Association of early-term birth and breastfeeding practices with nutritional outcomes in singleton term infants: a multicenter cross-sectional study.

BACKGROUND: Limited research has explored the associations of gestational age (GA) and breastfeeding practices with growth and nutrition in term infants. METHODS: This multicenter cross-sectional study recruited 7299 singleton term infants from well-child visits in Shandong, China, between March 2021 and November 2022. Data on GA, gender, ethnicity, birth weight, parental heights, gestational diabetes and hypertension, age at visit, breastfeeding practices (point-in-time data at visit for infants < 6 months and retrospective data at 6 months for infants ≥ 6 months), complementary foods introduction, infant length and weight, were collected. 7270 infants were included in the analysis after excluding outliers with Z-scores of length (LAZ), weight or weight for length (WLZ) <-4 or > 4. Linear regression models adjused for covariates explored the impact of GA and breastfeeding practices on LAZ and WLZ, while logistic regression models evaluated their effect on the likelihood of moderate and severe stunting (MSS, LAZ<-2), moderate and severe acute malnutrition (MSAM, WLZ<-2) and overweight/obesity (WLZ > 2). Sensitivity analysis was conducted on normal birth weight infants (2.5-4.0 kg). RESULTS: Infants born early-term and exclusively breastfed accounted for 31.1% and 66.4% of the sample, respectively. Early-term birth related to higher WLZ (< 6 months: ß = 0.23, 95% confidence interval (CI): 0.16, 0.29; ≥6 months: ß = 0.12, 95% CI: 0.04, 0.20) and an increased risk of overweight/obesity throughout infancy (< 6 months: OR: 1.41, 95% CI 1.08, 1.84; ≥6 months: OR: 1.35, 95% CI 1.03, 1.79). Before 6 months, early-term birth correlated with lower LAZ (ß=-0.16, 95% CI: -0.21, -0.11) and an increased risk of MSS (OR: 1.01, 95%CI 1.00, 1.02); Compared to exclusive breastfeeding, exclusive formula-feeding and mixed feeding linked to lower WLZ (ß=-0.15, 95%CI -0.30, 0.00 and ß=-0.12, 95%CI -0.19, -0.05, respectively) and increased risks of MSAM (OR: 5.57, 95%CI 1.95, 15.88 and OR: 3.19, 95%CI 1.64, 6.19, respectively). Sensitivity analyses confirmed these findings. CONCLUSIONS: The findings emphasize the health risks of early-term birth and the protective effect of exclusive breastfeeding in singleton term infants, underscoring the avoidance of nonmedically indicated delivery before 39 weeks and promoting exclusive breastfeeding before 6 months.

Positive feedback loop of c-myc/XTP6/NDH2/NF-κB to promote malignant progression in glioblastoma.

BACKGROUND: Recent studies have highlighted the significant role of the NF-κB signaling pathway in the initiation and progression of cancer. Furthermore, long noncoding RNAs (lncRNAs) have been identified as pivotal regulators in sustaining the NF-κB signaling pathway's functionality. Despite these findings, the underlying molecular mechanisms through which lncRNAs influence the NF-κB pathway remain largely unexplored. METHODS: Bioinformatic analyses were utilized to investigate the differential expression and prognostic significance of XTP6. The functional roles of XTP6 were further elucidated through both in vitro and in vivo experimental approaches. To estimate the interaction between XTP6 and NDH2, RNA pulldown and RNA Immunoprecipitation (RIP) assays were conducted. The connection between XTP6 and the IκBα promoter was examined using Chromatin Isolation by RNA Purification (ChIRP) assays. Additionally, Chromatin Immunoprecipitation (ChIP) assays were implemented to analyze the binding affinity of c-myc to the XTP6 promoter, providing insights into the regulatory mechanisms at play. RESULTS: XTP6 was remarkedly upregulated in glioblastoma multiforme (GBM) tissues and was connected with adverse prognosis in GBM patients. Our investigations revealed that XTP6 can facilitate the malignant progression of GBM both in vitro and in vivo. Additionally, XTP6 downregulated IκBα expression by recruiting NDH2 to the IκBα promoter, which resulted in elevated levels of H3K27me3, thereby reducing the transcriptional activity of IκBα. Moreover, the progression of GBM was further driven by the c-myc-mediated upregulation of XTP6, establishing a positive feedback loop with IκBα that perpetuated the activation of the NF-κB signaling pathway. Notably, the application of an inhibitor targeting the NF-κB signaling pathway effectively inhibited the continuous activation induced by XTP6, leading to a significant reduction in tumor formation in vivo. CONCLUSION: The results reveal that XTP6 unveils an innovative epigenetic mechanism instrumental in the sustained activation of the NF-κB signaling pathway, suggesting a promising therapeutic target for the treatment of GBM.

