[Distribution of Typical Resistant Bacteria and Resistance Genes in Source Water of the Middle and Lower Reaches of the Yellow River].

The Yellow River water of an urban area located in the middle and lower reaches of the Yellow River was taken as the research object， in which the seasonal and along-range distribution of total culturable bacteria， typical antibiotic resistant bacteria （amoxicillin resistant bacteria and sulfamethoxazole-resistant bacteria）， and their corresponding typical resistance genes ï¼»ß-lactam resistance gene （blaCTX-M） and sulfamamide resistance genes （sulI and sulⅡ）， as well as intⅠ1 were investigated. The results showed that the total culturable bacteria， ß-lactam-resistant bacteria and sulfonamide-resistant bacteria in the Yellow River Basin were significantly affected by temperature and human activities. The composition and quantity of their genera had obvious spatiotemporal distribution characteristics， in which Bacillus and Pseudomonas were dominant in the composition and number of bacteria. The abundance of resistance genes decreased with the decrease in temperature. The proportion of ß-lactam resistance genes in the total genes was higher than that of sulfanilamide genes， and sulI was the dominant gene in sulfanilamide genes. Correlation analysis showed that class Ⅰ integron played an important role in accelerating the spread of resistance genes. This study offers insight into the status quo of water resistance pollution in the Yellow River and provides theoretical support for the risk assessment of resistance genes in the middle and lower reaches of the Yellow River Basin.

Identification of a marine-derived sesquiterpenoid, Compound-8, that inhibits tumour necrosis factor-induced cell death by blocking complex II assembly.

BACKGROUND AND PURPOSE: Tumour necrosis factor (TNF) is a pleiotropic inflammatory cytokine that not only directly induces inflammatory gene expression but also triggers apoptotic and necroptotic cell death, which leads to tissue damage and indirectly exacerbates inflammation. Thus, identification of inhibitors for TNF-induced cell death has broad therapeutic relevance for TNF-related inflammatory diseases. In the present study, we isolated and identified a marine fungus-derived sesquiterpenoid, 9α,14-dihydroxy-6ß-p-nitrobenzoylcinnamolide (named as Cpd-8), that inhibits TNF receptor superfamily-induced cell death by preventing the formation of cytosolic death complex II. EXPERIMENTAL APPROACH: Marine sponge-associated fungi were cultured and the secondary metabolites were extracted to yield pure compounds. Cell viability was measured by ATP-Glo cell viability assay. The effects of Cpd-8 on TNF signalling pathway were investigated by western blotting, immunoprecipitation, and immunofluorescence assays. A mouse model of acute liver injury (ALI) was employed to explore the protection effect of Cpd-8, in vivo. KEY RESULTS: Cpd-8 selectively inhibits TNF receptor superfamily-induced apoptosis and necroptosis. Cpd-8 prevents the formation of cytosolic death complex II and subsequent RIPK1-RIPK3 necrosome, while it has no effect on TNF receptor I (TNFR1) internalization and the formation of complex I in TNF signalling pathway. In vivo, Cpd-8 protects mice against TNF-α/D-GalN-induced ALI. CONCLUSION AND IMPLICATIONS: A marine fungus-derived sesquiterpenoid, Cpd-8, inhibits TNF receptor superfamily-induced cell death, both in vitro and in vivo. This study not only provides a useful research tool to investigate the regulatory mechanisms of TNF-induced cell death but also identifies a promising lead compound for future drug development.

Harnessing the potential of long non-coding RNAs in breast cancer: from etiology to treatment resistance and clinical applications.

