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Abstract Tumor growth inhibition (TGI) modeling attempts to describe the time course changes in tumor size for patients undergoing cancer therapy. TGI models present several advantages over traditional exposure–response models that are based explicitly on clinical end points and have become a popular tool in the pharmacometrics community. Unfortunately, the data required to fit TGI models, namely longitudinal tumor measurements, are sparse or often not available in literature or publicly accessible databases. On the contrary, common end points such as progression‐free survival (PFS) and objective response rate (ORR) are directly derived from longitudinal tumor measurements and are routinely published. To this end, a Bayesian generative model relating underlying tumor dynamics to summary PFS and ORR data is introduced to learn TGI model parameters using only published summary data. The parameterized model can describe the tumor dynamics, quantify treatment effect, and account for differences in the study population. The utility of this model is shown by applying it to several published studies, and learned parameters are combined to simulate an in silico trial of a novel combination therapy in a novel setting.

Abstract There has been an increasing level of recognition of the interaction between cultural mega-events and built heritage in recent years. While research has broadly identified the need to align strategies and visions, as well as involve heritage actors and local communities, there has not been a systematic investigation of the position of industrial heritage within this tableau. This paper examines in depth the European Capital of Culture (ECoC) programme, as it is one of the longest standing Capital of Culture programmes in the world and has a significant record of investment and urban transformation. In this paper, we survey and categorise the inclusion of industrial heritage within the ECoC programme in 36 host cities and regions spread across Europe. This research provides the most comprehensive understanding to date of the specific forms of interaction between industrial heritage and ECoCs to better understand the kinds of relationships that have taken place. We then explore in detail the projects and decisions made in the cases of the 2023 Elefsina, 2017 Pafos and 2008 Liverpool ECoCs.

Ideal medical implant materials should have the qualities of osteoinduction, osteoconduction, nontoxicity, non-sensitivity and non-carcinogenicity to the body. Although its high melting point and high elastic modulus pose difficulties for processing technology, tantalum has become a popular research topic in the field of medical implant materials because of its excellent biocompatibility and bone inductivity. In this paper, the performance of the bone-inducing properties of tantalum in different applications, including its combination with other elements, its use as a coating, its porous structure and its surface modification ability, are summarized. The mechanism of promoting bone formation and the clinical application of tantalum are reviewed.

BackgroundCervical cancer stands as one of the leading causes of cancer-related mortality in women worldwide, yet the precise functions of host genes implicated in its pathogenesis remain elusive. Genome-wide association studies (GWAS) have revealed a significant association between the CLPTM1L locus and cervical cancer risk in European women, and aberrant expression of CLPTM1L has been noted in various malignant tumors. However, the role of CLPTM1L in cervical cancer remains largely unexplored.MethodsThe expression of CLPTM1L in cervical cancer cells and tissues was detected by RT-qPCR. Furthermore, the potential biological functions of CLPTM1L in the context of cervical cancer were explored via RNA sequencing. Cell proliferation rates and the responsiveness of cervical cancer cells to cisplatin were evaluated using the CCK-8 assay, while cell apoptosis was quantified through the utilization of flow cytometry. Nude mouse xenograft models were utilized to explore the impact of CLPTM1L on tumor formation in vivo.ResultsOur findings demonstrated a significant increase in CLPTM1L mRNA expression levels in HeLa and C33A cells, as well as in cervical carcinoma tissues, compared to ECT1/E6E7 cells and adjacent normal tissues. Genes related to CLPTM1L were found to be enriched in the Hedgehog signaling pathway. In vitro and in vivo studies showed that reducing CLPTM1L expression markedly inhibited cell proliferation via downstream candidate genes BOC and LRP2. Furthermore, the downregulation of CLPTM1L was found to enhance cisplatin-induced cell apoptosis and increase the susceptibility of cervical cancer cells to cisplatin through DAP1.ConclusionsCLPTM1L could impact cervical cancer cell proliferation and cisplatin-induced cell apoptosis, as well as cisplatin susceptibility in cervical cancer cells. This investigation has bestowed upon us novel insights into the pathogenesis of cervical cancer, underscoring the potential of CLPTM1L as a promising target for chemotherapeutic sensitization in the management of this malignancy.

Due to the growing safety and environmental concerns associated with biocides, phenolic-soy branched chain fatty acids (phenolic-soy BCFAs) are synthesized as new bio-based antimicrobial agents. Safety evaluation is essential before the wide adoption of these new antimicrobial products. This study was initiated to evaluate the safety of four phenolic-soy BCFAs (with phenol, thymol, carvacrol, or creosote branches). Methyl-branched iso-oleic acid, phenol, and creosote were included in the study as controls. In silico toxicity simulation tools predicted that the phenolic BCFAs had much higher toxicities to aquatic organisms than free phenolics did, while the opposite was predicted for rats. The developmental toxicity of four phenolic-soy BCFAs was assessed using an in vivo chicken embryonic assay. Results showed that creosote-soy BCFA had much lower mortality rates than creosote at the same dosages. Additionally, creosote-soy BCFA and methyl-branched iso-oleic acid induced minimal estrogenic activity in the concentration range of 10 nM - 1 µM. Carvacrol-soy BCFA treatments significantly increased (p < 0.05) oxidative stress levels with higher thiobarbituric acid reactive substances in the livers of chicken embryos. Altogether, the phenolic-soy BCFAs, especially creosote-soy BCFA, reported in this study are potentially promising and safer bio-based antimicrobial products.

BackgroundThe evidence supporting a connection between elevated serum uric acid (SUA) levels and diabetic peripheral neuropathy (DPN) is controversial. The present study performed a comprehensive evaluation of this correlation by conducting a systematic review and meta-analysis of relevant research.MethodPubMed, Web of Science (WOS), Embase, and the Cochrane Library were searched for published literature from the establishment of each database to January 8, 2024. In total, 5 cohort studies and 15 cross-sectional studies were included, and 2 researchers independently screened and extracted relevant data. R 4.3.0 was used to evaluate the included literature. The present meta-analysis evaluated the relationship between SUA levels and the risk of DPN in type 2 diabetes (T2DM) by calculating the ratio of means (RoM) and 95% confidence intervals (CIs) using the method reported by JO Friedrich, and it also analyzed continuous outcome measures using standardized mean differences (SMDs) and 95% CIs to compare SUA levels between DPN and non-DPN groups. Funnel plot and Egger’s test were used to assess publication bias. Sensitivity analysis was conducted by sequentially removing each study one-by-one.ResultsThe meta-analysis included 20 studies, with 12,952 T2DM patients with DPN and 16,246 T2DM patients without DPN. There was a significant correlation between SUA levels and the risk of developing DPN [odds ratio (OR) = 1.23; 95% CI: 1.07-1.41; p = 0.001]. Additionally, individuals with DPN had higher levels of SUA compared to those without DPN (SMD = 0.4; 95% CI: -0.11-0.91; p < 0.01).ConclusionT2DM patients with DPN have significantly elevated SUA levels, which correlate with a heightened risk of peripheral neuropathy. Hyperuricemia (HUA) may be a risk indicator for assessing the risk of developing DPN in T2DM patients.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO, identifier CRD42024500373.