Reactivity-matched synthesis of monodisperse Ag(In,Ga)S2 QDs with efficient luminescence.

I-III-VI quantum dots (QDs) have gained widespread attention owing to their significant advantages of non-toxicity, large structural tolerance, and efficient photoluminescence potential. However, the disbalance of reactivity between the elements will result in undesired products and compromised optical properties. Reducing the activity of highly reactive group IB elements is the most common approach, but it will reduce the overall reactivity and lead to a wide dispersion of QD sizes. In this study, we propose a method to improve the overall reactivity of the reaction system using the highly active IIIA precursor InI3, which triggers rapid nucleation and promotes the formation of Ag(In,Ga)S2 (AIGS) QDs, resulting in monodisperse particle size distributions and a significantly improved photoluminescence quantum yield (PLQY) (from 12% to 72%). Furthermore, narrow band edge emission is realized by coating a gallium sulfide (GaSx) shell on the basis of obtaining high-quality AIGS QDs. The core/shell QDs exhibit a 90% PLQY with a full width at half maximum (FWHM) of only 31 nm at 530 nm. This study provides a viable design strategy to synthesize monodisperse AIGS QDs with a narrow peak width and efficient luminescence, promoting the application of AIGS QDs in the field of luminescent displays.

Long-term blood pressure variability and risk of cardiovascular diseases in populations with different blood pressure status: an ambispective cohort study.

OBJECTIVE: We aimed to investigate the correlation between long-term blood pressure variability (BPV) and the risk of cardiovascular diseases (CVDs) among population with different blood pressure statuses (normotension, well-controlled hypertension, and uncontrolled hypertension). METHODS: In this ambispective cohort study, CVD-free residents aged over 50 years were consecutively enrolled from two community health service centers (CHCs) in Tianjin, China from April 2017 to May 2017. Information on blood pressure was retrospectively extracted from electronic medical records of CHCs between January 2010 and May 2017, and the occurrence of new-onset CVDs was prospectively observed during follow-up until September 2019. Long-term variation of SBP and DBP was assessed using four indicators: SD, coefficient of variation (CV), average successive variability (ASV), and average real variability (ARV). Cox proportional hazards regression model was developed to identify the potential impact of BPV on the incidence of CVDs. The receiver operating characteristic curve (ROC) was utilized to evaluate the predictive value of BPV indicators for the occurrence of CVDs. RESULTS: Of 1275 participants included, 412 (32.3%) experienced new CVD events during the median 7.7 years of follow-up, with an incidence density of 499/10 000 person-year in the whole cohort. Cox regression analysis revealed that almost all SBP and DBP variability indicators (except for SBP-SD) were significantly related to the risk of CVDs, especially among individuals with well-controlled hypertension. A trend toward an increased risk of CVDs across BPV quartiles was also observed. Moderate predictive abilities of BPV were observed, with the area under ROC curves ranging between 0.649 and 0.736. For SBP variability, SD had the lowest predictive ability, whereas for DBP variability, ARV had the lowest predictive ability. No significant association of CVDs with SBP-SD was found in all analyses, no matter as a continuous or categorical variable. CONCLUSION: Elevated long-term BPV is associated with an increased risk of CVDs, especially among individuals with well-controlled hypertension. CV and ASV had higher predictive values than SD and ARV.

