Search

Abstract Background Limited data exists on the efficacy of immune checkpoint inhibitor (ICI) combinations in non-small-cell lung cancer (NSCLC) with uncommon driver alterations in genes such as ERBB2, BRAF, RET, and MET. This study retrospectively assessed ICI-combination therapy outcomes in this molecular subset of NSCLC. Methods We retrospectively analyzed patients with advanced NSCLC confirmed with driver alterations in genes including ERBB2, BRAF, RET or MET, and received ICI combined with chemotherapy (ICI + chemo) and/or targeted therapy (ICI + chemo/TT) as first-line (1L) or second- or third-line (≥ 2L) treatment at Hunan Cancer Hospital between January 2018 and May 2024. Results Of the 181 patients included in the study, 131 patients received 1L-ICI + chemo (ERBB2, n = 64; BRAF, n = 34; RET, n = 23; and MET, n = 10), and 50 patients received ≥ 2L-ICI + chemo/TT (ERBB2, n = 16; BRAF, n = 7; RET, n = 14; MET, n = 13). The full cohort had an overall response rate (ORR) of 45.9% and disease control rate of 84.0%. Among patients who received 1L-ICI + chemo, ORR ranged between 51.6% and 60.0%, with the median progression-free survival (mPFS) and overall survival (mOS) of 8.2 and 21.0 months for those with ERBB2-altered tumors, 10.0 and 15.0 months for BRAF-altered tumors, 12.1 months and OS not reached for RET-altered tumors, and 6.2 and 28.0 months for MET-altered tumors, respectively. Additionally, ORR ranged between 14.3% and 30.8% for ≥ 2L-ICI + chemo/TT; mPFS and mOS were 5.4 and 16.2 months for patients with ERBB2-altered tumors, 2.7 and 5.0 months for BRAF-altered tumors, 6.2 and 14.3 months for RET-altered tumors, and 5.7 and 11.5 months for MET-altered tumors, respectively. Conclusion ICI-based combination therapies, regardless of treatment line, were effective in treating patients with advanced NSCLC harboring driver alterations in ERBB2, BRAF, RET, or MET. This suggests their potential as alternative treatment options in this patient population.

Abstract SARS-CoV-2 infection is initiated by Spike glycoprotein binding to the human angiotensin-converting enzyme 2 (ACE2) receptor via its receptor binding domain. Blocking this interaction has been proven to be an effective approach to inhibit virus infection. Here we report the discovery of a neutralizing nanobody named VHH60, which was directly produced from an engineering nanobody library based on a commercialized nanobody within a very short period. VHH60 competes with human ACE2 to bind the receptor binding domain of the Spike protein at S351, S470-471and S493-494 as determined by structural analysis, with an affinity of 2.56 nM. It inhibits infections of both ancestral SARS-CoV-2 strain and pseudotyped viruses harboring SARS-CoV-2 wildtype, key mutations or variants at the nanomolar level. Furthermore, VHH60 suppressed SARS-CoV-2 infection and propagation 50-fold better and protected mice from death for twice as long as the control group after SARS-CoV-2 nasal infections in vivo. Therefore, VHH60 is not only a powerful nanobody with a promising profile for disease control but also provides evidence for a highly effective and rapid approach to generating therapeutic nanobodies.

Abstract The escalation of urban traffic congestion has reached a critical extent due to rapid urbanization, capturing considerable attention within urban science and transportation research. Although preceding studies have validated the scale-free distributions in spatio-temporal congestion clusters across cities, the influence of travel demand on that distribution has yet to be explored. Using a unique traffic dataset during the COVID-19 pandemic in Shanghai 2022, we present empirical evidence that travel demand plays a pivotal role in shaping the scaling laws of traffic congestion. We uncover a noteworthy negative linear correlation between the travel demand and the traffic resilience represented by scaling exponents of congestion cluster size and recovery duration. Additionally, we reveal that travel demand broadly dominates the scale of congestion in the form of scaling laws, including the aggregated volume of congestion clusters, the number of congestion clusters, and the number of congested roads. Subsequent micro-level analysis of congestion propagation also unveils that cascade diffusion determines the demand sensitivity of congestion, while other intrinsic components, namely spontaneous generation and dissipation, are rather stable. Our findings of traffic congestion under diverse travel demand can profoundly enrich our understanding of the scale-free nature of traffic congestion and provide insights into internal mechanisms of congestion propagation.

Ischemic heart disease refers to the imbalance between the supply and demand of myocardial blood; it has various causes and results in a class of clinical diseases characterized by myocardial ischemia (MI). In recent years, the incidence of cardiovascular disease has become higher and higher, and the number of patients with ischemic heart disease has also increased year by year. Traditional treatment methods include drug therapy and surgical treatment, both of which have limitations. The former maybe develop risks of drug resistance and has more significant side effects, while the latter may damage blood vessels and risk infection. At this stage, a new cell-free treatment method needs to be explored. Many research results have shown that exosomes from different cell sources can protect the ischemic myocardium via intercellular action methods, such as promoting angiogenesis, inhibiting myocardial fibrosis, apoptosis and pyroptosis, and providing a new basis for the treatment of MI. In this review, we briefly introduce the formation and consequences of myocardial ischemia and the biology of exosomes, and then focus on the role and mechanism of exosomes from different sources in MI. We also discuss the role and mechanism of exosomes pretreated with Chinese and Western medicines on myocardial ischemia. We also discuss the potential of exosomes as diagnostic markers and therapeutic drug for MI.

Thirteen previously undescribed lindenane sesquiterpenoid dimers (LSDs), named chlorahololides G–S (1–13), were isolated from the whole plants of Chloranthus holostegius var. shimianensis, along with ten known analogues (14–23). The structures and absolute configurations of compounds 1–13 were elucidated through comprehensive spectroscopic analysis, NMR and electronic circular dichroism (ECD) calculations, and X-ray single-crystal diffraction. Chlorahololide G (1) represents the first instance of LSDs formed via a C-15–C-9′ carbon-carbon single bond, whose plausible biosynthetic pathway was also proposed. Chlorahololides I and J (3 and 4) were deduced to be rare 8,9-seco and 9-deoxy LSDs with C-11–C-7′ carbon-carbon bond, respectively. The inhibitory activity against NLRP3 inflammasome activation was evaluated for all isolates, with six compounds (5, 7, 8, 17, 22, and 23) exhibiting significant effects, and IC50 values ranging from 2.99 to 8.73 µM. Additionally, a preliminary structure-activity relationship analysis regarding their inhibition of NLRP3 inflammasome activation was summarized. Compound 17 exhibited dose-dependent inhibition of nigericin-induced pyroptosis in J774A.1 cells. Molecular docking studies suggested a strong interaction between compound 17 and NLRP3.