Abstract Background The selection of post-core material holds significant importance in endodontically treated teeth, influencing stress distribution in the dental structure after restoration. The use of computer-aided design/computer-aided manufacturing (CAD/CAM) glass fiber post-core possesses a better adaptation for different root canal morphologies, but whether this results in a more favorable stress distribution has not been clearly established. Materials and methods This study employed finite element analysis to establish three models of post-core crown restoration with normal, oversized, and dumbbell-shaped root canals. The three models were restored using three different materials: CAD/CAM glass fiber post-core (CGF), prefabricated glass fiber post and resin core (PGF), and cobalt-chromium integrated metal post-core (Co-Cr), followed by zirconia crown restoration. A static load was applied and the maximum equivalent von Mises stress, maximum principal stress, stress distribution plots, and the peak of maximum displacement were calculated for dentin, post-core, crown, and the cement acting as the interface between the post-core and the dentin. Results In dentin of three different root canal morphology, it was observed that PGF exhibited the lowest von Mises stresses, while Co-Cr exhibited the highest ones under a static load. CGF showed similar stress distribution to that of Co-Cr, but the stresses were more homogeneous and concentrated apically. In oversized and dumbbell-shaped root canal remnants, the equivalent von Mises stress in the cement layer using CGF was significantly lower than that of PGF. Conclusions In oversized root canals and dumbbell-shaped root canals, CGF has shown good performance for restoration of endodontically treated teeth. Clinical relevance This study provides a theoretical basis for clinicians to select post-core materials for residual roots with different root canal morphologies and should help to reduce the occurrence of complications such as root fracture and post-core debonding.

Abstract Background This study aimed to evaluate stomatological students’ learning efficacy and their attitude towards Lecture-Team-Based Learning (LTBL) on topics regarding the design of removable partial dentures via in-class, online, and both in combination. Methods Students from seven distinct grades participated in the course in their fourth academic year (Years 2015, 2016, 2017, 2018, 2019, 2020, and 2021). Students of Years 2015–2019 attended in-class LTBL, students of Year 2020 attended online LTBL, and students of Year 2021 attended the combination mode. The scores of three examinations were compared, namely, individual readiness assessment test, team readiness assurance test, and individual application test. Visual Analog Scales (VAS) were used for students to self-assess their mastery of prosthodontics knowledge before and after the course. Anonymous questionnaires were delivered to evaluate their satisfaction with LTBL via a Likert scale. Results In each academic year, the three exam scores were significantly improved as the course progressed and VAS-post scores were significantly higher than VAS-pre scores. The three examination and VAS scores of students in Year 2020 were significantly lower than those in Years 2019 and 2021. Students were highly satisfied with the LTBL course based on the three parameters of knowledge acquisition, teamwork, and classroom atmosphere. Conclusion Students were highly satisfied with the LTBL course and their learning performance was improved as the course progressed both in-class and online. Online LTBL could be adopted when students have to study online, while in-class LTBL could perform better when combined with video records of an online LTBL course.

ABSTRACTCervical cancer, among the deadliest cancers affecting women globally, primarily arises from persistent infection with high-risk human papillomavirus (HPV). To effectively combat persistent infection and prevent the progression of precancerous lesions into malignancy, a therapeutic HPV vaccine is under development. This study utilized an immunoinformatics approach to predict epitopes of cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTLs) using the E6 and E7 oncoproteins of the HPV16 strain as target antigens. Subsequently, through meticulous selection of T-cell epitopes and other necessary elements, a multi-epitope vaccine was constructed, exhibiting good immunogenic, physicochemical, and structural characteristics. Furthermore, in silico simulations showed that the vaccine not only interacted well with toll-like receptors (TLR2/TLR3/TLR4), but also induced a strong innate and adaptive immune response characterized by elevated Th1-type cytokines, such as interferon-gamma (IFN-γ) and interleukin-2 (IL2). Additionally, our study investigated the effects of different immunization intervals on immune responses, aiming to optimize a time-efficient immunization program. In animal model experiments, the vaccine exhibited robust immunogenic, therapeutic, and prophylactic effects. Administered thrice, it consistently induced the expansion of specific CD4 and CD8 T cells, resulting in substantial cytokines release and increased proliferation of memory T cell subsets in splenic cells. Overall, our findings support the potential of this multi-epitope vaccine in combating HPV16 infection and signify its candidacy for future HPV vaccine development.

Given the tremendous potential for continental shale oil in China, many oilfields in the central and eastern parts of the country are involved in the exploration and development of shale oil resources. Besides engineering factors, shale oil mobility is the key to determining its commercial viability. This study explores the Hetaoyuan Formation in the Biyang Depression as an example to determine the influence of reservoir properties on the movable oil volume and its mechanisms. Multiple techniques were used, including displacement nuclear magnetic resonance (NMR), low-temperature nitrogen adsorption (LTNA), X-ray diffraction (XRD) bulk mineral analysis, and scanning electron microscopy (SEM), and the results suggest that large average pore diameter, high throat to pore ratio, single pore morphology, and small specific surface area can weaken the boundary layer effect and reduce the amount of adsorbed oil. Our observations reveal that compared to the dissolution pores and intergranular pores in brittle minerals, the intercrystalline pores in terrigenous clastic clay minerals are more affected by compaction. Furthermore, authigenic clay minerals notably block the intergranular pores in the interbedded sandstones. Clay minerals are identified as the main contributor to the specific surface area, with high clay mineral content enhancing the pore heterogeneity of the reservoir. Thus, positive shale oil mobility occurs in shale with a weak boundary layer effect, which is attributed to the high brittle mineral content, large average pore diameter, small specific surface area, single pore morphology, and reservoir homogeneity.

Abstract Ultrasmall metal nanoclusters (NCs) exhibit a quantized conduction band, hence, a distinct HOMO‐LUMO gap (Eg). Such a quantized electronic structure gives rise to multiple discrete peaks in the optical absorption spectrum of the NCs. As the size grows to 130 gold atoms (Au130 protected by ligands), electrical charging and optical behaviors seem to show certain metal‐like features (hence, transition‐sizes). To probe such behaviors, especially the potential ligand effect, we have devised the synthesis of Au130 NCs protected by phenylethanethiolate and naphthalenethiolate, respectively, with the former having a nonconjugated separation between the aromatic molecular group and the metal core while the latter being in direct bonding. A careful comparison of these two Au130 nanoclusters with the earlier reported analogues is carried out, including the structurally characterized Au130(pMBT)50 and the aqueous counterpart. While all of these nanoclusters possess the same 80 free electron counts in the core, some notable differences in electrochemical and optical properties are found, which are attributed to the ligand effects. The obtained insights may stimulate further interest in the transition‐sized nanoclusters and also promote their applications in optics, energy conversion, and biomedicine.

