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Abstract Backgrounds The incidence of extramedullary diseases (EMDs) in patients diagnosed with acute myeloid leukemia (AML) is approximately 10–20%. These patients exhibit a significantly distinct etiology, therapeutic response, and prognosis compared to patients without EMDs. CLL1 CAR-T therapy has been demonstrated satisfactory efficacy and safety in the treatment of refractory and relapsed AML patients. However, concerns have been raised regarding the potential impact of extramedullary niduses on the effectiveness of CLL1 CAR-T therapy. Methods A total of 47 patients were enrolled in this study, including 27 patients with isolated AML tumor bone marrow infiltration and 20 patients with both extramedullary and bone marrow infiltration of AML. CLL1 CAR-T cells were manufactured and subjected to rigorous quality control in the hematology laboratory of Tianjin First Central Hospital. The efficacy and adverse reactions were assessed following CAR-T cell infusion, while expansion of CAR-T cells, levels of cytokines releasing, and other indicators were closely monitored. Results Among the 20 patients with EMDs and the 27 individuals without EMDs, complete remission in bone marrow was achieved by 65.00% and 81.48% of patients, respectively. Meanwhile, among the patients with EMDs, 55.00% achieved complete remission while 10.00% achieved partial remission when assessing the efficacy of CLL1 CAR-T cells against extramedullary niduses. Although the overall survival, progression-free survival, and duration of remission period appeared to be shorter for patients with EMDs compared to those without EMDs, this difference did not reach statistical significance. The incidence rates of complications were comparable between both groups. Meanwhile, there were no significant differences observed in the levels of CAR-T cell expansion and accompanying cytokines release between patients with and without EMDs. Conclusions Our study findings have demonstrated the efficacy of CLL1 CAR-T therapy in the treatment of AML patients with EMDs, while also indicating manageable occurrence rates of complications within a tolerable range. The CLL1 CAR-T therapy, serving as an ideal strategy for AML patients irrespective of the presence of EMDs, effectively ameliorates the conditions of AML patients and provides them with an opportunity to undergo curative hematopoietic stem cell transplantation while significantly enhancing their prognosis.

Abstract The BESIII experiment has been operating since 2009 and has received several upgrades, to study the $$\tau $$ τ -charm physics utilizing the BEPCII accelerator. The BEPCII is a double-ring multi-bunch collider with a luminosity of $$1 \times 10^{33} \, {\text {cm}}^{-2} \, {\text {s}}^{-1}$$ 1 × 10 33 cm - 2 s - 1 optimized at a center-of-mass (cms) energy of $$2 \times 1.89$$ 2 × 1.89 GeV. The rich physics topics, long lifetime and the large volume of data present challenges to offline data processing. This paper describes the design and implementation of the offline software system to meet the requirements and challenges of BESIII, including offline software architecture, geometry management, database management, event data model and tag-based analysis.

In the era of antiretroviral therapy (ART), mortality among people living with the human immunodeficiency virus (HIV) has significantly decreased, yet the population of people living with HIV remains substantial. Among people living with HIV (PLWH), HIV-associated lymphoma (HAL) has surpassed Kaposi’s sarcoma to become the most common tumor in this population in developed countries. However, there remains a dearth of comprehensive and systematic understanding regarding HIV-associated lymphomas. This review aims to shed light on the changes in the immune system among PLWH and the characteristics of the immune microenvironment in HIV-associated lymphoma, with a specific focus on the immune system’s role in these individuals. Additionally, it seeks to explore recent advancements in immunotherapy for the treatment of HIV-associated lymphoma, intending to enhance strategies for immunotherapy in this specific population.

ObjectiveTo analyze the prevalence and genetic variations of SARS-CoV-2 variants in Baiyin city, Gansu province in 2023, and provide scientific basis for epidemic prevention and control and vaccine development. MethodsA total of 200 nasal/oropharyngeal swab samples were collected from COVID-19 cases who visited medical institutions, were hospitalized, or under monitoring in Baiyin city, Gansu province from January to September 2023. Next-generation sequencing technology was used for whole-genome sequencing. MGI metargetCOVID software was used for sequence assembly analysis and Pangolin platform for typing. FREEBAYES was used to detect mutation sites, and annotation was performed based on NIRVANA. MAFFT software was used for multiple sequence alignment, and IQTREE was used to construct the phylogenetic tree. GGTREE and GGTREEEXTRA software were used for visualization analysis of the phylogenetic tree and related clinical information. ResultsFrom January to September 2023, all detected SARS-CoV-2 in Baiyin city were Omicron variants, with BA.5.2 (32 cases, 100.00%) in the first quarter (January-March), mainly XBB (56 cases, 62.92%) and FL (20 cases, 22.47%) families in the second quarter (April-June), and mainly dominated by EG.5.1.1 (52 cases, 65.82%) in the third quarter (July-September). Forty-two mutation sites were significantly enriched in moderate cases, including 25 mutations in the ORF1ab gene, 9 mutations in the S gene, 3 mutations each in the ORF3a and ORF8 genes, and 2 mutations in the N gene. ConclusionThe SARS-CoV-2 genomes circulating in Baiyin city were in different branches from the Wuhan reference strain and were basically consistent with the Pangolin typing lineages and input time. There were genetic associations between different clinical symptoms, and the association of vaccination and previous infection with the phylogenetic tree was not significant.

