Search

Abstract Metabolic reprogramming of amino acids has been increasingly recognized to initiate and fuel tumorigenesis and survival. Therefore, there is emerging interest in the application of amino acid metabolic strategies in antitumor therapy. Tremendous efforts have been made to develop amino acid metabolic node interventions such as amino acid antagonists and targeting amino acid transporters, key enzymes of amino acid metabolism, and common downstream pathways of amino acid metabolism. In addition to playing an essential role in sustaining tumor growth, new technologies and studies has revealed amino acid metabolic reprograming to have wide implications in the regulation of antitumor immune responses. Specifically, extensive crosstalk between amino acid metabolism and T cell immunity has been reported. Tumor cells can inhibit T cell immunity by depleting amino acids in the microenvironment through nutrient competition, and toxic metabolites of amino acids can also inhibit T cell function. In addition, amino acids can interfere with T cells by regulating glucose and lipid metabolism. This crucial crosstalk inspires the exploitation of novel strategies of immunotherapy enhancement and combination, owing to the unprecedented benefits of immunotherapy and the limited population it can benefit. Herein, we review recent findings related to the crosstalk between amino acid metabolism and T cell immunity. We also describe possible approaches to intervene in amino acid metabolic pathways by targeting various signaling nodes. Novel efforts to combine with and unleash potential immunotherapy are also discussed. Hopefully, some strategies that take the lead in the pipeline may soon be used for the common good.

Background: EGFR and ERBB2 exon 20 insertion (Ex20ins) account for a small fraction of patients with EGFR mutations. The efficacy of immune checkpoint inhibitors (ICIs) for these patients was still controversial. Methods: This retrospective study enrolled lung cancer patients harboring either EGFR or ERBB2 Ex20ins mutations. All the patients were treated with platinum-based chemotherapy plus ICIs, or platinum-based chemotherapy. The demographic features and clinical outcome of each patient were reviewed and analyzed. Results: When treated with immunochemotherapy, patients with EGFR/ERBB2 Ex20ins mutations (n = 31) had poor PFS compared with those without EGFR mutations (n = 141, 5.0 mon and 11.2 mon, p < 0.001). When compared with those with EGFR classic mutations who received immunotherapy as the salvage therapy (n = 24), these patients with EGFR/ERBB2 Ex20ins mutations had similar PFS (5.0 mon and 4.1 mon, p = 0.625), ORR (37.5% vs. 48.4%), and DCR (70.8% vs. 77.4%). In the patients with EGFR/ERBB2 Ex20ins mutations, the PFS of those treated with chemotherapy (n = 54) and those treated with immunochemotherapy (n = 31) was 6.5 mon vs. 5.0 mon (p = 0.066). In the EGFR Ex20ins subgroup, the PFS of addition of bevacizumab to chemotherapy (n = 20) and chemotherapy alone (n = 16) was 8.8 mon and 5.2 mon, respectively (p = 0.082) or immunochemotherapy (n = 15, 8.8 mon and 5.0 mon, p = 0.097). Similarly, in the ERBB2 subgroup, the combination of bevacizumab and chemotherapy achieved a numerically longer PFS over chemotherapy alone (9.1 mon and 4.5 mon, p = 0.253), but there was no statistical significance. Conclusions: This study showed that platinum-based chemotherapy plus ICIs had limited efficiency compared to platinum-based chemotherapy for patients with EGFR/ERBB2 Ex20ins. Chemotherapy plus bevacizumab may be a potential scheme for these patients.

Objective To establish a paper-free system of the total whole blood donation flow in constructing intelligent blood stations, and build digitalized whole blood donation system for practice. Methods A paper-free whole blood collection system was constructed through information process reforming, system frame designing and data network transportation constructing, and was applied in various blood donation scenario. Results Fixed blood collection sites carried out 49 063 donations via paper-free information system from November 2022 to July 2023, and 24 822 donations( group blood donation) were conducted via paper-free system from April to July 2022. Compared with the traditional paper-based model, paper-free system is safer, more standardized and more convenient, effectively enhancing the experience of blood donors. Conclusion The construction of paper-free whole blood collection system effectively enhances the experience of blood donors, improves the safety, accuracy, traceability of the data, and has good social value and economic value, which is worth popularizing.

Abstract As a highly enriched endosomal protein within neuronal cells, NSG1 has been discovered to facilitate the process of epithelial-mesenchymal transition (EMT) in esophageal squamous cell carcinoma (ESCC). However, the precise mechanisms behind this phenomenon have yet to be elucidated. The pivotal role of transforming growth factor-β (TGF-β) in triggering the EMT and its significant contribution towards tumor metabolic reprogramming—responsible for EMT activation—has been robustly established. Nevertheless, the extent of TGF-β involvement in the NSG1-mediated EMT within ESCC and the processes through which metabolic reprogramming participates remain ambiguous. We accessed an array of extensive public genome databases to analyze NSG1 expression in ESCC. Regulation of TGF-β by NSG1 was analyzed by transcriptome sequencing, quantitative Real-Time PCR (qRT-PCR), co-immunoprecipitation (CO-IP), and immunofluorescence (IF). Additionally, cellular functional assays and western blot analyses were conducted to elucidate the effect of NSG1 on TGF-β/Smad signaling pathway, as well as its role in ESCC cell metastasis and proliferation. We validated the influence of the NSG1/TGF-β axis on metabolic reprogramming in ESCC by measuring extracellular acidification, glucose uptake, and lactate production. Our findings identify an oncogenic role for NSG1 in ESCC and show a correlation between high NSG1 expression and poor prognosis in ESCC patients. Additional research indicated TGF-β’s involvement in the NSG1-induced EMT process. From a mechanistic perspective, NSG1 upregulates TGF-β, activating the TGF-β/Smad signaling pathway and subsequently fostering the EMT process by inducing cell metabolic reprogramming—evident from elevated glycolysis levels. In conclusion, our study highlights the NSG1/TGF-β axis as a promising therapeutic target for ESCC.

Abstract The hippocampus plays major roles in learning and memory, and its formation requires precise coordination of patterning, cell proliferation, differentiation, and migration. Here we removed the chromatin-association capability of KDM2B in the progenitors of developing dorsal telencephalon (Kdm2b ∆CxxC ) to discover that Kdm2b ∆CxxC hippocampus, particularly the dentate gyrus, became drastically smaller with disorganized cellular components and structure. Kdm2b ∆CxxC mice display prominent defects in spatial memory, motor learning and fear conditioning, resembling patients with KDM2B mutations. The migration and differentiation of neural progenitor cells is greatly impeded in the developing Kdm2b ∆CxxC hippocampus. Mechanism studies reveal that Wnt signaling genes in developing Kdm2b ∆CxxC hippocampi are de-repressed due to reduced enrichment of repressive histone marks by polycomb repressive complexes. Activating the Wnt signaling disturbs hippocampal neurogenesis, recapitulating the effect of KDM2B loss. Together, we unveil a previously unappreciated gene repressive program mediated by KDM2B that controls progressive fate specifications and cell migration, hence morphogenesis of the hippocampus.

Abstract Plant growth‐promoting bacterias (PGPBs) can increase crop output under normal and abiotic conditions. However, the mechanisms underlying the plant salt tolerance‐promoting role of PGPBs still remain largely unknown. In this study, we demonstrated that Halomonas ventosae JPT10 promoted the salt tolerance of both dicots and monocots. Physiological analysis revealed that JPT10 reduced reactive oxygen species accumulation by improving the antioxidant capability of foxtail millet seedlings. The metabolomic analysis of JPT10‐inoculated foxtail millet seedlings led to the identification of 438 diversely accumulated metabolites, including flavonoids, phenolic acids, lignans, coumarins, sugar, alkaloids, organic acids, and lipids, under salt stress. Exogenous apigenin and chlorogenic acid increased the salt tolerance of foxtail millet seedlings. Simultaneously, JPT10 led to greater amounts of abscisic acid (ABA), indole‐3‐acetic acid (IAA), salicylic acid (SA), and their derivatives but lower levels of 12‐oxo‐phytodienoic acid (OPDA), jasmonate (JA), and JA‐isoleucine (JA‐Ile) under salt stress. Exogenous JA, methyl‐JA, and OPDA intensified, whereas ibuprofen or phenitone, two inhibitors of JA and OPDA biosynthesis, partially reversed, the growth inhibition of foxtail millet seedlings caused by salt stress. Our results shed light on the response of foxtail millet seedlings to H. ventosae under salt stress and provide potential compounds to increase salt tolerance in foxtail millet and other crops.

