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BACKGROUND: Macrophage-driven inflammation critically involves in cardiac injury and repair following myocardial infarction (MI). However, the intrinsic mechanisms that halt the immune response of macrophages, which is critical to preserve homeostasis and effective infarct repair, remain to be fully defined. Here, we aimed to determine the ubiquitination-mediated regulatory effects on averting exaggerated inflammatory responses in cardiac macrophages. METHODS: We used transcriptome analysis of mouse cardiac macrophages and bone marrow-derived macrophages to identify the E3 ubiquitin ligase RNF149 (ring finger protein 149) as a modulator of macrophage response to MI. Employing loss-of-function methodologies, bone marrow transplantation approaches, and adenovirus-mediated RNF149 overexpression in macrophages, we elucidated the functional role of RNF149 in MI. We explored the underlying mechanisms through flow cytometry, transcriptome analysis, immunoprecipitation/mass spectrometry analysis, and functional experiments. RNF149 expression was measured in the cardiac tissues of patients with acute MI and healthy controls. RESULTS: RNF149 was highly expressed in murine and human cardiac macrophages at the early phase of MI. Knockout of RNF149, transplantation of Rnf149-/- bone marrow, and bone marrow macrophage-specific RNF149-knockdown markedly exacerbated cardiac dysfunction in murine MI models. Conversely, overexpression of RNF149 in macrophages attenuated the ischemia-induced decline in cardiac contractile function. RNF149 deletion increased infiltration of proinflammatory monocytes/macrophages, accompanied by a hastened decline in reparative subsets, leading to aggravation of myocardial apoptosis and impairment of infarct healing. Our data revealed that RNF149 in infiltrated macrophages restricted inflammation by promoting ubiquitylation-dependent proteasomal degradation of IFNGR1 (interferon gamma receptor 1). Loss of IFNGR1 rescued deleterious effects of RNF149 deficiency on MI. We further demonstrated that STAT1 (signal transducer and activator of transcription 1) activation induced Rnf149 transcription, which, in turn, destabilized the IFNGR1 protein to counteract type-II IFN (interferon) signaling, creating a feedback control mechanism to fine-tune macrophage-driven inflammation. CONCLUSIONS: These findings highlight the significance of RNF149 as a molecular brake on macrophage response to MI and uncover a macrophage-intrinsic posttranslational mechanism essential for maintaining immune homeostasis and facilitating cardiac repair following MI.

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BACKGROUND: Implementation of the Sensory Organization Test (SOT) under the rambling-trembling (RM-TR) framework allows for an examination of both individual sensory contributions and compensatory mechanisms, a valuable insight in research and clinical settings. Such investigation could substantially improve our ability to assess and treat fall risk in older adults and people living with neurological disorders. RESEARCH QUESTION: How are RM and TR components of sway influenced by SOT-induced challenges in healthy adults? METHODS: Twenty-three healthy adults (27.4±8 years; 10 male) volunteered to participate in this cross-sectional study. Each participant completed a VR-based SOT program, which included six conditions with varied visual environments (normal, blacked-out, conflict) and support surfaces (stable, unstable foam), while a force plate captured forces at the plantar surface. Center of pressure (COP) was calculated and decomposed into RM-TR components. For each time series, range, root-mean-square (RMS) and sample entropy (SampEn) were extracted. Individual contributions of somatosensation, vision, and vestibular sense, as well as the preference ratio, were calculated. Repeated measures ANOVA were used to compare the effects of time series type (COP, RM, TR) and SOT condition. Paired t-tests were used to assess the difference in preference ratio between RM and TR components. RESULTS AND SIGNIFICANCE: TR sway behavior was impacted significantly by the sensory challenges induced by the SOT procedure, while RM was largely unaffected. Such findings are characteristic of healthy individuals, capable of competently re-weighting sensory input, but still facing challenge-based adaptations. Additionally, the mediolateral SampEn preference ratio was higher in TR compared to RM, indicating potential differences in compensation strategies between supraspinal and spinal/peripheral control mechanisms. These findings serve as a foundation for future RM-TR analyses using SOT procedures, aiding in our ability to implement targeted diagnostic and treatment methods, ultimately reducing the incidence of falls in aging and individuals with neurological conditions.