In this study, the properties of controlled low strength material (CLSM) made from waste soil were examined, utilizing 53 different mix proportions, and a dataset was subsequently constructed. Models, such as particle swarm optimization (PSO)-support vector regression (SVR), genetic algorithm (GA)-SVR, and grid search (GS)-SVR, were developed to predict both flowability and unconfined compressive strength (UCS). To assess the models’ performance, comparisons between experimental and predicted values, residual distribution histograms, and evaluation criteria were conducted. Results revealed that all three models effectively predicted the flowability and UCS of CLSM made from waste soil. Predicted values closely aligned with experimental values in both training and testing sets. Notably, GA-SVR exhibited greater accuracy when compared to PSO-SVR and GS-SVR. Evaluation criteria, including correlation coefficient (R2), mean square error (MSE), root mean square error (RMSE), mean absolute error (MAE), and mean absolute percentage error (MAPE) for GA-SVR in assessing flowability were 0.948, 77.899, 8.826, 7.608, and 3.061 %, respectively. Correspondingly, for UCS, the values were 0.934, 0.032, 0.178, 0.115, and 8.956 %, respectively. Furthermore, the histogram depicting the residual distribution of the GA-SVR model closely resembled a normal distribution, characterized by a small mean and standard deviation. Extending the analysis to 45 compression strength data points obtained from public literature, the three models continued to demonstrate effective predictive capabilities, with the GA-SVR model outperforming the others. The evaluation criteria, including R2, MSE, RMSE, MAE, and MAPE in this context were 0.909, 0.011, 0.105, 0.085, and 15.502 %, respectively. Shapley additive explanation (SHAP) values highlighted water as the most crucial input variable in the flowability model. Additionally, water, superplasticizer (SP), and sand positively impacted flowability, whereas soil, fly ash (FA), and cement exerted negative effects. In the UCS model, curing age (CA) emerged as the most important input variable. CA, cement, FA, sand, and soil positively influenced UCS, while water and SP had negative effects. This study is of considerable importance in the accurate prediction and evaluation of CLSM engineering properties, as well as in optimizing mix proportions.

Background: Gastrointestinal perforation in extremely low birth weight infants, characterized by its rapid onset, multiple complications, and critical condition, poses a significant risk of infant mortality. The aim of this study was to investigate the clinical characteristics of pneumoperitoneum in extremely low birth weight infants (ELBWI) and explore the risk factors associated with gastrointestinal perforation in very low birth weight preterm infants. Additionally, we shared our surgical experiences in managing gastrointestinal perforation among extremely low birth weight infants. Methods: The Department of Neonatology at Chengdu Women and Children's Central Hospital conducted a retrospective study on gastrointestinal perforation in extremely low birth weight infants (birth weight

Abstract To explore the differences and relationships between the available SARS-CoV-2 strains and predict the potential evolutionary direction of these strains, we employ the hierarchical clustering analysis to investigate the evolutionary relationships between the SARS-CoV-2 strains utilizing the genomic sequences collected in China till January 7, 2023. We encode the sequences of the existing SARS-CoV-2 strains into numerical data through k-mer algorithm, then propose four methods to select the representative sample from each type of strains to comprise the dataset for clustering analysis. Three hierarchical clustering algorithms named Ward-Euclidean, Ward-Jaccard, and Average-Euclidean are introduced through combing the Euclidean and Jaccard distance with the Ward and Average linkage clustering algorithms embedded in the OriginPro software. Experimental results reveal that BF.28, BE.1.1.1, BA.5.3, and BA.5.6.4 strains exhibit distinct characteristics which are not observed in other types of SARS-CoV-2 strains, suggesting their being the majority potential sources which the future SARS-CoV-2 strains’ evolution from. Moreover, BA.2.75, CH.1.1, BA.2, BA.5.1.3, BF.7, and B.1.1.214 strains demonstrate enhanced abilities in terms of immune evasion, transmissibility, and pathogenicity. Hence, closely monitoring the evolutionary trends of these strains is crucial to mitigate their impact on public health and society as far as possible.

Abstract Aims We previously showed that the nab-paclitaxel plus S-1 (NPS) regimen had promising effects against metastatic pancreatic ducal adenocarcinoma (mPDAC), whose efficacy however could not be precisely predicted by routine biomarkers. This prospective study aimed to investigate the values of mutations in circulating tumor DNA (ctDNA) and their dynamic changes in predicting response of mPDAC to NPS chemotherapy. Methods Paired tumor tissue and blood samples were prospectively collected from patients with mPDAC receiving first-line NPS chemotherapy, and underwent next-generation sequencing with genomic profiling of 425 genes for ctDNA. High mutation allelic frequency (MAF) was defined as ≥ 30% and ≥ 5% in tumor tissue and blood, respectively. Kappa statistics were used to assess agreement between mutant genes in tumor and ctDNA. Associations of mutations in ctDNA and their dynamic changes with tumor response, overall survival (OS), and progression-free survival (PFS) were assessed using the Kaplan–Meier method, multivariable-adjusted Cox proportional hazards regression, and longitudinal data analysis. Results 147 blood samples and 43 paired tumor specimens from 43 patients with mPDAC were sequenced. The most common driver genes with high MAF were KRAS (tumor, 35%; ctDNA, 37%) and TP53 (tumor, 37%; ctDNA, 33%). Mutation rates of KRAS and TP53 in ctDNA were significantly higher in patients with liver metastasis, with baseline CA19-9 ≥ 2000 U/mL, and/or without an early CA19-9 response. κ values for the 5 most commonly mutated genes between tumor and ctDNA ranged from 0.48 to 0.76. MAFs of the genes mostly decreased sequentially during subsequent measurements, which significantly correlated with objective response, with an increase indicating cancer progression. High mutations of KRAS and ARID1A in both tumor and ctDNA, and of TP53, CDKN2A, and SMAD4 in ctDNA but not in tumor were significantly associated with shorter survival. When predicting 6-month OS, AUCs for the 5 most commonly mutated genes in ctDNA ranged from 0.59 to 0.84, larger than for genes in tumor (0.56 to 0.71) and for clinicopathologic characteristics (0.51 to 0.68). Repeated measurements of mutations in ctDNA significantly differentiated survival and tumor response. Among the 31 patients with ≥ 2 ctDNA tests, longitudinal analysis of changes in gene MAF showed that ctDNA progression was 60 and 58 days ahead of radiologic and CA19-9 progression for 48% and 42% of the patients, respectively. Conclusions High mutations of multiple driving genes in ctDNA and their dynamic changes could effectively predict response of mPDAC to NPS chemotherapy, with promising reliable predictive performance superior to routine clinicopathologic parameters. Inspiringly, longitudinal ctDNA tracking could predict disease progression about 2 months ahead of radiologic or CA19-9 evaluations, with the potential to precisely devise individualized therapeutic strategies for mPDAC.

Background: Circular RNAs (circRNAs) are involved in the progression of colon cancer (CC). This study aimed to examine the role of a new circRNA circ_0101050 in CC. Methods: Dual-luciferase reporter and RNA immunoprecipitation analyses were performed to validate the target relationships among maternal embryonic leucine zipper kinase (MELK), microRNA (miR)-140–3 p, and circ_0101050. Expression levels were calculated using western blotting and/or quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Western blotting was performed to evaluate the relative expression of Bcl-2 and Bax proteins to determine cell death. Cell Counting Kit-8 (CCK-8) and colony formation assays were performed to determine the proliferative potential of CC cells. The migration rate of CC cells was evaluated using wound healing assays. Tumor formation tests were performed to determine the effect of circ_0101050 on tumor development in vivo. Results: Elevated levels of circ_0101050 and MELK were observed in CC. By inhibiting circ 0,101,050 or MELK, CC cell proliferation and migration were inhibited, but CC cell apoptosis was promoted. Silencing circ_0101050 also inhibited CC growth in vivo. We also found that miR-140–3 p was downregulated, which alleviated the repressive effects of circ_0101050 knockdown on proliferating and migrating CC cells, as well as the stimulating effect on apoptosis. In addition, the absence of MELK alleviated the effects of miR-140–3 p downregulation, which enhanced CC cell malignancy. Conclusions: Circ_0101050 exacerbates malignant phenotypes in CC by targeting the miR-140–3 p/MELK axis. These findings suggested that the circ_0101050/miR-140–3 p/MELK network may be a prospective target for CC treatment.

