Positive feedback regulation between glycolysis and histone lactylation drives oncogenesis in pancreatic ductal adenocarcinoma.

BACKGROUND: Metabolic reprogramming and epigenetic alterations contribute to the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). Lactate-dependent histone modification is a new type of histone mark, which links glycolysis metabolite to the epigenetic process of lactylation. However, the role of histone lactylation in PDAC remains unclear. METHODS: The level of histone lactylation in PDAC was identified by western blot and immunohistochemistry, and its relationship with the overall survival was evaluated using a Kaplan-Meier survival plot. The participation of histone lactylation in the growth and progression of PDAC was confirmed through inhibition of histone lactylation by glycolysis inhibitors or lactate dehydrogenase A (LDHA) knockdown both in vitro and in vivo. The potential writers and erasers of histone lactylation in PDAC were identified by western blot and functional experiments. The potential target genes of H3K18 lactylation (H3K18la) were screened by CUT&Tag and RNA-seq analyses. The candidate target genes TTK protein kinase (TTK) and BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) were validated through ChIP-qPCR, RT-qPCR and western blot analyses. Next, the effects of these two genes in PDAC were confirmed by knockdown or overexpression. The interaction between TTK and LDHA was identified by Co-IP assay. RESULTS: Histone lactylation, especially H3K18la level was elevated in PDAC, and the high level of H3K18la was associated with poor prognosis. The suppression of glycolytic activity by different kinds of inhibitors or LDHA knockdown contributed to the anti-tumor effects of PDAC in vitro and in vivo. E1A binding protein p300 (P300) and histone deacetylase 2 were the potential writer and eraser of histone lactylation in PDAC cells, respectively. H3K18la was enriched at the promoters and activated the transcription of mitotic checkpoint regulators TTK and BUB1B. Interestingly, TTK and BUB1B could elevate the expression of P300 which in turn increased glycolysis. Moreover, TTK phosphorylated LDHA at tyrosine 239 (Y239) and activated LDHA, and subsequently upregulated lactate and H3K18la levels. CONCLUSIONS: The glycolysis-H3K18la-TTK/BUB1B positive feedback loop exacerbates dysfunction in PDAC. These findings delivered a new exploration and significant inter-relationship between lactate metabolic reprogramming and epigenetic regulation, which might pave the way toward novel lactylation treatment strategies in PDAC therapy.

Association between cheese and fish consumption and the occurrence of depression based on European population: mediating role of metabolites.

Background: The consumption of cheese and fish has been linked to the onset of depression. However, the connection between consuming cheese, consuming fish, experiencing depression, and the pathways that mediate this relationship remains unclear. The purpose of this research was to investigate the potential association between the consumption of cheese and fish and the occurrence of depression. Moreover, it is important to identify any metabolites that might be involved and understand their respective roles and functions. Methods: A two-step, two-sample Mendelian randomization (MR) study was conducted using genome-wide association study (GWAS) data on cheese, non-oily fish, and oily fish consumption and depression, along with 12 alternate mediators. The study included a total of 451,486 participants in the cheese consumption group, 460,880 in the non-oily fish consumption group, 460,443 in the oily fish consumption group, and 322,580 with a diagnosis of depression. The single nucleotide polymorphism (SNP) estimates were pooled using inverse-variance weighted, weighted median, MR-Egger, simple mode, and weighted mode. Results: The data we collected suggested that consuming more cheese correlated with a lower likelihood of experiencing depression (OR: 0.95; 95% CI: 0.92 to 0.98). Neither non-oily fish nor oily fish consumption was directly linked to depression onset (p = 0.08, p = 0.78, respectively). Although there was a direct causal relationship with depression, the mediating relationship of triglycerides (TG), total cholesterol in large HDL, cholesterol to total lipids ratio in large HDL, free cholesterol to total lipids ratio in large HDL, glycine, and phospholipids to total lipids ratio in very large HDL of cheese intake on depression risk were - 0.002 (95% CI: -0.023 - 0.020), -0.002 (95% CI: -0.049 - 0.045), -0.001 (95% CI: -0.033 - 0.031), -0.001 (95% CI: -0.018 - 0.015), 0.001 (95% CI: -0.035 - 0.037), and - 0.001 (95% CI: -0.024 - 0.021), respectively. The mediating relationship of uridine, free cholesterol to total lipids ratio in large HDL, total cholesterol in large HDL, acetoacetate, and 3-hydroxybutyrate (3-HB) between non-oily fish consumption and depression risk were 0.016 (95% CI: -0.008 - 0.040), 0.011 (95% CI: -1.269 - 1.290), 0.010 (95% CI: -1.316 - 1.335), 0.011 (95% CI: -0.089 - 0.110), and 0.008 (95% CI: -0.051 - 0.068), respectively. The mediation effect of uridine and free cholesterol to total lipids ratio in large HDL between intake of oily fish and the risk of depression was found to be 0.006 (95% CI: -0.015 - 0.028) and - 0.002 (95% CI: -0.020 - 0.017), respectively. The correlation between eating cheese and experiencing depression persisted even when adjusting for other variables like Indian snacks, mango consumption, sushi consumption, and unsalted peanuts using multivariable MR. Conclusion: The consumption of cheese and fish influenced the likelihood of experiencing depression, and this may be mediated by certain metabolites in the body. Our study provided a new perspective on the clinical treatment of depression.

