Electrochemically Driven Denitrative Cyanation of Nitroarenes.

A practical denitrative cyanation of feedstock nitroarenes under mild and transition metal-free reaction conditions has been developed. The key to success lies in the use of electrochemically driven, inexpensive ionic liquid N-methylimidazolium p-toluenesulfonate-promoted selective cathode reduction of nitroarenes to anilines, followed by diazoation, cathode reduction to form the aryl radical, and the essential radical cyanation process in one pot. Our protocol shows broad functional group tolerance and can be applied for the modification of bioactive targets.

Prostate cancer treatment recommendation study based on machine learning and SHAP interpreter.

This study utilized data from 140,294 prostate cancer cases from the Surveillance, Epidemiology, and End Results (SEER) database. Here, 10 different machine learning algorithms were applied to develop treatment options for predicting patients with prostate cancer, differentiating between surgical and non-surgical treatments. The performances of the algorithms were measured using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value, negative predictive value. The Shapley Additive Explanations (SHAP) method was employed to investigate the key factors influencing the prediction process. Survival analysis methods were used to compare the survival rates of different treatment options. The CatBoost model yielded the best results (AUC = 0.939, sensitivity = 0.877, accuracy = 0.877). SHAP interpreters revealed that the T stage, cancer stage, age, cores positive percentage, prostate-specific antigen, and Gleason score were the most critical factors in predicting treatment options. The study found that surgery significantly improved survival rates, with patients undergoing surgery experiencing a 20.36% increase in 10-year survival rates compared with those receiving non-surgical treatments. Among surgical options, radical prostatectomy had the highest 10-year survival rate at 89.2%. This study successfully developed a predictive model to guide treatment decisions for prostate cancer. Moreover, the model enhanced the transparency of the decision-making process, providing clinicians with a reference for formulating personalized treatment plans.

Exploring the behavioral intentions of PICC-related thrombosis prevention in breast cancer patients undergoing chemotherapy: a qualitative study based on theory of planned behavior.

PURPOSE: To explore the behavioral intention of breast cancer patients undergoing chemotherapy to prevent PICC-related thrombosis based on the theory of planned behavior (TPB). METHODS: This qualitative study employed purposive sampling and conducted semi-structured interviews with 14 breast cancer patients undergoing chemotherapy in the outpatient chemotherapy ward of a tertiary A-level comprehensive hospital in Beijing from July to August 2023. Data were analyzed using Colaizzi's descriptive analysis framework. RESULTS: Data analysis identified 10 themes that were derived from 4 aspects. Regarding behavioral attitude, three themes were condensed: (1) Considering the benefits of preventive measures, (2) Simple and easy preventive measures, and (3) Underestimating the importance of PICC-related thrombosis prophylaxis. Subjective norms yielded two main themes and five sub-themes: (1) Support from those close to the patient motivates adherence to prophylaxis (support from the patient's family, healthcare professionals, and other patients) and (2) Patients are influenced by personal factors to form an internal driving force (physical symptoms, fear of PICC-related thrombosis). Regarding perceived behavioral control, three main themes and four sub-themes were extracted: (1) Obstacles before actual prevention exercise (prevention information, hard-to-remember information), (2) Forgetfulness is the main obstacle factor, and (3) Wanting to overcome barriers to adhere to regular prevention (confidence to overcome obstacles, hope to get support). CONCLUSIONS: The impediments and facilitators identified in this study may provide a scientific foundation for subsequent targeted non-pharmacological preventive interventions for PICC-related thrombosis based on TPB in breast cancer patients undergoing chemotherapy. Special interventions should be designed for the patients in three areas: the patients themselves, the supporters around the patient, and the healthcare professionals.

Melatonin downregulates angiogenesis and lymphangiogenesis by regulating tumor-associated macrophages via NLRP3 inflammasomes in lung adenocarcinoma.

