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Abstract Background The leading cause of end-stage renal disease (ESRD) is diabetic nephropathy (DN). Podocyte damage is an early event in the development of DN. Currently, there is no effective treatment strategy that can slow the progression of DN or reverse its onset. The role of mesenchymal stem cells (MSCs) transplantation in diabetes and its complications has been extensively studied, and diabetic nephropathy has been a major focus. Irbesartan exerts reno-protective effects independent of lowering blood pressure, can reduce the incidence of proteinuria in rats, and is widely used clinically. However, it remains undetermined whether the combined utilization of the angiotensin II receptor antagonist irbesartan and MSCs could enhance efficacy in addressing DN. Methods A commonly used method for modeling type 2 diabetic nephropathy (T2DN) was established using a high-fat diet and a single low-dose injection of STZ (35 mg/kg). The animals were divided into the following 5 groups: (1) the control group (CON), (2) the diabetic nephropathy group (DN), (3) the mesenchymal stem cells treatment group (MSCs), (4) the irbesartan treatment group (Irb), and (5) the combined administration group (MSC + Irb). MSCs (2 × 106 cells/rat) were injected every 10 days through the tail vein for a total of three injections; irbesartan (30 mg/kg/d) was administered by gavage. Additionally, the safety and homing of mesenchymal stem cells were verified using positron emission tomography (PET) imaging. Results The combination treatment significantly reduced the UACR, kidney index, IGPTT, HOMA-IR, BUN, serum creatine, and related inflammatory factor levels and significantly improved renal function parameters and the expression of proteins related to glomerular podocyte injury in rats. Moreover, MSCs can homing target to damaged kidneys. Conclusions Compared to the administration of MSCs or irbesartan alone, the combination of MSCs and irbesartan exerted better protective effects on glomerular podocyte injury, providing new ideas for the clinical application of mesenchymal stem cells.

Abstract Background Cardiometabolic multimorbidity (CMM) is a growing global health problem, and obstructive sleep apnea (OSA) is recognized as an important risk factor for cardiovascular disease. However, the impact of OSA on the prognosis of CMM patients remains unclear. Methods This study was a sub-study of OSA-acute coronary syndrome (ACS) and included 1, 927 hospitalized ACS patients. Patients were divided into the CMM group and the non-CMM group. OSA was diagnosed using the apnea-hypopnea index (AHI). The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE). The secondary endpoint included cardiac events, all-cause death and all repeat revascularizations. Results This study enrolled 1, 927 patients hospitalized for ACS, with a median follow-up of 3 years. Among them, 723 patients (37.5%) had CMM, while 1, 204 patients (62.5%) did not have CMM. Over half of the patients in each group had OSA. OSA patients exhibited worse cardiometabolic profiles than their non-OSA counterparts, including higher body mass index (BMI), glycemic indices, lipids and inflammation. In the CMM group, OSA patients had a significantly higher incidence of MACCE than non-OSA patients (34.7% vs. 23.7%, p = 0.004). These results remained significant after adjustment, indicating that OSA substantially increased the risk of MACCE in the CMM group (adjusted hazard ratio [HR]: 1.432; 95% confidence interval [CI]: 1.017–2.016; p = 0.040). Conversely, the incidence of MACCE was similar between OSA and non-OSA subgroups within the non-CMM cohort. Subgroup analyses showed that OSA increased the risk of MACCE in CMM patients aged ≥ 60 years (adjusted HR: 1.642; 95% CI: 1.031–2.615; p = 0.037) and in those with specific clinical characteristics. Conclusion OSA significantly impacts the prognosis of CMM patients, highlighting the need for targeted OSA screening and management strategies to improve outcomes in this population potentially.

Sapphire exhibits typical anisotropy due to its unique crystal structure, and there are significant property differences in different processing areas during the machining of curved sapphire component, making it essential to investigate the anisotropy in the removal process of sapphire materials for efficient curved surface machining. In this study, the force and acoustic emission (AE) signals were monitored at different scratch stages and orientations, and the anisotropic characteristics of ductile-brittle transition (DBT) depths, material removal morphology, and subsurface crack propagation direction were analyzed. The results indicate that the anisotropy of force signals and DBT depths is mainly reflected in the differences between crystal planes. In addition, the removal morphology of materials with different crystal orientations showed smooth scratch grooves with unclear anisotropic characteristics during the ductile removal (DR) stage, while the crack propagation direction with different scratch orientations during the DBT stage showed significant anisotropic characteristics. The brittle removal (BR) stage is characterized by brittle spalling in the form of shell-like, blocky, and fishbone spalling, and there is a significant anisotropic difference in the spalling shapes on both sides of the scratch. The original AE signals, Fast Fourier Transform (FFT), and Short Time Fourier Transform (STFT) results show that the AE frequencies of different crystal planes are different, and the differences in different scratch orientations on the same crystal plane are reflected in the peak amplitude. Finally, the propagation directions of subsurface cracks with different directions are anisotropic due to different scratching crystal planes, and propagate mainly along directions of 15°, 29°, 32°, 58°, and 105°.

Abstract Fluorescence nanoscopy, also known as super-resolution microscopy, has transcended the conventional resolution barriers and enabled visualization of biological samples at nanometric resolutions. A series of super-resolution techniques have been developed and applied to investigate the molecular distribution, organization, and interactions in blood cells, as well as the underlying mechanisms of blood-cell-associated diseases. In this review, we provide an overview of various fluorescence nanoscopy technologies, outlining their current development stage and the challenges they are facing in terms of functionality and practicality. We specifically explore how these innovations have propelled forward the analysis of thrombocytes (platelets), erythrocytes (red blood cells) and leukocytes (white blood cells), shedding light on the nanoscale arrangement of subcellular components and molecular interactions. We spotlight novel biomarkers uncovered by fluorescence nanoscopy for disease diagnosis, such as thrombocytopathies, malignancies, and infectious diseases. Furthermore, we discuss the technological hurdles and chart out prospective avenues for future research directions. This review aims to underscore the significant contributions of fluorescence nanoscopy to the field of blood cell analysis and disease diagnosis, poised to revolutionize our approach to exploring, understanding, and managing disease at the molecular level. Graphical Abstract

Abstract A kind of all‐dielectric circularly polarised (CP) loop antenna made of high‐permittivity material is proposed. The leaky‐wave radiation from a high‐permittivity dielectric waveguide is utilised here to support the operation of the proposed antenna. A non‐closed dielectric loop covering a three‐quarter circle is adopted to generate CP radiation and it is connected with the dielectric ground via one of bending ends to form an all‐in‐one structure of the antenna. The other end is also bent and vertical to the ground, but hanging in the air for probe feed. As two kinds of typical high‐permittivity dielectric materials, zirconia ceramic and pure water are used to implement the proposed design respectively. On one hand, an all‐ceramic CP loop antenna made of zirconia is proposed. And benefiting from the low loss and high melting point of zirconia, the proposed ceramic antenna has superiority in radiation efficiency and could adapt to a harsh environment. On the other hand, by using pure water and transparent container, a fully‐transparent CP water loop antenna can be obtained. Finally, a 3‐D printing technology is adopted in the manufacturing of ceramic structure and resin container. Measured results of both antennas demonstrate the validity of the proposed design.

