We report an implementation of the McMurchie-Davidson evaluation scheme for 1- and 2-particle Gaussian AO integrals designed for processors with Single Instruction Multiple Data (SIMD) instruction sets. Like in our recent MD implementation for graphical processing units (GPUs) [Asadchev, A.; Valeev, E. F.. J. Chem. Phys. 2024, 160, 244109.], variable-sized batches of shellsets of integrals are evaluated at a time. By optimizing for the floating point instruction throughput rather than minimizing the number of operations, this approach achieves up to 50% of the theoretical hardware peak FP64 performance for many common SIMD-equipped platforms (AVX2, AVX512, NEON), which translates to speedups of up to 30 over the state-of-the-art one-shellset-at-a-time implementation of Obara-Saika-type schemes in Libint for a variety of primitive and contracted integrals. As with our previous work, we rely on the standard C++ programming language─such as the std::simd standard library feature to be included in the 2026 ISO C++ standard─without any explicit code generation to keep the code base small and portable. The implementation is part of the open source LibintX library freely available at https://github.com/ValeevGroup/libintx.
Approximate string matching (ASM) is the problem of finding all occurrences of a pattern in a text while allowing up to k errors. Many modern methods use seed-chain-extend, which is fast in practice, but does not guarantee finding all matches with ≤k errors. However, applications such as CRISPR off-target detection require exhaustive results. We introduce Sassy, a library and tool for ASM of short patterns in long texts. Sassy splits the text into four parts that are searched in parallel, and uses bitvectors in the text direction rather than the pattern direction. This has complexity O(k⌈n/W⌉) when searching a random text of length n, where W=256 is the SIMD width, and provides significant speedups for small k. Separately, we allow matches of the pattern to extend beyond the text for an overhang cost of, e.g. α=0.5 per character, to find matches near contig or read ends.Sassy is 4× to 15× faster than Edlib for patterns ≤1000 bp, and can search text with a throughput near 2 Gbp/s. Likewise, Sassy is over 100× faster than parasail. We apply Sassy to CRISPR off-target detection by searching 61 guide sequences in a human genome. Sassy is 100× faster than SWOffinder and only slightly slower (for k≤3) than CHOPOFF, for which building its index takes 20 min. Sassy also scales well to larger k, unlike CHOPOFF whose index took over 10 h to build for k=5. Sassy is available as library and binary at https://github.com/RagnarGrootKoerkamp/sassy, and archived at swh:1:dir:e884758dce5777a441bc2799dc8824e563c5f97b.
This study aimed to introduce a synergistic integration platform based on single-cell and proteotranscriptomics for drug repositioning (SIMD) to repurpose breast cancer drug candidates by considering the bidirectional nature of molecular dynamics in protein transcriptomics and tumor heterogeneity at the single-cell level. SMID consists of two core methods: the anti-correlated proteotranscriptome perturbation score (ACPS), which measures the negative correlation between perturbagen-induced expression signatures and multi-omic expression profiles from patient-derived breast cancer samples; and perturbagen repositioning scoring and scRNA-seq data (PPNE), which ranks perturbagens exhibiting high ACPS scores and inverse transcriptomic associations with neoplastic epithelial (NE) cells identified through single-cell RNA sequencing data. We validated the top five SIMD-prioritized perturbagens by assessing cell viability in five breast cancer cell lines. Many perturbagens ranked highest by the ACPS have been ascertained in clinical trials for breast cancer or other cancer treatments. Validation revealed a substantial reduction in cell viability for the majority of perturbagens in most cell types. Our result observed significantly overexpressed phosphorylation sites within the AKT1 and PI3K genes, which are buparlisib target genes, suggesting that buparlisib may exert its effects across a spectrum of breast cancer types, including triple-negative breast cancer, by modulating molecular mechanisms within the PI3K pathway.
To date, there has been no command line utility for performing index-free alignment-based filtering of records. Since filtering using command line tools is a staple of Bioinformatics, this leaves a gap in command line workflows. Ish is the first composable unix-style command line tool for filtering the input target records to only those that match the input query with a threshold alignment score, using a selectable alignment algorithm and selectable record type. The core alignment algorithms for ish meet or exceed the performance of their reference implementations in Parasail for both SIMD and GPU alignment, as measured by gigacell updates per second (GCUPs). The source code and documentation are available at https://github.com/BioRadOpenSource/ish under the Apache-2.0 License and open for community contributions. Ish is installable with Conda and supports Linux and macOS.