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The recent growth in global warming, soil contamination, and climate instability have widely disturbed ecosystems, and will have a significant negative impact on the growth of plants that produce grains, fruits and woody biomass. To conquer this difficult situation, we need to understand the molecular bias of plant environmental responses and promote development of new technologies for sustainable maintenance of crop production. Accumulated molecular biological data have highlighted the importance of RNA-based mechanisms for plant stress responses. Here, we report the most advanced plant RNA research presented in the 33rd International Conference on Arabidopsis Research (ICAR2023), held as a hybrid event on June 5-9, 2023 in Chiba, Japan, and focused on "Arabidopsis for Sustainable Development Goals". Six workshops/concurrent sessions in ICAR2023 targeted plant RNA biology, and many RNA-related topics could be found in other sessions. In this meeting report, we focus on the workshops/concurrent sessions targeting RNA biology, to share what is happening now at the forefront of plant RNA research.

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BACKGROUND: Tuberculosis (TB) remains prevalent worldwide, and anti-TB drugs are associated with drug-induced liver injury (DILI). Statins have pleiotropic effects which may decrease inflammation and achieve immunomodulation. However, few studies have investigated the pleiotropic effects of statins on the risk of DILI. The purpose of this study was to investigate whether statins prevent anti-tuberculosis DILI among active TB patients on standard anti-TB drug therapy. METHODS: We conducted a hospital-based retrospective cohort study using claims data from the Integrated Medical Database of National Taiwan University Hospital (NTUH-iMD). Patients with a positive TB culture were included. The use of statins was defined as a daily equivalent dose >0.5 mg of pitavastatin. Deterioration in liver function was evaluated according to elevated liver enzyme levels. The primary and secondary endpoints were the DILI and the severe DILI. The prognostic value of statins was evaluated by Kaplan-Meier analysis, and Cox proportional hazards models. RESULTS: A total of 1312 patients with a diagnosis of TB and receiving anti-TB treatment were included. During the study period, 193 patients had the DILI and 140 patients had the severe DILI. Kaplan-Meier analysis showed a significant difference between the usual statin users and controls in the DILI. In multivariable Cox proportional hazards analysis, statins showed a protective effect against the primary and secondary endpoints. In addition, the protective effect of statins showed a dose-response relationship against the DILI. CONCLUSION: Statin treatment had a protective effect against the risk of anti-TB DILI with a positive dose-response relationship.

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Aims: Balance requires the cortical control of visual, somatosensory, and vestibular inputs. The aim of this cross-sectional study was to compare the contributions of each of these systems on postural control and cortical activity using a sensory reweighting approach between participants with Parkinson's disease (PD) and controls. Methods: Ten participants with PD (age: 72 ± 9; 3 women; Hoehn & Yahr: 2 [1.5 - 2.50]) and 11 controls (age: 70 ± 3; 4 women) completed a sensory organization test in virtual reality (VR-SOT) while cortical activity was being recorded using electroencephalography (EEG). Conditions 1 to 3 were completed on a stable platform; conditions 4 to 6 on a foam. Conditions 1 and 4 were done with eyes open; conditions 2 and 5 in a darkened VR environment; and conditions 3 and 6 in a moving VR environment. Linear mixed models were used to evaluate changes in center of pressure (COP) displacement and EEG alpha and theta/beta ratio power between the two groups across the postural control conditions. Condition 1 was used as reference in all analyses. Results: Participants with PD showed greater COP displacement than controls in the anteroposterior (AP) direction when relying on vestibular input (condition 5; p<0.0001). The mediolateral (ML) COP sway was greater in PD than in controls when relying on the somatosensory (condition 2; p = 0.03), visual (condition 4; p = 0.002), and vestibular (condition 5; p < 0.0001) systems. Participants with PD exhibited greater alpha power compared to controls when relying on visual input (condition 2; p = 0.003) and greater theta/beta ratio power when relying on somatosensory input (condition 4; p = 0.001). Conclusions: PD affects reweighting of postural control, exemplified by greater COP displacement and increased cortical activity. Further research is needed to establish the temporal dynamics between cortical activity and COP displacement.

