Clofazimine broadly inhibits coronaviruses including SARS-CoV-2.

The COVID-19 pandemic is the third outbreak this century of a zoonotic disease caused by a coronavirus, following the emergence of severe acute respiratory syndrome (SARS) in 20031 and Middle East respiratory syndrome (MERS) in 20122. Treatment options for coronaviruses are limited. Here we show that clofazimine-an anti-leprosy drug with a favourable safety profile3-possesses inhibitory activity against several coronaviruses, and can antagonize the replication of SARS-CoV-2 and MERS-CoV in a range of in vitro systems. We found that this molecule, which has been approved by the US Food and Drug Administration, inhibits cell fusion mediated by the viral spike glycoprotein, as well as activity of the viral helicase. Prophylactic or therapeutic administration of clofazimine in a hamster model of SARS-CoV-2 pathogenesis led to reduced viral loads in the lung and viral shedding in faeces, and also alleviated the inflammation associated with viral infection. Combinations of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted viral shedding from the upper respiratory tract. Clofazimine, which is orally bioavailable and comparatively cheap to manufacture, is an attractive clinical candidate for the treatment of outpatients and-when combined with remdesivir-in therapy for hospitalized patients with COVID-19, particularly in contexts in which costs are an important factor or specialized medical facilities are limited. Our data provide evidence that clofazimine may have a role in the control of the current pandemic of COVID-19 and-possibly more importantly-in dealing with coronavirus diseases that may emerge in the future.

Supramolecular coordination platinum metallacycle-based multilevel wound dressing for bacteria sensing and wound healing.

The exploitation of novel wound healing methods with real-time infection sensing and high spatiotemporal precision is highly important for human health. Pt-based metal-organic cycles/cages (MOCs) have been employed as multifunctional antibacterial agents due to their superior Pt-related therapeutic efficiency, various functional subunits and specific geometries. However, how to rationally apply these nanoscale MOCs on the macroscale with controllable therapeutic output is still challenging. Here, a centimeter-scale Pt MOC film was constructed via multistage assembly and subsequently coated on a N,N'-dimethylated dipyridinium thiazolo[5,4-d]thiazole (MPT)-stained silk fabric to form a smart wound dressing for bacterial sensing and wound healing. The MPT on silk fabric could be used to monitor wound infection in real-time through the bacteria-mediated reduction of MPT to its radical form via a color change. The MPT radical also exhibited an excellent photothermal effect under 660 nm light irradiation, which could not only be applied for photothermal therapy but also induce the disassembly of the Pt MOC film suprastructure. The highly ordered Pt MOC film suprastructure exhibited high biosafety, while it also showed improved antibacterial efficiency after thermally induced disassembly. In vitro and in vivo studies revealed that the combination of the Pt MOC film and MPT-stained silk can provide real-time information on wound infection for timely treatment through noninvasive techniques. This study paves the way for bacterial sensing and wound healing with centimeter-scale metal-organic materials.

The RNA ligase RNA terminal phosphate cyclase B regulates mRNA alternative splicing and is required for mouse oocyte development and maintenance.

Recent large-scale mRNA sequencing has shown that introns are retained in 5-10% of mRNA, and these events are named intron retention (IR). IR has been recognized as a key mechanism in the regulation of gene expression. However, the role of this mechanism in female reproduction in mammals remains unclear. RNA terminal phosphate cyclase B (RTCB) is a RNA ligase; we found that RTCB conditional knockout mice have premature ovarian failure and that RTCB plays a crucial role in follicular development. RTCB regulated the splicing of transcripts related to DNA methylation and DNA damage repair. In addition, it regulated the resumption of oocyte meiosis by affecting CDK1 activation. Moreover, the loss of RTCB suppressed zygotic genome activation (ZGA) and decreased translation at the global level. In addition, Rtcb deletion resulted in the accumulation of maternal mRNAs containing unspliced introns and in a decline in the overall level of transcripts. As a result, the Rtcb-/- females were sterile. Our study highlights the important role of RTCB-regulated noncanonical alternative splicing in female reproduction.

Molecular insight into the specific enzymatic properties of TREX1 revealing the diverse functions in processing RNA and DNA/RNA hybrids.

