HyperGen: Compact and Efficient Genome Sketching using Hyperdimensional Vectors.

MOTIVATION: Genomic distance estimation is a critical workload since exact computation for whole-genome similarity metrics such as Average Nucleotide Identity (ANI) incurs prohibitive runtime overhead. Genome sketching is a fast and memory-efficient solution to estimate ANI similarity by distilling representative k-mers from the original sequences. In this work, we present HyperGen that improves accuracy, runtime performance, and memory efficiency for large-scale ANI estimation. Unlike existing genome sketching algorithms that convert large genome files into discrete k-mer hashes, HyperGen leverages the emerging hyperdimensional computing (HDC) to encode genomes into quasi-orthogonal vectors (Hypervector, HV) in high-dimensional space. HV is compact and can preserve more information, allowing for accurate ANI estimation while reducing required sketch sizes. In particular, the HV sketch representation in HyperGen allows efficient ANI estimation using vector multiplication, which naturally benefits from highly optimized general matrix multiply (GEMM) routines. As a result, HyperGen enables the efficient sketching and ANI estimation for massive genome collections. RESULTS: We evaluate HyperGen 's sketching and database search performance using several genome datasets at various scales. HyperGen is able to achieve comparable or superior ANI estimation error and linearity compared to other sketch-based counterparts. The measurement results show that HyperGen is one of the fastest tools for both genome sketching and database search. Meanwhile, HyperGen produces memory-efficient sketch files while ensuring high ANI estimation accuracy. AVAILABILITY: A Rust implementation of HyperGen is freely available under the MIT license as an open-source software project at https://github.com/wh-xu/Hyper-Gen. The scripts to reproduce the experimental results can be accessed at https://github.com/wh-xu/experiment-hyper-gen.

Effects of circulating inflammatory proteins on spinal degenerative diseases: Evidence from genetic correlations and Mendelian randomization study.

Background: Numerous investigations have suggested links between circulating inflammatory proteins (CIPs) and spinal degenerative diseases (SDDs), but causality has not been proven. This study used Mendelian randomization (MR) to investigate the causal associations between 91 CIPs and cervical spondylosis (CS), prolapsed disc/slipped disc (PD/SD), spinal canal stenosis (SCS), and spondylolisthesis/spondylolysis. Methods: Genetic variants data for CIPs and SDDs were obtained from the genome-wide association studies (GWAS) database. We used inverse variance weighted (IVW) as the primary method, analyzing the validity and robustness of the results through pleiotropy and heterogeneity tests and performing reverse MR analysis to test for reverse causality. Results: The IVW results with Bonferroni correction indicated that beta-nerve growth factor (ß-NGF), C-X-C motif chemokine 6 (CXCL6), and interleukin-6 (IL-6) can increase the risk of CS. Fibroblast growth factor 19 (FGF19), sulfotransferase 1A1 (SULT1A1), and tumor necrosis factor-beta (TNF-ß) can increase PD/SD risk, whereas urokinase-type plasminogen activator (u-PA) can decrease the risk of PD/SD. FGF19 and TNF can increase SCS risk. STAM binding protein (STAMBP) and T-cell surface glycoprotein CD6 isoform (CD6 isoform) can increase the risk of spondylolisthesis/spondylolysis, whereas monocyte chemoattractant protein 2 (MCP2) and latency-associated peptide transforming growth factor beta 1 (LAP-TGF-ß1) can decrease spondylolisthesis/spondylolysis risk. Conclusions: MR analysis indicated the causal associations between multiple genetically predicted CIPs and the risk of four SDDs (CS, PD/SD, SCS, and spondylolisthesis/spondylolysis). This study provides reliable genetic evidence for in-depth exploration of the involvement of CIPs in the pathogenic mechanism of SDDs and provides novel potential targets for SDDs.

Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma.

BACKGROUND: The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown. METHODS: We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles. RESULTS: In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively. CONCLUSIONS: Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).

