Hyperglycemia facilitates EV71 replication: Insights into miR-206-mediated regulation of G3BP2 promoting EV71 IRES activity.

Background: Neurotropic virus infections actively manipulate host cell metabolism to enhance virus neurovirulence. Although hyperglycemia is common during severe infections, its specific role remains unclear. This study investigates the impact of hyperglycemia on the neurovirulence of enterovirus 71 (EV71), a neurovirulent virus relying on internal ribosome entry site (IRES)-mediated translation for replication. Methods: Utilizing hSCARB2-transgenic mice, we explore the effects of hyperglycemia in EV71 infection and elucidate the underlying mechanisms. Results: Remarkably, administering insulin alone to reduce hyperglycemia in hSCARB2-transgenic mice results in a decrease in brainstem encephalitis and viral load. Conversely, induced hyperglycemia exacerbates neuropathogenesis, highlighting the pivotal role of hyperglycemia in neurovirulence. Notably, miR-206 emerges as a crucial mediator induced by viral infection, with its expression further heightened by hyperglycemia and concurrently repressed by insulin. The use of antagomiR-206 effectively mitigates EV71-induced brainstem encephalitis and reduces viral load. Mechanistically, miR-206 facilitates IRES-driven virus replication by repressing the stress granule protein G3BP2. Conclusions: Novel therapeutic approaches against severe EV71 infections involve managing hyperglycemia and targeting the miR-206-stress granule pathway to modulate virus IRES activity.

Analyzing Immune Cell Infiltration and Copper Metabolism in Diabetic Foot Ulcers.

Background: Diabetes impairs wound healing, notably in diabetic foot ulcers (DFU). Stress, marked by the accumulation of lipoylated mitochondrial enzymes and the depletion of Fe-S cluster proteins, triggers cuproptosis-a distinct form of cell death. The involvement of copper in the pathophysiology of DFU has been recognized, and currently, a copper-based therapeutic strategy is emerging as a viable option for enhancing ulcer healing. This study investigates genes linked to copper metabolism in DFU, aiming to uncover potential targets for therapeutic intervention. Methods: Two diabetic wound Gene Expression Omnibus (GEO) datasets were analyzed to study immune cell dysregulation in diabetic wounds. Differentially expressed genes related to copper metabolism were identified and analyzed using machine learning methods. Gene ontology, pathway enrichment, and immune infiltration analyses were performed using DFU samples. The expression of identified genes was validated using qRT-PCR and single-cell RNA sequencing. Results: Ten genes associated with copper metabolism were identified. Among these, SLC31A1 and ADNP were found to be significantly differentially expressed in DFU. Notably, SLC31A1 exhibited higher expression in macrophages, whereas ADNP was found to be highly expressed in fibroblasts and chondrocytes. Conclusion: The study indicates a close link between copper metabolism, the infiltration of immune cells, and DFU. It proposes that copper metabolism could influence the progression of DFU through the activation of immune responses. These observations offer fresh perspectives on the underlying mechanisms of DFU and identify potential targets for therapeutic intervention.

Diagnostic ability of macular nerve fiber layer thickness measured by swept-source OCT in preperimetric glaucoma.