Breast cancer (BC) is the most common malignancy among women and a leading cause of cancer-related deaths of females worldwide. It is a complex and molecularly heterogeneous disease, with various subtypes that require different treatment strategies. Despite advances in high-resolution single-cell and multinomial technologies, distant metastasis and therapeutic resistance remain major challenges for BC treatment. Long non-coding RNAs (lncRNAs) are non-coding RNAs with more than 200 nucleotides in length. They act as competing endogenous RNAs (ceRNAs) to regulate post-transcriptional gene stability and modulate protein-protein, protein-DNA, and protein-RNA interactions to regulate various biological processes. Emerging evidence suggests that lncRNAs play essential roles in human cancers, including BC. In this review, we focus on the roles and mechanisms of lncRNAs in BC progression, metastasis, and treatment resistance, and discuss their potential value as therapeutic targets. Specifically, we summarize how lncRNAs are involved in the initiation and progression of BC, as well as their roles in metastasis and the development of therapeutic resistance. We also recapitulate the potential of lncRNAs as diagnostic biomarkers and discuss their potential use in personalized medicine. Finally, we provide lncRNA-based strategies to promote the prognosis of breast cancer patients in clinical settings, including the development of novel lncRNA-targeted therapies.

Oxygen-Activated Boron Nitride for Selective Photocatalytic Coupling of Methanol to Ethylene Glycol.

The controllable photocatalytic C-C coupling of methanol to produce ethylene glycol (EG) is a highly desirable but challenging objective for replacing the current energy-intensive thermocatalytic process. Here, we develop a metal-free porous boron nitride catalyst that demonstrates exceptional selectivity in the photocatalytic production of EG from methanol under mild conditions. Comprehensive experiments and calculations are conducted to thoroughly investigate the reaction mechanism, revealing that the OB3 unit in the porous BN plays a critical role in the preferential activation of C-H bond in methanol to form ⋅CH2OH via a concerted proton-electron transfer mechanism. More prominent energy barriers are observed for the further dehydrogenation of the ⋅CH2OH intermediate on the OB3 unit, inhibiting the formation of some other by-products during the catalytic process. Additionally, a small downhill energy barrier for the coupling of ⋅CH2OH in the OB3 unit promotes the selective generation of EG. This study provides valuable insights into the underlying mechanisms and can serve as a guide for the design and optimization of photocatalysts for efficient and selective EG production under mild conditions.

Discovery of WS-384, a first-in-class dual LSD1 and DCN1-UBC12 protein-protein interaction inhibitor for the treatment of non-small cell lung cancer.

Abnormally high expression of lysine-specific demethylase 1 A (LSD1) and DCN1 plays a vital role in the occurrence, development, and poor prognosis of non-small cell lung cancer (NSCLC). Accumulating evidence has shown that the development of small-molecule inhibitors dually targeting LSD1 and the DCN1-UBC12 interaction probably have therapeutic promise for cancer therapy. This work reported that WS-384 dually targeted LSD1 and DCN1-UBC12 interactions and evaluated its antitumor effects in vitro and in vivo. Specifically, WS-384 inhibited A549 and H1975 cells viability and decreased colony formation and EdU incorporation. WS-384 could also trigger cell cycle arrest, DNA damage, and apoptosis. Moreover, WS-384 significantly decreased tumor weight and volume in A549 xenograft mice. Mechanistically, WS-384 increased the gene and protein level of p21 by suppressing the neddylation of cullin 1 and decreasing H3K4 demethylation at the CDKN1A promoter. The synergetic upregulation of p21 contributed to cell cycle arrest and the proapoptotic effect of WS-384 in NSCLC cells. Taken together, our proof of concept studies demonstrated the therapeutic potential of dual inhibition of LSD1 and the DCN1-UBC12 interaction for the treatment of NSCLC. WS-384 could be used as a lead compound to develop new dual LSD1/DCN1 inhibitors for the treatment of human diseases in which LSD1 and DCN1 are dysregulated.

The Effect of Peer Victimization During Adolescence on Depression and Gender Differences: A Systematic Review and Meta-analysis.