Evaluating the efficacy and safety of Alzheimer's disease drugs: A meta-analysis and systematic review.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and daily living ability. Currently, there are not many drugs that can be selected to treat mild to moderate AD, and the value of drugs remains controversial. OBJECTIVE: The aim of this study is to quantitatively evaluate the efficacy and safety of cholinesterase inhibitors (ChEIs), memantine, and sodium oligomannate (GV-971) in the treatment of patients with AD. Additionally, molecular docking analysis will be used to investigate the binding affinities of donepezil, galantamine, rivastigmine, and memantine with key receptor proteins associated with AD, including beta-amyloid (Abeta), microtubule-associated protein (MAP), apolipoprotein E4 (APOE4), and Mitofusin-2 (MFN2), to further validate the results of the meta-analysis. METHODS: We obtained clinical trials characterized by randomization, placebo control, and double-blinded methodologies concerning ChEIs, memantine, and GV-971. Statistical analysis was performed using Review Manager Version 5.4 software. Molecular docking was also conducted to evaluate the results. RESULTS: All drugs improved the cognitive function, with the effect value ranging from -1.23 (95% CI -2.17 to -0.30) for 20 mg memantine to -3.29 (95% CI -4.14 to -2.45) for 32 mg galantamine. Although 32 mg galanthamine and GV-971 did not improve the clinicians' Global Impression of Change scale, other drugs showed significant results compared with placebo. On NPI, only 10 mg of donepezil and 24 mg of galantamine had improvement effects. On ADCS/ADL, only 20 mg memantine and 900 mg GV-971 had no significant difference from the placebo. Donepezil 5 mg and GV-971 900 mg did not increase the drug withdrawal rates due to various reasons or adverse reactions when compared to the placebo. Donepezil demonstrated superior binding to the protein and exhibited greater efficacy compared to other drugs. CONCLUSION: ChEIs, memantine, and GV-971 all can slow the progression of AD but have different effects on respective assessments. Donepezil and GV-971 were relatively well tolerated.

Pregnancy and the disease recurrence of patients previously treated for differentiated thyroid cancer: A systematic review and meta analysis.

BACKGROUND: Differentiated thyroid cancer (DTC) is commonly diagnosed in women of child-bearing age, but whether pregnancy influences the prognosis of DTC remains controversial. This study aimed to summarize existing evidence regarding the association of pregnancy with recurrence risk in patients previously treated for DTC. METHODS: We searched PubMed, Embase, Web of Science, Cochrane, and Scopus based on the prespecified protocol registered at PROSPERO (CRD42022367896). After study selection, two researchers independently extracted data from the included studies. For quantitative data synthesis, we used random-effects meta-analysis models to pool the proportion of recurrence (for pregnant women only) and odds ratio (OR; comparing the risk of recurrence between the pregnancy group and the nonpregnancy group), respectively. Then we conducted subgroup analyses to explore whether risk of recurrence differed by response to therapy status or duration of follow-up time. We also assessed quality of the included studies. RESULTS: A total of ten studies were included. The sample size ranged from 8 to 235, with participants' age at pregnancy or delivery ranging from 28 to 35 years. The follow-up time varied from 0.1 to 36.0 years. The pooled proportion of recurrence in all pregnant patients was 0.13 (95% confidence intervals [CI]: 0.06-0.25; I2 : 0.58). Among six included studies reporting response to therapy status before pregnancy, we observed a trend for increasingly higher risk of recurrence from excellent, indeterminate, and biochemically incomplete to structurally incomplete response to therapy ( Ptrend <0.05). The pooled risk of recurrence in the pregnancy group showed no evidence of a significant difference from that in the nonpregnancy group (OR: 0.75; 95% CI: 0.45-1.23; I2 : 0). The difference in follow-up time (below/above five years) was not associated with either the proportion of recurrence in all pregnant patients ( P >0.05) or the OR of recurrence in studies with a comparison group ( P >0.05). Two included studies that focused on patients with distant metastasis also did not show a significant difference in disease recurrence between pregnancy and nonpregnancy groups (OR: 0.51 [95% CI: 0.14-1.87; I2 : 59%]). CONCLUSION: In general, pregnancy appears to have a minimal association with the disease recurrence of DTC with initial treatment. Clinicians should pay more attention to progression of DTC among pregnant women with biochemical and/or structural persistence. REGISTRATION: PROSPERO, https://www.crd.york.ac.uk/PROSPERO/ ; No. CRD42022367896.