BackgroundParents of children with cleft lip with or without cleft palate (CL/P) often face stigmatization, which has a significant impact on their quality of life and mental health. However, to date, there is a lack of comprehensive, multicenter empirical research on parents of children with CL/P in China, particularly those with large-scale samples. ObjectiveThis study aimed to identify major factors that contribute to the perception of stigma experienced by parents of children with CL/P. MethodsA cross-sectional survey was conducted. A total of 104 parents of children diagnosed with CL/P in 2 hospitals were selected by convenience sampling. Demographics and disease information, the Chinese Perception of Stigma Questionnaire, the Center for Epidemiological Studies Depression Scale, and the Social Anxiety Scale were used in this study. Descriptive statistics, t tests, and one-way ANOVA were used to compare the differences between participants’ demographic information and perception of stigma. Multivariable linear regression was performed to assess associations between demographic factors, social anxiety, depression, and perception of stigma. ResultsThe mean scores for the dimensions of perception of stigma, depression, and social anxiety were 22.97 (SD 9.21), 38.34 (SD 8.25), and 22.86 (SD 6.69), respectively. Depression and social anxiety were positively associated with discrimination, while surgery status was a negatively associated variable. Parents with a college education or higher had significantly lower levels of perceived stigma compared to parents with a junior high school education (all P values

AMG 256 is a bi-specific, heteroimmunoglobulin molecule with an anti-PD-1 antibody domain and a single IL-21 mutein domain on the C-terminus. Nonclinical studies in cynomolgus monkeys revealed that AMG 256 administration led to the development of immunogenicity-mediated responses and indicated that the IL-21 mutein domain of AMG 256 could enhance the anti-drug antibody response directed toward the monoclonal antibody domain. Anti-AMG 256 IgE were also observed in cynomolgus monkeys. A first-in-human (FIH) study in patients with advanced solid tumors was designed with these risks in mind. AMG 256 elicited ADA in 28 of 33 subjects (84.8%). However, ADA responses were only robust and exposure-impacting at the 2 lowest doses. At mid to high doses, ADA responses remained low magnitude and all subjects maintained exposure, despite most subjects developing ADA. Limited drug-specific IgE were also observed during the FIH study. ADA responses were not associated with any type of adverse event. The AMG 256 program represents a unique case where nonclinical studies informed on the risk of immunogenicity in humans, due to the IL-21-driven nature of the response.

Mangrove forests are crucial in absorbing, storing, and purifying pollutants while maintaining ecological balance. A study was conducted in 2020 to investigate the biogeochemical processes of seawater and sedimentary environmental factors in the Qi'ao Island mangrove wetland. The study comprised two survey sections and ten survey stations within the mangrove forest and 16 large-scale survey stations in the adjacent sea area. During ebb tides, the mean concentrations of inorganic nitrogen and phosphate in Section D1 of the mangrove forest were 0.63 mg/L and 0.003 mg/L, respectively. These levels were significantly lower than the results observed in the adjacent sea area and Section D2 of the mangrove forest during flood tides. The mangrove forest efficiently absorbed and consumed nutrients, with the nitrogen-to-phosphorus ratio of consumed nutrients being notably higher than that typically utilized by plants during growth. We identified various biogeochemical processes, including nitrogen fixation, mineralization, nitrification, and denitrification, occurring within the mangrove forest. Seawater measurements in Section D1 during ebb tides showed the mean pH of 7.58 and dissolved oxygen levels of 4.52 mg/L, resulting in a dissolved oxygen saturation level of only 57.0 %. The low dissolved oxygen levels were attributed to organic matter degradation in the forest. Consequently, the longer the water retention time, the more obvious the trend of hypoxia and acidification was observed. In the adjacent sea area, the sedimentary environment was deemed healthy, with pollutants primarily originating from runoff and ship discharge from waterways and ports. However, within the mangrove forest, the sediments exhibited higher enrichment factors for organic carbon and sulfide, indicating significant pollution compared to the adjacent sea area. The sediments were conducive to the accumulation and burial of total Hg, Zn, and Cu, while other heavy metals did not show prominent deposition and enrichment. Notably, the enrichment factor of oils was as high as 4.37, leading to the formation of an oil pollution zone at the forest edge, and the enrichment of pollutants in sediment may inhibit the growth and expansion of mangroves. Overall, this study shed light on the occurrence of seawater acidification, hypoxia, and the behavior of sediment pollutants within the mangrove forest. The findings provide valuable insights to support efforts aimed at promoting and maintaining the ecosystem health of mangrove forests.

Abstract Gray mold is a destructive disease caused by Botrytis cinerea, a pervasive plant pathogen, which poses a threat to both tomato growth and postharvest storage. The utilization of induced resistance presents a potential strategy for combating plant pathogenic attacks. ZNC (zhinengcong), an extract derived from the endophytic fungus Paecilomyces variotii, has been discovered to play a vital role in preventing diverse forms of bacterial infections. Nevertheless, the precise mechanism behind its ability to enhance tomato resistance to fungi remains unclear. In this study, we found that the exogenous spraying of ZNC could significantly improve the resistance of tomato plants to B. cinerea. The results of both the metabolomic analysis and high-performance liquid chromatography (HPLC) demonstrated that tomato plants responded to ZNC treatment by accumulating high levels of rutin. Additional transcriptome analysis uncovered that rutin enhances tomato resistance possible by initiating the generation of reactive oxygen species (ROS) and phosphorylation of mitogen-activated protein kinases (MPKs) related genes expression during the initial phase of invasion by B. cinerea. In addition, we also found that rutin might activate plant immunity by eliciting ethylene (ET) and jasmonic acid (JA)-mediated pathways. Therefore, plant immune inducer ZNC and rutin has bright application prospects and high utilization value to control gray mold. Graphical Abstract

Abstract Ferroptosis is an iron-dependent form of cell death induced by lipid oxidation with an essential role in diseases, including cancer. Since prognostic value of ferroptosis-dependent related genes (FDRGs) in colorectal cancer (CRC) remains unclear, we explored the significance of FDRGs in CRC through comprehensive single-cell analysis. We downloaded the GSE161277 dataset for single-cell analyses and calculated the ferroptosis-dependent gene score (FerrScore) for each cell type. According to each cell type-specific median FerrScore, we categorized the cells into low- and high-ferroptosis groups. By analyzing differentially-expressed genes across the two groups, we identified FDRGs. We further screened these prognosis-related genes used to develop a prognostic signature and calculated its correlation with immune infiltration. We also compared immune checkpoint gene efficacy among different risk groups, and qRT-PCR was performed in colorectal normal and cancer cell lines to explore whether the signature genes could be used as clinical prognostic indicators. In total, 523 FDRGs were identified. A prognostic signature including five signature genes was constructed, and patients were divided into two risk groups. The high-risk group had poor survival rates and displayed high levels of immune infiltration. Our newly developed ferroptosis-based prognostic signature possessed a high predictive ability for CRC.