Patients with non-small cell lung cancer (NSCLC) and anaplastic lymphoma kinase (ALK) mutations have previously derived substantial benefits from ALK tyrosine kinase inhibitors (ALK-TKIs). However, resistance may develop in some patients. We present a case of co-mutation with anaplastic lymphoma kinase (ALK) and rearranged during transfection (RET)-rearranged NSCLC, representing a novel resistance mechanism to ALK-TKIs, in which the patient exhibited a favorable response to combination therapy with ensartinib and pralsetinib. Notably, the patient survived 12 months without experiencing adverse events, a rare occurrence in ALK-rearranged lung adenocarcinoma cases. This case provides further evidence for the existence of RET rearrangements in ALK-positive lung cancer and their potential treatment response to a combination of ALK inhibitors and pralsetinib. This case underscores that a dual-target therapy involving ALK inhibitors, specifically ensartinib and pralsetinib, could be a viable approach in cases of RET-rearranged lung cancer with concurrent targetable ALK mutations. We propose the consideration of this dual-target approach, specifically employing ensartinib and pralsetinib, in managing RET-rearranged lung cancer coexisting with targetable ALK mutations. Given the potential efficacy of these treatments, it is imperative to proactively conduct molecular profiling tests in NSCLC patients upon the emergence of resistance.

Pregabalin is the first-line treatment for neuropathic pain. Cases of cutaneous hypersensitivity reactions caused by pregabalin generally occur within 2 weeks of initiating medication. We report a rare case of a delayed cutaneous hypersensitivity reaction caused by pregabalin, which was confirmed by a drug provocation test. A 72-year-old man with severe herpes zoster neuralgia developed maculopapular drug eruption covering 80% to 90% of his total body surface area after 40 days of combined multidrug analgesia. A drug provocation test for pregabalin was positive. The time interval between initiating medication and the onset of the patient’s rash was the longest and he also had the largest area of skin affected compared with patients with a similar condition in previous related reports. Remaining vigilant for possible adverse cutaneous hypersensitivity reactions during treatment is important because of the long-term course of pregabalin treatment for neuropathic pain.

Abstract Background Immunotherapy in combination with platinum-etoposide (EP) chemotherapy has been approved as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). However, real-world (RW) data regarding the use of immune checkpoint inhibitors (ICIs) in ES-SCLC are lacking. We aimed to assess the differences between programmed death protein 1 (PD-1) inhibitors and programmed death ligand 1 (PD-L1) inhibitors, both in conjunction with EP chemotherapy, as first-line treatment for ES SCLC. Methods We conducted a real-world, multicenter, retrospective cohort, controlled study to compare the prognosis, efficacy, and safety of PD-1 and PD-L1 inhibitors in ES-SCLC patients when used along with chemotherapy. Each patient received up to six cycles of etoposide, carboplatin, or cisplatin combined with ICI drugs, including PD-1 and PD-L1 inhibitors. The primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). The secondary endpoints were the investigator-assessed objective response rate (ORR) and disease control rate (DCR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Results Between January 2017 and December 2021, 194 patients with ES-SCLC from three clinical centers in a PLA general hospital were included in our study, including 93 patients in the PD-1 group and 101 patients in the PD-L1 group. At the time of data cutoff, progression-free survival in the PD-1 group (median PFS, 6.8 months; 95% CI, 5.3–8.1) was similar to that in the PD-L1 group (median PFS, 6.4 months; 95% CI, 5.5–7.5); the stratified hazard ratio for PFS was 1.12 (95% CI, 0.83–1.53; P = 0.452). The median OS was similar in the PD-1 and PD-L1 groups (15.8 m vs. 17.7 m, P = 0.566); the hazard ratio was 0.90 (95% CI, 0.62–1.30, P = 0.566). The two groups had comparable investigator-assessed confirmed objective response rates (ORR) (76.3% vs. 76.2%). Adverse effect (AE)-related discontinuation occurred in 4 (4.3%) patients in the PD-1 group and 2 (2.0%) patients in the PD-L1 group. Deaths due to AEs of any cause occurred in 2 (2.2%) patients in the PD-1 inhibitor group and 1 (1.0%) patient in the PD-L1 inhibitor group. Conclusions Our research revealed that there were no significant differences in efficacy or prognosis between PD-1 inhibitor + EP chemotherapy and PD-L1 inhibitor + EP chemotherapy. The two groups seemed to have comparable safety profiles, but the number of discontinuation or death events was too small to draw a firm conclusion.

Abstract Vehicle trajectory data underpins various applications in intelligent transportation systems, such as traffic surveillance, traffic prediction, and traffic control. Traditional vehicle trajectory datasets, recorded by GPS devices or single cameras, are often biased towards specific vehicles (e.g., taxis) or incomplete (typically

Abstract Aim Analysed clinical characteristics and influencing factors for hypoglycemia in hospitalized patients with type 2 diabetes mellitus (T2DM), and providing a scientific reference for precision nursing care of hypoglycemia in hospitalized patients with T2DM. Design A cross‐sectional study. Methods This study involved 378 hospitalized patients diagnosed with T2DM who have suffered hypoglycemia. Through questionnaires and electronic medical records to obtain the data concerning the general information, clinical symptoms, all recorded blood glucose information, and the diabetes knowledge and self‐management level of the patients. The clinical characteristics and influencing factors for hypoglycemia were analysed on the basis of the classification of hypoglycemia published by the American Diabetes Association in 2020. Results Among 378 patients, 207 patients (54.76%) were experiencing Grade 1 hypoglycemia and 171 patients (45.24%) were experiencing Grade 2 hypoglycemia. Hypoglycemia and Grade 2 hypoglycemia in patients with T2DM occurred predominantly within the first 3 days of hospitalization. Hypoglycemia occurred most frequently after breakfast (74 cases, 19.6%), of which Grade 1 hypoglycemia and Grade 2 hypoglycemia accounted for 50%, respectively. Multivariable logistic regression identified risk factors for Grade 2 hypoglycemia in hospitalized patients with type 2 diabetes: older age, longer duration of diabetes, low body weight, diabetic nephropathy stages 4–5, diabetic autonomic neuropathy, inadequate self‐management ability and diabetes knowledge, and lower educational background. Conclusions Hypoglycemia in type 2 diabetes occurs in the first 3 days during the hospitalization and most often after breakfast during the full day. Identifying high‐risk individuals and providing a scientific reference for precision nursing care of hypoglycemia in hospitalized patients with T2DM.

The integration of renewable energy units into power systems brings a huge challenge to the flexible regulation ability. As an efficient and convenient flexible resource, energy storage systems (ESSs) have the advantages of fast-response characteristics and bi-directional power conversion, which can provide flexible support for the power system. This paper establishes an optimization model for the ESS based on a bi-level programming model. The upper-level model optimizes the decision strategy of ESS configuration planning. The lower-level model is based on scenario analysis theory to simulate the operation of typical daily scenarios. Flexibility requirement constraints are added to characterize the required flexibility resources of the power system. In addition, the conditional value-at-risk (CVaR) is applied to characterize the risk of wind curtailment and load shedding during operation. To simplify the model, a set of association constraints is introduced to convert the original bi-level programming model into a direct-solvable single-level mixed-integer linear programming (MILP) model. Finally, the effectiveness of the proposed model is verified through case studies.

Most of vaccinees and COVID-19 convalescents can build effective anti-SARS-CoV-2 humoral immunity, which helps preventing infection and alleviating symptoms. However, breakthrough viral infections caused by emerging SARS-CoV-2 variants, especially Omicron subvariants, still pose a serious threat to global health. By monitoring the viral infections and the sera neutralization ability of a long-tracked cohort, we found out that the immune evasion of emerging Omicron subvariants and the decreasing neutralization led to the mini-wave of SARS-CoV-2 breakthrough infections. Meanwhile, no significant difference had been found in the infectivity of tested SARS-CoV-2 variants, even though the affinity between human angiotensin-converting enzyme 2 (hACE2) and receptor-binding domain (RBDs) of tested variants showed an increasing trend. Notably, the immune imprinting of inactivated COVID-19 vaccine can be relieved by infections of BA.5.2 and XBB.1.5 variants sequentially. Our data reveal the rising reinfection risk of immune evasion variants like Omicron JN.1 in China, suggesting the importance of booster with updated vaccines.