Is Type 2 Diabetes Mellitus Associated with Spinal Degenerative Disorders?: Evidence from Observational and 2-Sample Mendelian Randomization Analyses.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and spinal degenerative disorders (SDD) are common diseases that frequently coexist. However, both traditional observational studies and recent Mendelian randomization (MR) studies have demonstrated conflicting evidence on the association between T2DM and SDD. This comparative study explored and compared the association between T2DM and SDD using observational and MR analyses. METHODS: For observational analyses, cross-sectional studies (44,972 participants with T2DM and 403,095 participants without T2DM), case-control studies (38,234 participants with SDD and 409,833 participants without SDD), and prospective studies (35,550 participants with T2DM and 392,046 participants without T2DM with follow-up information until 2022) were performed to test the relationship between T2DM and SDD using individual-level data from the U.K. Biobank from 2006 to 2022. For MR analyses, the associations between single-nucleotide polymorphisms with SDD susceptibility obtained using participant data from the U.K. Biobank, which had 407,938 participants from 2006 to 2022, and the FinnGen Consortium, which had 227,388 participants from 2017 to 2022, and genetic predisposition to T2DM obtained using summary statistics from a pooled genome-wide association study involving 1,407,282 individuals were examined. The onset and severity of T2DM are not available in the databases being used. RESULTS: Participants with T2DM were more likely to have SDD than their counterparts. Logistic regression analysis identified T2DM as an independent risk factor for SDD, which was confirmed by the Cox proportional hazard model results. However, using single-nucleotide polymorphisms as instruments, the MR analyses demonstrated no causal relationship between T2DM and SDD. The lack of such an association was robust in the sensitivity analysis, and no pleiotropy was seen. CONCLUSIONS: Our results suggest that the association between T2DM and SDD may be method-dependent. Researchers and clinicians should be cautious in interpreting the association, especially the causal association, between T2DM and SDD. Our findings provide fresh insights into the association between T2DM and SDD by various analysis methods and guide future research and clinical efforts in the effective prevention and management of T2DM and SDD. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Comparative simulations of methanol steam reforming on PdZn alloy using kinetic Monte Carlo and mean-field microkinetic model.

Methanol steam reforming (MSR) is an attractive route for producing clean energy hydrogen. PdZn alloys are extensively studied as potential MSR catalysts for their stability and high CO2 selectivity. Here, we investigated the reaction mechanism using density functional calculations, mean-field microkinetic modeling (MF-MKM), and kinetic Monte Carlo (kMC) simulations. To overcome the over-underestimation of CO2 selectivity by log-kMC, an ads-kMC algorithm is proposed in which the adsorption/desorption rate constants were reduced under certain requirements and the diffusion process was treated by redistributing surface species each time an event occured. The simulations show that the dominant pathway to CO2 at low temperatures is CH3OH → CH3O → CH2O → H2COOH → H2COO → HCOO → CO2. The ads-kMC predicted OH coverage is 2-3 times that of MF-MKM, while they produce similar coverage for other species. Analyses indicate that surface OH promotes the dehydrogenation of CH3OH, CH3O, and H2COOH significantly and plays a key role in the MSR process. The dissociation of water/methanol is the most important rate-limiting/rate-inhibiting step. The CO2 selectivity obtained by the two methods is close to each other and consistent with the experimental trend with temperature. Generally, the ads-kMC results agree with the MF-MKM ones, supporting the previous finding that kMC and MF-MKM predict similar results if the diffusion is very fast and adsorbate interactions are neglected. The present study sheds light on the MSR process on PdZn alloys, and the proposed scheme to overcome the stiff problems in kMC simulations is worthy of being extended to other systems.

Adsorption performance and mechanism of pectin modified with ß-cyclodextrin for Zn2+ and Cu2.

Removing heavy metals from aqueous solutions has drawn more and more attentions these years because of their serious global health challenge to human society. To develop an adsorbent with green, stable and high-efficiency for adsorption of heavy metals, pectin ß-cyclodextrin composite was successfully prepared and used for Zn2+ and Cu2+ adsorption for the first time. Various variables that influence the adsorption performance were explored, and the optimal adsorption conditions were determined. According to the pseudo-second-order kinetic model, the adsorption process of Zn2+ and Cu2+ by the adsorbent was mainly chemical adsorption. The adsorbent adsorption process was an exothermic and non-spontaneous process. According to the Langmuir isotherm model, the maximum adsorption capacity was 12.51 ± 0.33 and 24.98 ± 0.23 mg/g for Zn2+ and Cu2+, respectively. The FTIR, EDX and XPS results revealed that the main mechanisms of removing pollutants by adsorbent were ion exchange and coordination. In addition, electrostatic attraction and chelation were present in the adsorption process. After five adsorption desorption cycles, the pectin ß-cyclodextrin composite adsorbent still exhibited adsorption and regeneration capabilities. This study provides a low-cost, effective and simple method for preparation of modified pectin, which has excellent application potential in the removal of heavy metal ions from wastewater.

Association of serum interleukin-6 with negative symptoms in stable early-onset schizophrenia.