Peer victimization during adolescence has a detrimental impact on the mental health of victims throughout their lives. However, it remains unclear whether these effects are gender-specific. The present study conducted a systematic review to examine the effects of peer victimization on depression status, explore potential sources of heterogeneity, and investigate gender differences in these effects. We systematically searched four electronic databases (Web of Science, PubMed, Embase, and CNKI) for relevant articles that published as far as July 2022. We then extracted odds ratios (OR) and 95% confidence intervals (CI) to assess the association between peer victimization during adolescence and depression, and potential gender differences in the relation. Meta-analysis was performed, using fixed effects models and random effects models, to evaluate the association between each exposure and the outcome. A meta-analysis of 27 studies revealed that peer victimization during adolescence was significantly associated with higher risks of depression (OR = 2.79, 95% CI [2.43, 3.21], p < .001). This finding was consistent across subgroup analyses. In particular, the effect of peer victimization during adolescence on depression was found to be more pronounced in studies conducted in Asia (OR = 3.06, 95% CI [2.38, 3.92], p < .001). Furthermore, five studies focused on gender differences demonstrated that peer victimization has a stronger association with the risk of depression in women (OR = 2.84, 95% CI [2.49, 3.26], p < .001). Peer victimization during adolescence is a significant risk factor for depression, with a greater impact on women and individuals residing in Asia. Further prospective studies are needed to investigate the relationship between peer victimization and depression.

Proapoptotic effect of WS-299 induced by NOXA accumulation and NRF2-counterbalanced oxidative stress damage through targeting RBX1-UBE2M interaction in gastric cancers.

The abnormal activation of Cullin RING E3 Ligases (CRLs) is closely associated with the occurrence and development of various cancers. Targeting the neddylation pathway represents an effective approach for cancer treatment. In this work, we reported that WS-299, structurally featuring a coumarin moiety attached to the triazolopyrimidine, exhibited excellent anti-proliferative activity in MGC-803 and HGC-27 cells. WS-299 exerted potent anticancer effects by inhibiting clone formation, EdU incorporation and inducing cell cycle arrest. WS-299 inhibited CUL3/5 neddylation and caused an obvious accumulation of Nrf2 and NOXA, substrates of CRL3 and CRL5, respectively. Biochemical studies showed that WS-299 inhibited CUL3 neddylation by inhibiting RBX1-UBE2M interaction. The anti-proliferative effect of WS-299 was mainly induced by NOXA-mediated apoptosis. Of note, Nrf2 attenuated WS-299-induced reactive oxygen species (ROS) levels. Furthermore, Nrf2 accumulation also had an antagonistic effect on NOXA-induced apoptosis. Therefore, WS-299 and siNrf2 synergistically increased ROS levels, apoptotic cells and suppressed tumor growth in vivo. Taken together, our research clarified the anti-cancer mechanisms of WS-299 through targeting the RBX1-UBE2M protein-protein interaction and inhibiting the neddylation modification of CUL3 and CUL5. More importantly, our studies also demonstrated that combination of WS-299 with shNrf2 could be an effective strategy for treating gastric cancers.

The Cross-Regulation Between Set1, Clr4, and Lsd1/2 in Schizosaccharomyces pombe.

Eukaryotic chromatin is organized into either silenced heterochromatin or relaxed euchromatin regions, which controls the accessibility of transcriptional machinery and thus regulates gene expression. In fission yeast, Schizosaccharomyces pombe, Set1 is the sole H3K4 methyltransferase and is mainly enriched at the promoters of actively transcribed genes. In contrast, Clr4 methyltransferase initiates H3K9 methylation, which has long been regarded as a hallmark of heterochromatic silencing. Lsd1 and Lsd2 are two highly conserved H3K4 and H3K9 demethylases. As these histone-modifying enzymes perform critical roles in maintaining histone methylation patterns and, consequently, gene expression profiles, cross-regulations among these enzymes are part of the complex regulatory networks. Thus, elucidating the mechanisms that govern their signaling and mutual regulations remains crucial. Here, we demonstrated that C-terminal truncation mutants, lsd1-ΔHMG and lsd2-ΔC, do not compromise the integrity of the Lsd1/2 complex but impair their chromatin-binding capacity at the promoter region of target genomic loci. We identified protein-protein interactions between Lsd1/2 and Raf2 or Swd2, which are the subunits of the Clr4 complex (CLRC) and Set1-associated complex (COMPASS), respectively. We showed that Clr4 and Set1 modulate the protein levels of Lsd1 and Lsd2 in opposite ways through the ubiquitin-proteasome-dependent pathway. During heat stress, the protein levels of Lsd1 and Lsd2 are upregulated in a Set1-dependent manner. The increase in protein levels is crucial for differential gene expression under stress conditions. Together, our results support a cross-regulatory model by which Set1 and Clr4 methyltransferases control the protein levels of Lsd1/2 demethylases to shape the dynamic chromatin landscape.