Abstract Human immunodeficiency virus (HIV) infection is strongly associated with a heightened incidence of lymphomas. To mirror the natural course of human HIV infection, animal models have been developed. These models serve as valuable tools to investigate disease pathobiology, assess antiretroviral and immunomodulatory drugs, explore viral reservoirs, and develop eradication strategies. However, there are currently no validated in vivo models of HIV‐associated lymphoma (HAL), hampering progress in this crucial domain, and scant attention has been given to developing animal models dedicated to studying HAL, despite their pivotal role in advancing knowledge. This review provides a comprehensive overview of the existing animal models of HAL, which may enhance our understanding of the underlying pathogenesis and approaches for malignancies linked to HIV infection.

Abstract Background Tongoloa is a genus comprising approximately 20 species, primarily distributed in the mountainous regions of southwest China. The insufficiency of specimen materials and morphological similarities among species render it a taxonomically challenging genus within the Apiaceae family. To elucidate the phylogenetic relationships and taxonomy of Chinese Tongoloa, this study utilized a total of 115 nrITS sequences, including 47 recently obtained sequences, for phylogenetic reconstruction. Results Phylogenetic relationships reconstructed from ITS sequences indicate that the East Asia Clade and the Komarovia Clade are sister groups, and Tongoloa belongs to the East Asia Clade. Species of Tongoloa are subdivided into 3 distinct groups, all sharing similar fruit morphologies and are clearly differentiated from related taxa. Several Tongoloa-like members classified under other genera are interpreted to be closely related to Tongoloa. Morphological and molecular data indicate that Tongoloa, Sinolimprichtia subclade and Chinese Trachydium subclade are separate yet genetically contiguous taxa. It is confirmed that Tongoloa zhongdianensis belongs to the Hymenidium Clade, while Sinocarum is classified within the Acronema Clade. Two new taxa are found in the Hengduan Mountains. Conclusion Tongoloa is a genus within the East Asia Clade of Apiaceae, and the phylogeny reconstructed based on ITS sequences divides it into 3 main groups. By integrating fruit morphology and molecular phylogenetic analyses, we preliminary clarified the intricate taxonomic relationships among Tongoloa and related taxa. These results provide valuable opportunities for a deeper understanding of the phylogeny of Tongoloa.

Abstract Background Microtubule polymerization is usually considered as the upstream of apoptotic cell death induced by taxanes, but recently published studies provide more insights into the mechanisms responsible for the antineoplastic effect of taxanes. In this study, we figure out the role of the stress-related PERK/eIF2α axis in tumor cell death upon taxane treatment along with paclitaxel resistance. Methods Utilizing immunoblot assay, the activation status of PERK-eIF2α signaling was detected in a panel of cancer cell lines after the treatment of taxanes. The causal role of PERK-eIF2α signaling in the cancer cell apoptosis induced by taxanes was examined via pharmacological and genetic inhibitions of PERK. The relationship between microtubule polymerization and PERK-eIF2α activation was explored by immunofluorescent and immunoblotting assays. Eventaually, the combined therapeutic effect of paclitaxel (PTX) and CCT020312, a PERK agonist, was investigated in PTX-resistant breast cancer cells in vitro and in vivo. Results PERK-eIF2α axis was dramatically activated by taxanes in several cancer cell types. Pharmacological or genetic inhibition of PERK efficiently impaired taxane-induced apoptotic cell death, independent of the cellular microtubule polymerization status. Moreover, PTX was able to activate the PERK/eIF2α axis in a very low concentration without triggering microtubule polymerization. In PTX-resistant breast cancer cells, the PERK/eIF2α axis was attenuated in comparison with the PTX-sensitive counterparts. Reactivation of the PERK/eIF2α axis in the PTX-resistant breast cancer cells with PERK agonist sensitized them to PTX in vitro. Combination treatment of the xenografted PTX-resistant breast tumors with PERK agonist and PTX validated the synergic effect of PTX and PERK activation in vivo. Conclusion Activation of the PERK/eIF2α axis is a pivotal prerequisite of taxanes to initiate cancer cell apoptosis, which is independent of the well-known microtubule polymerization-dependent manner. Simultaneous activation of PERK-eIF2α signaling would be a promising therapeutic strategy to overcome PTX resistance in breast cancer or other cancers.

Abstract Killer cell lectin-like receptor G1 (KLRG1) is an immune checkpoint receptor expressed predominantly in NK and T-cell subsets that downregulates the activation and proliferation of immune cells and participates in cell-mediated immune responses. Accumulating evidence has demonstrated the importance of KLRG1 as a noteworthy disease marker and therapeutic target that can influence disease onset, progression, and prognosis. Blocking KLRG1 has been shown to effectively mitigate the effects of downregulation in various mouse tumor models, including solid tumors and hematologic malignancies. However, KLRG1 inhibitors have not yet been approved for human use, and the understanding of KLRG1 expression and its mechanism of action in various diseases remains incomplete. In this review, we explore alterations in the distribution, structure, and signaling pathways of KLRG1 in immune cells and summarize its expression patterns and roles in the development and progression of autoimmune diseases, infectious diseases, and cancers. Additionally, we discuss the potential applications of KLRG1 as a tool for tumor immunotherapy.