BACKGROUND: We evaluated the diagnostic ability of macula retinal nerve fiber layer (mRNFL) thickness in preperimetric glaucoma (PPG) patients. METHODS: This prospective study included 83 patients with PPG and 83 age- and refractive error-matched normal control subjects. PPG was defined as a localized RNFL defect corresponding to glaucomatous optic disc changes with a normal visual field test. We used spectral-domain (SD) OCT to measure the circumpapillary RNFL (cpRNFL) thickness and macular ganglion cell-inner plexiform layer (GCIPL) thickness. Swept-source (SS) OCT was used to measure cpRNFL thickness, macular ganglion cell layer + inner plexiform layer (IPL) thickness (GCL+), and macular ganglion cell layer + IPL+ mRNFL thickness (GCL++). The mRNFL thickness was defined as GCL++ minus GCL+. To evaluate the diagnostic power of each parameter, the area under the receiver operating characteristics curve (AUROC) was analyzed to differentiate PPG from the normal groups. RESULTS: Using SD-OCT, all GCIPL parameters and most cpRNFL parameters, except at the nasal and temporal quadrant, were significantly lower in PPG versus normal controls. PPG eyes had significantly smaller values than normal controls for all cpRNFL and GCL parameters measured by SS-OCT, except mRNFL at the superonasal area. The inferotemporal GCL++ had the largest AUROC value (0.904), followed by inferotemporal GCL+ (0.882), inferotemporal GCIPL thickness (0.871), inferior GCL++ (0.866), inferior cpRNFL thickness by SS-OCT (0.846), inferior cpRNFL thickness by SD-OCT (0.841), and inferotemporal mRNFL thickness (0.840). The diagnostic performance was comparable between inferotemporal mRNFL thickness and the best measures of GCL (inferotemporal GCL++, p = 0.098) and cpRNFL (inferior cpRNFL thickness by SS-OCT, p = 0.546). CONCLUSION: The diagnostic ability of mRNFL thickness was comparable to that of the best measures of cpRNFL and GCL analysis for eyes with PPG. Therefore, mRNFL thickness could be a new parameter to detect early structural changes in PPG.

Relationships among Physical Fitness, External Loads, and Heart Rate Recovery: A Study on Futsal Players during an Overseas Congested-Weeks Training Camp.

This study examined relationships among players' physical characteristics, match external loads, and heart rate recovery (HRR) during match substitutions in a congested fixture of an overseas futsal training camp. Eleven under-20 national futsal players' anthropometric characteristics (age, body height, body mass, % fat, and % muscle) and physical fitness [HRmax, VO2max, maximal aerobic speed (MAS) during the 30-15 intermittent fitness test (IFT)] were determined. Additionally, locomotion profiles during field play and HRR sitting on the bench were recorded during five matches. A repeated-measures analysis of variance and Pearson's correlation coefficient were used for statistical analysis. The results revealed that the overall observed correlations among anthropometry, body composition, physical fitness, and HRR were inconsistent across all the matches and substitutions. However, the numbers of moderate (1.00-1.99 m/s2), moderate-to-high (2.00-2.99 m/s2), and high (3.00-50.00 m/s2) intensities of acceleration presented negative correlations in the last match (r < -0.76; p < 0.05). HRR during match substitutions may have been influenced by uncontrolled factors across all the match play and recovery. HRR measures may be affected mainly by fatigue caused by the accumulation of accelerations throughout a congested fixture during a congested-schedule of a futsal training camp.

Microbiome of periodontitis and peri-implantitis before and after therapy: Long-read 16S rRNA gene amplicon sequencing.

AIMS: The microbial profiles of peri-implantitis and periodontitis (PT) are inconclusive. The controversies mainly arise from the differences in sampling sites, targeted gene fragment, and microbiome analysis techniques. The objective of this study was to explore the microbiomes of peri-implantitis (PI), control implants (CI), PT and control teeth (CT), and the microbial change of PI after nonsurgical treatment (PIAT). METHODS: Twenty-two patients diagnosed with both PT and peri-implantitis were recruited. Clinical periodontal parameters and radiographic bone levels were recorded. In each patient, the subgingival and submucosal plaque samples were collected from sites with PI, CI, PT, CT, and PIAT. Microbiome diversity was analyzed by high-throughput amplicon sequencing using full-length of 16S rRNA gene by next generation sequencing. RESULTS: The 16S rRNA gene sequencing analysis revealed 512 OTUs in oral microbiome and 377 OTUs reached strain levels. The PI and PT groups possessed their own unique core microbiome. Treponema denticola was predominant in PI with probing depth of 8-10 mm. Interestingly, Thermovirga lienii DSM 17291 and Dialister invisus DSM 15470 were found to associate with PI. Nonsurgical treatment for peri-implantitis did not significantly alter the microbiome, except Rothia aeria. CONCLUSION: Our study suggests Treponemas species may play a pivotal role in peri-implantitis. Nonsurgical treatment did not exert a major influence on the peri-implantitis microbiome in short-term follow-up. PT and peri-implantitis possess the unique microbiome profiles, and different therapeutic strategies may be suggested in the future.

Pyroptosis inhibitors MCC950 and VX-765 mitigate myocardial injury by alleviating oxidative stress, inflammation, and apoptosis in acute myocardial hypoxia.

