Miracle-dz/UniFAR-FTUs huggingface dataset:
Causality between Peripheral Immune Cell Counts and Membranous Nephropathy: A Bidirectional Mendelian Randomization Study

Background: Membranous nephropathy (MN), an autoimmune disease, has not yet been fully elucidated regarding its relationship with immune cells. Methods: As a primary method in this Mendelian randomization (MR) analysis, we employed the Inverse Variance Weighted (IVW) Wald Ratio (WR), Steiger filtering, Weighted Median, Weighted mode, MR-Egger, Mendelian randomization pleiotropy residual sum, and outlier (MR-PRESSO) and Leave-one-out sensitivity test. Reverse MR analysis was utilized to investigate whether MN affects immune cells. Results After False Discovery Rate multiple correction (threshold was 10%), it was determined that CD45RA+ CD8+ T cell (IVW OR=1.074, 95%CI: 1.034-1.114, P=0.0001, PFDR=0.036), Effector Memory CD8+ T cell (IVW OR=0.929, 95%CI: 0.895-0.964, P=0.0001, PFDR=0.036), HLA DR+ CD8+ T cell (IVW OR=0.921, 95%CI: 0.884-0.960, P=0.0001, PFDR=0.036) are significantly affected by MN. CD28+ CD45RA- CD8+ T cell (WR OR=0.513, 95%CI: 0.357-0.793, P=0.0003, PFDR=0.061), CD8 on Terminally Differentiated CD8+ T cell (WR OR=0.378, 95%CI: 0.219-0.652, P=0.0005, PFDR=0.061), and HVEM on Effector Memory CD4+ T cell (WR OR=0.378, 95%CI: 0.219-0.652, P=0.0005, PFDR=0.065), among others, are considered immune cells that possess protective factors against MN. However, HLA DR on CD33+ HLA DR+ CD14- (WR OR=1.910, 95%CI: 1.269-2.876, P=0.002, PFDR=0.065), CD80 on granulocyte (WR OR=2.606, 95%CI: 1.417-4.792, P=0.002, PFDR=0.065), and CD62L- plasmacytoid Dendritic Cell (WR OR=1.508, 95%CI: 1.138-1.998, P=0.004, PFDR=0.071) pose a risk to MN. When increased by one standard deviation in peripheral blood, these immune cells positively or negatively impact the risk of MN with an odds ratio (OR). Conclusions: The MR analysis unveiled the association between immune cells and MN. We have deepened our understanding of the pathogenic mechanisms linking MN and immune cells and also identified new targets for immunotherapy in MN.
Angiographic Report Generation for the 3rd APTOS's Competition: Dataset and Baseline Methods

Fundus angiography, including fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA), are essential examination tools for visualizing lesions and changes in retinal and choroidal vasculature. However, the interpretation of angiography images is labor-intensive and time-consuming. In response to this, we are organizing the third APTOS competition for automated and interpretable angiographic report generation. For this purpose, we have released the first angiographic dataset, which includes over 50,000 images labeled by retinal specialists. This dataset covers 24 conditions and provides detailed descriptions of the type, location, shape, size and pattern of abnormal fluorescence to enhance interpretability and accessibility. Additionally, we have implemented two baseline methods that achieve an overall score of 7.966 and 7.947 using the classification method and language generation method in the test set, respectively. We anticipate that this initiative will expedite the application of artificial intelligence in automatic report generation, thereby reducing the workload of clinicians and benefiting patients on a broader scale.
Home-based transcranial direct current stimulation RCT in major depression