PurposeWe aimed to investigate risk factors for COVID-19 pneumonia in patients with hematological malignancies (HM) after Omicron infection.MethodsData from a registered multi-center, prospective, observational study (ChiCTR2300071830) during the latest Omicron BA.5.2 wave in Chongqing, China was used for analysis.ResultsA total of 475 HM patients enrolled in this study. COVID-19 pneumonia was observed in 15.8% (75/475) of patients, with a median age of 58 years (interquartile range [IQR], 48-69 years) and males accounting for 61.3%. Risk factors associated with COVID-19 pneumonia included: 1) Active disease status of HM at infection, with an odds ratio (OR) of 3.42 (95% confidence interval [CI]: 1.59-7.37, P=0.002) compared to complete remission (CR); 2) Incomplete COVID-19 vaccination, 1-2 doses of the vaccine (OR=2.55, 95% CI: 1.28-5.10, P=0.008) or no vaccination (OR=4.81, 95% CI: 2.45-9.43, P

Long-term excessive fertilization and irrigation under greenhouse cultivation systems cause nitrogen leaching, while the residual content varies at different soil depths with cultivation durations. However, it remains unclear whether it changes the composition and assemblage of the soil bacterial community, especially at deeper layers (as deep as 4 m), after long-term intensified cultivation. This study selected soils from three sites in Shouguang (a typical representative intensive planting area), i.e., greenhouse monoculturing for 20 years (G20), greenhouse monoculturing for 10 years (G10), and an adjacent rotation field (F) for physicochemical property determination and high-throughput pyrosequencing. The results showed that, contrary to the vertical characterization of soil bacterial community composition, the 2-m soil was dominated by Methylomirabilota, a nitrate/nitrite-dependent anaerobic methane oxidizer, uncovered for the first time in the soil habitat. This was attributed to the high levels of dissolved organic carbon (DOC, 201.2–255.7 mg kg−1), proving that applying C-rich organic fertilizers, e.g. plant residues, is effective in preventing accumulated nitrate from moving downward and threatening groundwater in greenhouse soils. Besides, greenhouse cultivation increased the inter-layer composition differences of the bacterial community, and compared with the abundant, the rare subcommunity showed higher sensitivity to environmental changes. The total nitrogen most significantly affected the bacterial community composition and assemblage. Therefore, 20 years of consecutive monocropping significantly decreased the microbial co-occurrence network complexity and species dispersal rate, yielding a low-fitted neutral community model (NCM) and more specialized ecological niches, especially for the rare subcommunity. As far as is known, this is the first study that explores the likely changes in the bacterial community composition and quantifies the responses of the rare subcommunity to long-term greenhouse cultivation at this soil depth. Discovery of Methylomirabilota broadens our understanding of micro-biodiversity in deep-soil ecosystem, and hints its application potential in soil remediation.

Abstract Host immunity is central to the virus's spread dynamics, which is significantly influenced by vaccination and prior infection experiences. In this work, we analyzed the co‐evolution of SARS‐CoV‐2 mutation, angiotensin‐converting enzyme 2 (ACE2) receptor binding, and neutralizing antibody (NAb) responses across various variants in 822 human and mice vaccinated with different non‐Omicron and Omicron vaccines is analyzed. The link between vaccine efficacy and vaccine type, dosing, and post‐vaccination duration is revealed. The classification of immune protection against non‐Omicron and Omicron variants is co‐evolved with genetic mutations and vaccination. Additionally, a model, the Prevalence Score (P‐Score) is introduced, which surpasses previous algorithm‐based models in predicting the potential prevalence of new variants in vaccinated populations. The hybrid vaccination combining the wild‐type (WT) inactivated vaccine with the Omicron BA.4/5 mRNA vaccine may provide broad protection against both non‐Omicron variants and Omicron variants, albeit with EG.5.1 still posing a risk. In conclusion, these findings enhance understanding of population immunity variations and provide valuable insights for future vaccine development and public health strategies.

BackgroundChronic kidney disease (CKD) is a prevalent chronic condition that poses a significant threat to human health. There is a close connection between the gut and kidneys, jointly influencing the onset and progression of CKD through the “gut-kidney axis.” Traditional Chinese medicine has shown potential in CKD treatment, but the specific mechanisms require further investigation.ObjectivesThis study aims to explore the protective effects of Mizhuo Enema (MZGCY) on kidney function in CKD rats by regulating the TLR4/MyD88/NF-κB signaling pathway.MethodsThe researcher employed a CKD rat model, which was divided into four groups: Control, Model, half-dose Mizhuo Guanchangye (1/2 MZGCY), and full-dose Mizhuo Guanchangye (MZGCY). Post enema administration, assessments were conducted on kidney function indicators, which included blood urea nitrogen (BUN), serum creatinine (SCR), and 24-h urinary protein. Additionally, measurements were taken for intestinal toxic substances such as indoxyl sulfate (IS) and lipopolysaccharide (LPS), as well as inflammatory factors interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Examinations of pathological changes in both the intestines and kidneys were also performed. During this process, immunofluorescence was utilized to detect the expression levels of proteins toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), and nuclear factor kappa B (NF-κB) in the intestinal tissues.ResultsIt was found that after enema treatment, the BUN, SCR, and 24-h urinary protein levels in the MZGCY and 1/2 MZGCY groups significantly decreased, indicating notable improvement in kidney function. Compared to the model group, the IS, LPS, IL-6, and TNF-α levels in the MZGCY and 1/2 MZGCY groups were significantly reduced. Immunofluorescence showed a marked decrease in the expression of TLR4, MyD88, and NF-κB proteins in the intestines of the MZGCY group.ConclusionMZGCY significantly reduces the levels of intestinal toxins and inflammatory factors in the serum of CKD rats by interfering with the TLR4/MyD88/NF-κB signaling pathway, thereby improving intestinal and renal pathological changes and delaying CKD progression. This study demonstrates that MZGCY has significant renal protective effects, providing a new potential approach for CKD treatment.