Sepsis-induced myocardial dysfunction (SIMD) is a frequent consequence in septic patients and is correlated with higher mortality. Recent research suggests that activating autophagy might alleviate SIMD. Thus, this study aims to identify the autophagy-related gene (ARG) and assess its diagnostic value in SIMD patients. We conducted a sequential and extensive bioinformatics analysis of human SIMD transcriptome data from the Gene Expression Omnibus (GEO) database. Target ARG in SIMD were identified through weighted gene co-expression network analysis (WGCNA), differential expression analysis, and protein-protein interaction (PPI) network construction. The diagnostic value of the key ARG and its association with immune cell infiltration were evaluated. The role of target ARG in SIMD was validated using a lipopolysaccharide (LPS)-induced cell SMID model. We identified 12 ARGs associated with SIMD pathogenesis based on the human SIMD transcriptome data and investigated their potential biological processes. MYC was identified as a key ARG in SIMD by constructing a protein-protein interaction network. MYC was highly expressed in patients with SIMD and had excellent diagnostic capability for SIMD. Subsequently, we predicted drugs associated with MYC expression and constructed a crucial transcription factor (TF)-miRNA-mRNA co-regulatory network. Finally, we found that several immune-related signaling pathways were significantly activated in the MYChigh group, and MYC was correlated with the infiltration of immune cells in SIMD patients. In an LPS-induced SIMD cellular model, Myc knockdown attenuated the LPS-induced enhancement of autophagic flux. We identified MYC, an autophagy-related gene, as a potential diagnostic marker for SIMD, offering insights into autophagic mechanisms and informing future diagnostic approaches.
Substance-induced mental disorders (SIMD) are an under-recognized consequence of psychoactive substance use, despite major implications for treatment needs, health service demand and outcomes. In the context of British Columbia's (BC's) ongoing toxic drug emergency, we aimed to (1) estimate the incidence and prevalence of SIMD in the provincial population and (2) describe socio-demographic, geographic, clinical and substance-specific patterns over a two-year period. We conducted a retrospective, population-based study using linked administrative health data from Population Data BC for residents aged ≥12 years between 1 January 2022 and 31 December 2023. SIMD cases were identified using a novel algorithm combining diagnostic codes with temporal linkage between substance-related events (poisoning, withdrawal or substance use disorder) and subsequent psychiatric diagnoses. Incident cases had no record of the same mental disorder in the previous two years; prevalent cases met SIMD criteria at any point in the study period. We calculated monthly, annual and cumulative incidence and prevalence rates per 10,000 population, stratified by sex, age group, health authority, urban/rural residence, neighbourhood income, psychiatric diagnosis, substance class, concurrent substance use disorder, involuntary treatment and mortality. We identified 37,474 incident and 83,307 prevalent SIMD cases over two years, corresponding to a cumulative incidence of 77.5 and prevalence of 171.4 per 10,000 population. Monthly rates fluctuated in 2022, followed by a rise through 2023, with highest incidence (35.2 per 10,000) and prevalence (328.3 per 10,000) in May 2023. Males accounted for 62% of incident and 59% of prevalent cases; mean age was 43 years, with highest proportions in the 25-44 age range. Northern and Vancouver Island Health Authorities had the greatest burden. On average, individuals with SIMD had 3.2-3.6 healthcare visits per month. Cannabis- and hallucinogen-induced disorders were concentrated among younger people, while alcohol- and tobacco-related SIMD predominated in older adults; stimulant-related SIMD showed the highest hospitalization and involuntary treatment rates. Only about one-third of prevalent and fewer than one in five incident cases had a recorded concurrent substance use disorder. SIMDs are common, clinically complex and unevenly distributed across demographic and geographic groups in BC. The high rates, substantial service use and frequent occurrence outside documented substance use disorder diagnoses underscore the need for improved detection of SIMD, integration of psychiatric and addiction care and regionally tailored prevention and treatment strategies within the ongoing toxic drug emergency.