Metagenomic next-generation sequencing reveals co-infection with Legionella pneumophila and Fusobacterium necrophorum in a patient with severe pneumonia: a case report.

BACKGROUND: Legionella pneumonia is one of the most severe types of atypical pneumonia, impairing multiple organ systems, posing a threat to life. Diagnosing Legionella pneumonia is challenging due to difficulties in culturing the bacteria and limitations in immunoassay sensitivity and specificity. CASE PRESENTATION: This paper reports a rare case of sepsis caused by combined infection with Legionella pneumophila and Fusobacterium necrophorum, leading to respiratory failure, acute kidney injury, acute liver injury, myocardial damage, and electrolyte disorders. In addition, we systematically reviewed literature on patients with combined Legionella infections, analyzing their clinical features, laboratory results and diagnosis. CONCLUSIONS: For pathogens that require prolonged incubation periods and are less sensitive to conventional culturing methods, metagenomic next-generation sequencing (mNGS) can be a powerful supplement to pathogen screening and plays a significant role in the auxiliary diagnosis of complex infectious diseases.

Molecular targets of glucocorticoids that elucidate their therapeutic efficacy in aggressive lymphomas.

Glucocorticoids have been used for decades to treat lymphomas without an established mechanism of action. Using functional genomic, proteomic, and chemical screens, we discover that glucocorticoids inhibit oncogenic signaling by the B cell receptor (BCR), a recurrent feature of aggressive B cell malignancies, including diffuse large B cell lymphoma and Burkitt lymphoma. Glucocorticoids induce the glucocorticoid receptor (GR) to directly transactivate genes encoding negative regulators of BCR stability (LAPTM5; KLHL14) and the PI3 kinase pathway (INPP5D; DDIT4). GR directly represses transcription of CSK, a kinase that limits the activity of BCR-proximal Src-family kinases. CSK inhibition attenuates the constitutive BCR signaling of lymphomas by hyperactivating Src-family kinases, triggering their ubiquitination and degradation. With the knowledge that glucocorticoids disable oncogenic BCR signaling, they can now be deployed rationally to treat BCR-dependent aggressive lymphomas and used to construct mechanistically sound combination regimens with inhibitors of BTK, PI3 kinase, BCL2, and CSK.

Effects of circulating inflammatory proteins on osteoporosis and fractures: evidence from genetic correlation and Mendelian randomization study.

Objective: There is a controversy in studies of circulating inflammatory proteins (CIPs) in association with osteoporosis (OP) and fractures, and it is unclear if these two conditions are causally related. This study used MR analyses to investigate the causal associations between 91 CIPs and OP and 9 types of fractures. Methods: Genetic variants data for CIPs, OP, and fractures were obtained from the publicly available genome-wide association studies (GWAS) database. We used inverse variance weighted (IVW) as the primary analysis, pleiotropy, and heterogeneity tests to analyze the validity and robustness of causality and reverse MR analysis to test for reverse causality. Results: The IVW results with Bonferroni correction indicated that CXCL11 (OR = 1.2049; 95% CI: 1.0308-1.4083; P = 0.0192) can increase the risk of OP; IL-4 (OR = 1.2877; 95% CI: 1.1003-1.5070; P = 0.0016), IL-7 (OR = 1.2572; 95% CI: 1.0401-1.5196; P = 0.0180), IL-15RA (OR = 1.1346; 95% CI: 1.0163-1.2668; P = 0.0246), IL-17C (OR = 1.1353; 95% CI: 1.0272-1.2547; P = 0.0129), CXCL10 (OR = 1.2479; 95% CI: 1.0832-1.4377; P = 0.0022), eotaxin/CCL11 (OR = 1.1552; 95% CI: 1.0525-1.2678; P = 0.0024), and FGF23 (OR = 1.9437; 95% CI: 1.1875-3.1816; P = 0.0082) can increase the risk of fractures; whereas IL-10RB (OR = 0.9006; 95% CI: 0.8335-0.9730; P = 0.0080), CCL4 (OR = 0.9101; 95% CI: 0.8385-0.9878; P = 0.0242), MCP-3/CCL7 (OR = 0.8579; 95% CI: 0.7506-0.9806; P = 0.0246), IFN-γ [shoulder and upper arm (OR = 0.7832; 95% CI: 0.6605-0.9287; P = 0.0049); rib(s), sternum and thoracic spine (OR = 0.7228; 95% CI: 0.5681-0.9197; P = 0.0083)], ß-NGF (OR = 0.8384; 95% CI: 0.7473-0.9407; P = 0.0027), and SIRT2 (OR = 0.5167; 95% CI: 0.3296-0.8100; P = 0.0040) can decrease fractures risk. Conclusion: Mendelian randomization (MR) analyses indicated the causal associations between multiple genetically predicted CIPs and the risk of OP and fractures.