A novel environmentally friendly resorcinol–formaldehyde-free impregnation solution was successfully developed to enhance the interfacial adhesion of ultra-high molecular weight polyethylene (UHMWPE) fiber cords with rubber. The UHMWPE fiber cords were first treated by dopamine (DA) and N-(β-aminoethyl)-γ-aminopropylmethyldimethoxysilane (KH602), followed by impregnation in a mixture of glycerol triglycidyl ether (GTE), diethylenetriamine (DETA) and vinyl pyridine latex. Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) were used to characterize the chemical composition of the fiber cords surface. The results showed that the impregnation process successfully modified the surface of the UHMWPE fiber cords and did not deteriorate the fiber strength. The H pull-out results showed that the adhesion strength between the modified UHMWPE fiber cords and the rubber increased by 257 % compared to the untreated cords. In addition, scanning electron microscopy-energy dispersive spectrometry (SEM-EDS) was employed to characterize the interface morphology of the fiber cords/rubber composites. The formation of a transition layer and the migration of the curatives contributed to the improvement in the interfacial adhesive properties.

Angiotensin-converting enzyme 2 (ACE2) was recognized as an entry receptor shared by coronaviruses from Sarbecovirus and Setracovirus subgenera, including three human coronaviruses: SARS-CoV, SARS-CoV-2, and NL63. We recently disclosed that NeoCoV and three other merbecoviruses (PDF-2180, MOW15-22, PnNL 2018B), which are MERS-CoV relatives found in African and European bats, also utilize ACE2 as their functional receptors through unique receptor binding mechanisms. This unexpected receptor usage assumes significance, particularly in light of the prior recognition of Dipeptidyl peptidase-4 (DPP4) as the only known protein receptor for merbecoviruses. In contrast to other ACE2-using coronaviruses, NeoCoV and PDF-2180 engage a distinct and relatively compact binding surface on ACE2, facilitated by protein-glycan interactions, which is demonstrated by the Cryo-EM structures of the receptor binding domains (RBDs) of these viruses in complex with a bat ACE2 orthologue. These findings further support the hypothesis that phylogenetically distant coronaviruses, characterized by distinct RBD structures, can independently evolve to acquire ACE2 affinity during inter-species transmission and adaptive evolution. To date, these viruses have exhibited limited efficiency in entering human cells, although single mutations like T510F in NeoCoV can overcome the incompatibility with human ACE2. In this review, we present a comprehensive overview of ACE2-using merbecoviruses, summarize our current knowledge regarding receptor usage and host tropism determination, and deliberate on potential strategies for prevention and intervention, with the goal of mitigating potential future outbreaks caused by spillover of these viruses.

Tumor-associated macrophages (TAMs) are critical in the tumor microenvironment (TME) of hepatocellular carcinoma (HCC). Major vault protein (MVP) mediates multidrug resistance, cell growth and development, and viral immunity. However, the relationship between MVP and TAMs polarization has not been clarified in HCC. We found that MVP significantly increased M2-TAMs infiltration levels in tumor tissues of HCC patients. MVP promoted HCC proliferation, metastasis, and invasion by regulating M2 polarization in vivo and in vitro. Mechanistically, MVP associated with signal transducer and activator of transcription 6 (STAT6) and enhanced STAT6 phosphorylation. STAT6 translocated from the cytosol to the nucleus and regulated M2 macrophage-associated gene transcription. These findings suggest that MVP modulates the macrophage M2 transcriptional program, revealing its potential role in the TAMs of TME.

Abstract Coronavirus disease 2019 (COVID-19) was first reported three years ago, when a group of individuals were infected with the original SARS-CoV-2 strain, based on which vaccines were developed. Here, we develop six human monoclonal antibodies (mAbs) from two elite convalescents in Wuhan and show that these mAbs recognize diverse epitopes on the receptor binding domain (RBD) and can inhibit the infection of SARS-CoV-2 original strain and variants of concern (VOCs) to varying degrees, including Omicron strains XBB and XBB.1.5. Of these mAbs, the two most broadly and potently neutralizing mAbs (7B3 and 14B1) exhibit prophylactic activity against SARS-CoV-2 WT infection and therapeutic effects against SARS-CoV-2 Delta variant challenge in K18-hACE2 KI mice. Furthermore, post-exposure treatment with 7B3 protects mice from lethal Omicron variants infection. Cryo-EM analysis of the spike trimer complexed with 14B1 or 7B3 reveals that these two mAbs bind partially overlapped epitopes onto the RBD of the spike, and sterically disrupt the binding of human angiotensin-converting enzyme 2 (hACE2) to RBD. Our results suggest that mAbs with broadly neutralizing activity against different SARS-CoV-2 variants are present in COVID-19 convalescents infected by the ancestral SARS-CoV-2 strain, indicating that people can benefit from former infections or vaccines despite the extensive immune escape of SARS-CoV-2.

Abstract MAVS is an adapter protein involved in RIG-I-like receptor (RLR) signaling in mitochondria, peroxisomes, and mitochondria-associated ER membranes (MAMs). However, the role of MAVS in glucose metabolism and RLR signaling cross-regulation and how these signaling pathways are coordinated among these organelles have not been defined. This study reports that RLR action drives a switch from glycolysis to the pentose phosphate pathway (PPP) and the hexosamine biosynthesis pathway (HBP) through MAVS. We show that peroxisomal MAVS is responsible for glucose flux shift into PPP and type III interferon (IFN) expression, whereas MAMs-located MAVS is responsible for glucose flux shift into HBP and type I IFN expression. Mechanistically, peroxisomal MAVS interacts with G6PD and the MAVS signalosome forms at peroxisomes by recruiting TNF receptor-associated factor 6 (TRAF6) and interferon regulatory factor 1 (IRF1). By contrast, MAMs-located MAVS interact with glutamine-fructose-6-phosphate transaminase, and the MAVS signalosome forms at MAMs by recruiting TRAF6 and TRAF2. Our findings suggest that MAVS mediates the interaction of RLR signaling and glucose metabolism.

Gears fabricated using powder metallurgy technique (PMT) have the potential to replace traditional wrought gears due to their very high forming efficiency and relatively low cost. However, their practical applications are restricted due to the lack of understanding of their fatigue properties and failure mechanisms. This work investigates the contact fatigue performance and corresponding failure mechanism of a typical Fe-based small-module gears fabricated by PMT. The fatigue tests were conducted under grease lubrication condition, using a power-opened small-module gear testing rig. The experimental results show that the current PMT fabricated small-module gears exhibit contact fatigue properties comparable to those of traditional wrought steel gears. It has been found that the subsurface cracks induced from pores are the dominant cause of spalling of PMT fabricated small-module gears during rolling contact. The cracks tend to propagate between adjacent pores, playing a vital role in the overall fatigue life. Thus, this study suggests that PMT can be a successful method for fabricating Fe-based small-module gears with excellent contact fatigue property if formation of pores during fabrication is well inhibited.