Sepsis-induced myocardial dysfunction (SIMD), a severe sepsis complication, is characterized by immune dysregulation, with neutrophils playing a central role. While the immunity-related GTPase family M protein (IRGM) in humans and its murine ortholog Irgm1 are key immune regulators, the precise contribution of neutrophil Irgm1 to SIMD pathogenesis remains unclear. This study aims to explore the involvement of neutrophil Irgm1 in SIMD and uncover its mechanisms. This research found that IRGM expression was upregulated in peripheral blood neutrophils from patients with SIMD and inversely correlated with disease severity. In mice, neutrophil-specific Irgm1 deficiency worsened CLP-induced cardiac dysfunction and myocardial inflammation. Mechanistically, Irgm1 interacted with the E3 ubiquitin ligase RING finger protein 213 (RNF213) to facilitate 15-lipoxygenase (Alox15) ubiquitination and degradation, thereby inhibiting neutrophil ferroptosis and suppressing the production of 15-HETE, which alleviates SIMD. In patients with SIMD, the expression levels of Alox15 and the concentrations of 15-HETE were positively correlated with disease severity. Notably, intraperitoneal administration of Alox15-targeting drug PD146176 significantly improved cardiac function in SIMD mice. Collectively, this study highlights the pivotal role of the Irgm1 in attenuating SIMD by restraining neutrophil ferroptosis and 15-HETE production. Irgm1 may serve as a promising prognostic biomarker and a valuable therapeutic target for SIMD.
Sepsis-induced myocardial dysfunction (SIMD) is a worldwide health issue. Regarding malignant cardiac dysfunction and mortality, the fatality rate of SIMD accounts for 70-90%. The molecular mechanisms that underlie the inflammatory effects and cardiac function of SIMD appear to be intricate. A crucial cellular process associated with cardiomyopathy is the death of cardiomyocytes. In the review, we have summarized the present evidence on the role of autophagy in the pathomechanism of SIMD. The included studies suggest that cardiomyocyte death induced by SIMD might be partially regulated by autophagy and its associated genes and pathways, including but not limited to Unc-51 like-autophagy-activating kinase 1 (ULK1), Zinc finger antisense 1 (ZFAS1), miR-590-3p, miR-214-3p, miR-21-3p, Silent information regulator 1 (SIRT1), SH3 domain-containing protein 2 (SORBS2), AMP-activated protein kinase (AMPK), Mammalian target of rapamycin (mTOR), TLR4/ERK1/2/NF-κB, TFEB-CLEAR, and Tensin homolog deleted on chromosome 10/Protein kinase B (PTEN/AKT) pathway. The crosstalk among autophagy and its associated genes it might be one of the pivotal molecular and cellular mechanisms for SIMD. In addition, some interventions for treating SIMD, e.g. exogenous fibroblast growth factor 21, melatonin, urolithin A, and minocycline, were reported to be associated with their effects on the regulation of autophagy. However, due to limited research, the potential molecular mechanism underlying autophagy in regulating SIMD is unclear and requires further exploration through in vitro and in vivo experiments. Overall, a deeper understanding of SIMD pathogenesis may facilitate new prospects of therapeutic applications targeted to autophagy.
To evaluate immune microenvironment markers for predicting sepsis-induced myocardial dysfunction (SIMD) and establish three predictive models-nomogram, decision tree, and gradient boosting machine (GBM)-to compare their efficacy in assessing SIMD risk. A retrospective analysis was conducted on the clinical data of 165 patients with sepsis who were admitted between January 2022 and February 2025. Patients were divided into SIMD and non-SIMD groups according to the occurrence of SIMD. Risk factors influencing the occurrence of SIMD in patients with sepsis were screened using univariate and multivariate logistic regression analyses. Nomogram, decision tree, and GBM models were constructed based on the results of the multivariate logistic regression analysis. The area under the receiver operating characteristic curve (AUC) was used to evaluate the discrimination of each model. The accuracy, sensitivity, specificity, and F1 scores of the three models were calculated. : Among the 165 patients with sepsis included in the study, 75 were in the SIMD group, accounting for 45.45% (75/165). Univariate analysis showed significant differences between the two groups in APACHE II score, white blood cell count, N-terminal pro-brain natriuretic peptide (NT-proBNP), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), and high mobility group box 1 (HMGB1) levels (P < 0.05). Logistic regression analysis revealed that a high APACHE II score (OR = 1.480, 95% CI: 1.127-1.945), high NT-proBNP level (OR = 1.013, 95% CI: 1.005-1.021), high sTREM-1 level (OR = 1.116, 95% CI: 1.034-1.205), and high HMGB1 level (OR = 1.006, 95% CI: 1.002-1.011) were risk factors for SIMD in patients with sepsis (P < 0.05). All three prediction models demonstrated excellent performance in the training set: nomogram (AUC = 0.843), decision tree (AUC = 0.815), and GBM (AUC = 0.885). No significant differences were observed in the AUC values among the models (all P > 0.05). The immune markers, sTREM-1 and HMGB1, were associated with SIMD. Elevated APACHE II score and NT-proBNP, sTREM-1, and HMGB1 levels are risk factors for SIMD in patients with sepsis. Predictive models based on these factors demonstrate strong performance and effectively identify high-risk individuals, aiding in early clinical intervention.