Ectopic expression of the transcription factor ONECUT3 drives a complex karyotype in myelodysplastic syndromes.

Chromosomal instability is a prominent biological feature of myelodysplastic syndromes (MDS), with over 50% of patients with MDS harboring chromosomal abnormalities or a complex karyotype (CK). Despite this observation, the mechanisms underlying mitotic and chromosomal defects in MDS remain elusive. In this study, we identified ectopic expression of the transcription factor ONECUT3, which is associated with CKs and poorer survival outcomes in MDS. ONECUT3-overexpressing cell models exhibited enrichment of several notable pathways, including signatures of sister chromosome exchange separation and mitotic nuclear division with the upregulation of INCENP and CDCA8 genes. Notably, dysregulation of chromosome passenger complex (CPC) accumulation, besides the cell equator and midbody, during mitotic phases consequently caused cytokinesis failure and defective chromosome segregation. Mechanistically, the homeobox (HOX) domain of ONECUT3, serving as the DNA binding domain, occupied the unique genomic regions of INCENP and CDCA8 and transcriptionally activated these 2 genes. We identified a lead compound, C5484617, that functionally targeted the HOX domain of ONECUT3, inhibiting its transcriptional activity on downstream genes, and synergistically resensitized MDS cells to hypomethylating agents. This study revealed that ONECUT3 promoted chromosomal instability by transcriptional activation of INCENP and CDCA8, suggesting potential prognostic and therapeutic roles for targeting high-risk MDS patients with a CK.

Highly selective detection of 2,4-dinitrophenol by fluorescent NH2-MIL-125(Ti) via dual-parameter sensing technology.

The organic contaminant 2,4-dinitrophenol (2,4-DNP) is widely prevalent and poses significant risks to human health. Although numerous in-depth studies having been reported on the highly sensitive detection of 2,4-DNP, there are still challenges to its selective detection. Here, the fluorescence intensity ratio (I0/I) and emission peak shift (Δλ) were utilized for selective detection of 2,4-DNP by NH2-MIL-125(Ti). Notably, the emission peak of the NH2-MIL-125(Ti) suspension exhibited a remarkable red shift in the presence of 2,4-DNP (Δλ = 26 nm), accompanied by the blue shift or weak red shift of analogs, which provided a solid basis for selective detection of 2,4-DNP. Meanwhile, the I0/I ratio of the NH2-MIL-125(Ti) suspension exhibited a robust linear correlation with 2,4-DNP at the low concentration range (0-70 µM). The interaction of the analyte with NH2-MIL-125(Ti) was revealed to involve intermolecular charge transfer (ICT) and fluorescence resonance energy transfer (FRET) through XPS, FTIR, and UV-vis absorption spectroscopy. Additionally, we achieved the detection of 2,4-DNP using a smartphone by recognizing both the blue (B) values and the luminance (L) values. The obtained results demonstrated that the NH2-MIL-125(Ti) probe based on dual-parameter sensing technology exhibited excellent potential for selectively detecting 2,4-DNP in water environments, thereby offering significant prospects for its application in water quality assessment.