Life cycle assessment of coal mines of diverse scales over time in China.

Coal mining has important detrimental effects on the environment and human health. By the end of 2022, China mined more than 4 billion tons of raw coal, and coal mining contributed to adverse environmental impacts. The objective of this work is to evaluate the environmental impacts emanated from coal mines in different periods (construction period, production period and closing period) and to find the relationship between coal mine scale and ecological impacts. This study uses coal mines that produce 0.45 Mt/a (considered a medium sized mine), 3 Mt/a and 8 Mt/a (both classified as large mines in this study) and a 12 Mt/a extra-large coal mine. Based on the time dimension, the mine life cycle was classified into construction, production and closing period, and the life cycle assessment method was used to conduct environmental assessment. The main influencing substances and key processes were tracked. The results indicated that mining engineering and gangue are the main factors affecting the construction and production periods of coal mines. Freshwater ecotoxicity, marine ecotoxicity, and human toxicity are the main environmental effects of coal produce, and they are mostly brought up by the release of hazardous elements like copper, chromium, zinc, nickel, and copper. Furan, formaldehyde, and chromium emissions during mine closure can be effectively reduced through environmental compensation, however coal mines' environmental compensation during mine closure is minimal. The environmental impact of coal mines producing 3 Mt and 8 Mt annually is minimal. The environmental impact of 0.45 Mt/a and 3 Mt/a coal mines is more prominent in the construction period. The pollutant discharge throughout the production phase, particularly the metal leaching discharge from gangue, needs to receive more attention from the 8 Mt/a and 12 Mt/a coal mines. Additionally, the larger the scale of coal mine production, the greater the proportion of the total environmental impact in the production stage.

[Therapeutic efficacy of volume-guaranteed high frequency oscillation ventilation on respiratory failure in preterm infants with a gestational age of 28-34 weeks: a prospective randomized controlled study]. / 容量保证的高频振荡通气模式对胎龄28~34å‘¨æ—©äº§å„¿å‘¼å¸è¡°ç«­ç–—æ•ˆçš„å‰çž»æ€§éšæœºå¯¹ç §ç ”ç©¶.

OBJECTIVES: To investigate the therapeutic efficacy of volume-guaranteed high frequency oscillation ventilation (HFOV-VG) versus conventional mechanical ventilation (CMV) in the treatment of preterm infants with respiratory failure. METHODS: A prospective study was conducted on 112 preterm infants with respiratory failure (a gestational age of 28-34 weeks) who were admitted to the Department of Neonatology, Jiangyin Hospital Affiliated to Medical School of Southeast University, from October 2018 to December 2022. The infants were randomly divided into an HFOV-VG group (44 infants) and a CMV group (68 infants) using the coin tossing method based on the mode of mechanical ventilation. The therapeutic efficacy was compared between the two groups. RESULTS: After 24 hours of treatment, both the HFOV-VG and CMV groups showed significant improvements in arterial blood pH, partial pressure of oxygen, partial pressure of carbon dioxide, and partial pressure of oxygen/fractional concentration of inspired oxygen ratio (P<0.05), and the HFOV-VG group had better improvements than the CMV group (P<0.05). There were no significant differences between the two groups in the incidence rate of complications, 28-day mortality rate, and length of hospital stay (P>0.05), but the HFOV-VG group had a significantly shorter duration of invasive mechanical ventilation than the CMV group (P<0.05). The follow-up at the corrected age of 6 months showed that there were no significant differences between the two groups in the scores of developmental quotient, gross motor function, fine motor function, adaptive ability, language, and social behavior in the Pediatric Neuropsychological Development Scale (P>0.05). CONCLUSIONS: Compared with CMV mode, HFOV-VG mode improves partial pressure of oxygen and promotes carbon dioxide elimination, thereby enhancing oxygenation and shortening the duration of mechanical ventilation in preterm infants with respiratory failure, while it has no significant impact on short-term neurobehavioral development in these infants.

