Puzzle Hi-C: An accurate scaffolding software.

High-quality, chromosome-scale genomes are essential for genomic analyses. Analyses, including 3D genomics, epigenetics, and comparative genomics rely on a high-quality genome assembly, which is often accomplished with the assistance of Hi-C data. Curation of genomes reveal that current Hi-C-assisted scaffolding algorithms either generate ordering and orientation errors or fail to assemble high-quality chromosome-level scaffolds. Here, we offer the software Puzzle Hi-C, which uses Hi-C reads to accurately assign contigs or scaffolds to chromosomes. Puzzle Hi-C uses the triangle region instead of the square region to count interactions in a Hi-C heatmap. This strategy dramatically diminishes scaffolding interference caused by long-range interactions. This software also introduces a dynamic, triangle window strategy during assembly. Initially small, the window expands with interactions to produce more effective clustering. Puzzle Hi-C outperforms available scaffolding tools.

Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis.

Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.

RNF8-mediated multi-ubiquitination of MCM7: Linking disassembly of the CMG helicase with DNA damage response in human cells.

DNA damage causes genomic instability. To maintain genome integrity, cells have evolved DNA damage response, which is involved in replication fork disassembly and DNA replication termination. However, the mechanism underlying the regulation of replication fork disassembly and its connection with DNA damage repair remain elusive. The CMG-MCM7 subunit ubiquitination functions on the eukaryotic replication fork disassembly at replication termination. Until now, only ubiquitin ligases CUL2LRR1 have been reported catalyzing MCM7 ubiquitination in human cells. This study discovered that in human cells, the ubiquitin ligase RNF8 catalyzes K63-linked multi-ubiquitination of MCM7 at K145 both in vivo and in vitro. The multi-ubiquitination of MCM7 is dynamically regulated during the cell cycle, primarily presenting on chromatin during the late S phase. Additionally, MCM7 polyubiquitylation is promoted by RNF168 and BRCA1 during DNA replication termination. Upon DNA damage, the RNF8-mediated polyubiquitination of MCM7 decreased significantly during the late S phase. This study highlights the novel role of RNF8-catalyzed polyubiquitination of MCM7 in the regulation of replication fork disassembly in human cells and linking it to DNA damage response.

A poly (lactic-co-glycolic acid) self-pumping Janus dressing with bidirectional biofluid transport for diabetic wound healing via anti-bacteria and pro-angiogenesis.

Diabetic wound healing poses a substantial challenge owing to bacterial infections, insufficient angiogenesis, and excessive exudates. Currently, most of the clinical dressings used for diabetic wounds are still conventional dressings such as gauze. In this study, a three-layer Janus dressing was developed via continuous electrostatic spinning. The top-layer was composed of polylactic acid-glycolic acid and hydroxyapatite doped with silver ions and silicate. The hydrophobic top-layer prevented the adhesion of foreign bacteria. The mid-layer was composed of polyethylene glycol, polylactic acid-glycolic acid and hydroxyapatite doped with silver ions and silicate facilitated exudate absorption and bioactive ion release. The modified sub-layer containing polylactic acid-glycolic acid, hydroxyapatite doped with silver ions and silicate and sodium alginate microspheres enabled both the transport of wound exudate from the wound bed to dressing and the backflow of bioactive silver ions and silicate to the wound bed, thereby reducing infection and stimulating angiogenesis. Through in vivo and in vivo experiments, the Janus dressing showed to have antimicrobial, angiogenic, and exudate-control properties that accelerate healing in diabetic wounds. As a novel dressing, the multifunctional, self-pumping Janus wound dressing with bi-directional biofluidic transport offers a new approach to diabetic wound healing.

Flavonoids: Potential therapeutic agents for cardiovascular disease.