The occurrence of an axlebox bearing ring raceway defect is an inevitable and commonly observed phenomenon in railway wheels. It not only leads to surface damage but also poses the potential threat of further damage and degradation, thereby increasing the risks associated with running safety and maintenance costs. Hence, it becomes imperative to detect raceway defects at an early stage to mitigate safety hazards and reduce maintenance efforts. In this study, the focus lies in investigating the effectiveness of vibration-based detection techniques for identifying raceway defects in high-speed train axlebox bearing systems. To achieve this, a dynamic model that accurately represents the coupling dynamics between the vehicle and the track is developed. This model incorporates various dynamic factors, such as traction transmission, gear transmission, and track geometry irregularities. By using the comprehensive dynamic model, the dynamic responses of the axlebox can be accurately calculated. The proposed methodology primarily revolves around analysing the vertical vibrations of the axlebox caused by raceway defects in both the time and frequency domains. Additionally, an envelope analysis using a developed band-pass filter is also employed. The results obtained from this study clearly demonstrate the successful detection of raceway defects in a more realistic vehicle model, thereby providing an efficient approach for the detection of axlebox bearing raceway defects. Consequently, this research contributes significantly to the field of high-speed train systems and paves the way for enhanced safety and maintenance practices.

Abstract Background Where the gene is expressed determines the function of the gene. Neuregulin 1 (Nrg1) encodes a tropic factor and is genetically linked with several neuropsychiatry diseases such as schizophrenia, bipolar disorder and depression. Nrg1 has broad functions ranging from regulating neurodevelopment to neurotransmission in the nervous system. However, the expression pattern of Nrg1 at the cellular and circuit levels in rodent brain is not full addressed. Methods Here we used CRISPR/Cas9 techniques to generate a knockin mouse line (Nrg1Cre/+) that expresses a P2A-Cre cassette right before the stop codon of Nrg1 gene. Since Cre recombinase and Nrg1 are expressed in the same types of cells in Nrg1Cre/+ mice, the Nrg1 expression pattern can be revealed through the Cre-reporting mice or adeno-associated virus (AAV) that express fluorescent proteins in a Cre-dependent way. Using unbiased stereology and fluorescence imaging, the cellular expression pattern of Nrg1 and axon projections of Nrg1-positive neurons were investigated. Results In the olfactory bulb (OB), Nrg1 is expressed in GABAergic interneurons including periglomerular (PG) and granule cells. In the cerebral cortex, Nrg1 is mainly expressed in the pyramidal neurons of superficial layers that mediate intercortical communications. In the striatum, Nrg1 is highly expressed in the Drd1-positive medium spiny neurons (MSNs) in the shell of nucleus accumbens (NAc) that project to substantia nigra pars reticulata (SNr). In the hippocampus, Nrg1 is mainly expressed in granule neurons in the dentate gyrus and pyramidal neurons in the subiculum. The Nrg1-expressing neurons in the subiculum project to retrosplenial granular cortex (RSG) and mammillary nucleus (MM). Nrg1 is highly expressed in the median eminence (ME) of hypothalamus and Purkinje cells in the cerebellum. Conclusions Nrg1 is broadly expressed in mouse brain, mainly in neurons, but has unique expression patterns in different brain regions.

Ferroptosis is an iron-dependent form of cell death whose role in infectious diseases is being elucidated. Here, Qiang et al. show that PtpA, an effector secreted by Mycobacterium tuberculosis, induces ferroptosis by hijacking host arginine methyltransferase PRMT6 to promote its pathogenicity and dissemination.

Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia, which results in atherosclerosis and cardiovascular disease (CVD). ATP-citrate lyase (ACLY) is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle (TCA cycle) to acetyl-CoA in the cytoplasm. Therefore, ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis. In this study, we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor, and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC50 = 5.31 ± 1.2 μmol/L in vitro. 326E treatment reduced de novo lipogenesis, and increased cholesterol efflux in vitro and in vivo. 326E was rapidly absorbed after oral administration, exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid (BA) used for hypercholesterolemia. Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia. Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE−/− mice to a greater extent than that of BA treatment. Taken together, our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.

Stem cells from human exfoliated deciduous teeth (SHED) uniquely exhibit high proliferative and neurogenic potential. Charged biomaterials have been demonstrated to promote neural differentiation of stem cells, but the dose-response effect of electrical stimuli from these materials on neural differentiation of SHED remains to be elucidated. Here, by utilizing different annealing temperatures prior to corona poling treatment, BaTiO3/P(VDF-TrFE) ferroelectric nanocomposite membranes with varying charge polarization intensity (d33 ≈ 0, 4, 12 and 19 pC N−1) were fabricated. Enhanced expression of neural markers, increased cell elongation and more prominent neurite outgrowths were observed with increasing surface charge of the nanocomposite membrane indicating a dose-response effect of surface electrical charge on SHED neural differentiation. Further investigations of the underlying molecular mechanisms revealed that intracellular calcium influx, focal adhesion formation, FAK-ERK mechanosensing pathway and neurogenic-related ErbB signaling pathway were implicated in the enhancement of SHED neural differentiation by surface electrical charge. Hence, this study confirms the dose-response effect of biomaterial surface charge on SHED neural differentiation and provides preliminary insights into the molecular mechanisms and signaling pathways involved.

Abstract Objective To identify new trends and potential hotspots in research on rheumatoid arthritis‐associated interstitial lung disease (RA‐ILD). Materials and Methods The Web of Science (WOS) database was used to search for RA‐ILD‐related literature published between August 31, 2002 and August 31, 2022. CiteSpace 6.1.R3, VOSviewer version 1.6.17, Scimago Graphica, and Pajek V2.0 visualization software were used to conduct a comprehensive analysis and network visualization mapping of the authors, countries, institutions, journals, cited references, and keywords. Results A total of 2412 articles were retrieved, and the number of articles published has grown annually since 2002. Eric L. Matteson was the most prolific author, and the Mayo Clinic and UNITED STATES have the highest publishing volume and influence. Clinical Rheumatology is the journal with the most papers published. Rheumatology was the most cited journal. The citation clusters and keywords concentrated on the mechanism, treatment, and predictive and prognostic factors. Conclusion Pathogenesis, treatment, and predictive and prognostic factors were among the RA‐ILD research directions and hotspots. Antirheumatoid drugs, especially biologics and small molecule inhibitors, were among the most actively researched treatment options. The results of this study provides an in‐depth understanding of the development of RA‐ILD publications, aids researchers in understanding hotspots and trends and provides a new perspective for future RA‐ILD research.

Abstract Background Homocystinuria due to methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. The purpose of this study is to expand the mutation site of the MTHFR gene and provide genetic counseling for this family. Methods A couple came to our hospital for pre-pregnancy genetic counseling. We collected the family history and detailed clinical information, then performed whole-exome sequencing, and analyzed the pathogenicity of the candidate mutations. Results We found that the father of the proband had homocystinuria, the proband and his brother had low blood methionine levels at birth, and the brain MRI showed brain dysplasia. The third fetus was found to have a broadened triangle of the bilateral ventricle at 19 weeks of pregnancy. The compound heterozygous variants of c.602 A > C (p.His201Pro) and c.1316T > C (p.Leu439Pro) of the MTHFR gene in the first three fetuses were found by whole-exome sequencing. The heterozygous c.602 A > C variant of the MTHFR gene is a novel missense variant that has been submitted to the ClinVar with Variation ID 992,662. Conclusion In consideration of the clinical phenotype, family history, and result of genetic testing, we speculated that both patients may have homocystinuria due to MTHFR deficiency. Homocystinuria due to MTHFR deficiency caused by compound heterozygous mutations composed of the MTHFR gene in this family may be associated with cerebral atrophy and cerebral dysplasia. The novel compound heterozygous mutations broaden the mutation spectrum of the MTHFR gene and enhance the application of genetic counseling and carrier screening in rare diseases.

