julilili42/papers huggingface dataset:
Population-specific variations in KCNH2 predispose patients to delayed ventricular repolarization upon dihydroartemisinin-piperaquine therapy
2024-03-28

ABSTRACT Dihydroartemisinin-piperaquine is efficacious for the treatment of uncomplicated malaria and its use is increasing globally. Despite the positive results in fighting malaria, inhibition of the Kv11.1 channel (hERG; encoded by the KCNH2 gene) by piperaquine has raised concerns about cardiac safety. Whether genetic factors could modulate the risk of piperaquine-mediated QT prolongations remained unclear. Here, we first profiled the genetic landscape of KCNH2 variability using data from 141,614 individuals. Overall, we found 1,007 exonic variants distributed over the entire gene body, 555 of which were missense. By optimizing the gene-specific parametrization of 16 partly orthogonal computational algorithms, we developed a KCNH2 -specific ensemble classifier that identified a total of 116 putatively deleterious missense variations. To evaluate the clinical relevance of KCNH2 variability, we then sequenced 293 Malian patients with uncomplicated malaria and identified 13 variations within the voltage sensing and pore domains of Kv11.1 that directly interact with channel blockers. Cross-referencing of genetic and electrocardiographic data before and after piperaquine exposure revealed that carriers of two common variants, rs1805121 and rs41314375, experienced significantly higher QT prolongations (ΔQTc of 41.8 ms and 61 ms, respectively, vs 14.4 ms in controls) with more than 50% of carriers having increases in QTc &gt;30 ms. Furthermore, we identified three carriers of rare population-specific variations who experienced clinically relevant delayed ventricular repolarization. Combined, our results map population-scale genetic variability of KCNH2 and identify genetic biomarkers for piperaquine-induced QT prolongation that could help to flag at-risk patients and optimize efficacy and adherence to antimalarial therapy.
ER-anchored protein sorting controls the fate of two proteasome activators for intracellular organelle communication during proteotoxic stress
2024-03-28

<title>Abstract</title> Proteotoxic stress, characterized by the accumulation of damaged proteins, poses a significant challenge to cellular homeostasis. To mitigate proteotoxicity eukaryotes employ the proteasome that is regulated by proteasome activators, e.g. transcription factors that promote gene expression of proteasome subunits. As proteotoxicity originates in different compartments, cells need to perceive signals from various locations. Understanding which components integrate signals to address proteotoxicity is essential to develop strategies to cope with proteotoxicity but remain elusive. Here, we identify that the proteasome autoregulatory feedback loop acts as a gatekeeper to facilitate the communication between nucleus and chloroplast. We reveal that the ER-anchored protein sorting system (ERAPS) controls the proteasomal degradation or nuclear translocation of proteasome activators NAC53 and NAC78. While both transcription factors activate the proteasome gene expression, they repress photosynthesis-associated nuclear genes during proteotoxicity through association with a conserved cis-element. Our data implicate a general trade-off between proteasome function and energy metabolism unravelling an unprecedented mechanism of how eukaryotic cells cope with proteotoxicity. Collectively, our discoveries provide a novel conceptual framework in which the proteasome autoregulatory feedback loop coordinates subcellular proteostasis and the trade-off between growth and defence.
Behavioral and Neurophysiological Effects of Electrical Stunning on Zebrafish Larvae
2024-03-28