PURPOSELeft ventricular non-compaction (LVNC) is considered rare; however, the use of cardiac magnetic resonance (CMR) has shown that its incidence is not uncommon, and its clinical presentation remains variable, with an uncertain prognosis. Risk stratification of major adverse cardiac events (MACE) in patients with LVNC remains complex. Therefore, this study aims to determine whether tissue heterogeneity from late gadolinium enhancement-derived entropy is associated with MACE in patients with LVNC.METHODSThis study was registered in the Clinical Trial Registry (CTR2200062045). Consecutive patients who underwent CMR imaging and were diagnosed with LVNC were followed up for MACE, which was defined by heart failure, arrhythmias, systemic embolism, and cardiac death. The patients were divided into MACE and non-MACE groups. The CMR parameters included left ventricular (LV) entropy, LV ejection fraction (LVEF), LV end-diastolic volume, LV end-systolic volume (LVESV), and LV mass (LVM).RESULTSEighty-six patients (age: 45.48 ± 16.64 years; female: 62.7%; LVEF: 42.58 ± 17.20%) were followed up for a median of 18 months and experienced 30 MACE events (34.9%). The MACE group showed higher LV entropy, LVESV, and LVM and lower LVEF than the non-MACE group. LV entropy [hazard ratio (HR): 1.710, 95% confidence interval (CI): 1.078–2.714, P = 0.023] and LVEF (HR: 0.961, 95% CI: 0.936–0.988, P = 0.004) were independent predictors of MACE (P

In the aquaculture system of ornamental fish, the interaction between bacterial microbiota and ciliate protozoa can prevent or promote disease outbreaks, and different physicochemical conditions will affect the relationships between them. We investigated the interaction between bacterial microbiota and the parasite Tetrahymena pyriformis when infecting Poecilia reticulata (guppy) under different physicochemical conditions. The abundance of T. pyriformis in water, the relative abundance of bacterial species, and histopathological observation were studied or monitored using environmental DNA (eDNA) extraction technology, the qPCR method, and 16s rRNA sequencing, respectively. The morphological identification and phylogenetic analysis of T. pyriformis were carried out. The infected guppy tissue was also stained by the hematoxylin and eosin methods. The results showed: (1) the bacterial communities of water samples were mainly composed of species assigned to Proteobacteria and Bacteroidetes, and Tabrizicola and Puniceicoccaceae were positively correlated with fish mortality, T. pyriformis abundance, and temperature. (2) Arcicella and Methyloversatilis universalis with different correlations between ciliates appeared in different treatment groups, the result of which proved that environmental factors affected the interaction between bacteria and T. pyriformis. (3) Lower temperatures and a higher pH were more beneficial for preventing disease outbreaks.

Hyperuricemia (HUA) may lead to myocardial cell damage, thereby promoting the occurrence and adverse outcomes of heart diseases. In this review, we discuss the latest clinical research progress, and explore the impact of HUA on myocardial damage-related diseases such as myocardial infarction, arrhythmias, and heart failure. We also combined recent findings from basic research to analyze potential mechanisms linking HUA with myocardial injury. In different pathological models (such as direct action of high uric acid on myocardial cells or combined with myocardial ischemia-reperfusion model), HUA may cause damage by activating the NOD-like receptor protein 3 inflammasome-induced inflammatory response, interfering with cardiac cell energy metabolism, affecting antioxidant defense systems, and stimulating reactive oxygen species production to enhance the oxidative stress response, ultimately resulting in decreased cardiac function. Additionally, we discuss the impact of lowering uric acid intervention therapy and potential safety issues that may arise. However, as the mechanism underlying HUA-induced myocardial injury is poorly defined, further research is warranted to aid in the development novel therapeutic strategies for HUA-related cardiovascular diseases.

With Cabernet Sauvignon grape seeds as raw materials, grape seed polyphenols were extracted and purified, the stability of grape seed polyphenols under different pH, light, temperature, carbohydrate, stabilizer, oxidant reducing agent, preservative and metal ion were studied during processing and storage conditions, and the biological activity in vitro was also discussed. The results showed that grape seed polyphenol was the best stability under the condition of low temperature (4 ℃), weak acid (pH4~6), avoiding light and low temperature (4 ℃), and the retention rate of grape seed polyphenols was above 95%. High concentration (40%~50%) of sucrose and glucose had enhanced effect on the stability of polyphenols, lactose concentration had no significant effects on the stability of polyphenols (P˃0.05), and different concentrations of starch could significantly reduce the stability of polyphenols (P

Objective To evaluate the efficacy and safety of autologous platelet-rich plasma (PRP) in the treatment of androgenetic alopecia and to investigate the correlation between concentrations of growth factors and efficacy. Methods Seven male patients with AGA were included in this prospective study. In each subject, one side of the alopecia area was randomly injected with PRP while the opposite side was injected with saline once every other week for 3 times, followed by follow-up at 1, 2, and 3 months. Clinical pictures and dermoscopy images were taken for assessment of efficacy by patients and doctors. ELISA was used to measure the levels of PDGF, TGF-β and VEGF in PRP and peripheral blood. Relationship between efficacy and concentration of growth factors was also determined. Results After the treatment, both hair density hair/follicle ratio were increased on the PRP side compared with the placebo side (P

Abstract Metformin is a well-known anti-diabetic drug that has been repurposed for several emerging applications, including as an anti-cancer agent. It boasts the distinct advantages of an excellent safety and tolerability profile and high cost-effectiveness at less than one US dollar per daily dose. Epidemiological evidence reveals that metformin reduces the risk of cancer and decreases cancer-related mortality in patients with diabetes; however, the exact mechanisms are not well understood. Energy metabolism may be central to the mechanism of action. Based on altering whole-body energy metabolism or cellular state, metformin’s modes of action can be divided into two broad, non-mutually exclusive categories: “direct effects”, which induce a direct effect on cancer cells, independent of blood glucose and insulin levels, and “indirect effects” that arise from systemic metabolic changes depending on blood glucose and insulin levels. In this review, we summarize an updated account of the current knowledge on metformin antitumor action, elaborate on the underlying mechanisms in terms of the hallmarks of cancer, and propose potential applications for repurposing metformin for cancer therapeutics.

Abstract Targeted chemo-phototherapy has received widespread attention in cancer treatment for its advantages in reducing the side effects of chemotherapeutics and improving therapeutic effects. However, safe and efficient targeted-delivery of therapeutic agents remains a major obstacle. Herein, we successfully constructed an AS1411-functionalized triangle DNA origami (TOA) to codeliver chemotherapeutic drug (doxorubicin, DOX) and a photosensitizer (indocyanine green, ICG), denoted as TOADI (DOX/ICG-loaded TOA), for targeted synergistic chemo-phototherapy. In vitro studies show that AS1411 as an aptamer of nucleolin efficiently enhances the nanocarrier’s endocytosis more than 3 times by tumor cells highly expressing nucleolin. Subsequently, TOADI controllably releases the DOX into the nucleus through the photothermal effect of ICG triggered by near-infrared (NIR) laser irradiation, and the acidic environment of lysosomes/endosomes facilitates the release. The downregulated Bcl-2 and upregulated Bax, Cyt c, and cleaved caspase-3 indicate that the synergistic chemo-phototherapeutic effect of TOADI induces the apoptosis of 4T1 cells, causing ~ 80% cell death. In 4T1 tumor-bearing mice, TOADI exhibits 2.5-fold targeted accumulation in tumor region than TODI without AS1411, and 4-fold higher than free ICG, demonstrating its excellent tumor targeting ability in vivo. With the synergetic treatment of DOX and ICG, TOADI shows a significant therapeutic effect of ~ 90% inhibition of tumor growth with negligible systemic toxicity. In addition, TOADI presents outstanding superiority in fluorescence and photothermal imaging. Taken together, this multifunctional DNA origami-based nanosystem with the advantages of specific tumor targeting and controllable drug release provides a new strategy for enhanced cancer therapy.