Association between burnout and post-traumatic stress disorder among frontline nurse during COVID-19 pandemic: A moderated mediation analysis.

AIMS AND OBJECTIVES: The aim of this study was to investigate the relationship between burnout and post-traumatic stress disorder (PTSD) among frontline nurses who went to assist the epidemic situation in Wuhan, China, during the outbreak in 2020. The study also explored the mediating role of depression and the moderating role of age in the main relationship. BACKGROUND: The relationship between burnout and PTSD in nurse has rarely been investigated in the context of the COVID-19 pandemic. Understand the relationship between these variables can provide empirical evidence for developing interventions and protocols that improve the health of nurses in future public health emergencies. DESIGN: An online cross-sectional survey of targeted local 327 nurses who went to assist the COVID-19 epidemic situation in Wuhan during the initial outbreak. METHODS: This study was conducted in August 2020, the burnout scale, the PTSD scale and the depression scale were used to survey participants. The moderated mediation model was used to test research hypotheses. RESULTS: Burnout could affect the PTSD symptoms in nursing staffs and depression could mediate this relationship. Age moderated the relationship between burnout/depression and PTSD, and the effects was strong and significant among younger participants in the relationship between burnout and PTSD. CONCLUSIONS: Burnout was identified as a core risk factor of PTSD in nurses. Depression and age played significant roles in the relationship between burnout and PTSD. RELEVANCE TO CLINICAL PRACTICE: PTSD, as a symptom that manifests after experiencing a stressful event, should be a key concern among frontline healthcare professionals. This study suggests that PTSD in nurses can be further reduced by reducing burnout. Attention should also be paid to the PTSD status of nurses of different age groups. PATIENT OR PUBLIC CONTRIBUTION: Patients and the public were not involved in the design and implementation of this study. Frontline nurses completed an online questionnaire for this study.

Modulating Charge Separation of Oxygen-Doped Boron Nitride with Isolated Co Atoms for Enhancing CO2 -to-CO Photoreduction.

To alleviate the greenhouse effect and address the related energy crisis, solar-driven reduction of carbon dioxide (CO2 ) to value-added products is considered as a sustainable strategy. However, the insufficient separation and rapid recombination of photogenerated charge carriers during photocatalysis greatly limit their reduction efficiency and practical application potential. Here, isolated Cobalt (Co) atoms are successfully decorated into oxygen-doped boron nitride (BN) via an in situ pyrolysis method, achieving greatly improved catalytic activity and selectivity to the carbon monoxide (CO) product. X-ray absorption fine spectroscopy demonstrates that the isolated Co atoms are stabilized by the O and N atoms with an unsaturated CoO2 N1 configuration. Further experimental investigation and theoretical simulations confirm that the decorated Co atoms not only work as the real active center during the CO2 reduction process, but also perform as the electron pump to promote the electron/hole separation and transfer, resulting in greatly accelerated reaction kinetics and improved activity. In addition, the CoO2 N1 coordination geometry is favorable to the conversion from *CO2 to *COOH, which shall be considered as a selectivity-determining step for the evolution of the CO products. The surface modulation strategy at the atomic level opens a new avenue for regulating the reaction kinetics for photocatalytic CO2 reduction.

DRMref: comprehensive reference map of drug resistance mechanisms in human cancer.

Drug resistance poses a significant challenge in cancer treatment. Despite the initial effectiveness of therapies such as chemotherapy, targeted therapy and immunotherapy, many patients eventually develop resistance. To gain deep insights into the underlying mechanisms, single-cell profiling has been performed to interrogate drug resistance at cell level. Herein, we have built the DRMref database (https://ccsm.uth.edu/DRMref/) to provide comprehensive characterization of drug resistance using single-cell data from drug treatment settings. The current version of DRMref includes 42 single-cell datasets from 30 studies, covering 382 samples, 13 major cancer types, 26 cancer subtypes, 35 treatment regimens and 42 drugs. All datasets in DRMref are browsable and searchable, with detailed annotations provided. Meanwhile, DRMref includes analyses of cellular composition, intratumoral heterogeneity, epithelial-mesenchymal transition, cell-cell interaction and differentially expressed genes in resistant cells. Notably, DRMref investigates the drug resistance mechanisms (e.g. Aberration of Drug's Therapeutic Target, Drug Inactivation by Structure Modification, etc.) in resistant cells. Additional enrichment analysis of hallmark/KEGG (Kyoto Encyclopedia of Genes and Genomes)/GO (Gene Ontology) pathways, as well as the identification of microRNA, motif and transcription factors involved in resistant cells, is provided in DRMref for user's exploration. Overall, DRMref serves as a unique single-cell-based resource for studying drug resistance, drug combination therapy and discovering novel drug targets.

