Long-term intermittent oral administration of selective COX-2 inhibitor improved the clinical outcomes of COVID-19 in patients with cirrhosis.

OBJECTIVES: Patients with cirrhosis are more susceptible to coronavirus disease 2019 (COVID-19) due to immune dysfunction. In this retrospective study we aimed to investigate whether suppression of mild systemic inflammation with selective cyclooxygenase-2 inhibitor (COX-2-I) during chronic care of cirrhotic patients would reduce the occurrence of acute decompensated events and improve patient prognosis of COVID-19. METHODS: Medical records of cirrhotic patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were sequentially reviewed. The patients were divided into the COX-2-I and control groups depending on whether they took oral selective COX-2-I for over 3 months or not. The primary outcomes included the occurrence of severe/critical COVID-19, acute decompensated events, and acute-on-chronic liver failure (ACLF). RESULTS: After propensity score matching analysis, there were 314 cases in the control group and 118 cases in the COX-2-I group. Compared with the control group, the risk of severe/critical COVID-19 in the COX-2-I group was significantly decreased by 83.1% (p = 0.004). Acute decompensated events and ACLF occurred in 23 (7.32%) and nine (2.87%) cases in the control group, but none in the COX-2-I group (p = 0.003 and 0.122). The rate of hospitalization in the COX-2-I group was significantly lower than that of the control group (3.39% vs 13.06%, p = 0.003). No patient in the COX-2-I group required intensive care unit admission. CONCLUSIONS: Long-term intermittent oral administration of selective COX-2-I in cirrhotic patients significantly reduces the occurrence of severe/critical COVID-19, acute decompensated events, and ACLF. It may also be used for systemic inflammation caused by other pathogens.

Clinical Analysis of Inhaled Nitric Oxide Therapy in Preterm Infants at Different Gestational Ages: A National Retrospective Multicenter Study.

OBJECTIVE: This study aimed to investigate clinical features of inhaled nitric oxide (iNO) in preterm infants with a gestational age (GA) < 34 weeks in China. STUDY DESIGN: The clinical data of 434 preterm infants with GA < 34 weeks, treated with iNO in the neonatology departments of eight Class A tertiary hospitals in China over a 10-year period from January 2013 to December 2022, were included in this retrospective multicenter investigation. The infants were divided into three groups based on GA: 24 to 27 weeks (extremely preterm infants), 28 to 31 weeks (very preterm infants), and 32 to 33 weeks (moderate preterm infants). The use of iNO, perinatal data, incidence and mortality of indication for iNO treatment, therapeutic effects of iNO, incidence of short-term complications for iNO treatment, and mortality were compared among these three groups. RESULTS: Over the past 10 years, the proportion of iNO use was highest in extremely preterm infants each year. The lower the GA, the higher the iNO use rate: 4.20% for GA 24 to 27 weeks, 1.54% for GA 28 to 31 weeks, and 0.85% for GA 32 to 33 weeks. There was no significant difference in the therapeutic effect of iNO among the three groups. The incidence of neonatal pulmonary hemorrhage, neonatal shock, late-onset diseases, retinopathy of prematurity requiring intervention, intracranial hemorrhage (grade 3 or 4), periventricular leukomalacia, neonatal necrotizing enterocolitis (≥stage II), and moderate to severe bronchopulmonary dysplasia was highest in extremely preterm infants and increased with decreasing GA. Mortality was negatively correlated with GA and birth weight. The highest rate of iNO treatment in 24 to 27 weeks' preterm infants was due to hypoxic respiratory failure (HRF), whereas the highest rate of iNO treatment in 32 to 33 weeks' preterm infants was due to documented persistent pulmonary hypertension of the newborn (PPHN). The rates of iNO treatment due to HRF and documented PPHN were 54.3 and 60.6%, respectively, in extremely preterm infants, significantly higher than in very preterm and moderate preterm infants (all p < 0.05). Within the same GA group, the proportion of preterm infants treated with iNO for HRF was lower than that for documented PPHN (all p < 0.05), but there was no statistically significant difference in mortality between HRF and documented PPHN treated with iNO (all p > 0.05). CONCLUSION: Among preterm infants with GA < 34 weeks, the rate of iNO usage was highest in extremely preterm infants. However, iNO failed to improve the clinical outcome of extremely preterm infants with refractory hypoxemia, and there was no significant difference in the therapeutic effect of iNO among preterm infants with different GAs.