Abstract Background Diagnosis of breast cancer in young women has been shown to affect their decision‐making with regard to fertility and family planning. Limited data are available from populations across the U.S. regarding this issue; thus, we sought to describe fertility concerns and efforts to preserve fertility in a national clinical trial population of young breast cancer patients. Methods The young and strong study was a cluster‐randomized controlled trial testing an intervention program for young women with breast cancer. Patients were surveyed within 3 months after diagnosis and at 3, 6, and 12 months after. Surveys asked about sociodemographics, psychosocial domains, fertility concerns, and fertility preservation strategies. Univariable and multivariable models were used to investigate sociodemographic, clinical, and psychosocial predictors of fertility concerns. Results Of 467 women from 54 clinical sites across the U.S. (14 academic, 40 community), 419 were evaluable regarding fertility concerns. Median age was 40 years (range 22–45), 11% were Black, 6% Hispanic, and 75% had children. Tumor stage was I (35%), II (51%), or III (14%); 82% received chemotherapy. At time of the treatment decision, 133 (32%) participants had fertility concerns, among whom 47% indicated this affected their treatment decisions. Sixty percent of participants reported having discussed fertility with their physician. Twenty percent of those with fertility concerns used fertility preservation strategies. History of difficulty becoming pregnant and younger age were associated with higher odds of fertility concerns in multivariable modeling. Conclusion Many young women with newly diagnosed breast cancer are concerned about fertility in a way that impacts their treatment decisions. Concerns were discussed, but few used fertility preservation strategies. These findings have implications for counseling young patients.

Rare and complex diseases pose significant challenges to both patients and healthcare providers. These conditions often present with atypical symptoms, making diagnosis and treatment a formidable task. In recent years, artificial intelligence and natural language processing technologies have shown great promise in assisting medical professionals in diagnosing and managing such conditions. This paper explores the role of ChatGPT, an advanced artificial intelligence model, in improving the diagnosis and treatment of rare and complex diseases. By analyzing its potential applications, limitations, and ethical considerations, we demonstrate how ChatGPT can contribute to better patient outcomes and enhance the healthcare system's overall effectiveness.

BackgroundNeoadjuvant immunochemotherapy may benefit patients with non-small cell lung cancer (NSCLC), but its impact requires further investigation.MethodsA meta-analysis was conducted. PubMed, Embase, Web of Science, and the Cochrane Library were searched. The study was registered in PROSPERO (registration no. CRD42022360893).Results60 studies of 3,632 patients were included. Comparing with neoadjuvant chemotherapy, neoadjuvant immunochemotherapy showed higher pCR (RR: 4.71, 95% CI: 3.69, 6.02), MPR (RR, 3.20, 95% CI: 2.75, 3.74), and ORR (RR, 1.46, 95% CI: 1.21, 1.77), fewer surgical complications (RR: 0.67, 95%CI: 0.48, 0.94), higher R0 resection rate (RR: 1.06, 95%CI: 1.03, 1.10, I2 = 52%), and longer 1-year and 2-year OS, without affecting TRAEs. For neoadjuvant immunochemotherapy in NSCLC, the pooled pCR rate was 0.35 (95% CI: 0.31, 0.39), MPR was 0.59 (95% CI: 0.54, 0.63), and ORR was 0.71 (95% CI: 0.66, 0.76). The pooled incidence of all grade TRAEs was 0.70 (95% CI: 0.60, 0.81), and that of >= grade 3 TRAEs was 0.24 (95% CI: 0.16, 0.32). The surgical complications rate was 0.13 (95% CI: 0.07, 0.18) and R0 resection rate was 0.98 (95% CI: 0.96, 0.99). The pooled 1-year OS was 0.97 (95%CI: 0.96, 0.99), and 2-year OS was 0.89 (95%CI: 0.83, 0.94). Patients with squamous cell carcinoma, stage III or higher PD-L1 performed better. Notably, no significant differences were observed in pCR, MPR, and ORR between 2 or more treatment cycles. Pembrolizumab-, or toripalimab-based neoadjuvant immunochemotherapy demonstrated superior efficacy and tolerable toxicity.ConclusionAccording to our analysis, reliable efficacy, safety, and survival of neoadjuvant immunochemotherapy for operable NSCLC were demonstrated.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022360893, identifier CRD42022360893.

The dynamic phase transition of fluid has been specifically induced by the shockwave within the context of the hard-sphere model. Fundamental thermal and dynamic attributes of the fluid have been primarily examined, and the conditions following the Rankine–Hugoniot (RH) theory have been applied using the Euler equations. Due to the magnitude of the shockwave’s impact on the undisturbed equilibrium of the fluid, three archetypal states of excitation are manifested, encompassing liquid–liquid, liquid–solid, and liquid-coexistence states, categorized according to RH conditions subsequent to the influence of the shockwave. The characteristics of the fluid are portrayed employing the hard-sphere model, while the excited state of the fluid has been substantiated through an inquiry into the RH conditions and the generation of entropy. In consonance with the research, the excited state of the fluid exhibits a robust interrelation with its unperturbed equilibrium. The hard-sphere model stands as a suitable framework for examination of the shock-induced phase transition of the fluid.

The effects of ultrasonic brine on the physicochemical properties, sensory quality and microstructure of low-sodium beef jerkies were investigated. Compared with control jerky brined in 1.5% NaCl solution, both of the direct reduction and partial replacement of 50% NaCl by KCl decreased the sodium content. Ultrasonic treatment resulted in sharp reduction in shear force. KCl substitution together with ultrasonic treatment caused the highest yield, a* value and water content, and the water activity of all groups were below 0.85. Only the direct reduction of NaCl had negative effects on the sensory quality. KCl substitution combined with ultrasonic treatment was the most suitable for producing low-sodium beef jerkies with high quality, possibly because the mixed salt had equal total salt content to control. Meanwhile, the cavitation and mechanical effects of ultrasound may unfold protein structure, increase myofibrillar fragmentation index and break the muscle fiber, thus improving the quality of beef jerky.

ABSTRACTPharmaceutical companies have recently focused on accelerating the timeline for initiating first-in-human (FIH) trials to allow quick assessment of biologic drugs. For example, a stable cell pool can be used to produce materials for the toxicology (Tox) study, reducing time to the clinic by 4–5 months. During the coronavirus disease 2019 (COVID-19) pandemic, the anti-COVID drugs timeline from DNA transfection to the clinical stage was decreased to 6 months using a stable pool to generate a clinical drug substrate (DS) with limited stability, virus clearance, and Tox study package. However, a lean chemistry, manufacturing, and controls (CMC) package raises safety and comparability risks and may leave extra work in the late-stage development and commercialization phase. In addition, whether these accelerated COVID-19 drug development strategies can be applied to non-COVID projects and established as a standard practice in biologics development is uncertain. Here, we present a case study of a novel anti-tumor drug in which application of “fast-to-FIH” approaches in combination with BeiGene’s de-risk strategy achieved successful delivery of a complete CMC package within 10 months. A comprehensive comparability study demonstrated that the DS generated from a stable pool and a single-cell-derived master cell bank were highly comparable with regards to process performance, product quality, and potency. This accomplishment can be a blueprint for non-COVID drug programs that approach the pace of drug development during the pandemic, with no adverse impact on the safety, quality, and late-stage development of biologics.