Response to Bruton's tyrosine kinase inhibitors in aggressive lymphomas linked to chronic selective autophagy.

Diffuse large B cell lymphoma (DLBCL) is an aggressive, profoundly heterogeneous cancer, presenting a challenge for precision medicine. Bruton's tyrosine kinase (BTK) inhibitors block B cell receptor (BCR) signaling and are particularly effective in certain molecular subtypes of DLBCL that rely on chronic active BCR signaling to promote oncogenic NF-κB. The MCD genetic subtype, which often acquires mutations in the BCR subunit, CD79B, and in the innate immune adapter, MYD88L265P, typically resists chemotherapy but responds exceptionally to BTK inhibitors. However, the underlying mechanisms of response to BTK inhibitors are poorly understood. Herein, we find a non-canonical form of chronic selective autophagy in MCD DLBCL that targets ubiquitinated MYD88L265P for degradation in a TBK1-dependent manner. MCD tumors acquire genetic and epigenetic alterations that attenuate this autophagic tumor suppressive pathway. In contrast, BTK inhibitors promote autophagic degradation of MYD88L265P, thus explaining their exceptional clinical benefit in MCD DLBCL.

Biomechanical evaluation of different oblique lumbar interbody fusion constructs: a finite element analysis.

BACKGROUND: Finite element analysis (FEA) was performed to investigate the biomechanical differences between different adjunct fixation methods for oblique lumbar interbody fusion (OLIF) and to further analyze its effect on adjacent segmental degeneration. METHODS: We built a single-segment (Si-segment) finite element model (FEM) for L4-5 and a double-segment (Do-segment) FEM for L3-5. Each complete FEM was supplemented and modified, and both developed two surgical models of OLIF with assisted internal fixation. They were OLIF with posterior bilateral percutaneous pedicle screw (TINA system) fixation (OLIF + BPS) and OLIF with lateral plate system (OLIF + LPS). The range of motion (ROM) and displacement of the vertebral body, cage stress, adjacent segment disc stress, and spinal ligament tension were recorded for the four models during flexion/extension, right/left bending, and right/left rotation by applying follower load. RESULTS: For the BPS and LPS systems in the six postures of flexion, extension, right/left bending, and right/left rotation, the ROM of L4 in the Si-segment FEM were 0.32°/1.83°, 0.33°/1.34°, 0.23°/0.47°, 0.24°/0.45°, 0.33°/0.79°, and 0.34°/0.62°; the ROM of L4 in the Do-segment FEM were 0.39°/2.00°, 0.37°/1.38°, 0.23°/0.47°, 0.21°/0.44°, 0.33°/0.57°, and 0.31°/0.62°, and the ROM of L3 in the Do-segment FEM were 6.03°/7.31°, 2.52°/3.50°, 4.21°/4.38°, 4.21°/4.42°, 2.09°/2.32°, and 2.07°/2.43°. BPS system had less vertebral displacement, less cage maximum stress, and less spinal ligament tension in Si/Do-segment FEM relative to the LPS system. BPS system had a smaller upper adjacent vertebral ROM, greater intervertebral disc stress in terms of left and right bending as well as left and right rotation compared to the LPS system in the L3-4 of the Do-segment FEM. There was little biomechanical difference between the same fixation system in the Si/Do-segment FEM. CONCLUSIONS: Our finite element analysis showed that compared to OLIF + LPS, OLIF + BPS (TINA) is more effective in reducing interbody stress and spinal ligament tension, and it better maintains the stability of the target segment and provides a better fusion environment to resist cage subsidence. However, OLIF + BPS (TINA) may be more likely to cause adjacent segment degeneration than OLIF + LPS.

Enhanced axon outgrowth of spinal motor neurons in co-culturing with dorsal root ganglions antagonizes the growth inhibitory environment.