BACKGROUND: Accumulating evidence suggests that the inflammatory cytokine interleukin-6 (IL-6) contributes to the pathophysiology of psychiatric disorders. However, there was no study concerning the relationship between IL-6 concentrations and clinical features in the chronic phase of early-onset schizophrenia (EOS). AIM: To investigate the relationship between serum IL-6 concentration and the clinical features of EOS. METHODS: We measured serum IL-6 Levels from 74 patients with chronic schizophrenia, including 33 with age at onset < 21 years (EOS group) and 41 with onset ≥ 21 years in [adult-onset schizophrenia (AOS) group], and from 41 healthy controls. Symptom severities were evaluated using the Positive and Negative Syndrome Scale (PANSS). RESULTS: Serum IL-6 concentrations were higher in both EOS and AOS groups than healthy controls (F = 22.32, P < 0.01), but did not differ significantly between EOS and AOS groups (P > 0.05) after controlling for age, body mass index, and other covariates. Negative symptom scores were higher in the EOS group than the AOS group (F = 6.199, P = 0.015). Serum IL-6 concentrations in the EOS group were negatively correlated with both total PANSS-negative symptom score (r = -0.389, P = 0.032) and avolition/asociality subscore (r = -0.387, P = 0.026). CONCLUSION: Patients with EOS may have more severe negative symptoms than those with adult-onset schizophrenia during the chronic phase of the illness. IL-6 signaling may regulate negative symptoms and its avolition/asociality subsymptoms among the early-onset chronic schizophrenic patients.

Immune checkpoint inhibitor combinations for patients with advanced endometrial cancer: a network meta-analysis and cost-utility analysis.

BACKGROUND: Immune checkpoint inhibitor combinations show significant survival advantages compared with chemotherapy for patients with advanced endometrial cancer. OBJECTIVE: To compare the efficacy, safety, and cost-effectiveness of different immunotherapy combinations for clinician and patient decision-making. METHODS: The PubMed, Embase, Cochrane, and Web of Science Databases were reviewed from January 1, 2010 to October 30, 2023, for phase III randomized controlled trials of first-line immunotherapy combinations in patients with advanced endometrial cancer. Bayesian network meta-analysis was performed to obtain hazard ratios (HRs) of overall survival and progression-free survival, relative risks (RRs) of adverse events, and corresponding p value. The lifetime Markov model of cost-effectiveness analysis was developed to summarize the cost, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios at the US$150 000/QALY of willingness-to-pay of six first-line treatment strategies. RESULTS: Four trials were identified, involving 2577 patients. Dostarlimab plus chemotherapy or durvalumab plus chemotherapy with olaparib was associated with more survival benefits than other immunotherapy regimens and chemotherapy in the mismatch repair-deficient microsatellite instability-high (dMMR/MSI-H) and mismatch repair-proficient microsatellite-stable (pMMR/MSS) population, respectively. Further, pembrolizumab plus chemotherapy versus chemotherapy increased efficacy (cost) by 3.76 QALYs and US$540 817, which yielded incremental cost-effectiveness ratios of US$143 894/QALY in the dMMR/MSI-H population. CONCLUSION: First-line durvalumab plus chemotherapy with olaparib, and dostarlimab plus chemotherapy, were more beneficial for survival in the pMMR/MSS and dMMR/MSI-H populations, respectively. Only pembrolizumab plus chemotherapy versus chemotherapy was cost-effective for patients with dMMR/MSI-H endometrial cancer in the USA.

IDD10-NAC079 transcription factor complex regulates sheath blight resistance by inhibiting ethylene signaling in rice.

INTRODUCTION: Rhizoctonia solani Kühn is a pathogen causing rice sheath blight (ShB). Ammonium transporter 1 (AMT1) promotes resistance of rice to ShB by activating ethylene signaling. However, how AMT1 activates ethylene signaling remains unclear. OBJECTIVE: In this study, the indeterminate domain 10 (IDD10)-NAC079 interaction model was used to investigate whether ethylene signaling is modulated downstream of ammonium signaling and modulates ammonium-mediated ShB resistance. METHODS: RT-qPCR assay was used to identify the relative expression levels of nitrogen and ethylene related genes. Yeast two-hybrid assays, Bimolecular fluorescence complementation (BiFC) and Co-immunoprecipitation (Co-IP) assay were conducted to verify the IDD10-NAC079-calcineurin B-like interacting protein kinase 31 (CIPK31) transcriptional complex. Yeast one-hybrid assay, Chromatin immunoprecipitation (ChIP) assay, and Electrophoretic mobility shift assay (EMSA) were used to verify whether ETR2 was activated by IDD10 and NAC079. Ethylene quantification assay was used to verify ethylene content in IDD10 transgenic plants. Genetic analysis is used to detect the response of IDD10, NAC079 and CIPK31 to ShB infestation. RESULTS: IDD10-NAC079 forms a transcription complex that activates ETR2 to inhibit the ethylene signaling pathway to negatively regulating ShB resistance. CIPK31 interacts and phosphorylates NAC079 to enhance its transcriptional activation activity. In addition, AMT1-mediated ammonium absorption and subsequent N assimilation inhibit the expression of IDD10 and CIPK31 to activate the ethylene signaling pathway, which positively regulates ShB resistance. CONCLUSION: The study identified the link between ammonium and ethylene signaling and improved the understanding of the rice resistance mechanism.