Abstract Ferroptosis, an iron-dependent form of programmed cell death, is a promising strategy for cancer treatment. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader and a promising target for cancer therapeutics. However, the role of BRD4 in ferroptosis is controversial and the value of the interaction between BRD4 inhibitors and ferroptosis inducers remains to be explored. Here, we found that BRD4 inhibition greatly enhanced erastin-induced ferroptosis in different types of cells, including HEK293T, HeLa, HepG2, RKO, and PC3 cell lines. Knocking down BRD4 in HEK293T and HeLa cells also promoted erastin-induced cell death. BRD4 inhibition by JQ-1 and I-BET-762 or BRD4 knockdown resulted in substantial accumulation of reactive oxygen species (ROS) in both HEK293T and HeLa cells. The effect of BRD4 inhibition on ferroptosis-associated genes varied in different cells. After using BRD4 inhibitors, the expression of FTH1, Nrf2, and GPX4 increased in HEK293T cells, while the levels of VDAC2, VDAC3, and FSP1 decreased. In HeLa cells, the expression of FTH1, VDAC2, VDAC3, Nrf2, GPX4, and FSP1 was reduced upon treatment with JQ-1 and I-BET-762. Consistently, the level of FSP1 was greatly reduced in HEK293T and HeLa cells with stable BRD4 knockdown compared to control cells. Furthermore, ChIP-sequencing data showed that BRD4 bound to the promoter of FSP1, but the BRD4 binding was greatly reduced upon JQ-1 treatment. Our results suggest that ROS accumulation and FSP1 downregulation are common mechanisms underlying increased ferroptosis with BRD4 inhibitors. Thus, BRD4 inhibitors might be more effective in combination with ferroptosis inducers, especially in FSP1-dependent cancer cells.

As exemplified by the COVID-19 pandemic, the design and implementation of data-driven health surveillance, like digital contact tracing (DCT) apps, carry significant implications for society. However, its rushed development calls for careful consideration from all involved stakeholders to achieve a shared understanding and engage in joint-sensemaking in order to implement DCT collaboratively and effectively utilize it in the fight against the pandemic. Yet, the empirical ground truth and theoretical mechanism of joint-sensemaking are both unclear. Drawing on this gap, this article applies a multistep approach, including sentiment analysis, topic analysis coupled with regression and unique network analysis, to thoroughly explore, examine, and explain the dynamic process of joint-sensemaking in the context of a public crisis. Based on evidence from 113,264 Weibo posts, we illustrate two joint-sensemaking pathways and three key interventions using the case of China's Health Code in the context of the DCT. We reveal that the effectiveness of different interventions and contributions made by stakeholders vary significantly between different joint-sensemaking pathways. Specifically, we find that official media and opinion leaders act as crucial mediators in bridging intervention conductors and the public. However, their influence presents heterogeneity toward different network modularity, thus leading to distinct patterns. Additionally, inconsistent with previous literature, we find that within the context of the China Health Code, official media has a greater impact on opinion leaders in engaging the public.

AbstractAlismataceae is one of the early diverged families of monocotyledonous plants. We report the complete chloroplast genomes of three Alisma species, including Alisma orientale (Sam.) Juzep. 1934, A. subcordatum Raf. 1908, and A. triviale Pursh 1813, of which A. orientale is a traditional Chinese medical plant used widely to treat diuretics, diabetes, hepatitis, and inflammation. We sequenced the complete chloroplast genomes with the Illumina Nova-Seq 6000 platform using herbarium collections. The chloroplast genomes of A. orientale, A. subcordatum and A. triviale are 159,861 bp, 160,180 bp, and 159,727 bp in length, respectively. The three chloroplast genomes each contain 113 genes, including four rRNAs, 30 tRNAs genes, and 79 protein-coding genes, and the average GC content is 36.0%. Based on the whole chloroplast genomes of 19 species of Alismataceae and the close allies, the medicinally important A. orientale was found to be closely related to another medicinal plant Alisma plantago-aquatica L. 1753 in the phylogenetic analysis. The genus Alisma was supported to be monophyletic.

Abstract CircLRIG1, a newly discovered circRNA, has yet to have its potential function and biological processes reported. This study explored the role of circLRIG1 in the development and progression of bladder carcinoma and its potential molecular mechanisms. Techniques such as qRT-PCR, Western blot, various cellular assays, and in vivo models were used to investigate mRNA and protein levels, cell behavior, molecular interactions, and tumor growth. The results showed that both circLRIG1 and LRIG1 were significantly reduced in bladder carcinoma tissues and cell lines. Low circLRIG1 expression was associated with poor patient prognosis. Overexpressing circLRIG1 inhibited bladder carcinoma cell growth, migration, and invasion, promoted apoptosis, and decreased tumor growth and metastasis in vivo. Importantly, circLRIG1 was found to sponge miR-214-3p, enhancing LRIG1 expression, and its overexpression also modulated protein levels of E-cadherin, N-cadherin, Vimentin, and LRIG1. Similar effects were observed with LRIG1 overexpression. Notably, a positive correlation was found between circLRIG1 and LRIG1 expression in bladder carcinoma tissues. Additionally, the tumor-suppressing effect of circLRIG1 was reversed by overexpressing miR-214-3p or silencing LRIG1. The study concludes that circLRIG1 suppresses bladder carcinoma progression by enhancing LRIG1 expression via sponging miR-214-3p, providing a potential strategy for early diagnosis and treatment of bladder carcinoma.

Abstract Background Classical Hodgkin lymphoma (cHL) is a highly curable disease, while novel therapy is needed for refractory or relapsed (R/R) patients. This phase II trial aimed to evaluate the role of camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in R/R cHL patients. Methods Transplant-eligible patients with R/R cHL were enrolled and received two 14-day cycles of camrelizumab 200 mg intravenously (IV) and two 28-day cycles of camrelizumab 200 mg IV, gemcitabine 1000 mg/m2 IV, and oxaliplatin 100 mg/m2 IV on days 1 and 15. Patients with partial response (PR) or stable disease received an additional cycle of combination therapy. Those who achieved complete response (CR) or PR proceeded to autologous stem cell transplantation (ASCT). The primary endpoint was the CR rate at the end of protocol therapy before ASCT. Results Forty-two patients were enrolled. At the end of protocol therapy, the objective response rate and CR rate were 94.9% (37/39) and 69.2% (27/39) in the evaluable set, and 88.1% (37/42) and 64.3% (27/42) in the full analysis set, respectively. Twenty-nine patients (69.0%) proceeded to ASCT, and 4 of 5 patients with PR achieved CR after ASCT. After a median follow-up of 20.7 months, the 12-month progression-free survival rate was 96.6% and the 12-month overall survival rate was 100%. Grade 3 or higher treatment emergent adverse events occurred in 28.6% of patients (12/42), mainly hematological toxicity. Conclusions Camrelizumab combined with GEMOX constitutes an effective salvage therapy for R/R cHL, proving to be relatively well-tolerated and facilitating ASCT in most patients, thus promoting sustained remission. Trial registration ClinicalTrials.gov NCT04239170. Registered on January 1, 2020.

A class of dielectric filtering inverted-L antenna with reflective- and quasi-reflectionless-type radiation nulls is proposed to achieve wideband or dual-band operation. To this aim, a dual-function dissipative branch is exploited, which is in-parallel loaded at the feedline of the microstrip-fed dielectric inverted-L antenna. This absorptive branch, which is terminated in a grounded resistor, exhibits a quasi-complementary frequency response with regard to the one of the antenna. In this manner, it can mostly absorb the out-of-band RF-signal power not radiated by the antenna, hence creating quasi-reflectionless-type radiation nulls. Furthermore, the loaded branch can also generate a notch band giving rise to a reflective-type radiation null, which comes determined by the length of the branch and it is independent of the quasi-reflectionless radiation nulls. Thus, by controlling the spectral location of the notch band out of or within the operational frequency band of the dielectric inverted-L antenna, wideband or dual-band operational capabilities can be functionalized into it. For experimental-validation purposes, proof-of-concept prototypes for the two devised wideband and dual-band antenna approaches are designed, manufactured, and characterized. The measured results are in reasonably-close agreement with the simulated ones. The measured fractional impedance bandwidths of the two antenna prototypes are 28.3% (wideband one), 3.1% and 4.2% (dual-band one), respectively.

