Miracle-dz/UniFAR-FTUs huggingface dataset:
Parallel Genomic Changes Drive Repeated Evolution of Placentas in Live-Bearing Fish

Abstract The evolutionary origin of complex organs challenges empirical study because most organs evolved hundreds of millions of years ago. The placenta of live-bearing fish in the family Poeciliidae represents a unique opportunity to study the evolutionary origin of complex organs, because in this family a placenta evolved at least nine times independently. It is currently unknown whether this repeated evolution is accompanied by similar, repeated, genomic changes in placental species. Here, we compare whole genomes of 26 poeciliid species representing six out of nine independent origins of placentation. Evolutionary rate analysis revealed that the evolution of the placenta coincides with convergent shifts in the evolutionary rate of 78 protein-coding genes, mainly observed in transporter- and vesicle-located genes. Furthermore, differences in sequence conservation showed that placental evolution coincided with similar changes in 76 noncoding regulatory elements, occurring primarily around genes that regulate development. The unexpected high occurrence of GATA simple repeats in the regulatory elements suggests an important function for GATA repeats in developmental gene regulation. The distinction in molecular evolution observed, with protein-coding parallel changes more often found in metabolic and structural pathways, compared with regulatory change more frequently found in developmental pathways, offers a compelling model for complex trait evolution in general: changing the regulation of otherwise highly conserved developmental genes may allow for the evolution of complex traits.
Diversity in visual sensitivity across Neotropical cichlid fishes via differential expression and intraretinal variation of opsin genes

The visual system of vertebrates has greatly contributed to our understanding of how different molecular mechanisms shape adaptive phenotypic diversity. Extensive work on African cichlid fishes has shown how variation in opsin gene expression mediates diversification as well as convergent evolution in colour vision. This trait has received less attention in Neotropical cichlids, the sister lineage to African cichlids, but the work done so far led to the conclusion that colour vision is much less variable in Neotropical species. However, as only few taxa have been investigated and as recent work found contradicting patterns, the diversity in meotropical cichlids might be greatly underestimated. Here, we survey patterns of opsin gene expression in 35 representative species of Neotropical cichlids, revealing much more variation than previously known. This diversity can be attributed to two main mechanisms: (i) differential expression of the blue‐sensitive sws2a, the green‐sensitive rh2a, and the red‐sensitive lws opsin genes, and (ii) simultaneous expression of up to five opsin genes, instead of only three as commonly found, in a striking dorsoventral pattern across the retina. This intraretinal variation in opsin genes expression results in steep gradients in visual sensitivity that may represent a convergent adaptation to clear waters with broad light environments. These results highlight the role and flexibility of gene expression in generating adaptive phenotypic diversification.
Structure and ligand-based drug discovery of IL-4 inhibitors via interaction-energy-based learning approaches

Abstract Interleukin-4 (IL-4), an anti-inflammatory cytokine plays significant in the development of various diseases especially asthmatic allergies. Previous structural and functional studies of IL-4 with its receptor bring forth different types of inhibitors to block their interaction but each of them failed in clinical trials. Since, no synthetic molecules have been identified against IL-4, so far. Therefore, 21 in-house tested IL-4 inhibitors were blindly docked over the entire surface of IL-4 to predict a suitable and druggable binding site as the crystal structure of IL-4 protein in complex with ligand has not been reported yet. After binding site prediction, both ligand-based and structure-based pharmacophore were generated to screen three ZINC libraries (24.5 M) i.e. purchasable, natural product and natural derivative. A total 5,800 top-scored compounds were further subjected towards score-based screening to find the potential leads. Following protein-ligand interaction fingerprints (PLIF) and molecular visualization of selected hits, six top-scored compounds (five from purchasable and one from natural product library) were further moved towards their stability dynamics, followed by their absolute binding free energy and residue-based energy decomposition calculation by MM-GBSA method. These efforts help us to reveal the key factors responsible for ligand binding that might help to improve the binding and stability of these newly discovered hits by structural modifications. Communicated by Freddie R. Salsbury
Comparative Effectiveness and Harms of Antibiotics for Outpatient Diverticulitis