In various autoimmune diseases, dysfunctional TREX1 (Three prime Repair Exonuclease 1) leads to accumulation of endogenous single-stranded DNA (ssDNA), double-stranded DNA (dsDNA) and DNA/RNA hybrids in the cytoplasm and triggers immune activation through the cGAS-STING pathway. Although inhibition of TREX1 could be a useful strategy for cancer immunotherapy, profiling cellular functions in terms of its potential substrates is a key step. Particularly important is the functionality of processing DNA/RNA hybrids and RNA substrates. The exonuclease activity measurements conducted here establish that TREX1 can digest both ssRNA and DNA/RNA hybrids but not dsRNA. The newly solved structures of TREX1-RNA product and TREX1-nucleotide complexes show that 2'-OH does not impose steric hindrance or specific interactions for the recognition of RNA. Through all-atom molecular dynamics simulations, we illustrate that the 2'-OH-mediated intra-chain hydrogen bonding in RNA would affect the binding with TREX1 and thereby reduce the exonuclease activity. This notion of higher conformational rigidity in RNA leading TREX1 to exhibit weaker catalytic cleavage is further validated by the binding affinity measurements with various synthetic DNA-RNA junctions. The results of this work thus provide new insights into the mechanism by which TREX1 processes RNA and DNA/RNA hybrids and contribute to the molecular-level understanding of the complex cellular functions of TREX1 as an exonuclease.

AKT1 Promotes Tumorigenesis and Metastasis by Directly Phosphorylating Hexokinases.

The importance of protein kinase B (AKT) in tumorigenesis and development is well established, but its potential regulation of metabolic reprogramming via phosphorylation of the hexokinase (HK) isozymes remains unclear. There are two HK family members (HK1/2) and three AKT family members (AKT1/2/3), with varied distribution of AKTs exhibiting distinct functions in different tissues and cell types. Although AKT is known to phosphorylate HK2 at threonine 473, AKT-mediated phosphorylation of HK1 has not been reported. We examined direct binding and phosphorylation of HK1/2 by AKT1 and identified the phosphorylation modification sites using coimmunoprecipitation, glutathione pull-down, western blotting, and in vitro kinase assays. Regulation of HK activity through phosphorylation by AKT1 was also examined. Uptake of 2-[1,2-3H]-deoxyglucose and production of lactate were investigated to determine whether AKT1 regulates glucose metabolism by phosphorylating HK1/2. Functional assays, immunohistochemistry, and tumor experiments in mice were performed to investigate whether AKT1-mediated regulation of tumor development is dependent on its kinase activity and/or the involvement of HK1/2. AKT interacted with and phosphorylated HK1 and HK2. Serine phosphorylation significantly increased AKT kinase activity, thereby enhancing glycolysis. Mechanistically, the phosphorylation of HK1 at serine 178 (S178) by AKT significantly decreased the Km and enhanced the Vmax by interfering with the formation of HK1 dimers. Mutations in the AKT phosphorylation sites of HK1 or HK2 significantly abrogated the stimulatory characteristics of AKT on glycolysis, tumorigenesis, and cell migration, invasion, proliferation, and metastasis. HK1-S178 phosphorylation levels were significantly correlated with the occurrence and metastasis of different types of clinical tumors. We conclude that AKT not only regulates tumor glucose metabolism by directly phosphorylating HK1 and HK2, but also plays important roles in tumor progression, proliferation, and migration.

Inhibiting Mg Diffusion and Evaporation by Forming Mg-Rich Reservoir at Grain Boundaries Improves the Thermal Stability of N-Type Mg3 Sb2 Thermoelectrics.