Flavonoids are found in the roots, stems, leaves, and fruits of many plant taxa. They are related to plant growth and development, pigment formation, and protection against environmental stress. Flavonoids function as antioxidants and exert anti-inflammatory effects in the cardiovascular system by modulating classical inflammatory response pathways, such as the TLR4-NF-ĸB, PI3K-AKT, and Nrf2/HO-1 signalling pathways. There is increasing evidence for the therapeutic effects of flavonoids on hypertension, atherosclerosis, and other diseases. The potential clinical value of flavonoids for diseases of the cardiovascular system has been widely explored. For example, studies have evaluated the roles of flavonoids in the regulation of blood pressure via endothelium-dependent and non-endothelium-dependent pathways and in the regulation of myocardial systolic and diastolic functions by influencing calcium homeostasis and smooth muscle-related protein expression. Flavonoids also have hypoglycaemic, hypolipidemic, anti-platelet, autophagy, and antibacterial effects. In this paper, the role and mechanism of flavonoids in cardiovascular diseases were reviewed in order to provide reference for the clinical application of flavonoids in the future.

Preparation of Graphene Oxide/Polymer Hybrid Microcapsules via Photopolymerization for Double Self-Healing Anticorrosion Coatings.

In this work, graphene oxide (GO)/polymer hybrid microcapsule-loaded self-healing agents were prepared via the combination of the emulsion template method and photopolymerization technology. The incorporation of GO in the microcapsule shell not only improved the impermeability, mechanical property, and solvent resistance property of the microcapsules significantly but also endowed the microcapsules with photothermal conversion property. By incorporating GO/polymer hybrid microcapsules in water-borne epoxy resin, a novel kind of anticorrosion coating with a double self-healing property was successfully fabricated. When the coating was scratched, the linseed oil (LO) encapsulated in the microcapsules could fill the crack, and the photothermal conversion property of GO could promote the molecular chain movement of the damaged area under near-infrared (NIR) irradiation to realize the close of the crack. Based on the filling of LO and photothermal conversion-induced scratch narrowing, the "filling" and "close" double self-healing effect can be realized under temporal NIR irradiation, which could lead to the complete recovery of the scratched coating. The |Z|f=0.1Hz value of the damaged coating with GO/polymer microcapsules after double healing was comparable to that of the intact coating, which was about 4 orders of magnitude higher than that of the scratched blank coating and single self-healing coating. As to the neutral salt spray test, the scratched blank coating failed in protection after 100 h, while the healed composite coating did not show any corrosion after 300 h.

Rapid diagnosis of alveolar echinococcosis from lung puncture sample using metagenomic next-generation sequencing: a case report.

INTRODUCTION: Alveolar echinococcosis (AE), caused by the larval forms of Echinococcus multilocularis, is a zoonotic disease affecting the liver, lungs, lymph nodes, kidneys, brain, bones, thyroid, and other organs. Diagnosing AE in a non-endemic area is usually challenging. With the rapid development and increasing application of sequencing techniques in recent years, metagenomic next-generation sequencing (mNGS) has become a powerful tool for diagnosing rare infectious diseases. CASE PRESENTATION: A 45-year-old woman was admitted to the hospital for the presence of pulmonary shadows for more than 3 months. The lung computed tomography (CT) at a local hospital revealed scattered solid and quasi-circular nodules in the left upper lobe, left lower lobe, right middle lobe, and right lower lobe. The largest nodule was located in the dorsal part of the right lung, measuring 2.0 × 1.7 × 1.5 cm. Moreover, abdominal CT revealed one space-occupying lesion each in the left and right lobes. The pathological analysis of the lung biopsy specimen revealed infiltration of lymphocytes, plasma cells, and eosinophils in the alveolar wall and interstitial area. No pathogenic bacteria were observed in the sputum smear and culture tests. There were no parasite eggs in the stool. The mNGS of the lung puncture tissue revealed 6156 sequence reads matching E. multilocularis; thus, the condition was diagnosed as AE. Albendazole 400 mg was administered twice daily, and the patient was stable during follow-up. CONCLUSION: This case emphasizes the role of mNGS in diagnosing AE. As a novel, sensitive, and accurate diagnostic method, mNGS could be an attractive approach for facilitating early diagnosis and prompt treatment of infectious diseases, especially when the infection was caused by rare pathogens.