BACKGROUND Outpatient diverticulitis is commonly treated with either a combination of metronidazole and a fluoroquinolone (metronidazole-with-fluoroquinolone) or amoxicillin-clavulanate alone. The U.S. Food and Drug Administration advised that fluoroquinolones be reserved for conditions with no alternative treatment options. The comparative effectiveness of metronidazole-with-fluoroquinolone versus amoxicillin-clavulanate for diverticulitis is uncertain. OBJECTIVE To determine the effectiveness and harms of metronidazole-with-fluoroquinolone versus amoxicillin-clavulanate for outpatient diverticulitis. DESIGN Active-comparator, new-user, retrospective cohort studies. SETTING Nationwide population-based claims data on U.S. residents aged 18 to 64 years with private employer-sponsored insurance (2000 to 2018) or those aged 65 years or older with Medicare (2006 to 2015). PARTICIPANTS Immunocompetent adults with diverticulitis in the outpatient setting. INTERVENTION Metronidazole-with-fluoroquinolone or amoxicillin-clavulanate. MEASUREMENTS 1-year risks for inpatient admission, urgent surgery, and Clostridioides difficile infection (CDI) and 3-year risk for elective surgery. RESULTS In MarketScan (IBM Watson Health), new users of metronidazole-with-fluoroquinolone (n = 106 361) and amoxicillin-clavulanate (n = 13 160) were identified. There were no differences in 1-year admission risk (risk difference, 0.1 percentage points [95% CI, -0.3 to 0.6]), 1-year urgent surgery risk (risk difference, 0.0 percentage points [CI, -0.1 to 0.1]), 3-year elective surgery risk (risk difference, 0.2 percentage points [CI, -0.3 to 0.7]), or 1-year CDI risk (risk difference, 0.0 percentage points [CI, -0.1 to 0.1]) between groups. In Medicare, new users of metronidazole-with-fluoroquinolone (n = 17 639) and amoxicillin-clavulanate (n = 2709) were identified. There were no differences in 1-year admission risk (risk difference, 0.1 percentage points [CI, -0.7 to 0.9]), 1-year urgent surgery risk (risk difference, -0.2 percentage points [CI, -0.6 to 0.1]), or 3-year elective surgery risk (risk difference, -0.3 percentage points [CI, -1.1 to 0.4]) between groups. The 1-year CDI risk was higher for metronidazole-with-fluoroquinolone than for amoxicillin-clavulanate (risk difference, 0.6 percentage points [CI, 0.2 to 1.0]). LIMITATION Residual confounding is possible, and not all harms associated with these antibiotics, most notably drug-induced liver injury, could be assessed. CONCLUSION Treating diverticulitis in the outpatient setting with amoxicillin-clavulanate may reduce the risk for fluoroquinolone-related harms without adversely affecting diverticulitis-specific outcomes. PRIMARY FUNDING SOURCE National Institutes of Health.
Evaluation of the Use of Single- and Multi-Magnification Convolutional Neural Networks for the Determination and Quantitation of Lesions in Nonclinical Pathology Studies

Digital pathology platforms with integrated artificial intelligence have the potential to increase the efficiency of the nonclinical pathologist’s workflow through screening and prioritizing slides with lesions and highlighting areas with specific lesions for review. Herein, we describe the comparison of various single- and multi-magnification convolutional neural network (CNN) architectures to accelerate the detection of lesions in tissues. Different models were evaluated for defining performance characteristics and efficiency in accurately identifying lesions in 5 key rat organs (liver, kidney, heart, lung, and brain). Cohorts for liver and kidney were collected from TG-GATEs open-source repository, and heart, lung, and brain from internally selected R&D studies. Annotations were performed, and models were trained on each of the available lesion classes in the available organs. Various class-consolidation approaches were evaluated from generalized lesion detection to individual lesion detections. The relationship between the amount of annotated lesions and the precision/accuracy of model performance is elucidated. The utility of multi-magnification CNN implementations in specific tissue subtypes is also demonstrated. The use of these CNN-based models offers users the ability to apply generalized lesion detection to whole-slide images, with the potential to generate novel quantitative data that would not be possible with conventional image analysis techniques.
Concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