Comparative efficacy and tolerability of probiotic, prebiotic, and synbiotic formulations for adult patients with mild-moderate ulcerative colitis in an adjunctive therapy: A network meta-analysis.

BACKGROUND & AIMS: Probiotics, prebiotics, and synbiotics (PPS) have been widely used as adjuvant treatments in patients with ulcerative colitis (UC) in recent years. However, the most effective formulations of PPS have yet to be identified. We thus aimed to compare the efficacy and tolerability of different PPS formulations for mild-moderate UC. METHODS: We searched PubMed, Embase, Web of Science, and Cochrane CENTRAL from inception to June 24, 2023 for double-blind randomized controlled trials. We used a frequentist approach in random-effects models for network meta-analysis and the Grading of Recommendations Assessment, Development, and Evaluation approach to evaluate the certainty of evidence. RESULTS: We analysed data from 20 trials involving 1153 patients. The combinations of specific strains of Lactobacillus and Bifidobacterium (CLB) (odds ratio (OR), 3.85; 95 % confidence interval (CI), 1.40-10.60; low certainty) and combinations of specific strains of Lactobacillus, Bifidobacterium, and Streptococcus (CLBS) (OR, 2.20; 95 % CI, 1.47-3.28; low certainty) significantly increased the clinical remission rate in intention-to-treat analysis (ITT) when compared to placebo. Similarly, compared with placebo, the two combinations significantly reduced clinical activity scores (standardized mean difference (SMD), -1.17 (95 % CI, -1.68 to -0.65), low certainty; and SMD, -1.33 (95 % CI, -1.81 to -0.86), low certainty, respectively). Hierarchical cluster analyses showed the two combinations formed clusters with high efficacy (clinical remission in ITT and clinical activity score) and tolerability (withdrawal due to worsening symptoms) within 12 weeks. CONCLUSION: In this systematic review, we found CLB and CLBS demonstrated a clinical benefit in adjuvant treatments, with a comparable tolerability and safety profile to placebo. Further trials are needed. TRIAL REGISTRATION NUMBER: CRD42022344905.

Enabling the clinical application of artificial intelligence in genomics: a perspective of the AMIA Genomics and Translational Bioinformatics Workgroup.

OBJECTIVE: Given the importance AI in genomics and its potential impact on human health, the American Medical Informatics Association-Genomics and Translational Biomedical Informatics (GenTBI) Workgroup developed this assessment of factors that can further enable the clinical application of AI in this space. PROCESS: A list of relevant factors was developed through GenTBI workgroup discussions in multiple in-person and online meetings, along with review of pertinent publications. This list was then summarized and reviewed to achieve consensus among the group members. CONCLUSIONS: Substantial informatics research and development are needed to fully realize the clinical potential of such technologies. The development of larger datasets is crucial to emulating the success AI is achieving in other domains. It is important that AI methods do not exacerbate existing socio-economic, racial, and ethnic disparities. Genomic data standards are critical to effectively scale such technologies across institutions. With so much uncertainty, complexity and novelty in genomics and medicine, and with an evolving regulatory environment, the current focus should be on using these technologies in an interface with clinicians that emphasizes the value each brings to clinical decision-making.