<title>Abstract</title> In today’s scientific research, two methods dominate the way zebrafish larvae are euthanized after experimental procedures: anesthetic overdose and rapid cooling. Although easy to apply, the anesthetic MS-222 takes about a minute to act, fish show aversive reactions, and inter-individual differences limit its reliability. Rapid cooling only kills larvae after many minutes and is not listed as approved method in the relevant EU directive. Electrical stunning is a promising alternative euthanasia method but hasn’t been established yet for zebrafish. In this study, we characterize both behavioral and neurophysiological effects of electrical stunning in 4 dpf zebrafish larvae. We identified the electric field magnitude and stimulus duration (32 s at 50 V/cm) that reliably euthanize free-swimming larvae and agarose-embedded larvae and provide an easy-to-implement protocol. Behavioral analysis and calcium neurophysiology show that larvae lose consciousness very fast and stop responding to touch and visual stimuli (&lt; 1 second). Electrically stunned larvae do not show coordinated brain activity anymore and their brains will instead undergo a series of concerted whole-brain calcium waves over the course of many minutes before the ultimate cessation of all brain signals. Consistent with the imperative of implementing the 3R at all stages of animal experiments, the rapid and reliable euthanasia achieved by electrical stunning has the potential to bring about a real refinement of the welfare of more than 5 million zebrafish used annually in biomedical research worldwide.
Unraveling the Predictors for Delirium and ICU Stay Duration in Patients with Heart Failure and Reduced Ejection Fraction (HFrEF) Undergoing Coronary Artery Bypass Grafting—A Multicentric Analysis
2024-03-28

Objective: This study assesses predictors for postoperative delirium (POD) and ICU stay durations in HFrEF patients undergoing CABG, focusing on ONCAB versus OPCAB surgical methods. Summary Background Data: In cardiac surgery, especially CABG, POD significantly impacts patient recovery and healthcare resource utilization. With varying incidences based on surgical techniques, this study provides an in-depth analysis of POD in the context of HFrEF patients, a group particularly susceptible to this complication. Methods: A retrospective analysis of 572 patients who underwent isolated CABG surgery with a preoperative ejection fraction under 40% was conducted at four German university hospitals. Patients were categorized into ONCAB and OPCAB groups for comparative analysis. Results: Age and Euro Score II were significant predictors of POD. The ONCAB group showed higher incidences of re-sternotomy (OR: 3.37), ECLS requirement (OR: 2.29), and AKI (OR: 1.49), whereas OPCAB was associated with a lower incidence of delirium. Statistical analysis indicated a significant difference in ICU stay durations between the two groups, influenced by surgical complexity and postoperative complications. Conclusions: This study underscores the importance of surgical technique in determining postoperative outcomes in HFrEF patients undergoing CABG. OPCAB may offer advantages in reducing POD incidence. These findings suggest the need for tailored surgical decisions and comprehensive care strategies to enhance patient recovery and optimize healthcare resources.
FRET-based visualization of cGMP signaling in glomerular endothelial cells and podocytes
2024-03-28

<p class="first" dir="auto" id="d1207999e200">Background: Drugs targeting the cGMP pathway have been successful in the treatment of vascular diseases and sparked interest in translation to renal diseases. In the kidney field, the literature relies on methods lacking both temporal and spatial resolution to reveal the dynamic and regulatory differences in the synthesis of cGMP in glomerular endothelial cells (GECs) and podocytes. <p dir="auto" id="d1207999e202">Methods: Acute kidney slices from mice expressing the genetically encoded fluorescent FRET-based cGMP biosensor cGi500 exclusively in the cytosol of endothelial cells or podocytes were prepared. Slices were stimulated with the atrial natriuretic peptide (ANP) or/and SNAP (NO donor) without or with several phosphodiesterase (PDE) inhibitors. <p dir="auto" id="d1207999e204">Results: Both GECs and podocytes respond to stimulation with ANP (via pGC) and SNAP (via sGC) with an increase in cytosolic cGMP concentrations. GECs exhibited a transient cGMP signaling in response to the activation of both signaling pathways. Podocytes, however, showed a prolonged cGMP signal after activation of the pGC pathway. Simultaneous stimulation with ANP and SNAP led to an additive response in GECs, whereas cGMP levels in podocytes were less elevated compared to ANP stimulation alone. The use of PDE inhibitors revealed a lower PDE activity in podocytes (predominated by PDE3 and PDE5) compared to GECs (predominated by PDE2a). <p dir="auto" id="d1207999e206">Conclusion: Both cGMP signaling pathways are present in GECs and podocytes and show cell-specific differences in synthesis and degradation. Further insights into cell-specific cGMP signaling could provide new therapeutic options for treating kidney diseases.
Genotype–phenotype correlation in PRKN-associated Parkinson’s disease
2024-03-29

