The RIPK1 death domain restrains ZBP1- and TRIF-mediated cell death and inflammation.

RIPK1 is a multi-functional kinase that regulates cell death and inflammation and has been implicated in the pathogenesis of inflammatory diseases. RIPK1 acts in a kinase-dependent and kinase-independent manner to promote or suppress apoptosis and necroptosis, but the underlying mechanisms remain poorly understood. Here, we show that a mutation (R588E) disrupting the RIPK1 death domain (DD) caused perinatal lethality induced by ZBP1-mediated necroptosis. Additionally, these mice developed postnatal inflammatory pathology, which was mediated by necroptosis-independent TNFR1, TRADD, and TRIF signaling, partially requiring RIPK3. Our biochemical mechanistic studies revealed that ZBP1- and TRIF-mediated activation of RIPK3 required RIPK1 kinase activity in wild-type cells but not in Ripk1R588E/R588E cells, suggesting that DD-dependent oligomerization of RIPK1 and its interaction with FADD determine the mechanisms of RIPK3 activation by ZBP1 and TRIF. Collectively, these findings revealed a critical physiological role of DD-dependent RIPK1 signaling that is important for the regulation of tissue homeostasis and inflammation.

[Preparation technology comparison and performance evaluation of different protein A affinity chromatographic materials].

Protein A affinity chromatographic materials are widely used in clinical medicine and biomedicine because of their specific interactions with immunoglobulin G (IgG). Both the characteristics of the matrix, such as its structure and morphology, and the surface modification method contribute to the affinity properties of the packing materials. The specific, orderly, and oriented immobilization of protein A can reduce its steric hindrance with the matrix and preserve its bioactive sites. In this study, four types of affinity chromatographic materials were obtained using agarose and polyglycidyl methacrylate (PGMA) spheres as substrates, and multifunctional epoxy and maleimide groups were used to fix protein A. The effects of the ethylenediamine concentration, reaction pH, buffer concentration, and other conditions on the coupling efficiency of protein A and adsorption performance of IgG were evaluated. Multifunctional epoxy materials were prepared by converting part of the epoxy groups of the agarose and PGMA matrices into amino groups using 0.2 and 1.6 mol/L ethylenediamine, respectively. Protein A was coupled to the multifunctional epoxy materials using 5 mmol/L borate buffer (pH 8) as the reaction solution. When protein A was immobilized on the substrates by maleimide groups, the agarose and PGMA substrates were activated with 25% (v/v) ethylenediamine for 16 h to convert all epoxy groups into amino groups. The maleimide materials were then converted into amino-modified materials by adding 3 mg/mL 3-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS) dissolved in dimethyl sulfoxide (DMSO) and then suspended in 5 mmol/L borate buffer (pH 8). The maleimide groups reacted specifically with the C-terminal of the sulfhydryl group of recombinant protein A to achieve highly selective fixation on both the agarose and PGMA substrates. The adsorption performance of the affinity materials for IgG was improved by optimizing the bonding conditions of protein A, such as the matrix type, matrix particle size, and protein A content, and the adsorption properties of each affinity material for IgG were determined. The column pressure of the protein A affinity materials prepared using agarose or PGMA as the matrix via the maleimide method was subsequently evaluated at different flow rates. The affinity materials prepared with PGMA as the matrix exhibited superior mechanical strength compared with the materials prepared with agarose. Moreover, an excellent linear relationship between the flow rate and column pressure of 80 mL/min was observed for this affinity material. Subsequently, the effect of the particle size of the PGMA matrix on the binding capacity of IgG was investigated. Under the same protein A content, the dynamic binding capacity of the affinity materials on the PGMA matrix was higher when the particle size was 44-88 µm than when other particle sizes were used. The properties of the affinity materials prepared using the multifunctional epoxy and maleimide-modified materials were compared by synthesizing affinity materials with different protein A coupling amounts of 1, 2, 4, 6, 8, and 10 mg/mL. The dynamic and static binding capacities of each material for bovine IgG were then determined. The prepared affinity material was packed into a chromatographic column to purify IgG from bovine colostrum. Although all materials showed specific adsorption selectivity for IgG, the affinity material prepared by immobilizing protein A on the PGMA matrix with maleimide showed significantly better performance and achieved a higher dynamic binding capacity at a lower protein grafting amount. When the protein grafting amount was 15.71 mg/mL, the dynamic binding capacity of bovine IgG was 32.23 mg/mL, and the dynamic binding capacity of human IgG reached 54.41 mg/mL. After 160 cycles of alkali treatment, the dynamic binding capacity of the material reached 94.6% of the initial value, indicating its good stability. The developed method is appropriate for the production of protein A affinity chromatographic materials and shows great potential in the fields of protein immobilization and immunoadsorption material synthesis.