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The widespread adoption of genetically modified (GM) crops has escalated concerns about their safety and ethical implications, underscoring the need for efficient GM crop detection methods. Conventional detection methods, such as polymerase chain reaction, can be costly, lab-bound, and time-consuming. To overcome these challenges, we have developed RapiSense, a cost-effective, portable, and sensitive biosensor platform. This sensor generates a measurable voltage shift (0.1-1 V) in the system's current-voltage characteristics, triggered by an increase in membrane's negative charge upon hybridization of DNA/RNA targets with a specific DNA probe. Probes designed to identify the herbicide resistance gene hygromycin phosphotransferase show a detection range from ∼1 nM to ∼10 µM and can discriminate between complementary, non-specific, and mismatched nucleotide targets. The incorporation of a small membrane sensor to detect fragmented RNA samples substantially improve the platform's sensitivity. In this study, RapiSense has been effectively used to detect specific DNA and fragmented RNA in transgenic variants of Arabidopsis, sweet potato, and rice, showcasing its potential for rapid, on-site GM crop screening.

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BACKGROUND: This study investigates the impact of nontuberculous mycobacterial lung disease (NTM-LD) on mortality and mechanical ventilation use in critically ill patients. METHODS: We enrolled patients with NTM-LD or tuberculosis (TB) in intensive care units (ICU) and analysed their association with 30-day mortality and with mechanical ventilator-free survival (VFS) at 30 days after ICU admission. RESULTS: A total of 5996 ICU-admitted patients were included, of which 541 (9.0 %) had TB and 173 (2.9 %) had NTM-LD. The overall 30-day mortality was 22.2 %. The patients with NTM-LD had an adjusted hazard ratio (aHR) of 1.49 (95 % CI, 1.06-2.05), and TB patients had an aHR of 2.33 (95 % CI, 1.68-3.24), compared to ICU patients with negative sputum mycobacterial culture by multivariable Cox proportional hazard (PH) regression. The aHR of age<65 years, obesity, idiopathic pulmonary fibrosis, end-stage kidney disease, active cancer and autoimmune disease and diagnosis of respiratory failure were also significantly positively associated with ICU 30-day mortality. In multivariable Cox PH regression for VFS at 30 days in patients requiring invasive mechanical ventilation, NTM-LD was negatively associated with VFS (aHR 0.71, 95 % CI: 0.56-0.92, p = 0.009), while TB showed no significant association. The diagnosis of respiratory failure itself predicted unfavourable outcome for 30-day mortality and a negative impact on VFS at 30 days. CONCLUSIONS: NTM-LD and TB were not uncommon in ICU and both were correlated with increasing 30-day mortality in ICU patients. NTM-LD was associated with a poorer outcome in terms of VFS at 30 days.

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BACKGROUND: In this study, we retrospectively analysed macrophage infiltration and podocyte injury in three patients with diffuse proliferative lupus nephritis (LN) who underwent repeated renal biopsy. CASE SUMMARY: Clinical data of three diffuse proliferative LN patients with different pathological characteristics (case 1 was LN IV-G (A), case 2 was LN IV-G (A) + V, and case 3 was LN IV-G (A) + thrombotic microangiopathy) were reviewed. All patients underwent repeated renal biopsies 6 mo later, and renal biopsy specimens were studied. Macrophage infiltration was assessed by CD68 expression detected by immunohistochemical staining, and an immunofluorescence assay was used to detect podocin expression to assess podocyte damage. After treatment, Case 1 changed to LN III-(A), Case 2 remained as type V LN lesions, and Case 3, which changed to LN IV-S (A), had the worst prognosis. We observed reduced macrophage infiltration after therapy. However, two of the patients with active lesions after treatment still showed macrophage infiltration in the renal interstitium. Before treatment, the three patients showed discontinuous expression of podocin. Notably, the integrity of podocin was restored after treatment in Case 1. CONCLUSION: It may be possible to reverse podocyte damage and decrease the infiltrating macrophages in LN patients through effective treatment.