Purpose Optimal serological biomarkers have been absent for the early diagnosis of endometrial cancer, to date. In this study, we aimed to define the diagnostic performances of individual and combined detection of serum cysteine protease inhibitor 1 (CST1) with traditional tumor markers, including glycated antigen 125 (CA125) and human epididymis protein 4 (HE4), in patients with early-stage endometrial cancer (EC). Methods The performances of individual and combined detection of serum CST1, HE4, and CA125 were evaluated by enzyme-linked immunosorbent assay (ELISA) and chemiluminescent immunoassay, respectively. A training data set of 67 patients with early EC, 67 patients with endometrial benign lesion (EBL), and 67 healthy controls (HC) was used to develop a predictive model for early EC diagnosis, which was validated by an independent validation data set. Results In the training data set, serum CST1 and HE4 levels in the early EC group were significantly higher than in EBL/HC groups (P < 0.05), while there was no significant difference of serum CA125 level between the early EC and EBL/HC groups (P > 0.05). Serum CST1 and HE4 exhibited areas under the curve (AUC) of 0.715 with 31.3% sensitivity at 90.3% specificity, and 0.706 with 23.9% sensitivity at 95.5% specificity, respectively. Combined detection of serum CST1 and HE4 exhibited an AUC of 0.788 with 49.3% sensitivity at 92.5% specificity. The combination of serum CST1 and HE4 showed promise in diagnosis. Conclusion CST1 is a prospective serological biomarker for early EC diagnosis, and the combination of CST1 and HE4 contributes to the further improvement in the diagnosis of patients with early-stage EC.

Summary: Appropriate histone modifications emerge as essential cell fate regulators of neuronal identities across neocortical areas and layers. Here we showed that NSD1, the methyltransferase for di-methylated lysine 36 of histone H3 (H3K36me2), controls both area and layer identities of the neocortex. Nsd1-ablated neocortex showed an area shift of all four primary functional regions and aberrant wiring of cortico-thalamic-cortical projections. Nsd1 conditional knockout mice displayed defects in spatial memory, motor learning, and coordination, resembling patients with the Sotos syndrome carrying NSD1 mutations. On Nsd1 loss, superficial-layer pyramidal neurons (PNs) progressively mis-expressed markers for deep-layer PNs, and PNs remained immature both morphologically and electrophysiologically. Loss of Nsd1 in postmitotic PNs causes genome-wide loss of H3K36me2 and re-distribution of DNA methylation, which accounts for diminished expression of neocortical layer specifiers but ectopic expression of non-neural genes. Together, H3K36me2 mediated by NSD1 is required for the establishment and maintenance of region- and layer-specific neocortical identities.

Abstract It is unclear whether membrane vitamin D receptor (mVDR) exists on the macrophage membrane or whether mVDR is associated with lipopolysaccharide (LPS) tolerance. Herein, we report that interfering with caveolae and caveolae-dependent lipid rafts inhibited the formation of LPS tolerance. VDR was detected as co-localized with membrane molecular markers. VDR was detected on the cell membrane and its level was higher in LPS-tolerant cells than that in only LPS treatment cells. Anti-VDR antibodies could abolish the effect of artesunate (AS) to reverse LPS tolerance, and the wild-type peptides (H397 and H305) of VDR, but not the mutant peptide (H397D and H305A), led to the loss of AS’s effect. AS decreased the mVDR level in LPS-tolerant cells. In vivo, AS significantly reduced VDR level in the lung tissue of LPS-tolerant mice. In summary, mVDR exists on the cell membrane of macrophages and is closely associated with the formation of LPS tolerance and the effects of AS. Video Abstract

Economic Load Dispatch (ELD) is an effective dispatch strategy to improve economic efficiency while ensuring the safety and stability of the power system. It minimizes production costs by rationally allocating the power generated by each power system unit. In this paper, an Manta Ray Foraging Optimization (MRFO) algorithm based on the mathematical spiral foraging strategy is proposed to solve the ELD problem in power systems considering transmission losses. Eight different mathematical spirals were introduced into the MRFO algorithm's foraging strategy, including the Rose spiral, Archimedes spiral, Fermat spiral, Cycloid spiral, Hypotrochoid spiral, Epitrochoid spiral, Inverse spiral and Lituus spiral. The mathematical spiral foraging strategy can enhance the global search ability of the MRFO algorithm and improves its convergence velocity. To verify the performance of the proposed improved MRFO algorithm, 30 benchmark functions are tested and the optimization performances are compared with BOA, AOA, SCA, HHO, WOA, RSA, and GWO. The simulation experimental results show that the performance and application of the manta ray foraging optimization algorithm based on the mathematical spiral foraging strategy outperform other intelligent optimization algorithms tested on 30 benchmark functions. Finally, two ELD cases with total demands of 2500 MW and 10500 MW are selected and solved using the improved manta ray foraging optimization algorithm. Comparing the simulation results with other optimization algorithms, it is shown that the proposed improved algorithm obtains the best fuel cost and smaller transmission loss in almost every test case, which canl help to improve the economic efficiency of the power system and achieve the goal of economic load dispatch.

Abstract Extended adjuvant endocrine therapy (eET) improves outcomes in breast cancer survivors. Most studies however have been limited to postmenopausal women, and optimal eET for young survivors is uncertain. We report eET use among participants in the Young Women’s Breast Cancer Study (YWS), a multicenter prospective cohort of women age ≤40 newly diagnosed with breast cancer enrolled between 2006–2016. Women with stage I–III hormone receptor-positive breast cancer, ≥6 years from diagnosis without recurrence were considered eET candidates. Use of eET was elicited from annual surveys sent years 6–8 after diagnosis, censoring for recurrence/death. 663 women were identified as eET candidates with 73.9% (490/663) having surveys eligible for analysis. Among eligible participants, mean age was 35.5 (±3.9), 85.9% were non-Hispanic white, and 59.6% reported eET use. Tamoxifen monotherapy was the most reported eET (77.4%), followed by aromatase inhibitor (AI) monotherapy (21.9%), AI-ovarian function suppression (AI-OFS) (6.8%) and tamoxifen-OFS (3.1%). In multivariable analysis, increasing age (per year odds ratio [OR]: 1.10, 95% confidence interval [CI]: 1.04–1.16), stage (II v. I: OR: 2.86, 95% CI: 1.81–4.51; III v. I: OR: 3.73, 95%CI: 1.87–7.44) and receipt of chemotherapy (OR: 3.66, 95% CI: 2.16–6.21) were significantly associated with eET use. Many young breast cancer survivors receive eET despite limited data regarding utility in this population. While some factors associated with eET use reflect appropriate risk-based care, potential sociodemographic disparities in uptake warrants further investigation in more diverse populations.