Axonal trafficking deficits and neurodegeneration in C9ORF72 motoneurons are mediated by GOF and LOF mechanisms with RNA foci and DPRs as upstream events, whereas DNA damage appears downstream. Intronic hexanucleotide repeat expansions (HREs) in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis, a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOFs) through DPRs versus loss of C9ORF72 functions (LOFs). Through multiparametric high-content (HC) live profiling in spinal MNs from induced pluripotent stem cells and comparison to mutant FUS and TDP43, we show that HRE C9ORF72 caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA double-strand breaks (DSBs), RNA foci, DPRs, and apoptosis. We show that both GOFs and LOFs were necessary to yield the overall C9ORF72 pathology. Increased RNA foci and DPRs concurred with onset of axon trafficking defects, DSBs, and cell death, although DSB induction itself did not phenocopy C9ORF72 mutants. Interestingly, the majority of LOF-specific DEGs were shared with HRE-mediated GOF DEGs. Finally, C9ORF72 LOF was sufficient—albeit to a smaller extent—to induce premature distal axonal trafficking deficits and increased DSBs.
Early apathetic, but not depressive, symptoms are associated with poor outcome after stroke

Depression and apathy are frequent neuropsychiatric disturbances after stroke and may appear together. Despite the overlap in symptoms between poststroke depression and apathy, these two syndromes might be associated with different prognoses and benefit from different treatments. We aimed to disentangle the relationship between early depressive and apathetic symptoms and outcome after stroke.
Four-pronged negative feedback of DSB machinery in meiotic DNA-break control in mice

Abstract In most taxa, halving of chromosome numbers during meiosis requires that homologous chromosomes (homologues) pair and form crossovers. Crossovers emerge from the recombination-mediated repair of programmed DNA double-strand breaks (DSBs). DSBs are generated by SPO11, whose activity requires auxiliary protein complexes, called pre-DSB recombinosomes. To elucidate the spatiotemporal control of the DSB machinery, we focused on an essential SPO11 auxiliary protein, IHO1, which serves as the main anchor for pre-DSB recombinosomes on chromosome cores, called axes. We discovered that DSBs restrict the DSB machinery by at least four distinct pathways in mice. Firstly, by activating the DNA damage response (DDR) kinase ATM, DSBs restrict pre-DSB recombinosome numbers without affecting IHO1. Secondly, in their vicinity, DSBs trigger IHO1 depletion mainly by another DDR kinase, ATR. Thirdly, DSBs enable homologue synapsis, which promotes the depletion of IHO1 and pre-DSB recombinosomes from synapsed axes. Finally, DSBs and three DDR kinases, ATM, ATR and PRKDC, enable stage-specific depletion of IHO1 from all axes. We hypothesize that these four negative feedback pathways protect genome integrity by ensuring that DSBs form without excess, are well-distributed, and are restricted to genomic locations and prophase stages where DSBs are functional for promoting homologue pairing and crossover formation.
The accuracy and influencing factors for preference of self-sampling in group B streptococcus screening: a cross-sectional study

Abstract Objective Self-sampling with proper instruction in 35–37 weeks’ gestation is an option to clinician sampling to prevent early-onset invasive group B streptococcal disease of infants. We aimed to assess the accuracy of self-sampling and influencing factors of preference for collection method in Chinese women. Methods We compared the screening results of self-sampling with clinician collection in a sample of 520 women in late pregnancy. We collected their demographics, clinical information and preference for collection method. A multi-nominal logistic regression model was used to measure the association between the influencing factors and these participants’ preference. Results A good agreement between the two collection methods was found with a Cohen’s Kappa coefficient 0.83 (95%CI = 0.71–0.95). The prevalence of GBS infection in the two methods is statistically different in this low-risk group when self-sampling presented a better outcome in terms of detecting positive cases. Self-sampling is preferable by 20.9% of the participants. No less pain during self-sampling and age older than 35 years old was statistically related to preference for clinician collection. Conclusion The accuracy of self-sampling is no worse than clinician collection. It could be an option for those younger than 35 years old, especially for those who report low pain threshold. Pregnant women are able to collect rectovaginal samples prior to their antenatal visit. Self-sampling followed by appropriate transportation of the sample to an advanced laboratory could eliminate the effects of local laboratory capacity. There are implications in increasing GBS screening participation in resource-limited settings.
Interprofessional perceptions of emotional, social, and ethical effects of multidrug-resistant organisms: A qualitative study