Introduction: Forming a bridge made of functional axons to span the lesion is essential to reconstruct the motor circuitry following spinal cord injury (SCI). Dorsal root ganglion (DRG) axons are robust in axon growth and have been proved to facilitate the growth of cortical neurons in a process of axon-facilitated axon regeneration. However, whether DRG transplantation affects the axon outgrowth of spinal motor neurons (SMNs) that play crucial roles in motor circuitry remains unclear. Methods: We investigated the axonal growth patterns of co-cultured DRGs and SMN aggregates (SMNAs) taking advantage of a well-designed 3D-printed in vitro system. Chondroitin sulphate proteoglycans (CSPG) induced inhibitory matrix was introduced to imitate the inhibitory environment following SCI. Axonal lengths of DRG, SMNA or DRG & SMNA cultured on the permissive or CSPG induced inhibitory matrix were measured and compared. Results: Our results indicated that under the guidance of full axonal connection generated from two opposing populations of DRGs, SMNA axons were growth-enhanced and elongated along the DRG axon bridge to distances that they could not otherwise reach. Quantitatively, the co-culture increased the SMNA axonal length by 32.1 %. Moreover, the CSPG matrix reduced the axonal length of DRGs and SMNAs by 46.2 % and 17.7 %, respectively. This inhibitory effect was antagonized by the co-culture of DRGs and SMNAs. Especially for SMNAs, they extended the axons across the CSPG-coating matrix, reached the lengths close to those of SMNAs cultured on the permissive matrix alone. Conclusions: This study deepens our understanding of axon-facilitated reconstruction of the motor circuitry. Moreover, the results support SCI treatment utilizing the enhanced outgrowth of axons to restore functional connectivity in SCI patients.

Quercetin is a Potential Therapy for Rheumatoid Arthritis via Targeting Caspase-8 Through Ferroptosis and Pyroptosis.

Background: Rheumatoid arthritis (RA) is one of the most common chronic inflammatory autoimmune diseases. However, the underlying molecular mechanisms of its pathogenesis are unknown. This study aimed to identify the common biomarkers of ferroptosis and pyroptosis in RA and screen potential drugs. Methods: The RA-related differentially expressed genes (DEGs) in GSE55235 were screened by R software and intersected with ferroptosis and pyroptosis gene libraries to obtain differentially expressed ferroptosis-related genes (DEFRGs) and differentially expressed pyroptosis-related genes (DEPRGs). We performed Gene Ontology (GO), Kyoto Encyclopedia of the Genome (KEGG), ClueGO, and Protein-Protein Interaction (PPI) analysis for DEFRGs and DEPRGs and validated them by machine learning. The microRNA/transcription factor (TF)-hub genes regulatory network was further constructed. The key gene was validated using the GSE77298 validation set, cellular validation was performed in in vitro experiments, and immune infiltration analysis was performed using CIBERSORT. Network pharmacology was used to find key gene-targeting drugs, followed by molecular docking and molecular dynamics simulations to analyze the binding stability between small-molecule drugs and large-molecule proteins. Results: Three hub genes (CASP8, PTGS2, and JUN) were screened via bioinformatics, and the key gene (CASP8) was validated and obtained through the validation set, and the diagnostic efficacy was verified to be excellent through the receiver operating characteristic (ROC) curves. The ferroptosis and pyroptosis phenotypes were constructed by fibroblast-like synoviocytes (FLS), and caspase-8 was detected and validated as a common biomarker for ferroptosis and pyroptosis in RA, and quercetin can reduce caspase-8 levels. Quercetin was found to be a potential target drug for caspase-8 by network pharmacology, and the stability of their binding was further verified using molecular docking and molecular dynamics simulations. Conclusion: Caspase-8 is an important biomarker for ferroptosis and pyroptosis in RA, and quercetin is a potential therapy for RA via targeting caspase-8 through ferroptosis and pyroptosis.

Mendelian randomization analysis suggests no associations of human herpes viruses with amyotrophic lateral sclerosis.