Synthesis and Preclinical Evaluation of Novel 68Ga-DOTA-RBB as Potential PET Radiotracer for Imaging CDK4/6 in Tumors.

Many malignant tumors, including breast cancer, exhibit amplification and overexpression of cyclin-dependent kinase 4 and 6 (CDK4/6). Ribociclib, approved and used in clinical treatment, acts as a highly selective CDK4/6 inhibitor for ER+/HER2- breast cancer. By modifying ribociclib with the chelator DOTA, we designed and synthesized a novel CDK4/6-positive PET imaging agent, which was radiolabeled by 68Ga for radioactive tagging. The radiotracer demonstrates high radiochemical purity, excellent stability in vitro and in vivo, and favorable pharmacokinetic characteristics. Cell uptake experiments using MCF-7 cells indicate that an excess of ribociclib (RBB) can inhibit cellular uptake of 68Ga-DOTA-RBB. Imaging and biodistribution experiments in MCF-7 tumor-bearing nude mice show significant radioactive accumulation in the tumor. However, preadministration of excess ribociclib results in a substantial reduction in radioactive accumulation within the tumor. On the basis of our explorations, 68Ga-DOTA-RBB, as a targeted imaging agent for CDK4/6-positive tumors, holds significant potential application values.

A novel NIR-II albumin-escaping probe for cerebral arteries and perfusion imaging in stroke mice model.

In order to guide the formulation of post-stroke treatment strategy in time, it is necessary to have real-time feedback on collateral circulation and revascularization. Currently used near-infrared II (NIR-II) probes have inherent binding with endogenous albumin, resulting in significant background signals and uncontrollable pharmacokinetics. Therefore, the albumin-escaping properties of the new probe, IR-808AC, was designed, which achieved timely excretion and low background signal, enabling the short-term repeatable injection for visualization of cerebral vessels and perfusion. We further achieved continuous observation of changes in collateral vessels and perfusion during the 7-d period in middle cerebral artery occlusion mice using IR-808AC in vivo. Furthermore, using IR-808AC, we confirmed that remote ischemic conditioning could promote collateral vessels and perfusion. Finally, we evaluated the revascularization after thrombolysis on time in embolic stroke mice using IR-808AC. Overall, our study introduces a novel methodology for safe, non-invasive, and repeatable assessment of collateral circulation and revascularization in real-time that is crucial for the optimization of treatment strategies.

Podocyte OTUD5 alleviates diabetic kidney disease through deubiquitinating TAK1 and reducing podocyte inflammation and injury.

Recent studies have shown the crucial role of podocyte injury in the development of diabetic kidney disease (DKD). Deubiquitinating modification of proteins is widely involved in the occurrence and development of diseases. Here, we explore the role and regulating mechanism of a deubiquitinating enzyme, OTUD5, in podocyte injury and DKD. RNA-seq analysis indicates a significantly decreased expression of OTUD5 in HG/PA-stimulated podocytes. Podocyte-specific Otud5 knockout exacerbates podocyte injury and DKD in both type 1 and type 2 diabetic mice. Furthermore, AVV9-mediated OTUD5 overexpression in podocytes shows a therapeutic effect against DKD. Mass spectrometry and co-immunoprecipitation experiments reveal an inflammation-regulating protein, TAK1, as the substrate of OTUD5 in podocytes. Mechanistically, OTUD5 deubiquitinates K63-linked TAK1 at the K158 site through its active site C224, which subsequently prevents the phosphorylation of TAK1 and reduces downstream inflammatory responses in podocytes. Our findings show an OTUD5-TAK1 axis in podocyte inflammation and injury and highlight the potential of OTUD5 as a promising therapeutic target for DKD.

The circular RNA hsa_circ_0045800 serves as a favorable biomarker in pathogenesis of sjögren's syndrome.