N-type Mg3 Sb2 -based thermoelectric materials show great promise in power generation due to their mechanical robustness, low cost of Mg, and high figure of merit (ZT) over a wide range of temperatures. However, their poor thermal stability hinders their practical applications. Here, MgB2 is introduced to improve the thermal stability of n-type Mg3 Sb2 . Enabled by MgB2 decomposition, extra Mg can be released into the matrix for Mg compensation thermodynamically, and secondary phases of Mg─B compounds can kinetically prevent Mg diffusion along grain boundaries. These synergetic effects inhibit the formation of Mg vacancies at elevated temperatures, thereby enhancing the thermal stability of n-type Mg3 Sb2 . Consequently, the Mg3.05 (Sb0.75 Bi0.25 )1.99 Te0.01 (MgB2 )0.03 sample exhibits negligible variation in thermoelectric performance during the 120-hour continuous measurement at 673 K. Moreover, the ZT of n-type Mg3 Sb2 can be maintained by adding MgB2 , reaching a high average ZT of ≈1.1 within 300-723 K. An eight-pair Mg3 Sb2 -GeTe-based thermoelectric device is also fabricated, achieving an energy conversion efficiency of ≈5.7% at a temperature difference of 438 K with good thermal stability. This work paves a new way to enhance the long-term thermal stability of n-type Mg3 Sb2 -based alloys and other thermoelectrics for practical applications.

Risk factors for invasive pulmonary aspergillosis in patients with severe fever with thrombocytopenia syndrome: A multicenter retrospective study.

Invasive pulmonary aspergillosis (IPA) is a life-threatening complication in patients with severe fever with thrombocytopenia syndrome (SFTS), yet SFTS-associated IPA (SAPA)'s risk factors remain undefined. A multicenter retrospective cohort study across Hubei and Anhui provinces (May 2013-September 2022) utilized least absolute shrinkage and selection operator (LASSO) regression for variable selection. Multivariable logistic regression identified independent predictors of SAPA, Cox regression highlighted mortality-related risk factors. Of the 1775 screened SFTS patients, 1650 were included, with 169 developing IPA, leading to a 42-day mortality rate of 26.6% among SAPA patients. Multivariable logistic regression revealed SAPA risk factors including advanced age, petechia, hemoptysis, tremor, low albumin levels, elongated activated partial thromboplastin time (APTT), intensive care unit (ICU) admission, glucocorticoid usage, intravenous immunoglobulin (IVIG) and prolonged hospital stays. Cox regression identified predictors of 42-day mortality, including ecchymosis at venipuncture sites, absence of ICU admission, elongated prothrombin time (PT), vasopressor and glucocorticoid use, non-antifungals. Nomograms constructed on these predictors registered concordance indexes of 0.855 (95% CI: 0.826-0.884) and 0.778 (95% CI: 0.702-0.854) for SAPA onset and 42-day mortality, respectively. Lower survival rates for SAPA patients treated with glucocorticoids (p < 0.001) and improved 14-day survival with antifungal therapy (p = 0.036). Improving IPA management in SFTS-endemic areas is crucial, with effective predictive tool.

Analysis of the Trends and Influencing Factors for Postoperative Cough in Patients with Esophageal Cancer Based on Patient-Reported Outcomes.

BACKGROUND: Cough is a common symptom that affects patients' recovery and quality of life after esophagectomy. This study sought to investigate trends in postoperative cough and the factors that influence cough. METHODS: A total of 208 of 225 patients were enrolled in this study. The Mandarin Chinese version of the Leicester Cough Questionnaire was administered the day before surgery and at three time points (1 week, 1 month, and 3 months) after esophagectomy to assess patient-reported outcomes. RESULTS: All patients' LCQ-MC scores after surgery were lower than presurgery (P < 0.05), with the lowest score found 1 week after esophagectomy. Factors associated with a cough 1 week after surgery included clinical stage of cancer (OR 0.782, 95% CI 0.647-0.944, P = 0.011), anastomotic position (OR 1.241, 95% CI 1.069-1.441, P = 0.005), duration of surgery (OR 0.759, 95% CI 0.577-0.998, P = 0.049), and subcarinal lymph node dissection (OR 0.682, 95% CI 0.563-0.825, P < 0.001). Factors associated with a cough one month after surgery included clinical stage (OR 0.782, 95% CI 0.650-0.940, P = 0.009), anastomotic position (OR 1.293, 95% CI 1.113-1.503, P = 0.001), and maintaining a semi-reclining position (OR 1.440, 95% CI 1.175-1.766, P < 0.001). Factors associated with a cough 3 months after surgery were clinical stage (OR 0.741, 95% CI 0.591-0.928, P = 0.009) and anastomotic position (OR 1.220, 95% CI 1.037-1.435, P = 0.016). CONCLUSIONS: This study showed that the factors influencing postoperative cough differed over time following esophagectomy. These results may warrant prospective intervention to better manage patients undergoing surgery for esophageal cancer to prevent postoperative cough.