BackgroundAsthma, depression, and sleep problems are three significant public health issues that are closely interrelated. This study aims to explore the relationship between depression, sleep status and asthma, as well as the potential interaction among these conditions and their effects on asthma.MethodThis cross-sectional study utilized data from the 2005-2008 National Health and Nutritional Examination Survey, including information on asthma, depression, sleep status and confounding factors. Multivariate logistic regression analyses were conducted to investigate the relationship between depression, sleep status, and asthma. Subgroup analyses were conducted to test the p-interaction between depression and each stratified variable. Additionally, both multiplicative and additive approaches were employed to assess the interaction between depression and sleep status on asthma, as well as to quantify their combined effects.ResultsA total of 8,327 participants (mean age 46.53 years) were included in this study. Compared to the individuals without depression, those with depression have an increased risk of asthma [Odds ratio (OR) = 1.57, 95% Confidence interval (CI) = 1.22-2.03], and an increase in the severity of depressive symptoms is associated with a higher risk of developing asthma. Additionally, poor sleep quality, sleep disorders, and insufficient sleep was associated with an increased risk of asthma. Effect modification was observed between depression and PIR status, smoking status, and sleep disorders in relation to asthma (p-interaction

The incidence of Acute myeloid leukemia (AML) increases with advancing age, and the prognosis for elderly patients is significantly poorer compared to younger patients. Although the combination therapy of venetoclax and hypomethylating agents has demonstrated improved prognosis in patients unable to tolerate intensive chemotherapy, there remains a therapeutic blank for those who fail to achieve remission with current treatment regimens. Here, we report the successful clinical utilization of autogenous CLL1 CAR-T therapy combined with hematopoietic stem cell transplantation in a 73-year-old patient diagnosed with refractory AML. The patient achieved morphological complete remission (CR) with incomplete marrow recovery and a slight presence of minimal residual disease (MRD) after receiving CLL1 CAR-T therapy. To further enhance the treatment and promote the recovery of hemopoiesis, we performed bridged allogenic hematopoietic stem cell transplantation (allo-HSCT) 20 days after the infusion of CLL1 CAR-T cells. The patient achieved MRD-negative CR following HSCT treatment. His primary disease maintained a complete remission status during the 11-month follow-up period. The patient encountered grade 2 cytokine release syndrome and grade 4 granulocytopenia subsequent to the infusion of CAR-T cells, while several rounds of infection and graft-versus-host disease were observed following allo-HSCT. Nevertheless, all these concerns were successfully addressed through comprehensive provision of supportive treatments. We have successfully demonstrated a highly effective and safe combination strategy involving CLL1 CAR-T therapy and allo-HSCT, which has exhibited remarkable tolerability and holds great promise even for elderly patients with AML.

Pyridaben is a broad-spectrum, contact-killing acaricide that can be used to control a variety of harmful food and plant mites. Pyridaben displays cardiotoxicity and liver toxicity toward fish, but the effects on fish embryonic development have not been characterized. We exposed early zebrafish embryos to 20, 30, and 40 μg/L concentrations of pyridaben. The exposure caused developmental abnormalities, including delayed embryonic shield formation, yolk sac resorption, decreases in body length, reduced pigmentation, and delays in hatching. Pyridaben caused a significant increase in the transcription level of the endoderm marker foxa2, but the transcription levels of the ectoderm development marker foxb1a and the mesoderm development marker snaila were not significantly altered. The transcription levels of the genes SOX17 in early embryos were significantly reduced. After exposure to pyridaben, catalase (CAT) activity and glutathione (GSH) content were increased, and cyclin D1, that is involved in early embryonic development, was abnormally expressed. This study shows that pyridaben causes anomalous development in zebrafish embryos by interfering with the cell cycle order of early embryonic development and inducing excessive oxidative stress. Colivelin, an agonist of the STAT3 signaling pathway, acted as a salvage drug to restore the cell cycle order during embryonic development following exposure to pyridaben. Thus, the toxic effects may be caused by pyridaben’s regulation of the STAT3 signaling pathway.

Abstract The incidence, clinical characteristics, and prognostic factors of HIV-associated lymphoma remain poorly defined compared to HIV-negative lymphoma. Currently, there are no standard guidelines for treatment of these patients. We summarized several latest reports of HIV associated lymphoma from the 2023 ASH Annual Meeting (ASH2023).

Abstract Triple negative breast cancer (TNBC) accounts for 15–20% of breast cancer cases in the United States. Systemic neoadjuvant chemotherapy (NACT), with or without immunotherapy, is the current standard of care for patients with early-stage TNBC. However, up to 70% of TNBC patients have significant residual disease once NACT is completed, which is associated with a high risk of developing recurrence within two to three years of surgical resection. To identify targetable vulnerabilities in chemoresistant TNBC, we generated longitudinal patient-derived xenograft (PDX) models from TNBC tumors before and after patients received NACT. We then compiled transcriptomes and drug response profiles for all models. Transcriptomic analysis identified the enrichment of aberrant protein homeostasis pathways in models from post-NACT tumors relative to pre-NACT tumors. This observation correlated with increased sensitivity in vitro to inhibitors targeting the proteasome, heat shock proteins, and neddylation pathways. Pevonedistat, a drug annotated as a NEDD8-activating enzyme (NAE) inhibitor, was prioritized for validation in vivo and demonstrated efficacy as a single agent in multiple PDX models of TNBC. Pharmacotranscriptomic analysis identified a pathway-level correlation between pevonedistat activity and post-translational modification (PTM) machinery, particularly involving neddylation and sumoylation targets. Elevated levels of both NEDD8 and SUMO1 were observed in models exhibiting a favorable response to pevonedistat compared to those with a less favorable response in vivo. Moreover, a correlation emerged between the expression of neddylation-regulated pathways and tumor response to pevonedistat, indicating that targeting these PTM pathways may prove effective in combating chemoresistant TNBC.