A memory access gate controlled by dynamic contexts.

Temporary difficulties in accessing the contents of memories are a common experience in everyday life, for example, when we try to recognize a known person in an unusual context. In addition, recent experiments seem to indicate that retrograde amnesia in the early stages of Alzheimer's disease is due to disorders in accessing memories that were installed normally. These facts suggest the existence of an intermediate step between the stimulus arrival and the associative recognition. In this work, a multimodular neurocomputational model is presented postulating the existence of a neural gate that controls the access of the stimulus with its context to the consolidated memory. If recognition is not achieved, a random search is initiated in a contextual network aroused by the initial context. The search continues until the appropriate context that allows for recognition is found or until the process is turned off because the initial stimulus is no longer maintained in the working memory. The model is based on vector patterns of neural activity and context-dependent matrix memories. Simple Markov chain simulations are presented to exemplify possible search scenarios in the contextual network. Finally, we discuss some of the characteristics of the model and the phenomenon under study.

Impact of Alcian blue and periodic acid Schiff expression on the prognosis of gastric signet ring cell carcinoma.

BACKGROUND: The Alcian blue (AB) and periodic acid Schiff (PAS) stains are representative mucus markers in gastric signet ring cell carcinoma (SRCC). They are low-cost special staining methods used to detect acidic mucus and neutral mucus, respectively. However, the clinical importance of the special combined AB and PAS stain is unclear. AIM: To investigate AB expression, PAS expression and the AB-to-PAS (A/P) ratio in gastric SRCC patients and to assess patient prognosis. METHODS: Paraffin-embedded sections from 83 patients with gastric SRCC were stained with AB and PAS, and signet ring cell positivity was assessed quantitatively. Immunohistochemical staining for Ki67, protein 53 (P53) and human epidermal growth factor receptor 2 (HER2) was performed simultaneously. The cancer-specific survival (CSS) rate was estimated via Kaplan-Meier analysis. Cox proportional hazards models were used for univariate and multivariate survival analyses. RESULTS: Kaplan-Meier survival analysis revealed that the 3-year CSS rate was significantly greater in the high-PAS-expression subgroup than in the low-PAS-expression subgroup (P < 0.001). The 3-year CSS rate in the A/P ≤ 0.5 group was significantly greater than that in the A/P > 0.5 group (P = 0.042). Univariate Cox regression analysis revealed that the factors affecting prognosis included tumor diameter, lymph node metastasis, vessel carcinoma embolus, tumor stage, the A/P ratio and the expression of Ki67, P53 and the PAS. Cox multivariate regression analysis confirmed that low PAS expression [hazard ratio (HR) = 3.809, 95% confidence interval (CI): 1.563-9.283, P = 0.003] and large tumor diameter (HR = 2.761, 95%CI: 1.086-7.020, P = 0.033) were independent risk factors for poor prognosis. CONCLUSION: A/P > 0.5 is potentially a risk factor for prognosis, and low PAS expression is an independent risk factor in the prognosis of gastric SRCC. PAS expression and the A/P ratio could help in predicting the clinical prognosis of patients with SRCC.

Real-world application of nirmatrelvir/ritonavir in hospitalized COVID-19 patients with onset of symptoms beyond 5 days: a comparative study.

PURPOSE: Physicians may administer Nirmatrelvir-ritonavir to patients who have been symptomatic for more than 5 days. There is currently no clear evidence to support this approach. METHODS: A real-world study was conducted to investigate the potential relationship between the administration of Nirmatrelvir-ritonavir and the rates of intubation or in-hospital mortality among COVID-19 patients who experienced symptoms for more than 5 days. The end point was a composite event of intubation or in-hospital mortality. The outcomes between those patients who received Nirmatrelvir-ritonavir and those who did not were compared. RESULTS: A total of 847 patients were included in the analysis. Among them, 312 patients (36.84%) received Nirmatrelvir-ritonavir. Within the entire population, 86 patients (10.15%) experienced intubation or in-hospital mortality. The main analysis indicated that there was a significant association between the application of Nirmatrelvir-ritonavir and intubation or in-hospital mortality, with an odds ratio of 0.50 (95% confidence interval, 0.28 to 0.87; P = 0.0153) using inverse probability of treatment weighting. The finding was consistent with multiple sensitivity analyses. CONCLUSIONS: The application of Nirmatrelvir-ritonavir was associated with a significantly reduced risk of intubation or death in hospitalized COVID-19 patients who experienced symptoms for more than 5 days as compared to those who did not receive the treatment.