Integrated waveguide coupled ultralow-loss multimode waveguides based on silicon nitride resonators.

On-chip micro-ring resonators (MRRs) with low loss and large free spectral ranges (FSRs) are important for photonic devices. So far, ultra-low-loss silicon-nitride (Si3N4) waveguides are primarily fabricated in laboratories, as they often demand special processes to reduce transmission losses. While, Si3N4 waveguides fabricated by the standard multi-project wafer (MPW)-based processes often suffer from significant sidewall scattering, resulting in high scattering losses. Here, we present an innovative approach to photonics by introducing a compact and multi-mode structure. This approach significantly reduces the contact between the optical field and the rough sidewalls in the high-confinement Si3N4 waveguide. By incorporating modified Euler bends, and a weakly tapered gap directional coupler, adiabatic transmission with simultaneous ultra-low loss and compact size is achieved even in 7-µm wide waveguide. Results show that the intrinsic quality factor Qi of MRR is (6.8 ± 0.4) × 106 at the wavelength of 1550 nm, which is approximately four times higher than the previously reported by the same fabrication process. An ultra-low loss of 0.051 ± 0.003 dB/cm is achieved based on the standard LIGENTEC-AN800 technology. This accomplishment addresses a critical challenge in high-confinement waveguides. Our work provides new insights into the low propagation loss in Si3N4 waveguides and provides a broader prospect for integrated photonics in the ultra-high-Q regime.

Broadband stepped-frequency radar waveform generation by Fourier domain mode-locking period-one laser dynamics.

A stepped-frequency (SF) radar waveform generation method based on Fourier domain mode-locking (FDML) period-one laser dynamics is proposed and demonstrated. By fast controlling the optical injection strength of a semiconductor laser through electro-optical modulation, a broadband SF signal is generated. By further introducing an optoelectronic feedback loop with its round trip time delay matched with the temporal period of the SF signal, FDML is enabled through which the frequency stability, accuracy, and in-band signal-to-noise ratio are greatly improved. In the experiment, SF signals with a bandwidth of 6 GHz (12-18 GHz) and a frequency step of 150 MHz are generated. By comparing the qualities of signals generated with and without FDML, advantages of the proposed SF signal generation method are verified. Based on the proposed SF signal generation method, high-resolution inverse synthetic aperture radar (ISAR) imaging is also demonstrated, in which the 2D imaging resolution reaches 2.6 cm × 3.82 cm.

STAT3: Key targets of growth-promoting receptor positive breast cancer.

Breast cancer has become the malignant tumor with the first incidence and the second mortality among female cancers. Most female breast cancers belong to luminal-type breast cancer and HER2-positive breast cancer. These breast cancer cells all have different driving genes, which constantly promote the proliferation and metastasis of breast cancer cells. Signal transducer and activator of transcription 3 (STAT3) is an important breast cancer-related gene, which can promote the progress of breast cancer. It has been proved in clinical and basic research that over-expressed and constitutively activated STAT3 is involved in the progress, proliferation, metastasis and chemotherapy resistance of breast cancer. STAT3 is an important key target in luminal-type breast cancer and HER2-positive cancer, which has an important impact on the curative effect of related treatments. In breast cancer, the activation of STAT3 will change the spatial position of STAT3 protein and cause different phenotypic changes of breast cancer cells. In the current basic research and clinical research, small molecule inhibitors activated by targeting STAT3 can effectively treat breast cancer, and enhance the efficacy level of related treatment methods for luminal-type and HER2-positive breast cancers.

A radiomics signature derived from CT imaging to predict MSI status and immunotherapy outcomes in gastric cancer: a multi-cohort study.