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Pyrazinamide (PZA) is considered to be a pivotal drug to shorten the treatment of both drug-susceptible and drug-resistant tuberculosis, but its use is challenged by the reliability of drug-susceptibility testing (DST). PZA resistance in Mycobacterium tuberculosis (MTB) is relevant to the amino acid substitution of pyrazinamidase that is responsible for the conversion of PZA to active pyrazinoic acid (POA). The single nucleotide variants (SNVs) within ribosomal protein S1 (rpsA) or aspartate decarboxylase (panD), the binding targets of POA, has been reported to drive the PZA-resistance signature of MTB. In this study, whole genome sequencing (WGS) was used to identify SNVs within the pncA, rpsA and panD genes in 100 clinical MTB isolates associated with DST results for PZA. The potential influence of high-confidence, interim-confidence or emerging variants on the interplay between target genes and PZA or POA was simulated computationally, and predicted with a protein structure modelling approach. The DST results showed weak agreement with the identification of high-confidence variants within the pncA gene (Cohen's kappa coefficient=0.58), the analytic results of WGS coupled with protein structure modelling on pncA mutants (Cohen's kappa coefficient=0.524) or related genes (Cohen's kappa coefficient=0.504). Taken together, these results suggest the practicable application of a genotypic-coupled bioinformatic approach to manage PZA-containing regimens for patients with MTB.

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Pathological cardiac hypertrophy is a key contributor to heart failure, and the molecular mechanisms underlying honokiol (HNK)-mediated cardioprotection against this condition remain worth further exploring. This study aims to investigate the effect of HNK on angiotensin II (Ang II)-induced myocardial hypertrophy and elucidate the underlying mechanisms. Sprague-Dawley rats were exposed to Ang II infusion, followed by HNK or vehicle treatment for 4 weeks. Our results showed that HNK treatment protected against Ang II-induced myocardial hypertrophy, fibrosis and dysfunction in vivo and inhibited Ang II-induced hypertrophy in neonatal rat ventricular myocytes in vitro. Mechanistically, HNK suppressed the Ang II-induced Nur77 expression at the transcriptional level and promoted ubiquitination-mediated degradation of Nur77, leading to dissociation of the Nur77-LKB1 complex. This facilitated the translocation of LKB1 into the cytoplasm and activated the LKB1-AMPK pathway. Our findings suggest that HNK attenuates pathological remodelling and cardiac dysfunction induced by Ang II by promoting dissociation of the Nur77-LKB1 complex and subsequent activation of AMPK signalling. This study uncovers a novel role of HNK on the LKB1-AMPK pathway to protect against cardiac hypertrophy.

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AIMS: Left ventricular remodelling subsequent to myocardial infarction (MI) constitutes a pivotal underlying cause of heart failure. Intervention with the nontoxic endogenous aryl hydrocarbon receptor (AHR) agonist 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) in the acute phase of MI has been shown to ameliorate cardiac function, but its role in the chronic phase remains obscured. This study explores the beneficial role of ITE in delaying the progression of heart failure in the chronic phase of MI. METHODS AND RESULTS: MI rats established by ligating the left anterior descending coronary artery were treated with the indicated concentration of the AHR agonist ITE or vehicle alone. Echocardiography was performed to determine cardiac structure and function; myocardial morphology and fibrosis were observed by haematoxylin and eosin and Masson's trichrome staining; serum biochemical indices, BNP, and inflammatory cytokine levels were detected by enzyme-linked immunosorbent assay; F4/80+ iNOS+ M1 macrophages and F4/80+ CD206+ M2 macrophages were detected by immunofluorescence; the terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling assay was used to detect the apoptosis of cardiomyocytes; ultrastructural changes in myocardial tissue were observed by transmission electron microscopy; and Cyp1a1, Akt, P-Akt, p70S6K, P-p70S6K, Bcl-2, Bax, caspase-3, and cleaved caspase-3 protein levels were determined via Western blotting. We found that therapy with the AHR agonist ITE rescued cardiac remodelling and dysfunction in rats with MI and attenuated myocardial fibrosis, inflammation, and mitochondrial damage. Further studies confirmed that ITE dose-dependently improved myocardial cell apoptosis after MI, as demonstrated by reduced levels of the apoptosis-related proteins cleaved caspase-3 and Bax but increased expression levels of Bcl-2. These effects were attributed to ITE-induced activation of AHR receptors, leading to the down-regulation of Akt and p70S6K phosphorylation. CONCLUSIONS: The AHR agonist ITE alleviates cardiomyocyte apoptosis through the Akt/p70S6K signalling pathway, thereby rescuing left ventricular adverse remodelling and cardiac dysfunction after MI.