Autophagy and the pancreas: Healthy and disease states.

Macroautophagy/autophagy is an intracellular degradation pathway that has an important effect on both healthy and diseased pancreases. It protects the structure and function of the pancreas by maintaining organelle homeostasis and removing damaged organelles. A variety of pancreas-related diseases, such as diabetes, pancreatitis, and pancreatic cancer, are closely associated with autophagy. Genetic studies that address autophagy confirm this view. Loss of autophagy homeostasis (lack or overactivation) can lead to a series of adverse reactions, such as oxidative accumulation, increased inflammation, and cell death. There is growing evidence that stimulating or inhibiting autophagy is a potential therapeutic strategy for various pancreatic diseases. In this review, we discuss the multiple roles of autophagy in physiological and pathological conditions of the pancreas, including its role as a protective or pathogenic factor.

Estimation of transpulmonary driving pressure using a lower assist maneuver (LAM) during synchronized ventilation in patients with acute respiratory failure: a physiological study.

BACKGROUND: We previously showed in animals that transpulmonary driving pressure (PL) can be estimated during Neurally Adjusted Ventilatory Assist (NAVA) and Neural Pressure Support (NPS) using a single lower assist maneuver (LAM). The aim of this study was to test the LAM-based estimate of PL (PL_LAM) in patients with acute respiratory failure. METHODS: This was a prospective, physiological, and interventional study in intubated patients with acute respiratory failure. During both NAVA and simulated NPS (high and low levels of assist), a LAM was performed every 3 min by manually reducing the assist to zero for one single breath (by default, ventilator still provides 2 cmH2O). Following NAVA and NPSSIM periods, patients were sedated and passively ventilated in volume control and pressure control ventilation, to obtain PL during controlled mechanical ventilation (PL_CMV). PL using an esophageal balloon (PL_Pes) was also compared to PL_LAM and PL_CMV. We measured diaphragm electrical activity (Edi), ventilator pressure (PVent), esophageal pressure (Pes) and tidal volume. PL_LAM and PL_Pes were compared to themselves, and to PL_CMV for matching flows and volumes. RESULTS: Ten patients were included in the study. For the group, PL_LAM was closely similar to PL_CMV, with a high correlation (R2 = 0.88). Bland-Altman analysis revealed a low Bias of 0.28 cmH2O, and 1.96SD of 5.26 cmH2O. PL_LAM vs PL_Pes were also tightly related (R2 = 0.77). CONCLUSION: This physiological study in patients confirms our previous pre-clinical data that PL_LAM is as good an estimate as PL_Pes to determine PL, in spontaneously breathing patients on assisted mechanical ventilation. Trial registration The study was registered at clinicaltrials.gov (ID NCT05378802) on November 6, 2021.

[Retracted] SRC­like adaptor protein negatively regulates Wnt signaling in intrahepatic cholangiocarcinoma.

[This retracts the article DOI: 10.3892/ol.2019.9901.].

Hypothalamus-sympathetic-liver axis mediates the early phase of stress-induced hyperglycemia in the male mice.

Rapid glucose supply is crucial for animal survival during stress response. How the timescale of stress-induced glucose release precisely controlled by hypothalamic corticotropin-releasing hormone (CRH) neurons remains unclear. Here, we show that stress-induced hyperglycemia can be divided into at least two stages in male mice: the first fast stage is mediated by hypothalamus (paraventricular to ventromedial hypothalamus)-sympathetic (raphe pallidus nucleus to intermediolateral nucleus)-liver (HSL) axis activity; the second delayed stage is mediated by adrenal activity. Blocking the activity of HSL axis impairs predatory evoked flight responses, indicating that the HSL pathway activity is necessary for stress coping. We further reveal the intracellular signal cascade for CRH signal in the hypothalamus, which is mediated by GABAA receptor ß3 subunit phosphorylation at S408/409, results in prevention of GABAA receptor membrane recruitment. Thus, we uncovered the precise timescale of glucose supply during stress which is mediated by adrenal independent HSL and adrenal dependent pathway respectively.