Background Transcranial direct current stimulation (tDCS) has been proposed as a novel treatment in major depressive disorder (MDD). However, efficacy and safety of home-based tDCS treatment have not been investigated. Methods Fully remote, multisite, double-blind, placebo-controlled, randomized superiority trial of home-based tDCS treatment in MDD was conducted in UK and USA. Participants were adults 18 years or older, having MDD diagnosis based on DSM-5 criteria, in current depressive episode of at least moderate severity, measured by score > 16 on 17-item Hamilton Depression Rating Scale (HDRS), without treatment resistant depression history. Protocol was 10-week blinded phase: 5 tDCS sessions per week for 3 weeks then 3 sessions per week for 7 weeks; followed by 10-week open label phase. tDCS montage was bifrontal, 30-minute sessions, active tDCS 2 mA, and sham tDCS 0 mA with brief ramp up and down to mimic active device. Primary outcome was HDRS change at week 10 in modified intention-to-treat analysis. Results 174 MDD participants were randomized: active (n=87; mean age 37.1 + 11.1 years) and sham (n=87; mean age 38.3 + 10.9 years) treatment. Significant improvement in HDRS was observed in active (9.4 + 6.25 points) relative to sham treatment (7.1 + 6.10 points) (95% CI 0.5 to 4.0, p = 0.012), with no differences in discontinuation rates between active (n=13) and sham (n=12). Conclusions Home-based tDCS with remote supervision is a potential first line treatment for MDD that is acceptable and safe. Consideration of continuing effective safety monitoring is required. Trial registration number NCT05202119
Large-scale proteogenomics characterization of the Mycobacterium tuberculosis hidden microproteome

Tuberculosis remains a burden to this day, due to the rise of multi and extensively drug-resistant bacterial strains. The genome of Mycobacterium tuberculosis (Mtb) underwent an annotation process that excluded small Open Reading Frames (smORFs), which encode a class of peptides and small proteins collectively known as microproteins. As a result, there is an overlooked part of its proteome that is a rich source of potentially essential, druggable molecular targets. Here, we employed our recently developed proteogenomics pipeline to identify novel microproteins encoded by smORFs in the genome of Mtb usings hundreds of mass spectrometry experiments in a large-scale approach. We found protein evidence for hundreds of novel microproteins and identified smORFs potentially involved in bacterial growth and virulence. Moreover, many smORFs are co-expressed or share operons with a myriad of biologically relevant genes and may play a role in antibiotic response. Together, our data presents a resource of unknown genes that play a role in the success of Mtb as a widespread pathogen.
How do sapling and adult demography explain beech predominance along environmental gradients in Central European forests?

Understanding how species abundances are driven by biotic interactions along environmental gradients is a fundamental question in ecology. For abundances at competitive equilibria in Central European forests, a classical ecological theory formulated by Ellenberg (1963) predicts that beech (Fagus sylvatica L.) outcompetes other tree species within a mesic range of soil pH and water levels, while other species prevail under less favorable conditions. While the theory is generally accepted in forest ecology, only certain aspects of it have been substantiated by empirical evidence. Moreover, the demographic processes driving the turnover from beech to other tree species at the extremes of the soil gradients remain mostly unexplained. To address this, we inversely calibrated a parsimonious forest model (JAB model) with a sapling stage and interacting populations with short time series of observed tree abundances from the German national forest inventory. By modelling how demographic rates vary along pH and soil water gradients, we were able to test the prediction that beech naturally predominates only at favorable soil conditions. Moreover, we tested with simulations how the environmental response of demographic rates explains Fagus’ changing relative abundance along the soil gradients. Our results largely confirm that Fagus out competes other species in a central environmental range. Environmental change of Fagus’ relative abundance is primarily explained by environmental variation of its net basal area increment, followed by its competition response at the overstory and at the sapling stage. We found that even though sapling tolerance to shading is the primary mechanism for Fagus predominance, it only plays a secondary role for the environmental variation of its relative abundance. Synthesis: By inverse calibration of a forest population model with demographic rates that respond to the environment, we confirm the predictions of Ellenberg’s classical, albeitonlypartially-evidenced, theory on F. sylvatica’s predominance in Central European forests. Furthermore, for thefirsttime, we substantiate the theory by elucidating how the environmental variation in species composition is based in demographic processes. This demonstrates that our approach can be utilized to predict distributions of interacting species and to explain the dynamics between species, as influenced by their environment.
Fine-tuning of RecBCD expression by post-transcriptional regulation is required for optimal DNA repair in Escherichia coli