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Overnutrition with a high-fat or high-sugar diet is widely considered to be the risk factor for various metabolic, chronic, or malignant diseases that are accompanied by alterations in gut microbiota, metabolites, and downstream pathways. In this study, we investigated supplementation with soybean fermentation broth containing saponin (SFBS, also called SAPOZYME) in male C57BL/6 mice fed a high-fat-fructose diet or normal chaw. In addition to the lessening of weight gain, the influence of SFBS on reducing hyperlipidemia and hyperglycemia associated with a high-fat-fructose diet was estimated using the results of related biological tests. The results of gut microbial profiling indicated that the high-fat-fructose diet mediated increases in opportunistic pathogens. In contrast, SFBS supplementation reprogrammed the high-fat-fructose diet-related microbial community with a relatively high abundance of potential probiotics, including Akkermansia and Lactobacillus genera. The metagenomic functions of differential microbial composition in a mouse model and enrolled participants were assessed using the PICRUSt2 algorithm coupled with the MetaCyc and the KEGG Orthology databases. SFBS supplementation exerted a similar influence on an increase in the level of 4-aminobutanoate (also called GABA) through the L-glutamate degradation pathway in the mouse model and the enrolled healthy population. These results suggest the beneficial influence of SFBS supplementation on metabolic disorders associated with a high-fat-fructose diet, and SFBS may function as a nutritional supplement for people with diverse requirements.

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BACKGROUND: The BODE index, consisting of body mass index (B), airflow obstruction (O), dyspnea score (D), and exercise capacity (E), can predict outcomes in COPD. However, when spirometry was restricted to prevent cross-infection such as COVID-19 pandemic, a modified index would be needed. Because cardiovascular dysfunction is associated with poor clinical outcomes in COPD, we conducted a novel BHDE-index by replacing spirometry with post-exercise heart rate recovery (HRR, H) and evaluated its predictive performance in this observational study. METHODS: From January 2019 to December 2019, enrolled patients were analyzed as a derivation cohort for the setup of the model. This model was verified in another group of patients generated between January 2020 and December 2020, as the validation cohort. The post exercise HRR was defined as the difference of heart rate immediately after and 1 min after test cessation. RESULTS: A total of 447 patients with COPD were enrolled. Patients with abnormal HRR were older, with more severe airway obstruction, severe airway symptoms, faster resting heart rate, shorter 6-min walk distance and higher frequency of severe acute exacerbation in previous one year. The prediction performance of the BHDE-index for one-year severe COPD exacerbation was similar to that of the BODE-index in both the derivation and validation groups [area under the receiver operating characteristic curve (AUROC) 0.76 vs. 0.75, p = 0.369; AUROC 0.74 vs. 0.79, p = 0.05]. The prediction performance for 1 year mortality was also similar between BHDE-index and BODE-index in both cohorts [AUROC 0.80 vs. 0.77, p = 0.564; 0.76 vs. 0.70, p = 0.234]. Univariate and multivariate analyses also showed that the BHDE-index was an independent and important predictor of annual severe COPD exacerbation in the derivation and validation cohorts. CONCLUSIONS: The BHDE-index is a good and easy-to-perform prediction model for the risk of severe acute exacerbation and 1-year mortality in COPD wherever spirometry results are unavailable.