Acute myocardial infarction (AMI) is a prevalent cardiovascular disease with high morbidity and mortality rates worldwide. Pyroptosis is an inflammatory form of programmed cell death that has been linked to various pathological conditions. However, its exact contribution to the onset and progression of heart injury in AMI has not yet fully elucidated. Herein, we established mouse AMI model by ligating the left anterior descending artery and performed transcriptome analysis during the early phase of AMI. Mouse HL-1 and human AC-16 cardiomyocytes were subjected to hypoxia to simulate ischemic injury in vitro. Our results revealed a significant activation of the inflammatory response at 3 h post-ligation, as confirmed by RNA sequencing. We identified the occurrence of NLRP3 inflammasome-mediated pyroptosis in the cardiac tissues of human cases with AMI, as well as in mouse models of AMI and hypoxia-induced cardiomyocytes, using immunohistochemistry staining and Western blotting assays. Concurrently, pharmacological inhibition of NLRP3 inflammasome-mediated pyroptosis with MCC950 and VX-765 effectively decreased hypoxia-induced cardiomyocytes injury, while mitigating myocardial oxidative stress, apoptosis and inflammation caused by hypoxia. Moreover, the circulating levels of gasdermin D (GSDMD), the pyroptosis executor, were remarkably elevated in the plasma of mice with early AMI and in the supernatant of hypoxia-exposed cardiomyocytes in a time-dependent manner using ELISA and Western blotting. Furthermore, the change in circulating GSDMD positively correlated with Creatine Kinase-MB (CK-MB) in the plasma of early-stage AMI mouse. In summary, these findings indicated a critical role for NLRP3 inflammasome-mediated pyroptosis in the progression of AMI, the administration of MCC950 and VX-765 may be attractive candidate therapeutic approaches for cardiac injury caused by acute hypoxia or even AMI. Additionally, the circulating GSDMD exhibits potential as a newly diagnostic biomarker for AMI.

Integrating predictive coding and a user-centric interface for enhanced auditing and quality in cancer registry data.

Data curation for a hospital-based cancer registry heavily relies on the labor-intensive manual abstraction process by cancer registrars to identify cancer-related information from free-text electronic health records. To streamline this process, a natural language processing system incorporating a hybrid of deep learning-based and rule-based approaches for identifying lung cancer registry-related concepts, along with a symbolic expert system that generates registry coding based on weighted rules, was developed. The system is integrated with the hospital information system at a medical center to provide cancer registrars with a patient journey visualization platform. The embedded system offers a comprehensive view of patient reports annotated with significant registry concepts to facilitate the manual coding process and elevate overall quality. Extensive evaluations, including comparisons with state-of-the-art methods, were conducted using a lung cancer dataset comprising 1428 patients from the medical center. The experimental results illustrate the effectiveness of the developed system, consistently achieving F1-scores of 0.85 and 1.00 across 30 coding items. Registrar feedback highlights the system's reliability as a tool for assisting and auditing the abstraction. By presenting key registry items along the timeline of a patient's reports with accurate code predictions, the system improves the quality of registrar outcomes and reduces the labor resources and time required for data abstraction. Our study highlights advancements in cancer registry coding practices, demonstrating that the proposed hybrid weighted neural-symbolic cancer registry system is reliable and efficient for assisting cancer registrars in the coding workflow and contributing to clinical outcomes.

Alpha-Lipoic Acid Induces Adipose Tissue Browning through AMP-Activated Protein Kinase Signaling in Vivo and in Vitro.