Abstract Cold-induced injuries severely limit opportunities and outcomes of hypothermic therapies and organ preservation, calling for better understanding of cold adaptation. Here, by surveying cold-altered chromatin accessibility and integrated CUT&Tag/RNA-seq analyses in human stem cells, we reveal forkhead box O1 (FOXO1) as a key transcription factor for autonomous cold adaptation. Accordingly, we find a nonconventional, temperature-sensitive FOXO1 transport mechanism involving the nuclear pore complex protein RANBP2, SUMO-modification of transporter proteins Importin-7 and Exportin-1, and a SUMO-interacting motif on FOXO1. Our conclusions are supported by cold survival experiments with human cell models and zebrafish larvae. Promoting FOXO1 nuclear entry by the Exportin-1 inhibitor KPT-330 enhances cold tolerance in pre-diabetic obese mice, and greatly prolongs the shelf-life of human and mouse pancreatic tissues and islets. Transplantation of mouse islets cold-stored for 14 days reestablishes normoglycemia in diabetic mice. Our findings uncover a regulatory network and potential therapeutic targets to boost spontaneous cold adaptation.

Salmonella enterica serovar Abortusovis is a ovine-adapted pathogen that causes spontaneous abortion. Salmonella Abortusovis was reported in poultry in 2009 and has since been reported in human infections in New South Wales, Australia. Phylogenomic analysis revealed a clade of 51 closely related isolates from Australia originating in 2004. That clade was genetically distinct from ovine-associated isolates. The clade was widespread in New South Wales poultry production facilities but was only responsible for sporadic human infections. Some known virulence factors associated with human infections were only found in the poultry-associated clade, some of which were acquired through prophages and plasmids. Furthermore, the ovine-associated clade showed signs of genome decay, but the poultry-associated clade did not. Those genomic changes most likely led to differences in host range and disease type. Surveillance using the newly identified genetic markers will be vital for tracking Salmonella Abortusovis transmission in animals and to humans and preventing future outbreaks.

Background: Emotion regulation is a crucial skill that can significantly impact mental health, social interactions, and overall well-being. Dance Movement Therapy (DMT) is a form of psychotherapy that uses dance and movement to promote emotional, social, cognitive, and physical integration. Objectives: This literature review aims to provide a comprehensive and systematic analysis of scholarly research and publications exploring the impact of DMT on enhancing emotion regulation capabilities. Methods: A literature search was conducted in various databases, and specific inclusion and exclusion criteria were established to ensure the relevance and quality of the chosen research. The data extraction and analysis phase involved carefully extracting pertinent information from each selected study and a methodical approach to analysis aimed at synthesizing and interpreting the findings cohesively. Results: The review highlights the potential benefits of DMT in regulating emotions and identifies gaps and disparities in existing research, emphasizing potential areas that warrant further investigation. Conclusion: The findings of this review contribute to a robust exploration of the relationship between emotion regulation and DMT, shedding light on the impact of DMT on emotion regulation and providing insights into future research directions.

IntroductionThe management of Mild Autonomous Cortisol Secretion (MACS) remains a topic of debate among clinicians, with differing opinions on the effectiveness of surgical intervention compared to conservative treatment methods. This meta-analysis provides a comprehensive assessment of available literature to determine the most effective approach for treating this condition.MethodsOn December 1, 2023, an exhaustive literature search of English databases Embase, PubMed, the Cochrane Library, Scopus, Web of Science, as well as the Chinese databases China HowNet, Wanfang Database, SinoMed Database, and Weipu Database using the keywords “Mild Autonomous Cortisol Secretion”, “Subclinical Cushing’s Syndrome”, “Subclinical Hypercortisolism”, “Mild Cortisol Autonomous Secretion”, “Adrenal Incidentaloma”, “Surgical Treatment” and “Adrenalectomy”. The data were statistically analyzed using STATA version 15.0.ResultsIn this comprehensive analysis involving 629 patients with MACS, the therapeutic efficacy of adrenalectomy was evident. The meta-analysis results indicate that compared to conservative treatment, surgical intervention more effectively improves obesity indicators in patients: waist circumference (SMD=-0.62, 95% CI: -1.06 to -0.18), BMI (SMD=-0.41, 95% CI: -0.62 to -0.20), enhances glycemic control: fasting blood glucose (SMD=-0.47, 95% CI: -0.68 to -0.26), glycated hemoglobin (SMD=-0.66, 95% CI: -0.95 to -0.38), improves lipid metabolism: triglycerides (SMD=-0.45, 95% CI: -0.73 to -0.16), lowers blood pressure: systolic blood pressure (SMD=-1.04, 95% CI: -1.25 to -0.83), diastolic blood pressure (SMD=-0.89, 95% CI: -1.12 to -0.65), and ameliorates hormonal metabolic disorder: 24h urinary free cortisol (SMD=-1.10, 95% CI: -1.33 to -0.87), ACTH (SMD=2.30, 95% CI: 1.63 to 2.97). All these differences are statistically significant.ConclusionThis meta-analysis shows that, compared to conservative treatment, surgical treatment is more effective in improving obesity indicators, glycemic control, lipid metabolism, reducing blood pressure, and ameliorating hormonal metabolic disorders in patients with MACS. These statistically significant results highlight the importance of considering surgical intervention in the management of patients with MACS.Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42023492527.