BACKGROUND: Accurate microsatellite instability (MSI) testing is essential for identifying gastric cancer (GC) patients eligible for immunotherapy. We aimed to develop and validate a CT-based radiomics signature to predict MSI and immunotherapy outcomes in GC. METHODS: This retrospective multicohort study included a total of 457 GC patients from two independent medical centers in China and The Cancer Imaging Archive (TCIA) databases. The primary cohort (n = 201, center 1, 2017-2022), was used for signature development via Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression analysis. Two independent immunotherapy cohorts, one from center 1 (n = 184, 2018-2021) and another from center 2 (n = 43, 2020-2021), were utilized to assess the signature's association with immunotherapy response and survival. Diagnostic efficiency was evaluated using the area under the receiver operating characteristic curve (AUC), and survival outcomes were analyzed via the Kaplan-Meier method. The TCIA cohort (n = 29) was included to evaluate the immune infiltration landscape of the radiomics signature subgroups using both CT images and mRNA sequencing data. RESULTS: Nine radiomics features were identified for signature development, exhibiting excellent discriminative performance in both the training (AUC: 0.851, 95%CI: 0.782, 0.919) and validation cohorts (AUC: 0.816, 95%CI: 0.706, 0.926). The radscore, calculated using the signature, demonstrated strong predictive abilities for objective response in immunotherapy cohorts (AUC: 0.734, 95%CI: 0.662, 0.806; AUC: 0.724, 95%CI: 0.572, 0.877). Additionally, the radscore showed a significant association with PFS and OS, with GC patients with a low radscore experiencing a significant survival benefit from immunotherapy. Immune infiltration analysis revealed significantly higher levels of CD8 + T cells, activated CD4 + B cells, and TNFRSF18 expression in the low radscore group, while the high radscore group exhibited higher levels of T cells regulatory and HHLA2 expression. CONCLUSION: This study developed a robust radiomics signature with the potential to serve as a non-invasive biomarker for GC's MSI status and immunotherapy response, demonstrating notable links to post-immunotherapy PFS and OS. Additionally, distinct immune profiles were observed between low and high radscore groups, highlighting their potential clinical implications.

Radiomics using CT images for preoperative prediction of lymph node metastasis in perihilar cholangiocarcinoma: a multi-centric study.

OBJECTIVES: To develop a CT-based radiomics model for preoperative prediction of lymph node (LN) metastasis in perihilar cholangiocarcinoma (pCCA). METHODS: The study enrolled consecutive pCCA patients from three independent Chinese medical centers. The Boruta algorithm was applied to build the radiomics signature for the primary tumor and LN. The k-means algorithm was employed to cluster the selected LNs based on the radiomics signature LN. Support vector machines were used to construct the prediction models. The diagnostic efficiency was measured by the area under the receiver operating characteristic curve (AUC). The optimal model was evaluated in terms of calibration, clinical usefulness, and prognostic value. RESULTS: A total of 214 patients were included in the study (mean age: 61.6 years ± 9.4; 130 male). The selected LNs were classified into two clusters, which were significantly correlated with LN metastasis in all cohorts (p < 0.001). The model incorporated the clinical risk factors, radiomics signature primary tumor, and the LN cluster obtained the best discrimination, with AUC values of 0.981 (95% CI: 0.962-1), 0.896 (95% CI: 0.810-0.982), and 0.865 (95% CI: 0.768-0.961) in the training, internal validation, and external validation cohorts, respectively. High-risk patients predicted by the optimal model had shorter overall survival than low-risk patients (median, 13.7 vs. 27.3 months, p < 0.001). CONCLUSIONS: The study proposed a radiomics model with good performance to predict LN metastasis in pCCA. As a noninvasive preoperative prediction tool, this model may help in patient risk stratification and personalized treatment. CLINICAL RELEVANCE STATEMENT: A CT-based radiomics model accurately predicts lymph node metastasis in perihilar cholangiocarcinoma patients. This noninvasive preoperative tool can aid in patient risk stratification and personalized treatment, potentially improving patient outcomes. KEY POINTS: • The radiomics model based on contrast-enhanced CT is a useful tool for preoperative prediction of lymph node metastasis in perihilar cholangiocarcinoma. • Radiomics features extracted from lymph nodes show great potential for predicting lymph node metastasis. • The study is the first to identify a lymph node phenotype with a high probability of metastasis based on radiomics.

Aldehyde Dehydrogenase 2 Preserves Mitochondrial Function in the Ischemic Heart: A Redox-dependent Mechanism for AMPK Activation by Thioredoxin-1.