Short-term Pre-operative Methionine Restriction Induces Browning of Perivascular Adipose Tissue and Improves Vein Graft Remodeling in Mice.

Short-term preoperative methionine restriction (MetR) shows promise as a translatable strategy to modulate the body's response to surgical injury. Its application, however, to improve post-interventional vascular remodeling remains underexplored. Here, we find that MetR protects from arterial intimal hyperplasia in a focal stenosis model and adverse vascular remodeling after vein graft surgery. RNA sequencing reveals that MetR enhances the brown adipose tissue phenotype in arterial perivascular adipose tissue (PVAT) and induces it in venous PVAT. Specifically, PPAR-α was highly upregulated in PVAT-adipocytes. Furthermore, MetR dampens the post-operative pro-inflammatory response to surgery in PVAT-macrophages in vivo and in vitro . This study shows for the first time that the detrimental effects of dysfunctional PVAT on vascular remodeling can be reversed by MetR, and identifies pathways involved in browning of PVAT. Furthermore, we demonstrate the potential of short-term pre-operative MetR as a simple intervention to ameliorate vascular remodeling after vascular surgery.

Effectiveness and safety of umbilical cord milking in premature infants: A randomized controlled trial.

INTRODUCTION: Both UCM and DCC are used to treat preterm infants, but there is no uniform standard for the length of UCM. The aim of this work was to explore the effectiveness and safety of different umbilical cord milking (UCM) lengths versus delayed cord clamping (DCC). METHODS: We enrolled premature infants from the Affiliated Hospital of Zunyi Medical University between September 2019 and October 2020 with random allocation (1:1:1:1) to the UCM 10 cm, UCM 20 cm, UCM 30 cm, and DCC groups. The primary outcome was hemoglobin at birth. RESULTS: Ultimately, 143 participants completed the trial (UCM 10 cm, n = 35; UCM 20 cm, n = 35; UCM 30 cm, n = 38; DCC, n = 35). The hemoglobin levels were significantly lower at birth in the UCM 10 cm group than in the UCM 20 and 30 cm and DCC groups (182.29 ±â€…22.15 vs 202.83 ±â€…21.46, 208.82 ±â€…20.72, and 198.46 ±â€…24.92, P = .001, .001, and .003, respectively). The systolic blood pressure and diastolic pressures in the UCM 30 cm group were higher than those in the UCM 10 and 20 cm and DCC groups at birth, postnatal day 3 and postnatal day 7 (P < .05). The occurrence rates of anemia were significantly higher in the UCM 10 cm group than in the UCM 20 and 30 cm and DCC groups (42.9% vs 14.3%, 10.5%, and 14.3%, all P < .0083). There were no significant differences in heart rate or complications among the 4 groups. CONCLUSIONS: A UCM of 20 or 30 cm is a safe, effective operation for preterm infants and could improve blood pressure and hemoglobin levels and reduce anemia.

Treatment of Candida albicans liver abscess complicated with COVID-19 after liver metastasis ablation: A case report.

BACKGROUND: Liver interventional surgery is a relatively safe and minimally invasive surgery. However, for patients who have undergone Whipple surgery, the probability of developing a liver abscess after liver interventional surgery is very high. Fungal liver abscess has a high mortality rate, especially when complicated with malignant tumors, diabetes, coronavirus disease 2019 (COVID-19) and other complications. Fungal liver abscess is rare, and there are no guidelines or expert consensus on the course of antifungal therapy. CASE SUMMARY: A 54-year-old woman with pancreatic head cancer received albumin-bound paclitaxel in combination with gemcitabine chemotherapy after laparoscopic pancreaticoduodenectomy. Liver metastasis was found 1 mo after completion of 8 cycles of chemotherapy, followed by ablation of the liver metastasis. After half a month of liver metastasis ablation, the patient experienced fever after chemotherapy and was diagnosed with liver abscess complicated with COVID-19 by contrast-enhanced abdominal computed tomography and real-time polymerase chain reaction detection. The results of pus culture showed Candida albicans, which was sensitive to fluconazole. The patient underwent percutaneous catheter drainage, antifungal therapy with fluconazole, and antiviral therapy with azvudine. During antifungal therapy, the patient showed a significant increase in liver enzyme levels and was discharged after liver protection therapy. Oral fluconazole was continued for 1 wk outside the hospital, and fluconazole was used for a total of 5 wk. The patient recovered well and received 4 cycles of fluorouracil, leucovorin, oxaliplatin, and irinotecan after 2 mo of antifungal therapy. CONCLUSION: Effective treatment of Candida albicans liver abscess requires early detection, percutaneous catheter drainage, and 5 wk of antifungal therapy. Meanwhile, complications such as COVID-19 should be actively managed and nutritional support should be provided.