Abstract Background Acute kidney injury (AKI) is a frequent syndrome in the intensive care unit (ICU). AKI patients with kidney function recovery have better short-term and long-term prognoses compared with those with non-recovery. Numerous studies focus on biomarkers to distinguish them. To better understand the predictive performance of urinary biomarkers of renal recovery in patients with AKI, we evaluated C–C motif chemokine ligand 14 (CCL14) and two first-generation biomarkers (cell cycle arrest biomarkers and neutrophil gelatinase-associated lipocalin) in two ICU settings. Methods We performed a prospective study to analyze urinary biomarkers for predicting renal recovery from AKI. Patients who developed AKI after ICU admission were enrolled and urinary biomarkers including tissue inhibitor of metalloproteinase-2 (TIMP-2), insulin-like growth factor-binding protein 7 (IGFBP7), CCL14, and neutrophil gelatinase-associated lipocalin (NGAL) were detected on the day of AKI diagnosis. The primary endpoint was non-recovery from AKI within 7 days. The individual discriminative ability of CCL14, [TIMP-2] × [IGFBP7] and NGAL to predict renal non-recovery were evaluated by the area under receiver operating characteristics curve (AUC). Results Of 164 AKI patients, 64 (39.0%) failed to recover from AKI onset. CCL14 showed a fair prediction ability for renal non-recovery with an AUC of 0.71 (95% CI 0.63–0.77, p

Isomaltulose is a novel sweetener and is considered healthier than the common sugars, such as sucrose or glucose. It has been internationally recognized as a safe food product and holds vast potential in pharmaceutical and food industries. Sucrose isomerase is commonly used to produce isomaltulose from the substrate sucrose in vitro and in vivo. However, free cells/enzymes were often mixed with the product, making recycling difficult and leading to a significant increase in production costs. Immobilized cells/enzymes have the following advantages including easy separation from products, high stability, and reusability, which can significantly reduce production costs. They are more suitable than free ones for industrial production. Recently, immobilized cells/enzymes have been encapsulated using composite materials to enhance their mechanical strength and reusability and reduce leakage. This review summarizes the advancements made in immobilized cells/enzymes for isomaltulose production in terms of refining traditional approaches and innovating in materials and methods. Moreover, innovations in immobilized enzyme methods include cross-linked enzyme aggregates, nanoflowers, inclusion bodies, and directed affinity immobilization. Material innovations involve nanomaterials, graphene oxide, and so on. These innovations circumvent challenges like the utilization of toxic cross-linking agents and enzyme leakage encountered in traditional methods, thus contributing to enhanced enzyme stability.

Salmonella infection causes serious economic losses, threatens food safety, and is one of the most important diseases threatening meat duck farming. The gut microbiome is critical in providing resistance against colonization by exogenous microorganisms. Studying the relationship between Salmonella and gut microbiota can help us better understand the threat of the pathogenic mechanism of Salmonella and provide a more scientific theoretical basis for its prevention and treatment. This study uses Salmonella Typhimurium as the research object and Cherry Valley meat duck as the model with which to study the impact of Salmonella infection on ducks. In this field trial, 2 × 108 CFUs Salmonella Typhimurium were administered to 3-day-old ducks. After infection, duck viscera were collected to detect the colonization of Salmonella, and cecal contents were collected to analyze the changes in gut microbiota. The results show that Salmonella Typhimurium can colonize ducks three days after infection and alter the gut microbiota composition, mainly by increasing the abundance of Ruminococcaceae and Lachnospiraceae. In conclusion, Salmonella Typhimurium infection significantly alters the intestinal microbiota of ducks and poses a serious public health risk.

Humor, a higher-order social cognitive process unique to humans, is commonly impaired in patients with chronic schizophrenia. However, humor processing and its association with the clinical characteristics in the early stage of the illness remain unknown. In this study, we investigated humor processing and its relationship with clinical features in patients with first-episode schizophrenia (FES). We recruited 45 patients with FES and 44 healthy controls matched for age, sex, and education level. The participants completed the Picture Humor Processing Task (HPT-p) and Video Humor Processing Task (HPT-v), which evaluated humor comprehension and appreciation, and a questionnaire assessing their humor styles. Clinical participants also completed clinical and social functioning measurements. Signal detection theory analysis was used to calculate the d' and β values, which represent the detection of humor signals in the comprehension phase and inner criteria of the humor appreciation phase, respectively. In the HPT-p, patients with FES showed a higher false alarm rate (p = 0.048) than healthy controls, whereas the hitting rate, signal recognition ability (d' value), and intrinsic evaluation criterion (β value) were comparable between the two participants groups. In the HPT-v, patients with FES showed lower within-group coherence in the funniness rating (p = 0.023) than healthy controls. In addition, the false alarm rate in the HPT-p and negative symptoms effectively predicted social functioning in patients with FES (R2 = 0.681, p

Summary: Phosphatidylglycerol (PG) is a mitochondrial phospholipid required for mitochondrial cristae structure and cardiolipin synthesis. PG must be remodeled to its mature form at the endoplasmic reticulum (ER) after mitochondrial biosynthesis to achieve its biological functions. Defective PG remodeling causes MEGDEL (non-alcohol fatty liver disease and 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like) syndrome through poorly defined mechanisms. Here, we identify LPGAT1, an acyltransferase that catalyzes PG remodeling, as a candidate gene for MEGDEL syndrome. We show that PG remodeling by LPGAT1 at the ER is closely coordinated with mitochondrial transport through interaction with the prohibitin/TIMM14 mitochondrial import motor. Accordingly, ablation of LPGAT1 or TIMM14 not only causes aberrant fatty acyl compositions but also ER retention of newly remodeled PG, leading to profound loss in mitochondrial crista structure and respiration. Consequently, genetic deletion of the LPGAT1 in mice leads to cardinal features of MEGDEL syndrome, including 3-methylglutaconic aciduria, deafness, dilated cardiomyopathy, and premature death, which are highly reminiscent of those caused by TIMM14 mutations in humans.

IntroductionAdenoid hypertrophy (AH) is a common upper respiratory disorder in children. Disturbances of gut microbiota have been implicated in AH. However, the interplay of alteration of gut microbiome and enlarged adenoids remains elusive.Methods119 AH children and 100 healthy controls were recruited, and microbiome profiling of fecal samples in participants was performed using 16S rRNA gene sequencing. Fecal microbiome transplantation (FMT) was conducted to verify the effects of gut microbiota on immune response in mice.ResultsIn AH individuals, only a slight decrease of diversity in bacterial community was found, while significant changes of microbial composition were observed between these two groups. Compared with HCs, decreased abundances of Akkermansia, Oscillospiraceae and Eubacterium coprostanoligenes genera and increased abundances of Bacteroides, Faecalibacterium, Ruminococcus gnavus genera were revealed in AH patients. The abundance of Bacteroides remained stable with age in AH children. Notably, a microbial marker panel of 8 OTUs were identified, which discriminated AH from HC individuals with an area under the curve (AUC) of 0.9851 in the discovery set, and verified in the geographically different validation set, achieving an AUC of 0.9782. Furthermore, transfer of mice with fecal microbiota from AH patients dramatically reduced the proportion of Treg subsets within peripheral blood and nasal-associated lymphoid tissue (NALT) and promoted the expansion of Th2 cells in NALT.ConclusionThese findings highlight the effect of the altered gut microbiota in the AH pathogenesis.

BackgroundThe ongoing COVID-19 pandemic has had an unprecedented impact on blood transfusion and collection. At the beginning of the pandemic, most blood transfusion services had a tough challenge in maintaining an optimal blood inventory. ObjectiveThis study aims to understand the public's psychological cognition and intention toward blood donation as well as the factors influencing their worries. We aimed to find a solution for increasing blood donations and provide a scientific reference for policy formulation regarding blood donation during the COVID-19 pandemic and in the future. MethodsA random survey with a 14-item scale on worries related to blood donation was conducted from December 31, 2022, to January 3, 2023, among residents aged 18-60 years in Zhejiang province via SMS text messaging. The results of 8 worry items in this study were compared with the survey results of March 2022, during which COVID-19 was not considered as an epidemic in Zhejiang province. Chi-square test and logistic regression analysis were performed to analyze the factors affecting respondents’ blood donation intention and concerns. The degree of worry about blood donation was assigned from 1 (completely disagree) to 5 (completely agree), and 2-sided t tests were performed to analyze the differences in blood donation intention and worries about blood donation. ResultsIn total, 1254 valid questionnaire responses were obtained. Males accounted for 62.36% (782/1254) of the sample, 78.39% (983/1254) were 18-45 years old, 60.61% (760/1254) had a university education, and 69.06% (866/1254) had no previous blood donation experience. Approximately 36.52% (458/1254) of the public clearly expressed that they had blood donation worries regarding COVID-19. The main concerns of the respondents were temporary physical weakness caused by blood donation, their own physical conditions not meeting the requirements of blood donation, inconvenient location and working hours for blood donation, and family (or friends) worrying about blood donation. Compared with the results in 2022, the results in 2023 regarding the harmful effects of blood donation on health, temporary physical weakness, infection in donated blood, and family (friends) worrying increased significantly (P