Background: The causal associations between infections with human herpes viruses (HHVs) and amyotrophic lateral sclerosis (ALS) has been disputed. This study investigated the causal associations between herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), HHV-6, and HHV-7 infections and ALS through a bidirectional Mendelian randomization (MR) method. Methods: The genome-wide association studies (GWAS) database were analyzed by inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods. MR-Egger intercept test, MR-PRESSO test, Cochran's Q test, funnel plots, and leaveone-out analysis were used to verify the validity and robustness of the MR results. Results: In the forward MR analysis of the IVW, genetically predicted HSV infections [odds ratio (OR) = 0.9917; 95% confidence interval (CI): 0.9685-1.0154; p = 0.4886], HSV keratitis and keratoconjunctivitis (OR = 0.9897; 95% CI: 0.9739-1.0059; p = 0.2107), anogenital HSV infection (OR = 1.0062; 95% CI: 0.9826-1.0304; p = 0.6081), VZV IgG (OR = 1.0003; 95% CI: 0.9849-1.0160; p = 0.9659), EBV IgG (OR = 0.9509; 95% CI: 0.8879-1.0183; p = 0.1497), CMV (OR = 0.9481; 95% CI: 0.8680-1.0357; p = 0.2374), HHV-6 IgG (OR = 0.9884; 95% CI: 0.9486-1.0298; p = 0.5765) and HHV-7 IgG (OR = 0.9991; 95% CI: 0.9693-1.0299; p = 0.9557) were not causally associated with ALS. The reverse MR analysis of the IVW revealed comparable findings, indicating no link between HHVs infections and ALS. The reliability and validity of the findings were verified by the sensitivity analysis. Conclusion: According to the MR study, there is no evidence of causal associations between genetically predicted HHVs (HSV, VZV, EBV, CMV, HHV-6, and HHV-7) and ALS.

Exploring the underlying mechanisms of Ashitaba in the management of non-alcoholic fatty liver disease by integrating the analysis of transcriptomics and metabolomics.

Ashitaba seems to improve glucose intolerance and decrease triglyceride (TG) and total cholesterol (TC), which contribute to the development of non-alcoholic fatty liver disease (NAFLD). However, it remains to be explored the mechanism of Ashitaba in managing NAFLD. We determined the impact of Ashitaba on NAFLD, particularly its underlying mechanisms at the bioinformatic level. The established NAFLD mouse model was treated with or without Ashitaba, and the underlying mechanism was explored using transcriptomics paired with metabolomics. Ashitaba reduced obesity and liver steatosis in NAFLD mice. It identified 429 differentially expressed genes (DEGs) and verified 45 differential metabolites, especially those that alleviate NAFLD via the FXR signaling pathway. Our data may provide insight into the therapeutic impact of Ashitaba in the management of NAFLD and may be useful in clinical interventions for NAFLD.

The mediating role of negative emotions in the relationship between smoking and health-related quality of life among Chinese individuals: A cross-sectional study.