In this paper, a kind of half-loop Yagi-Uda antenna made of high-permittivity dielectric is proposed to realize end-fire radiation. As two typical materials with high permittivity, low-loss zirconia ceramic and liquid pure water are here employed for the proposed antenna to attain high radiation efficiency and support the characteristic of pattern reconfigurability, respectively. The thin dielectric waveguide with high permittivity is here used as the metal wire of conventional wire antennas, due to its traveling-wave radiation under TM01 mode. The different radiation characteristics of the electrically small loop and full-wave loop antennas are discussed. And the dielectric large half-loop antenna with ground plane and bi-directional radiation is utilized to form a Yagi-Uda array for desired end-fire radiation. Moreover, circular loop elements are subsequently transformed into rectangular shape to reduce the profile of antenna and a comparison between the conventional metal Yagi-Uda antenna and the proposed dielectric one is provided. It is found that the dielectric parasitic element could play a more flexible role. Both ceramic and pure-water antenna prototypes are fabricated and tested. Measured results match the simulated ones well, which validates the predicted antenna performance.

Tracking single-cell lineages and their phenotypes longitudinally would help us better study skin development. Brainbow multicolor labeling approach is a genetic cell-labeling technique that tracks individual cells or analyzes cell lineages during development. Hence, we generated a stable Cre-inducible rainbow reporter human embryonic stem cell line (Named SMUDHe010-A-1A) by inserting the fluorescent protein gene (nGFP, YFP, RFP and CFP) at AAVS1 safe harbor locus using CRISPR/Cas9 technology. We verified that SMUDHe010-A-1A expressed the pluripotency markers and showed normal stem cell morphology. Furthermore, SMUDHe010-A-1A preserves normal karyotype and the ability to differentiate toward three germ layers. So the SMUDHe010-A-1A is effective for identifying and track cell populations.

Out-of-hospital cardiac arrest is a major public health problem worldwide due to its high burden and poor outcomes. Despite progress in treatment, patient outcomes remain unsatisfactory, particularly in low-resource settings. The establishment of a registry is the first step towards gaining a comprehensive understanding of prevailing local conditions and identifying potential opportunities for improving patient survival. Here, we provide a narrative review of the BASeline Investigation of Out-of-hospital Cardiac Arrest (BASIC-OHCA), the first national OHCA registry in China, to introduce its development history, current state, challenges and future directions. We aim to enhance cross-cultural understanding by providing insights from China, while also serving as a reference for the implementation of large-scale registries in low-resource settings.

BackgroundRecent studies have revealed changes in microbiota constitution and metabolites associated with tumor progression, however, no causal relation between microbiota or metabolites and diffuse large B-cell lymphoma (DLBCL) has yet been reported.MethodsWe download a microbiota dataset from the MiBioGen study, a metabolites dataset from the Canadian Longitudinal Study on Aging (CLSA) study, and a DLBCL dataset from Integrative Epidemiology Unit Open genome-wide association study (GWAS) project. Mendelian randomization (MR) analysis was conducted using the R packages, TwoSampleMR and MR-PRESSO. Five MR methods were used: MR-Egger, inverse variance weighting (IVW), weighted median, simple mode, and weighted mode. Reverse MR analyses were also conducted to explore the causal effects of DLBCL on the microbiome, metabolites, and metabolite ratios. Pleiotropy was evaluated by MR Egger regression and MR-PRESSO global analyses, heterogeneity was assessed by Cochran’s Q-test, and stability analyzed using the leave-one-out method.Results119 microorganisms, 1,091 plasma metabolite, and 309 metabolite ratios were analyzed. According to IVW analysis, five microorganisms were associated with risk of DLBCL. The genera Terrisporobacter (OR: 3.431, p = 0.049) andgenera Oscillibacter (OR: 2.406, p = 0.029) were associated with higher risk of DLBCL. Further, 27 plasma metabolites were identified as having a significant causal relationships with DLBCL, among which citrate levels had the most significant protective causal effect against DLBCL (p = 0.006), while glycosyl-N-tricosanoyl-sphingadienine levels was related to higher risk of DLBCL (p = 0.003). In addition, we identified 19 metabolite ratios with significant causal relationships to DLBCL, of which taurine/glutamate ratio had the most significant protective causal effect (p = 0.005), while the phosphoethanolamine/choline ratio was related to higher risk of DLBCL (p = 0.009). Reverse MR analysis did not reveal any significant causal influence of DLBCL on the above microbiota, metabolites, and metabolite ratios (p > 0.05). Sensitivity analyses revealed no significant heterogeneity or pleiotropy (p > 0.05).ConclusionWe present the first elucidation of the causal influence of microbiota and metabolites on DLBCL using MR methods, providing novel insights for potential targeting of specific microbiota or metabolites to prevent, assist in diagnosis, and treat DLBCL.

Summary: Early detection of left ventricular remodeling (LVR) is crucial. While cardiac magnetic resonance (CMR) provides valuable information, it has limitations. Coronary angiography-derived fractional flow reserve (caFFR) and index of microcirculatory resistance (caIMR) offer viable alternatives. 157 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention were prospectively included. 23.6% of patients showed LVR. Machine learning algorithms constructed three LVR prediction models: Model 1 incorporated clinical and procedural parameters, Model 2 added CMR parameters, and Model 3 included echocardiographic and functional parameters (caFFR and caIMR) with Model 1. The random forest algorithm showed robust performance, achieving AUC of 0.77, 0.84, and 0.85 for Models 1, 2, and 3. SHAP analysis identified top features in Model 2 (infarct size, microvascular obstruction, admission hemoglobin) and Model 3 (current smoking, caFFR, admission hemoglobin). Findings indicate coronary physiology and echocardiographic parameters effectively predict LVR in patients with STEMI, suggesting their potential to replace CMR.

In order to choose a suitable thawing method for Micropterus salmoides (room temperature thawing, running water thawing, saltwater thawing, ultrasonic static water thawing and ultrasonic running water thawing), this paper took Micropterus salmoides as the research subject. To investigate the effects of different thawing methods on water retention, total volatile base nitrogen (TVB-N), malondialdehyde content, peroxide value, total sulfhydryl content and Ca2+-ATPase activity of Micropterus salmoides. At the same time, the changes of texture properties such as hardness, elasticity and adhesion of fish were analyzed. The results showed that the normal temperature thaw 219 min, longest, fish water retention, lipid and protein oxidation was the most serious. Thawing water and salt water thawing time consuming 35 and 55 min, respectively, was the shorter of the normal temperature thaw, but fish water retention, protein oxidation, quality and structure characteristics of the various quality indexes such as the change was still serious. After ultrasonic static water thawing, the fish had better water retention and texture characteristics, and could effectively alleviate the oxidation of fish protein, but the lipid oxidation was more serious. Ultrasonic flow water thawing could complete the thawing of fish within 24 minutes, which was more efficient. Compared with other thawing methods, it could effectively maintain the water retention and texture characteristics of fish, and effectively delay the oxidation of fish protein and lipid. Ultrasonic thawing of frozen water, therefore, Micropterus salmoides had little effect on quality, was the most suitable thawing method.