In situ fabrication of covalent organic frameworks on solid-phase microextraction probes coupled with electrospray ionization mass spectrometry for enrichment and determination of androgens in biosamples.

Solid-phase microextraction (SPME) coupled with electrospray ionization mass spectrometry (ESI-MS) was developed for rapid and sensitive determination of endogenous androgens. The SPME probe is coated with covalent organic frameworks (COFs) synthesized by reacting 1,3,5-tri(4-aminophenyl)benzene (TPB) with 2,5-dioctyloxybenzaldehyde (C8PDA). This COFs-SPME probe offers several advantages, including enhanced extraction efficiency and stability. The analytical method exhibited wide linearity (0.1-100.0 µg L-1), low limits of detection (0.03-0.07 µg L-1), high enrichment factors (37-154), and satisfactory relative standard deviations (RSDs) for both within one probe (4.0-14.8%) and between different probes (3.4-12.7%). These remarkable performance characteristics highlight the reliability and precision of the COFs-SPME-ESI-MS method. The developed method was successfully applied to detect five kinds of endogenous androgens in female serum samples, indicating that the developed analytical method has great potential for application in preliminary clinical diagnosis.

Distinct fibroblast subpopulations associated with bone, brain or intrapulmonary metastasis in advanced non-small-cell lung cancer.

BACKGROUND: Bone or brain metastases may develop in 20-40% of individuals with late-stage non-small-cell lung cancer (NSCLC), resulting in a median overall survival of only 4-6 months. However, the primary lung cancer tissue's distinctions between bone, brain and intrapulmonary metastases of NSCLC at the single-cell level have not been underexplored. METHODS: We conducted a comprehensive analysis of 14 tissue biopsy samples obtained from treatment-naïve advanced NSCLC patients with bone (n = 4), brain (n = 6) or intrapulmonary (n = 4) metastasis using single-cell sequencing originating from the lungs. Following quality control and the removal of doublets, a total of 80 084 cells were successfully captured. RESULTS: The most significant inter-group differences were observed in the fraction and function of fibroblasts. We identified three distinct cancer-associated fibroblast (CAF) subpopulations: myofibroblastic CAF (myCAF), inflammatory CAF (iCAF) and antigen-presenting CAF (apCAF). Notably, apCAF was prevalent in NSCLC with bone metastasis, while iCAF dominated in NSCLC with brain metastasis. Intercellular signalling network analysis revealed that apCAF may play a role in bone metastasis by activating signalling pathways associated with cancer stemness, such as SPP1-CD44 and SPP1-PTGER4. Conversely, iCAF was found to promote brain metastasis by activating invasion and metastasis-related molecules, such as MET hepatocyte growth factor. Furthermore, the interaction between CAFs and tumour cells influenced T-cell exhaustion and signalling pathways within the tumour microenvironment. CONCLUSIONS: This study unveils the direct interplay between tumour cells and CAFs in NSCLC with bone or brain metastasis and identifies potential therapeutic targets for inhibiting metastasis by disrupting these critical cell-cell interactions.

Interactive effects and relative contribution of prepregnancy overweight and obesity, excessive gestational weight gain and gestational diabetes mellitus to macrosomia: A retrospective cohort in Fujian, China.