Tumor-associated macrophages (TAMs), present within the tumor microenvironment (TME), strictly modulate tumor angiogenesis and lymphangiogenesis. Nevertheless, the associated signaling networks and candidate drug targets for these events remains to be elucidated. Given its antioxidative activities, we speculated that melatonin may reduce pyroptosis, and thereby modulate both angiogenesis and lymphangiogenesis. We revealed that a co-culture of A549 cells and THP-1 macrophages strongly enhanced expressions of the NLRP3 inflammasome axis members, and augmented angiogenesis and lymphangiogenesis. Next, we overexpressed NLRP3 in the A549 cells, and demonstrated that excess NLRP3 expression substantially upregulated VEGF and CXCL cytokine expressions, and enhanced lymphatic endothelial cells (LECs) tube formation. In contrast, NLRP3 inhibition produced the opposite effect. In addition, relative to controls, melatonin administration strongly inhibited the NLRP3 inflammasome axis, as well as angiogenesis and lymphangiogenesis in the co-culture system. Subsequent animal experiments using a Lewis Lung Carcinoma (LLC) subcutaneous tumor model in mice corroborate these findings. Melatonin treatment and NLRP3 knockdown significantly inhibit tumor growth and downregulate NLRP3 and IL-1ß expression in tumor tissues. Furthermore, melatonin downregulates the expression of angiogenic and lymphangiogenic markers in tumor tissues. Taken together, the evidence suggested that a THP-1 macrophage and A549 cell co-culture stimulates angiogenesis and lymphangiogenesis via the NLRP3 axis. Melatonin protected against the TAMs- and NLRP3 axis-associated promotion of the aforementioned events in vitro and in vivo. Hence, melatonin is a promising candidate for managing for tumor-related angiogenesis and lymphangiogenesis in lung adenocarcinoma.

Correlation analysis of cofilin-1 with renal prognosis in primary IgA nephropathy.

PURPOSE: The purpose of this study was to investigate the correlation between podocyte related biomarker cofilin-1 and renal function, and explore the value of cofilin-1 in predicting the risk of renal adverse prognosis in IgA nephropathy (IgAN). METHODS: Patients with primary IgAN diagnosed by initial renal biopsy performed in our hospital from January 2019 to February 2022 were included. This study was a prospective cohort study. All IgAN patients were detected the expression of cofilin-1 and other related biomarkers (RhoA, NGAL) in urine by enzyme-linked immunosorbent assay (ELISA) and follow-up at least 6 months. We also collected baseline clinicopathologial data of IgAN. The decreased renal function group was defined as baseline eGFR < 60 ml/min/1.73m2. Logistic and Cox regression model were used to analyze the correlation among cofilin-1 and renal prognosis. RESULTS: 133 IgAN patients were included, with a male-to-female ratio of 1.25:1 and an age of 37.67 ± 13.78 years, as well as an average of eGFR was 71.63 (40.42,109.33) ml/min/1.73m2. 56 patients (42.1%) had decreased renal function at baseline, with the average of eGFR was 34.07 (16.72, 49.21) ml/min/1.73 m2. 12 of which developed to renal adverse prognosis. The average of follow-up time was 22.035 ± 8.992 months. The multivariate regression analysis showed that increased urinary cofilin-1 was an independent risk factor associated with baseline renal function decline and renal adverse prognosis in IgAN patients (P < 0.05). ROC curves showed great efficacy of urinary cofilin-1 levels in diagnosing baseline renal function decline and predicting renal adverse prognosis (the area under the ROC curve was 0.708 and 0.803). CONCLUSION: Cofilin-1 as a novel biomarker of podocyte lesion is closely related to renal function decline in IgAN. Cofilin-1 has certain clinical value in predicting the risk of renal adverse prognosis. Podocyte fusion affects the renal prognosis of IgAN.

Global, regional, and national burden of inflammatory bowel disease, 1990-2021: Insights from the global burden of disease 2021.

PURPOSE: The prevalence of inflammatory bowel disease (IBD) is on the rise worldwide. We utilizes data from the Global Burden of Diseases (GBD) 2021 to analyze the national-level burden of IBD, trends in disease incidence, and epidemiological characteristics. METHODS: Detailed information on IBD was gathered from 204 countries and territories spanning 1990 to 2021, sourced from the GBD 2021. Calculations were performed for incidence rates, mortality rates, disease-adjusted life years (DALYs), and estimated annual percentage changes (EAPCs). These trends were analyzed based on region, nationality, age, gender, and World Bank income level stratifications. RESULTS: The global age-standardised incident rate (ASIR) of IBD increased from 4.22 per 100000 in 1990 to 4.45 per 100000 in 2021. However, the age-standardised mortality rate (ASMR) decreased from 0.60 per 100000 in 1990 to 0.52 per 100000 in 2021. Similarly, the age-standardised DALYs rate decreased from 21.55 per 100000 in 1990 to 18.07 per 100000 in 2021. Gender comparisons showed negligible differences in disease burden. The greatest increase in IBD-associated ASIR and ASMR occurred in World Bank upper-middle income region (EAPCs, 1.25) and World Bank high-income region (EAPCs, 1.00), respectively. Regionally, East Asia experienced the largest increase in ASIR (EAPCs, 2.89). Among 204 countries, China had the greatest increases in ASIR (EAPCs, 2.93), Netherlands had the highest ASMR in 2021 (2.21 per 100000). CONCLUSIONS: Global incidence rate of IBD have been increasing from 1990 to 2021, while the DALYs and mortality have been decreasing. The escalating incident rates in select Asian regions deserves further attention.