Abstract Background Multiple myeloma (MM) is an incurable plasma cell malignancy. Red cell distribution width (RDW) is a prognostic marker in various diseases, solid tumors, and hematologic neoplasms, but its prognostic significance in MM is controversial. In this study, we aimed to assess the relationship between RDW and the clinical prognosis of MM patients through a meta-analysis. Methods Relevant literature were retrieved from PubMed, Embase, and Web of Science databases according to PRISMA guideline. All relevant parameters were extracted and combined for statistical analysis. The effect size was presented as hazard ratio (HR)/odds ratio (OR) and 95% confidence interval (CI). HR/OR > 1 in MM patients with high RDW suggested a worse prognosis. Heterogeneity test evaluation was performed using Cochran's Q test and I2 statistics. A P heterogeneity 50% suggested significant heterogeneity. P

Spines are an important physical defense for many plant species. Here, the authors describe seven different spine morphologies from the Eocene of central Tibet associated with regional aridification and expansion of herbivorous mammals.

Abstract Background To investigate the genetic causes of hearing loss in patients with enlarged vestibular aqueduct (EVA), the SLC26A4-related genotypes and phenotypes were analyzed. SLC26A4 gene is closely associated with EVA and its homozygous mutations or compound heterozygous mutations may cause deafness and strongly affect quality of life. Methods The patients who came to our hospital for hearing test and accompanied by bilateral hearing abnormalities were collected for fifteen deafness-related gene mutations detection. Those who are positive will be verified by Sanger sequencing, combined with family history, hearing test, and computerized tomography (CT) of the temporal bone, aiming to diagnose the enlarged vestibular aqueducts. Whole-exome sequencing were performed when necessary. Results Our patient failed hearing screening on both sides twice, and EVA (> 1.5 mm) was diagnosed by CT. This study has identified a novel missense mutation in the SLC26A4 gene, c.2069T>A, which in compound heterozygosity with c.1174A>T is likely to be the cause of hearing loss. The novel heterozygous c.2069T>A mutation of SLC26A4 gene has been submitted to Clinvar with Variation ID 1,048,780. Conclusion Our findings expand the gene mutation spectrum of SLC26A4 and provide additional knowledge for diagnosis and genetic counseling associated with EVA-induced hearing loss.

Abstract A number of strict lockdown measures were implemented in the areas most affected by COVID-19 in China, including Ji’nan city, from 24 January to 7 February 2020. Due to these forced restrictions, the pollution levels in cities across the country drastically decreased within just a few days. Since traffic pollution and industrial emissions are important factors affecting regional air quality, congestion has a significant impact on the environment. Therefore, using the aid of air quality data for six pollutants (PM10, PM2.5, SO2, NO2, CO and O3) from 11 monitoring stations (located in urban, suburban and urban-industrial regions) across Ji’nan, we employed the air quality index (AQI) to investigate the spatial pattern of air quality in the pre-COVID-19 (pre-COVID) and COVID-19-related lockdown (COVID lockdown) periods. The results showed that air quality significantly improved during the COVID lockdown period. Among the selected pollutants, compared to the corresponding pre-COVID levels, the greatest reduction was observed for the concentration of NO2 (54.02%), while the smallest reduction was observed for the concentration of SO2 (27.92%). The PM2.5 (38.73%), PM10 (44.92%) and CO (30.60%) levels also decreased during the COVID lockdown period; only the O3 concentration increased (37.42%) during this period. Overall, air quality improved by approximate improvements of 37.33% during the COVID lockdown period. Approximately 35.48%, 37.01% and 43.43% in the AQI were observed in urban, suburban and urban-industrial regions, respectively. Therefore, the AQI exhibited remarkable regional differences in Ji'nan. This study demonstrates the contributions of the transportation sector and local emissions to improving air quality in typical urban areas, and these research results can provide guidance for the further monitoring of air pollution in northern Chinese cities.

Co9S8 is a highly promising electrochemically active material for energy devices; its rational design and manufacture for further enhancing the electrochemical activity and durability are still challenging. Herein, Co9S8@CNT compounds are synthesized by one-step pyrolysis, which self-assembled the monomolecular precursor and carbon nanotubes (CNTs). The CNTs effectively improve the electrical conductivity of the materials and availability of the catalytically active sites, which means that the electrochemical ability of Co9S8@CNT is better than that of individual Co9S8 and CNTs. The onset potential of Co9S8@CNT is 132 mV, which has greatly decreased. At the mass current density of 10 mA mg−1, the overpotential is 337 mV, and the Tafel slope is 49.8 mV dec−1. The addition of CNTs makes up for the deficiency of low electrical conductivity of the CoSx. Furthermore, the three-dimensional (3D) structure of the composite improves its electrocatalytically active surface area, and the electrocatalytic ability has been improved efficiently, owing to the increased number of catalytic sites on the surface.

Summary: The regulation of antiviral immunity is crucial in maintaining host immune homeostasis, a process that involves dynamic modulations of host organelles. The Golgi apparatus is increasingly perceived as a host organelle functioning as a critical platform for innate immunity, but the detailed mechanism by which it regulates antiviral immunity remains elusive. Here, we identify the Golgi-localized G protein-coupled receptor 108 (GPR108) as a regulator of type Ι interferon responses by targeting interferon regulatory factor 3 (IRF3). Mechanistically, GPR108 enhances the ubiquitin ligase Smad ubiquitylation regulatory factor 1 (Smurf1)-mediated K63-linked polyubiquitination of phosphorylated IRF3 for nuclear dot 10 protein 52 (NDP52)-dependent autophagic degradation, leading to suppression of antiviral immune responses against DNA or RNA viruses. Taken together, our study provides insight into the crosstalk between the Golgi apparatus and antiviral immunity via a dynamic and spatiotemporal regulation of GPR108-Smurf1 axis, thereby indicating a potential target for treating viral infection.

Abstract Stretchable organic light‐emitting diodes (OLEDs) are important components for flexible/wearable electronics. However, the efficiency of the existing stretchable OLEDs is still much lower as compared with their rigid counterparts, one of the main reasons being the lack of ideal flexible transparent electrodes. Herein, we propose and develop a printed embedded metal composite electrode (PEMCE) strategy that enables the fabrication of ultra‐thin, highly flexible transparent electrodes with robust mechanical properties. With the flexible transparent electrodes serves as the anodes, flexible/stretchable white OLEDs have been successfully constructed, achieving a current efficiency of up to 77.4 cd A−1 and a maximum luminance of 34 787 cd m−2. The current efficiency of the resulting stretchable OLEDs is the highest ever reported for flexible/stretchable white OLEDs, which is about 1.2 times higher than that of the reference rigid devices based on ITO/glass electrodes. The excellent optoelectronic properties of the printed embedded transparent electrodes and the light extraction effect of the Ag‐mesh account for the significant increase in current efficiency. Remarkably, the electroluminescence performance still retains ~83% of the original luminance even after bending the device 2000 cycles at a radii of ~0.5 mm. More importantly, the device can withstand tensile strains of up to ~100%, and even mechanical deformation of 90% tensile strain does not result in a significant loss of electroluminescence performance with current efficiency and luminance maintained at over 85%. The results confirm that the PEMCE strategy is effective for constructing ultra‐flexible transparent electrodes, showing great promise for use in a variety of flexible/stretchable electronics.