To preserve genome integrity, all living organisms have developed strategies to respond to chromosomal damage. One such response is the repair of DNA double-strand breaks (DSBs), one of the most toxic forms of DNA lesions. In E. coli, DSBs are repaired via the homologous recombination pathway, initiated by the RecBCD enzyme. RecBCD is essential for accurate chromosome maintenance but its over-expression can lead to reduced DNA repair ability. This apparent paradox suggests that RecBCD copy number may need to be tightly controlled within an optimal range. Using single-molecule fluorescence microscopy, we have established that RecB is present in very low abundance at mRNA and protein levels. RecB transcription shows high levels of fluctuations yet cell-to-cell protein variability remains remarkably low. We show that the post-transcriptional regulator Hfq binds to recBCD mRNAs and down-regulates RecB protein expression in vivo. Furthermore, when Hfq-mediated regulation is perturbed, we observe less effective noise reduction and reduced DNA repair capacity. Taken together, our results suggest a post-transcriptional regulatory mechanism where Hfq fine-tunes RecB expression by inhibiting RecB translation. This fine-tuning of RecB expression contributes to reducing noise in RecB protein expression and protects cells against the toxic consequences of too high RecBCD numbers.
The cytokine genes of Oncorhynchus masou formosanus include a defective interleukin-4A gene

Oncorhynchus masou formosanus (Formosa land-locked salmon) is a critically endangered salmonid fish endemic to Taiwan. To begin to understand how its drastic change in lifestyle from anadromous to exclusively river-dwelling is reflected in its immune genes, we characterized the genes encoding six cytokines (IL-2A, IL-2B, IL-4A, IL-4B1, IL-4B2, and IL-17A/F2a) important for T cell responses as no genomic data is available for this fish. Interestingly, all genes appeared homozygous indicative of a genetic bottleneck. The IL2 and IL17A/F2a genes and their products are highly similar to their characterized homologs in Oncorhynchus mykiss (rainbow trout) and other salmonid fish. Two notable differences were observed in IL4 family important for type 2 immune responses. First, O. m. formosanus carries not only one but two genes encoding IL-4B1 proteins and expansions of these genes are present in other salmonid fish. Second, the OmfoIL4A gene carries a 228 bp deletion that results in a premature stop codon and hence a non-functional IL-4A cytokine. This suggests a reduced ability for T cell responses against parasitic infections in this species.
A cholesterol switch controls phospholipid scrambling by G protein-coupled receptors

Class A G protein-coupled receptors (GPCRs), a superfamily of cell membrane signaling receptors, moonlight as constitutively active phospholipid scramblases. The plasma membrane of metazoan cells is replete with GPCRs, yet has a strong resting trans-bilayer phospholipid asymmetry, with the signaling lipid phosphatidylserine confined to the cytoplasmic leaflet. To account for the persistence of this lipid asymmetry in the presence of GPCR scramblases, we hypothesized that GPCR-mediated lipid scrambling is regulated by cholesterol, a major constituent of the plasma membrane. We now present a technique whereby synthetic vesicles reconstituted with GPCRs can be supplemented with cholesterol to a level similar to that of the plasma membrane and show that the scramblase activity of two prototypical GPCRs, opsin and the β1-adrenergic receptor, is impaired upon cholesterol loading. Our data suggest that cholesterol acts as a switch, inhibiting scrambling above a receptor-specific threshold concentration to disable GPCR scramblases at the plasma membrane.
A planar neuromuscular controller to simulate compensation strategies in the sit-to-walk movement

Standing up from a chair is a key daily life activity that is sensitive to functional limitations as we age and associated with falls, frailty, and institutional living. Predictive neuromusculoskeletal models can potentially shed light on the interconnectivity and interdependency of age-related changes in neuromuscular capacity, reinforcement schemes, sensory integration, and adaptation strategies during stand-up. Most stand-up movements transfer directly into walking (sit-to-walk). The aim of this study was to develop and validate a neuromusculoskeletal model with reflex-based muscle control that enables simulation of the sit-to-walk movement under various conditions (seat height, foot placement). We developed a planar sit-to-walk musculoskeletal model (11 degrees-of-freedom, 20 muscles) and neuromuscular controller, consisting of a two-phase stand-up controller and a reflex-based gait controller. The stand-up controller contains generic neural pathways of delayed proprioceptive feedback from muscle length, force, velocity, and upper-body orientation (vestibular feedback) and includes both monosynaptic an antagonistic feedback pathways. The control parameters where optimized using a shooting-based optimization method, based on a high-level optimization criterium. Simulations were compared to recorded kinematics, ground reaction forces, and muscle activation. The simulated kinematics resemble the measured kinematics and muscle activations. The adaptation strategies that resulted from alterations in seat height, are comparable to those observed in adults. The simulation framework and model are publicly available and allow to study age-related compensation strategies, including reduced muscular capacity, reduced neural capacity, external perturbations, and altered movement objectives.
RECONSTRUCTING THE GLOBAL GEOMAGNETIC FIELD OF THE HOLOCENE