Exploring the anticancer mechanism of cardiac glycosides using proteome integral solubility alteration approach.

BACKGROUND AND AIMS: Cardiac glycosides (CGs), traditionally used for heart failure, have shown potential as anti-cancer agents. This study aims to explore their multifaceted mechanisms in cancer cell biology using proteome integral solubility alteration (PISA), focusing on the interaction with key proteins implicated in cellular metabolism and mitochondrial function. METHODS: We conducted lysate-based and intact-cell PISA assays on cancer cells treated with CGs (Digoxin, Digitoxin, Ouabain) to analyze protein solubility changes. This was followed by mass spectrometric analysis and bioinformatics to identify differentially soluble proteins (DSPs). Molecular docking simulations were performed to predict protein-CG interactions. Public data including gene expression changes upon CG treatment were re-analyzed for validation. RESULTS: The PISA assays revealed CGs' broad-spectrum interactions, particularly affecting proteins like PKM2, ANXA2, SLC16A1, GOT2 and GLUD1. Molecular docking confirmed stable interactions between CGs and these DSPs. Re-analysis of public data supported the impact of CGs on cancer metabolism and cell signaling pathways. CONCLUSION: Our findings suggest that CGs could be repurposed for cancer therapy by modulating cellular processes. The PISA data provide insights into the polypharmacological effects of CGs, warranting further exploration of their mechanisms and clinical potential.

Overcoming Biopotency Barriers: Advanced Oral Delivery Strategies for Enhancing the Efficacy of Bioactive Food Ingredients.

Bioactive food ingredients contribute to the promotion and maintenance of human health and wellbeing. However, these functional ingredients often exhibit low biopotency after food processing or gastrointestinal transit. Well-designed oral delivery systems can increase the ability of bioactive food ingredients to resist harsh environments inside and outside the human body, as well as allow for controlled or triggered release of bioactives to specific sites in the gastrointestinal tract or other tissues and organs. This review presents the characteristics of common bioactive food ingredients and then highlights the barriers to their biopotency. It also discusses various oral delivery strategies and carrier types that can be used to overcome these biopotency barriers, with a focus on recent advances in the field. Additionally, the advantages and disadvantages of different delivery strategies are highlighted. Finally, the current challenges facing the development of food-grade oral delivery systems are addressed, and areas where future research can lead to new advances and industrial applications of these systems are proposed.

Development and validation of machine learning-based prediction model for severe pneumonia: A multicenter cohort study.

Severe pneumonia (SP) is a prevalent respiratory ailment characterized by high mortality and poor prognosis. Current scoring systems for pneumonia are not only time-consuming but also exhibit limitations in early SP prediction. To address this gap, this study aimed to develop a machine-learning model using inflammatory markers from peripheral blood for early prediction of SP. A total of 204 pneumonia patients from seven medical centers were studied, with 143 (68 SP cases) in the training cohort and 61 (32 SP cases) in the test cohort. Clinical characteristics and laboratory test results were collected at diagnosis. Various models including Logistic Regression, Random Forest, Naïve Bayes, XGBoost, Support Vector Machine, and Decision Tree were built and evaluated. Seven predictors-age, sex, WBC count, T-lymphocyte count, NLR, CRP, TNF-α, IL-4/IFN-γ ratio, IL-6/IL-10 ratio-were selected through LASSO regression and clinical insight. The XGBoost model, exhibiting best performance, achieved an AUC of 0.901 (95 % CI: 0.827 to 0.985) in the test cohort, with an accuracy of 0.803, sensitivity of 0.844, specificity of 0.759, and F1_score of 0.818. Indeed, SHAP analysis emphasized the significance of elevated WBC counts, older age, and elevated CRP as the top predictors. The use of inflammatory biomarkers in this concise predictive model shows significant potential for the rapid assessment of SP risk, thereby facilitating timely preventive interventions.