Sepsis-induced myocardial dysfunction (SIMD) is an acute cardiac dysfunction syndrome associated with sepsis but independent of ischemia, serving as a critical contributor to cardiogenic shock, refractory shock and mortality. Current clinical treatments remain far from achieving satisfactory outcomes. Our previous study found that serum melatonin levels were significantly lower in septic patients compared to healthy volunteers. Building on this finding, the present study further confirmed in septic mice via cecal ligation and puncture procedures that exhibited significantly decreased melatonin levels in both serum and cardiac tissues. Exogenous melatonin supplementation was observed to reduce inflammatory cytokine release and ameliorate cardiac dysfunction. These findings collectively suggest that melatonin exerts protective effects against SIMD. However, the precise molecular mechanisms underlying melatonin's ameliorative effects on SIMD remain incompletely understood. Current evidence indicates that impaired autophagic flux represents one of the key pathogenic mechanisms in SIMD, a finding supported by our preliminary omics analyses. We discovered that melatonin's amelioration of SIMD is mediated through enhanced autophagic flux. Mechanistically, we discovered that melatonin increases transcription factor EB (TFEB) content by enhancing silent information regulator 1 (SIRT1) protein levels, thereby modulating autophagy-related proteins to restore impaired autophagic flux during SIMD. Notably, SIRT1-mediated deacetylation of TFEB inhibits its ubiquitination-dependent proteasomal degradation, thereby stabilizing TFEB protein level and enhancing cardiomyocyte autophagy. This study unveils a novel mechanism whereby melatonin enhances autophagic flux through the SIRT1/TFEB axis, ultimately ameliorating SIMD. These findings provide a theoretical foundation for developing new clinical therapeutic strategies against SIMD.
Colon cancer and socioeconomic deprivation (SED) are associated with adverse outcomes. This study examined correlations between clinicopathological variables and both SED and survival in tumour node metastasis (TNM) I-III and III cohorts. Patients undergoing elective curative resection for TNM I-III colon cancer were identified from the West of Scotland cancer registry. The primary outcome of interest was the association between SED (defined using the Scottish Index of Multiple Deprivation (SIMD); SIMD 1 = most deprived; SIMD 5 = least deprived), short-term (30- and 90-day mortality), mid-term (3-year overall (OS) and cancer-specific (CSS) survival). Secondary outcomes compared SED, the administration of adjuvant chemotherapy and significant tumour and clinical factors (overall and in TNM III patients). Multivariable analyses were conducted to correlate these findings with survival. A total of 2264 patients were included in the study (790 TNM III). Overall, there was no significant difference between SIMD 1 and 5 in 30-day mortality (2.3 versus 1.8%, respectively; P = 0.480) and 90-day mortality (3.2 versus 2.0%, respectively; P = 0.616). OS was lower in SIMD 1 than 5 (83 versus 86%; P = 0.008), as was CSS (90 versus 92%; P = 0.024). There was no significant association between SIMD and the receipt of chemotherapy (29.4% versus 34.7%, P = 0.152) or any tumour factors. Compared with SIMD 5 patients, SIMD 1 patients had a higher American Society of Anesthesiologists (ASA) grade (P < 0.001), more current smokers (17.5 versus 4.0%; P < 0.001), an RCS Charlson Score > 3 (6.6 versus 4.3%; P < 0.001), obesity (36.0 versus 22.7%; P < 0.001), and modified Glasgow Prognostic Score (mGPS) = 2 (18.5 versus 14.2%; P = 0.007). Multivariable analysis confirmed the association with ASA (odds ratio (OR) 1.70; 95% confidence interval (c.i.) 1.31 to 2.20; P < 0.001), smoking (OR 1.59; 95% c.i. 1.24 to 2.03; P < 0.001), and body mass index (BMI) (OR 1.23; c.i. 1.01 to 1.50; P = 0.045). Similar associations were seen among TNM III patients, although SIMD 1 (versus 5) patients were less likely to commence adjuvant chemotherapy (59.4 versus 73.0%; P < 0.10). Overall, SIMD 1 patients had worse OS in both the both TNM I-III and III cohorts, with co-morbidity and lifestyle factors most likely being responsible.