BackgroundThe role of cranial radiation therapy with hippocampus avoidance (HA-CRT) in neurocognitive function (NCF), brain metastasis (BM), and overall survival (OS) in lung cancer remains unclear.MethodsA meta-analysis was conducted to evaluate the impact of HA-CRT in lung cancer. Data from studies on hippocampal-avoidance prophylactic cranial irradiation (HA-PCI) and whole brain radiotherapy (HA-WBRT) were pooled.ResultsA total of 14 studies, including 5 randomized controlled trials, were included. The focus of NCF was mainly via the Hopkins Verbal Learning Test—Revised or the Free and Cued Selective Reminding Test. At 6 months post-radiotherapy, the pooled proportion of participants with decline in the performance of total recall, delayed recall, and discrimination in neurocognitive tests were 0.22 (95% CI 0.15, 0.29), 0.20 (95% CI 0.13, 0.27), and 0.14 (95% CI 0.05, 0.24) respectively. After 12 months, the proportion were 0.16 (95% CI 0.08, 0.23), 0.10 (95% CI 0.04, 0.16), and 0.04 (95% CI 0, 0.09) respectively. For HA zone relapse, the RR of HA-CRT versus CRT was 2.72 (95% CI 0.53, 13.87), and for 2-year BM, it was 1.20 (95% CI 0.82, 1.75). Regarding HA-PCI in SCLC, the 1-year BM rate was 0.12 (95% CI 0.07, 0.17), and the 2-year BM rate was 0.20 (95% CI 0.16, 0.25). For HA-WBRT in NSCLC with BM, the 2-year intracranial progression rate was 0.38 (95% CI 0.13, 0.62). There was no significant difference in OS between HA-CRT and CRT.ConclusionsHA-CRT appears to be safe in lung cancer, but it may not outperform conventional CRT. Larger RCTs comparing HA-CRT and CRT are warranted.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022360890, identifier CRD42022360890.

Primary urethral carcinoma (PUC) has a low incidence, but with high aggressiveness. Most of the patients are found in late stage, with poor prognosis. At present, chemotherapy is still the main treatment for metastatic PUC, but it has limited effect. Here, we report a case of metastatic PUC with low HER2 expression that developed disease progression after multiline therapy including chemotherapy, programmed death-1 (PD-1) inhibitors and multi-targeted receptor tyrosine kinase (RTK) inhibitor. After receiving Disitamab Vedotin(a novel antibody drug conjugate, ADC) and toripalimab (a PD-1 inhibitor), the patient achieved persistent PR, and the PFS exceeded 12 months up to now. Our report indicates that, despite the patient of metastatic PUC has low expression of HER2, it is still possible to benefit from Disitamab Vedotin combined with PD-1 inhibitor, which may reverse the drug resistance of PD-1 inhibitor and chemotherapy to a certain extent. But larger sample studies are needed to determine the efficacy of this treatment strategy and its impact on survival.

Abstract Background Residual somatic symptoms (RSS) are common in depressed patients, predicting treatment effectiveness. However, sex differences in RSS have received little systematic study. This study was conducted to compare sex differences of RSS in patients with first-episode depression (FED). Methods Nine hundred eighty-two patients with FED were selected and treated for 8 to 12 weeks. We evaluated the subjects' socio-demographic characteristics and residual depressive symptoms. Using the Patient Health Questionnaire-15 (PHQ-15) scale to assess residual somatic symptoms, the Sheehan Disability Scale (SDS) for the assessment of patients' function, the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) for quality of life. Results The incidence of RSS with FED was 46.4%. For patients with residual symptoms, the age and age of onset in females were higher than males, but males had more years of education than females. The degree of "stomach pain" in females was more severe than in males, while "trouble sleeping" in males was more severe than that in females. Multiple regression analysis showed that the total Q-LES-Q-SF score was an independent influencing factor of RSS in both males and females, while the total SDS score only affected female RSS. Conclusions The prevalence of RSS in FED after acute-phase treatment is high. The symptom of "stomachache" is more pronounced in females, while "trouble sleeping" is more severe in males. Quality of life plays an essential role in RSS in both genders. Thus, sex needs to be considered when assessing the relationship between RSS and therapeutic effect in depression.

The composition of endophytic bacteria in different tissues of Artemisia argyi var. argyi ‘Qiai’, and the antibacterial activities of their secondary metabolites were the main focus of this study. The tissue culture method was used to isolate the endophytic bacteria from roots, stems and leaves of Artemisia argyi var. argyi ‘Qiai’ and then, the antibacterial activity of the volatiles from endophytic bacterial fermentation broth against six common pathogenic bacteria was assayed by the disk diffusion test. Meanwhile, the minimum inhibitory concentrations(MICs) and the minimum bactericidal concentrations(MBCs) were also determined. Finally, the isolated strains were identified based on phenotypical and biochemical properties as well as 16S rRNA gene sequencing. The results showed that, (1)among the thirteen strains isolated, strains lzy-21, lzy-20 and lzy-1 have strong capacity of producing cellulase, protease and lipase respectively. (2)The MICs of the volatiles of lzy-20 and wnn4-3 to Escherichia coli, Enterobacter aerogenes and Bacillus subtilis were all 16 μg·mL-1. The MBCs of the them were 32, 32, 16 μg·mL-1 and 16, 32, 32 μg·mL-1, respectively. (3)The MICs of lzy-12 against Staphylococcus aureus and Yersinia enterocolitica were 16 μg·mL-1, and the MBCs of them were 32 μg·mL-1 and 16 μg·mL-1, respectively. (4)The MICs of both lzy-17 and lzy-21 against Y. enterocolitica were 16 μg·mL-1, and the MBCs were 16 μg·mL-1 and 32 μg·mL-1 respectively. Strain lzy-1 was identified as Acinetobacter pittii, which was isolated from plants for the first time. lzy-20, lzy-21, wnn4-3, lzy-12, and lzy-17 were identified as Bacillus altitudinis, B. koreensis, B. siamensis, Luteibacter pinisoli, and Paenarthrobacter nicotinovorans, respectively. The above results lay a foundation for making full use of endophytic bacteria resources to produce industrial enzymes, and further exploring the mechanisms of how endophytic bacteria interact with Artemisia argyi var. argyi ‘Qiai’.

Electroencephalogram (EEG) recordings often contain artifacts that would lower signal quality. Many efforts have been made to eliminate or at least minimize the artifacts, and most of them rely on visual inspection and manual operations, which is time/labor-consuming, subjective, and incompatible to filter massive EEG data in real-time. In this paper, we proposed a deep learning framework named Artifact Removal Wasserstein Generative Adversarial Network (AR-WGAN), where the well-trained model can decompose input EEG, detect and delete artifacts, and then reconstruct denoised signals within a short time. The proposed approach was systematically compared with commonly used denoising methods including Denoised AutoEncoder, Wiener Filter, and Empirical Mode Decomposition, with both public and self-collected datasets. The experimental results proved the promising performance of AR-WGAN on automatic artifact removal for massive data across subjects, with correlation coefficient up to 0.726±0.033, and temporal and spatial relative root-mean-square error as low as 0.176±0.046 and 0.761±0.046, respectively. This work may demonstrate the proposed AR-WGAN as a high-performance end-to-end method for EEG denoising, with many on-line applications in clinical EEG monitoring and brain-computer interfaces.