Background: AMP-activated protein kinase (AMPK) is a key enzyme for cellular energy homeostasis and improves metabolic disorders. Brown and beige adipose tissues exert thermogenesis capacities to dissipate energy in the form of heat. Here, we investigated the beneficial effects of the antioxidant alpha-lipoic acid (ALA) in menopausal obesity and the underlying mechanisms. Methods: Female Wistar rats (8 weeks old) were subjected to bilateral ovariectomy (Ovx) and divided into four groups: Sham (n=8), Ovx (n=11), Ovx+ALA2 (n=10), and Ovx+ALA3 (n=6) (ALA 200 and 300 mg/kg/day, respectively; gavage) for 8 weeks. 3T3-L1 cells were used for in vitro study. Results: Rats receiving ALA2 and ALA3 treatment showed significantly lower levels of body weight and white adipose tissue (WAT) mass than those of the Ovx group. ALA improved plasma lipid profiles including triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Hematoxylin & eosin staining of inguinal WAT showed that ALA treatment reduced Ovx-induced adipocyte size and enhanced uncoupling protein 1 (UCP1) expression. Moreover, plasma levels of irisin were markedly increased in ALA-treated Ovx rats. Protein expression of brown fat-specific markers including UCP1, PRDM16, and CIDEA was downregulated by Ovx but markedly increased by ALA. Phosphorylation of AMPK, its downstream acetyl-CoA carboxylase, and its upstream LKB1 were all significantly increased by ALA treatment. In 3T3-L1 cells, administration of ALA (100 and 250 µM) reduced lipid accumulation and enhanced oxygen consumption and UCP1 protein expression, while inhibition of AMPK by dorsomorphin (5 µM) significantly reversed these effects. Conclusion: ALA improves estrogen deficiency-induced obesity via browning of WAT through AMPK signaling.

Perinuclear Antineutrophil Cytoplasmic Antibody-Associated Ocular Manifestations: Case Series and Literature Review.

PURPOSE: To investigate the diversity of ocular manifestations in patients with positive perinuclear antineutrophil cytoplasmic antibody (p-ANCA). METHODS: The clinical records of five patients exhibiting ocular manifestations and testing positive for serum MPO-ANCA were retrospectively reviewed. RESULTS: Three out of five patients were female. The youngest patient was aged 26, whereas the eldest was 83 years old. 80% (n = 4) of them had purely anterior segment involvement, with the commonest manifestation being peripheral ulcerative keratitis and scleritis. Only one patient had posterior segment involvement, specifically posterior ischemic optic neuropathy. Two patients demonstrated unilateral involvement. There was only one patient diagnosed with systemic involvement, presenting as mixed nephrotic and nephritic syndrome, who required a course of intravenous methylprednisolone during the active stage. Three patients required second-line immunosuppressants throughout the course due to frequent relapse. CONCLUSION: Anterior segment ocular manifestations are not uncommon and can be the initial presentation of p-ANCA-associated vasculitis (AAV). Therefore, its evaluation should be considered in establishing the diagnosis of AAV, a life-threatening disease.

An ensemble machine learning model generates a focused screening library for the identification of CDK8 inhibitors.

The identification of an effective inhibitor is an important starting step in drug development. Unfortunately, many issues such as the characterization of protein binding sites, the screening library, materials for assays, etc., make drug screening a difficult proposition. As the size of screening libraries increases, more resources will be inefficiently consumed. Thus, new strategies are needed to preprocess and focus a screening library towards a targeted protein. Herein, we report an ensemble machine learning (ML) model to generate a CDK8-focused screening library. The ensemble model consists of six different algorithms optimized for CDK8 inhibitor classification. The models were trained using a CDK8-specific fragment library along with molecules containing CDK8 activity. The optimized ensemble model processed a commercial library containing 1.6 million molecules. This resulted in a CDK8-focused screening library containing 1,672 molecules, a reduction of more than 99.90%. The CDK8-focused library was then subjected to molecular docking, and 25 candidate compounds were selected. Enzymatic assays confirmed six CDK8 inhibitors, with one compound producing an IC50 value of ≤100 nM. Analysis of the ensemble ML model reveals the role of the CDK8 fragment library during training. Structural analysis of molecules reveals the hit compounds to be structurally novel CDK8 inhibitors. Together, the results highlight a pipeline for curating a focused library for a specific protein target, such as CDK8.

Acupoint Catgut Embedding for Treatment of Chronic Pelvic Pain due to the Sequelae of Pelvic Inflammatory Disease.