Red blood cell distribution width to albumin ratio associates with prevalence and long-term diabetes mellitus prognosis: an overview of NHANES 1999-2020 data.

Background: Erythrocyte dysfunction is a characteristic of diabetes mellitus (DM). However, erythrocyte-associated biomarkers do not adequately explain the high prevalence of DM. Here, we describe red blood cell distribution width to albumin ratio (RAR) as a novel inflammatory biomarker for evaluating an association with DM prevalence and prognosis of all-cause mortality. Methods: Data analyzed in this study were extracted from the National Health and Nutrition Examination Survey (NHANES) 1999-2020. A total of 40,558 participants (non-DM and DM) were enrolled in the study; RAR quartiles were calibrated at Q1 [2.02,2.82] mL/g, Q2 (2.82,3.05] mL/g, Q3 (3.05,3.38] mL/g, and Q4 (3.38,12.08] mL/g. A total of 8,482 DM patients were followed (for a median of 84 months), of whom 2,411 died and 6,071 survived. The prevalence and prognosis associated with RAR and DM were analyzed; age and sex were stratified to analyze the prevalence of RAR in DM and the sensitivity of long-term prognosis. Results: Among non-DM (n=30,404) and DM (n=10,154) volunteers, DM prevalence in RAR quartiles was 8.23%, 15.20%, 23.92%, and 36.39%. The multivariable odds ratio (OR) was significant for RAR regarding DM, at 1.68 (95% CI 1.42, 1.98). Considering Q1 as a foundation, the Q4 OR was 2.57 (95% CI 2.11, 3.13). The percentages of DM morbidity varied across RAR quartiles for dead (n=2,411) and surviving (n=6,071) DM patients. Specifically, RAR quartile mortality ratios were 20.31%, 24.24%, 22.65%, and 29.99% (P<0.0001). The multivariable hazard ratio (HR) for RAR was 1.80 (95% CI 1.57, 2.05). Considering Q1 as a foundation, the Q4 HR was 2.59 (95% CI 2.18, 3.09) after adjusting for confounding factors. Sensitivity analysis revealed the HR of male DM patients to be 2.27 (95% CI 1.95, 2.64), higher than females 1.56 (95% CI 1.31, 1.85). DM patients who were 60 years of age or younger had a higher HR of 2.08 (95% CI1.61, 2.70) as compared to those older than 60 years, who had an HR of 1.69 (95% CI 1.47, 1.94). The HR of RAR in DM patients was optimized by a restricted cubic spline (RCS) model; 3.22 was determined to be the inflection point of an inverse L-curve. DM patients with a RAR >3.22 mL/g suffered shorter survival and higher mortality as compared to those with RAR ≤3.22 mL/g. OR and HR RAR values were much higher than those of regular red blood cell distribution width. Conclusions: The predictive value of RAR is more accurate than that of RDW for projecting DM prevalence, while RAR, a DM risk factor, has long-term prognostic power for the condition. Survival time was found to be reduced as RAR increased for those aged ≤60 years among female DM patients.

Iron Chelator Deferiprone Restores Iron Homeostasis and Inhibits Retinal Neovascularization in Experimental Neovascular Age-Related Macular Degeneration.