Introduction Multi-drug-resistant organisms (MDRO) are usually managed by separating the infected patients to protect others from colonization and infection. Isolation precautions are associated with negative experiences by patients and their relatives, while hospital staff experience a heavier workload and their own emotional reactions. Methods In 2018, 35 participants (nurses, physicians, pharmacists) in an antimicrobial-stewardship program participated in facilitated discussion groups working on the emotional impact of MDRO. Deductive codings were done by four coders focusing on the five basic emotions described by Paul Ekmans. Results All five emotions revealed four to 11 codes forming several subthemes: Anger is expressed because of incompetence, workflow-impairment and lack of knowledge. Anxiety is provoked by inadequate knowledge, guilt, isolation, bad prognoses, and media-related effects. Enjoyment is seldom. Sadness is experienced in terms of helplessness and second-victim effects. Disgust is attributed to shame and bad associations, but on the other hand MDROs seem to be part of everyday life. Deductive coding yielded additional codes for bioethics and the Calgary Family Assessment Method. Conclusion MDRO are perceived to have severe impact on emotions and may affect bioethical and family psychological issues. Thus, further work should concentrate on these findings to generate a holistic view of MDRO on human life and social systems.
Zirconium silicide and germanide chalcogenides preparation and crystal structures

The tetragonal sublimates obtained by prolonged tempering of preparations of compositions about ZrX0.75 (X = S, Se, Te) in evacuated quartz tubes1, 2, are found to be ternary compounds ZrSiX. These novel compounds can be prepared conveniently by reaction of “SiX” with zirconium metal at elevated temperatures. The analogous germanium compounds are prepared in a similar way. The crystal structures of the ZrSiX and ZrGeX phases are related to the PbFCl structure type. Unit-cell dimensions, atomic parameters (see Table I) and interatomic distances (see Table II) have been determined; they are discussed in some detail.
Long-Term Effect of Different Carbon Management Strategies on Water Flow and Related Processes for Three Loamy Soils

Abstract The decline in organic matter of arable land, induced and accelerated by modern agriculture, has been identified as a threat to sustained soil quality. In this article, we studied strategies to counter this decrease by building up soil organic carbon (SOC) levels in the soils using several approaches. They included return of organic matter, such as straw, animal manure, and slurry, to the soil and diverse crop rotations with, for example, grass-clover leys. We used three field sites in Denmark with different C repletion strategies to assess and quantify the effect of these approaches on preferential flow and loss of colloids during heavy irrigation events. The field sites were all under long-term management and therefore represent up to 30 years of pairwise different management strategies. One field in each field pair was managed with a more C-repleting strategy (HighC) than the other (LowC). Only small differences in SOC contents were identified, and none of the management strategies had succeeded in building up SOC pools large enough to saturate the soil with C. Only at one field site was the content of water-dispersible colloids lower in the HighC than the LowC treatment. Preferential flow patterns showed a rapid breakthrough of irrigation water but only little or negligible effect in reducing the risk of colloid loss and chemicals leaching from the root zone, despite 20 to 30 years of different management strategies with this aim. Previous studies reported in the literature have emphasized high SOC contents and grass ley soils to significantly reduce nonequilibrium water flow. Our results thus indicate the need for more effective management options than those addressed in this study.
Two-Dimensional 1H and 13C Nuclear Magnetic Resonance Studies of Poly(acrylamide)