INTRODUCTION: Although the negative impact of smoking on health has been confirmed in various studies, few have explored psychological factors mediating the relationship between smoking and health-related quality of life (HRQOL). This study aimed to investigate the relationship between smoking and HRQOL in the Chinese population and the mediating role of negative emotions (NEs). METHODS: Survey data were derived from a cross-sectional study conducted in China from 20 June to 31 August 2022. We recruited participants from 148 cities across the country using a stratified multistage sampling method. The HRQOL of the dependent variable was measured using the Chinese version of European Quality of Life-5 Dimensions (EQ-5D-5L). The Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder (GAD-7), and Perceived Stress Scale (PSS-4) were used to measure NE parameters including depression, anxiety, and perceived stress, as the intermediate variables. A multiple parallel mediation model was used to analyze the mediating role of NEs in smoking and HRQOL. RESULTS: A total of 21916 valid questionnaires were collected, of which 3010 (13.7%) and 18906 (86.3%) were categorized into smokers and non-smokers, respectively. The HRQOL (EQ-VAS score) of smokers (71.70 ± 23.08) was lower than that of non-smokers (73.69 ± 21.32), whereas the depression and anxiety levels of smokers were higher than those of non-smokers (all p<0.001). Moreover, smoking, NEs (depression and anxiety), and HRQOL showed pairwise correlations. According to the mediation analysis, depression (ß= -0.461; 95% BCa CI: -0.664 - -0.268) and anxiety (ß= -0.279; 95% BCa CI: -0.435 - -0.138) mediated the relationship between smoking and HRQOL after adjusting for demographic and life factors. CONCLUSIONS: These findings emphasize the necessity of studying the interaction between smoking, HRQOL, and Nes, and complementing the research on the impact of psychological factors on the HRQOL of smokers. Public health activities should focus on mental health and take targeted measures for the prevention, treatment, and rehabilitation of smokers.

CaHMA1 promotes Cd accumulation in pepper fruit.

The main planting areas for pepper (Capsicum sp.) are high in cadmium (Cd), which is the most prevalent heavy metal pollutant worldwide. Breeding pepper cultivars with low Cd levels can promote sustainable agricultural production and ensure the safety of pepper products. To identify breeding targets for reducing Cd accumulation in pepper fruits, we performed a genome-wide association study on 186 accessions. Polymorphisms were associated with fruit Cd content in a genomic region containing a homolog of Arabidopsis (Arabidopsis thaliana) Heavy metal-transporting ATPase 1 (HMA1) encoding a P-type ATPase. In two cultivars with contrasting Cd accumulation, transcriptome analysis revealed differentially expressed genes enriched for carbohydrate metabolism and photosynthesis in fruits with high Cd accumulation, and a Cd2+/Zn2+-exporting ATPase gene (HMA). Heterologous expression of CaHMA1 in yeast increases Cd sensitivity. Overexpression of CaHMA1 conferred a severe increase in Cd content in Arabidopsis plants, whereas reduced CaHMA1 expression in pepper fruits decreased Cd content. We propose that CaHMA1 expression may be an important component of the high Cd accumulation in pepper plants.

TLR8 aggravates skin inflammation and fibrosis by activating skin fibroblasts in systemic sclerosis.

OBJECTIVES: Innate immunity significantly contributes to systemic sclerosis (SSc) pathogenesis. TLR8 is an important innate immune mediator that is implicated in autoimmunity and fibrosis. However, the expression, mechanism of action, and pathogenic role of TLR8 in SSc remain unclear. The aim of this study was to explore the roles and underlying mechanisms of TLR8 in SSc. METHODS: The expression of TLR8 was analyzed based on a public dataset and then verified in skin tissues and skin fibroblasts of SSc patients. The role of TLR8 in inflammation and fibrosis was investigated using a TLR8-overexpression vector, activator (VTX-2337), inhibitor (cu-cpt-8m), and TLR8 siRNA in skin fibroblasts. The pathogenic role of TLR8 in skin inflammation and fibrosis was further validated in a bleomycin (BLM)-induced mouse skin inflammation and fibrosis model. RESULTS: TLR8 levels were significantly elevated in SSc skin tissues and myofibroblasts, along with significant activation of the TLR8 pathway. In vitro studies showed that overexpression or activation of TLR8 by a recombinant plasmid or VTX-2337 upregulated IL-6, IL-1ß, COL I, COL III, and α-SMA in skin fibroblasts. Consistently, both TLR8-siRNA and cu-cpt-8m reversed the phenotypes observed in TLR8-activating fibroblasts. Mechanistically, TLR8 induces skin fibrosis and inflammation in a manner dependent on the MAPK, NF-κB, and SMAD2/3 pathways. Subcutaneous injection of cu-cpt-8m significantly alleviated BLM-induced skin inflammation and fibrosis in vivo. CONCLUSION: TLR8 might be a promising therapeutic target to improve the treatment strategy for SSc skin inflammation and fibrosis.