[Application effect and influencing factors of early awake prone position in patients with mild-to-moderate acute respiratory distress syndrome].

OBJECTIVE: To investigate the application effect of early awake prone position in mild-to-moderate acute respiratory distress syndrome (ARDS) patients, and analyze the related factors affecting the prone position outcome. METHODS: A prospective cohort study was conducted. The mild-to-moderate ARDS patients admitted to the emergency department of Yingshang County People's Hospital from January 2020 to June 2023 were enrolled as the research subjects. According to the results of prone tolerance test, the patients were divided into awake prone position group and non-prone position group. All patients were given high flow nasal cannula (HFNC) according to the standard procedures. The patients in the awake prone position group received prone position treatment within 12 hours after admission, in addition to the standard treatment. This could be performed in several times, at least once a day, and at least 2 hours each time. In order to prolong the prone position as much as possible, the patients were allowed to move or keep a small angle side prone. The changes of oxygenation index (PaO2/FiO2) at 0, 24, 48, and 72 hours after admission, the rate of intensive care unit (ICU) transfer, the use rate and use time of non-invasive ventilation (NIV), the total hospital stay, and the daily prone position time and 2-hour ROX index [ratio of pulse oxygen saturation/fraction of inspired oxygen (SpO2/FiO2) and respiratory rate (RR)] of prone position patients were recorded. The successful termination of HFNC was defined as the successful prone position, and the failure of prone position was defined as switching to NIV or transferring to ICU. Subgroup analysis was performed, and the binary multivariate Logistic regression analysis was used to screen the influencing factors of the early awake prone position outcome. RESULTS: A total of 107 patients were finally enrolled, with 61 in the awake prone position group and 46 in the non-prone position group. Both groups showed a gradual increase in PaO2/FiO2 with prolonged admission time. The PaO2/FiO2 at 24 hours after admission in the awake prone position group was significantly higher than that at 0 hour [mmHg (1 mmHg ≈ 0.133 kPa): 191.94±17.86 vs. 179.24±29.27, P < 0.05], while the difference in the non-prone position group was only statistically significant at 72 hours (mmHg: 198.24±17.99 vs. 181.24±16.62, P < 0.05). Furthermore, the PaO2/FiO2 at 48 hours and 72 hours after admission in the awake prone position group was significantly higher than that in the non-prone position group. The use rate of NIV in the awake prone position group was significantly lower than that in the non-prone position group [36.1% (22/61) vs. 56.5% (26/46), P < 0.05]; Kaplan-Meier curve analysis further confirmed that the patients in the awake prone position group used NIV later, and the cumulative rate of NIV usage was significantly lower than that in the non-prone position group (Log-Rank test: χ 2 = 5.402, P = 0.020). Compared with the non-prone position group, the ICU transfer rate in the awake prone position group was significantly lowered [11.5% (7/61) vs. 28.3% (13/46), P < 0.05], and the HFNC time, NIV time, and total hospital stay were significantly shortened [HFNC time (days): 5.71±1.45 vs. 7.24±3.36, NIV time (days): 3.27±1.28 vs. 4.40±1.47, total hospital stay (days): 11 (7, 13) vs. 14 (10, 19), all P < 0.05]. Of the 61 patients who underwent awake prone positioning, 39 were successful, and 22 failed. Compared with the successful group, the patients in the failure group had a higher body mass index [BMI (kg/m2): 26.61±4.70 vs. 22.91±5.50, P < 0.05], lower PaO2/FiO2, proportion of asymptomatic hypoxemia and 2-hour ROX index of prone position [PaO2/FiO2 (mmHg): 163.73±24.73 vs. 185.69±28.87, asymptomatic hypoxemia proportion: 18.2% (4/22) vs. 46.2% (18/39), 2-hour ROX index of prone position: 5.75±1.18 vs. 7.21±1.45, all P < 0.05], and shorter daily prone positioning time (hours: 5.87±2.85 vs. 8.05±1.99, P < 0.05). Binary multivariate Logistic regression analysis showed that all these factors were influencing factors for the outcome of awake prone positioning (all P < 0.05), among which BMI [odds ratio (OR) = 1.447, 95% confidence interval (95%CI) was 1.105-2.063] and non-asymptomatic hypoxemia (OR = 13.274, 95%CI was 1.548-117.390) were risk factors for failure of prone position, while PaO2/FiO2 (OR = 0.831, 95%CI was 0.770-0.907), daily prone positioning time (OR = 0.482, 95%CI was 0.236-0.924), and 2-hour ROX index of prone position (OR = 0.381, 95%CI was 0.169-0.861) were protective factors. CONCLUSIONS: Early awake prone positioning in patients with mild-to-moderate ARDS supported by HFNC is safe and feasible, reducing the use rate and duration of NIV, lowering the ICU transfer rate, and shortening the hospital stay. High BMI and non-asymptomatic hypoxemia are risk factors for failed prone position, while higher PaO2/FiO2 and the ROX index within 2 hours of prone position (the patient's good response to prone position), and prolonged daily prone position can improve the success rate of prone position.