BACKGROUND: Circular RNAs (circRNAs) play various roles in the development of many autoimmune diseases. However, their expression profiles and specific function in Sjögren's Syndrome remains largely unknown. OBJECTIVES: We aimed to investigate circRNAs potential diagnostic value in primary Sjögren's syndrome (pSS) and contribution to the pathogenesis of pSS. METHODS: This study included 102 subjects, 51 pSS patients and 51 healthy controls. The concentration of hsa_circ_0045800 was analyzed in peripheral blood mononuclear cells obtained from 51 pSS patients and 51 healthy controls by qRT-PCR. We established a receiver operating characteristic curve (ROC) to assess the biological diagnostic value of hsa_circ_0045800 for pSS. In addition, we analyzed the correlation between hsa_circ_0045800 and disease activity in Sjogren's syndrome. A differential analysis was also conducted on the concentration of hsa_circ_0045800 in patients in pSS patients before and after treatment. We studied the downstream mechanism of hsa_circ_0045800 through bioinformatics analysis and confirmed it using luciferase reporter gene assay. RESULTS: We confirmed that the concentration of hsa_circ_0045800 was elevated 10.4-fold in peripheral blood mononuclear cells of pSS patients than in healthy controls (p = 0.00). In the pSS active disease group, the concentration of hsa_circ_0045800 is 2.5-fold higher compared to the pSS non-active disease group (p = 0.04). The concentration of hsa_circ_0045800 after treatment was decreased by 80% compared with that before treatment (p = 0.037), suggesting its utility as a potential marker for monitoring treatment efficacy. ROC curve analysis showed that the diagnostic value of hsa_circ_0045800 in pSS patients was significantly higher than that in healthy controls, with an area under the curve of 0.865, a sensitivity of 74%, and a specificity of 92%. The concentration of hsa_circ_0045800 is correlated with various clinical factors: the concentration of hsa_circ_0045800 is positively associated with age (r = 0.328, P = 0.019), oral dryness (r = 0.331, P = 0.017), while it is negatively correlated with HGB (r = -0.435, P = 0.001) and and hypothyroidism (r = -0.318, P = 0.023). Bioinformatics predictions and luciferase assays indicated that hsa_circ_0045800 acts as a molecular sponge for miR-1247-5p, with SMAD2 being a target gene of miR-1247-5p. CONCLUSION: Our study results show that hsa_circ_0045800 potentially contributes to the development and progression of pSS via the miR-1247-5p/SMAD2 pathway. Peripheral blood mononuclear cells are directly involved in the pathogenesis of pSS, and the discovery of hsa_circ_0045800 in peripheral blood mononuclear cells highlights its potential as a novel biomarker for disease activity and diagnosis in patients with pSS. Key Points • The concentration of hsa_circ_0045800 was higher in peripheral blood mononuclear cells of pSS patients. • Hsa_circ_0045800 promoted pSS progression through miR-1247-5p-SMAD2 axis. • Hsa_circ_0045800 is a potential biomarker for pSS.

IP3R2 regulates apoptosis by Ca2+ transfer through mitochondria-ER contacts in hypoxic photoreceptor injury.

Mitochondria-associated ER membranes (MAMs) are contact sites that enable bidirectional communication between the ER (endoplasmic reticulum) and mitochondria, including the transfer of Ca2+ signals. MAMs are essential for mitochondrial function and cellular energy metabolism. However, unrestrained Ca2+ transfer to the mitochondria can lead to mitochondria-dependent apoptosis. IP3R2 (Inositol 1,4,5-trisphosphate receptor 2) is an important intracellular Ca2+ channel. This study investigated the contribution of IP3R2-MAMs to hypoxia-induced apoptosis in photoreceptor cells. A photoreceptor hypoxia model was established by subretinal injection of hyaluronic acid (1%) in C57BL/6 mice and 1% O2 treatment in 661W cells. Transmission electron microscopy (TEM), ER-mitochondria colocalization, and the MAM reporter were utilized to evaluate MAM alterations. Cell apoptosis and mitochondrial homeostasis were evaluated using immunofluorescence (IF), flow cytometry, western blotting (WB), and ATP assays. SiRNA transfection was employed to silence IP3R2 in 661W cells. Upon hypoxia induction, MAMs were significantly increased in photoreceptors both in vivo and in vitro. This was accompanied by the activation of mitochondrial apoptosis and disruption of mitochondrial homeostasis. Elevated MAM-enriched IP3R2 protein levels induced by hypoxic injury led to mitochondrial calcium overload and subsequent photoreceptor apoptosis. Notably, IP3R2 knockdown not only improved mitochondrial morphology but also restored mitochondrial function in photoreceptors by limiting MAM formation and thereby attenuating mitochondrial calcium overload under hypoxia. Our results suggest that IP3R2-MAM-mediated mitochondrial calcium overload plays a critical role in mitochondrial dyshomeostasis, ultimately contributing to photoreceptor cell death. Targeting MAM constitutive proteins might provide an option for a therapeutic approach to mitigate photoreceptor death in retinal detachment.