Purpose: Retinal neovascularization is a significant feature of advanced age-related macular degeneration (AMD) and a major cause of blindness in patients with AMD. However, the underlying mechanism of this pathological neovascularization remains unknown. Iron metabolism has been implicated in various biological processes. This study was conducted to investigate the effects of iron metabolism on retinal neovascularization in neovascular AMD (nAMD). Methods: C57BL/6J and very low-density lipoprotein receptor (VLDLR) knockout (Vldlr-/-) mice, a murine model of nAMD, were used in this study. Bulk-RNA sequencing was used to identify differentially expressed genes. Western blot analysis was performed to test the expression of proteins. Iron chelator deferiprone (DFP) was administrated to the mice by oral gavage. Fundus fluorescein angiography was used to evaluate retinal vascular leakage. Immunofluorescence staining was used to detect macrophages and iron-related proteins. Results: RNA sequencing (RNA-seq) results showed altered transferrin expression in the retina and RPE of Vldlr-/- mice. Disrupted iron homeostasis was observed in the retina and RPE of Vldlr-/- mice. DFP mitigated iron overload and significantly reduced retinal neovascularization and vascular leakage. In addition, DFP suppressed the inflammation in Vldlr-/- retinas. The reduced signals of macrophages were observed at sites of neovascularization in the retina and RPE of Vldlr-/- mice after DFP treatment. Further, the IL-6/JAK2/STAT3 signaling pathway was activated in the retina and RPE of Vldlr-/- mice and reversed by DFP treatment. Conclusions: Disrupted iron metabolism may contribute to retinal neovascularization in nAMD. Restoring iron homeostasis by DFP could be a potential therapeutic approach for nAMD.

Circulating glycated albumin levels and gestational diabetes mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) is characterized by glucose intolerance that is first diagnosed during pregnancy, making it the most common complication associated with this period. Early detection and targeted treatment of GDM can minimize foetal exposure to maternal hyperglycaemia and subsequently reduce the associated adverse pregnancy outcomes. Previous studies have inconsistently suggested that the level of glycated albumin (GA) might predict GDM. AIM: To review and synthesize existing evidence to evaluate the relationship between GA levels and the development of GDM. METHODS: We sought to compare GA levels between GDM and control groups in this meta-analysis by systematically searching the Web of Science, PubMed, Cochrane Library, and Embase databases for articles published up to June 2023. The analysis utilized the weighted mean difference (WMD) as the primary metric. The data were meticulously extracted, and the quality of the included studies was assessed. Additionally, we conducted a subgroup analysis based on study region and sample size. We assessed heterogeneity using I 2 statistics and evaluated publication bias through funnel plots. Additionally, trim-and-fill analysis was employed to detect and address any potential publication bias. RESULTS: The meta-analysis included a total of 11 studies involving 5477 participants, comprising 1900 patients with GDM and 3577 control individuals. The synthesized results revealed a notable correlation between elevated GA levels and increased susceptibility to GDM. The calculated WMD was 0.42, with a 95% confidence interval (95%CI) ranging from 0.11 to 0.74, yielding a P value less than 0.001. Concerning specific GA levels, the mean GA level in the GDM group was 12.6, while for the control group, it was lower, at 11.6. This discrepancy underscores the potential of GA as a biomarker for assessing GDM risk. Moreover, we explored the levels of glycated haemoglobin (HbA1c) in both cohorts. The WMD for HbA1c was 0.19, with a 95%CI ranging from 0.15 to 0.22 and a P value less than 0.001. This observation suggested that both GA and HbA1c levels were elevated in individuals in the GDM group compared to those in the control group. CONCLUSION: Our meta-analysis revealed a substantial correlation between elevated GA levels and increased GDM risk. Furthermore, our findings revealed elevated levels of HbA1c in GDM patients, emphasizing the significance of monitoring both GA and HbA1c levels for early GDM detection and effective management.

Limosilactobacillus fermentum HNU312 alleviates lipid accumulation and inflammation induced by a high-fat diet: improves lipid metabolism pathways and increases short-chain fatty acids in the gut microbiome.

A high-fat diet can cause health problems, such as hyperlipidemia, obesity, cardiovascular disease, and metabolic disorders. Dietary supplementation with beneficial microbes might reduce the detrimental effects of a high-fat diet by modulating the gut microbiome, metabolic pathways and metabolites. This study assessed the effects of Limosilactobacillus fermentum HNU312 (L. fermentum HNU312) on blood lipid levels, fat accumulation, inflammation and the gut microbiome in mice on a high-fat diet. The results indicate that L. fermentum HNU312 supplementation to high-fat diet-fed mice led to decreases of 7.52% in the final body weight, 22.30% in total triglyceride, 24.87% in total cholesterol, and 27.3% in low-density lipoprotein cholesterol. Furthermore, the addition of L. fermentum HNU312 significantly reduced the fat accumulation in the liver and adipose tissue by 18.99% and 32.55%, respectively, and decreased chronic inflammation induced by a high-fat diet. Further analysis of the gut microbiome revealed that on the one hand, L. fermentum HNU312 changed the structure of the intestinal microbiota, increased the abundance of beneficial intestinal bacteria related to lipid metabolism, and reversed the enrichment of lipid-related metabolic pathways. On the other hand, L. fermentum HNU312 increased the production of short-chain fatty acids, which can reduce liver inflammation and chronic inflammation induced by a high-fat diet. In summary, by regulating gut microbiota, L. fermentum HNU312 improved lipid metabolism pathways and increased short-chain fatty acids, which reduced body weight, blood lipids, fat accumulation and chronic inflammation caused by high-fat diets. Therefore, L. fermentum HNU312 could be a good candidate probiotic for ameliorating metabolic syndrome.