The question of the use of fashionable words as markers that contribute to the identification of social characteristics of various subjects of speech is considered. The material for the study was the texts of microblogs of the Weibo Internet platform dedicated to China. We study the use of 10 fashion words of 2021, identified by the National Center for Monitoring and Research of Language Resources. Their functioning on the Weibo Internet site is analyzed. It has been established that the majority of Weibo users belong to the younger generation. The relevance of the study is due to the desire of Chinese society to build a strong welfare state, in which a significant role is given to young people. The novelty of the work lies in the fact that earlier the analysis of fashionable words of the Chinese language in the Internet discourse as a means of characterizing the younger generation was not carried out. It is shown that fashionable words on Weibo in most cases are used in positive contexts, which can be considered as “achieving a stable development of the country”, since all microblogs are dedicated to China. The author comes to the conclusion that the topics of blogs and the nature of the use of fashionable words in youth accounts testify to the confidence of Chinese youth in their future and the future of the country.

Abstract Patients with advanced non-small cell lung cancer (NSCLC) are prone to brain metastases (BM), which essentially include brain parenchymal metastases (PM) and leptomeningeal metastases (LM). We conducted a retrospective study to comprehensively assess the clinical characteristics and risk factors of patients with advanced NSCLC who develop PM and LM. Patients with advanced NSCLC were enrolled. These patients were then divided into three groups for analysis: patients without BM (No-BM), patients with PM and patients with LM. Data on clinical characteristics of each patient at the time of diagnosis advanced NSCLC were extracted and analyzed. In addition, prediction models were developed and evaluated for PM and LM. A total of 592 patients were enrolled in the study. BM was present in 287 patients (48.5%). Among them, 185 and 102 patients had PM or LM. Patients with LM had a higher proportion of EGFR exon 21point mutations (L858R) compared to patients with No-BM and PM (p

Abstract In the ATEMPT trial, adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel plus trastuzumab (TH) for stage I HER2-positive breast cancer improved patient-reported outcomes (PROs), while maintaining excellent disease outcomes. We report treatment discontinuation and use multivariable models to compare, patient-reported toxicity and quality-of-life (QOL) by age (≤50, >50) and treatment arm at 18 months post-enrollment among 366 eligible participants randomized in a 3:1 ratio to T-DM1 or TH. T-DM1 discontinuation was higher among women >50 vs. ≤50 (23% vs. 9%, p = 0.003, Fisher’s Exact test) with 4%, 8%, and 17% of older patients discontinuing treatment by 3, 6, and 9 months, respectively. Superior QOL with T-DM1 vs. TH was observed among women ≤50 with estimated mean difference of 6.48 (95% confidence interval (CI) 0.51–12.46) and driven by better social/family well-being and breast cancer-specific sub-scores. Among women >50, T-DM1 was associated with superior physical well-being and less activity impairment, with no differences in global QOL. Older women had decreased neuropathy with T-DM1 vs. TH. De-escalated treatment regimens for HER2 positive breast cancer may have age-varying impact on treatment tolerance, toxicities and subsequent QOL, which should be considered when selecting therapy options. Clinical Trial Registration: ClinicalTrials.gov, NCT01853748

ObjectiveThe performance of government functions is an important guarantee for the standardized operation of the elderly service market. The objective of this study is to explore the optimal path for the government to govern the elderly care service market.MethodsThe tripartite evolutionary game model is proposed in the paper, which composed of local governments, private elderly care institutions and the public. Furthermore, three mechanisms, i.e. dynamic penalty and static subsidy, static penalty and dynamic subsidy, dynamic penalty and dynamic subsidy, are designed. Under these different mechanisms, the stability of each subject’s strategy choice is analyzed by using system dynamics simulation.ResultsThe introduction of dynamic mechanisms can compensate for the inability of static mechanisms to bring the system to a steady state. The dynamic penalty and dynamic subsidy mechanism allows the system to evolve to the desired point of stability. The self-discipline behavior of private elderly care institutions is positively correlated with penalties and reputation gains-losses, negatively correlated with subsidies, and not correlated with supervision rewards. Excessive subsidies will promote the collusion of private elderly institutions.ConclusionOnly when the local government adopts the dynamic penalty and dynamic subsidy mechanism will private elderly care institutions choose to operate in a fully self-disciplined manner. Reasonable adjustments of penalties, reputation gains-losses and subsidies can not only further optimize the dynamic penalty and dynamic subsidy mechanism, but also help to achieve diversified regulatory objectives of the government. This study would provide a reference for local governments seeking to develop effective regulatory policies for the elderly service market.

Abstract Semiconducting molybdenum ditelluride (MoTe2) is widely reported owing to its favorable electronic and optoelectronic properties. The effective modulation of its electrical characteristics has garnered growing attention in regard to building high‐performance MoTe2‐based complementary devices. However, the inherent Schottky barrier (SB) in MoTe2‐based devices severely inhibits the charge‐carrier injection efficiency, leading to a high contact resistance between MoTe2 and contact metals. Here, an efficient method is presented for reducing the SB height of field‐effect transistors (FETs) based on MoTe2 by in situ potassium modification. Interestingly, the electrons transported from K continuously change the electrical characteristics of MoTe2 FET from ambipolar to n‐type with an improvement of electron mobility of over one order of magnitude. Meanwhile, the contact resistance of MoTe2 FET is significantly decreased from 11.5 to 0.4 kΩ µm. By regulating the modification region spatially, it is possible to create a complementary inverter with a high gain of ≈32 at VDD = 3 V. This research demonstrates a relatively simple method for optimizing the contact for MoTe2‐based devices and tuning the electrical properties of MoTe2 for future high‐performance complementary electronics.

Neuromorphic computing architecture is considered to be a highly desirable next-generation computing architecture as it simulates the way the brain processes information. The basic device supporting such an architecture is called an artificial synapse, which possesses synapse-like functionalities. Here in this work, an Au–TiO2 composite thin film (Au nanoparticles embedding into TiO2 matrix) based memristive artificial synapse has been fabricated with excellent interface-type resistive switching (RS) characteristics. The conductivity of the device can be continuously tuned by applying different sequences of pulses, which could be analogous to the weight change of synapses. Various synaptic behaviors have been emulated, such as long-term potentiation/depression, short-term/long-term memory, learning-forgetting process, and paired-pulse facilitation. Finally, an artificial neural network for hand-written digits recognition has been constructed with an accuracy level as high as ∼90%. The excellent performance of the Au–TiO2 based device demonstrates the availability of incorporating the second phase to tune RS properties and shows its potential in a memristor for artificial synapses and neuromorphic computing with enhanced performance.

ObjectiveThe incidence of thyroid dysfunction (TD) and major depressive disorder (MDD) is increasing year by year in the general population. However, the prevalence and correlates of TD in first-episode drug-naive (FEDN) MDD patients have not been explored. This study sought to fill this gap and examine the association between TD and MDD.MethodsWe recruited 1,289 FEDN MDD patients aged 18 ~ 45 years. A total of 1,289 FEDN MDD outpatients were recruited. Demographical and suicide data were collected for each patient, and lipid profiles, thyroid function, and fasting blood glucose (FBG) levels were measured. The Hamilton Depression Scale 17 (HAMD-17) was assessed for depression.ResultsThe prevalence of TD in young FEDN MDD patients was 64.86%. Compared with those without TD, patients with TD had longer duration of illness, greater HAMD score, higher BMI, TG, TC, and LDL-C levels, and higher suicide attempt rates, but lower HDL-C and FBG levels. Further logistic regression indicated that duration of illness, HAMD score, TC, HDL-C, BMI, and FBG levels were significantly associated with TD.LimitationsNo causal relationship can be drawn due to the cross-sectional design.ConclusionTD is common in young FEDN MDD patients. So clinicians should monitor thyroid function in patients with MDD.

