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[[alternative]]Wolfram syndrome 2 gene (CISD2) deficiency disrupts Ca2+-mediated insulin secretion in β-cells
No full text[[abstract]]Objective: Diabetes, characterized by childhood-onset, autoantibody-negativity and insulin-deficiency, is a major manifestation of Wolfram syndrome 2 (WFS2), which is caused by recessive mutations of CISD2. Nevertheless, the mechanism underlying 3-cell dysfunction in WFS2 remains elusive. Here we delineate the essential role of CISD2 in 3-cells. Methods: We use 3-cell specific Cisd2 knockout (Cisd2KO) mice, a CRISPR-mediated Cisd2KO MIN6 3-cell line and transcriptomic analysis. Results: Four findings are pinpointed. Firstly, 3-cell specific Cisd2KO in mice disrupts systemic glucose homeostasis via impairing 3-granules synthesis and insulin secretion; hypertrophy of the 3-islets and the presence of a loss of identity that affects certain 3-cells. Secondly, Cisd2 deficiency leads to impairment of glucose-induced extracellular Ca2influx, which compromises Ca2-mediated insulin secretory signaling, causing mitochondrial dysfunction and, thereby impairing insulin secretion in the MIN6-Cisd2KO 3-cells. Thirdly, transcriptomic analysis of 3islets reveals that Cisd2 modulates proteostasis and ER stress, mitochondrial function, insulin secretion and vesicle transport. Finally, the activated state of two potential upstream regulators, Glis3 and Hnf1a, is significantly suppressed under Cisd2 deficiency; notably, their downstream target genes are deeply involved in 3-cell function and identity. Conclusions: These findings provide mechanistic insights and form a basis for developing therapeutics for the effective treatment of diabetes in WFS2 patients
Reliability of brain localization using task-based fMRI for late-life depression with suicidal risk
No full text[[abstract]]Late-life depression (LLD) is a heterogeneous mental disorder with a high risk of suicide, often linked to abnormalities in brain networks, particularly the prefrontal cortex. While transcranial magnetic stimulation targeting the dorsal and ventral lateral prefrontal cortex (DLPFC and VLPFC) has shown promise, its treatment efficacy may be compromised by the imprecise group-level standard methods. Although a personalized localization approach using fMRI is available, no study has yet systematically evaluated its reliability in LLD. This study evaluated the reliability of functional magnetic resonance imaging (fMRI) for targeting DLPFC and VLPFC using numerical Stroop and face/shape matching tasks in LLD patients with varying degrees of suicidality, the disorder's most devastating consequence. A total of 103 LLD patients, including 42 with non-suicidal risk (NS), 37 with suicidal ideation or plans (IP), and 24 with past suicide attempts (SA), underwent task-based fMRI. We performed both voxel-wise statistical analyses and the success rate of DLFPC/VLPFC localization in each subgroup by detecting significant brain activity within predefined masks. The numerical Stroop task reliably localized the bilateral DLPFC in all subgroups and the VLPFC in two-thirds. Success rates for localizing DLPFC were 98 % (41 out of 42 NS), 100 % (IP), and 100 % (SA), while VLPFC localization rates were 95 %, 97 %, and 88 %, respectively. Conversely, the face/shape matching task localized bilateral DLPFC in two-thirds and failed to detect the VLPFC in any subgroup. These findings underscore the potential of task-based fMRI, particularly the numerical Stroop task, as a reliable method for personalized targeting in LLD patients with different suicidality degrees
Impact of weather, air pollution and virus variant on COVID-19 with acute respiratory failure in the emergency department
No full text[[abstract]]Background: Air pollution and meteorological factors are thought to contribute to increased risk of severe COVID-19, but the evidence is still controversial. This study aimed to assess the effects of weather, air pollution and SARS-CoV-2 variants on COVID-19 with acute respiratory failure (ARF) and investigate the respiratory management in the emergency department (ED). Methods: We conducted a prospective observational study of 469 COVID-19 ED visits from March 1, 2020 to December 31, 2023. Data on air pollutant levels and weather variables was obtained from Taiwan Central Weather Bureau (CWB) and Environmental Protection Administration (EPA). The generalized linear models extending bivariate and multivariable Poisson regression models were used to estimate the association between the weather variables, air pollutants, virus variants, and COVID-19 patients with ARF. Results: Among the 469 patients, 64 % were male, and the mean age was 70 ± 6 years. Overall, 18 % (n = 84) of the cohort died, 43 % (n = 200) were intubated, and 70 % (n = 326) were admitted to the ICU. We observed significantly positive associations between PM2.5, PM10, temperature, and wind speed with ED visits for COVID-19 with ARF. Every 1 μg/m3 increase in PM2.5, PM10, each 1 m/s increase in wind speed, and 1 °C increase in temperature were significantly associated with a 34.1 % (95 % CI: 8.2 %–66.1 %), 45.4 % (95 % CI: 39.4 %–46.6 %), 19.0 % (95 % CI: 11.4 %–27.0 %), and 10.4 % (95 % CI: 6.9 %–13.9 %) increase in the average daily number of COVID-19 patients respectively. In contrast, NO2, SO2, relative humidity, and sunshine were significantly associated with lower average daily numbers of severe COVID-19 patients. Moreover, virus variants were significantly positive associations between humidity and sunshine, 53.9 % (95 % CI: 37.0 %–70.3 %) and 5.4 % (95 % CI: 0.6 %–10.4 %) respectively. Conclusion: The relationship between air pollution, climate change, virus variants, and COVID-19 is highly intricate. Air pollution exacerbates the severity of COVID-19, climate change influences virus transmission and human immune responses, and viral variants make pandemic control more challenging. These interactions are critical for future prediction, prevention and responses to global health crises