Surface Ammonium Ions Assisted Decoration of Monodisperse Cobalt Nanoparticles on Molybdenum Oxide Films as Efficient Electrocatalysts for Hydrogen Evolution Reaction.

The high expense associated with electrocatalysts poses a challenge to the advancement of a hydrogen-based energy economy. The utilization of nonprecious metal-based electrocatalysts that are easily prepared and cost-effective is imperative for the future sustainability of a hydrogen society. The semiconductive MoO3-x has been identified as a promising nonprecious electrocatalyst for the hydrogen evolution reaction (HER). Nevertheless, enhancing its relatively low electrocatalytic activity toward HER remains a top priority. This study illustrates the manipulation of surface ammonium ions (NH4+) to produce uniform and distinct cobalt nanoparticles (Co NPs) on active MoO3-x supports, resulting in a more effective heterostructured composite electrocatalyst for HER. The presence of NH4+ ions in the MoO3-x film was extensively examined using infrared spectroscopy, X-ray photoelectron spectroscopy, and UV-visible colorimetric techniques. Additionally, the firmly attached NH4+ ions were employed as binding sites to precipitate Co-containing complex ions. Due to the monolayer-like adsorption of NH4+ ions, only a small quantity of Co precipitate was formed, which was subsequently electrochemically transformed into Co atoms that diffused and created well-separated uniform metallic Co nanoparticles (with an average size of less than 10 nm) on the MoO3-x film. The resulting heterostructure displays a 4.5-fold increase in current density for HER compared to the MoO3-x electrocatalyst through electrochemical assessments. The enhanced catalytic activity was ascribed to the optimized adsorption/desorption of the species involved in water reduction at the heterointerfaces and improved charge transfer rates. These nanoheterostructures hold great promise for a variety of applications in heterogeneous electrocatalysis, while the novel approach could potentially direct the creation of more heterostructures.

Multinodular and vacuolating neuronal tumor in the thalamus: case report and systematic review of literature.

The authors present the first reported case of MVNT in the thalamus in a 60-year-old man with a 20-year history of epilepsy and recent progressive neurological decline presented for neurosurgical evaluation for a non-enhancing mass predominantly in the right thalamus presumed to be a low-grade glioma. The tumor was subtotally resected using a left contralateral interhemispheric transcallosal approach. Histological and molecular assessment revealed an MVNT with MAPK pathway-activating mutation. The authors also conducted a systematic review of pathology-proven cases of MVNT to provide an up-to-date overview of the literature on the localization, presenting symptoms, and recurrence of this tumor.

Activation of GPR30 Ameliorates Cerebral Ischemia-Reperfusion Injury by Suppressing Ferroptosis Through Nrf2/GPX4 Signaling Pathway.

The newly identified estrogen receptor, G protein-coupled receptor 30 (GPR30), is prevalent in the brain and has been shown to provide significant neuroprotection. Recent studies have linked ferroptosis, a newly characterized form of programmed cell death, closely with cerebral ischemia-reperfusion injury (CIRI), highlighting it as a major contributing factor. Consequently, our research aimed to explore the potential of GPR30 targeting in controlling neuronal ferroptosis and lessening CIRI impacts. Results indicated that GPR30 activation not only improved neurological outcomes and decreased infarct size in a mouse model but also lessened iron accumulation and malondialdehyde formation post-middle cerebral artery occlusion (MCAO). This protective effect extended to increased levels of Nrf2 and GPX4 proteins. Similar protective results were replicated in PC12 cells subjected to Oxygen Glucose Deprivation and Reoxygenation (OGD/R) using the GPR30-specific agonist G1. Importantly, inhibition of Nrf2 with ML385 curtailed the neuroprotective effects of GPR30 activation, suggesting that GPR30 mitigates CIRI primarily through inhibition of neuronal ferroptosis via upregulation of Nrf2 and GPX4.