Summary: Neoadjuvant therapy (NAT) is currently recommended to patients with human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) that typically exhibit a poor prognosis. The tumor immune microenvironment profoundly affects the efficacy of NAT. However, the correlation between tumor-infiltrating lymphocytes or their specific subpopulations and the response to NAT in HER2+ BC remains largely unknown. In our study, the immune infiltration status of 295 patients was classified as “immune-rich” or “immune-poor” phenotypes. The “immune-rich” phenotype was significantly positively related to pathological complete response (pCR). Ten genes were correlated with both pCR and the immune phenotype based on the results of spline and logistic regression. We constructed a generalized non-linear model combining linear and non-linear gene effects and successfully validated its predictive power using an internal and external validation set (AUC = 0.819, 0.797; respectively) and a clinical set (accuracy = 0.75).

Background: Functional ankle instability (FAI) is the primary classification of ankle injuries. Competitive activities have complicated movements that can result in ankle re-injury among patients with FAI. Unanticipated movement state (MS) and mental fatigue (MF) could also happen in these activities, which may further increase their joint injury risk.Objective: This study aimed to clarify the biomechanical characteristics difference of the lower extremity (LE) between the injured side and the uninjured side among patients with FAI when they perform unanticipated side-step cutting after MF.Methods: Fifteen males with unilateral FAI participated in this study (age: 20.7 ± 1.3 years, height: 173.6 ± 4.4 cm, weight: 70.1 ± 5.0 kg). They used the injured side and the uninjured side of LE to complete anticipated and unanticipated side-step cutting before and after MF. The kinematic and kinetics data were evaluated using three-way ANOVA with repeated measures.Results: During patients with FAI performed anticipated side-step cutting, the ankle stiffness of both sides showed no significant change after MF; During they performed unanticipated side-step cutting, their injured side presented significantly lower ankle stiffness after MF, while the uninjured side did not have such change. In addition, after MF, the injured side exhibited increased ankle inversion, knee valgus and LR, but the uninjured side did without these changes.Conclusion: Influenced by MF, when patients with FAI use their injured side of LE to perform side-step cutting, this side LE has a higher risk of musculoskeletal injuries such as lateral ankle sprains and anterior cruciate ligament injury. The ankle stiffness of the injured side will be further reduced when patients with FAI perform unanticipated side-step cutting, which increases ankle instability and the risk of re-injury.

Dual-active bridge (DAB) converters are receiving increasing attention from researchers as a critical part of the power transmission of energy routers. However, the DAB converter generates a large backflow power in conventional control mode, and when the load is mutated, its output voltage takes longer to return to the reference value accompanied by large fluctuations. To solve the above problems, a hybrid strategy is proposed in this paper to optimize the converter. The mathematical models of the transmitted power and the backflow power were firstly derived through in-depth analysis of the DAB converter under extended-phase-shift (EPS) modulation, and the suppression of the backflow power was performed according to the improved Lagrange method utilized in the obtained results. Moreover, considering the poor dynamic characteristics of DAB converters under PI control, according to the state space average model of output voltage in the paper, a model prediction control equation is established to improve the dynamic response of the converter by predicting the output voltage value at the next moment. The simulation results verify the effectiveness of the optimization strategy presented in the text.

Diabetes, which is mainly characterized by increased apoptosis and dysfunction of beta (β) cells, is a metabolic disease caused by impairment of pancreatic islet function. Previous studies have demonstrated that death-associated protein kinase-related apoptosis-inducing kinase-2 (Drak2) is involved in regulating β cell survival. Since natural products have multiple targets and often are multifunctional, making them promising compounds for the treatment of diabetes, we identified Drak2 inhibitors from a natural product library. Among the identified products, luteolin, a flavonoid, was found to be the most effective compound. In vitro, luteolin effectively alleviated palmitate (PA)-induced apoptosis of β cells and PA-induced impairment of primary islet function. In vivo, luteolin showed a tendency to lower blood glucose levels. It also alleviated STZ-induced apoptosis of β cells and metabolic disruption in mice. This function of luteolin partially relied on Drak2 inhibition. Furthermore, luteolin was also found to effectively relieve oxidative stress and promote autophagy in β cells, possibly improving β cell function and slowing the progression of diabetes. In conclusion, our findings show the promising effect of Drak2 inhibitors in relieving diabetes and offer a potential therapeutic target for the protection of β cells. We also reveal some of the underlying mechanisms of luteolin’s cytoprotective function.

Objectives: To quantify the integrated levels of ACE2 and TMPRSS2, the two well-recognized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry-related genes, and to further identify key factors contributing to SARS-CoV-2 susceptibility in head and neck squamous cell carcinoma (HNSC). Methods: We developed a metric of the potential for tissue infected with SARS-CoV-2 (“TPSI”) based on ACE2 and TMPRSS2 transcript levels and compared TPSI levels between tumor and matched normal tissues across 11 tumor types. For further analysis of HNSC, weighted gene co-expression network analysis (WGCNA), functional analysis, and single sample gene set enrichment analysis (ssGSEA) were conducted to investigate TPSI-relevant biological processes and their relationship with the immune landscape. TPSI-related factors were identified from clinical and mutational domains, followed by lasso regression to determine their relative effects on TPSI levels. Results: TPSI levels in tumors were generally lower than in the normal tissues. In HNSC, the genes highly associated with TPSI were enriched in viral entry-related processes, and TPSI levels were positively correlated with both eosinophils and T helper 17 (Th17) cell infiltration. Furthermore, the site of onset, human papillomaviruses (HPV) status, and nuclear receptor binding SET domain protein 1 (NSD1) mutations were identified as the most important factors shaping TPSI levels. Conclusions: This study identified the infection risk of SARS-CoV-2 between tumor and normal tissues, and provided evidence for the risk stratification of HNSC.

Scientific identification of the ecological and economic value of water and soil resources and quantitative evaluation are the basis for scientifically guiding the rational allocation of water and soil resources. Various values in previous studies were difficult to measure and compare uniformly, owing to their different manifestations. Based on ecological economics, the energy conversion mechanism of the interaction process of water and soil resources was described, and the ecological and economic values of the water and soil resources generated in the accompanying process were identified in this study. Then, for industrial and mining, residential, and public service land subsystems, the energy analysis method was used to obtain the unified calculation of the ecological and economic value of the water and soil resources. Using Luoyang City, Henan Province, China as the research area, the ecological and economic value of water and soil resources for residential and industrial land from 2015 to 2019 was calculated and according to the results, they were ranked as industrial and mining land > residential land > public service land. This study provides a unified quantitative analysis method for comprehensive decision-making for the rational utilisation of water and soil resources in specific counties, cities, and provinces.