Objective To explore the impact of sports on aggression in children and adolescents and analyze whether different conditions in the intervention, such as type of sports, or intervention duration, have different influences on the effect of interventions. Method The study protocol was registered in PROSPERO (CRD42022361024). We performed a systematic search of Pubmed, Web of Science, Cochrane library, Embase and Scopus databases from database inception to 12 October 2022 for all studies written in English. Studies were included if they met the following PICO criteria. All analyses were carried out using the Review Manager 5.3 Software. We summarized aggression, hostility and anger scores using SMDs. Summary estimates with 95% confidence intervals were pooled using DerSimonian-Laird random effects model or fixed effects model according to between-study heterogeneity. Results A total of 15 studies were deemed eligible for inclusion in this review. The overall mean effect size indicated that sport interventions was associated with lower aggression (SMD = −0.37, 95% CI [−0.69 to −0.06], P = 0.020; I2 = 88%). Subgroup analyses showed that non-contact sports were associated with lower aggression (SMD = −0.65, 95% CI [−1.17 to −0.13], P = 0.020; I2 = 92%) but high-contact sports were not (SMD = −0.15, 95% CI [−0.55 to 0.25], P = 0.470; I2 = 79%). In addition, when intervention duration

ObjectiveTo compare and analyze the mucosal metabolites and mucosal microbiota of different parts of colon in patients with IBS.MethodsA total of 10 patients with IBS-D and six healthy controls (HC) were enrolled. All enrolled participants underwent two biopsies of the ileocecal and sigmoid colon during colonoscopy. Metabolomic profiling of one piece of tissue was conducted using desorption electrospray ionization-mass spectrometry (DESI-MS), and the gut flora of the other piece was examined using 16S rRNA sequencing. The metabolic profiles and flora of the ileocecal and sigmoid colonic mucosa in each group were further analyzed in this study.Results(1) Principal components analysis (PCA) indicated that mucosal metabolites did not differ in different parts of the colon in either the IBS-D or HC groups. (2) In the mucosal microbiome analyses, no differences between the microbiota of the two parts of the colon were found by using Principal Co-ordinates Analysis (PCoA). In IBS group, comparing with sigmoid mucosa, the chao1 richness indice was higher and the Shannon index was lower in the ileocecal mucosa (p = 0.40, p = 0.22). However, in the HC group, microbiome analysis of the ileocecal mucosa showed lower values for Chao 1 and Shannon indices than those of the sigmoid colon mucosa (p = 0.06, p = 0.86). (3) Compared with the HC group, 1,113 metabolic signal peaks were upregulated, whereas 594 metabolites were downregulated in the IBS-D samples. Moreover, the PCA of the metabolites showed significant separation between the IBS-D and HC groups. (4) Chao1 expression was significantly higher in the mucosal microbiota with IBS-D than in the HC (p = 0.03). The Shannon index was lower in IBS-D, but the difference was not statistically significant (p = 0.53). PCoA revealed a significant difference in the microflora structure between the IBS-D and HC groups.ConclusionThe mucosal metabolic profile and mucosal flora structure of the colon were similar, despite different locations in IBS and healthy subjects. IBS had abnormal colonic mucosal metabolism and flora disturbances.

Abstract β-catenin-dependent canonical Wnt signaling plays a plethora of roles in neocortex (Ncx) development, but its function in regulating the abundance of intermediate progenitors (IPs) is elusive. Here we identified neCtnnb1, an evolutionarily conserved cis-regulatory element with typical enhancer features in developing Ncx. neCtnnb1 locates 55 kilobase upstream of and spatially close to the promoter of Ctnnb1, the gene encoding β-catenin. CRISPR/Cas9-mediated activation or interference of the neCtnnb1 locus enhanced or inhibited transcription of Ctnnb1. neCtnnb1 drove transcription predominantly in the subventricular zone of developing Ncx. Knock-out of neCtnnb1 in mice resulted in compromised expression of Ctnnb1 and the Wnt reporter in developing Ncx. Importantly, knock-out of neCtnnb1 lead to reduced production and transit-amplification of IPs, which subsequently generated fewer upper-layer Ncx projection neurons (PNs). In contrast, enhancing the canonical Wnt signaling by stabilizing β-catenin in neCtnnb1-active cells promoted the production of IPs and upper-layer Ncx PNs. ASH2L was identified as the key trans-acting factor that associates with neCtnnb1 and Ctnnb1’s promoter to maintain Ctnnb1’s transcription in both mouse and human Ncx progenitors. These findings advance understanding of transcriptional regulation of Ctnnb1, and provide insights into mechanisms underlying Ncx expansion during development.

Abstract Mechanical control of ferroelectric domain evolution has attracted much interest over the past decade. Nevertheless, bidirectional 180° mechanical switching, i.e., a complete cycle of mechanical writing and then erasing of a ferroelectric nanodomain, has not yet been realized in tip-film architectures. Here, via first-principles-based molecular dynamics simulations, we demonstrate that bidirectional 180° mechanical switching is possible in tip-film architectures when screening condition of ferroelectric films and tip loading force are within an appropriate window. The switching utilizes a delicate competition between the flexoelectric field and an overlooked effective dipolar field. The effective dipolar field dominates at small tip force and trigger switching from a downward single-domain state to an upward poly-domain state, whereas the flexoelectric field dominates at relatively large tip force and enables a back-switching. Bidirectional mechanical switching is achieved by applying tip force pulses with alternatively varying strength. The dipole-dipole interaction dynamics play important roles in mechanical switching.

The objective is to examine the separate and joint effects of dynapenia and abdominal obesity on the prevalence of peripheral artery disease (PAD) in older adults of different ages (60-74 and over 75 years old). This study comprised 1293 community-dwelling Chinese participants recruited from Shanghai, China, who were aged at least 60 years (753 women; mean age: 72.0 ± 5.9 years). Dynapenia was defined as low-grip strength (

Objective: Postoperative infection is a common but costly complication. The neutrophil-lymphocyte ratio is a promising marker for the identification of postsurgical infectious events. We aimed to perform this meta-analysis to assessed the accuracy of the neutrophil-lymphocyte ratio for the prediction of postsurgical infection. Methods: We searched PubMed, Embase, Web of Science, and Cochrane Library without language restriction from their inceptions to April 2022, and checked reference lists of included studies. Studies were included if they assessed predictive accuracy of neutrophil-lymphocyte ratio for postsurgical infection. We estimated its predictive value and explored the source of heterogeneity. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to assess methodological quality and the Deeks’ test to evaluate publication bias. The bivariate model and hierarchical summary receiver operating characteristic (HSROC) curve were used for meta-analysis and generated a summary receiver operating characteristic space (ROC) curve. Results: Our search returned 379 reports, of which 12 fulfilled the inclusion criteria, accounting for 4375 cases. The bivariate analysis yielded a pooled sensitivity of 0.77 (95%C.I.: 0.65–0.85) and specificity of 0.78 (95%C.I.: 0.67–0.86). Pooled positive LR and negative LR were 3.48 (95%C.I.: 2.26–5.36) and 0.30 (95%C.I.: 0.20–0.46), respectively. A negative LR of 0.30 reduces the post-test probability to 2% for a negative test result. The area under of receiver operating characteristic curve was 0.84 (95%C.I.: 0.80–0.87). Subgroups comparisons revealed difference by study design, surgical site, presentence of implant, time of sampling, type of infection event and prevalence of infection. The Deeks’ test showed no publication bias. The sensitivity analysis showed no study affected the robustness of combined results. Conclusions: Low-certainty evidence suggests that the neutrophil-lymphocyte ratio is a helpful marker for predicting postoperative infectious complication. The negative predictive value of the neutrophil-lymphocyte ratio enables for reliable exclusion of postoperative infection.Trial registrationPROSPERO registration number CRD42022321197. Registered on 27 April 2022.