Abstract Recently, two Middle East respiratory syndrome coronavirus (MERS-CoV) closely related to bat merbecoviruses, NeoCoV and PDF-2180, were discovered to use angiotensin-converting enzyme 2 (ACE2) for entry. The two viruses cannot use human ACE2 efficiently, and their host range and cross-species transmissibility across a wide range of mammalian species remain unclear. Herein, we characterized the species-specific receptor preference of these viruses by testing ACE2 orthologues from 49 bats and 53 non-bat mammals through receptor-binding domain (RBD)-binding and pseudovirus entry assays. Results based on bat ACE2 orthologues revealed that the two viruses were unable to use most, but not all, ACE2 from Yinpterochiropteran bats (Yin-bats), which is distinct from NL63 and SARS-CoV-2. Besides, both viruses exhibited broad receptor recognition spectra across non-bat mammals. Genetic and structural analyses of bat ACE2 orthologues highlighted four crucial host range determinants, all confirmed by subsequent functional assays in human and bat cells. Notably, residue 305, participating in a critical viral receptor interaction, plays a crucial role in host tropism determination, particularly in non-bat mammals. Furthermore, NeoCoV and PDF-2180 mutants with enhanced human ACE2 recognition expanded the potential host range, especially by enhancing their interaction with an evolutionarily conserved hydrophobic pocket. Our results elucidate the molecular basis for the species-specific ACE2 usage of MERS-related viruses and shed light on their zoonotic risks.

The creation of safe and effective vaccines that induce potent cellular and humoral immune responses against SARS-CoV-2 is urgently needed to end the global COVID-19 epidemic. Here, we developed an alphavirus-derived self-replicating RNA (repRNA)-based vaccine platform encoding the receptor-binding domain (RBD) of SARS-CoV-2 spike glycoprotein. The repRNA triggers prolonged antigen expression compared with conventional mRNA due to the replication machinery of repRNA. To improve the delivery and vaccine efficacy of repRNA, we developed a self-assembling liposome-protamine-RNA (LPR) nanoparticle with highly efficient encapsulation and transfection of repRNA. LPR-repRNA vaccines substantially activated type I interferon response and innate immune signaling pathways. Subcutaneous immunization of LPR-repRNA-RBD led to prolonged antigen expression, stimulation of innate immune cells, and induction of germinal center response in draining lymph nodes. LPR-repRNA-RBD induced antigen-specific T cell responses and skewed cellular immunity toward an effector memory CD8+ T cell response. Immunizations with LPR-repRNA-RBD triggered the production of anti-RBD IgG antibodies and induced neutralizing antibody response against SARS-CoV-2 pseudovirus. LPR-repRNA-RBD vaccines reduced SARS-CoV-2 infection and lung inflammation in mice. Altogether, these data suggest that the LPR-repRNA platform can be a promising avenue for COVID-19 vaccine development.

Abstract Background Immune checkpoint inhibitors (ICI)-based combination strategies have improved the survival outcomes in advanced non-small cell lung cancers; however, data regarding their efficacy remains limited for uncommon histological types, including large-cell carcinoma (LCC) and large-cell neuroendocrine carcinoma (LCNEC). Methods We retrospectively analyzed a total of 60 patients with advanced LCC and LCNEC – 37 treatment-naïve and 23 pre-treated – who received pembrolizumab with or without chemotherapy. Treatment and survival outcomes were analyzed. Results Of the 37 treatment-naïve patients who received first-line pembrolizumab combined with chemotherapy, the 27 patients with LCC had an overall response rate (ORR) of 44.4% (12/27) and a disease control rate (DCR) of 88.9% (24/27); whereas 10 patients with LCNEC had an ORR of 70% (7/10) and DCR of 90% (9/10). The median progression-free survival (mPFS) was 7.0 months (95% confidence intervals [CI]: 2.2–11.8) and median overall survival (mOS) was 24.0 months (95%CI: 0.0–50.1) for first-line pembrolizumab plus chemotherapy of LCC (n = 27), whereas mPFS was 5.5 months (95%CI: 2.3–8.7) and mOS was 13.0 months (95%CI: 11.0–15.0) for first-line pembrolizumab plus chemotherapy of LCNEC (n = 10). Of the 23 pre-treated patients who received subsequent-line pembrolizumab with or without chemotherapy, mPFS was 2.0 months (95% CI: 0.6–3.4) and mOS was 4.5 months (95% CI: 0.0–9.0) for LCC and mPFS was 3.8 months (95% CI: 0.0–7.6) and mOS was not reached for LCNEC. Conclusion Our study provides real-world clinical evidence of the anti-tumor activity of pembrolizumab plus chemotherapy in advanced LCC and LCNEC, indicating that this regimen could serve as a treatment option, particularly as first-line therapy, for improving the survival outcomes of patients with these rare histological subtypes of lung cancer. Trial registration NCT05023837(ESPORTA, 27/08/2021).

Abstract Chronic wounds seriously affect the quality of life of the elderly, obese people, and diabetic patients. The excessive inflammatory response is a key driver of delayed chronic wound healing. Although lavender essential oil (EO [lav]) has been proven to have anti‐inflammatory and accelerate wound curative effects, the specific molecular mechanism involved is still ambiguous. The results showed that the wounds treated with lipopolysaccharide (LPS) not only had delayed healing, but also the expression levels of pro‐inflammatory cytokines, such as tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), and the inflammatory mediator protein, high‐mobility group box 1 protein (HMGB‐1), in the wound tissues were significantly increased. However, treatment of LPS‐induced chronic wounds with EO (lav) accelerated wound healing and decreased IL‐1β and HMGB‐1 expression levels. It was further found that LPS induced macrophage pyroptosis to produce IL‐1β. After treatment with EO (lav), the expression level of macrophage pyroptosis marker Gasdermin D (GSDMD) and pyroptosis‐related cytotoxic effects were significantly reduced. Immunofluorescence results also directly indicate that EO (lav) can protect macrophages from LPS‐induced pyroptosis. Moreover, EO (lav) can down‐regulate expression levels of IL‐1β, GSDMD, and nucleotide‐binding oligomerization domain‐like receptor protein 3 (NLRP3) in the caspase‐11‐related pyroptotic signaling pathway. This study demonstrates that EO (lav) can reduce proinflammatory factor production and ameliorate inflammatory response by inhibiting macrophage pyroptosis, which accelerates LPS‐induced chronic wound healing.

Chronic hepatitis B virus (HBV) infection is a major cause of liver cirrhosis and liver cancer, despite strong prevention and treatment efforts. The study of the epigenetic modification of HBV has become a research hotspot, including the N6-methyladenosine (m6A) modification of HBV RNA, which plays complex roles in the HBV life cycle. In addition to m6A modification, 5-methylcytosine (m5C) is another major modification of eukaryotic mRNA. In this study, we explored the roles of m5C methyltransferase and demethyltransferase in the HBV life cycle. The results showed that m5C methyltransferase NSUN2 deficiency could negatively regulate the expression of HBV while m5C demethyltransferase TET2 deficiency positively regulates the expression of HBV. Subsequently, we combined both in vitro bisulfite sequencing and high-throughput bisulfite sequencing methods to determine the distribution and stoichiometry of m5C modification in HBV RNA. Two sites: C2017 and C131 with the highest-ranking methylation rates were identified, and mutations at these two sites could lead to the decreased expression and replication of HBV, while the mutation of the "fake" m5C site had no effect. Mechanistically, NSUN2-mediated m5C modification promotes the stability of HBV RNA. In addition, compared with wild-type HepG2-NTCP cells and primary human hepatocytes, the replication level of HBV after NSUN2 knockdown decreased, and the ability of the mutant virus to infect and replicate in wild-type HepG2-NTCP cells and PHHs was substantially impaired. Similar results were found in the experiments using C57BL/6JGpt-Nsun2+/- mice. Interestingly, we also found that HBV expression and core protein promoted the endogenous expression of NSUN2, which implied a positive feedback loop. In summary, our study provides an accurate and high-resolution m5C profile of HBV RNA and reveals that NSUN2-mediated m5C modification of HBV RNA positively regulates HBV replication by maintaining RNA stability.