Sepsis-induced myocardial dysfunction (SIMD), also known as septic cardiomyopathy in sepsis patients is associated with worse prognosis and higher mortality compared to sepsis cases without SIMD. Early intervention and comprehensive management are crucial for improving survival, particularly in the early stages of sepsis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising therapeutic target in the cardiovascular system. While PCSK9 has been implicated in cardiovascular inflammation and injury, specific evidence regarding the potential of PCSK9 inhibition to mitigate SIMD remains limited. An in vivo mouse model of sepsis was established using cecal ligation and puncture (CLP), and SIMD was assessed through echocardiography and right ventricular systolic pressure measurements. For in vitro cellular SIMD models, lipopolysaccharide was administered to HL-1 and H9c2 cardiomyocytes. Data concerning apoptosis, inflammatory responses, oxidative stress, and mitophagy were evaluated across both models. The SIMD models were successfully established both in vivo and in vitro. PCSK9 inhibition visibly attenuated myocardial dysfunction, cellular injury, apoptosis, inflammation, and oxidative stress, which was accompanied by enhanced mitophagic clearance. Furthermore, the application of Mdivi-1, a mitochondrial division inhibitor that impairs mitophagy, revealed that the cardioprotective effects of PCSK9 inhibition are at least partially dependent on the preservation of mitophagy. Mechanistically, PCSK9 inhibition appeared to facilitate mitophagic flux in SIMD, potentially via the PINK1/Parkin signaling pathway. These findings suggest that the protective effects of PCSK9 inhibition against SIMD are closely associated with the enhancement of mitophagy and the modulation of the PINK1/Parkin pathway. Furthermore, this intervention correlates with attenuated oxidative stress, inflammation, and apoptosis, ultimately offering a potential therapeutic strategy for myocardial injury.
Sepsis, an infection‑triggered systemic inflammatory response syndrome, ranks as the third leading cause of death worldwide due to its high incidence and mortality. Sepsis‑induced myocardial dysfunction (SIMD) is a frequent and serious complication that notably increases patient morbidity and mortality. The underlying pathophysiology of SIMD involves a complex interplay of inflammation, oxidative stress, mitochondrial impairment and apoptosis, yet no effective therapies have been established. Thus, uncovering the molecular mechanisms of SIMD, identifying novel therapeutic targets and developing efficacious agents are key. For centuries, natural products have been used in traditional medical systems across China and Asia to manage cardiovascular disease. These compounds can confer cardioprotection by modulating inflammatory pathways, decreasing oxidative stress, inhibiting apoptotic cell death and improving mitochondrial function. The present review aimed to summarize the clinical manifestations and pathophysiology of SIMD and how natural products exert their protective effects. The present study aimed to explore structure‑activity relationships and highlight key molecular targets and representative natural product binding affinities for SIMD‑related proteins. In summary, the present study presents a comprehensive overview of the multi‑targeted strategies employed by natural products against SIMD and provides guidance for the discovery of SIMD‑focused dietary supplements and lead compounds, laying the groundwork for future translational research.