Chronic pelvic pain caused by the sequelae of inflammatory pelvic disease is a common clinical condition of pelvic pain in women. At present, the main challenges in its treatment are the limited effectiveness of pain relief and the frequent recurrence of symptoms, which significantly impact patients' quality of life and impose a considerable psychological burden on them. It is a clinically challenging disease. After summarizing years of treatment experience, the author's team discovered that acupoint catgut embedding demonstrated notable clinical efficacy in managing chronic pelvic pain stemming from pelvic inflammatory disease sequelae. Compared to existing Western medicine treatment methods, acupoint catgut embedding offers advantages such as a good analgesic effect, lower recurrence rate, economic benefits, and a relatively straightforward procedure. This article provides a comprehensive guide on embedding absorbable catgut into patients' acupoints for the treatment of chronic pelvic pain in females resulting from the sequelae of pelvic inflammatory disease.

Ethylene promotes fruit ripening initiation by downregulating photosynthesis, enhancing abscisic acid and suppressing jasmonic acid in blueberry (Vaccinium ashei).

BACKGROUND: Blueberry fruit exhibit atypical climacteric ripening with a non-auto-catalytic increase in ethylene coincident with initiation of ripening. Further, application of ethephon, an ethylene-releasing plant growth regulator, accelerates ripening by increasing the proportion of ripe (blue) fruit as compared to the control treatment. To investigate the mechanistic role of ethylene in regulating blueberry ripening, we performed transcriptome analysis on fruit treated with ethephon, an ethylene-releasing plant growth regulator. RESULTS: RNA-Sequencing was performed on two sets of rabbiteye blueberry ('Powderblue') fruit: (1) fruit from divergent developmental stages; and (2) fruit treated with ethephon, an ethylene-releasing compound. Differentially expressed genes (DEGs) from divergent developmental stages clustered into nine groups, among which cluster 1 displayed reduction in expression during ripening initiation and was enriched with photosynthesis related genes, while cluster 7 displayed increased expression during ripening and was enriched with aromatic-amino acid family catabolism genes, suggesting stimulation of anthocyanin biosynthesis. More DEGs were apparent at 1 day after ethephon treatment suggesting its early influence during ripening initiation. Overall, a higher number of genes were downregulated in response to ethylene. Many of these overlapped with cluster 1 genes, indicating that ethylene-mediated downregulation of photosynthesis is an important developmental event during the ripening transition. Analyses of DEGs in response to ethylene also indicated interplay among phytohormones. Ethylene positively regulated abscisic acid (ABA), negatively regulated jasmonates (JAs), and influenced auxin (IAA) metabolism and signaling genes. Phytohormone quantification supported these effects of ethylene, indicating coordination of blueberry fruit ripening by ethylene. CONCLUSION: This study provides insights into the role of ethylene in blueberry fruit ripening. Ethylene initiates blueberry ripening by downregulating photosynthesis-related genes. Also, ethylene regulates phytohormone-metabolism and signaling related genes, increases ABA, and decreases JA concentrations. Together, these results indicate that interplay among multiple phytohormones regulates the progression of ripening, and that ethylene is an important coordinator of such interactions during blueberry fruit ripening.

Gut microbiota induced abnormal amino acids and their correlation with diabetic retinopathy.

AIM: To explore the correlation of gut microbiota and the metabolites with the progression of diabetic retinopathy (DR) and provide a novel strategy to elucidate the pathological mechanism of DR. METHODS: The fecal samples from 32 type 2 diabetes patients with proliferative retinopathy (PDR), 23 with non-proliferative retinopathy (NPDR), 27 without retinopathy (DM), and 29 from the sex-, age- and BMI- matched healthy controls (29 HC) were analyzed by 16S rDNA gene sequencing. Sixty fecal samples from PDR, DM, and HC groups were assayed by untargeted metabolomics. Fecal metabolites were measured using liquid chromatography-mass spectrometry (LC-MS) analysis. Associations between gut microbiota and fecal metabolites were analyzed. RESULTS: A cluster of 2 microbiome and 12 metabolites accompanied with the severity of DR, and the close correlation of the disease progression with PDR-related microbiome and metabolites were found. To be specific, the structure of gut microbiota differed in four groups. Diversity and richness of gut microbiota were significantly lower in PDR and NPDR groups, than those in DM and HC groups. A cluster of microbiome enriched in PDR group, including Pseudomonas, Ruminococcaceae-UCG-002, Ruminococcaceae-UCG-005, Christensenellaceae-R-7, was observed. Functional analysis showed that the glucose and nicotinate degradations were significantly higher in PDR group than those in HC group. Arginine, serine, ornithine, and arachidonic acid were significantly enriched in PDR group, while proline was enriched in HC group. Functional analysis illustrated that arginine biosynthesis, lysine degradation, histidine catabolism, central carbon catabolism in cancer, D-arginine and D-ornithine catabolism were elevated in PDR group. Correlation analysis revealed that Ruminococcaceae-UCG-002 and Christensenellaceae-R-7 were positively associated with L-arginine, ornithine levels in fecal samples. CONCLUSION: This study elaborates the different microbiota structure in the gut from four groups. The relative abundance of Ruminococcaceae-UCG-002 and Parabacteroides are associated with the severity of DR. Amino acid and fatty acid catabolism is especially disordered in PDR group. This may help provide a novel diagnostic parameter for DR, especially PDR.