Archeomagnetic results and high resolution sedimentary records have been used to reconstruct the global geomagnetic field for millennial time-scales. Here I present a series of models named CALSxk, Continuous models based on Archeomagnetic and Lake Sediment data of the past x kyrs, and in particular CALS10k.1b, the first regularized spherical harmonic field model for the past 10 kyrs. The effects of uncertainties in both magnetic elements and their ages and of uneven global data distribution are assessed by a bootstrap resampling scheme. I discuss the evolution of the dipole moment and tilt and features of the radial field component at the core-mantle boundary. The model also provides estimates for field directions and intensity for any location at Earth's surface. However, as the presently available data distribution is uneven and strongly biased towards the northern hemisphere and Europe in particular, the accuracy and resolution of global models remains limited. More high resolution lake or marine paleomagnetic sediment records and archeomagnetic results from from the southern hemisphere, e.g. the South American countries, are necessary to improve global field reconstructions. Archeomagnetic resultados y registros de alta resolucion sedimentarias se han utilizado para reconstruir el campo magnetico global para escalas de tiempo del milenio. Aqui presento una serie de modelos llamado CALSxk, los modelos Continua basados en datos Archeomagnetic y de Sedimentos Lacustres de x kyrs, y en particular CALS10k.1b, la primera regularizo modelo esferico campo armonico de los ultimos 10 kyrs. Los efectos de la incertidumbre tanto en los elementos magneticos y sus edades y la distribucion desigual de los datos globales son evaluadas por un esquema de remuestreo bootstrap. Discutir la evolucion del momento dipolar y sus inclinacion y las caracteristicas de la componente del campo radial en la frontera entre el nucleo y el manto. El modelo tambien proporciona las estimaciones de las direcciones y la intensidad de campo de cualquier lugar de la superficie terrestre. Sin embargo, como la distribucion de los datos disponibles en la actualidad es desigual y muy sesgada hacia el hemisferio norte y Europa en particular, la precision y resolucion de los modelos globales sigue siendo limitada. Mas resultados alta resolucion paleomagneticos de sedimentos des lagos o del mar y datos archeomagnetic desde el hemisferio sur, por ejemplo, los paises de America del Sur, son necesarias para mejorar la reconstruccion de campo magnetico global.
Learning sequence, structure, and function representations of proteins with language models

The sequence-structure-function relationships that ultimately generate the diversity of extant observed proteins is complex, as proteins bridge the gap between multiple informational and physical scales involved in nearly all cellular processes. One limitation of existing protein annotation databases such as UniProt is that less than 1% of proteins have experimentally verified functions, and computational methods are needed to fill in the missing information. Here, we demonstrate that a multi-aspect framework based on protein language models can learn sequence-structure-function representations of amino acid sequences, and can provide the foundation for sensitive sequence-structure-function aware protein sequence search and annotation. Based on this model, we introduce a multi-aspect information retrieval system for proteins, Protein-Vec, covering sequence, structure, and function aspects, that enables computational protein annotation and function prediction at tree-of-life scales.
De novo design and optimization of aptamers with AptaDiff

