Risk factors for AKI or mortality and long-term follow-up in COVID-19 infected patients in the era nefore vaccination.

BACKGROUND: Acute kidney injury (AKI) is a severe complication of coronavirus disease 2019 (COVID-19) and is associated with a higher risk of mortality. Understanding the risk factors contributing to COVID-19-related AKI and mortality before vaccination is important for the initiation of preventative measures and early treatment strategies. METHODS: This study included patients aged ≥18 years diagnosed with COVID-19 through polymerase chain reaction from May 2020 to July 2021, admitted in three local hospitals in Taiwan, with an extended follow-up until June 30, 2022. A median follow-up period of 250 days was used to assess AKI development and mortality. AKI was defined according to the Kidney Disease Improving Global Outcomes criteria. Multivariate Cox regression analysis of AKI and mortality-related risk factors was performed. RESULTS: Of the 720 hospitalized patients with COVID-19, 90 (22%) developed AKI. Moreover, 80%, 10.1%, and 8.9% of the patients had stage 1, 2, and 3 AKI, respectively. Patients with stage 1-3 AKI had significantly lower survival rates than those without AKI (p = 0.0012). The mean duration of post-admission AKI occurrence was 9.50 ± 11.32 days. Older age, hypoalbuminemia, and higher D-dimer and ferritin levels were associated with COVID-19 mortality. In COVID-19 AKI, in addition to older age and high D-dimer and ferritin levels, chronic kidney disease emerged as an independent risk factor. CONCLUSION: COVID-19-related AKI develops early, exhibits a temporal association with respiratory failure, and is linked to an unfavorable prognosis. The mortality rate increased according to the AKI stage (p = 0.0012). Age; albumin, D-dimer, and ferritin levels; and the underlying chronic kidney disease status upon admission are crucial factors for predicting AKI development, which increases the mortality risk. Monitoring the renal function not only within 10 days of COVID-19 onset, but also within one month after the disease onset.

Sequential closed-loop Bayesian optimization as a guide for organic molecular metallophotocatalyst formulation discovery.

Conjugated organic photoredox catalysts (OPCs) can promote a wide range of chemical transformations. It is challenging to predict the catalytic activities of OPCs from first principles, either by expert knowledge or by using a priori calculations, as catalyst activity depends on a complex range of interrelated properties. Organic photocatalysts and other catalyst systems have often been discovered by a mixture of design and trial and error. Here we report a two-step data-driven approach to the targeted synthesis of OPCs and the subsequent reaction optimization for metallophotocatalysis, demonstrated for decarboxylative sp3-sp2 cross-coupling of amino acids with aryl halides. Our approach uses a Bayesian optimization strategy coupled with encoding of key physical properties using molecular descriptors to identify promising OPCs from a virtual library of 560 candidate molecules. This led to OPC formulations that are competitive with iridium catalysts by exploring just 2.4% of the available catalyst formulation space (107 of 4,500 possible reaction conditions).

Targeting TGFß receptor-mediated snail and twist: WSG, a polysaccharide from Ganoderma lucidum, and it-based dissolvable microneedle patch suppress melanoma cells.

Cutaneous melanoma is a lethal skin cancer variant with pronounced aggressiveness and metastatic potential. However, few targeted medications inhibit the progression of melanoma. Ganoderma lucidum, which is a type of mushroom, is widely used as a non-toxic alternative adjunct therapy for cancer patients. This study determines the effect of WSG, which is a water-soluble glucan that is derived from G. lucidum, on melanoma cells. The results show that WSG inhibits cell viability and the mobility of melanoma cells. WSG induces changes in the expression of epithelial-to-mesenchymal transition (EMT)-related markers. WSG also downregulates EMT-related transcription factors, Snail and Twist. Signal transduction assays show that WSG reduces the protein levels in transforming growth factor ß receptors (TGFßRs) and consequently inhibits the phosphorylation of intracellular signaling molecules, such as FAK, ERK1/2 and Smad2. An In vivo study shows that WSG suppresses melanoma growth in B16F10-bearing mice. To enhance transdermal drug delivery and prevent oxidation, two highly biocompatible compounds, polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP), are used to synthesize a dissolvable microneedle patch that is loaded with WSG (MN-WSG). A functional assay shows that MN-WSG has an effect that is comparable to that of WSG alone. These results show that WSG has significant potential as a therapeutic agent for melanoma treatment. MN-WSG may allow groundbreaking therapeutic approaches and offers a novel method for delivering this potent compound effectively.