Diphtheria toxin A (DTA) is an exotoxin secreted by Corynebacterium diphtheriae. After entering the cell through receptor-mediated manner, DTA can trigger the programmed cell death mechanism and lead to cell death. In 2001, Michiko Saito established a Diphtheria toxin receptor–mediated cell knockout system, which can conditional deplete specific cell type in transgenic mice. This system is not only very useful in the pathogenesis study of human diseases, but also has a wide application prospect in the study of organ development and regeneration. In 2008, David Voehringer described a newly generated mouse strain that encodes DTA under control of a loxP-flanked stop cassette in the ubiquitously expressed ROSA26 locus. Thereby, it can be used in combination with tissue-specific and/or inducible Cre-expressing mouse strains to achieve toxin-mediated cell ablation in vivo. The application of DTA–mediated cell knockout system in mice has been widely reported, but it has rarely been used in human cells. Accordingly, we generated a human embryonic stem cell line (SMUDHe010-A-1B) carrying inducible DTA expression cassette (loxp-stop-loxp-DTA, LSL-DTA) using CRISPR/Cas9-mediated homologous recombination. The cell line preserves normal karyotype, pluripotency and the ability to differentiate into all three germ layers. Moreover, the cell line can be used to prepare human organoid, which may provide a model for achieving conditional cell ablation in human tissues and organs.

ARHGEF17 encodes the protein RhoGEF17, which is highly expressed in vascular endothelial cells. It is a guanine nucleotide exchange factor (GEF) that accelerates the exchange of GDP with GTP on many small GTPases through its Dbl homology (DH) domain, enabling the activation of Rho-GTPases such as RhoA, RhoB, and RhoC. Rho GTPase-regulated changes in the actin cytoskeleton and cell adhesion kinetics are the main mechanisms mediating many endothelial cell (EC) alterations, including cell morphology, migration, and division changes, which profoundly affect EC barrier function. This review focuses on ARHGEF17 expression, activation and biological functions in ECs, linking its regulation of cellular morphology, migration, mitosis and other cellular behaviors to disease onset and progression. Understanding ARHGEF17 mechanisms of action will contribute to the design of therapeutic approaches targeting RhoGEF17, a potential drug target for the treatment of various endothelium-related diseases, Such as vascular inflammation, carcinogenesis and transendothelial metastasis of tumors.

Abstract Long non-coding RNAs (lncRNAs) could modulate expression of immune checkpoints (ICPs) in tumor-immune. However, precise functions in immunity and potential for predicting ICP inhibitors (ICI) response have been described for only a few lncRNAs. Here, a multiple-step pipeline was developed to identify cancer- and immune-context ICP and lncRNA cooperative regulation pairs (ICPaLncCRPs) across cancers. Immune-related ICPs and lncRNAs were extracted follow immune cell lines and immunologic constant of rejection groups. ICPaLncCRP networks were constructed, which likely to modulate tumor-immune by specific patterns. Common and specific hub ICPaLncs such as MIR155HG, TRG-AS1 and PCED1B-AS1 maybe play central roles in prognosis and circulating. Moreover, these hub ICPaLncs were significantly correlated with immune cell infiltration based on bulk and single-cell RNA sequencing data. Some ICPaLncCRPs such as IDO1-MIR155HG could predict three- and five-year prognosis of melanoma in two independent datasets. We also validated that some ICPaLncCRPs could effectively predict ICI-response follow six independent datasets. Collectively, this study will enhance our understanding of lncRNA functions and accelerate discovery of lncRNA-based biomarkers in ICI treatment.

Abstract Background Food protein-induced enterocolitis syndrome (FPIES) is a delayed, non-IgE-mediated food allergy. This syndrome was once thought to be rare, but emerging literature suggests an increasing incidence along with more foods being implicated. Also, with the introduction of guidelines on early peanut introduction, peanut-induced FPIES seems to be increasing in Australia and USA. Although most patients are diagnosed with FPIES within the first year of life, most commonly with food triggers to cow’s milk or soy, other phenotypes exist in comparison to this classic presentation. In this case report, we present a patient with late onset of acute FPIES at age 3 to walnut. Case Presentation We describe a case of FPIES in a 12-year-old boy who had recurrent episodes of repetitive emesis, that began at age 3, each time after consuming walnuts. Mom does not give a history of intentional feeding (or avoidance) of walnut and/ or pecans. She also described possible reactions with pine nuts and macadamia. He was assessed with an oral food challenge to walnut, which triggered an episode of acute FPIES. He developed vomiting with onset 2 h post-ingestion, pallor, lethargy, and required an emergency department visit for anti-emetic medications and oral rehydration therapy. He improved on the therapy and now avoids cashew, pistachio, hazelnuts, walnuts, pecans, pine nuts, and macadamia nuts. Conclusions This case report adds to the limited literature that exists on culprit food allergens in FPIES. We present an acute FPIES triggered by the ingestion of walnuts. The diagnosis, common food triggers, and natural history of FPIES are described. There remains a lack of information on the natural history of FPIES, especially towards uncommon food triggers and on FPIES that present beyond infancy.

Comorbidities are prevalent in digestive cancers, intensifying patient discomfort and complicating prognosis. Identifying potential comorbidities and investigating their genetic connections in a systemic manner prove to be instrumental in averting additional health challenges during digestive cancer management. Here, we investigated 150 diseases across 18 categories by collecting and integrating various factors related to disease comorbidity, such as disease-associated SNPs or genes from sources like MalaCards, GWAS Catalog and UK Biobank. Through this extensive analysis, we have established an integrated pleiotropic gene set comprising 548 genes in total. Particularly, there enclosed the genes encoding major histocompatibility complex or related to antigen presentation. Additionally, we have unveiled patterns in protein-protein interactions and key hub genes/proteins including TP53, KRAS, CTNNB1 and PIK3CA, which may elucidate the co-occurrence of digestive cancers with certain diseases. These findings provide valuable insights into the molecular origins of comorbidity, offering potential avenues for patient stratification and the development of targeted therapies in clinical trials.

Abstract Background Accurately classifying complex diseases is crucial for diagnosis and personalized treatment. Integrating multi-omics data has been demonstrated to enhance the accuracy of analyzing and classifying complex diseases. This can be attributed to the highly correlated nature of the data with various diseases, as well as the comprehensive and complementary information it provides. However, integrating multi-omics data for complex diseases is challenged by data characteristics such as high imbalance, scale variation, heterogeneity, and noise interference. These challenges further emphasize the importance of developing effective methods for multi-omics data integration. Results We proposed a novel multi-omics data learning model called MODILM, which integrates multiple omics data to improve the classification accuracy of complex diseases by obtaining more significant and complementary information from different single-omics data. Our approach includes four key steps: 1) constructing a similarity network for each omics data using the cosine similarity measure, 2) leveraging Graph Attention Networks to learn sample-specific and intra-association features from similarity networks for single-omics data, 3) using Multilayer Perceptron networks to map learned features to a new feature space, thereby strengthening and extracting high-level omics-specific features, and 4) fusing these high-level features using a View Correlation Discovery Network to learn cross-omics features in the label space, which results in unique class-level distinctiveness for complex diseases. To demonstrate the effectiveness of MODILM, we conducted experiments on six benchmark datasets consisting of miRNA expression, mRNA, and DNA methylation data. Our results show that MODILM outperforms state-of-the-art methods, effectively improving the accuracy of complex disease classification. Conclusions Our MODILM provides a more competitive way to extract and integrate important and complementary information from multiple omics data, providing a very promising tool for supporting decision-making for clinical diagnosis.

The international standards IEEE 1474 and IEC 62290 for fully automatic operation (FAO) systems in urban rail transit were respectively set by IEEE-SA (institute of electrical and electronics engineers-standard association) and IEC (international electrotechnical commission) in 1999 and 2004. These two standards are different but related. In this paper, the working progress, relevance, the driverless definition, application scope, architecture, functional requirements and focus issues of IEC 62290 and IEEE 1474 are compared and analyzed respectively. IEEE 1474 is the theoretical foundation for research and development personnel in the field of railway signaling, which is applicable to operation control systems of urban rail transit, trunk railways and medium to high speed maglev, and IEC 62290 is more suitable for FAO systems in urban rail transit.