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Retinoid X receptor (RXR), particularly RXRα, has been implicated in cardiovascular diseases. However, the functional role of RXR activation in myocardial infarction (MI) remains unclear. This study aimed to determine the effects of RXR agonists on MI and to dissect the underlying mechanisms. Sprague-Dawley (SD) rats were subjected to MI and then treated (once daily for 4 weeks) with either RXR agonist bexarotene (10 or 30 mg/kg body weight) or vehicle. Heart function was determined using echocardiography and cardiac hemodynamic measurements. Four weeks post MI, myocardial tissues were collected to evaluate cardiac remodeling. Primary cardiac fibroblasts (CFs) were treated with or without RXR ligand 9-cis-RA followed by stimulation with TGF-ß1. Immunoblot, immunofluorescence, and co-immunoprecipitation were performed to elucidate the regulatory role of RXR agonists in TGF-ß1/Smad signaling. In vivo treatment with Bexarotene moderately affects systemic inflammation and apoptosis and ameliorated left ventricular dysfunction after MI in rat model. In contrast, bexarotene significantly inhibited post-MI myocardial fibrosis. Immunoblot analysis of heart tissue homogenates from MI rats revealed that bexarotene regulated the activation of the TGF-ß1/Smad signaling pathway. In vitro, 9-cis-RA inhibited the TGF-ß1-induced proliferation and collagen production of CFs. Importantly, upon activation by 9-cis-RA, RXRα interacted with p-Smad2 in cytoplasm, inhibiting the TGF-ß1-induced nuclear translocation of p-Smad2, thereby negatively regulating TGF-ß1/Smad signaling and attenuating the fibrotic response of CFs. These findings suggest that RXR agonists ameliorate post-infarction myocardial fibrosis, maladaptive remodeling, and heart dysfunction via attenuation of fibrotic response in CFs through inhibition of the TGF-ß1/Smad pathway activation.

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PURPOSE: This study assessed the association between changes in sublingual microcirculation after a spontaneous breathing trial (SBT) and successful extubation. MATERIALS AND METHODS: Sublingual microcirculation was assessed using an incident dark-field video microscope before and after each SBT and before extubation. Microcirculatory parameters before the SBT, at the end of the SBT, and before extubation were compared between the successful and failed extubation groups. RESULTS: Forty-seven patients were enrolled and analysed in this study (34 patients in the successful extubation group and 13 patients in the failed extubation group). At the end of the SBT, the weaning parameters did not differ between the two groups. However, the total small vessel density (21.2 [20.4-23.7] versus 24.9 [22.6-26.5] mm/mm2), perfused small vessel density (20.6 [18.5-21.8] versus 23.1 [20.9-25] mm/mm2), proportion of perfused small vessels (91 [87-96] versus 95 [93-98] %), and microvascular flow index (2.8 [2.7-2.9] versus 2.9 [2.9-3]) were significantly lower in the failed extubation group than in the successful extubation group. The weaning and microcirculatory parameters did not differ significantly between the two groups before the SBT. CONCLUSIONS: More patients are required to investigate the difference between baseline microcirculation before a successful SBT and the change in microcirculation at the end of the SBT between the successful and failed extubation groups. Better sublingual microcirculatory parameters at the end of SBT and before extubation are associated with successful extubation.

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Partial denitrification-anaerobic ammonium oxidation (PD/A) was considered a novel technology for biological nitrogen removal. In this study, a glycerol-driven PD/A granular sludge reactor was constructed, and its nitrogen removal efficiency and microbial mechanisms were investigated systematically. After optimization, the PD/A reactor achieved 92.3 % of the nitrogen removal (~90 % by anammox) with the influent COD/NO3--N ratio of 2.6, and approximate 1.36 mol NO3--N was required for removing 1 mol NH4+-N. Granular sludge with layered structure (anaerobic ammonium oxidizing bacteria (AnAOB) was wrapped by the heterotrophic bacteria) was successfully developed, which resulted in the sludge floating. Bacillus was firstly found to be the dominant genus in PD/A system with an abundance of 46.1 %, whereas the AnAOB only accounted for 0.2-2.8 %. Metatranscriptomic analysis showed that the metabolic characteristics obviously changed during the operation, and the differential expressing genes mainly belonged to ABC transport and quorum sensing pathway. Further analysis about the expressing patterns of nitrogen metabolism related genes indicated that the anammox related genes (mainly from Candidatus Brocadia and Candidatus Jettenia) exhibited a much higher expressing level than other genes. Interestingly, the assimilatory nitrate reduction process in Bacillus showed great NO2--N producing potential, so it was considered to be an essential pathway participating in PD/A process. This study provided a comprehensive insight into the glycerol-driven PD/A system.