Abstract Background Cathepsin H (CatH) is a lysosomal cysteine protease with a unique aminopeptidase activity. Its expression level is increased in activated immune cells including dendritic cells, macrophages, and microglia. We have previously reported that CatH deficiency impairs toll-like receptor 3 (TLR3)-mediated activation of interferon regulatory factor 3 (IRF3), and the subsequent secretion of interferon (IFN)-β from dendritic cells. Furthermore, there is increasing evidence that IFN-β secreted from microglia/macrophages has neuroprotective effects. These observations prompted further investigation into the effects of CatH deficiency on neuropathological changes. Methods In this study, neuropathological changes were examined using histochemical staining (both hematoxylin-eosin (H&E) and Nissl) of the hippocampus of wild-type (WT) and CatH-deficient (CatH −/−) mice after hypoxia-ischemia (HI). The density and the localization of CatH and TLR3 were examined by immunofluorescent staining. CatH processing in microglia was assayed by pulse-chase experiments, while immunoblotting was used to examine TLR3 expression and IRF3 activation in microglia/macrophages in the presence of poly(I:C). Microglial cell death was examined by fluorescence-activated cell sorting (FACS), and primary astrocyte proliferation in the presence of IFN-β was examined using scratch wound assay. Results WT mice displayed severe atrophy in association with neuronal death and moderate astrogliosis in the hippocampus following neonatal HI. Somewhat surprisingly, CatH −/− mice showed marked neuronal death without severe atrophy in the hippocampus following HI. Furthermore, there was notable microglia/macrophages cell death and strong astrogliosis in the hippocampus. The TLR3 and phosphorylated IRF3 expression level in the hippocampus or splenocytes (mainly splenic macrophages); from CatH −/− mice was lower than in WT mice. In vitro experiments demonstrated that recombinant IFN-β suppressed HI-induced microglial cell death and astrocyte proliferation. Conclusion These observations suggest that CatH plays a critical role in the proteolytic maturation and stabilization of TLR3, which is necessary for IFN-β production. Therefore, impaired TLR3/IFN-β signaling resulting from CatH deficiency may induce microglial cell death after activation and astrogliosis/glial scar formation in the hippocampus following HI injury, leading to suppression of hippocampal atrophy.

After bone defects reach a certain size, the body can no longer repair them. Tantalum, including its porous form, has attracted increasing attention due to good bioactivity, biocompatibility, and biomechanical properties. After a metal material is implanted into the body as a medical intervention, a series of interactions occurs between the material’s surface and the microenvironment. The interaction between cells and the surface of the implant mainly depends on the surface morphology and chemical composition of the implant’s surface. In this context, appropriate modification of the surface of tantalum can guide the biological behavior of cells, promote the potential of materials, and facilitate bone integration. Substantial progress has been made in tantalum surface modification technologies, especially nano-modification technology. This paper systematically reviews the progress in research on tantalum surface modification for the first time, including physicochemical properties, biological performance, and surface modification technologies of tantalum and porous tantalum.

This study aims to examine the nonlinear relationship between environmental, social and governance (ESG) and corporate financial performance (CFP) using Taiwan Stock Exchange (TSE) listed firms with ESG disclosure between 2005 and 2019. The pooled ordinary least square (OLS) regression estimation results indicate the ESG-CFP nexus is a nonlinear (inverted U-shaped pattern). Furthermore, the individual ESG pillars each have a different relationship with CFP. Both the environmental and social pillars have an inverted U-shaped relationship with CFP, whereas there is no significant relationship between the governance pillar and CFP. The concave nonlinear relationship also supports the tenets of the “too-much-of-a-good-thing” effect. This research confirms that TSE listed firms should identify the optimal ESG value (threshold point), where ESG costs and benefits balance, to maintain sustainable development and stakeholder engagement.

Capital asset pricing is very important to the development of listed companies. It is not only related to the performance of micro enterprises, but also related to the stability and development of macro financial markets. Therefore, the in-depth study of the law and influencing factors of listed companies’ return on capital assets is a theoretical problem worthy of in-depth exploration, but also has significant practical significance. In this paper, 160 stocks from 2012 to 2021 are selected for empirical analysis, and it is concluded that stocks of small-scale companies can realize good risk hedging as a hedge tool, and the trend of large-scale high-yield stocks conforms to the traditional capital asset pricing theory.

BackgroundPLIN2 (adipose differentiation-related protein) belongs to the perilipin family and is a marker of lipid droplets (LDs). Numerous types of tumor exhibit a high PLIN2 level, but its tumorigenic or tumor-suppressive role has been in debate. Recently, LDs serve as innate immune hubs and show antimicrobial capacity. We here aimed to investigate the heterogeneous functions of PLIN2 in the tumor microenvironment and immune regulation.MethodsThis retrospective study included 96 oral squamous cell carcinoma (OSCC) samples and analyzed the spatial distribution of PLIN2 by immunohistochemistry (IHC) and LD level by oil red O staining. A total of 21 serial sections were obtained to analyze the relationship between PLIN2 and immune cells by IHC and immunofluorescence (IF). Single-cell sequencing was used to analyze the cell locations of PLIN2. The values of diagnosis and prognosis of PLIN2 were also evaluated. Tumor Immune Estimation Resource (TIMER), cBioPortal databases, and IHC analysis were used to investigate the relationship between PLIN2 and OSCC immune microenvironment.ResultsPLIN2 was mainly expressed in tumor-infiltrating immunocytes (TIIs) of OSCC. Patients with high PLIN2 harbored more cytoplastic LDs. CD68+ tumor-associated macrophages (TAMs), instead of T cells and B cells, were found to be the main resource of PLIN2 in OSCC stroma and lung, pancreas, prostate, and testis. However, CD56+ NK cells also showed less extent of PLIN2 staining in OSCC. Moreover, patients with a high PLIN2 level in immune cells had a higher TNM stage and were susceptible to postoperative metastasis, but the escalated PLIN2 level in invasive tumor front independently predicted shorter metastasis-free survival. Furthermore, a high PLIN2 presentation in the microenvironment induced immune suppression which was featured as less infiltration of CD8+ T cells and more CD68+ TAMs and Foxp3+ Tregs, accompanied by more immune checkpoint molecules such as CSF1R, LGALS9, IL-10, CTLA-4, and TIGIT.ConclusionCD68+ TAM-derived PLIN2 might participate in regulating immune balance of OSCC patients, which provides new insight into immune checkpoint therapy.

Objective: This study aims to explore the clinical characteristics and genetic basis of a patient with unilateral ptosis and unilateral hearing impairment in pedigree analysis.Methods: The clinical data of the child and his father were collected. The genomic DNA of the patient and his relatives were extracted from their peripheral blood samples and subjected to trio-whole-exome sequencing (trio-WES) and copy number variation analysis. Sanger sequencing was used to verify the potential variant.Results: The sequencing analysis identified a heterozygous nonsense variant c.6431C > A (p.Ser2144*) in the ZNF462 gene (NM_021224.6) in the child and his father, whereas the locus in his asymptomatic mother, brother, and grandparents was found to be the wild type, which is an autosomal dominant inheritance. The new genetic variant has not been previously reported in the ClinVar and HGMD databases and the Genome Aggregation Database (gnomAD).Conclusion: This is the first incidence of Weiss–Kruszka syndrome relating to the nonsense variant in the ZNF462 gene in China. The finding from this study is novel in its expansion of the variant spectrum of the ZNF462 gene and clarifies the genetic etiology of the patient and his father.