IntroductionThis study aimed to evaluate the feasibility of using general Raman spectroscopy as a method to screen for breast cancer. The objective was to develop a machine learning model that utilizes Raman spectroscopy to detect serum samples from breast cancer patients, benign cases, and healthy subjects, with puncture biopsy as the gold standard for comparison. The goal was to explore the value of Raman spectroscopy in the differential diagnosis of breast cancer, benign lesions, and healthy individuals.MethodsIn this study, blood serum samples were collected from a total of 333 participants. Among them, there were 129 cases of tumors (pathologically diagnosed as breast cancer and labeled as cancer), 91 cases of benign lesions (pathologically diagnosed as benign and labeled as benign), and 113 cases of healthy controls (labeled as normal). Raman spectra of the serum samples from each group were collected. To classify the normal, benign, and cancer sample groups, principal component analysis (PCA) combined with support vector machine (SVM) was used. The SVM model was evaluated using a cross-validation method. ResultsThe results of the study revealed significant differences in the mean Raman spectra of the serum samples between the normal and tumor/benign groups. Although the mean Raman spectra showed slight variations between the cancer and benign groups, the SVM model achieved a remarkable prediction accuracy of up to 98% for classifying cancer, benign, and normal groups. DiscussionIn conclusion, this exploratory study has demonstrated the tremendous potential of general Raman spectroscopy as a clinical adjunctive diagnostic and rapid screening tool for breast cancer.

Global concern has been raised by the emergence and rapid transmission of the heavily mutated SARS-CoV-2 Omicron variant (B.1.1.529). So far, the infection features and immune escape ability of the Omicron variant have not been extensively studied. Here, we produced the Omicron pseudovirus and compared its entry, membrane fusion, and immune escape efficiency with the original strain and the dominating Delta variant. We found the Omicron variant showed slightly higher infectivity than the Delta variant and a similar ability to compete with the Delta variant in using Angiotensin-converting enzyme 2 (ACE2) in a BHK21-ACE2 cell line. However, the Omicron showed a significantly reduced fusogenicity than the original strain and the Delta variant in both BHK21-ACE2 and Vero-E6 cells. The neutralization assay testing the Wuhan convalescents’ sera one-year post-infection showed a more dramatic reduction (10.15 fold) of neutralization against the Omicron variant than the Delta variant (1.79 fold) compared with the original strain with D614G. Notably, immune-boosting through three vaccine shots significantly improved the convalescents’ immunity against the Omicron variants. Our results reveal a reduced fusogenicity and a striking immune escape ability of the Omicron variant, highlighting the importance of booster shots against the challenge of the SARS-CoV-2 antigenic drift.

Song, Zeng, Yan et al. validate the E1L3N monoclonal antibody for the detection of PD-L1 in NSCLC samples. The authors show that PD-L1 scores assessed with E1L3N are concordant with the 22C3 assay and are associated with response to first-line pembrolizumab monotherapy.

High-throughput sequencing of microbial 16S rRNA gene has been conducted to explore microbial diversity and community structure in the Yuqi oil and gas reservoir sites of Tarim Basin. Soil samples were collected from Yuqi oil and gas reservoir sites (YQ-y) to the east of well YQ 5 and prospecting areas (YQ-wz) to the west of well YQ 12. Most of the two groups of sample have similar microbial community. Both α- and β-diversity analyses show that YQ-y and YQ-wz samples have great similarity in species abundance, diversity and community structure. Ten major hydrocarbon-oxidizing bacteria were identified in the YQ-y and YQ-wz samples, including Methylophaga, Bacteroides, Nocardioides, and Bacillus. Moreover, a large number of unknown bacteria were noticed, indicating that both of the samples contain abundant unknown microbial resources. Oil and gas microbial diversity in the Yuqi area was obtained through high-throughput sequencing. The two groups of samples from YQ-y and YQ-wz areas have similar microbial community. Preliminary discussion on microbial anomaly in the eastern part of Yuqi was also carried out.

ABSTRACT Autoimmune hepatitis (AIH) is a liver disease characterized by chronic liver inflammation. The intestinal barrier and microbiome play critical roles in AIH progression. AIH treatment remains challenging because first-line drugs have limited efficacy and many side effects. Thus, there is growing interest in developing synbiotic therapies. This study investigated the effects of a novel synbiotic in an AIH mouse model. We found that this synbiotic (Syn) ameliorated liver injury and improved liver function by reducing hepatic inflammation and pyroptosis. The Syn reversed gut dysbiosis, as indicated by an increase in beneficial bacteria (e.g., Rikenella and Alistipes) and a decrease in potentially harmful bacteria (e.g., Escherichia-Shigella) and lipopolysaccharide (LPS)-bearing Gram-negative bacterial levels. The Syn maintained intestinal barrier integrity, reduced LPS, and inhibited the TLR4/NF-κB and NLRP3/Caspase-1 signaling pathway. In addition, microbiome phenotype prediction by BugBase and bacterial functional potential prediction using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) showed that Syn improved gut microbiota function involving inflammatory injury, metabolism, immune response, and pathopoiesia. Furthermore, the new Syn was as effective as prednisone against AIH. Therefore, this novel Syn could be a candidate drug for alleviating AIH through its anti-inflammatory and antipyroptosis properties that relieve endothelial dysfunction and gut dysbiosis. IMPORTANCE Synbiotics can ameliorate liver injury and improve liver function by reducing hepatic inflammation and pyroptosis. Our data indicate that our new Syn not only reverses gut dysbiosis by increasing beneficial bacteria and decreasing lipopolysaccharide (LPS)-bearing Gram-negative bacteria but also maintains intestinal barrier integrity. Thus, its mechanism might be associated with modulating gut microbiota composition and intestinal barrier function by inhibiting the TLR4/NF-κB/NLRP3/pyroptosis signaling pathway in the liver. This Syn is as effective as prednisone in treating AIH without side effects. Based on these findings, this novel Syn represents a potential therapeutic agent for AIH in clinical practice.

The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the model of antitumor therapy. With the continuous deepening of the research on the mechanism of immunotherapy, ICIs, such as programmed cell death protein 1 (PD-1), programmed death-ligand 1 inhibitors and cytotoxic T lymphocyte-associated protein 4 inhibitors, have been widely used in a variety of tumors. Nevertheless, the use of ICI can also lead to a series of immune-related adverse events. Common immune-related adverse events include gastrointestinal toxicity, pulmonary toxicity, endocrine system toxicity, and skin toxicity. Neurologic adverse events are relatively rare, but they seriously affect the quality of life and shorten the survival time of patients. This article reports cases of peripheral neuropathy mediated by PD-1 inhibitors and retrieves the relevant literatures at home and abroad to summarize the neurotoxicity caused by PD-1 inhibitors, so as to strengthen the awareness of clinicians and patients on neurologic adverse reactions and mitigate potential adverse effects of implemented therapies.

Abstract Phytochemical reinvestigation on the whole plants of Ypsilandra thibetica obtained four new spirostanol glycosides, named ypsilandrosides U-X (1–4), and one new cholestanol glycoside, named ypsilandroside Y (5). Their structures have been established by extensive spectroscopic data and chemical methods. Among them, compound 4 is a rare spirostanol glycoside which possesses a novel 5(6 → 7) abeo-steroidal aglycone, while compound 1 is a first spirostanol bisdesmoside attached to C-3 and C-12, respectively, isolated from the genus Ypsilandra. The induced platelet aggregation activity of the isolates was tested. Graphical Abstract

With the increasing requirements of power density，load capacity and service life of gear transmission for aviation，wind power and other equipment，gear contact fatigue failure has become an important bottleneck limiting the service performance and reliability of modern gear equipment，and the material microstructure characteristics determine the fatigue performance of gear and other service parts. Through the surveys of the current related research situation both at home and abroad，the main microstructure features of gear materials such as retained austenite，carbide，grain size and their influence on the contact fatigue performance of gears are introduced. The reported numerical simulations of gear contact fatigue based on microstructure modeling and micromechanics constitutive model are summarized to describe the microscopic mechanical behavior of in gear contact fatigue，and to improve the understanding of the key characteristics and mechanism of gear fatigue. The various contact fatigue failure forms of gears occurred in the engineering practice are expounded in detail，and the main factors affecting the contact fatigue failure of gears，the induced microstructure evolution and degradation of mechanical properties，as well as the potential mechanisms of the gear contact fatigue failure，are analyzed. This review aims to provide the further understanding of the relationship between microstructure evolution characteristics and mechanical property degradation during the service process of gears，as well as the internal mechanism of contact fatigue failure，and providing the reference for anti-fatigue design and manufacturing method of high-performance gears.