ABSTRACT: Aldehyde dehydrogenase 2 (ALDH2) protects the ischemic heart by activating adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling. However, the molecular mechanisms linking ALDH2 and AMPK signaling are not fully understood. This study aimed to explore the potential mechanisms linking ALDH2 and AMPK in myocardial ischemic injury. An ischemic model was established by ligating the left anterior descending coronary artery in rats. The overexpression or knockdown of ALDH2 in H9c2 cells treated with oxygen-glucose deprivation was obtained through lentivirus infection. Transferase-mediated dUTP nick-end labeling was used to evaluate apoptosis in an ischemic rat model and oxygen-glucose deprivation cells. ALDH2 activity, mitochondrial oxidative stress markers, adenosine triphosphate, respiratory control ratio, and cell viability in H9c2 cells were evaluated using a biological kit and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide. Protein expression of ALDH2 , 4-hydroxynonenal, thioredoxin-1 (Trx-1), and AMPK-proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling pathway was detected through Western blotting. ALDH2 activation reduced ischemic-induced myocardial infarct size and apoptosis. ALDH2 protected mitochondrial function by enhancing mitochondrial respiratory control ratio and adenosine triphosphate production, alleviated mitochondrial oxidative stress, and suppressed myocardial apoptosis. Moreover, ALDH2 attenuated ischemia-induced oxidative stress and maintained Trx-1 levels by reducing 4-hydroxynonenal, thereby promoting AMPK-PGC-1α signaling activation. Inhibiting Trx-1 or AMPK abolished the cardioprotective effect of ALDH2 on ischemia. ALDH2 alleviates myocardial injury through increased mitochondrial biogenesis and reduced oxidative stress, and these effects were achieved through Trx1-mediating AMPK-PGC1-α signaling activation.

Theoretical Analysis of Selectivity Differences in Ketoreductases toward Aldehyde and Ketone Carbonyl Groups.

Lactobacillus kefir alcohol dehydrogenase (LkADH) and ketoreductase from Chryseobacterium sp. CA49 (ChKRED12) exhibit different chemoselectivity and stereoselectivity toward a substrate with both keto and aldehyde carbonyl groups. LkADH selectively reduces the keto carbonyl group while retaining the aldehyde carbonyl group, producing optically pure R-alcohols. In contrast, ChKRED12 selectively reduces the aldehyde group and exhibits low reactivity toward ketone carbonyls. This study investigated the structural basis for these differences and the role of specific residues in the active site. Molecular dynamics (MD) simulations and quantum chemical calculations were used to investigate the interactions between the substrate and the enzymes and the essential cause of this phenomenon. The present study has revealed that LkADH and ChKRED12 exhibit significant differences in the structure of their respective active pockets, which is a crucial determinant of their distinct chemoselectivity toward the same substrate. Moreover, residues N89, N113, and E144 within LkADH as well as Q151 and D190 within ChKRED12 have been identified as key contributors to substrate stabilization within the active pocket through electrostatic interactions and van der Waals forces, followed by hydride transfer utilizing the coenzyme NADPH. Furthermore, the enantioselectivity mechanism of LkADH has been elucidated using quantum chemical methods. Overall, these findings not only provide fundamental insights into the underlying reasons for the observed differences in selectivity but also offer a detailed mechanistic understanding of the catalytic reaction.

Optimal resource allocation model for COVID-19: a systematic review and meta-analysis.