Astrocytes play an important role in the central nervous system (CNS). Ion channels in these cells not only function in ion transport, and maintain water/ion metabolism homeostasis, but also participate in physiological processes of neurons and glial cells by regulating signaling pathways. Increasing evidence indicates the ion channel proteins of astrocytes, such as aquaporins (AQPs), transient receptor potential (TRP) channels, adenosine triphosphate (ATP)-sensitive potassium (K-ATP) channels, and P2X7 receptors (P2X7R), are strongly associated with oxidative stress, neuroinflammation and characteristic proteins in neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). Since ion channel protein dysfunction is a significant pathological feature of astrocytes in neurodegenerative diseases, we discuss these critical proteins and their signaling pathways in order to understand the underlying molecular mechanisms, which may yield new therapeutic targets for neurodegenerative disorders.

The mutation of K‐RAS represents one of the most frequent genetic alterations in cancer. Targeting of downstream effectors of RAS, including of MEK and ERK, has limited clinical success in cancer patients with K‐RAS mutations. The reduced sensitivity of K‐RAS‐mutated cells to certain MEK inhibitors (MEKi) is associated with the feedback phosphorylation of MEK by C‐RAF and with the reactivation of mitogen‐activated protein kinase (MAPK) signaling. Here, we report that the RAF dimer inhibitors lifirafenib (BGB‐283) and compound C show a strong synergistic effect with MEKi, including mirdametinib (PD‐0325901) and selumetinib, in suppressing the proliferation of K‐RAS‐mutated non‐small‐cell lung cancer and colorectal cancer (CRC) cell lines. This synergistic effect was not observed with the B‐RAFV600E selective inhibitor vemurafenib. Our mechanistic analysis revealed that RAF dimer inhibition suppresses RAF‐dependent MEK reactivation and leads to the sustained inhibition of MAPK signaling in K‐RAS‐mutated cells. This synergistic effect was also observed in several K‐RAS mutant mouse xenograft models. A pharmacodynamic analysis supported a role for the synergistic phospho‐ERK blockade in enhancing the antitumor activity observed in the K‐RAS mutant models. These findings support a vertical inhibition strategy in which RAF dimer and MEKi are combined to target K‐RAS‐mutated cancers, and have led to a Phase 1b/2 combination therapy study of lifirafenib and mirdametinib in solid tumor patients with K‐RAS mutations and other MAPK pathway aberrations.

To study delayed cerebral vasospasm (DCVS) induced by subarachnoid hemorrhage (SAH), 60 healthy Sprague Dawley (SD) rats were randomly divided into 5 groups (12 rats in each group), namely sham operation group, blood injection model group, nimodipine group, flunarizine hydrochloride group, and normal group. Then, the physiological parameters were detected, and after the rats were killed under anesthesia, the degree of nerve injury, vasospasm as well as the therapeutic effect of drugs were evaluated by Western Blot (WB). Neurological impairment (NI), endothelial contraction and spasm were obvious in rats following blood injection. The expression of Cav3.1 on T-type calcium channels was significantly higher in the blood injection model group than in the sham operation group along with the normal group. Moreover, Cav3.1 mRNA was expressed in all groups. The Cav3.1 expression in blood injection model group and two drug groups were significantly higher than that in sham operation group and lower than that in blood injection model group. Vasospasm was improved in two drug groups, which indicated that calcium channel antagonists nimodipine and flunarizine hydrochloride had a certain therapeutic effect on DCVS in rats. The decrease in body weight and food intake of the two groups of rats treated with drugs decreased, and the delayed vasospasm was improved, but the expression of Cav3.1 was not changed significantly, indicating nimodipine and flunarizine hydrochloride had a therapeutic effect on delayed vasospasm in rats, but Cav3.1 expression on calcium channels was not affected.

Abstract Background Antigen-processing machinery molecules play crucial roles in infectious diseases and cancers. Studies have shown that polymorphisms in endoplasmic reticulum aminopeptidase (ERAP) genes can influence the enzymatic activity of ERAP proteins and are associated with the risk of diseases. In the current study, we evaluated the influence of ERAP gene (ERAP1 and ERAP2) polymorphisms on susceptibility to cervical intraepithelial neoplasia (CIN) and cervical cancer. Methods Six single nucleotide polymorphisms (SNPs) in ERAP1 and 5 SNPs in ERAP2 were selected and genotyped in 556 CIN patients, 1072 cervical cancer patients, and 1262 healthy control individuals. Candidate SNPs were genotyped using SNaPshot assay. And the association of these SNPs with CIN and cervical cancer was analysed. Results The results showed that allelic and genotypic frequencies of rs26653 in ERAP1 were significantly different between cervical cancer and control groups (P = 0.001 and 0.004). The allelic frequencies of rs27044 in ERAP1 and rs2287988 in ERAP2 were significantly different between control and cervical cancer groups (P = 0.003 and 0.004). Inheritance model analysis showed that genotypes of rs27044, rs26618, rs26653 and rs2287988 SNPs may be associated with the risk of cervical cancer (P = 0.003, 0.004, 0.001 and 0.002). Additionally, haplotype analysis results showed that the ERAP1 haplotype, rs27044C-rs30187T-rs26618T-rs26653G-rs3734016C, was associated with a lower risk of cervical cancer (P = 0.001). The ERAP2 haplotypes rs2549782G- rs2548538A-rs2248374A-rs2287988G-rs1056893T (P = 0.009 and 0.006) and rs2549782T-rs2548538T-rs2248374G-rs2287988A-rs1056893T (P = 0.003 and 0.009) might be associated with cervical cancer and the development from CIN to cervical cancer. Conclusion Our results indicated that rs27044, rs26618 and rs26653 in ERAP1 and rs2287988 in ERAP2 influenced susceptibility to cervical cancer.

This paper focuses on the optimal scheduling of the district energy system with multiple energy supply modes and flexible loads. For multi-energy system (MES), the energy hub (EH) model including energy storage system and integrated electric vehicle (EV) is established. Based on the model, the influence of pollutant trading market on total operation cost is analyzed, and the optimal scheduling strategy is further put forward to realize the minimum purchase cost and emission tax cost of the MES. Finally, this paper compares the economic benefit of the fixed mode and the response mode, and discusses the contribution of the energy storage device and the multi-energy complementary mode to energy utilization efficiency. The simulation results indicate that optimal scheduling strategy of the EH can coordinate various energy complementary modes reasonably. Meanwhile, the proposed strategy is able to improve the operation economy of the EH, and ensure the better response effect of the demand side. The sensitivity analysis demonstrates the impact of pollutant emission price change on emission reduction.