Pathology steered stratification network for subtype identification in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a heterogeneous, multifactorial neurodegenerative disorder characterized by three neurobiological factors beta-amyloid, pathologic tau, and neurodegeneration. There are no effective treatments for AD at a late stage, urging for early detection and prevention. However, existing statistical inference approaches in neuroimaging studies of AD subtype identification do not take into account the pathological domain knowledge, which could lead to ill-posed results that are sometimes inconsistent with the essential neurological principles. PURPOSE: Integrating systems biology modeling with machine learning, the study aims to assist clinical AD prognosis by providing a subpopulation classification in accordance with essential biological principles, neurological patterns, and cognitive symptoms. METHODS: We propose a novel pathology steered stratification network (PSSN) that incorporates established domain knowledge in AD pathology through a reaction-diffusion model, where we consider non-linear interactions between major biomarkers and diffusion along the brain structural network. Trained on longitudinal multimodal neuroimaging data, the biological model predicts long-term evolution trajectories that capture individual characteristic progression pattern, filling in the gaps between sparse imaging data available. A deep predictive neural network is then built to exploit spatiotemporal dynamics, link neurological examinations with clinical profiles, and generate subtype assignment probability on an individual basis. We further identify an evolutionary disease graph to quantify subtype transition probabilities through extensive simulations. RESULTS: Our stratification achieves superior performance in both inter-cluster heterogeneity and intra-cluster homogeneity of various clinical scores. Applying our approach to enriched samples of aging populations, we identify six subtypes spanning AD spectrum, where each subtype exhibits a distinctive biomarker pattern that is consistent with its clinical outcome. CONCLUSIONS: The proposed PSSN (i) reduces neuroimage data to low-dimensional feature vectors, (ii) combines AT[N]-Net based on real pathological pathways, (iii) predicts long-term biomarker trajectories, and (iv) stratifies subjects into fine-grained subtypes with distinct neurological underpinnings. PSSN provides insights into pre-symptomatic diagnosis and practical guidance on clinical treatments, which may be further generalized to other neurodegenerative diseases.

A noninvasive multianalytical approach establishment for risk assessment and gastric cancer screening.

Effective screening and early detection are critical to improve the prognosis of gastric cancer (GC). Our study aims to explore noninvasive multianalytical biomarkers and construct integrative models for preliminary risk assessment and GC detection. Whole genomewide methylation marker discovery was conducted with CpG tandems target amplification (CTTA) in cfDNA from large asymptomatic screening participants in a high-risk area of GC. The methylation and mutation candidates were validated simultaneously using one plasma from patients at various gastric lesion stages by multiplex profiling with Mutation Capsule Plus (MCP). Helicobacter pylori specific antibodies were detected with a recomLine assay. Integrated models were constructed and validated by the combination of multianalytical biomarkers. A total of 146 and 120 novel methylation markers were found in CpG islands and promoter regions across the genome with CTTA. The methylation markers together with the candidate mutations were validated with MCP and used to establish a 133-methylation-marker panel for risk assessment of suspicious precancerous lesions and GC cases and a 49-methylation-marker panel as well as a 144-amplicon-mutation panel for GC detection. An integrated model comprising both methylation and specific antibody panels performed better for risk assessment than a traditional model (AUC, 0.83 and 0.63, P < .001). A second model for GC detection integrating methylation and mutation panels also outperformed the traditional model (AUC, 0.82 and 0.68, P = .005). Our study established methylation, mutation and H. pylori-specific antibody panels and constructed two integrated models for risk assessment and GC screening. Our findings provide new insights for a more precise GC screening strategy in the future.

Sample average treatment effect on the treated (SATT) analysis using counterfactual explanation identifies BMT and SARS-CoV-2 vaccination as protective risk factors associated with COVID-19 severity and survival in patients with multiple myeloma.