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The intimate correlation of chronic kidney disease (CKD) with structural alteration in gut microbiota or metabolite profile has been documented in a growing body of studies. Nevertheless, a paucity of demonstrated knowledge regarding the impact and underlying mechanism of gut microbiota or metabolite on occurrence or progression of CKD is unclarified thus far. In this study, a liquid chromatography coupled-mass spectrometry and long-read sequencing were applied to identify gut metabolites and microbiome with statistically-discriminative abundance in diabetic CKD patients (n = 39), hypertensive CKD patients (n = 26), or CKD patients without comorbidity (n = 40) compared to those of healthy participants (n = 60). The association between CKD-related species and metabolite was evaluated by using zero-inflated negative binomial (ZINB) regression. The predictive utility of identified operational taxonomic units (OTUs), metabolite, or species-metabolite association toward the diagnosis of incident chronic kidney disease with distinct pathogenic factor was assessed using the random forest regression model and the receiver operating characteristic (ROC) curve. The results of statistical analyses indicated alterations in the relative abundances of 26 OTUs and 41 metabolites that were specifically relevant to each CKD-patient group. The random forest regression model with only species, metabolites, or its association differentially distinguished the hypertensive, diabetic CKD patients, or enrolled CKD patients without comorbidity from the healthy participants. IMPORTANCE Gut dysbiosis-altered metabolite association exhibits specific and convincing utility to differentiate CKD associated with distinct pathogenic factor. These results present the validity of pathogenesis-associated markers across healthy participants and high-risk population toward the early screening, prevention, diagnosis, or personalized treatment of CKD.

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Arrhythmia and cardiac hypertrophy are two very common cardiovascular diseases that can lead to heart failure and even sudden death, thus presenting a serious threat to human life and health. According to global statistics, nearly one million people per year die from arrhythmia, cardiac hypertrophy and other associated cardiovascular diseases. Hence, there is an urgent need to find new treatment targets and to develop new intervention measures. Recently, mitochondrial dysfunction has been examined in relation to heart disease with a view to lowering the incidence of arrhythmia and cardiac hypertrophy. The heart is the body's largest energy consuming organ, turning over about 20 kg of adenosine triphosphate (ATP) per day in the mitochondria. Mitochondrial oxidative phosphorylation (OXPHOS) produces up to 90% of the ATP needed by cardiac muscle cells for contraction and relaxation. Dysfunction of heart mitochondria can therefore induce arrhythmia, cardiac hypertrophy and other cardiovascular diseases. Mitochondrial DNA (mtDNA) mutations cause disorders in OXPHOS and defects in the synthesis of muscle contraction proteins. These lead to insufficient production of secondary ATP, increased metabolic requirements for ATP by the myocardium, and the accumulation of reactive oxygen species (ROS). The resulting damage to myocardial cells eventually induces arrhythmia and cardiac hypertrophy. Mitochondrial damage decreases the efficiency of energy production, which further increases the production of ROS. The accumulation of ROS causes mitochondrial damage and eventually leads to a vicious cycle of mitochondrial damage and low efficiency of mitochondrial energy production. In this review, the mechanism underlying the development of arrhythmia and cardiac hypertrophy is described in relation to mitochondrial energy supply, oxidative stress, mtDNA mutation and Mitochondrial dynamics. Targeted therapy for arrhythmia and cardiac hypertrophy induced by mitochondrial dysfunction is also discussed in terms of its potential clinical value. These strategies should improve our understanding of mitochondrial biology and the pathogenesis of arrhythmia and cardiac hypertrophy. They may also identify novel strategies for targeting mitochondria in the treatment of these diseases.