Aptamers are single-strand nucleic acid ligands, featuring high affinity and specificity to target molecules. Traditionally they are identified from large DNA/RNA libraries using in vitro methods, like Systematic Evolution of Ligands by Exponential Enrichment (SELEX). However, these libraries capture only a small fraction of theoretical sequence space, and various aptamer candidates are constrained by actual sequencing capabilities from the experiment. Addressing this, we proposed AptaDiff, the first in silico aptamer design and optimization method based on the diffusion model. Our Aptadiff can generate aptamers beyond the constraints of high-throughput sequencing data, leveraging motif-dependent latent embeddings from variational autoencoder, and can optimize aptamers by affinity-guided aptamer generation according to Bayesian optimization. Comparative evaluations revealed AptaDiff’s superiority over existing aptamer generation methods in terms of quality and fidelity across four high-throughput screening data targeting distinct proteins. Moreover, Surface Plasmon Resonance (SPR) experiments were conducted to validate the binding affinity of aptamers generated through Bayesian optimization for two target proteins. The results unveiled a significant boost of 87.9% and 60.2% in RU values 1, along with a 3.6-fold and 2.4-fold decrease in KD values 2 for the respective target proteins. Notably, the optimized aptamers demonstrated superior binding affinity compared to top experimental candidates selected through SELEX, underscoring the promising outcomes of our AptaDiff in accelerating the discovery of superior aptamers.
An Efficient Computational Method to Simulate Autosomal Chromosomes with Trisomy Aberrations

Noninvasive prenatal test (NIPT) has been widely used for screening trisomy on chromosomes 13 (T13), 18 (T18), and 21 (T21). However, the false negative rate of NIPT algorithms has not been thoroughly evaluated due to the lack of positive samples. In this study, we present an efficient computational approach to simulate positive samples with autosomal trisomy from negative samples. We applied the method to create a dataset of 1440 positive samples with T13, T18, and T21 aberrations for both mosaic and non-mosaic conditions. We also introduced VINIPT algorithm, an improvement of the widely-used algorithm WisecondorX. We examined the performance of WisecondorX and VINIPT on both negative and positive datasets. Experiments showed that WisecondorX and VINIPT were able to detect all non-mosaic samples with T13, T18, and T21 aberrations (i.e., the sensitivity of 100%). For mosaic samples, WisecondorX and VINIPT have the overall sensitivity of 99.7% on detecting T13, T18, and T21 aneuploidy. WisecondorX has a specificity of 98.5% for the non-mosaic analysis, but a considerably lower specificity of 95% for the mosaic analysis. VINIPT has a much better specificity than WisecondorX, i.e., 99.9% for the non-mosaic analysis, and 98.2% for the mosaic analysis. The results suggest that VINIPT can play as a powerful tool for detecting autosomal trisomy.
DecLog: Decentralized Logging in Non-Volatile Memory for Time Series Database Systems

Growing demands for the efficient processing of extreme-scale time series workloads call for more capable time series database management systems (TSDBMS). Specifically, to maintain consistency and durability of transaction processing, systems employ write-ahead logging (WAL) whereby transactions are committed only after the related log entries are flushed to disk. However, when faced with massive I/O, this becomes a throughput bottleneck. Recent advances in byte-addressable Non-Volatile Memory (NVM) provide opportunities to improve logging performance by persisting logs to NVM instead. Existing studies typically track complex transaction dependencies and use barrier instructions of NVM to ensure log ordering. In contrast, few studies consider the heavy-tailed characteristics of time series workloads, where most transactions are independent of each other. We propose DecLog, a decentralized NVM-based logging system that enables concurrent logging of TSDBMS transactions. Specifically, we propose data-driven log sequence numbering and relaxed ordering strategies to track transaction dependencies and resolve serialization issues. We also propose a parallel logging method to persist logs to NVM after being compressed and aligned. An experimental study on the YCSB-TS benchmark offers insight into the performance properties of DecLog, showing that it improves throughput by up to 4.6× while offering lower recovery time in comparison to the open source TSDBMS Beringei.
Explicit formulas for calculating surges in throttled surge chamber

An analytical study was conducted for water mass oscillation in a surge chamber of hydroelectric station under combined load cases. The asymptotic method of nonlinear oscillation was used to solve the nonlinear ordinary differential equation of mass oscillation in throttled surge chambers under combined load cases. Analytical formulas were derived for the lowest water level in surge chamber under the condition in which loads increase at adverse time after load rejection, and for the highest water level in surge chamber under the condition in which loads were rejected at adverse time after increasing load, respectively. The results obtained by using the analytical formulas were compared with that of numerical calculation. It was found that good agreement was achieved.