SGLT-2 inhibitors and high-dose acarbose as potential high-risk combinations for ketosis and ketoacidosis in Asian patients with T2DM: A case series.

Key Clinical Message: High-dose acarbose may increase the risk of diabetic ketosis/diabetic ketoacidosis in Asian patients on sodium-glucose cotransporter-2 inhibitors. Healthcare providers and patients should be cautious to avoid this combination. Abstract: Low-calorie diets should be avoided in patients receiving sodium-glucose cotransporter-2 (SGLT-2) inhibitors to decrease the risk of diabetic ketoacidosis (DKA). High-dose acarbose can decelerate carbohydrate absorption. We detail three cases of diabetic ketosis (DK) following concurrent SGLT-2 inhibitor and high-dose acarbose therapy (acarbose 300 mg/day and dapagliflozin 10 mg/day). Patients, aged 38-63 years with 3-10 years of type 2 diabetes mellitus (T2DM), developed DK, indicated by moderate urinary ketones and high glucose (urine ketone 2+ to 3+ and glucose 3+ to 4+) without acidosis, within 4 days to 1 month post-therapy initiation. Serum glucose was 172.8-253.8 mg/dL; HbA1c was 9.97%-10.80%. The combination therapy was halted, and DK was managed with low-dose intravenous insulin and fluids, followed by intensive insulin therapy. High-dose acarbose with SGLT-2 inhibitors may increase the risk of DK/DKA in Asian patients.

Absorption and transport mechanism of colloidal nanoparticles (CNPs) in lamb soup based on Caco-2 cell.

Soup is an important presence in diet, but its absorption and transport mechanism by the human body remains unclear. In this study, Caco-2 intact cell and monolayer cell models were constructed to simulate small intestine absorption on colloidal nanoparticles (CNPs) isolated from lamb soup. The intracellular localization of CNPs was viewed by laser confocal microscopy (LSCM). CNPs uptake and release pathways were explored by differences in CNPs concentrations in 5 endocytosis inhibitor models and 4 exocytosis inhibitor models. Results indicated that CNPs endocytosis by Caco-2 cells was restrained by Nystatin and Cytochalasin D, with exocytosis being inhibited by Nocodazole and Monensin. Therefore, the major absorption pathways for CNPs were caveolin-dependent endocytosis, macropinocytosis and phagocytosis. The major transport pathways were microtubule-vesicle-mediated protein transport to the membrane and transportation between the Golgi apparatus and membrane. This study may provide theoretical support for the transport mechanism of soup products in the small intestine.

Nontarget analysis and characterization of p-phenylenediamine-quinones and -phenols in tire rubbers by LC-HRMS and chemical species-specific algorithm.