Abstract Background The coronavirus disease 2019 (COVID-19) has increased the physical and psychological stress of medical workers. This study was designed to investigate the prevalence and risk factors of job burnout and its impact on work ability among Biosafety Laboratory (BSL) staffs during the COVID-19 epidemic in Xinjiang. Methods A total of 7911 qualified BSL staffs in Xinjiang were investigated by electronic questionnaires. The Maslach Burnout Inventory-General Survey (MBI-GS) was used for job burnout survey. Work Ability Index (WAI) was used for work ability survey. The prevalence and risk factors of job burnout in BSL staffs were analyzed through chi square test, t-test and one-way ANOVA. And then, the influence of demographic and job-related variables, i.e., confounding factors, were eliminated to the greatest extent by the propensity score analysis (PSA) method, to investigate the impact of job burnout on work ability in BSL staffs. Results A total of 67.6% BSL staffs experienced job burnout. There were significant differences in the detection rate of job burnout among demographic and job-related variables, including gender, age, ethnicity, education, working years, professional title, marital status, number of night shift per month and overall sleep condition (all P

Objective This study was designed to explore the impact of occupational hazards and occupational stress on job burn-out among factory workers and miners. This study also aimed to provide a scientific basis for the prevention and control of job burn-out among factory workers and miners.Design A cross-sectional study based on the factory Workers and Miners of Urumqi, Xinjiang. Demographic biases, that is, confounding factors, were eliminated by the propensity score-matched analysis method.Participants An electronic questionnaire was used to survey 7500 eligible factory workers and miners in Urumqi, the capital of Xinjiang, and 7315 complete questionnaires were returned.Primary outcome measures A general demographic questionnaire, the Effort–Reward Imbalance (ERI) and the Chinese Maslach Burnout Inventory.Results The total rate of burn-out was 86.5%. Noise (OR 1.34, 95% CI 1.09 to 1.64) and ERI (OR 2.16, 95% CI 1.78 to 2.61) were the risk factors for job burn-out among factory workers and miners (p

BackgroundProbiotics have shown potential antidepressant effects. This study evaluated the effect and probable mechanisms of bifid triple viable capsules (BTVCs) on a rat model of chronic unpredictable mild stress (CUMS).Materials and methodsRats were randomly divided into Normal, CUMS model, fluoxetine hydrochloride (FLX), BTVCs, and FLX+BTVCs groups. Depressive-like behaviours, pathological changes in the hippocampus, changes in serum metabolites and potential biomarkers, and metabolic pathways were detected via behavioural tests, haematoxylin-eosin staining, nissl staining, non-targetted metabolomics, and ingenuity pathway analysis (IPA).ResultsThe rats displayed depressive-like behaviours after CUMS exposure, but BTVCs ameliorated the depressive-like behaviours. In addition, the pathological results showed that the hippocampal tissue was damaged in rats after CUMS exposure and that the damage was effectively alleviated by treatment with BTVCs. A total of 20 potential biomarkers were identified. Treatment with BTVCs regulated D-phenylalanine, methoxyeugenol, (±)-myristoylcarnitine, 18:3 (6Z, 9Z, 12Z) /P-18:1 (11Z), propionyl-L-carnitine, and arachidonic acid (AA) concentrations, all compounds that are involved with biosynthesis of unsaturated fatty acids, glycerophospholipid metabolism, linoleic acid metabolism and AA metabolism. The IPA demonstrated that endothelin-1 signalling and cyclic adenosine monophosphate response element binding protein (CREB) signalling in neurons may be involved in the development of depression.ConclusionOur findings suggest that BTVCs can alleviate depressive-like behaviours, restore damage to the hippocampus in CUMS rats and regulate serum metabolism, which may be related to endothelin-1 signalling or CREB signalling in neurons.

Objective A nomogram for predicting the risk of mental health problems was established in a population of factory workers and miners, in order to quickly calculate the probability of a worker suffering from mental health problems.Methods A cross-sectional survey of 7500 factory workers and miners in Urumqi was conducted by means of an electronic questionnaire using cluster sampling method. Participants were randomly assigned to the training group (70%) and the validation group (30%). Questionnaire-based survey was conducted to collect information. A least absolute shrinkage and selection operator (LASSO) regression model was used to screen the predictors related to the risk of mental health problems of the training group. Multivariate logistic regression analysis was applied to construct the prediction model. Calibration plots and receiver operating characteristic-derived area under the curve (AUC) were used for model validation. Decision curve analysis was applied to calculate the net benefit of the screening model.Results A total of 7118 participants met the inclusion criteria and the data were randomly divided into a training group (n=4955) and a validation group (n=2163) in a ratio of 3:1. A total of 23 characteristics were included in this study and LASSO regression selected 12 characteristics such as education, professional title, age, Chinese Maslach Burnout Inventory, effort–reward imbalance, asbestos dust, hypertension, diabetes, working hours per day, working years, marital status and work schedule as predictors for the construction of the nomogram. In the validation group, the Brier score was 0.176, the calibration slope was 0.970 and the calibration curve of nomogram showed a good fit. The AUC of training group and verification group were 0.785 and 0.784, respectively.Conclusion The nomogram combining these 12 characteristics can be used to predict the risk of suffering mental health problems, providing a useful tool for quickly and accurately screening the risk of mental health problems.

BackgroundFruquintinib, a vascular endothelial growth factor receptor inhibitor, is a new anticancer drug independently developed in China to treat refractory metastatic colorectal cancer (mCRC). In Japan, regorafenib combined with nivolumab has been demonstrated to be promising in patients with refractory mCRC. Here, in a real-world study, we were aimed to evaluate the efficacy of fruquintinib with various programmed death-1 (PD-1) inhibitors after standard treatment in Chinese non-microsatellite instability-high (MSI-H)/mismatch repair proficient mCRC patients.MethodsA total of 45 patients with refractory mCRC were involved in the study. They received fruquintinib (3 or 5 mg, orally administered once a day for 3 weeks followed by 1 week off in 4-week cycles) and a PD-1 inhibitor(200 mg pembrolizumab, 3 mg/kg nivolumab, 200 mg sintilimab or camrelizumab, intravenously administered on D1 once every 3 weeks). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and objective response rate (ORR) were reviewed and evaluated.ResultsAmong the 45 patients, the median age was 54 years (29-85). The ORR was 11.1% (5/45), DCR 62.2% (28/45), median PFS equal 3.8 months, and median OS was 14.9 months. The response duration was 3.4 months. PFS between left and right primary tumors and PFS with or without lung metastases were both not significantly different (p > 0.05), which was inconsistent with the result of REGONIVO study. The multivariate analysis indicated no association of OS benefit in the specified subgroups. No adverse-effect-related deaths were reported.ConclusionsFruquintinib, in combination with anti-PD-1, was observed to have clinical activity in a small population of patients with heavily pretreated mCRC in our center. Further studies are needed to verify this outcome in a large population.