We report a case of lupus erythematosus panniculitis misdiagnosed as vasculitis. A 7-year-old boy presented with a 2-year history of erythema and ulceration on the left lower abdomen and depressed skin on the left buttock. He had been diagnosed with vasculitis and skin infection in other hospitals for many times. Dermatological examination showed scattered dark erythema on the left lower abdomen, green bean to nail sized necrosis and ulcers with adhesive black crusts on some areas, and several porcelain-white mild atrophic scars. Non-atrophic band-like depression in normal color was observed on the left hip, ilium, left lower abdomen and the left groin. The skin could be pinched. Histopathological changes in the skin lesions included liquefaction degeneration of basal cells, pigment incontinence, infiltration of lymphocytes and plasma cells around dermal vessels and appendages, mucin deposition between collagen bundles, adipose atrophy, encapsulation of fatty lobules, and positive for Alcian blue staining. The final diagnosis was lupus erythematosus panniculitis. The patient was treated with oral hydroxychloroquine 0.1 g/qd and methylprednisolone 16 mg/qd, and topical mucopolysaccharide polysulfate cream, centella triterpenes cream and crisaborole ointment. Ulcers were healed without new lesion and erythema at one-year follow-up.

Epilepsy is a group of enduring neurological disorder characterized by spontaneous and recurrent seizures with heterogeneous etiology, clinical expression, severity, and prognosis. Growing body of research investigates that epileptic seizures are originated from neuronal synchronized and excessive electrical activity. However, the underlying molecular mechanisms of epileptogenesis have not yet been fully elucidated and 30% of epileptic patients still are resistant to the currently available pharmacological treatments with recurrent seizures throughout life. Over the past two decades years accumulated evidences provide strong support to the hypothesis that neuroinflammation, including microglia and astrocytes activation, a cascade of inflammatory mediator releasing, and peripheral immune cells infiltration from blood into brain, is associated with epileptogenesis. Meanwhile, an increasing body of preclinical researches reveal that the anti-inflammatory therapeutics targeting crucial inflammatory components are effective and promising in the treatment of epilepsy. The aim of the present study is to highlight the current understanding of the potential neuroinflammatory mechanisms in epileptogenesis and the potential therapeutic targets against epileptic seizures.

Abstract Background Premature infants are inevitably exposed to painful events, including repetitive procedures, inflammation, or mixed stimulation that may induce long‐term behavioral outcomes. Here, we set up three neonatal painful models to investigate their long‐term effect on somatosensation and cognition. Methods Three types of neonatal pain models in rat were set up. Rat pups were randomly assigned to four groups. The needling pain (NP) group received repetitive needle pricks on the paws from the day of birth (PD0) to postnatal day 7 (PD7) to mimic the diagnostic and therapeutic procedures. The inflammatory pain (IP) group received the injection of carrageenan into the left hindpaw at PD3 to induce IP in peripheral tissues. The mixed pain group received a combination of the NP and IP (NIP). The control (CON) group was untreated. We performed behavioral and biochemical testing of juvenile rats (PD21–PD26). Results The NIP group showed a longer hypersensitivity than the NP group, when given a secondary inflammatory stimulation. NP led to insensitivity to anxiety‐causing stimuli and impairment of fear memory both aggravated by NIP. NP reduced the expression of synapse‐related molecules (GluN1/PSD95/GFAP) in the medial prefrontal cortex, and NIP exacerbated this decrease. The corticosterone secretion in the NIP group increased after the behavioral task, compared with those in other three groups. Conclusion A combination of NP with inflammation occurring in the neonatal period might aggravate the adverse effects of each on somatosensory and cognitive development of rats, the mechanism of which might be associated with the increase of corticosterone secretion and the dysregulation of synaptic molecules.

Abstract The risk of cardiovascular disease (CVD) is a serious health threat to human society worldwide. The use of machine learning methods to predict the risk of CVD is of great relevance to identify high-risk patients and take timely interventions. In this study, we propose the XGBH machine learning model, which is a CVD risk prediction model based on key contributing features. In this paper, the generalisation of the model was enhanced by adding retrospective data of 14,832 Chinese Shanxi CVD patients to the kaggle dataset. The XGBH risk prediction model proposed in this paper was validated to be highly accurate (AUC = 0.81) compared to the baseline risk score (AUC = 0.65), and the accuracy of the model for CVD risk prediction was improved with the inclusion of the conventional biometric BMI variable. To increase the clinical application of the model, a simpler diagnostic model was designed in this paper, which requires only three characteristics from the patient (age, value of systolic blood pressure and whether cholesterol is normal or not) to enable early intervention in the treatment of high-risk patients with a slight reduction in accuracy (AUC = 0.79). Ultimately, a CVD risk score model with few features and high accuracy will be established based on the main contributing features. Of course, further prospective studies, as well as studies with other populations, are needed to assess the actual clinical effectiveness of the XGBH risk prediction model.

Abstract Background and objective Whether obstructive sleep apnea (OSA) is associated with worse prognosis in patients with acute coronary syndrome (ACS) with or without prior stroke remains unclear. We investigated the association of OSA with cardiovascular events in ACS patients with or without prior stroke. Methods Between June 2015 and January 2020, we prospectively recruited eligible ACS patients who underwent cardiorespiratory polygraphy during hospitalization. We defined OSA as an apnea hypopnea index (AHI) ≥ 15 events/hour. The primary composite end point was major adverse cardiovascular and cerebrovascular events (MACCEs), including cardiovascular death, myocardial infarction, stroke, ischemia-driven revascularization, or hospitalization for unstable angina or heart failure. Results Among 1927 patients enrolled, 207 patients had prior stroke (10.7%) and 1014 had OSA (52.6%). After a mean follow-up of 2.9 years, patients with stroke had significantly higher risk of MACCEs than those without stroke (hazard ratio [HR]:1.49; 95% confidence interval [CI]: 1.12–1.98, P = 0.007). The multivariate analysis showed that patients with OSA had 2.0 times the risk of MACCEs in prior stroke group (41 events [33.9%] vs 18 events [20.9%]; HR:2.04, 95% CI:1.13–3.69, P = 0.018), but not in non-prior stroke group (186 events [20.8%] vs 144 events [17.4]; HR:1.21, 95% CI 0.96–1.52, P = 0.10). No significant interaction was noted between prior stroke and OSA for MACCE (interaction P = 0.17). Conclusions Among ACS patients, the presence of OSA was associated with an increased risk of cardiovascular events in patients with prior stroke. Further trials exploring the efficacy of OSA treatment in high-risk patients with ACS and prior stroke are warranted. Trial registration Clinicaltrials.gov identifier NCT03362385.

Angiopoietin-like protein 3 (ANGPTL3) is an important regulator of lipoproteins by inhibiting both lipoprotein and endothelial lipases. It has been intensively investigated as a drug target for the treatment of dyslipidemia. In the present study, a modified small interfering RNA (siRNA) conjugated with GalNAc ANGsiR10 was characterized by in vivo and in vitro studies for its effect on ANGPTL3 silencing, the reduction of plasma triglycerides (TGs), and cholesterol levels in disease models. The results showed that ANGsiR10 displayed a significant and long-lasting efficacy in reducing blood TG and cholesterol levels in both mice and monkeys. Remarkably, the maximal reductions of plasma TG levels in the hApoC3-Tg mice, a model with high TG levels, and the spontaneous dyslipidemia model of rhesus monkey were 96.3% and 67.7%, respectively, after a single dose of ANGsiR10, with long-lasting effects up to 15 weeks. The cholesterol levels were also reduced in response to treatment, especially the non-HDL-c level, without altering the ApoA/ApoB ratio. This study showed that ANGsiR10 is effective in treating dyslipidemia and is worth further development.