Association between 24-hour blood pressure parameters and 90-day functional outcome in acute ischemic stroke patients with early anticoagulation.

This study aimed to examine the relationship between blood pressure (BP) and blood pressure variability (BPV) during the first 24 hours from admission with 90-day functional outcomes in acute ischemic stroke (AIS) patients whose onset within 24 hours and receiving early argatroban treatment. The study recruited 214 AIS patients. BP was monitored using a cuff at 1-hour fixed intervals, and BP/BPV parameters [standard deviation (SD), coefficient of variation (CV), successive variation (SV), and average real variability (ARV)] were collected. Age, the National Institutes of Health Stroke Scale (NIHSS) score at admission, previous history of diabetes mellitus (DM), and infarction site (located in anterior circulation) were identified as independent factors affecting 90-day outcomes in multiple logistic regression. After adjusting for confounding variables, association between BP/BPV and 90-day modified Rankin Scale (mRS) was assessed using logistic regression models. In model 1 (adjusted for age and NIHSS score at admission), mean-systolic blood pressure (SBP) showed association with 90-day outcomes [1.068 (1.008, 1.131), P = .025]. In model 2 (adjusted for age, NIHSS score at admission, previous history of DM), mean-SBP [1.061 (1.001, 1.123), P = .045] and max-SBP [0.951 (0.906, 0.998), P = .040] showed relatively weak association with outcomes. In model 3 [adjusted for age, NIHSS score at admission, previous history of DM, infarct site (located in anterior circulation)], all BP values were not related with outcomes, meanwhile, none of the BPV parameters calculated from SBP, diastolic blood pressure and mean arterial pressure showed association with 90-day outcomes. Future prospective studies are required to assess the relationship between early BP/BPV parameters with 90-day outcomes and further clarify the reference values for BP parameters. This is important for effective BP/BPV management and improved patient prognosis.

Potential biomarkers of recurrent FSGS: a review.

Focal segmental glomerulosclerosis (FSGS), a clinicopathological condition characterized by nephrotic-range proteinuria, has a high risk of progression to end-stage renal disease (ESRD). Meanwhile, the recurrence of FSGS after renal transplantation is one of the main causes of graft loss. The diagnosis of recurrent FSGS is mainly based on renal puncture biopsy transplants, an approach not widely consented by patients with early mild disease. Therefore, there is an urgent need to find definitive diagnostic markers that can act as a target for early diagnosis and intervention in the treatment of patients. In this review, we summarize the domestic and international studies on the pathophysiology, pathogenesis and earliest screening methods of FSGS and describe the functions and roles of specific circulating factors in the progression of early FSGS, in order to provide a new theoretical basis for early diagnosis of FSGS recurrence, as well as aid the exploration of therapeutic targets.

An additional proofreader contributes to DNA replication fidelity in mycobacteria.

The removal of mis-incorporated nucleotides by proofreading activity ensures DNA replication fidelity. Whereas the ε-exonuclease DnaQ is a well-established proofreader in the model organism Escherichia coli, it has been shown that proofreading in a majority of bacteria relies on the polymerase and histidinol phosphatase (PHP) domain of replicative polymerase, despite the presence of a DnaQ homolog that is structurally and functionally distinct from E. coli DnaQ. However, the biological functions of this type of noncanonical DnaQ remain unclear. Here, we provide independent evidence that noncanonical DnaQ functions as an additional proofreader for mycobacteria. Using the mutation accumulation assay in combination with whole-genome sequencing, we showed that depletion of DnaQ in Mycolicibacterium smegmatis leads to an increased mutation rate, resulting in AT-biased mutagenesis and increased insertions/deletions in the homopolymer tract. Our results showed that mycobacterial DnaQ binds to the ß clamp and functions synergistically with the PHP domain proofreader to correct replication errors. Furthermore, the loss of dnaQ results in replication fork dysfunction, leading to attenuated growth and increased mutagenesis on subinhibitory fluoroquinolones potentially due to increased vulnerability to fork collapse. By analyzing the sequence polymorphism of dnaQ in clinical isolates of Mycobacterium tuberculosis (Mtb), we demonstrated that a naturally evolved DnaQ variant prevalent in Mtb lineage 4.3 may enable hypermutability and is associated with drug resistance. These results establish a coproofreading model and suggest a division of labor between DnaQ and PHP domain proofreader. This study also provides real-world evidence that a mutator-driven evolutionary pathway may exist during the adaptation of Mtb.