Abstract Background NRG1 fusion is a promising therapeutic target for various tumors but its prevalence is extremely low, and there are no standardized testing algorithms for genetic assessment. Mothods In this study, we analyzed 3008 tumors using Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) to screen for NRG1 translocation and p-HER3 expression. Results Our results demonstrated no cases with p-HER3 positivity through IHC. Nonetheless, 29 cases (0.96%) were identified positive for NRG1 translocation through FISH, with three different signal types. FISH-positive cases were subsequently subjected to next-generation sequencing (NGS) testing. However, only eight of these cases were confirmed with NRG1 fusion through NGS. Notably, we divided FISH into three types and FISH type C group was consistent with NGS results. All NGS NRG1 fusion tumors were adenocarcinomas, with a higher prevalence in females. Our findings indicate that although FISH has limitations in screening NRG1 gene rearrangements, NRG1 fusions can be reliably detected with signals exhibiting low copy numbers of the 5’-end of the gene and no fusion signals. Conclusion Considering the high cost of NGS, FISH remains a useful method for screening NRG1 fusions in various types of tumors. This study provides valuable insights into the molecular mechanisms of NRG1 fusion and identifies potential treatment targets for patients suffering from this disease.

Abstract Background In the context of the COVID-19 pandemic and extensive vaccination, it is important to explore the immune response of elderly adults to homologous and heterologous booster vaccines of COVID-19. At this point, we detected serum IgG antibodies and PBMC sample transcriptome profiles in 46 participants under 70 years old and 25 participants over 70 years old who received the third dose of the BBIBP-CorV and ZF2001 vaccines. Results On day 7, the antibody levels of people over 70 years old after the third dose of booster vaccine were lower than those of young people, and the transcriptional responses of innate and adaptive immunity were also weak. The age of the participants showed a significant negative correlation with functions related to T-cell differentiation and costimulation. Nevertheless, 28 days after the third dose, the IgG antibodies of elderly adults reached equivalence to those of younger adults, and immune-related transcriptional regulation was significantly improved. The age showed a significant positive correlation with functions related to "chemokine receptor binding", "chemokine activity", and "chemokine-mediated signaling pathway". Conclusions Our results document that the response of elderly adults to the third dose of the vaccine was delayed, but still able to achieve comparable immune effects compared to younger adults, in regard to antibody responses as well as at the transcript level.

Abstract Background Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease discovered in China in 2009. The purpose of this study was to describe the spatiotemporal distribution of SFTS and to identify its environmental influencing factors and potential high-risk areas in Shandong Province, China. Methods Data on the SFTS incidence from 2010 to 2021 were collected. Spatiotemporal scan statistics were used to identify the time and area of SFTS clustering. The maximum entropy (MaxEnt) model was used to analyse environmental influences and predict high-risk areas. Results From 2010 to 2021, a total of 5705 cases of SFTS were reported in Shandong. The number of SFTS cases increased yearly, with a peak incidence from April to October each year. Spatiotemporal scan statistics showed the existence of one most likely cluster and two secondary likely clusters in Shandong. The most likely cluster was in the eastern region, from May to October 2021. The first secondary cluster was in the central region, from May to October 2021. The second secondary cluster was in the southeastern region, from May to September 2020. The MaxEnt model showed that the mean annual wind speed, NDVI, cattle density and annual cumulative precipitation were the key factors influencing the occurrence of SFTS. The predicted risk map showed that the area of high prevalence was 28,120 km2, accounting for 18.05% of the total area of the province. Conclusions The spatiotemporal distribution of SFTS was heterogeneous and influenced by multidimensional environmental factors. This should be considered as a basis for delineating SFTS risk areas and developing SFTS prevention and control measures.

Abstract RTKN2 is a new effector protein of Rho GTPase, and has been indicated to be a tumor inhibitor in colon cancer. In this article, we explored the function of RTKN2 in BC cell development. RTKN2 expression in BC tissues and BC cell lines was evaluated by RT-qPCR and Western blot assay. CCK-8, Wound-healing and Transwell assays were carried out to examine the role of RTKN2 knockdown on proliferation, the migratory ability and the invasive ability of BC cells. FCM and Western blot assay were performed to measure the function of RTKN2 silencing on BC cell apoptosis. In addition, the regulatory effect of RTKN2 on Wnt/β-catenin pathway was studied via Western blot assay. RTKN2 expression was elevated in BC tissues and BC cells. Down-regulation of RTKN2 restrained BC cell progression by suppressing cell proliferation, migratory ability, invasive ability, and inducing apoptosis. In addition, reduced of RTKN2 sharply reduced the expressing levels of Wnt3A, β-catenin, C-Myc, and Cyclin D1, suggesting that RTKN2 silencing blocked the motivation of Wnt/β-catenin pathway in BC development. The in vivo experiment also confirmed the inhibitory effect of RTKN2 on BC tumors. Our study confirmed that RTKN2 was highly expressed in BC. Moreover, RTKN2 knockdown suppressed the development of BC through affecting the Wnt/β-catenin pathway. Hence, we deduced that RTKN2 was a possible treatment target for BC.