Abstract Progressive albuminuria is the primary clinical symptom of diabetic nephropathy (DN), leading to a gradual decline in kidney function. DLX6-AS1 was the first reported long non-coding RNA (lncRNA) to participate in organogenesis and play crucial roles in the brain or neural cell development. Herein, we investigated the DLX6-AS1 (Dlx6-os1 in mice) role in DN pathogenesis. We found that DLX6-AS1 expression in DN patients correlated with the extent of albuminuria. Dlx6-os1 overexpression induced cellular damage and inflammatory responses in cultured podocytes through miR-346-mediated regulation of the GSK-3β pathway. In various established diabetic and newly developed knockout mouse models, Dlx6-os1 knockdown/knockout significantly reduced podocyte injury and albuminuria. The Dlx6-os1 effects were remarkably modulated by miR-346 mimics or mutants and significantly diminished in podocyte-specific GSK-3β-knockout mice. Thus, DLX6-AS1 (Dlx6-os1) promotes DN development by accelerating podocyte injury and inflammation through the upregulation of the GSK-3β pathway, providing a novel molecular target for DN therapy.

Abstract Evidence on the association of 25‐hydroxyvitamin D (25[OH]D) and obesity during the first 5 years of life is limited in China. The objective of this study was to examine the associations between weight, weight for age z score (ZWAZ), weight for length/height z score (ZWHZ), and body mass index for age z score (ZBMI) and 25(OH)D. This was a large population‐based cross‐sectional multicenter study in which the children aged 0–5 years were recruited from 12 children's healthcare centers by a stratified cluster random‐sampling method in 10 cities of the Jiangsu province, China. The 25(OH)D concentration was determined by ELISA. A total of 5289 children were investigated. For 0–71 months children with obesity and nonobesity, the prevalence of vitamin D deficiency was 36.0% and 29.8%, and the 25(OH)D level was 59.8 and 64.0 nmol/L, respectively, and there were all significant difference. Compared with children with nonobesity, children with obesity had higher risk of vitamin D deficiency (OR [95% CI]: 1.33 [1.02, 1.72], p

Genetic epilepsy with febrile seizures plus (GEFSP) is a familial epileptic syndrome that is genetically heterogeneous and inherited in an autosomal dominant form in most cases. To date, at least seven genes have been reported to associate with GEFSP. This study aimed to identify the disease-causing variant in a Chinese Tujia ethnic family with GEFSP by using whole exome sequencing, Sanger sequencing, and in silico prediction. A heterozygous missense variant c.5725A>G (p.T1909A) was identified in the sodium voltage-gated channel alpha subunit 1 gene (SCN1A) coding region. The variant co-segregated with the GEFSP phenotype in this family, and it was predicted as disease-causing by multiple in silico programs, which was proposed as the genetic cause of GEFSP, further genetically diagnosed as GEFSP2. These findings expand the genetic and phenotypic spectrum of GEFSP and should contribute to genetic diagnoses, personalized therapies, and prognoses.

SARS-CoV-2 infection causes most cases of severe illness and fatality in older age groups. Over 92% of the Chinese population aged ≥12 years has been fully vaccinated against COVID-19 (albeit with vaccines developed against historical lineages). At the end of October 2021, the vaccination programme has been extended to children aged 3–11 years. Here, we aim to assess whether, in this vaccination landscape, the importation of Delta variant infections could shift COVID-19 burden from adults to children. We developed an age-structured susceptible-infectious-removed model of SARS-CoV-2 transmission to simulate epidemics triggered by the importation of Delta variant infections and project the age-specific incidence of SARS-CoV-2 infections, cases, hospitalizations, intensive care unit admissions, and deaths. In the context of the vaccination programme targeting individuals aged ≥12 years, and in the absence of non-pharmaceutical interventions, the importation of Delta variant infections could have led to widespread transmission and substantial disease burden in mainland China, even with vaccination coverage as high as 89% across the eligible age groups. Extending the vaccination roll-out to include children aged 3–11 years (as it was the case since the end of October 2021) is estimated to dramatically decrease the burden of symptomatic infections and hospitalizations within this age group (39% and 68%, respectively, when considering a vaccination coverage of 87%), but would have a low impact on protecting infants. Our findings highlight the importance of including children among the target population and the need to strengthen vaccination efforts by increasing vaccine effectiveness.

Abstract Background A major hand-foot-and-mouth disease (HFMD) pathogen, coxsackievirus A16 (CVA16), has predominated in several of the last 10 years and caused the largest number of HFMD outbreaks between 2011 and 2018 in China. We evaluated the efficacy of maternal anti-CVA16 antibody transfer via the placenta and explored the dynamics of maternal and natural infection-induced neutralizing antibodies in children. Methods Two population-based longitudinal cohorts in southern China were studied during 2013–2018. Participants were enrolled in autumn 2013, including 2475 children aged 1–9 years old and 1066 mother-neonate pairs, and followed for 3 years. Blood/cord samples were collected for CVA16-neutralizing antibody detection. The maternal antibody transfer efficacy, age-specific seroprevalence, geometric mean titre (GMT) and immune response kinetics were estimated. Results The average maternal antibody transfer ratio was 0.88 (95% CI 0.80–0.96). Transferred maternal antibody levels declined rapidly (half-life: 2.0 months, 95% CI 1.9–2.2 months). The GMT decayed below the positive threshold (8) by 1.5 months of age. Due to natural infections, it increased above 8 after 1.4 years and reached 32 by 5 years of age, thereafter dropping slightly. Although the average duration of maternal antibody-mediated protection was < 3 months, the duration extended to 6 months on average for mothers with titres ≥ 64. Conclusions Anti-CVA16 maternal antibodies are efficiently transferred to neonates, but their levels decline quickly. Children aged 0–5 years are the main susceptible population and should be protected by CVA16 vaccination, with the optimal vaccination time between 1.5 months and 1 year of age.

Abstract Background Obstructive sleep apnea (OSA) is a modifiable risk factor for acute coronary syndrome (ACS), with high prevalence but low diagnostic rates. Therefore, it is particularly important to develop strategies for better screening for OSA in newly admitted ACS patients. Methods From March 2017 to October 2019, consecutive eligible patients with ACS underwent cardiorespiratory polygraphy during hospitalization. OSA was defined as an apnea–hypopnea index (AHI) ≥ 15 events/h. All anthropometric and oropharyngeal parameters are measured by specialist nurses. Results Finally, 761 ACS patients were recruited in the present study. Prevalence of moderate/severe OSA was 53.2% based on diagnostic criteria of AHI ≥ 15. Correlation analysis illustrated that AHI was positively correlated with anthropometric characteristics. In the multivariate model, only micrognathia (OR 2.02, 95% CI 1.02–4.00, P = 0.044), waist circumference (OR 1.08, 95% CI 1.04–1.11, P

Dusp6, an ERK specific phosphatase, was identified as a regenerative repressor during zebrafish heart regeneration. Here, the authors show that Dusp6 deficiency improves post infarctional cardiac repair by predominantly attenuating neutrophil-mediated myocardial damage in mammalian hearts.