Sepsis-induced myocardial dysfunction (SIMD) is a prevalent complication among septic patients, significantly worsening patient prognosis and elevating the mortality rate. Connexin 43 (Cx43), a pivotal cardiac gap junction protein, maintains cardiac function, and its disarrangement is closely linked to cardiac diseases. However, the role of Cx43 localization changes in SIMD remains unclear. Amphiregulin (AREG) was recently reported to promote the recovery of Cx43 disarrangements. This research aimed to explore the role of Cx43 in SIMD and the preventive potential of AREG. A mouse model of SIMD was induced using lipopolysaccharide (LPS) and treated with AREG. Cardiac function and electrical conduction were assessed using echocardiography and an electrocardiogram. Inflammatory responses, Cx43 regulation, and related signaling pathways were further investigated in serum and cardiac tissues. Relevant signal pathway analysis was investigated in cultured cardiomyocytes. LPS administration significantly reduced cardiac ejection fraction and left ventricular fractional shortening, which were accompanied by disorganization, fragmentation, and lateralization of Cx43 at 6 h. These pathological alterations were associated with increased phosphorylation of pS368-Cx43, mediated by p38 activation. AREG pretreatment improved cardiac function and QRS interval, and preserved Cx43 localization at intercellular discs, along with pS368-Cx43 phosphorylation with reduction of p38 inhibition. Myocardial cell studies confirmed that AREG inhibited p38 phosphorylation, independent of AKT, in LPS-induced cardiac dysfunction. This study highlights the role of Cx43 phosphorylation in SIMD and demonstrates the preventive potential of AREG in SIMD, which is associated with a reduction in p38 activation and a decrease in the phosphorylation level of pS368-Cx43. These findings may provide a novel therapeutic target for SIMD.
Ultrasonic examinations showed significant limitations in the early detection and prognostic prediction of sepsis-induced myocardial dysfunction (SIMD), needing assisting biomarkers. The diagnostic and prognostic potential of miR-324-3p in SIMD was evaluated in this study, aiming to explore a novel biomarker. The functional role of miR-324-3p in regulating myocardial cell injury was assessed in H9c2 cells. The study enrolled 210 sepsis patients, including 98 patients diagnosed with SIMD. The significance of miR-324-3p in SIMD risk prediction, screening, and prognosis prediction was evaluated. Moreover, ultrasonic parameters, involving LVEF, LVDd, LAD, and FS, were compared between sepsis and SIMD patients, and the diagnostic and prognostic values of these parameters were also assessed. Silencing miR-324-3p exerted significantly protective effects on myocardial cell injury. Increasing serum miR-324-3p was observed in SIMD patients and was positively correlated with Dallas grades. LVEF, LVDd, LAD, and FS also showed significance in discriminating SIMD patients, but a single parameter cannot possess both satisfactory sensitivity and specificity. Serum miR-324-3p could help improve the diagnostic accuracy, sensitivity, and specificity of ultrasonic parameters in screening SIMD, and miR-324-3p was also identified as an independent risk factor for the adverse prognosis of SIMD patients.
Background: Sepsis-induced myocardial dysfunction (SIMD) is a life-threatening complication with limited therapeutic options. Jaceosidin (JAC), a natural flavonoid from Folium Artemisiae Argyi, shows potential in cardiovascular diseases, but its role and mechanism in SIMD remain unclear. This study aims to investigate the protective effects of JAC against SIMD and explore the underlying molecular mechanisms. Methods: In vitro, AC16 human cardiomyocytes were stimulated with TNF-α and treated with JAC. Cell viability and apoptosis were assessed using CCK-8 and flow cytometry, respectively. Transcriptomic and metabolomic analyses were performed to identify altered pathways. Molecular docking evaluated JAC's interaction with SIRT2. The SIRT2 inhibitor AGK2 was used to validate its role. Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) determined H3K18la enrichment on target gene promoters. In vivo, a murine SIMD model was established via LPS injection, and cardiac function was evaluated by echocardiography. Serum markers (cTnT, CK-MB) and myocardial lactylation levels were measured. Results: JAC significantly attenuated TNF-α-induced injury in AC16 cells by enhancing viability and reducing apoptosis. Multi-omics analyses revealed JAC suppressed glycolysis and lactate production. JAC specifically inhibited histone H3K18 lactylation (H3K18la), and molecular docking indicated strong binding affinity with SIRT2. AGK2 treatment reversed JAC-mediated suppression of H3K18la. ChIP-qPCR confirmed H3K18la directly regulates IL-6, BAX, and BCL-2 expression. In vivo, JAC improved cardiac function (LVEF, LVFS, LVDd, LVDs), reduced serum cTnT and CK-MB levels, and decreased myocardial H3K18la in LPS-treated mice. Conclusions: JAC alleviates SIMD by activating SIRT2, which inhibits H3K18la, thereby modulating inflammatory and apoptotic pathways. This study identifies JAC as a novel metabolic-epigenetic therapeutic agent for SIMD.