Patients with multiple myeloma (MM), an age-dependent neoplasm of antibody-producing plasma cells, have compromised immune systems and might be at increased risk for severe COVID-19 outcomes. This study characterizes risk factors associated with clinical indicators of COVID-19 severity and all-cause mortality in myeloma patients utilizing NCATS' National COVID Cohort Collaborative (N3C) database. The N3C consortium is a large, centralized data resource representing the largest multi-center cohort of COVID-19 cases and controls nationwide (>16 million total patients, and >6 million confirmed COVID-19+ cases to date). Our cohort included myeloma patients (both inpatients and outpatients) within the N3C consortium who have been diagnosed with COVID-19 based on positive PCR or antigen tests or ICD-10-CM diagnosis code. The outcomes of interest include all-cause mortality (including discharge to hospice) during the index encounter and clinical indicators of severity (i.e., hospitalization/emergency department/ED visit, use of mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)). Finally, causal inference analysis was performed using the Coarsened Exact Matching (CEM) and Propensity Score Matching (PSM) methods. As of 05/16/2022, the N3C consortium included 1,061,748 cancer patients, out of which 26,064 were MM patients (8,588 were COVID-19 positive). The mean age at COVID-19 diagnosis was 65.89 years, 46.8% were females, and 20.2% were of black race. 4.47% of patients died within 30 days of COVID-19 hospitalization. Overall, the survival probability was 90.7% across the course of the study. Multivariate logistic regression analysis showed histories of pulmonary and renal disease, dexamethasone, proteasome inhibitor/PI, immunomodulatory/IMiD therapies, and severe Charlson Comorbidity Index/CCI were significantly associated with higher risks of severe COVID-19 outcomes. Protective associations were observed with blood-or-marrow transplant/BMT and COVID-19 vaccination. Further, multivariate Cox proportional hazard analysis showed that high and moderate CCI levels, International Staging System (ISS) moderate or severe stage, and PI therapy were associated with worse survival, while BMT and COVID-19 vaccination were associated with lower risk of death. Finally, matched sample average treatment effect on the treated (SATT) confirmed the causal effect of BMT and vaccination status as top protective factors associated with COVID-19 risk among US patients suffering from multiple myeloma. To the best of our knowledge, this is the largest nationwide study on myeloma patients with COVID-19.

Physiological and molecular bases of the boron deficiency response in tomatoes.

Boron is an essential microelement for plant growth. Tomato is one of the most cultivated fruits and vegetables in the world, and boron deficiency severely inhibits its yield and quality. However, the mechanism of tomato in response to boron deficiency remains largely unclear. Here, we investigated the physiological and molecular bases of the boron deficiency response in hydroponically grown tomato seedlings. Boron deficiency repressed the expression of genes associated with nitrogen metabolism, while it induced the expression of genes related to the pentose phosphate pathway, thereby altering carbon flow to provide energy for plants to cope with stress. Boron deficiency increased the accumulation of copper, manganese and iron, thereby maintaining chlorophyll content and photosynthetic efficiency at the early stage of stress. In addition, boron deficiency downregulated the expression of genes involved in cell wall organization and reduced the contents of pectin and cellulose in roots, ultimately retarding root growth. Furthermore, boron deficiency markedly altered phytohormone levels and signaling pathways in roots. The contents of jasmonic acid, jasmonoy1-L-isoleucine, trans-zeatin riboside, abscisic acid, salicylic acid, and SA glucoside were decreased; in contrast, the contents of isopentenyladenine riboside and ethylene precursor 1-aminocyclopropane-1-carboxylic acid were increased in the roots of boron-deficient tomato plants. These results collectively indicate that tomato roots reprogram carbon/nitrogen metabolism, alter cell wall components and modulate phytohormone pathways to survive boron deficiency. This study provides a theoretical basis for further elucidating the adaptive mechanism of tomato in response to boron deficiency.

Impact of Comorbidity on the Duration from Symptom Onset to Death in Patients with Coronavirus Disease 2019: A Retrospective Study of 104,753 Cases in Pakistan.