AIM: To explore the correlation by analyzing and comparing the expression of inflammatory factors in peripheral blood of human leukocyte antigen-B27(HLA-B27)positive and negative uveitis patients.METHODS: All 76 patients first diagnosed with uveitis in our hospital from January 2020 to April 2022 were screened in this retrospective study. Nucleated cells were isolated from human venous blood, and HLA-B27 was detected by flow cytometry(direct immunofluorescence), the patients were divided into the HLA-B27-positive group(≥90%)in 35 cases and HLA-B27-negative group(≤5%)in 41 cases. The whole blood RNA was extracted. The mRNA expression of interleukin-1β(IL-1β), interleukin-6(IL-6), interleukin-10(IL-10), protease activated receptor 2(PAR2), tumor necrosis factor-α(TNF-α), interleukin enhancer-binding factor -3(ILF3)were detected and compared by RT-qPCR.RESULTS: The IL-1β, IL-10, PAR2 and TNF-α mRNA were observed no difference between the two groups of patients(all P>0.05). The IL-6 mRNA in the patients of HLA-B27-positive group was higher than in the HLA-B27-negative group, the ILF3 mRNA was lower than that in the negative group(all P

Objective To establish keratin 5-IRES-eGFP knockin hESCs cell line by using CRISPR/Cas9 technique, which could provide a cell model for the study of skin diseases with abnormal basal keratinocytes in the epidermis. Methods The sgRNA plasmid and target Donor plasmid targeting gene keratin 5 were constructed, and IRES-eGFP was knocked-in the target gene keratin 5 via CRISPR/Cas9 technique in hESCs, then the cell line were differentiated to basal keratinocytes with green fluorescent protein (GFP). Results PCR and Sanger sequencing results showed that IRES-eGFP was successfully integrated into the upstream of keratin 5 in hESCs cell line. The cell morphology was consistent with that of keratinocytes cell line HaCaT after differentiation and culture and the ES-KC cell line derived from hESCs differentiation was confirmed to express GFP and Keratin 5 stably by immunofluorescence staining. Conclusion Keratin 5-IRES-eGFP knockin hESCs cell lines are successfully constructed and are differentiated into basal keratinocytes labeled with GFP, which laid a foundation for subsequent experiments.

Widespread drug resistance and limited antibiotics challenge the treatment of pathogenic bacteria, which leads to a focus on searching for new antimicrobial lead compounds. We found the endophytic fungus Biscogniauxia petrensis MFLUCC14-0151 from the medicinal plant Dendrobium harveyanum had antibacterial activity for the first time. This work aimed to reveal the capacity of Biscogniauxia petrensis MFLUCC14-0151 against foodborne pathogenic bacteria and identify its bioactive substances. Bioassay-guided isolation led to the discovery of six infrequent active monomers, including (10R)-Xylariterpenoid B (1), Xylariterpenoid C (2), Tricycloalternarene 1b (3), Tricycloalternarene 3b (4), Funicin (5) and Vinetorin (6) from MFLUCC14-0151 for the first time. The results of antibacterial tests showed that (10R)-Xylariterpenoid B and Xylariterpenoid C exhibited inhibitory activities against Streptococcus agalactiae with MIC values ranging from 99.21 to 100.00 μM, and against Streptococcus aureus with MIC values ranging from 49.60 to 50.00 μM. Tricycloalternarene 1b and Tricycloalternarene 3b showed inhibitory effects on Streptococcus agalactiae with MIC values ranging from 36.13 to 75.76 μM. Unexpectedly, Funicin and Vinetorin exhibited remarkable antagonistic activities against Streptococcus agalactiae with MIC values of 10.35 and 10.21 μM, respectively, and against Streptococcus aureus with MIC values of 5.17 and 20.42 μM, respectively. In conclusion, we suggest that the isolated compounds Funicin and Vinetorin may be promising lead compounds for natural antibacterial agents.

BackgroundTuberous sclerosis complex (TSC) is a genetic, variably expressed, multisystem disease characterized by benign tumors. It is caused by pathogenic variants of the TSC complex subunit 1 gene (TSC1) and the TSC complex subunit 2 gene (TSC2). Genetic testing allows for early diagnosis, genetic counseling, and improved outcomes, but it did not identify a pathogenic variant in up to 25% of all TSC patients. This study aimed to identify the disease-causing variant in a Han-Chinese family with TSC.MethodsA six-member, three-generation Han-Chinese family with TSC and three unrelated healthy women were recruited. A comprehensive medical examination, a 3-year follow-up, whole exome sequencing, Sanger sequencing, and segregation analysis were performed in the family. The splicing analysis results obtained from six in silico tools, minigene assay, and patients' lymphocyte messenger RNA were compared, and quantitative reverse transcription PCR was used to confirm the pathogenicity of the variant.ResultsTwo affected family members had variable clinical manifestations including a rare bilateral cerebellar ataxia symptom. The 3-year follow-up results suggest the effects of a combined treatment of anti-epilepsy drugs and sirolimus for TSC-related epilepsy and cognitive deficits. Whole exome sequencing, Sanger sequencing, segregation analysis, splicing analysis, and quantitative reverse transcription PCR identified the TSC2 gene c.2742+5G>A variant as the genetic cause. This variant inactivated the donor splice site, a cryptic non-canonical splice site was used for different splicing changes in two affected subjects, and the resulting mutant messenger RNA may be degraded by nonsense-mediated decay. The defects of in silico tools and minigene assay in predicting cryptic splice sites were suggested.ConclusionsThis study identified a TSC2 c.2742+5G>A variant as the genetic cause of a Han-Chinese family with TSC and first confirmed its pathogenicity. These findings expand the phenotypic and genetic spectrum of TSC and may contribute to its diagnosis and treatment, as well as a better understanding of the splicing mechanism.

In response to external stimuli during immune responses, monocytes can have multifaceted roles such as pathogen clearance and tissue repair. However, aberrant control of monocyte activation can result in chronic inflammation and subsequent tissue damage. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces monocyte differentiation into a heterogenous population of monocyte-derived dendritic cells (moDCs) and macrophages. However, the downstream molecular signals that dictate the differentiation of monocytes under pathological conditions is incompletely understood. We report here that the GM-CSF-induced STAT5 tetramerization is a critical determinate of monocyte fate and function. Monocytes require STAT5 tetramers to differentiate into moDCs. Conversely, the absence of STAT5 tetramers results in a switch to a functionally distinct monocyte-derived macrophage population. In the dextran sulfate sodium (DSS) model of colitis, STAT5 tetramer-deficient monocytes exacerbate disease severity. Mechanistically, GM-CSF signaling in STAT5 tetramer-deficient monocytes results in the overexpression of arginase I and a reduction in nitric oxide synthesis following stimulation with lipopolysaccharide. Correspondingly, the inhibition of arginase I activity and sustained supplementation of nitric oxide ameliorates the worsened colitis in STAT5 tetramer-deficient mice. This study suggests that STAT5 tetramers protect against severe intestinal inflammation through the regulation of arginine metabolism.

IntroductionThe treatment for relapsed/refractory peripheral T-cell lymphoma (r/r PTCL) is suboptimal. This open-label, multicenter, single-arm study aimed to investigate the antitumor activity and safety of camrelizumab (a PD-1 blockade) plus apatinib (an antiangiogenic agent) for patients with r/r PTCL.MethodsEligible patients with r/r PTCL were enrolled and received camrelizumab 200 mg intravenously every 2 weeks and apatinib 500 or 250 mg orally once daily, 4 weeks as a cycle. The primary endpoint was overall response rate (ORR).ResultsA total of 20 patients were enrolled and received study medications in the study, with a median number of prior treatment line of 3 (range 1-6). At the cutoff date of March 4, 2022, the median follow-up was 27.2 months (range: 0.5-39.9), and three patients remained on treatment. Six patients had early discontinuation without tumor response evaluation. For all patients, the ORR was 30% (6/20) (95% confidence interval [CI], 11.9% to 54.3%), with two patients (10%) achieving complete response. The median progression-free survival (PFS) and median overall survival for all patients were 5.6 months (95% CI, 1.8 to not reached) and 16.7 months (95% CI, 2.8 to not reached), respectively. Patients with PD-L1 expression ≥50% (3 patients) had a numerically higher ORR and longer median PFS than those with PD-L1 expression < 50% (5 patients). The most commonly reported grade 3 or higher adverse events were hyperlipidemia (15%), hypokalemia (15%) and anemia (15%). No treatment-related deaths occurred.DiscussionIn this study, PD-1 inhibitors plus low-dose antiangiogenic drugs presented preliminary antitumor activity and manageable toxicity in patients with r/r PTCL.

