/neu. Also, a borderline significance was found between p27 expression and microscopic grade. Conclusion Our findings strongly suggest that p27Kip1 expression may be used as a potential prognostic marker for human breast cancer, allowing therapy to be adjusted more appropriately for individual tumors.
Hopeful monsters: unintended sequencing of famously malformed mite mitochondrial tRNAs reveals widespread expression and processing of sense–antisense pairs

Although tRNA structure is one of the most conserved and recognizable shapes in molecular biology, aberrant tRNAs are frequently found in the mitochondrial genomes of metazoans. The structure of several mitochondrial tRNAs is so degenerate that doubts have been raised about their expression and function. Mites from the arachnid superorder Acariformes are predicted to have some of the shortest mitochondrial tRNAs, with apparent base mismatches in acceptor stems and a complete loss of cloverleaf-life shape. While performing mitochondrial isolations and recently developed RNA-seq methods to capture mature, CCA-tailed tRNAs in plant tissue, we inadvertently sequenced the mitochondrial tRNAs from a common plant pest, the acariform mite Tetranychus urticae, to a high enough coverage to detect all previously annotated T. urticae tRNA regions. The results not only confirm expression, CCA-tailing and post-transcriptional base modification of these highly divergent tRNAs, but also revealed widespread sense and antisense expression of tRNA genes in the T. urticae mitochondrial genome. Mirrored expression of mitochondrial tRNA genes has been previously hypothesized but not demonstrated to be extensive in any system. We discuss the functional roles that these divergent tRNAs could have as both decoding molecules in translation and processing signals in transcript maturation pathways for other genes, as well as how the surprising finding of sense-antisense tRNA pairs adds another dimension to the bizarre tRNA biology of mitochondrial genomes.
Caenorhabditis elegans: a model to study the anthelmintic effects of polyphenolic compounds on the fertility of parasitic gastrointestinal nematodes?

We set up a Caenorhabditis elegans model to extrapolate anthelmintic (AH) effects of commercial polyphenols to related gastrointestinal zoonotic species. We compared the practical convenience of S liquid to solid agar Nematode grown medium in daily reproduction patterns and total brood size. Solid agar resulted a highly effective, reproducibly medium, in a less costly and rapid time manner. A minimum of three replications per monomer concentration are suggested to get a robust statistical analysis. Flavonoids Quercetin and Rutin potentially decrease brood sizes and percentage of development, with the exception of 20μM concentration. Flavanols resulted heterogeneous. In a dose-dependent manner Catechin 20μM significantly decreased egg output, and egg hatching in a 15% on respect to control values. Contrary, Epigallocatechin-gallate, seems to stimulate brood sizes and egg-hatching, however, EGCG10μM decreased reproduction but with no in a significative manner. We found a nematocidal effect on the reproductive parameters of C. elegans exposed to the chalcones Phloretin and Phloridzin, and Flavones Flavone and Genistein. A significant general decrease on reproductive parameters were found, particularly significant for Genistein 20μM in the percentage of hatching respect to control. Effects of time schedule and monomer concentration were found for the Hydrolysable tannins Gallic and Tannic acid. Tannic acid showed effectiveness against egg-hatching. The spectrum of percentages of change compared to each blank resulted negative decreasing fertility values, but for GA5, associated with a net increase of larvae hatched. 1 AH, GIN, CTS, HTs Q) Quercetin, (R) Rutin, (C) (+)-Catechin hydrate, (EGCG) (-)-Epigallocatechin Gallate, (PTN) Phloretin, (PDN) Phloridzin Dihydrate, (GE) Genistein, (FLA) Flavone, (GA) Gallic acid and (TA) Tannic acid. , G1 (adult worm originally seeded per plate and monomer concentration at time 0. Two replications were performed per plate). Solvents: PBS (Phosphate Buffer Solution), CH4O (Methanol 0,002%) L3
Fine–mapping identifies NAD–ME1 as a candidate underlying a major locus controlling temporal variation in primary and specialized metabolism in Arabidopsis

Plant metabolism is modulated by a complex interplay between internal signals and external cues. A major goal of all quantitative metabolomic studies is to clone the underlying genes to understand the mechanistic basis of this variation. Using fine-scale genetic mapping, in this work we report the identification and initial characterization of NAD-DEPENDENT MALIC ENZYME 1 (NAD-ME1) as the candidate gene underlying the pleiotropic network Met.II. 15 QTL controlling variation in plant metabolism and circadian clock outputs in the Bay × Sha Arabidopsis population. Transcript abundance and promoter analysis in NAD-ME1Bay-0 and NAD-ME1Sha alleles confirmed allele-specific expression that appears to be due a polymorphism disrupting a putative circadian cis-element binding site. Analysis of T-DNA insertion lines and heterogeneous inbred families (HIFs) showed that transcript variation of the NAD-ME1 gene led to temporal shifts of tricarboxylic acid cycle (TCA) intermediates, glucosinolate (GSL) accumulation and altered regulation of several GSL biosynthesis pathway genes. Untargeted metabolomics analyses reveal complex regulatory networks of NAD-ME1 dependent upon the day-time. The mutant lead to shifts in plant primary metabolites, cell-wall components, isoprenoids, fatty acids and plant immunity phytochemicals, among others. Our findings suggest that NAD-ME1 may act as a key component to coordinate plant primary and secondary metabolism in a time-dependent manner.
Visual cortex cTBS increases mixed percept duration while a-tDCS has no effect on binocular rivalry

Neuromodulation of the primary visual cortex using anodal transcranial direct current stimulation (a-tDCS) can alter visual perception and enhance neuroplasticity. However, the mechanisms that underpin these effects are currently unknown. When applied to the motor cortex, a-tDCS reduces the concentration of the inhibitory neurotransmitter gamma aminobutyric acid (GABA), an effect that has been linked to increased neuroplasticity. The aim of this study was to assess whether a-tDCS also reduces GABA-mediated inhibition when applied to the human visual cortex. Changes in visual cortex inhibition were measured using the mixed percept duration in binocular rivalry. Binocular rivalry mixed percept duration has recently been advocated as a direct and sensitive measure of visual cortex inhibition whereby GABA agonists decrease mixed percept durations and agonists of the excitatory neurotransmitter acetylcholine increase them. Our hypothesis was that visual cortex a-tDCS would increase mixed percept duration by reducing GABA-mediated inhibition and increasing cortical excitation. In addition, we measured the effect of continuous theta-burst transcranial magnetic stimulation (cTBS) of the visual cortex on binocular rivalry dynamics. When applied to the motor or visual cortex, cTBS increases GABA concentration and we therefore hypothesized that visual cortex cTBS would decrease the mixed percept duration. Binocular rivalry dynamics were recorded before and after active and sham a-tDCS (N=15) or cTBS (N=15). Contrary to our hypotheses, a-tDCS had no effect, whereas cTBS significantly increased mixed percepts during rivalry. These results suggest that the neurochemical mechanisms of a-tDCS may differ between the motor and visual cortices.