Pleural carbohydrate antigen 50 and malignant pleural effusion: a prospective, double-blind diagnostic accuracy test.

Background: Serum carbohydrate antigen 50 (CA50) is an auxiliary diagnostic marker for various solid tumors, but it remains unclear whether CA50 in pleural fluid can assist in the diagnosis of malignant pleural effusion (MPE). This study aimed to evaluate the diagnostic accuracy of pleural fluid CA50 for MPE in pleural effusion patients with undetermined causes. Methods: This study prospectively recruited pleural effusion patients with undetermined causes who visited the Affiliated Hospital of Inner Mongolia Medical University between September 2018 and July 2021. We measured pleural fluid CA50 level with an electrochemiluminescence assay. We analyzed the diagnostic accuracy of CA50 and carcinoembryonic antigen (CEA) for MPE with the receiver operating characteristic (ROC) curve. The net benefits of CA50 and CEA were analyzed using the decision curve analysis (DCA). Results: We enrolled 66 MPEs and 87 benign pleural effusions (BPEs). MPE patients had significantly higher CA50 and CEA than BPE patients. The area under the ROC curve (AUC) of CA50 was 0.72 (95% CI: 0.63-0.80). CA50 had a sensitivity of 0.30 (95% CI: 0.19-0.41) and a specificity of 1.00 (95% CI: 1.00-1.00) at the threshold of 15 IU/mL. The decision curve of CA50 was above the reference line at the calculated risk probability of between 0.30 and 1.00. Venn diagram indicated that some patients with low CEA (<50 or <150 ng/mL) and/or negative cytology can be identified by positive CA50 (>15 IU/mL). Conclusions: Pleural fluid CA50 has moderate accuracy and net benefit for detecting MPE. CA50 >15 IU/mL can be used to diagnose MPE. The combination of CA50 and CEA improves the diagnostic sensitivity for MPE.

Immunotherapy plus chemotherapy in patients with advanced endometrial cancer: a cost-effectiveness analysis.

OBJECTIVE: Pembrolizumab and dostarlimab are immune checkpoint inhibitors that target programmed death receptor 1 (PD-1). Combination anti-PD-1 regimens have been shown to exhibit favorable survival benefits when treating advanced endometrial cancer (EC). Which treatment was preferable will need to be confirmed by a cost-effectiveness comparison between them. METHODS: Based on patient and clinical parameters from RUBY and NRG-GY018 phase III randomized controlled trials, the Markov model with a 20-year time horizon was established to evaluate the cost-effectiveness of dostarlimab plus chemotherapy (DC), pembrolizumab plus chemotherapy (PC), and chemotherapy alone (C) treatment for patients with mismatch repair-proficient microsatellite-stable (pMMR-MSS) and mismatch repair-deficient microsatellite instability-high (dMMR-MSI-H) advanced EC from the American payers' perspective. The main results include total cost, life-years (LYs), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) at a $150,000/QALY of willingness-to-pay. RESULTS: In the pMMR-MSS population, DC, PC, and C produced costs (QALYs) of $99,205 (3.02), $322,530 (3.25), and $421,923 (4.40), resulting in corresponding ICERs of $974,177/QALY (PC vs. C), $234,527/QALY (DC vs. C), $86,671/QALY (DC vs. PC), respectively; In the dMMR-MSI-H population, DC, PC, and C obtained costs (QALYs) of $120,177 (5.73), $691,399 (8.43), and $708,787 (11.26), yielding ICERs of $266,423/QALY (PC vs. C), $135,165/QALY (DC vs. C), $7,866/QALY (DC vs. PC), respectively. CONCLUSION: In the US, DC was a more cost-effective treatment than PC for patients with advanced EC irrespective of MMR status. However, compared to C, DC was associated with more cost-effectiveness in the dMMR-MSI-H population.

Analysis of gastric electrical rhythm in patients with type 2 diabetes mellitus.