BACKGROUND: A lack of health resources is a common problem after the outbreak of infectious diseases, and resource optimization is an important means to solve the lack of prevention and control capacity caused by resource constraints. This study systematically evaluated the similarities and differences in the application of coronavirus disease (COVID-19) resource allocation models and analyzed the effects of different optimal resource allocations on epidemic control. METHODS: A systematic literature search was conducted of CNKI, WanFang, VIP, CBD, PubMed, Web of Science, Scopus and Embase for articles published from January 1, 2019, through November 23, 2023. Two reviewers independently evaluated the quality of the included studies, extracted and cross-checked the data. Moreover, publication bias and sensitivity analysis were evaluated. RESULTS: A total of 22 articles were included for systematic review; in the application of optimal allocation models, 59.09% of the studies used propagation dynamics models to simulate the allocation of various resources, and some scholars also used mathematical optimization functions (36.36%) and machine learning algorithms (31.82%) to solve the problem of resource allocation; the results of the systematic review show that differential equation modeling was more considered when testing resources optimization, the optimization function or machine learning algorithm were mostly used to optimize the bed resources; the meta-analysis results showed that the epidemic trend was obviously effectively controlled through the optimal allocation of resources, and the average control efficiency was 0.38(95%CI 0.25-0.51); Subgroup analysis revealed that the average control efficiency from high to low was health specialists 0.48(95%CI 0.37-0.59), vaccines 0.47(95%CI 0.11-0.82), testing 0.38(95%CI 0.19-0.57), personal protective equipment (PPE) 0.38(95%CI 0.06-0.70), beds 0.34(95%CI 0.14-0.53), medicines and equipment for treatment 0.32(95%CI 0.12-0.51); Funnel plots and Egger's test showed no publication bias, and sensitivity analysis suggested robust results. CONCLUSION: When the data are insufficient and the simulation time is short, the researchers mostly use the constructor for research; When the data are relatively sufficient and the simulation time is long, researchers choose differential equations or machine learning algorithms for research. In addition, our study showed that control efficiency is an important indicator to evaluate the effectiveness of epidemic prevention and control. Through the optimization of medical staff and vaccine allocation, greater prevention and control effects can be achieved.

Predicting Portal Pressure Gradient in Patients with Decompensated Cirrhosis: A Non-invasive Deep Learning Model.

BACKGROUND: A high portal pressure gradient (PPG) is associated with an increased risk of failure to control esophagogastric variceal hemorrhage and refractory ascites in patients with decompensated cirrhosis. However, direct measurement of PPG is invasive, limiting its routine use in clinical practice. Consequently, there is an urgent need for non-invasive techniques to assess PPG. AIM: To develop and validate a deep learning model that predicts PPG values for patients with decompensated cirrhosis and identifies those with high-risk portal hypertension (HRPH), who may benefit from early transjugular intrahepatic portosystemic shunt (TIPS) intervention. METHODS: Data of 520 decompensated cirrhosis patients who underwent TIPS between June 2014 and December 2022 were retrospectively analyzed. Laboratory and imaging parameters were used to develop an artificial neural network model for predicting PPG, with feature selection via recursive feature elimination for comparison experiments. The best performing model was tested by external validation. RESULTS: After excluding 92 patients, 428 were included in the final analysis. A series of comparison experiments demonstrated that a three-parameter (3P) model, which includes the international normalized ratio, portal vein diameter, and white blood cell count, achieved the highest accuracy of 87.5%. In two distinct external datasets, the model attained accuracy rates of 85.40% and 90.80%, respectively. It also showed notable ability to distinguish HRPH with an AUROC of 0.842 in external validation. CONCLUSION: The developed 3P model could predict PPG values for decompensated cirrhosis patients and could effectively distinguish HRPH.

NLRC3 expression in macrophage impairs glycolysis and host immune defense by modulating the NF-κB-NFAT5 complex during septic immunosuppression.

Impairment of innate immune cell function and metabolism underlies immunosuppression in sepsis; however, a promising therapy to orchestrate this impairment is currently lacking. In this study, high levels of NOD-like receptor family CARD domain containing-3 (NLRC3) correlated with the glycolytic defects of monocytes/macrophages from septic patients and mice that developed immunosuppression. Myeloid-specific NLRC3 deletion improved macrophage glycolysis and sepsis-induced immunosuppression. Mechanistically, NLRC3 inhibits nuclear factor (NF)-κB p65 binding to nuclear factor of activated T cells 5 (NFAT5), which further controls the expression of glycolytic genes and proinflammatory cytokines of immunosuppressive macrophages. This is achieved by decreasing NF-κB activation-co-induced by TNF-receptor-associated factor 6 (TRAF6) or mammalian target of rapamycin (mTOR)-and decreasing transcriptional co-activator p300 activity by inducing NLRC3 sequestration of mTOR and p300. Genetic inhibition of NLRC3 disrupted the NLRC3-mTOR-p300 complex and enhanced NF-κB binding to the NFAT5 promoter in concert with p300. Furthermore, intrapulmonary delivery of recombinant adeno-associated virus harboring a macrophage-specific NLRC3 deletion vector significantly improved the defense of septic mice that developed immunosuppression upon secondary intratracheal bacterial challenge. Collectively, these findings indicate that NLRC3 mediates critical aspects of innate immunity that contribute to an immunocompromised state during sepsis and identify potential therapeutic targets.