Development and validation of a geriatric depression knowledge scale for older adults with depression.

Poor adherence to antidepressants increases the risk of suicide, while greater mental health awareness promotes seeking appropriate treatment, highlighting the urgent need to assess depression knowledge. This study aimed to develop and assess the psychometrics of a Geriatric Depression Knowledge Scale (GDKS) for older adults with depression. In phase 1, 18 items were generated through an intensive literature review and clinical experiences. Phase 2 involved assessing content and face validities of the GDKS. In phase 3, a cross-sectional study (206 older adults, 100 psychiatric professionals) determined construct validity, internal consistency, and test-retest reliability. GDKS demonstrated excellent content and face validity. Older participants scored significantly lower than psychiatric professionals, confirming excellent construct validity. Reliability was evident with a Kuder-Richardson formula 20 score of 0.72 and a 4-week test-retest reliability of 0.86 (p < 0.01). The GDKS provides a reliable tool for evaluating geriatric depression knowledge in psychiatric outpatient settings.

Determination of Azole Fungicide Residues in Fresh Juice by Magnetic Solid Phase Extraction Based on Fe3O4@ZnAl-LDH@MIL-53(Al) Sorbent in Combination with High-Performance Liquid Chromatograph.

In this work, a magnetic adsorption material based on metal-organic framework (Fe3O4@ZnAl-LDH@MIL-53(Al)) was synthesized and used as an adsorbent in the process of magnetic solid phase extraction. Then, a high-performance liquid chromatograph was used to quantitatively detect triazole fungicides in samples. In order to verify the successful preparation of the material, a series of characterization analyses were carried out. Besides, the key parameters that may affect the extraction efficiency have been optimized, and under optimal conditions the three triazole fungicides showed good linearity in the range of 10-1000 µg/L (R2 ≥ 0.9796); Limit of detections were ranged from 0.013 to 0.030 µg/mL. Finally, the established method was applied to the detection of triazole fungicides in four fresh juice samples. The results showed that the target analyte was not detected in all the test samples. By detecting the recoveries (73.3-104.3%) and coefficient variation (RSD ≤ 6.8%) of triazole fungicides in fortified samples, it proved that this established method meets the requirements of pesticide residue analysis and showed excellent application potential.

FOXC1 regulates endothelial CD98 (LAT1/4F2hc) expression in retinal angiogenesis and blood-retina barrier formation.

Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is essential for the development of new organ systems, but transcriptional control of angiogenesis remains incompletely understood. Here we show that FOXC1 is essential for retinal angiogenesis. Endothelial cell (EC)-specific loss of Foxc1 impairs retinal vascular growth and expression of Slc3a2 and Slc7a5, which encode the heterodimeric CD98 (LAT1/4F2hc) amino acid transporter and regulate the intracellular transport of essential amino acids and activation of the mammalian target of rapamycin (mTOR). EC-Foxc1 deficiency diminishes mTOR activity, while administration of the mTOR agonist MHY-1485 rescues perturbed retinal angiogenesis. EC-Foxc1 expression is required for retinal revascularization and resolution of neovascular tufts in a model of oxygen-induced retinopathy. Foxc1 is also indispensable for pericytes, a critical component of the blood-retina barrier during retinal angiogenesis. Our findings establish FOXC1 as a crucial regulator of retinal vessels and identify therapeutic targets for treating retinal vascular disease.