Abstract Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson’s disease (PD). 647 patients with PRKN -PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN -PD was also assessed. Among 133 variants in index cases ( n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion ( n = 145, 12.3%), followed by the p.R275W substitution ( n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN -PD respectively ( p &lt; 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN -PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN -PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials.
GenoTools: An Open-Source Python Package for Efficient Genotype Data Quality Control and Analysis
2024-03-29

Abstract GenoTools, a Python package, streamlines population genetics research by integrating ancestry estimation, quality control (QC), and genome-wide association studies (GWAS) capabilities into efficient pipelines. By tracking samples, variants, and quality-specific measures throughout fully customizable pipelines, users can easily manage genetics data for large and small studies. GenoTools’ “Ancestry” module renders highly accurate predictions, allowing for high-quality ancestry-specific studies, and enables custom ancestry model training and serialization, specified to the user’s genotyping or sequencing platform. As the genotype processing engine that powers several large initiatives, including the NIH’s Center for Alzheimer’s and Related Dementias (CARD) and the Global Parkinson’s Genetics Program (GP2). GenoTools was used to process and analyze the UK Biobank and major Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) datasets with over 400,000 genotypes from arrays and 5000 sequences and has led to novel discoveries in diverse populations. It has provided replicable ancestry predictions, implemented rigorous QC, and conducted genetic ancestry-specific GWAS to identify systematic errors or biases through a single command. GenoTools is a customizable tool that enables users to efficiently analyze and scale genotype data with reproducible and scalable ancestry, QC, and GWAS pipelines.
Deciphering UVA/Riboflavin Collagen Crosslinking: A Pathway to Improve Biomedical Materials
2024-03-29

Abstract Collagen crosslinking employing ultraviolet A rays and riboflavin (UVA/R) has emerged as a pivotal technique in clinical therapies, especially in ophthalmology since the 1990s. Despite its clinical adoption, the lack of clarity of the detailed mechanism and the imperative for a refined manufacturing process necessitates further investigation. This study advances the understanding of UVA/R crosslinked collagen, concentrating on identifying the primary crosslinking sites using seven synthetic peptides and exploring the pathways of riboflavin‐mediated crosslinking. The results demonstrate that tyrosine residues are key crosslinking sites, and riboflavin plays a dual role as both a catalyst and a competitive inhibitor in the crosslinking process. Furthermore, the UVA/R crosslinked collagen matrix exhibits a more harmonious balance between stability and degradability compared with chemically crosslinked collagen matrices, coupled with superior mechanical properties and augmented biocompatibility. In vivo experiments further validate its excellent biocompatibility, reduced tissue inflammation, and promotion of tissue regeneration. The research provides crucial insights into collagen crosslinking mechanisms, paving the way for the development of sophisticated collagen‐based biomaterials tailored for biomedical applications.
The impact of substrate stiffness on morphological, transcriptional and functional aspects in RPE
2024-03-29