Association of Methylenetetrahydrofolate Reductase rs1801133 Polymorphism with osteoporosis and fracture risk in Taiwan.

Introduction: Osteoporosis is a prevalent skeletal disorder influenced by age, hormonal changes, medication use, nutrition, and genetics. The relationship between MTHFR and osteoporosis remains unclear, especially in Asians. The aim of our study was to elucidate the impact of MTHFR on osteoporosis and fracture risk. Materials and Methods: Participants were recruited from the Taiwan Precision Medicine Initiative at Taichung Veterans General Hospital. A total of 3,503 subjects with available bone mineral density measurements were selected. Using the Axiom Genome-Wide TWB 2.0 Array, we identified the MTHFR rs1801133 variant. Among these subjects, 1,624 patients carrying the variant were included in the case group, while the remaining 1,879 patients without the variant served as the control group. Results: Overall, individuals carrying the MTHFR rs1801133 variant exhibited a significantly elevated risk of developing osteoporosis. Stratified analysis by different genotypes, the results revealed a statistically significant association between the heterozygous genotype of MTHFR rs1801133 and osteoporosis. However, there was no significant correlation between MTHFR genotypes and fracture risk. Furthermore, subgroup analysis of female patients revealed age, a known risk factor, was associated with both osteoporosis and fractures. Interestingly, the presence of the MTHFR rs1801133 variant did not confer an increased risk of osteoporosis or fractures in females. Conclusion: Our study revealed a notable increase in the prevalence of osteoporosis among individuals carrying the MTHFR rs1801133 variant. Nevertheless, these individuals did not exhibit a heightened risk of major or hip fractures compared to non-carriers. Our findings could be of value in raising awareness of the increased risk of osteoporosis among individuals with this genetic variant.

The characterization and comorbidities of heterozygous Bardet-Biedl syndrome carriers.

Introduction: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder with clinical features of retinal dystrophy, obesity, postaxial polydactyly, renal anomalies, learning disabilities, hypogonadism, and genitourinary abnormalities. Nevertheless, previous studies on the phenotypic traits of BBS heterozygous carriers have generated inconclusive results. The aim of our study was to investigate the impact of BBS heterozygosity on carriers when compared to non-carriers within the Taiwanese population. Materials and Methods: This study follows a hospital-based case-control design. We employed the Taiwan Biobank version 2 (TWBv2) array to identify three specific loci associated with BBS (rs773862084, rs567573386, and rs199910690). In total, 716 patients were included in the case group, and they were compared to a control group of 2,864 patients who lacked BBS alleles. The control group was selected through gender and age matching at a ratio of 1:4. The association between BBS-related loci and comorbidity was assessed using logistic regression models. Results: We found that BBS heterozygous carriers exhibited a significant association with elevated BMI levels, especially the variant rs199910690 in MKS1 (p=0.0037). The prevalence of comorbidities in the carriers' group was not higher than that in the non-carriers' group. Besides, the average values of the biochemistry data showed no significant differences, except for creatinine level. Furthermore, we conducted a BMI-based analysis to identify specific risk factors for chronic kidney disease (CKD). Our findings revealed that individuals carrying the CA/AA genotype of the BBS2 rs773862084 variant or the CT/TT genotype of the MKS1 rs199910690 variant showed a reduced risk of developing CKD, irrespective of their BMI levels. When stratified by BMI level, obese males with the MKS1 rs199910690 variant and obese females with the BBS2 rs773862084 variant exhibited a negative association with CKD development. Conclusion: We found that aside from the association with overweight and obesity, heterozygous BBS mutations did not appear to increase the predisposition of individuals to comorbidities and metabolic diseases. To gain a more comprehensive understanding of the genetic susceptibility associated with Bardet-Biedl Syndrome (BBS), further research is warranted.