AIM: To conduct a retrospective cohort study to investigate the association between prepregnancy overweight and obesity, excessive gestational weight gain (GWG), gestational diabetes mellitus (GDM) and macrosomia, both individually and in combination. METHODS: Binary logistic regression was used to analyse the effects of overweight and obesity, excessive GWG and GDM on macrosomia, both separately and in combination. The interaction effects between prepregnancy overweight and obesity, excessive GWG and GDM were tested. The population attributable fraction (PAF) was calculated separately when interaction terms were significant. RESULTS: When analysed separately, prepregnancy overweight and obesity, excessive GWG and GDM increased the risk of macrosomia significantly. The pairwise interactions of each pair of risk factors or all three risk factors on macrosomia appear to be greater than any of them individually. Prepregnancy overweight and obesity contributed the least (5.69%) to macrosomia, while GDM contributed the most (8.5%). The PAF values for prepregnancy overweight and obesity/GDM, excessive GWG/GDM, and prepregnancy overweight and obesity/excessive GWG were 13.6%, 16.25% and 14.45%, respectively, and the total PAF for all three risk factors was 22.63%. CONCLUSIONS: Prepregnancy overweight and obesity, excessive GWG and GDM were associated with newborn macrosomia.

Gestational weight trajectory and risk of adverse pregnancy outcomes among women with gestational diabetes mellitus: A retrospective cohort study.

The aim of this study was to explore gestational weight gain (GWG) trajectories and their associations with adverse pregnancy outcomes. A retrospective cohort study including 11,064 women with gestational diabetes mellitus (GDM) was conducted between 2015 and 2019 in China. The latent class trajectory model was used to identify GWG trajectories, and logistic regression was performed to examine odds ratio (OR) of pregnancy outcomes. Three trajectories of GWG were identified in these 11,604 women with GDM. Trajectory 1: 64.02% of women had sustained moderate GWG throughout pregnancy; Trajectory 2: 17.75% of women showed a high initial GWG but followed by a low GWG from the third trimester until delivery; Trajectory 3: 18.23% had low initial GWG but followed by drastic GWG from the second trimester until delivery. Compared with pregnant women with Trajectory 1, women with Trajectory 2 had a higher risk of large for gestational age (adjusted odds ratio [AOR]: 1.29, 95% confidence interval [CI]: 1.12-1.48) but at a lower risk of having hypertensive disorders of pregnancy (AOR: 0.76, 95% CI: 0.57-0.96). Women in Trajectory 3 were more likely to develop small for gestational age (AOR: 2.12, 95% CI: 1.62-2.78), low birthweight (AOR: 1.49, 95% CI: 1.07-2.08), preterm birth (AOR: 1.28, 95% CI: 1.05-1.63), caesarean section (AOR: 1.26, 95% CI: 1.112-1.42) and hypertensive disorders of pregnancy (AOR: 2.24, 95% CI: 1.82-2.76). The association of GWG trajectory with adverse pregnancy outcomes differs across prepregnancy body mass index and GWG categories. Women with a slow initial GWG but followed by drastic GWG had higher risks of adverse pregnancy outcomes. Early clinical recognition of poor GWG trajectory will contribute to early intervention in high-risk groups to minimise adverse outcomes.

Transcriptomic and Metabolomic Analyses Reveal the Response Mechanism of Ophiopogon japonicus to Waterlogging Stress.

Ophiopogon japonicus, a plant that thrives in river alluvial dams, often faces waterlogging stress due to sustained rainfall and flood seasons, which significantly impacts its growth and development. Currently, the mechanisms of waterlogging tolerance in Ophiopogon japonicus are still unclear. This study analyzed the transcriptome and metabolome data for Ophiopogon japonicus in the Sichuan region (referred to as CMD) under varying degrees of waterlogging stress: mild, moderate, and severe. The results indicate that the group exposed to flooding stress exhibited a higher number of differentially expressed genes (DEGs) compared to the control group. Notably, most DEGs were downregulated and primarily enriched in phenylpropanoid biosynthesis, starch and sucrose metabolism, and plant hormone signal transduction pathways. A total of 5151 differentially accumulated metabolites (DAMs) were identified, with significantly upregulated DAMs annotated to two clusters, namely flavonoids such as apiin, pelargonin, and others. Furthermore, our study revealed significant upregulation in the expression of C2H2 (C2H2 zinc finger proteins) and AP2/ERF-ERF (the subfamily ERF proteins of APETALA2/ethylene-responsive element binding factors) transcription factors in CMD under flooding stress, suggesting their critical roles in enabling CMD to adapt to these conditions. In conclusion, this research provides insights into the intricate molecular mechanisms underlying CMD's response to flooding stress and reports valuable genetic data for the development of transgenic plants with improved waterlogging tolerance.

Effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus (COVID-19) vaccination on male fertility.