A chromosome-level genome assembly for the astaxanthin-producing microalga Haematococcus pluvialis.

The green microalga Haematococcus pluvialis can synthesize high amounts of astaxanthin, which is a valuable antioxidant that has been utilized in human health, cosmetics, and aquaculture. To illustrate detailed molecular clues to astaxanthin yield, we performed PacBio HIFI along with Hi-C sequencing to construct an improved chromosome-level haplotypic genome assembly with 32 chromosomes and a genome size of 316.0 Mb. Its scaffold N50 (942.6 kb) and contig N50 (304.8 kb) have been upgraded remarkably from our previous genome draft, and a total of 32,416 protein-coding genes were predicted. We also established a high-evidence phylogenetic tree from seven representative algae species, with the main aim to calculate their divergence times and identify expanded/contracted gene families. We also characterized genome-wide localizations on chromosomes of some important genes such as five BKTs (encoding beta-carotene ketolases) that are putatively involved in astaxanthin production. In summary, we reported the first chromosome-scale map of H. pluvialis, which provides a valuable genetic resource for in-depth biomedical investigations on this momentous green alga and commercial astaxanthin bioproduction.

The effect of oropharyngeal colostrum administration on the clinical outcomes of premature infants: A meta-analysis.

BACKGROUND: Preterm complications are now the second leading cause of death in children under five years of age. Colostrum is essential to prevent infection and promote maturation in preterm infants. Guidelines recommend that preterm infants be fed colostrum by the oral and pharyngeal routes as early as possible after birth to provide immune protection; however, due to disease and an uncoordinated sucking and swallowing function, it is challenging to provide colostrum through the oropharyngeal route, which limits the immune protection it provides. OBJECTIVE: To update the existing meta-analysis, evaluate the effect of oropharyngeal colostrum administration on related outcomes in preterm infants and explore the optimal frequency and duration of oropharyngeal colostrum administration through subgroup analysis. METHODS: The Cochrane Library, PubMed, Web of Science, ScienceDirect, and Ovid databases were searched for randomized control trials (RCTs) of oropharyngeal colostrum administration for preterm infants. Two researchers screened the literature strictly according to the inclusion and exclusion criteria and evaluated the quality. Primary data and data from the included literature were extracted. Finally, the data were statistically analyzed by the Review Manager 5.3 software. RESULTS: A total of 1736 preterm infants were included in 16 RCTs. The meta-analysis showed that the incidence of necrotizing enterocolitis, late-onset sepsis, feeding intolerance, and death was lower, the time to full enteral feeding was shorter, and the day of recovery to birth weight was earlier in the intervention group (oropharyngeal colostrum administration group) than in the control group, and this difference was statistically significant. Subgroup analysis: Frequency of oropharyngeal colostrum administration: The incidence of necrotizing enterocolitis and late-onset sepsis in the once every 4 h group was lower than that in the control group, and the time to complete enteral feeding was shorter. Duration of oropharyngeal colostrum administration: In the 1-3 days group and 4-7 days group, the time to full enteral feeding in the intervention group was shorter. In the 8-10 days group, the incidence of necrotizing enterocolitis and late-onset sepsis was lower in the intervention group. CONCLUSIONS: Oropharyngeal colostrum administration can reduce the incidence of necrotizing enterocolitis, late-onset sepsis, feeding intolerance and mortality, shorten the time to full enteral feeding, and lead to a faster recovery to birth weight in preterm infants. The appropriate oropharyngeal colostrum administration frequency may be 4 h, and the optimal duration may be 8-10 days. Therefore, it is recommended that clinical medical staff implement oropharyngeal colostrum administration for premature infants based on existing evidence. TWEETABLE ABSTRACT: Oropharyngeal colostrum administration can reduce the incidence of complications in preterm infants and shorten the time to full enteral feeding.

Natural products regulate mitochondrial function in cognitive dysfunction-A scoping review.