The 1H and 13C nuclear magnetic resonance spectra of poly(acrylamide) (PAA) in D2O at a temperature of 343 K were analyzed by two-dimensional NMR (2D NMR) methods including 1H J-resolved spectroscopy, F1-axis (1H) broad-band decoupled correlation spectroscopy, and 1H broad-band decoupled 13C–1H chemical shift correlation spectroscopy. Combined use of these 2D NMR methods provided absolute assignments of 1H and 13C spectra at the triad–tetrad level. At the pentad–hexad level, the 13C spectra were assigned by the aid of spectral simulation. The polymerization of PAA proceeds in a Bernoulli-trial process with Pm=0.45.
Keller Box and Smoothed Particle Hydrodynamic Numerical Simulation of Two-Phase Transport in Blood Purification Auto- Transfusion Dialysis Hybrid Device with Stokes and Darcy Number Effects

A computational simulation of laminar natural convection fully-developed multi-phase suspension in a porous medium channel is presented. The Darcy model is employed for the porous material which is valid for low velocity, viscous-dominated flows. The Drew-Marble fluid-particle suspension model is employed to simulate both particulate (red blood cell) and fluid (plasma) phases. The transformed two-point nonlinear boundary value problem is shown to be controlled by a number of key dimensionless thermo-physical parameters, namely the Darcy number (Da), momentum inverse Stokes number (Sk m ), particle loading parameter (p L ), inverse thermal Stokes number (Sk T ), particle-phase wall slip parameter (W) and buoyancy parameter (B). Detailed numerical solutions are presented with an optimized K eller B ox implicit finite difference M ethod ( KBM ) for the influence of these parameters on the ﬂuid-phase velocity (U) and particle-phase velocity (Up). Validation is also included using the S moothed P article H ydrodynamic ( SPH ) Lagrangian method and excellent correlation achieved. Increasing Darcy number is observed to significantly accelerate the ﬂuid-phase flow and less dramatically enhance particle-phase velocity ﬁeld. Magnitudes of fluid phase velocity are also elevated with both increasing viscosity ratio and particle-phase wall slip parameter. Increasing buoyancy effect depresses particle phase velocity. An increase in particle loading parameter is also observed to suppress both fluid and particle phase velocities. No tangible change in fluid or particle phase temperatures is computed with increasing Darcy number. The study is relevant to dialysis devices exploiting thermal and porous media filtration features.
Selective shaped pulse decoupling in NMR: homonuclear [carbon-13]carbonyl decoupling

We introduce a novel pulse sequence that is capable of frequency-selective spin decoupling. This sequence uses radio-frequency pulse shaping to greatly attenuate off-resonance side bands which are inherent in broad-band decoupling sequences but, within the bandwidth of the sequence, retains the quality of decoupling possible with the commonly used WALTZ-16 sequence. Selective carbonyl decoupling is demonstrated in a heteronuclear multiple quantum correlation experiment where it is shown that efficient decoupling of the carbonyl from the Cα carbons occurs without distorting nearby aromatic coherences
No nursery ‘til school – the transition to primary school without institutional transition support due to the COVID-19 shutdown in Germany

ABSTRACT The early educational support of basic school skills during nursery can have a positive impact on a successful transition into primary school and future school success and achievement – especially for in this context low-performing children. Therefore, most German nurseries developed additional concepts to support the acquisition of basic school skills during the last year of nursery. However, due to the COVID-19 shutdown face-to-face support for pre-schoolers was closed down. This study attempts to examine how basic school skills with respect to language and mathematical skills of pre-schoolers developed during the COVID-19 nursery shutdown. 49 children were evaluated in a single-group pre-post test design using five subtests of the Intelligence and Development Scales 2 (IDS-2) before and after nurseries were shut down. Additionally, qualitative interviews were conducted at to provide further reliable and valuable information that goes beyond structured testing. Research showed significant decreases of language and mathematical skills. These findings support the conclusion that nursery shutdowns may have a negative impact on pre-schoolers’ educational skills which help to make transitions easier. Concludingly, the study stresses the particular role of nurseries with regard to early childhood education and childhood development in order to support the transition to school.