BACKGROUND: N,N'-disubstituted p-phenylenediamine-quinones (PPDQs) are oxidization derivatives of p-phenylenediamines (PPDs) and have raised extensive concerns recently, due to their toxicities and prevalence in the environment, particularly in water environment. PPDQs are derived from tire rubbers, in which other PPD oxidization products besides reported PPDQs may also exist, e.g., unknown PPDQs and PPD-phenols (PPDPs). RESULTS: This study implemented nontarget analysis and profiling for PPDQ/Ps in aged tire rubbers using liquid chromatography-high-resolution mass spectrometry and a species-specific algorithm. The algorithm took into account the ionization behaviors of PPDQ/Ps in both positive and negative electrospray ionization, and their specific carbon isotopologue distributions. A total of 47 formulas of PPDQ/Ps were found and elucidated with tentative or accurate structures, including 25 PPDQs, 18 PPDPs and 4 PPD-hydroxy-quinones (PPDHQs). The semiquantified total concentrations of PPDQ/Ps were 14.08-30.62 µg/g, and the concentrations followed the order as: PPDPs (6.48-17.39) > PPDQs (5.86-12.14) > PPDHQs (0.16-1.35 µg/g). SIGNIFICANCE: The high concentrations and potential toxicities indicate that these PPDQ/Ps could seriously threaten the eco-environment, as they may finally enter the environment, accordingly requiring further investigation. The analysis strategy and data-processing algorithm can be extended to nontarget analysis for other zwitterionic pollutants, and the analysis results provide new understandings on the environmental occurrence of PPDQ/Ps from source and overall perspectives.

Effect of fatty acid composition on the volatile compounds of pasteurized milk during low-temperature storage.

The change in milk fat during storage greatly influences its flavor. This study investigates the effect of fatty acid composition on milk flavor by analyzing volatile compounds in pasteurized whole milk (PWM) and pasteurized skim milk (PSM) during storage at 4 °C. 33 types of volatile compounds were detected and the content of ketones was highest, followed by esters and aldehydes. Based on variable importance in projection and relative odor activity value, 2-hexenal dimer, acetic acid ethyl ester dimer, acetic acid ethyl ester, and butanal were identified as the key differential volatile compounds. These compounds were found in higher concentrations in PWM than in PSM, indicating a close relationship with the changes in the fatty acid composition of milk fat. Among 11 fatty acids detected in PWM, the content of saturated fatty acids (SFA) and polyunsaturated fatty acids (PUFA) decreased by 0.69 % and 49.1 %, respectively, while the content of monounsaturated fatty acids increased by 46.8 % during 15 days storage, which suggests that the oxidation of SFA and PUFA contributed more to the volatile compound formation. Correlation analysis between fatty acid composition and volatile compounds found that fatty acid C18:2 and C16:0 were strongly associated for 2-hexenal, acetic acid ethyl ester, and butanal. These fatty acids were mainly derived from neutral lipids or phospholipids. These findings provide a new perspective for the formation pathway of milk flavor.

Molecular Characterization of Odorant-Binding Protein Genes Associated with Host-Seeking Behavior in Oides leucomelaena.

The identification of odorant-binding proteins (OBPs) involved in host location by Oides leucomelaena (O. leucomelaena Weise, 1922, Coleoptera, Galerucinae) is significant for its biological control. Tools in the NCBI database were used to compare and analyze the transcriptome sequences of O. leucomelaena with OBP and other chemosensory-related proteins of other Coleoptera insects. Subsequently, MEGA7 was utilized for OBP sequence alignment and the construction of a phylogenetic tree, combined with expression profiling to screen for candidate antennae-specific OBPs. In addition, fumigation experiments with star anise volatiles were conducted to assess the antennae specificity of the candidate OBPs. Finally, molecular docking was employed to speculate on the binding potential of antennae-specific OBPs with star anise volatiles. The study identified 42 candidate OBPs, 8 chemosensory proteins and 27 receptors. OleuOBP3, OleuOBP5, and OleuOBP6 were identified as classic OBP family members specific to the antennae, which was confirmed by volatile fumigation experiments. Molecular docking ultimately clarified that OleuOBP3, OleuOBP5, and OleuOBP6 all exhibit a high affinity for ß-caryophyllene among the star anise volatiles. We successfully obtained three antennae-specific OBPs from O. leucomelaena and determined their high-affinity volatiles, providing a theoretical basis for the development of attractants in subsequent stages.