Estradiol (E2) has been proven to be effective in treating perimenopausal depression (PD); however, the downstream signaling pathways have not been fully elucidated. Transient receptor potential channels 6 (TRPC6) plays a vital role in promoting neuronal development and the formation of excitatory synapses. At present, we found that the serum levels of E2 and brain-derived neurotrophic factor (BDNF) declined significantly in the women with PD compared to perimenopausal women, which was accompanied by a clear reduction in TRPC6 levels. To further reveal the effects of TRPC6 on neuronal survival and excitability, the PD-like rat model was established by the total removal of left ovary and 80% removal of right ovary followed by 21 days of the chronic unpredictable mild stress. Intragastric administration of E2 (2 mg/kg), intraperitoneal injection of BDNF/TrB signaling pathway inhibitor (K252a, 100 μg/kg) and TRPC6 agonist (OAG, 0.6 mg/kg), and intracerebroventricular infusion of anti-BDNF antibody for blocking BDNF (0.5 μg/24 μl/rat) daily for 21 days were conducted. The levels of BDNF and TRPC6 in rat serum were lower in PD rats compared to the control rats; the depression-like behavior was induced, the neuronal death rate in the hippocampus increased, and the thickness of postsynaptic density (PSD) and the number of asymmetric synapses decreased significantly in the PD group. E2 treatment greatly upregulated the serum levels of BDNF and TRPC6, the neuronal excitability indicated by an elevation in the PSD thickness and the numbers of asymmetric synapses, and these actions were reversed by K252a; co-administration of TRPC6 agonist and K252a improved neuronal degeneration and increased the neuronal excitability induced in the E2-treated PD rats. K252a or anti-BDNF antibody inhibited the increased neuronal BDNF and TRPC6 expression in E2-treated PD rats; co-treatment of TRPC6 agonist and anti-BDNF antibody reduced neuronal death and increased the BDNF and TRPC6 expression in the hippocampal CA1 neurons in the E2-treated PD rats. These results suggest that the neuroprotective role of E2 in PD is closely related to enhance the activity of BDNF/TRPC6 pathway and is helpful to provide new prevention and strategies.

The iron-catalyzed [4 ​+ ​2] annulation of α,β-unsaturated ketoxime acetates with enaminones has been developed, providing efficient access to highly substituted pyridines in moderate to good yields. Notable features of the present strategy include low-cost catalytic system, simple and mild reaction condition and wide substrate scope. Mechanistic studies reveal that FeCl2 may directly serve as a Lewis acid to activate the α,β-unsaturated ketoxime acetates for the nucleophilic addition.

The emergence of the SARS-CoV-2 Omicron variant poses a striking threat to human society. More than 30 mutations in the Spike protein of the Omicron variant severely compromised the protective immunity elicited by either vaccination or prior infection. The persistent viral evolutionary trajectory generates Omicron-associated lineages, such as BA.1 and BA.2. Moreover, the virus recombination upon Delta and Omicron co-infections has been reported lately, although the impact remains to be assessed. This minireview summarizes the characteristics, evolution and mutation control, and immune evasion mechanisms of SARS-CoV-2 variants, which will be helpful for the in-depth understanding of the SARS-CoV-2 variants and policy-making related to COVID-19 pandemic control.

BackgroundIn our previous phase II study, nab-paclitaxel plus S-1 (NPS) showed encouraging objective response rate (ORR) as first-line treatment for advanced pancreatic adenocarcinoma (APAC). This study aimed to evaluate the effectiveness and safety of S-1 maintenance after NPS in APAC and to explore factors predicting survival benefits when using S-1 maintenance.MethodsBetween 2014 and 2018 a total of 182 patients with APAC, who were primarily treated with NPS, were included. For patients without progression or with treatment discontinuation due to any reasons within 4 months during NPS treatment, S-1 monotherapy was administrable as maintenance therapy at the physicians’ discretion based on the patients’ preference and performance status. Efficacy and safety of S-1 maintenance were investigated.ResultsIn 123 patients without progression within 4 months during NPS treatment, 74 received S-1 maintenance and had median progression-free survival of 9.6 months and median overall survival of 16.7 months. Multivariable analysis showed that in patients receiving S-1 maintenance after first-line NPS therapy, an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, non-metastatic disease, and complete or partial response as best response to NPS chemotherapy were independently associated with better survival. The most common all-grade hematological and non-hematological adverse events were neutropenia (82.4%) and peripheral neurotoxicity (66.2%), respectively, and the most common ≥Grade 3 hematological and non-hematological adverse events were neutropenia (40.5%) and peripheral neurotoxicity (6.8%), respectively in patients who received S-1 maintenance.ConclusionsOur real-world study showed that S-1 maintenance after tumor response or stable disease induced by first-line NPS treatment was effective and well-tolerated for some patients with APAC, which offers a promising alternative treatment strategy with encouraging survival for APAC.

About ten years ago, Wenhui Li’s research group in China identified the sodium taurocholate co-transporting polypeptide (NTCP), a bile acid transporter predominantly expressed in the liver, as a functional receptor for hepatitis B virus (HBV) and its satellite hepatitis delta virus (HDV) through biochemical and genetic studies. This finding unraveled a longtime mystery in the HBV field and led to the establishment of efficient and easy-to-use HBV infection models, which paved the way for the in-depth study of the HBV entry mechanism and facilitated the development of therapeutics against HBV and HDV. The whole picture of the complex HBV entry process became clear upon the follow-up studies over the years, including the recent resolution found for the NTCP structure. As one of the first authors of the 2012 eLife paper on NTCP identification, here, I (H. Y.) share our experience on the bumpy and exciting journey of receptor hunting, particularly on the photo-cross-linking study and some detailed descriptions of the “fishing” process and summarize the key factors for our successful receptor identification. This review may also provide helpful insights for identifying a protein target by peptide or protein baits through cross-linking and immunoprecipitation.

G-protein-coupled receptors (GPCRs) belong to a cell surface receptor superfamily responding to a wide range of external signals. The binding of extracellular ligands to GPCRs activates a heterotrimeric G protein and triggers the production of numerous secondary messengers, which transduce the extracellular signals into cellular responses. GPCR signaling is crucial and imperative for maintaining normal tissue homeostasis. High-throughput sequencing analyses revealed the occurrence of the genetic aberrations of GPCRs and G proteins in multiple malignancies. The altered GPCRs/G proteins serve as valuable biomarkers for early diagnosis, prognostic prediction, and pharmacological targets. Furthermore, the dysregulation of GPCR signaling contributes to tumor initiation and development. In this review, we have summarized the research progress of GPCRs and highlighted their mechanisms in gastric cancer (GC). The aberrant activation of GPCRs promotes GC cell proliferation and metastasis, remodels the tumor microenvironment, and boosts immune escape. Through deep investigation, novel therapeutic strategies for targeting GPCR activation have been developed, and the final aim is to eliminate GPCR-driven gastric carcinogenesis.

Abstract Background Hypertension has been declared as a global public health crisis by the World Health Organization, because of its high prevalence. It affects the health of one billion people worldwide and is directly responsible for the deaths of more than 10 million people per year. The purpose of our research was to explore the influence of occupational stress and psychological health on hypertension of miners who work in a noisy environment and provide decision reference for relevant departments to keep miners’ health. Methods A case-control study was carried out in this research. The study subjects were divided into case groups and control groups based on whether they had hypertension or not. Effort-Reward Imbalance questionnaire and Self-Reporting Inventory questionnaire were used to investigate the psychological health status and occupational stress of the target population. General information was balanced between case and control groups through propensity score matching method. After propensity score matching, a multifactorial analysis was used to explore the impact of occupational stress and psychological health on hypertension. Results According to the result of the multivariate analysis, psychological health was hazard to hypertension (t = 5.080, P