Medicines from natural products can not only treat neurodegenerative diseases but also improve the cognitive dysfunction caused by treatments with western medicines. This study reviews the literature related to the regulation of mitochondrial participation in cognitive function by natural products. In this study, we focused on English articles in PubMed, Web of Science, and Google Scholar, from 15 October 2017, to 15 October 2022. Fourteen studies that followed the inclusion criteria were integrated, analyzed, and summarized. Several studies have shown that natural products can improve or reduce cognitive dysfunction by ameliorating mitochondrial dysfunction. These results suggest that natural products may serve as new therapeutic targets for neurodegenerative diseases.

Guanfacine for the Treatment of Attention-Deficit Hyperactivity Disorder: An Updated Systematic Review and Meta-Analysis.

Background: Non-stimulant guanfacine is a common second-line medication for attention-deficit hyperactivity disorder (ADHD). Numerous randomized controlled trials (RCTs) have explored the efficacy of guanfacine in ADHD treatment. This meta-analysis combined data from selected RCTs to analyze the efficacy and safety of guanfacine in treating ADHD. Methods: RCTs were identified from published sources through searches in PubMed, Cochrane Library, Web of Science, and Embase (up to February 2022), defining the Clinical Global Impression of Improvement (CGI-I) treatment response score of ≤2 as the primary outcome. Subgroup analysis was performed with a bound treatment duration of 10 weeks. Safety was defined by treatment-emergent adverse events (TEAEs). Results: Twelve out of 332 studies with 2653 participants were included. All studies compared guanfacine with placebos. Guanfacine was significantly more effective in treating ADHD (Risk Ratio [RR] 1.78, 95% CI: 1.59-2.01). In the <10 weeks subgroup, the efficacy in the guanfacine group compared with the placebo group was 58.5% versus 29.4%, respectively (RR 1.97, 95% CI: 1.71-2.26). In the >10 weeks subgroup, the efficacy in the guanfacine group compared with the placebo group was 63.6% versus 39.7%, respectively (RR 1.57, 95% CI: 1.37-1.79). Both subgroups lacked heterogeneity (I2 = 0), and a funnel plot showed a low publication bias risk. Around 80% of participants in the guanfacine group experienced at least one TEAE, compared with 66.5% in the placebo group (RR 1.23, 95% CI: 1.14-1.32), with low heterogeneity (I2 = 46, p = 0.05). The most common TEAEs in the guanfacine group were somnolence (38.6%), headaches (20.5%), and fatigue (15.2%). Conclusions: Guanfacine is safe and effective for treating ADHD, with no serious adverse events. Guanfacine should be considered as an effective treatment option where effectiveness or tolerability of the central nervous system stimulant is of concern. There is stronger evidence of efficacy for children; more clinical studies are needed for adults.

Time-Varying Pattern and Prediction Model for Geopolymer Mortar Performance under Seawater Immersion.

In this study, immersion experiments were conducted on the geopolymer mortar (GPM) by using artificial seawater, and the effects of alkali equivalent (AE) and waterglass modulus (WGM) on the resistance of geopolymer mortar (GPM) to seawater immersion were analyzed. The test subjected 300 specimens to 270 days of artificial seawater immersion and periodic performance tests. Alkali equivalent (AE) (3-15%) and waterglass modulus (WGM) (1.0-1.8) were employed as influencing factors, and the mass loss and uniaxial compressive strength (UCS) were used as the performance evaluation indexes, combined with X-ray diffraction (XRD) and scanning electron microscopy (SEM) to analyze the time-varying pattern of geopolymer mortar (GPM) performance with seawater immersion. The findings demonstrated a general trend of initially growing and then declining in the uniaxial compression strength (UCS) of geopolymer mortar (GPM) under seawater immersion. The resistance of geopolymer mortar (GPM) to seawater immersion decreased with both higher or lower alkali equivalent (AE), and the ideal range of alkali equivalent (AE) was 9-12%. The diffusion layer of the bilayer structure of the waterglass particle became thinner with an increase in waterglass modulus (WGM), which ultimately led to the reduction in the resistance of the geopolymer structure to seawater immersion. Additionally, a support vector regression (SVR) model was developed based on the experimental data to predict the uniaxial compression strength (UCS) of GPM under seawater immersion. The model performed better and was able to achieve accurate prediction within 1-2 months, and provided an accurate approach to predicting the strength of geopolymer materials in a practical offshore construction project.

Status and influencing factors of lower limb amputation in patients with diabetic foot ulcer.