Small intestinal microbial dysbiosis (SIMD) describes clinical syndromes attributed to overabundance of microbes within the small intestine. Usually attributed to bacteria (but also less commonly to archaea and fungi), SIMD arises as a secondary condition, when there is disruption of one or more key physiological mechanisms. We provide a comprehensive review of the current understanding of SIMD pathophysiology. We highlight the key physiological factors including gastric acid, pancreatic enzymes, bile acids, small intestinal dysmotility and obstruction, colonic motility, and intestinal mucosal immunity. We then describe the disease states associated with failure of these mechanisms, providing SIMD prevalence estimates for each. Finally, we address some of the controversies regarding SIMD including testing modalities, significance of intestinal methanogen overgrowth, and the role of SIMD in irritable bowel syndrome.
Sepsis-induced myocardial dysfunction (SIMD) is a common and heterogeneous complication in patients with sepsis and is associated with increased mortality. This study aimed to identify distinct clinical phenotypes of SIMD using unsupervised deep learning and to develop an optimal short-term survival prediction model based on phenotypic stratification. Data from SIMD patients in the MIMIC-III and MIMIC-IV databases were retrospectively analyzed. An autoencoder was used for feature compression, followed by Uniform Manifold Approximation and Projection (UMAP) and K-means clustering to identify phenotypes, with a novel composite scoring system applied to ensure robust cluster selection. Prognostic differences among phenotypes were evaluated using Kaplan-Meier and Cox regression analyses. XGBoost with SHAP (Shapley Additive Explanations) was used for phenotype prediction and model interpretability. Multi-strategy models (M1-M4) were further constructed to assess the predictive value of phenotypic stratification and determine the optimal modeling strategy for survival prediction. Three clusters (Cluster 0-2) with distinct prognostic profiles were identified. Cluster 2 (high-risk phenotype), characterized by metabolic acidosis and multiorgan dysfunction, showed the highest 90-day mortality (55.1% in the development cohort). SHAP analysis highlighted lactate, bilirubin, coagulation indices, and Glasgow Coma Scale as key drivers of phenotype differentiation. Phenotype-specific modeling (M3) significantly outperformed the global model (M1), achieving a validation AUC of 0.880 and a PR-AUC of 0.863 for Cluster 2. Further feature enhancement in M4 did not yield significant additional benefit, supporting M3 as the optimal modeling strategy. These findings delineate clinically actionable SIMD phenotypes using interpretable unsupervised learning and demonstrate that phenotype-specific modeling markedly improves mortality prediction, particularly for Cluster 2 (high-risk phenotype), underscoring the potential of phenotypic stratification to advance precision critical care in SIMD.
Sepsis-induced myocardial dysfunction (SIMD) is a prevalent complication of sepsis and correlates with high mortality. The study investigated the effect of inhibiting DNA methyltransferase 1 (DNMT1) on SIMD and its potential mechanism. In this study, an SIMD mouse model was established using lipopolysaccharide (LPS). Two weeks before modeling, mice were intraperitoneally injected with the DNMT1 inhibitor decitabine or Vehicle. Pretreatment with the DNMT1 inhibitor decitabine in SIMD mice improved survival, cardiac function, and reduced cardiomyocyte apoptosis. In LPS-stimulated RAW264.7 macrophages, DNMT1 knockdown promoted M2 polarization while suppressing M1 polarization, and reduced apoptosis in cardiomyocytes cultured with conditioned media. Mechanistically, DNMT1 depletion upregulated mitochondrial transcription factor A (TFAM) by reducing DNA methylation modification, which alleviated mitochondrial dysfunction and limited mitochondrial DNA (mtDNA) release into the cytosol. This subsequently inactivated the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. TFAM downregulation reversed the improvement in mitochondrial function achieved by DNMT1 knockdown, while cGAS upregulation averted DNMT1 knockdown-inhibited mtDNA cytosolic escape-mediated cGAS-STING. In vivo validation confirmed this mechanism. Collectively, DNMT1 regulates mitochondrial dysfunction and cytosolic mtDNA release by modulating TFAM promoter DNA methylation, thereby activating the cGAS-STING pathway, further influencing macrophage polarization and cardiomyocyte apoptosis, and ultimately exacerbating SIMD.