Synthesis of Unsymmetrical Trisulfides from S-Substituted Sulphenylthiosulphates.

Trisulfide unit is widely found in natural products and has garnered attention due to the unique pharmacological and physiochemical properties. However, despite limited progress, widely applicable approaches for constructing unsymmetrical trisulfides have so far remain scarce. In this work, an easy-to-prepare, solid-state and scalable reagent, S-substituted sulphenylthiosulphate, has been developed for the divergent synthesis of unsymmetrical trisulfides. Alkyl electrophile substrates, including bromides, chlorides, iodides and tosylates, with diverse substituents are smoothly converted to the corresponding trisulfides with S-substituted sulphenylthiosulphates and thiourea as another sulfur source. Furthermore, the late-stage modification of drug molecules was successfully achieved through this method.

Mitigating treatment failure of pulmonary pre-extensively drug-resistant tuberculosis: The role of new and repurposed drugs.

BACKGROUND: Pre-extensively drug-resistant tuberculosis (pre-XDR-TB), defined as multidrug-resistant TB (MDR-TB) with additional resistance to any fluoroquinolone (FQ) is difficult to treat. We assessed whether the use of new or repurposed drugs (bedaquiline, delamanid, linezolid, carbapenem, clofazimine, pretomanid) mitigated treatment failure of pre-XDR-TB. METHODS: MDR-TB patients managed in the Taiwan MDR-TB consortium between July 2009-December 2019 were eligible. Treatment outcomes at 30 months were assessed. Logistic regression models were constructed to investigate factors associated with treatment outcomes. RESULTS: 109 patients with FQ-resistant MDR-TB and 218 patients with FQ-susceptible MDR-TB were included. 60 (55.1%) patients with FQ-resistant MDR-TB and 63 (28.9%) patients with FQ-susceptible MDR-TB have been treated with new or repurposed drugs (p < 0.01). Of the 218 patients with FQ-susceptible MDR-TB, 187 (85.8%) had treatment success, 30 (13.8%) died, no treatment failure, and 1 (0.5%) was loss-to-follow-up; of the 109 patients with FQ-resistant MDR-TB, 78 (71.6%) had treatment success, 21 (19.3%) died, 9 (8.3%) had treatment failure, and 1 (0.9%) was loss-to-follow-up (p < 0.01). The use of new or repurposed drugs was not associated with treatment outcomes among patients with FQ-susceptible MDR-TB. No patients with FQ-resistant MDR-TB treated with ≥2 new or repurposed drugs within 6 months of treatment initiation had treatment failure (p = 0.03). Patients with FQ-resistant MDR-TB treated with 1 new or repurposed drugs was more likely to have treatment failure as compared with patients not treated with new or repurposed drugs (adjOR 7.06, 95% CI 1.72-29.06). CONCLUSIONS: Proper use of new or repurposed anti-TB drugs can mitigate treatment failure in FQ-resistant MDR-TB.

DNA Methylation in the Adaptive Response to Exercise.

Emerging evidence published over the past decade has highlighted the role of DNA methylation in skeletal muscle function and health, including as an epigenetic transducer of the adaptive response to exercise. In this review, we aim to synthesize the latest findings in this field to highlight: (1) the shifting understanding of the genomic localization of altered DNA methylation in response to acute and chronic aerobic and resistance exercise in skeletal muscle (e.g., promoter, gene bodies, enhancers, intergenic regions, un-annotated regions, and genome-wide methylation); (2) how these global/regional methylation changes relate to transcriptional activity following exercise; and (3) the factors (e.g., individual demographic or genetic features, dietary, training history, exercise parameters, local epigenetic characteristics, circulating hormones) demonstrated to alter both the pattern of DNA methylation after exercise, and the relationship between DNA methylation and gene expression. Finally, we discuss the changes in non-CpG methylation and 5-hydroxymethylation after exercise, as well as the importance of emerging single-cell analyses to future studies-areas of increasing focus in the field of epigenetics. We anticipate that this review will help generate a framework for clinicians and researchers to begin developing and testing exercise interventions designed to generate targeted changes in DNA methylation as part of a personalized exercise regimen.