Coronavirus disease 2019, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains an ongoing global public health challenge. This disease causes damage not only to the respiratory system, affecting the normal physiological function of the lungs, but also to other vital organs, such as the heart and testicles. Existing studies have shown that co-expression of angiotensin-converting enzyme 2 and transmembrane serine protease 2 is the main mechanism by which SARS-CoV-2 invades host cells. Angiotensin-converting enzyme 2-expressing cells are widespread in the corpus cavernosum, reproductive tract and testis of men, which has raised concerns. Furthermore, abnormal sex hormone levels and decreased semen parameters were observed in coronavirus disease 2019 patients. This study comprehensively assessed the effects of SARS-CoV-2 infection on the testis, semen parameters, sex hormone levels and erectile function, and discussed possible transmission routes during sexual intercourse and the effect of vaccination on male fertility.

An artificial biocatalytic cascade for efficient synthesis of norepinephrine by combination of engineered L-threonine transaldolase with multi-enzyme expression fine-tuning.

Norepinephrine, a kind of ß-adrenergic receptor agonist, is commonly used for treating shocks and hypotension caused by a variety of symptoms. The development of a straightforward, efficient and environmentally friendly biocatalytic route for manufacturing norepinephrine remains a challenge. Here, we designed and realized an artificial biocatalytic cascade to access norepinephrine starting from 3, 4-dihydroxybenzaldehyde and L-threonine mediated by a tailored-made L-threonine transaldolase PsLTTA-Mu1 and a newly screened tyrosine decarboxylase ErTDC. To overcome the imbalance of multi-enzymes in a single cell, engineering of PsLTTA for improved activity and fine-tuning expression mode of multi-enzymes in single E.coli cells were combined, leading to a robust whole cell biocatalyst ES07 that could produce 100 mM norepinephrine with 99% conversion, delivering a highest time-space yield (3.38 g/L/h) ever reported. To summarized, the current study proposed an effective biocatalytic approach for the synthesis of norepinephrine from low-cost substrates, paving the way for industrial applications of enzymatic norepinephrine production.

EGFR Oncogenic Mutations in NSCLC Impair Macrophage Phagocytosis and Mediate Innate Immune Evasion Through Up-Regulation of CD47.

INTRODUCTION: EGFR-mutated NSCLC is characterized by an immunosuppressive microenvironment that confers limited clinical effectiveness to anti-PD-1 or PD-L1 antibodies. Despite the discouraging outcomes of immunotherapy, novel immune checkpoints are constantly emerging, among which the specific vulnerability for therapeutic intervention in the context of EGFR-mutated NSCLC remains unresolved. METHODS: Data sets of patient- and cell line-levels were used for screening and mutual validation of association between EGFR mutation and a panel of immune checkpoint-related genes. Regulatory mechanism was elucidated through in vitro manipulation of EGFR signaling pathway and evaluated by immunoblot analysis, quantitative polymerase chain reaction, flow cytometry, immunofluorescence staining, and chromatin immunoprecipitation. In vivo investigation of different therapeutic strategies were conducted using both immunocompetent and immunodeficient mouse models. RESULTS: Among all screened immune checkpoints, CD47 emerged as the candidate most relevant to EGFR activation. Mechanistically, EGFR mutation constitutively activated downstream ERK and AKT pathways to respectively up-regulate the transcriptional factors c-Myc and NF-κB, both of which structurally bound to the promotor region of CD47 and actively transcribed this "don't eat me" signal. Impaired macrophage phagocytosis was observed on introduction of EGFR-sensitizing mutations in NSCLC cell line models, whereas CD47 blockade restored the phagocytic capacity and augmented tumor cell killing in both in vitro and in vivo models. Remarkably, the combination of anti-CD47 antibody with EGFR tyrosine kinase inhibitor revealed an additive antitumor activity compared with monotherapy of either antitumor agent in both immunocompetent and adaptive immunity-deficient mouse models. CONCLUSIONS: EGFR-sensitizing mutation facilitates NSCLC's escape from innate immune attack through up-regulating CD47. Combination therapy incorporating CD47 blockade holds substantial promise for clinical translation in developing more effective therapeutic approaches against EGFR-mutant NSCLC.

Sirt6 promotes DNA damage repair in osteoarthritis chondrocytes by activating the Keap1/Nrf2/HO-1 signaling pathway.