Characterizing dysregulations via cell-cell communications in Alzheimer's brains using single-cell transcriptomes.

BACKGROUND: Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting 44 million people worldwide, leading to cognitive decline, memory loss, and significant impairment in daily functioning. The recent single-cell sequencing technology has revolutionized genetic and genomic resolution by enabling scientists to explore the diversity of gene expression patterns at the finest resolution. Most existing studies have solely focused on molecular perturbations within each cell, but cells live in microenvironments rather than in isolated entities. Here, we leveraged the large-scale and publicly available single-nucleus RNA sequencing in the human prefrontal cortex to investigate cell-to-cell communication in healthy brains and their perturbations in AD. We uniformly processed the snRNA-seq with strict QCs and labeled canonical cell types consistent with the definitions from the BRAIN Initiative Cell Census Network. From ligand and receptor gene expression, we built a high-confidence cell-to-cell communication network to investigate signaling differences between AD and healthy brains. RESULTS: Specifically, we first performed broad communication pattern analyses to highlight that biologically related cell types in normal brains rely on largely overlapping signaling networks and that the AD brain exhibits the irregular inter-mixing of cell types and signaling pathways. Secondly, we performed a more focused cell-type-centric analysis and found that excitatory neurons in AD have significantly increased their communications to inhibitory neurons, while inhibitory neurons and other non-neuronal cells globally decreased theirs to all cells. Then, we delved deeper with a signaling-centric view, showing that canonical signaling pathways CSF, TGFß, and CX3C are significantly dysregulated in their signaling to the cell type microglia/PVM and from endothelial to neuronal cells for the WNT pathway. Finally, after extracting 23 known AD risk genes, our intracellular communication analysis revealed a strong connection of extracellular ligand genes APP, APOE, and PSEN1 to intracellular AD risk genes TREM2, ABCA1, and APP in the communication from astrocytes and microglia to neurons. CONCLUSIONS: In summary, with the novel advances in single-cell sequencing technologies, we show that cellular signaling is regulated in a cell-type-specific manner and that improper regulation of extracellular signaling genes is linked to intracellular risk genes, giving the mechanistic intra- and inter-cellular picture of AD.

Single-cell genomics and regulatory networks for 388 human brains.

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.

Spatially controlled diffusion range of tumor-associated angiogenic factors to develop a tumor model using a microfluidic resistive circuit.

Developing a tumor model with vessels has been a challenge in microfluidics. This difficulty is because cancer cells can overgrow in a co-culture system. The up-regulation of anti-angiogenic factors during the initial tumor development can hinder neovascularization. The standard method is to develop a quiescent vessel network before loading a tumor construct in an adjacent chamber, which simulates the interaction between a tumor and its surrounding vessels. Here, we present a new method that allows a vessel network and a tumor to develop simultaneously in two linked chambers. The physiological environment of these two chambers is controlled by a microfluidic resistive circuit using two symmetric long microchannels. Applying the resistive circuit, a diffusion-dominated environment with a small 2-D pressure gradient is created across the two chambers with velocity <10.9 nm s-1 and Péclet number <6.3 × 10-5. This 2-D pressure gradient creates a V-shaped velocity clamp to confine the tumor-associated angiogenic factors at pores between the two chambers, and it has two functions. At the early stage, vasculogenesis is stimulated to grow a vessel network in the vessel chamber with minimal influence from the tumor that is still developed in the adjacent chamber. At the post-tumor-development stage, the induced steep concentration gradient at pores mimics vessel-tumor interactions to stimulate angiogenesis to grow vessels toward the tumor. Applying this method, we demonstrate that vasculogenic vessels can grow first, followed by stimulating angiogenesis. Angiogenic vessels can grow into stroma tissue up to 1.3 mm long, and vessels can also grow into or wrap around a 625 µm tumor spheroid or a tumor tissue developed from a cell suspension. In summary, our study suggests that the interactions between a developing vasculature and a growing tumor must be controlled differently throughout the tissue development process, including at the early stage when vessels are still forming and at the later stage when the tumor needs to interact with the vessels.