Treadmill running on neuropathic pain: via modulation of neuroinflammation.

Neuropathic pain is a type of chronic pain caused by an injury or somatosensory nervous system disease. Drugs and exercise could effectively relieve neuropathic pain, but no treatment can completely stop neuropathic pain. The integration of exercise into neuropathic pain management has attracted considerable interest in recent years, and treadmill training is the most used among exercise therapies. Neuropathic pain can be effectively treated if its mechanism is clarified. In recent years, the association between neuroinflammation and neuropathic pain has been explored. Neuroinflammation can trigger proinflammatory cytokines, activate microglia, inhibit descending pain modulatory systems, and promote the overexpression of brain-derived neurotrophic factor, which lead to the generation of neuropathic pain and hypersensitivity. Treadmill exercise can alleviate neuropathic pain mainly by regulating neuroinflammation, including inhibiting the activity of pro-inflammatory factors and over activation of microglia in the dorsal horn, regulating the expression of mu opioid receptor expression in the rostral ventromedial medulla and levels of γ-aminobutyric acid to activate the descending pain modulatory system and the overexpression of brain-derived neurotrophic factor. This article reviews and summarizes research on the effect of treadmill exercise on neuropathic pain and its role in the regulation of neuroinflammation to explore its benefits for neuropathic pain treatment.

Sleep-wake changes and incident depressive symptoms in midlife women.

Our study aimed to investigate the relationship between sleep-wake changes and depressive symptoms events among midlife women. We enrolled 1579 women aged 44-56 years who had no clinically relevant depressive symptoms at baseline. Depressive symptoms were assessed at each visit using the Center for Epidemiologic Studies Depression scale. At the third and fourth follow-up visits, women reported their sleep habits. The sleep midpoint was defined as the time to fall asleep plus one-half of the sleep duration. Sleep-wake changes were determined by the difference in the midpoint of sleep between the third and fourth visits, which were 1 year apart. The median follow-up time was 7 years (range 1-7 years). Cox proportional hazard models were fitted to calculate hazard ratios and 95% confidence intervals for the incidence of depressive symptoms associated with sleep-wake changes. After adjusting for potential confounding factors, the hazard ratio (95% confidence interval) of depressive symptoms for severe sleep midpoint changes was 1.51 (1.12, 2.05) compared with mild sleep midpoint changes. This relationship remained statistically significant and changed little when additionally controlling for sleep duration, sleep quality, insomnia symptoms, use of sleep medications, use of nervous medications, glucose, insulin, lipids, dietary energy intake, and C-reactive protein. Our findings indicate that exposure to long-term severe sleep-wake changes increases the risk of depressive symptoms in midlife women.

Associations between adverse childhood experiences and pain in middle-aged and older adults: findings from the China Health and Retirement Longitudinal Study.

OBJECTIVE: Adverse childhood experiences (ACEs) have been associated with a range of adverse health outcomes, with pain being potentially one of them. This population-based cross-sectional study aimed to investigate the associations between Adverse Childhood Experiences (ACEs) and pain in Chinese adults and evaluate whether physical activity and demographic and socioeconomic characteristics modify this associations. METHODS: Cross-sectional data from the China Health and Retirement Longitudinal Study (CHARLS), were utilized in this study. A total of 9923 respondents with information on 12 ACE indicators and 15 self-reported body pains were included. Logistic regression models were used to assess associations of the ACEs and pain. Modification of the associations by physical activity, demographic and socioeconomic characteristics was assessed by stratified analyses and tests for interaction. RESULTS: Among the 9923 individuals included in the primary analyses, 5098 (51.4%) males and the mean (SD) age was 61.18 (10·.44) years. Compared with individuals with 0 ACEs, those who with ≥ 5 ACEs had increased risk of single pains and multiple pain. A dose-response association was found between the number of ACEs and the risk of pain (e.g. neck pain for ≥ 5 ACEs vs. none: OR, 1.107; 95% CI, 0.903-1.356; p < 0.001 for trend). In the associations of each body pain with each ACE indicator, most ACE indicators were associated with an increased risk of pain. In addition, physical activity, sociodemographic and socioeconomic characteristics, such as age, sex, educational level, area of residence, childhood economic hardship, did not demonstrate a significant modify on the associations between ACEs and pain. CONCLUSIONS: These findings indicate that cumulative ACE exposure is associated with increased odds of self-reported pain in Chinese adults, regardless of adult physical activity, sociodemographic and socioeconomic characteristics.