The aim of this study was to explore the effect and mechanism of Sirt6 on DNA damage repair in OA chondrocytes. Cartilage tissues were collected from OA patients with knee arthroplasty and traumatic amputation patients without OA. Besides, 7-week-old male C57BL/6 mice were randomly divided into Control and OA groups; CHON-001 cells of corresponding groups were treated with 10 ng/ml interleukin (IL)-1ß, respectively. Subsequently, Sirt6 or siNrf2 was over-expressed in CHON-001 cells to observe the effect of Sirt6 on DNA damage and senescence of chondrocytes by IL-1ß through the nuclear factor E2-related factor 2 (Nrf2) signaling pathway. The expression level of Sirt6 in human and mouse OA cartilage tissues was significantly decreased. However, 24 h of treatment with IL-1ß significantly decreased the expression of Sirt6 in chondrocytes, induced DNA damage, and promoted cellular senescence. In addition, over-expression of Sirt6 promoted DNA damage repair and inhibited cellular senescence in IL-1ß-induced chondrocytes. Moreover, the overexpression of Sirt6 activated the Keap1/Nrf2/HO-1 signaling pathway in chondrocytes, while knockdown of Nrf2 expression inhibited the DNA damage repair and anti-senescence effects of Sirt6 on IL-1ß-treated chondrocytes. Sirt6 may reduce DNA damage and cellular senescence in OA chondrocytes induced by IL-1ß through activating the Keap1/Nrf2/HO-1 signaling pathway.

Collecting duct NCOR1 controls blood pressure by regulating mineralocorticoid receptor.

INTRODUCTION: Nuclear receptor corepressor 1(NCOR1) is reported to play crucial roles in cardiovascular diseases, but its function in the kidney has remained obscure. OBJECTIVE: We aim to elucidate the role of collecting duct NCOR1 in blood pressure (BP) regulation. METHODS AND RESULTS: Collecting duct NCOR1 knockout (KO) mice manifested increased BP and aggravated vascular and renal injury in an angiotensin II (Ang II)-induced hypertensive model. KO mice also showed significantly higher BP than littermate control (LC) mice in deoxycorticosterone acetate (DOCA)-salt model. Further study showed that collecting duct NCOR1 deficiency aggravated volume and sodium retention after saline challenge. Among the sodium transporter in the collecting duct, the expression of the three epithelial sodium channel (ENaC) subunits was markedly increased in the renal medulla of KO mice. Consistently, BP in Ang II-infused KO mice decreased significantly to the similar level as those in LC mice after amiloride treatment. ChIP analysis revealed that NCOR1 deficiency increased the enrichment of mineralocorticoid receptor (MR) on the promoters of the three ENaC genes in primary inner medulla collecting duct (IMCD) cells. Co-IP results showed interaction between NCOR1 and MR, and luciferase reporter results demonstrated that NCOR1 inhibited the transcriptional activity of MR. Knockdown of MR eliminated the increased ENaC expression in primary IMCD cells isolated from KO mice. Finally, BP was significantly decreased in Ang II-infused KO mice after treatment of MR antagonist spironolactone and the difference between LC and KO mice was abolished. CONCLUSIONS: NCOR1 interacts with MR to control ENaC activity in the collecting duct and to regulate sodium reabsorption and ultimately BP. Targeting NCOR1 might be a promising tactic to interrupt the volume and sodium retention of the collecting duct in hypertension.

Association of maternal body mass index change with risk of large for gestational age among pregnant women with and without gestational diabetes mellitus: a retrospective cohort study.

OBJECTIVE: To investigate the associations of body mass index (BMI) change and large for gestational age (LGA) among prepregnancy normal-weight women with and without gestational diabetes mellitus (GDM). METHODS: The retrospective study including 9515 normal-weight pregnant women (1331 women with GDM and 8184 without GDM) was conducted in Fujian Maternity and Child Health Hospital in 2020. The BMI change was calculated as gestational weight gain in kilograms by maternal height in meters. The binary logistic regression, stratified analyses, restricted cubic spline models and additive interaction analysis were adopted to reveal the relationship between BMI change and LGA. RESULTS: Pregnant women with GDM had a lower level of BMI change but a higher incidence of LGA compared with those without GDM. After adjustment for covariates variables, we found that the risk of LGA was associated with the highest quartile of BMI change (OR = 1.89, 95%CI:1.27-2.8 for GDM and OR = 1.48,95%CI:1.27-1.75 for non-GDM). There were significant linear relationships of BMI change and LGA with the inflection point of 5.096 and 5.401 kg/m2 in GDM and non-GDM groups. Significant additive interaction was observed between parity and BMI change level concerning LGA. A significant difference in BMI change and gestational weight gain (GWG) for LGA prediction was detected. CONCLUSION: Higher BMI changes were significantly associated with a higher risk of LGA in pregnant women with or without GDM in a linear dose-response relationship, with the threshold around 5.096 and 5.401 kg/m2, respectively. These suggested that BMI changes may be a useful predictor for the incidence of LGA in singleton pregnant women.