Single-cell genomics and regulatory networks for 388 human brains.

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet, little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multi-omics datasets into a resource comprising >2.8M nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550K cell-type-specific regulatory elements and >1.4M single-cell expression-quantitative-trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.

Sequential multimodal treatments with chemotherapy and surgery for advanced soft tissue sarcoma may be associated with better survival than chemotherapy.

BACKGROUND: In patients with advanced soft tissue sarcoma (STS), surgery had been reported to be associated with superior overall survival (OS). Chemotherapy details for such patients were less reported, and whether multimodal treatment with surgery and chemotherapy provides extra survival benefit remains unclear. METHODS: We retrospectively reviewed patients with newly diagnosed advanced STS treated at National Taiwan University Hospital from January 1, 2011, to December 31, 2017. OS was calculated from the day of diagnosis of advanced STS to the day of death or last follow-up. Baseline patient characteristics and details regarding surgery and chemotherapy were recorded. RESULTS: A total of 545 patients were diagnosed with STS from 2011 to 2017, of which 226 patients had advanced STS. The median age was 54.7 years, and 54% of patients were women. Approximately 38% of patients with advanced STS underwent surgery and exhibited a trend of longer OS compared with who did not (median = 18.6 vs. 11.9 months, p = 0.083). In the chemotherapy subgroup, the benefit of surgery was more prominent (median = 21.9 vs. 16.5 months, p = 0.037). Patients who received chemotherapy prior to surgery exhibited numerically longer OS than those who underwent surgery first (median = 33.9 vs. 18.3 months, p = 0.155). After adjusting other clinical factors, chemotherapy remained an independent factor associated with favourable OS. CONCLUSION: Surgery may be more beneficial for the patients who receive chemotherapy. Our results support evaluation of sequential multimodal treatments strategy including surgery and chemotherapy in patients with advanced STS.

A Supramolecular Assembly of EGCG for Long-Term Treatment of Allergic Rhinitis.

Allergic rhinitis (AR) is a type-I hypersensitivity disease mediated by immunoglobulin E (IgE). Although antihistamines, glucocorticoids, leukotriene receptor antagonists, and other drugs are widely used to treat AR, the various adverse side effects of long-term use of these drugs should not be ignored. Therefore, more effective and safe natural alternative strategies are urgently needed. To this end, this study designed a nanosupramolecular delivery system composed of ß-cyclodextrin supramolecular polymer (PCD), thiolated chitosan (TCS), and natural polyphenol epigallocatechin gallate (EGCG) for intranasal topical continuous treatment of AR. The TCS/PCD@EGCG nanocarriers exhibited an excellent performance in terms of retention and permeability in the nasal mucosa and released the vast majority of EGCG responsively in the nasal microenvironment, thus resulting in the significantly high antibacterial and antioxidant capacities. According to the in vitro model, compared with free EGCG, TCS/PCD@EGCG inhibited mast cell activity and abnormal histamine secretion in a more long-term and sustained manner. According to the in vivo model, whether in the presence of continuous or intermittent administration, TCS/PCD@EGCG substantially inhibited the secretion of allergenic factors and inflammatory factors, mitigated the pathological changes of nasal mucosa, alleviated the symptoms of rhinitis in mice, and produced a satisfactory therapeutic effect on AR. In particular, the therapeutic effect of TCS/PCD@EGCG systems were even superior to that of budesonide during intermittent treatment. Therefore, the TCS/PCD@EGCG nanocarrier is a potential long-lasting antiallergic medicine for the treatment of AR.

scENCORE: leveraging single-cell epigenetic data to predict chromatin conformation using graph embedding.