Targeting cell death mechanisms: the potential of autophagy and ferroptosis in hepatocellular carcinoma therapy.

Ferroptosis is a type of cell death that plays a remarkable role in the growth and advancement of malignancies including hepatocellular carcinoma (HCC). Non-coding RNAs (ncRNAs) have a considerable impact on HCC by functioning as either oncogenes or suppressors. Recent research has demonstrated that non-coding RNAs (ncRNAs) have the ability to control ferroptosis in HCC cells, hence impacting the advancement of tumors and the resistance of these cells to drugs. Autophagy is a mechanism that is conserved throughout evolution and plays a role in maintaining balance in the body under normal settings. Nevertheless, the occurrence of dysregulation of autophagy is evident in the progression of various human disorders, specifically cancer. Autophagy plays dual roles in cancer, potentially influencing both cell survival and cell death. HCC is a prevalent kind of liver cancer, and genetic mutations and changes in molecular pathways might worsen its advancement. The role of autophagy in HCC is a subject of debate, as it has the capacity to both repress and promote tumor growth. Autophagy activation can impact apoptosis, control proliferation and glucose metabolism, and facilitate tumor spread through EMT. Inhibiting autophagy can hinder the growth and spread of HCC and enhance the ability of tumor cells to respond to treatment. Autophagy in HCC is regulated by several signaling pathways, such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs. Utilizing anticancer drugs to target autophagy may have advantageous implications for the efficacy of cancer treatment.

The association between overweight and varying degrees of obesity with subjective well-being and depressive symptoms: A two sample Mendelian randomization study.

OBJECTIVE: This study utilized the Mendelian randomization (MR) method to elucidate the causal relationship between genetically predicted overweight and various degrees of obesity with depressive symptoms and subjective well-being (SWB). METHODS: Pooled genome-wide association studies (GWAS) data for overweight (BMI ≥ 25 kg/m2), class 1 obesity (BMI ≥ 30 kg/m2), and class 2 obesity (BMI ≥ 35 kg/m2) were used as exposures. Summary GWAS data for depressive symptoms and SWB were used as outcomes. Multiple MR methods, primarily inverse-variance weighted (IVW), were applied, and sensitivity analyses were conducted to assess heterogeneity and pleiotropy. RESULTS: The MR analysis provided evidence that genetically predicted overweight(IVW ß = 0.033; 95 %CI 0.008-0.057; P = 0.010) and class 1 obesity(IVW ß = -0.033; 95 %CI -0.047 - -0.020; P < 0.001) were causally associated with increased depressive symptoms. Genetically predicted class 2 obesity(IVW ß = 1.428; 95 %CI 1.193-1.710; P < 0.001) were associated with reduced SWB. There was no strong evidence of a causal association between genetically predicted overweight and class 1 obesity with SWB. Similarly, genetically predicted class 2 and class 3 obesity did not show strong evidence of a causal association with depressive symptoms. Sensitivity analysis revealed relationships of a similar magnitude. CONCLUSION: This genetically informed MR study suggests that Overweight and class 1 obesity may causally increased depressive symptoms but not decrease SWB. In contrast, class 2 obesity may causally decrease SWB but not increase depressive symptoms.

Versatility of threose nucleic acids: synthesis, properties, and applications in chemical biology and biomedical advancements.