A Novel Oncogenic Role of Disulfidptosis-related Gene SLC7A11 in Anti--tumor Immunotherapy Response to Human Cancers.

BACKGROUND: The protein Solute Carrier Family 7 Member 11 (SLC7A11) plays a pivotal role in cellular redox homeostasis by suppressing disulfidptosis, which restricts tumor growth. Yet, its relevance in prognosis, immunity, and cancer treatment efficacy is not well understood. METHODS: We conducted a comprehensive analysis of the expression of SLC7A11 across 33 cancer types, employing datasets from public databases. Methods, such as Cox regression and survival analyses assessed its prognostic significance, while functional enrichment explored the biological processes tied to SLC7A11. The association between SLC7A11 expression, immune cell infiltration, and immune-related gene expression was also scrutinized. RESULTS: Notably, SLC7A11 expression was more pronounced in cancerous compared to normal samples and correlated with higher tumor grades. Increased SLC7A11 expression was linked to poor outcomes, particularly in liver hepatocellular carcinoma (LIHC). This protein's expression also showcased significant relationships with diverse molecular and immune subtypes. Additionally, a prognostic nomogram was devised, integrating SLC7A11 expression and clinical variables. High SLC7A11 levels corresponded with cell growth and senescence pathways in various cancers and with lipid and cholesterol metabolism in LIHC. Furthermore, potential therapeutic compounds for LIHC with high SLC7A11 were identified. Real-time PCR (qPCR) and Western blot were conducted to explore the expression of SLC7A11 in tumor tissues and cancer cell lines. CONCLUSION: In summation, this study emphasizes the prognostic and immunological importance of SLC7A11, spotlighting its potential as a therapeutic target in LIHC.

Ultra-selective uranium separation by in-situ formation of π-f conjugated 2D uranium-organic framework.

With the rapid development of nuclear energy, problems with uranium supply chain and nuclear waste accumulation have motivated researchers to improve uranium separation methods. Here we show a paradigm for such goal based on the in-situ formation of π-f conjugated two-dimensional uranium-organic framework. After screening five π-conjugated organic ligands, we find that 1,3,5-triformylphloroglucinol would be the best one to construct uranium-organic framework, thus resulting in 100% uranium removal from both high and low concentration with the residual concentration far below the WHO drinking water standard (15 ppb), and 97% uranium capture from natural seawater (3.3 ppb) with a record uptake efficiency of 0.64 mg·g-1·d-1. We also find that 1,3,5-triformylphloroglucinol can overcome the ion-interference issue such as the presence of massive interference ions or a 21-ions mixed solution. Our finds confirm the superiority of our separation approach over established ones, and will provide a fundamental molecule design for separation upon metal-organic framework chemistry.

Complications related to thyroidectomy among patients with hyperthyroidism: Exploring the potential for ambulatory surgery.

BACKGROUND: Total thyroidectomy for hyperthyroidism is typically followed by overnight admission to monitor for complications including thyrotoxicosis. Outpatient thyroid surgery is increasingly common, but its safety in patients with hyperthyroidism has not been well studied. METHODS: This retrospective study reviewed 183 patients with hyperthyroidism who underwent total thyroidectomy from 2015 to 2022 at one urban, academic center. The main outcomes were rates of thyroid storm, surgical complications, and 30-day ED visits and readmissions. RESULTS: Among 183 patients with hyperthyroidism (mean age, 45 ± 14.5 years; 82.5% female), there were no cases of thyroid storm and complications included recurrent laryngeal nerve (RLN) palsy (7.0%), symptomatic hypocalcemia (4.4%), and hematoma (1.6%). ED visits were present in 1.1% and no patients were readmitted. CONCLUSION: Total thyroidectomy was not associated with thyroid storm and <6% of patients required inpatient management. Ambulatory total thyroidectomy for hyperthyroidism warrants further consideration through identification of predictive factors for postoperative complications.