Dynamic compartmentalization of eukaryotic DNA into active and repressed states enables diverse transcriptional programs to arise from a single genetic blueprint, whereas its dysregulation can be strongly linked to a broad spectrum of diseases. While single-cell Hi-C experiments allow for chromosome conformation profiling across many cells, they are still expensive and not widely available for most labs. Here, we propose an alternate approach, scENCORE, to computationally reconstruct chromatin compartments from the more affordable and widely accessible single-cell epigenetic data. First, scENCORE constructs a long-range epigenetic correlation graph to mimic chromatin interaction frequencies, where nodes and edges represent genome bins and their correlations. Then, it learns the node embeddings to cluster genome regions into A/B compartments and aligns different graphs to quantify chromatin conformation changes across conditions. Benchmarking using cell-type-matched Hi-C experiments demonstrates that scENCORE can robustly reconstruct A/B compartments in a cell-type-specific manner. Furthermore, our chromatin confirmation switching studies highlight substantial compartment-switching events that may introduce substantial regulatory and transcriptional changes in psychiatric disease. In summary, scENCORE allows accurate and cost-effective A/B compartment reconstruction to delineate higher-order chromatin structure heterogeneity in complex tissues.

Zfra Overrides WWOX in Suppressing the Progression of Neurodegeneration.

We reported that a 31-amino-acid Zfra protein (zinc finger-like protein that regulates apoptosis) blocks neurodegeneration and cancer growth. Zfra binds WW domain-containing oxidoreductase (WWOX) to both N- and C-termini, which leads to accelerated WWOX degradation. WWOX limits the progression of neurodegeneration such as Alzheimer's disease (AD) by binding tau and tau-hyperphosphorylating enzymes. Similarly, Zfra binds many protein targets and accelerates their degradation independently of ubiquitination. Furthermore, Zfra4-10 peptide strongly prevents the progression of AD-like symptoms in triple-transgenic (3xTg) mice during aging. Zfra4-10 peptide restores memory loss in 9-month-old 3xTg mice by blocking the aggregation of a protein cascade, including TPC6AΔ, TIAF1, and SH3GLB2, by causing aggregation of tau and amyloid ß. Zfra4-10 also suppresses inflammatory NF-κB activation. Zfra-activated Hyal-2+ CD3- CD19- Z cells in the spleen, via Hyal-2/WWOX/Smad4 signaling, are potent in cancer suppression. In this perspective review, we provide mechanistic insights regarding how Zfra overrides WWOX to induce cancer suppression and retard AD progression via Z cells.

Metabolomics revealed more deleterious toxicity induced by the combined exposure of ammonia and nitrite on Ruditapes philippinarum compared to single exposure.

NH3-N and NO2-N always co-exist in the aquatic environment, but there is not a clear opinion on their joint toxicities to the molluscs. Presently, clams Ruditapes philippinarum were challenged by environmental concentrations of NH3-N and NO2-N, singly or in combination, and analyzed by metabolomics approaches, enzyme assays and transmission electron microscope (TEM) observation. Results showed that some same KEGG pathways with different enriched-metabolites were detected in the three exposed groups within one day, and completely different profiles of metabolites were found in the rest of the exposure period. The combined exposure induced heavier and more lasting toxicities to the clams compared with their single exposure. ACP activity and the number of secondary lysosomes were significantly increased after the combined exposure. The present study shed light on the joint-toxicity mechanism of NH3-N and NO2-N, and provided fundamental data for the toxicity research on inorganic nitrogen.

Machine Learning Accelerated Exploration of Ternary Organic Heterojunction Photocatalysts for Sacrificial Hydrogen Evolution.