[[alternative]]Structure-based design of potent and selective merTK inhibitors by modulating the conformation of αC Helix
No full text[[abstract]]Tumor-associated macrophages play an important role in cancer progression and immunosuppression, making their receptors promising therapeutic targets. MerTK, a TAM receptor, regulates macrophage efferocytosis and polarization, and its inhibition holds potential for tumor growth suppression and immune modulation. However, Tyro3, another TAM receptor, is involved in neurogenesis, highlighting the need to selectively target MerTK while avoiding Tyro3 inhibition to prevent neurotoxicity. In this study, we present a novel strategy for designing MerTK-selective inhibitors by modulating the conformational dynamics of its alpha C helix. By integrating structural biology, medicinal chemistry, protein stabilization assays, and molecular docking studies, we identified compound 11, which demonstrates potent inhibition and selectivity for MerTK. Pharmacokinetic evaluations and in vivo studies further reveal compound 11 as a promising candidate for further development. Our findings not only advance the understanding of the MerTK-specific mechanism but also propose a strategy for designing selective kinase inhibitors targeting the alpha C helix conformation
Clinical characteristics of patients with intra-abdominal infection caused by stenotrophomonas maltophilia
No full text[[abstract]]Background: Intra-abdominal infections (IAIs) caused by Stenotrophomonas maltophilia have rarely been reported. This study aimed to describe the clinical characteristics and risk factors for mortality among patients with S. maltophilia IAIs. Methods: A retrospective study was conducted on inpatients with IAIs caused by S. maltophilia at Tri Service General Hospital from 2004 to 2017. Clinical and microbiologic data of the included cases were reviewed via medical charts and microbiology databases. Multivariable logistic regression analyses were performed to identify risk factors for in-hospital death. Results: In total, 110 patients were diagnosed with S. maltophilia IAIs. Malignancy (56.3%) and liver cirrhosis (35.3%) were the most commonly identified underlying diseases. The major causes of S. maltophilia IAIs were biliary tract infection (42.7%), recent abdominal surgery (35.4%), and spontaneous bacterial peritonitis (20.0%). Polymicrobial infections were observed in 84 (76.4%) patients. In addition to S. maltophilia, co-cultured bacteria (n = 140) included Enterobacterales, representing 19.3% (27/140) of the total isolates, and non-fermentative aerobes, comprising 29.3% (41/140). In addition, anaerobic bacteria and fungi accounted for 9.2% (13/140) and 10% (14/140), respectively. The overall mortality rate was 40.9%. Multivariable logistic regression analysis revealed that high Sequential Organ Failure Assessment scores and malignancies were independent risk factors for mortality, while the immediate administration of appropriate antibiotics targeting S. maltophilia was a protective factor (p < 0.05). Conclusions: Patients with an underlying malignancy or liver cirrhosis were at risk for IAIs caused by S. maltophilia. The prompt initiation of effective antibiotics against S. maltophilia is critical for achieving favorable outcomes
The effect of exposure to ambient air fine particulate matter pollution on mortality among children aged under five in Taiwan
No full text[[abstract]]Exposure to ambient fine air particulate matter (PM2.5) pollution may pose an adverse health hazard risk to infants and children. The under-5 mortality rate serves as an estimate of probability that a child might die between birth and age of five following exposure. This rate has been used by the United Nations as a prime indicator of exposure when setting and evaluating sustainable development goals (SDGs). These particular SDGs targets were set to avoid preventable deaths in this age group. Few investigators examined the relationship between post-birth exposure to PM2.5 and under-5 mortality. To examine this association, the mean annual PM2.5 levels of 65 municipal districts were measured in Taiwan from 2013 to 2022 and then divided into tertiles. The under-5 mortality rates per 1000 live births included the following parameters PM2.5 levels, urbanization, physician density, and mean annual household income. Weighted-multiple linear regression was used to compute the adjusted risk ratios (RRs) and their 95% confidence intervals (CIs). Data demonstrated that children living in districts with the highest PM2.5 levels to be at significantly increased risk of mortality at under-5, with adjusted RR (95% CI) calculated at 1.12 (1.02-1,23) for those residing in municipalities with mean PM2.5 between 23.7 and 27.49 ug/m3 compared to those living in districts with the lowest PM2.5 levels. An increase a 0.7% in under-5 child mortality per each 1 ug/m3 rise in PM2.5, suggested long-term exposure to PM2.5 enhances the risk of mortality under-5 children in Taiwan
Distal electrical stimulation enhances neuromuscular reinnervation and satellite cell differentiation for functional recovery