Perfluorinated Amines: Accelerating Lithium Electrodeposition by Tailoring Interfacial Structure and Modulated Solvation for High-Performance Batteries.

Modulating interfacial electrochemistry represents a prevalent approach for mitigating lithium dendrite growth and enhancing battery performance. Nevertheless, while most additives exhibit inhibitory characteristics, the accelerating effects on interfacial electrochemistry have garnered limited attention. In this work, perfluoromorpholine (PFM) with facilitated kinetics is utilized to preferentially adsorb on the lithium metal interface. The PFM molecules disrupt the solvation structure of Li+ and enhance the migration of Li+. Combined with the benzotrifluoride, a synergistic acceleration-inhibition system is formed. The ab initio molecular dynamics (AIMD) and density functional theory (DFT) calculation of the loose outer solvation clusters and the key adsorption-deposition step supports the fast diffusion and stable interface electrochemistry with an accelerated filling mode with C─F and C─H groups. The approach induces the uniform lithium deposition. Excellent cycling performance is achieved in Li||Li symmetric cells, and even after 200 cycles in Li||NCM811 full cells, 80% of the capacity is retained. This work elucidates the accelerated electrochemical processes at the interface and expands the design strategies of acceleration fluorinated additives for lithium metal batteries.

Potential Mechanism and Therapeutic Targets of Polymyositis.

OBJECTIVE: To investigate the variability in the expression profile of genes associated with polymyositis (PM), explore the potential molecular mechanisms underlying PM, and predict novel targets for intervention. STUDY DESIGN: Descriptive study. Place and Duration of the Study: Department of Rheumatology, Taizhou Municipal Hospital, Taizhou, China, from August to November 2023. METHODOLOGY: Three microarray datasets (GSE3112, GSE39454, and GSE128470) were extracted from the gene expression omnibus (GEO). The analysis of this research involved identifying the differentially expressed genes (DEGs) in PM compared to normal samples. Enrichment analysis, gene-microRNA, gene-transcription factor (TF), and protein-protein interaction (PPI) network studies were conducted to identify hub genes and relevant pathways. Additionally, the drug-gene interaction database (DGIdb) was used to predict therapeutic medications. RESULTS: Eighty-eight DEGs were identified. The enrichment analysis results highlighted the significant involvement of downregulated DEGs in antigen processing and presentation. Based on the PPI networks, seven hub genes with high connectivity degrees were selected including a cluster of differentiation 74 (CD74), human leukocyte antigen (HLA)-DPA1, HLA-B, guanylate-binding protein 1 (GBP1), recombinant 2', 5'-oligoadenylate synthetase 1 (OAS1), HLA-C, and HLA-E. CONCLUSION: This research screened-out core genes, projected prospective therapeutic medications, discovered DEGs between PM and normal samples, and offered fresh perspectives for additional research into the possible mechanism and therapeutic targets of PM. KEY WORDS: Polymyositis, DEGs, Hub genes, Bioinformatics, Potential therapeutic agents.

The clinical antiprotozoal drug nitazoxanide and its metabolite tizoxanide extend Caenorhabditis elegans lifespan and healthspan.

The drugs extending healthspan in clinic have always been searched. Nitazoxanide is an FDA-approved clinical antiprotozoal drug. Nitazoxanide is rapidly metabolized to tizoxanide after absorption in vivo. Our previous studies find that nitazoxanide and its metabolite tizoxanide induce mild mitochondrial uncoupling and activate cellular AMPK, oral nitazoxanide protects against experimental hyperlipidemia, hepatic steatosis, and atherosclerosis. Here, we demonstrate that both nitazoxanide and tizoxanide extend the lifespan and healthspan of Caenorhabditis elegans through Akt/AMPK/sir 2.1/daf16 pathway. Additionally, both nitazoxanide and tizoxanide improve high glucose-induced shortening of C. elegans lifespan. Nitazoxanide has been a clinical drug with a good safety profile, we suggest that it is a novel anti-aging drug.