Donor-acceptor heterojunctions in organic photocatalysts can provide enhanced exciton dissociation and charge separation, thereby improving the photocatalytic activity. However, the wide choice of possible donors and acceptors poses a challenge for the rational design of organic heterojunction photocatalysts, particularly for large ternary phase spaces. We accelerated the exploration of ternary organic heterojunction photocatalysts (TOHP) by using a combination of machine learning and high-throughput experimental screening. This involved 736 experiments in all, out of possible 4320 ternary combinations. The top ten most active TOHPs discovered using this strategy showed outstanding sacrificial hydrogen production rates of more than 500 mmol g-1 h-1, with the most active ternary material reaching a rate of 749.8 mmol g-1 h-1 under 1 sun illumination. These rates of photocatalytic hydrogen generation are among the highest reported for organic photocatalysts in the literature.

Origin of outer tropical cyclone rainbands.

Outer tropical cyclone rainbands (TCRs) are a concentrated region of heavy precipitation and hazardous weather within tropical cyclones (TCs). Outer TCRs pose considerable risk to human societies, but their origin remains unresolved. Here, we identify a total of 1029 outer TCRs at their formative stage from 95 TCs and present a large collection of radar observations in order to establish a robust foundation of the natural diversity of rainband origin. The results show the dominance of outer origin for the observed outer TCRs, in distinct contrast to theoretical modeling works of outer TCRs, which propose inner-origin scenarios. Our analysis also suggests that squall-line dynamics are a common, but not the sole, mechanism responsible for outer TCR formation. The nature of preexisting outer precipitation is found to be an important factor to influence the squall-line and non-squall-line outer TCR initiation.

The Potential of Ultrasound Radiomics in Carpal Tunnel Syndrome Diagnosis: A Systematic Review and Meta-Analysis.

Background: Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy for which ultrasound imaging has recently emerged as a valuable diagnostic tool. This meta-analysis aims to investigate the role of ultrasound radiomics in the diagnosis of CTS and compare it with other diagnostic approaches. Methods: We conducted a comprehensive search of electronic databases from inception to September 2023. The included studies were assessed for quality using the Quality Assessment Tool for Diagnostic Accuracy Studies. The primary outcome was the diagnostic performance of ultrasound radiomics compared to radiologist evaluation for diagnosing CTS. Results: Our meta-analysis included five observational studies comprising 840 participants. In the context of radiologist evaluation, the combined statistics for sensitivity, specificity, and diagnostic odds ratio were 0.78 (95% confidence interval (CI), 0.71 to 0.83), 0.72 (95% CI, 0.59 to 0.81), and 9 (95% CI, 5 to 15), respectively. In contrast, the ultrasound radiomics training mode yielded a combined sensitivity of 0.88 (95% CI, 0.85 to 0.91), a specificity of 0.88 (95% CI, 0.84 to 0.92), and a diagnostic odds ratio of 58 (95% CI, 38 to 87). Similarly, the ultrasound radiomics testing mode demonstrated an aggregated sensitivity of 0.85 (95% CI, 0.78 to 0.89), a specificity of 0.80 (95% CI, 0.73 to 0.85), and a diagnostic odds ratio of 22 (95% CI, 12 to 41). Conclusions: In contrast to assessments by radiologists, ultrasound radiomics exhibited superior diagnostic performance in detecting CTS. Furthermore, there was minimal variability in the diagnostic accuracy between the training and testing sets of ultrasound radiomics, highlighting its potential as a robust diagnostic tool in CTS.

Beneficial Effects of Oral Nutrition Supplements on the Nutritional Status and Physical Performance of Older Nursing Home Residents at Risk of Malnutrition.

The purpose of this study was to compare the effects of nutritional supplement drinks (NSDs) and nutritional education (NE) on the nutritional status and physical performance of older nursing home residents who were at risk of malnutrition. This study was a clustered, randomized, parallel, multi-center clinical trial, with 107 participants more than 65 years old and at risk of malnutrition recruited from several nursing homes in this study. Participants were divided into two groups: an NE group (n = 50) and an NSD group (n = 57). The NE group was given NE by a dietitian, while the NSD group was provided with two packs of NSD except receiving NE (Mei Balance, Meiji Holdings, Tokyo, Japan) per day as a snack between meals and before bed. Anthropometric data, blood pressure, nutritional status, blood biochemical biomarkers, and physical performance were measured before and after 12-week interventions. After 12 weeks of NE combined with NSD intervention, body weight, body-mass index, the mini nutritional assessment-short form (MNA-SF) score, walking speed, and SF-36 questionnaire score were improved in older nursing home residents at risk of malnutrition.