Influence of social support on subjective well-being of patients with chronic diseases in China: chain-mediating effect of self-efficacy and perceived stress.

Introduction: The well-being of patients with chronic diseases is an issue of widespread concern in public health. While social support is thought to have a positive effect on it, the mechanisms of its influence have not been fully addressed. Thus, we explored the possible mediating effects of self-efficacy and perceived stress to determine the relationship between social support and well-being in these patients. Methods: A cross-sectional study was conducted among 4,657 patients with chronic diseases in China. The PROCESS Macro model 6 of SPSS was employed to explore the intermediary role between variables. Results: Self-efficacy and perceived stress played a partial intermediary role between social support and subjective well-being, with an effect ratio of 48.25% and 23.61%, respectively. Self-efficacy and perceived stress had a chain intermediary effect (28.14%) between social support and subjective well-being. Discussion: This study suggested that improving the self-efficacy of patients with chronic diseases to cope with the changes in social support caused by the disease could reduce stress and enhance subjective well-being.

Accelerating open modification spectral library searching on tensor core in high-dimensional space.

MOTIVATION: Driven by technological advances, the throughput and cost of mass spectrometry (MS) proteomics experiments have improved by orders of magnitude in recent decades. Spectral library searching is a common approach to annotating experimental mass spectra by matching them against large libraries of reference spectra corresponding to known peptides. An important disadvantage, however, is that only peptides included in the spectral library can be found, whereas novel peptides, such as those with unexpected post-translational modifications (PTMs), will remain unknown. Open modification searching (OMS) is an increasingly popular approach to annotate modified peptides based on partial matches against their unmodified counterparts. Unfortunately, this leads to very large search spaces and excessive runtimes, which is especially problematic considering the continuously increasing sizes of MS proteomics datasets. RESULTS: We propose an OMS algorithm, called HOMS-TC, that fully exploits parallelism in the entire pipeline of spectral library searching. We designed a new highly parallel encoding method based on the principle of hyperdimensional computing to encode mass spectral data to hypervectors while minimizing information loss. This process can be easily parallelized since each dimension is calculated independently. HOMS-TC processes two stages of existing cascade search in parallel and selects the most similar spectra while considering PTMs. We accelerate HOMS-TC on NVIDIA's tensor core units, which is emerging and readily available in the recent graphics processing unit (GPU). Our evaluation shows that HOMS-TC is 31× faster on average than alternative search engines and provides comparable accuracy to competing search tools. AVAILABILITY AND IMPLEMENTATION: HOMS-TC is freely available under the Apache 2.0 license as an open-source software project at https://github.com/tycheyoung/homs-tc.

HyperSpec: Ultrafast Mass Spectra Clustering in Hyperdimensional Space.

As current shotgun proteomics experiments can produce gigabytes of mass spectrometry data per hour, processing these massive data volumes has become progressively more challenging. Spectral clustering is an effective approach to speed up downstream data processing by merging highly similar spectra to minimize data redundancy. However, because state-of-the-art spectral clustering tools fail to achieve optimal runtimes, this simply moves the processing bottleneck. In this work, we present a fast spectral clustering tool, HyperSpec, based on hyperdimensional computing (HDC). HDC shows promising clustering capability while only requiring lightweight binary operations with high parallelism that can be optimized using low-level hardware architectures, making it possible to run HyperSpec on graphics processing units to achieve extremely efficient spectral clustering performance. Additionally, HyperSpec includes optimized data preprocessing modules to reduce the spectrum preprocessing time, which is a critical bottleneck during spectral clustering. Based on experiments using various mass spectrometry data sets, HyperSpec produces results with comparable clustering quality as state-of-the-art spectral clustering tools while achieving speedups by orders of magnitude, shortening the clustering runtime of over 21 million spectra from 4 h to only 24 min.