No full text[[abstract]]BackgroundPeripheral nerve injuries lead to significant motor deficits, with limited treatment options for full functional recovery. Distal electrical stimulation (E-stim) has shown promise in promoting neuromuscular reinnervation, though its mechanisms are not yet fully understood. This study aims to investigate the regulatory effects of distal E-stim on neuromuscular junction (NMJ) reinnervation and Satellite cell activity in denervated muscle injury.MethodsUsing a sciatic nerve critical gap model in Sprague-Dawley rats (8-week-old, random sex), we applied distal E-stim and assessed neuromuscular and functional recovery through histological, biochemical, and functional evaluations over six weeks. The Sciatic Function Index (SFI) was measured at baseline and at subsequent time points post-injury. We quantified muscle mass, NMJ morphology, and neurotransmitter levels (acetylcholine and acetylcholinesterase), and analyzed muscle fiber electrophysiology using single-muscle electromyography to assess denervated muscle autoelectricity. Additionally, single-cell RNA sequencing was performed to examine gene expression in Satellite cells.ResultsDistal E-stim significantly enhanced neuromuscular reinnervation, as evidenced by improved SFI scores, increased muscle mass, and reduced muscle atrophy. Histological analysis showed larger muscle fiber cross-sectional areas and enhanced NMJ structure. Elevated levels of acetylcholine and acetylcholinesterase, along with reduced fibrillation potentials in muscle fibers, further indicated preserved NMJ function. Single-cell RNA sequencing revealed upregulation of genes associated with muscle differentiation and angiogenesis in Satellite cell clusters, suggesting that distal E-stim fosters a regenerative environment.ConclusionsOur findings demonstrate that distal E-stim promotes functional recovery through NMJ preservation and Satellite cell differentiation, offering novel insights into molecular mechanisms that may enhance electroceutical therapies for peripheral nerve injuries. Further research could optimize E-stim protocols to maximize clinical benefits for patients with neuromuscular impairments
In vitro activity of cefepime-zidebactam, ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam, and other comparators against imipenem-non-susceptible Pseudomonas aeruginosa in Taiwan, 2022
No full text[[abstract]]OBJECTIVES: The global expansion of antimicrobial-resistant Pseudomonas aeruginosa, particularly imipenem-non-susceptible (INS) strains poses a formidable health threat. The COVID-19 pandemic has exacerbated antimicrobial resistance trends. We compared the pre- and post-pandemic antibiotic resistance patterns of INS-P. aeruginosa in Taiwan. METHODS: We analysed 503 P. aeruginosa isolates collected through the Taiwan Surveillance of Antimicrobial Resistance (TSAR) program during 2022. Minimum inhibitory concentrations of various antibiotics were determined by using broth microdilution. Carbapenemase-encoding genes were identified via multiplex PCR. Antimicrobial resistance trends were compared with data from 2018. RESULTS: INS-P. aeruginosa comprised 16.9% (85/503) of isolates and exhibited high-level multi-drug resistance. Novel β-lactam-β-lactamase inhibitor combinations (BL-BLIs) demonstrated the highest activity, with 89.4% of INS isolates remaining susceptible to cefepime-zidebactam. However, the susceptibility rates of INS-P. aeruginosa isolates to other BL-BLIs and comparators declined between 2018 and 2022. Specifically, susceptibility to ceftazidime-avibactam and imipenem-relebactam declined significantly from 81.5% and 85.2% in 2018 to 64.7% and 63.5% in 2022, respectively (both P < 0.05). Additionally, only 70.6% of isolates obtained during 2022 were susceptible to ceftolozane-tazobactam. Carbapenemase genes were detected in 10.6% of isolates, with a notable increase in bla(KPC) and bla(IMP) prevalence compared to pre-pandemic data. CONCLUSION: The COVID-19 pandemic intensified resistance trends in INS-P. aeruginosa in Taiwan, with increasing prevalence and diversity of carbapenemase-encoding genes. Continuous monitoring and expanded research are essential to combat evolving resistance patterns
[[alternative]]Correction: SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma
No full text[[abstract]]Following the publication of the original article [1], the authors discovered an error in Fig. 3D and the third panel from the left in Figure S9A, where Western blot images in the Actin blots were inadvertently duplicated. This oversight was not detected by either the authors or the reviewers during the review process. The correct figures are presented below
Hypoxia-inducible factors: Regulation and therapeutic potential
No full text[[abstract]]Tumor cells located distal to the functional blood vessels often experience hypoxic stress during tumor progression. Intratumoral hypoxia is known to promote angiogenesis, tumor metastasis, and the development of chemoresistance and radioresistance. The hypoxia-inducible factor 1 (HIF-1) and HIF-2 signaling pathways are two of the most studied pathways known for their roles in regulating the survival of cells, including tumor cells, under hypoxic conditions. This chapter discusses the regulation and effects of the HIF-1/HIF-2 signaling pathway in cells under normoxic and hypoxic conditions. The potential of reoxygenation and targeting the HIF-1/HIF-2 signaling pathway as anticancer therapies will also be discussed in detail