Abstract Alterations in the structure and composition of Bruch’s membrane (BrM) and loss of retinal pigment epithelial (RPE) cells are associated with various ocular diseases, notably age-related macular degeneration (AMD) as well as several inherited retinal diseases (IRDs). We explored the influence of stiffness as a major BrM characteristic on the RPE transcriptome and morphology. ARPE-19 cells were plated on soft ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mi>E</mml:mi> <mml:mo>=</mml:mo> <mml:mn>30</mml:mn> <mml:mspace/> <mml:mtext>kPa</mml:mtext> </mml:mrow> </mml:math> ) or stiff ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mi>E</mml:mi> <mml:mo>=</mml:mo> <mml:mn>80</mml:mn> <mml:mspace/> <mml:mtext>kPa</mml:mtext> </mml:mrow> </mml:math> ) polyacrylamide gels (PA gels) or standard tissue culture plastic (TCP). Next-generation sequencing (NGS) data on differentially expressed small RNAs (sRNAs) and messenger RNAs (mRNAs) were validated by qPCR, immunofluorescence or western blotting. The microRNA (miRNA) fraction of sRNAs grew with substrate stiffness and distinct miRNAs such as miR-204 or miR-222 were differentially expressed. mRNA targets of differentially expressed miRNAs were stably expressed, suggesting a homeostatic effect of miRNAs. mRNA transcription patterns were substrate stiffness-dependent, including components of Wnt/beta-catenin signaling, Microphthalmia-Associated Transcription Factor (MITF) and Dicer. These findings highlight the relevance of mechanical properties of the extracellular matrix (ECM) in cell culture experiments, especially those focusing on ECM-related diseases, such as AMD.
PD-L1 Expression in High-Risk Non-Muscle-Invasive Bladder Cancer Is Influenced by Intravesical Bacillus Calmette–Guérin (BCG) Therapy
2024-03-29

In the expanding landscape of immune checkpoint inhibitors (CPI) in high-risk (HR) non-muscle-invasive bladder cancer (NMIBC), the role of programmed death ligand 1 (PD-L1) as prognostic and predictive is increasingly significant. However, data evaluating its variability and susceptibility to Bacillus Calmette–Guérin (BCG) therapy in HR NMIBC patients is scarce. This retrospective study analyzed 126 HR NMIBC tissue samples from 63 patients (38× BCG-treated, 25× BCG-naïve) at two time points to assess PD-L1 expression using the ‘combined positivity score’ (CPS) with the 22C3 DAKO antibody method and correlated it with clinicopathological parameters. A CPS &gt; 10 defined PD-L1 positivity. The impact of initial PD-L1 status and its change over time on time-to-recurrence, progression-free survival, and overall survival (TTR, PFS, OS) was analyzed using Kaplan–Meier and Cox proportional hazard models. BCG treatment significantly increased PD-L1 expression (5.31 vs. 0.22, p = 0.0423), with PD-L1 positive cases rising post-treatment in the BCG group and remaining unchanged in BCG-naïve patients. Multivariate analysis including T-stage, CIS, grading, tumor size, multifocality, age, and sex revealed a significant correlation between PD-L1 status change to positivity and improved TTR (p = 0.03). Our findings demonstrate a potential modulation of the PD-L1 status by an intravesical BCG therapy. However, its prognostic value appears limited.
Unraveling Axonal Transcriptional Landscapes: Insights from iPSC-Derived Cortical Neurons and Implications for Motor Neuron Degeneration
2024-03-29

Abstract Neuronal function and pathology are deeply influenced by the distinct molecular profiles of the axon and soma. Traditional studies have often overlooked these differences due to the technical challenges of compartment specific analysis. In this study, we employ a robust RNA-sequencing (RNA-seq) approach, using microfluidic devices, to generate high-quality axonal transcriptomes from iPSC-derived cortical neurons (CNs). We achieve high specificity of axonal fractions, ensuring sample purity without contamination. Comparative analysis revealed a unique and specific transcriptional landscape in axonal compartments, characterized by diverse transcript types, including protein-coding mRNAs, RNAs encoding ribosomal proteins (RPs), mitochondrial-encoded RNAs, and long non-coding RNAs (lncRNAs). Previous works have reported the existence of transcription factors (TFs) in the axon. Here, we detect a set of TFs specific to the axon and indicative of their active participation in transcriptional regulation. To investigate transcripts and pathways essential for central motor neuron (MN) degeneration and maintenance we analyzed KIF1C-knockout (KO) CNs, modeling hereditary spastic paraplegia (HSP), a disorder associated with prominent length-dependent degeneration of central MN axons. We found that several key factors crucial for survival and health were absent in KIF1C-KO axons, highlighting a possible role of these also in other neurodegenerative diseases. Taken together, this study underscores the utility of microfluidic devices in studying compartment-specific transcriptomics in human neuronal models and reveals complex molecular dynamics of axonal biology. The impact of KIF1C on the axonal transcriptome not only deepens our understanding of MN diseases but also presents a promising avenue for exploration of compartment specific disease mechanisms.
Inferring Ancestry with the Hierarchical Soft Clustering Approach tangleGen
2024-03-29