To assess the status and change trend of forest in China, an indicator framework was developed using SDG sub-indicators. In this paper, we propose an improved methodology and a set of workflows for calculating SDG indicators. The main modification include the use of moderate and high spatial resolution satellite data, as well as state-of-the-art machine learning techniques for forest cover classification and estimation of forest above-ground biomass (AGB). This research employs GF-1 and GF-2 data with enhanced texture information to map forest cover, while time series Landsat data is used to estimate forest AGB across the whole territory of China. The study calculate two SDG sub-indicators: SDG15.1.1 for forest area and SDG15.2.1 for sustainable forest management. The evaluation results showed that the total forest area in China was approximately 219 million hectares at the end of 2021, accounting for about 23.51% of the land area. The average annual forest AGB from 2015 to 2021 was estimated to be 105.01Mg/ha, and the overall trend of forest AGB change in China was positive, albeit with some spatial differences.

BackgroundJuvenile dermatomyositis (JDM) is a systemic autoimmune disease primarily involving the muscles and skin; it can also affect the central nervous system (CNS). The relevant literature provides limited information regarding the characteristics of JDM with CNS involvement.MethodWe reviewed patients with JDM who were hospitalized at our center between January 2016 and August 2023, with a focus on those with CNS involvement. The aim was to provide detailed case reports on these patients, and to summarize the relevant literature about the characteristics of similar cases.ResultsAmong 193 hospitalized patients with JDM, two (1.03%) had CNS involvement. Two patients, a 5.5-year-old girl and an 11-year-old boy, were admitted with severe proximal muscle weakness and seizures, and presented with active cutaneous vasculitis. Both were ultimately diagnosed with JDM, with CNS involvement. Both patients had confirmed presence of anti-NXP2 antibody through myositis-specific antibody analysis. Additionally, they all exhibited hyperferritinemia and thrombocytopenia. Salvage therapies like intravenous methylprednisolone (IVMP) pulse therapy and/or plasma exchange were administered successfully. At final follow-up, both patients had achieved complete clinical response and full neurological recovery. Our literature review identified nine similar case studies. CNS involvement usually occurred within the first 10 months of the disease course, and most of these patients had fatal outcomes, with a mortality rate of 66.6% (6/9). Including the two patients described herein, the median age for disease onset is 10.5 years (range 4–17 years), and the male: female ratio is 6:5. Seizures are the most common neurological symptom, accompanied by active cutaneous vasculitis. The brain biopsies showed two distinct pathological presentations: one was central nervous system vasculitis, and the other was cerebral macrophage activation syndrome.ConclusionsCNS involvement is a rare but life-threatening JDM complication. Herein, our cases and the literature indicate that it typically occurs within the first 10 months of the disease course and manifests as seizures, often accompanied by active cutaneous vasculitis, with fatal outcomes. Timely implementation of salvage therapies, like IVMP pulse therapy and plasma exchange, may significantly impact patient outcomes.

Global climate change has intensified the water cycle, leading to frequent extreme precipitation events, posing a significant threat to railway infrastructure and safety operations. Based on the analysis of past and future precipitation changes in China, this study investigates the impact of climate change on railway safety operations. The study reveals the following findings: (1) Under the influence of the intensified East Asian summer monsoon and the northward shift of the subtropical high during the 2017–2021 compared to the 2012–2016, precipitation has significantly decreased (120 mm) in the regions south of the Yangtze River and South China, while it has increased (60 mm) in the regions from the eastern of Northwest China to the middle and lower reaches of Yangtze River; The operational precipitation risk has decreased for Urumqi, Lanzhou, Qinghai-Tibet Group, Xi’an, and Wuhan railway bureaus (abbreviated as Bureau), while it has increased for Nanchang, Chengdu, Zhengzhou, Shanghai, and Shenyang Bureaus. Particularly noteworthy is that despite a decrease in total annual precipitation for Nanchang bureau (15.3 mm/a), the frequency of intense precipitation events has increased, leading to an increased operational precipitation risk. (2) During the 21st century, under high (SSP5-8.5), medium (SSP2-4.5), and low (SSP1-2.6) forcing scenarios, all projections indicate that most of the China will experience an increasing trend in precipitation, with significant increases in precipitation observed in the regions south of the Yangtze Rive, South and Southwest China. The higher the greenhouse gas emissions, the more pronounced the increasing trend in precipitation. (3) Compared to the 20th century, under high (SSP5-8.5), medium (SSP2-4.5), and low (SSP1-2.6) forcing scenarios, all projections indicate that the total annual precipitation hours, railway inspection, speed limit, and closure risk hours have all increased on a national scale during the 21st century. The operational precipitation risk for railways has also increased. The higher the alert level for railway precipitation (precipitation < inspection < speed limit < closure), the higher the proportion of risk hours compared to the 20th century. By the late 21st century, the railway inspection, speed limit, and closure risk hours have increased by 175%, 463%, and 647%, respectively, compared to the 20th century.