Hemodynamic Force Based on Cardiac Magnetic Resonance Imaging: State of the Art and Perspective.

Intracardiac blood flow has long been proposed to play a significant role in cardiac morphology and function. However, absolute blood pressure within the heart has mainly been measured by invasive catheterization, which limits its application. Hemodynamic force (HDF) is the global force of intracavitary blood flow acquired by integrating the intraventricular pressure gradient over the entire ventricle and thus may be a promising tool for accurately characterizing cardiac function. Recent advances in magnetic resonance imaging technology allow for a noninvasive measurement of HDF through both 4D flow cardiac MRI and cine cardiac MRI. The HDF time curve provides comprehensive data for both qualitative and quantitative analysis. In this review, a series of HDF parameters is introduced and a summary of the current literature regarding HDF in clinical practice is presented. Additionally, the current dilemmas and future prospects are discussed in order to contribute to the future research. LEVEL OF EVIDENCE: 5. TECHNICAL EFFICACY: Stage 2.

Pinibarreniales, a new order of Sordariomycetes from pine barrens ecosystem.

Pinibarrenia chlamydospora, sp. nov. isolated from the roots of highbush blueberry in the New Jersey Pine Barrens, is described and illustrated. Based on multigene phylogenetic analysis, as well as morphological and ecological characteristics, Pinibarreniales and Pinibarreniaceae are established to accommodate this novel lineage in Sordariomycetidae, Sordariomycetes. Pinibarreniales, Tracyllalales, and Vermiculariopsiellales are proposed to be included in the subclass Sordariomycetidae. Pinibarreniales likely have a wide distribution and forms association with Ericaceae plants that live in acidic and oligotrophic environments because its DNA barcode matches with environmental sequences from other independent ecological studies. The plant-fungal interaction experiment revealed negative impacts on Arabidopsis, indicating its pathogenicity. This uncovered new fungal lineage will contribute to a better understanding of the diversity and systematics of Sordariomycetes.

The SSHVEP Paradigm-Based Brain Controlled Method for Grasping Robot Using MVMD Combined CNN Model.

In recent years, the steady-state visual evoked potentials (SSVEP) based brain control method has been employed to help people with disabilities because of its advantages of high information transmission rate and low training time. However, the existing SSVEP brain control methods cannot adapt to dynamic or unstructured environments. Moreover, the recognition accuracy from the conventional decoding algorithm still needs to improve. To address the above problems, this study proposed a steady-state hybrid visual evoked potentials (SSHVEP) paradigm using the grasping targets in their environment to improve the connection between the subjects' and their dynamic environments. Moreover, a novel EEG decoding method, using the multivariate variational mode decomposition (MVMD) algorithm for adaptive sub-band division and convolutional neural network (CNN) for target recognition, was applied to improve the decoding accuracy of the SSHVEPs. 18 subjects participated in the offline and online experiments. The offline accuracy across 18 subjects by the 9-target SSHVEP paradigm was up to 95.41 ± 2.70 %, which is a 5.80% improvement compared to the conventional algorithm. To further validate the performance of the proposed method, the brain-controlled grasping robot system using the SSHVEP paradigm was built. The average accuracy reached 93.21 ± 10.18 % for the online experiment. All the experimental results demonstrated the effectiveness of the brain-computer interaction method based on the SSHVEP paradigm and the MVMD combined CNN algorithm studied in this paper.

JAK inhibitors attenuate hyperactivation of nonswitched memory B cells in rheumatoid arthritis patients in remission.