To investigate the influencing factors of lower limb amputation in patients with diabetic foot ulcers. Patients with diabetic foot ulcers who were hospitalised in a tertiary general hospital in Guizhou Province from January 2019 to March 2022 were retrospectively collected. Sociological information of the general population, comorbidities, laboratory-related indicators, and information on the specialty situation, using univariate analysis and multifactor analysis, compared the influencing factors of amputation and non-amputee patients. A total of 205 patients with diabetic foot and 69 ampute patients (33.7%) were enrolled. The univariate analysis found that the decrease in HDL cholesterol levels was associated with the occurrence of lower extremity amputation, and logistic stepwise regression analysis showed that HDL-C was inversely correlated with the amputation rate of patients with diabetic foot ulcers, and the risk of amputation at low levels of HDL-C was 2.452 times higher than that of high-level HDL-C (95% CI: 1.105-5.846). Decreased HDL cholesterol levels are an independent predictor of amputation in patients with diabetic foot ulcers.

Calcium Channel α2δ1 is Essential for Pancreatic Tumor-Initiating Cells through Sequential Phosphorylation of PKM2.

BACKGROUND & AIMS: Tumor-initiating cells (TICs) drive pancreatic cancer tumorigenesis, therapeutic resistance, and metastasis. However, TICs are highly plastic and heterogenous, which impede the robust identification and targeted therapy of such a population. The aim of this study is to identify the surface marker and therapeutic target for pancreatic TICs. METHODS: We isolated voltage-gated calcium channel α2δ1 subunit (isoform 5)-positive subpopulation from pancreatic cancer cell lines and freshly resected primary tissues by fluorescence-activated cell sorting and evaluated their TIC properties by spheroid formation and tumorigenic assays. Coimmunoprecipitation was used to identify the direct substrate of CaMKⅡδ. RESULTS: We demonstrate that the voltage-gated calcium channel α2δ1 subunit (isoform 5) marks a subpopulation of pancreatic TICs with the highest TIC frequency among the known pancreatic TIC markers tested. Furthermore, α2δ1 is functionally sufficient and indispensable to promote TIC properties by mediating Ca2+ influx, which activates CaMKⅡδ to directly phosphorylate PKM2 at T454 that results in subsequent phosphorylation at Y105 to translocate into nucleus, enhancing the stem-like properties. Interestingly, blocking α2δ1 with its specific antibody has remarkably therapeutic effects on pancreatic cancer xenografts by reducing TICs. CONCLUSIONS: α2δ1 promotes pancreatic TIC properties through sequential phosphorylation of PKM2 mediated by CaMKⅡδ, and targeting α2δ1 provides a therapeutic strategy against TICs for pancreatic cancer.

Latent Class Analysis Identifies Distinct Phenotypes of Systemic Lupus Erythematosus Predictive of Flares after mRNA COVID-19 Vaccination: Results from the Coronavirus National Vaccine Registry for ImmuNe Diseases SINGapore (CONVIN-SING).

We recently reported that messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccination was associated with flares in 9% of patients with systemic lupus erythematosus (SLE). Herein, we focused our analysis on patients from a multi-ethnic Southeast Asian lupus cohort with the intention of identifying distinct phenotypes associated with increased flares after mRNA COVID-19 vaccination. METHODS: Six hundred and thirty-three SLE patients from eight public healthcare institutions were divided into test and validation cohorts based on healthcare clusters. Latent class analysis was performed based on age, ethnicity, gender, vaccine type, past COVID-19 infection, interruption of immunomodulatory/immunosuppressive treatment for vaccination, disease activity and background immunomodulatory/immunosuppressive treatment as input variables. Data from both cohorts were then combined for mixed effect Cox regression to determine which phenotypic cluster had a higher risk for time to first SLE flare, adjusted for the number of vaccine doses. RESULTS: Two clusters were identified in the test (C1 vs. C2), validation (C1' vs. C2') and combined (C1″ vs. C2″) cohorts, with corresponding clusters sharing similar characteristics. Of 633 SLE patients, 88.6% were female and there was multi-ethnic representation with 74.9% Chinese, 14.2% Malay and 4.6% Indian. The second cluster (C2, C2' and C2″) was smaller compared to the first. SLE patients in the second cluster (C2 and C2') were more likely to be male, non-Chinese and younger, with higher baseline disease activity. The second cluster (C2″) had more incident flares (hazard ratio = 1.4, 95% confidence interval 1.1-1.9, p = 0.014) after vaccination. A higher proportion of patients in C2″ had immunomodulatory/immunosuppressive treatment interruption for vaccination as compared to patients in C1″ (6.6% vs. 0.2%) (p < 0.001). CONCLUSION: We identified two distinct phenotypic clusters of SLE with different patterns of flares following mRNA COVID-19 vaccination. Caution has to be exercised in monitoring for post-vaccination flares in patients with risk factors for flares such as non-Chinese ethnicity, young age, male gender and suboptimal disease control at the time of vaccination.