Understanding the genetic ancestry of populations is central to numerous scientific and societal fields. It contributes to a better understanding of human evolutionary history, advances personalized medicine, aids in forensic identification, and allows individuals to connect to their genealogical roots. Existing methods, such as ADMIXTURE, have significantly improved our ability to infer ancestries. However, these methods typically work with a fixed number of independent ancestral populations. As a result, they provide insight into genetic admixture, but do not include a hierarchical interpretation. In particular, the intricate ancestral population structures remain difficult to unravel. Alternative methods with a consistent inheritance structure, such as hierarchical clustering, may offer benefits in terms of interpreting the inferred ancestries. Here, we present tangleGen, a soft clustering tool that transfers the hierarchical machine learning framework Tangles, which leverages graph theoretical concepts, to the field of population genetics. The hierarchical perspective of tangleGen on the composition and structure of populations improves the interpretability of the inferred ancestral relationships. Moreover, tangleGen adds a new layer of explainability, as it allows identifying the SNPs that are responsible for the clustering structure. We demonstrate the capabilities and benefits of tangleGen for the inference of ancestral relationships, using both simulated data and data from the 1000 Genomes Project.
Sustained ON alpha retinal ganglion cells in the temporal retina exhibit task-specific regional adaptions in dendritic signal integration
2024-03-29

Various retinal ganglion cells (RGCs) show regional adaptations, for instance, to increase visual acuity. However, for many RGC types, it is not known how they vary in their signalprocessing properties across the retina. In the mouse retina, sustained ON alpha (sONα) RGCs were found to have differences in morphology and receptive field sizes along the nasotemporal axis, and temporal sONα RGCs are likely to play a role in visually guided hunting. Thus, we hypothesised that this cell type also exhibits regional adaptations on the level of dendritic signal processing and that these adaptations are advantageous for prey capture. Here, we measured dendritic signals from individual sONα RGCs at different locations in the exvivo whole-mount mouse retina using two-photon microscopy. We measured both postsynaptic Ca 2+ signals at the dendrites of individual RGCs and presynaptic glutamate signals from bipolar cells (BCs). We found that temporal sONα RGC dendrites exhibit, in addition to the expected sustained-ON signals with only weak surrounds, signals with strong surround suppression, which were not present in nasal sONα RGCs. This difference was also present in the excitatory presynaptic inputs from BCs, suggesting a presynaptic origin. Finally, using population models in an encoder-decoder paradigm, we showed that these adaptations might be beneficial for detecting crickets in hunting behaviour.
Sustained bias of spatial attention in a 3T MRI scanner
2024-03-29

Abstract The static magnetic field of MRI scanners induces magneto-hydrodynamic stimulation of the vestibular organ (MVS) in the inner ear. This not only causes a horizontal vestibular nystagmus but also induces a horizontal bias in spatial attention. In this study, we aimed to determine the time course of MVS-induced biases in both VOR and spatial attention inside a 3T MRI-scanner as well as their respective aftereffects after participants left the scanner. Eye movements and overt spatial attention in a visual search task were assessed in healthy volunteers before, during and after a one-hour MVS period. All participants exhibited a VOR inside the scanner, which declined over time but never vanished completely. Importantly, there was also an MVS-induced horizontal bias in spatial attention and exploration, which persisted throughout the entire hour within the scanner. Upon exiting the scanner, we observed aftereffects in the opposite direction manifested in both the VOR and in spatial attention, lasting for about 6 minutes. Sustained MVS effects on spatial attention have important implications for the design and interpretation of fMRI-studies and for the development of therapeutic interventions counteracting spatial neglect.