Abstract Background Hundreds of millions of doses of coronavirus disease 2019 (COVID-19) vaccines have been administered globally, but progress on vaccination varies considerably between countries. We aimed to provide an overall picture of COVID-19 vaccination campaigns, including policy, coverage, and demand of COVID-19 vaccines. Methods We conducted a descriptive study of vaccination policy and doses administered data obtained from multiple public sources as of 8 February 2022. We used these data to develop coverage indicators and explore associations of vaccine coverage with socioeconomic and healthcare-related factors. We estimated vaccine demand as numbers of doses required to complete vaccination of countries’ target populations according to their national immunization program policies. Results Messenger RNA and adenovirus vectored vaccines were the most commonly used COVID-19 vaccines in high-income countries, while adenovirus vectored vaccines were the most widely used vaccines worldwide (180 countries). One hundred ninety-two countries have authorized vaccines for the general public, with 40.1% (77/192) targeting individuals over 12 years and 32.3% (62/192) targeting those ≥ 5 years. Forty-eight and 151 countries have started additional-dose and booster-dose vaccination programs, respectively. Globally, there have been 162.1 doses administered per 100 individuals in target populations, with marked inter-region and inter-country heterogeneity. Completed vaccination series coverage ranged from 0.1% to more than 95.0% of country target populations, and numbers of doses administered per 100 individuals in target populations ranged from 0.2 to 308.6. Doses administered per 100 individuals in whole populations correlated with healthcare access and quality index (R 2 = 0.59), socio-demographic index (R 2 = 0.52), and gross domestic product per capita (R 2 = 0.61). At least 6.4 billion doses will be required to complete interim vaccination programs—3.3 billion for primary immunization and 3.1 billion for additional/booster programs. Globally, 0.53 and 0.74 doses per individual in target populations are needed for primary immunization and additional/booster dose programs, respectively. Conclusions There is wide country-level disparity and inequity in COVID-19 vaccines rollout, suggesting large gaps in immunity, especially in low-income countries.

Since March 2020, the pandemic caused by SARS-CoV-2 has affected nearly all aspects of daily life. In this study, we investigated the age-stratified prevalence and genotype distribution of human papillomavirus (HPV) among females in Shandong province (eastern China) and aimed to provide guidance on HPV-based cervical cancer screening and vaccination. The distribution of HPV genotypes was analyzed using PCR-Reverse Dot Hybridization. The overall infection rate of HPV was 16.4%, which was dominated by high-risk genotypes. The most prevalent genotype was HPV16 (2.9%), followed by HPV52 (2.3%), HPV53 (1.8%), HPV58 (1.5%), and HPV51 (1.3%). Among the positive cases with HPV infection, single-genotype infection was significantly higher than that of multi-genotype infection. In subgroup analyses by age (≤25, 26–35, 36–45, 46–55, >55), HPV16, 52, and 53 were consistently the three most common hrHPV genotypes in all age groups. The infection rate of multi-genotypes in the ≤25 and >55 age groups was significantly higher than that in other age groups. A bimodal distribution of HPV infection rate was observed in different age groups. Among lrHPV genotypes, HPV6, HPV11, and HPV81 were the three most common types in the ≤25 age group, while in other age groups, HPV81, HPV42, and HPV43 are the three most common lrHPV genotypes. This study provides basic information on the distribution and genotypes of HPV in the female population in eastern China, which could improve the application of HPV diagnostic probes and vaccines.

Deep brain stimulation (DBS) of the nucleus accumbens (NAc) (NAc-DBS) is an effective solution to refractory obsessive-compulsive disorder (OCD). However, evidence for the neurobiological mechanisms of OCD and the effect of NAc-DBS is still lacking. One hypothesis is that the electrophysiological activities in the NAc are modulated by DBS, and another hypothesis is that the activities of neurotransmitters in the NAc are influenced by DBS. To investigate these potential alterations, rats with quinpirole (QNP)- induced OCD were treated with DBS of the core part of NAc. Then, extracellular spikes (SPK) and local field potentials (LFP) in the NAc were recorded, and the levels of relevant neurotransmitters and related proteins were measured. Analysis of SPK revealed that the firing rate was decreased and the firing pattern was changed after NAc-DBS, and analysis of LFP showed that overall power spectral density (PSD) levels were reduced after NAc-DBS. Additionally, we found that the relative powers of the theta band, alpha band and beta band were increased in OCD status, while the relative powers of the delta band and gamma band were decreased. This pathological pattern of power distribution was reformed by NAc-DBS. Furthermore, we found that the local levels of monoamines [dopamine (DA) and serotonin (5-HT)] and amino acids [glutamate (Glu) and gamma-aminobutyric acid (GABA)] in the NAc were increased in OCD status, and that the expression of the two types of DA receptors in the NAc exhibited an opposite change. These abnormalities could be reversed by NAc-DBS. These findings provide a more comprehensive understanding about the function of the NAc in the pathophysiology of OCD and provide more detailed evidence for the potential effect of NAc-DBS.

Abstract Despite decades of theoretical research, the nature of the self-driven collective motion remains indigestible and controversial, while the phase transition process of its dynamic is a major research issue. Recent methods propose to infer the phase transition process from various artificially extracted features using machine learning. In this thesis, we propose a new order parameter by using machine learning to quantify the synchronization degree of the self-driven collective system from the perspective of the number of clusters. Furthermore, we construct a powerful model based on the graph network to determine the long-term evolution of the self-driven collective system from the initial position of the particles, without any manual features. Results show that this method has strong predictive power, and is suitable for various noises. Our method can provide reference for the research of other physical systems with local interactions.

Abstract Stimulated Raman adiabatic passage (STIRAP) is a widely used protocol to realize high-fidelity and robust quantum control in various quantum systems. However, further application of this protocol in superconducting qubits is limited by population leakage caused by the only weak anharmonicity. Here, we introduce an optimally controlled shortcut-to-adiabatic (STA) technique to speed-up the STIRAP protocol in a superconducting qudit. By modifying the shapes of the STIRAP pulses, we experimentally realize a fast (32 ns) and high-fidelity (0.996 ± 0.005) quantum state transfer. In addition, we demonstrate that our protocol is robust against control parameter perturbations. Our stimulated Raman shortcut-to-adiabatic passage transition provides an efficient and practical approach for quantum information processing.

Abstract Background To allow a return to a pre-COVID-19 lifestyle, virtually every country has initiated a vaccination program to mitigate severe disease burden and control transmission. However, it remains to be seen whether herd immunity will be within reach of these programs. Methods We developed a compartmental model of SARS-CoV-2 transmission for China, a population with low prior immunity from natural infection. Two vaccination programs were tested and model-based estimates of the immunity level in the population were provided. Results We found that it is unlikely to reach herd immunity for the Delta variant given the relatively low efficacy of the vaccines used in China throughout 2021 and the lack of prior natural immunity. We estimated that, assuming a vaccine efficacy of 90% against the infection, vaccine-induced herd immunity would require a coverage of 93% or higher of the Chinese population. However, even when vaccine-induced herd immunity is not reached, we estimated that vaccination programs can reduce SARS-CoV-2 infections by 50–62% in case of an all-or-nothing vaccine model and an epidemic starts to unfold on December 1, 2021. Conclusions Efforts should be taken to increase population’s confidence and willingness to be vaccinated and to develop highly efficacious vaccines for a wide age range.