The Efficacy and Safety of Zaoren Anshen Capsule in Combination with Zolpidem for Insomnia: A Multicentre, Randomized, Double-Blinded, Placebo-Controlled Trial.

Purpose: Insomnia is the most common sleep disorder with high rate of prevalence, persistence, and leads to negative consequences. The mainstays of insomnia treatment have limitations due to either the side effects of hypnotics or limited accessibility to cognitive behavioral therapy. This study aims to compare the efficacy and safety of the traditional Chinese medicine (TCM) Zaoren Anshen capsule alone or as an adjunct treatment with different doses of the nonbenzodiazepine medication zolpidem tartrate in treating insomnia. Method: This randomized, double-blind, multicentre placebo control trial was conducted in 131 patients with chronic insomnia. The patients were randomly assigned to one of the following four regimen groups: Group ZA + Z5 : Zaoren Anshen capsule and 5 mg zolpidem tartrate (n = 32); Group Z5: 5 mg zolpidem tartrate and placebo capsule (n = 35); Group Z10 : 10 mg zolpidem tartrate and placebo capsule (n = 32); Group ZA : Zaoren Anshen capsule and placebo pill (n = 32). The drugs were administered for 4 weeks. All patients were evaluated by the Insomnia Severity Index (ISI) at 0, 2, 4, 5, and 6 weeks, and adverse events were recorded. Result: There are significant differences in the comparison between the four groups at each treatment stage (P < 0.05). Repeated measurement analysis of variance (ANOVA) of ISI scores in each treatment stage of the four groups exhibits significant differences in time effect, intergroup effect, and interaction effect (P < 0.05). After four weeks of drug administration, the treatment efficacy is similar in Groups ZA + Z5 and Z10 (93%) and in Groups Z5 and ZA (62% and 65%, respectively). Groups ZA + Z5 and Z10 present significantly lower ISI scores compared with Groups Z5 and ZA (P < 0.05), which indicates better treatment response of Groups ZA + Z5 and Z10. No significant difference was observed in the incidence of adverse events between the groups. Conclusion: Zaoren Anshen capsule can effectively treat insomnia disorder either alone or in combination with zolpidem tartrate. A preferred combination of TCM Zaoren Anshen capsule with zolpidem can provide a magnified therapeutic efficacy with fewer side effects than zolpidem-only management, clinical trial registration number: Chinese Clinical Trial Registry ChiCTR-IPR-1600969.

Cultural factors and senior tourism: Evidence from the Chinese context.

Recently, numerous studies have focused on tourism among the older population. Of them, most reported on status analysis, tourism motivation, and tourism model, to name a few; however, there was a lack of comprehensive synthesis and analysis of the motivation, influencing factors, policy impact, and other factors of older tourism. Thus, this study conducted various keyword searches among both English and Chinese publications. We found that older population's tourism is affected by various factors, such as travel expense, physical condition, the length and distance of a trip, and cultural influence. The results provide a reference for the development and implementation of tourism among the older population.

Microfluidic bioprinting of tough hydrogel-based vascular conduits for functional blood vessels.

Three-dimensional (3D) bioprinting of vascular tissues that are mechanically and functionally comparable to their native counterparts is an unmet challenge. Here, we developed a tough double-network hydrogel (bio)ink for microfluidic (bio)printing of mono- and dual-layered hollow conduits to recreate vein- and artery-like tissues, respectively. The tough hydrogel consisted of energy-dissipative ionically cross-linked alginate and elastic enzyme-cross-linked gelatin. The 3D bioprinted venous and arterial conduits exhibited key functionalities of respective vessels including relevant mechanical properties, perfusability, barrier performance, expressions of specific markers, and susceptibility to severe acute respiratory syndrome coronavirus 2 pseudo-viral infection. Notably, the arterial conduits revealed physiological vasoconstriction and vasodilatation responses. We further explored the feasibility of these conduits for vascular anastomosis. Together, our study presents biofabrication of mechanically and functionally relevant vascular conduits, showcasing their potentials as vascular models for disease studies in vitro and as grafts for vascular surgeries in vivo, possibly serving broad biomedical applications in the future.