AIM: To analysis the change of electrogastrogram (EGG) in patients with type 2 diabetes mellitus (T2DM), and evaluate the prevalence of abnormal gastric electrical rhythm (AGER) and its relative influencing factors. METHODS: A total of 65 patients with T2DM hospitalized at the Second Affiliated Hospital of Soochow University from Dec. 2020 to Dec. 2021 were included in the cross-sectional study. General information, clinical data, and medical history data of all study subjects, including name, gender, body mass index (BMI), duration of diabetes, anti-diabetic therapies, high blood pressure (HBP) history, smoking history, and medication history, were completely collected. The results of laboratory tests, including biochemical parameters, glycosylated hemoglobin (HbA1c), fasting C-peptide, 2 h postprandial C-peptide, 24 h urine total protein (24 hUTP), urine microalbumin creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were recorded. EGG, Gastroparesis Cardinal Symptom Index (GCSI), gastric emptying ultrasound, fundus examination, carotid artery ultrasonography, cardiac autonomic function test, heart rate variability (HRV) were all examined and recorded as well. According to the results of EGG, the subjects were divided into normal gastric electrical rhythm (NGER) group and abnormal gastric electrical rhythm (AGER) group. RESULTS: (1) Fasting blood glucose (FBG), HbA1c, the presence of diabetic peripheral neuropathy (DPN) and diabetic cardiac autonomic neuropathy (DCAN) were significantly higher in the AGER group (p < 0.05). Low frequency (LF) and high frequency (HF), the indicators of HRV, were significantly lower in the AGER group (p < 0.05). In addition, the prevalence of feeling excessively full after meals, loss of appetite, and stomach or belly visibly larger after meals of gastrointestinal symptoms of gastroparesis were significantly higher in the AGER group (p < 0.05). Multiple logistic regression analysis showed that FBG and the prevalence of DCAN were the independent risk factors. CONCLUSION: AGER was associated with high FBG and the presence of DCAN. EGG examination is recommended for patients with gastrointestinal symptoms and clues of DCAN.

A many-body energy decomposition analysis (MB-EDA) scheme based on a target state optimization self-consistent field (TSO-SCF) method.

In this paper, we combine an energy decomposition analysis (EDA) scheme with many-body expansion (MBE) to develop a MB-EDA method to study the cooperative and anti-cooperative effects in molecular cluster systems. Based on the target state optimization self-consistent field (TSO-SCF) method, the intermolecular interaction energy can be decomposed into five chemically meaningful terms, i.e., electrostatic, exchange, polarization, charge transfer and dispersion interaction energies. MB-EDA can decompose each of these terms in MBE. This MB-EDA has been applied to 3 different cluster systems: water clusters, ionic liquid clusters, and acetonitrile-methane clusters. This reveals that electrostatic, exchange, and dispersion interactions are highly pairwise additive in all systems. In water and ionic liquid clusters, the many-body effects are significant in both polarization and charge transfer interactions, but are cooperative and anti-cooperative, respectively. For acetonitrile-methane clusters, which do not involve hydrogen bonds or charge-charge Coulombic interactions, the many-body effects are quite small. The chemical origins of different many-body effects are deeply analyzed. The MB-EDA method has been implemented in Qbics (https://qbics.info) and can be a useful tool for understanding the many-body behavior in molecular aggregates at the quantum chemical level of theory.

AQP1 Deficiency Drives Phthalate-Induced Epithelial Barrier Disruption through Intestinal Inflammation.

Di-2-ethylhexyl phthalate (DEHP) is frequently used as a plasticizer to enhance the plasticity and durability of agricultural products, which pose adverse effects to human health and the environment. Aquaporin 1 (AQP1) is a main water transport channel protein and is involved in the maintenance of intestinal integrity. However, the impact of DEHP exposure on gut health and its potential mechanisms remain elusive. Here, we determined that DEHP exposure induced a compromised duodenum structure, which was concomitant with mitochondrial structural injury of epithelial cells. Importantly, DEHP exposure caused duodenum inflammatory epithelial cell damage and strong inflammatory response accompanied by activating the TLR4/MyD88/NF-κB signaling pathway. Mechanistically, DEHP exposure directly inhibits the expression of AQP1 and thus leads to an inflammatory response, ultimately disrupting duodenum integrity and barrier function. Collectively, our findings uncover the role of AQP1 in phthalate-induced intestinal disorders, and AQP1 could be a promising therapeutic approach for treating patients with intestinal disorders or inflammatory diseases.