[Comprehensive nursing intervention for advanced prostate cancer patients undergoing chemoradiotherapy].

OBJECTIVE: To explore the effect of comprehensive nursing intervention in advanced PCa patients receiving chemoradiotherapy. METHODS: This study included 70 patients with advanced PCa undergoing chemoradiotherapy in our department from January 2020 to April 2022, who were randomly divided into a control (n = 35) and an intervention group (n = 35), the former receiving routine nursing care while the latter comprehensive nursing intervention, including such measures as health education, psychological care, radiotherapy care, chemotherapy care, and complication care. After intervention, comparisons were made between the two groups of patients in the Expanded Prostate Cancer Index Composite (EPIC) scores and incidence of adverse reactions to chemoradiotherapy. RESULTS: The scores on all the dimensions of EPIC were significantly higher in the intervention than in the control group (P < 0.05) and the incidence rate of radiation-induced proctitis and cystitis remarkably lower in the former than in the latter (36.11% vs 71.43%, P < 0.05). CONCLUSION: Comprehensive nursing intervention can improve the quality of life of the PCa patients undergoing chemoradiotherapy, increase their compliance with treatment and reduce their adverse reactions, and therefore deserves clinical promotion.

Engineering Alkaline-Stable Barley Stripe Mosaic Virus-Like Particles for Efficient Surface Modification.

Viruses and virus-like particles are powerful templates for materials synthesis because of their capacity for precise protein engineering and diverse surface functionalization. We recently developed a recombinant bacterial expression system for the production of barley stripe mosaic virus-like particles (BSMV VLPs). However, the applicability of this biotemplate was limited by low stability in alkaline conditions and a lack of chemical handles for ligand attachment. Here, we identify and validate novel residues in the BSMV Caspar carboxylate clusters that mediate virion disassembly through repulsive interactions at high pH. Point mutations of these residues to create attractive interactions that increase rod length ~2 fold, with an average rod length of 91 nm under alkaline conditions. To enable diverse chemical surface functionalization, we also introduce reactive lysine residues at the C-terminus of BSMV coat protein, which is presented on the VLP surface. Chemical conjugation reactions with this lysine proceed more quickly under alkaline conditions. Thus, our alkaline-stable VLP mutants are more suitable for rapid surface functionalization of long nanorods. This work validates novel residues involved in BSMV VLP assembly and demonstrates the feasibility of chemical functionalization of BSMV VLPs for the first time, enabling novel biomedical and chemical applications.

First Trimester Prediction of Preterm Birth in Patient Plasma with Machine-Learning-Guided Raman Spectroscopy and Metabolomics.

Preterm birth (PTB) is the leading cause of infant deaths globally. Current clinical measures often fail to identify women who may deliver preterm. Therefore, accurate screening tools are imperative for early prediction of PTB. Here, we show that Raman spectroscopy is a promising tool for studying biological interfaces, and we examine differences in the maternal metabolome of the first trimester plasma of PTB patients and those that delivered at term (healthy). We identified fifteen statistically significant metabolites that are predictive of the onset of PTB. Mass spectrometry metabolomics validates the Raman findings identifying key metabolic pathways that are enriched in PTB. We also show that patient clinical information alone and protein quantification of standard inflammatory cytokines both fail to identify PTB patients. We show for the first time that synergistic integration of Raman and clinical data guided with machine learning results in an unprecedented 85.1% accuracy of risk stratification of PTB in the first trimester that is currently not possible clinically. Correlations between metabolites and clinical features highlight the body mass index and maternal age as contributors of metabolic rewiring. Our findings show that Raman spectral screening may complement current prenatal care for early prediction of PTB, and our approach can be translated to other patient-specific biological interfaces.