This feature article delves into the realm of α-L-threose nucleic acid (TNA), an artificial nucleic acid analog characterized by a backbone comprising an unconventional four-carbon sugar, α-L-threose, with phosphodiester linkages connecting at the 2' and 3' vicinal positions of the sugar ring. Within this article, we encapsulate the potential, progress, current state of the art, and persisting challenges within TNA research. Kicking off with a historical overview of xeno nucleic acids (XNAs), the discussion transitions to the compelling attributes and structure-property relationships of TNAs as advanced tools when contrasted with natural nucleic acids. Noteworthy aspects such as their advantageous spatial arrangements of functional groups around the sugar ring, stable Watson-Crick base pairing, high binding affinity, biostability, biocompatibility, and in vivo bio-safety are highlighted. Moreover, the narrative unfolds the latest advancements in chemical and biological methodologies for TNA synthesis, spanning from monomer and oligomer synthesis to polymerization, alongside cutting-edge developments in enzyme engineering aimed at bolstering large-scale TNA synthesis for in vitro selection initiatives. The article sheds light on the evolution of TNA aptamers over time, expounding on the tools and selection techniques engineered to unearth superior binding aptamers and TNA catalysts. Furthermore, the article accentuates the recent applications of TNAs across diverse domains such as molecular detection, immunotherapy, gene therapy, synthetic biology, and molecular computing. In conclusion, we summarize the key aspects of recent TNA research, address persisting gaps and challenges, and provide crucial insights and future perspectives in the dynamic domain of TNA research.

Stepwise de novo establishment of inactive X chromosome architecture in early development.

X chromosome inactivation triggers a dramatic reprogramming of transcription and chromosome architecture. However, how the chromatin organization of inactive X chromosome is established de novo in vivo remains elusive. Here, we identified an Xist-separated megadomain structure (X-megadomains) on the inactive X chromosome in mouse extraembryonic lineages and extraembryonic endoderm (XEN) cell lines, and transiently in the embryonic lineages, before Dxz4-delineated megadomain formation at later stages in a strain-specific manner. X-megadomain boundary coincides with strong enhancer activities and cohesin binding in an Xist regulatory region required for proper Xist activation in early embryos. Xist regulatory region disruption or cohesin degradation impaired X-megadomains in extraembryonic endoderm cells and caused ectopic activation of regulatory elements and genes near Xist, indicating that cohesin loading at regulatory elements promotes X-megadomains and confines local gene activities. These data reveal stepwise X chromosome folding and transcriptional regulation to achieve both essential gene activation and global silencing during the early stages of X chromosome inactivation.

A nationwide survey on the management of neonatal respiratory distress syndrome: insights from the MUNICH survey in 394 Chinese hospitals.

BACKGROUND: At present, preterm infants with respiratory distress syndrome (RDS) in China present higher mortality and morbidity rates than those in high-income countries. The aim of this nationwide survey was to assess the clinical management of RDS in China. METHODS: A nationwide cross-sectional survey to assess adherence to RDS management recommendations was performed. One neonatologist per hospital was randomly selected. The primary outcome was the key care of RDS management. RESULTS: Among the 394 participating hospitals, 88·3% were birthing centres. The number of doctors and nurses per bed were 0·27 and 0·72, respectively. Antenatal corticosteroids (any dose) were administered to 90% of the women at risk of preterm birth at < 34 weeks of gestation (90·0% inborn vs. 50·0% outborn, p < 0·001). The median fraction of inspired oxygen (FiO2) for initial resuscitation was 0·30 for babies born at ≤ 32 weeks of gestation and 0·25 for those born at > 32 weeks. T-piece resuscitators were available in 77·8% of delivery rooms (DRs) (tertiary hospitals: 82·5% vs. secondary hospitals: 63·0%, p < 0·001). Surfactant was used in 51·6% of the DRs. Less invasive surfactant administration (LISA) was used in 49·7% of the hospitals (tertiary hospitals: 55·3% vs. secondary hospitals: 31·5%, p < 0·001). Primary non-invasive ventilation was initiated in approximately 80·0% of the patients. High-frequency oscillation ventilation was primarily reserved for rescue after conventional mechanical ventilation (MV) failure. Caffeine was routinely used during MV in 59·1% of the hospitals. Bedside lung ultrasonography was performed in 54·3% of the health facilities (tertiary hospitals: 61·6% vs. secondary hospitals: 30·4%, p < 0·001). Qualified breast milk banks and Family Integrated Care (FICare) were present in 30·2% and 63·7% of the hospitals, respectively. CONCLUSIONS: Significant disparities in resource availability and guidelines adherence were evident across hospitals. Future strategies should address DR facilities and medication access, technical training, staff allocation, and ancillary facility development for a better management of RDS patients in China.