(1) Background: The evidence indicates that comorbidities are associated with an increase in the risk of death from coronavirus disease 2019 (COVID-19). It is unclear whether such an association is different for various combinations of chronic disease comorbidities. (2) Methods: From 16 March 2020 to 30 November 2021, 104,753 patients with confirmed COVID-19 from Khyber Pakhtunkhwa Province, Pakistan, were studied to determine the association between comorbidities and the duration from symptom onset to death in patients with COVID-19 by stratifying their comorbidity status. (3) Results: The patients with comorbidities had an 84% (OR, 0.16; 95% CI, 0.14 to 0.17) decrease in the duration from symptom onset to death, as opposed to patients without a comorbidity. Among the patients with only one comorbidity, chronic lung disease (OR, 0.06; 95% CI, 0.03 to 0.09) had a greater impact on the duration from symptom onset to death than hypertension (OR, 0.15; 95% CI, 0.13 to 0.18) or diabetes (OR, 0.15; 95% CI, 0.12 to 0.18). The patients with both hypertension and diabetes had the shortest duration (OR, 0.17; 95% CI, 0.14 to 0.20) among the patients with two comorbidities. (4) Conclusions: Comorbidity yielded significant adverse impacts on the duration from symptom onset to death in COVID-19 patients in Pakistan. The impact varied with different combinations of chronic disease comorbidities in terms of the number and type of comorbidities.

Paenibacillus spongiae sp. nov. isolated from deep-water marine sponge Theonella swinhoei.

A novel bacterial strain, designated as PHS-Z3T, was isolated from a marine sponge belonging to the genus Theonella on the Puerto Galera Deep Monkey, Philippines. Cells of PHS-Z3T were Gram-stain-positive, motile, oxidase- and catalase-positive, white-pigmented, spore-forming, short rods that could grow at 10-40 °C (optimum, 20 °C), pH 6.0-9.5 (optimum, pH 7.5) and with 2-16 % (w/v) NaCl (optimum, 7 %). The 16S rRNA gene sequence of PHS-Z3T showed 97.9 %, 96.7 %, and 96.2 % identities to Paenibacillus mendelii C/2T, Paenibacillus oenotherae DT7-4T and Paenibacillus aurantiacus RC11T, respectively. The results of phylogenetic analysis based on 16S rRNA gene sequences indicated that PHS-Z3T formed an independent cluster with Paenibacillus mendelii C/2T. The total genome of PHS-Z3T was approximately 7 613 364 bp in size with a DNA G+C content of 51.6 %. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between PHS-Z3T and other type strains of species of the genus Paenibacillus were 68.0-81.4 % [ANI by blast (ANIb)], 83.0-88.0 % [ANI by MUMmer (ANIm)] and 12.7-32.1 % (dDDH). The dDDH and ANI values were below the standard cut-off criteria for delineation of bacterial species. The percentage of conserved proteins (POCP) values between the genome of PHS-Z3T and those of members of the genus Paenibacillus were 39.7-75.7 %, while the average amino acid identity (AAI) values were 55.9-83.7 %. The sole respiratory quinone in the strain was MK-7, and the predominant fatty acids were anteiso-C15 : 0 and C16 : 0. The major polar lipids of PHS-Z3T consisted of diphosphatidylglycerol, phospholipid and phosphatidylglycerol. The characteristic amino acid in the cell wall of PHS-Z3T was diamino heptanoic acid (meso-DAP). On the basis of the molecular, physiological, biochemical and chemotaxonomic features, strain PHS-Z3T represents a novel species of the genus Paenibacillus, for which the name Paenibacillus spongiae sp. nov. is proposed, with the type strain PHS-Z3T (=MCCC 1K07848T=KCTC 43443T).

Opto-SICM framework combines optogenetics with scanning ion conductance microscopy for probing cell-to-cell contacts.

We present a novel framework, Opto-SICM, for studies of cellular interactions in live cells with high spatiotemporal resolution. The approach combines scanning ion conductance microscopy, SICM, and cell-type-specific optogenetic interrogation. Light-excitable cardiac fibroblasts (FB) and myofibroblasts (myoFB) were plated together with non-modified cardiomyocytes (CM) and then paced with periodic illumination. Opto-SICM reveals the extent of FB/myoFB-CM cell-cell contacts and the dynamic changes over time not visible by optical microscopy. FB-CM pairs have lower gap junctional expression of connexin-43 and higher contact dynamism compared to myoFB-CM pairs. The responsiveness of CM to pacing via FB/myoFB depends on the dynamics of the contact but not on the area. The non-responding pairs have higher net cell-cell movement at the contact. These findings are relevant to cardiac disease states, where adverse remodeling leads to abnormal electrical excitation of CM. The Opto-SICM framework can be deployed to offer new insights on cellular and subcellular interactions in various cell types, in real-time.