OBJECTIVE: To investigate the distribution and activation of B-cell subpopulations in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKis) and to analyze their correlation with disease remission. METHODS: Peripheral blood samples were collected from 23 adult healthy controls and 58 RA patients, 31 of whom were treated with JAKis and assessed during a 24-month follow-up. The number of peripheral B-cell subpopulations (including naive B cells, nonswitched memory B (NSMB) cells, switched memory B cells, and double-negative B cells), their activation, and phosphorylation of SYK and AKT upon B-cell receptor (BCR) stimulation in each population were analyzed by flow cytometry. RESULTS: Compared with that in healthy controls, the frequency of NSMB cells was significantly lower in new-onset untreated RA patients. However, expression of CD40, CD80, CD95, CD21low and pAKT significantly increased in these NSMB cells. Additionally, the number of NSMB cells correlated negatively with DAS28-ESR and IgG and IgA levels in these patients; expression of CD80, CD95 and CD21low on NSMB cells correlated positively with DAS28-ESR and IgG and IgA levels. After treatment with JAKis, the serum IgG concentration significantly decreased in RA patients in remission, but CD40, CD95 and pAKT levels in NSMB cells significantly decreased. CONCLUSION: RA patients present different B-cell subpopulations, in which the frequency of NSMB cells is negatively associated with disease activity. However, treatment with JAKis can inhibit activation of NSMB cells, restore the balance of kinase phosphorylation, and facilitate disease remission in RA patients.

Advancing perspectives on the off-label use of anticancer drugs: an updated classification and exploration of categories.

To date, the definition that the off-label usage of drugs refers to the unapproved use of approved drugs, which covers unapproved indications, patient populations, doses, and/or routes of administration, has been in existence for many years. Currently, there is a limited frequency and prevalence of research on the off-label use of antineoplastic drugs, mainly due to incomplete definition and classification issues. It is time to embrace new categories for the off-label usage of anticancer drugs. This review provided an insight into an updated overview of the concept and categories of the off-label use of anticancer drugs, along with illustrating specific examples to establish the next studies about the extent of the off-label usage of anticancer drugs in the oncology setting. The scope of the off-label use of current anticancer drugs beyond the previous definitions not only includes off-label uses in terms of indications, patient populations, doses, and/or routes of administration but also off-label use in terms of medication course, combination, sequence of medication, clinical purpose, contraindications scenarios, etc. In addition, the definition of the off-label usage of anticancer drugs should be added to the condition at a given time, and it varies from approval authorities. We presented a new and relatively comprehensive classification, providing extensive analysis and illustrative examples of the off-label usage of antineoplastic drugs for the first time. Such a classification has the potential to promote practical adoption and enhance management strategies for the off-label use of antitumor drugs.

Neurofunctional changes related to methamphetamine and sexual cues in methamphetamine dependence from short- to long-term abstinence.

AIMS: Abuse of methamphetamine has aroused concern worldwide. Stimulant use and sexual behaviours have been linked in behavioural and epidemiological studies. Although methamphetamine-related neurofunctional differences are reported in previous studies, only few studies have examined neurofunctional changes related to methamphetamine and sexual cues in methamphetamine dependence from short- to long-term abstinence. METHODS: Neurofunctional changes were measured using a cue-reactivity task involving methamphetamine, sexual, and neutral cues in 20 methamphetamine abusers who were evaluated after a short- (1 week to 3 months) and long-term (10-15 months) abstinence. RESULTS: Five brain regions mainly involved in the occipital lobe and the parietal lobe were found with the group-by-condition interaction. Region-of-interest analyses found higher sexual-cue-related activation than other two activations in all five brain regions in the long-term methamphetamine abstinence group while no group differences were found. Negative relationships between motor impulsivity and methamphetamine- or sexual-cue-related activations in the left middle occipital gyrus, the superior parietal gyrus and the right angular gyrus were found. CONCLUSIONS: The findings suggested that methamphetamine abstinence may change the neural response of methamphetamine abusers to methamphetamine and sexual cues, and the neurofunction of the five brain regions reported in this study may partly recover with long-term methamphetamine abstinence. Given the use and relapse of methamphetamine for sexual purposes, the findings of this study may have particular clinical relevance.