The production of N-linked glycoproteins in genetically engineered Escherichia coli holds significant potential for reducing costs, streamlining bioprocesses, and enhancing customization. However, the construction of a stable and low-cost microbial cell factory for the efficient production of humanized N-glycosylated recombinant proteins remains a formidable challenge. In this study, we developed a glyco-engineered E. coli chassis to produce N-glycosylated proteins with the human-like glycan Gal-β-1,4-GlcNAc-β-1,3-Gal-β-1,3-GlcNAc-, containing the human glycoform Gal-β-1,4-GlcNAc-β-1,3-. Our initial efforts were to replace various loci in the genome of the E. coli XL1-Blue strain with oligosaccharyltransferase PglB and the glycosyltransferases LsgCDEF to construct the E. coli chassis. In addition, we systematically optimized the promoter regions in the genome to regulate transcription levels. Subsequently, utilizing a plasmid carrying the target protein, we have successfully obtained N-glycosylated proteins with 100% tetrasaccharide modification at a yield of approximately 320 mg/L. Furthermore, we constructed the metabolic pathway for sialylation using a plasmid containing a dual-expression cassette of the target protein and CMP-sialic acid synthesis in the tetrasaccharide chassis cell, resulting in a 40% efficiency of terminal α-2,3- sialylation and a production of 65 mg/L of homogeneously sialylated glycoproteins in flasks. Our findings pave the way for further exploration of producing different linkages (α-2,3/α-2,6/α-2,8) of sialylated human-like N-glycoproteins in the periplasm of the plug-and-play E. coli chassis, laying a strong foundation for industrial-scale production.

Abstract Background Zostera marina L., or eelgrass, is the most widespread seagrass species throughout the temperate northern hemisphere. Unlike the dry seeds of terrestrial plants, eelgrass seeds must survive in water, and salinity is the key factor influencing eelgrass seed germination. In the present study, transcriptome and proteome analysis were combined to investigate the mechanisms via which eelgrass seed germination was stimulated by low salinity, in addition to the dynamics of key metabolic pathways under germination. Results According to the results, low salinity stimulated the activation of Ca2+ signaling and phosphatidylinositol signaling, and further initiated various germination-related physiological processes through the MAPK transduction cascade. Starch, lipids, and storage proteins were mobilized actively to provide the energy and material basis for germination; abscisic acid synthesis and signal transduction were inhibited whereas gibberellin synthesis and signal transduction were activated, weakening seed dormancy and preparing for germination; cell wall weakening and remodeling processes were activated to provide protection for cotyledon protrusion; in addition, multiple antioxidant systems were activated to alleviate oxidative stress generated during the germination process; ERF transcription factor has the highest number in both stages suggested an active role in eelgrass seed germination. Conclusion In summary, for the first time, the present study investigated the mechanisms by which eelgrass seed germination was stimulated by low salinity and analyzed the transcriptomic and proteomic features during eelgrass seed germination comprehensively. The results of the present study enhanced our understanding of seagrass seed germination, especially the molecular ecology of seagrass seeds.

Abstract Background Despite advances in our understanding of the critical role of the microbiota in stroke patients, the oral microbiome has rarely been reported to be associated with stroke-associated pneumonia (SAP). We sought to profile the oral microbial composition of SAP patients and to determine whether microbiome temporal instability and special taxa are associated with pneumonia progression and functional outcomes. Methods This is a prospective, observational, single-center cohort study that examined patients with acute ischemic stroke (AIS) who were admitted within 24 h of experiencing a stroke event. The patients were divided into three groups based on the occurrence of pneumonia and the use of mechanical ventilation: nonpneumonia group, SAP group, and ventilator-associated pneumonia (VAP) group. We collected oral swabs at different time points post-admission and analyzed the microbiota using 16 S rRNA high-throughput sequencing. The microbiota was then compared among the three groups. Results In total, 104 nonpneumonia, 50 SAP and 10 VAP patients were included in the analysis. We found that SAP and VAP patients exhibited significant dynamic differences in the diversity and composition of the oral microbiota and that the magnitude of this dysbiosis and instability increased during hospitalization. Then, by controlling the potential effect of all latent confounding variables, we assessed the changes associated with pneumonia after stroke and explored patients with a lower abundance of Streptococcus were more likely to suffer from SAP. The logistic regression analysis revealed that an increase in specific taxa in the phylum Actinobacteriota was linked to a higher risk of poor outcomes. A model for SAP patients based on oral microbiota could accurately predict 30-day clinical outcomes after stroke onset. Conclusions We concluded that specific oral microbiota signatures could be used to predict illness development and clinical outcomes in SAP patients. We proposed the potential of the oral microbiota as a non-invasive diagnostic biomarker in the clinical management of SAP patients. Clinical Trial registration NCT04688138. Registered 29/12/2020, https://clinicaltrials.gov/ct2/show/NCT04688138 .

Abstract Background Winter wheat grain samples from 185 sites across southern Shanxi region were processed and analyzed using a non-destructive approach. For this purpose, spectral data and protein content of grain and grain powder were obtained. After combining six types of preprocessed spectra and four types of multivariate statistical models, a relationship between hyperspectral datasets and grain protein is presented. Results It was found that the hyperspectral reflectance of winter wheat grain and powder was positively correlated with the protein contents, which provide the possibility for hyperspectral quantitative assessment. The spectral characteristic bands of protein content in winter wheat extracted based on the SPA algorithm were proved to be around 350–430 nm; 851–1154 nm; 1300–1476 nm; and 1990–2050 nm. In powder samples, SG-BPNN had the best monitoring effect, with the accuracy of R v 2 = 0.814, RMSEv = 0.024 g/g, and RPDv = 2.318. While in case of grain samples, the SG-SVM model exhibited the best monitoring effect, with the accuracy of R v 2 = 0.789, RMSEv = 0.026 g/g, and RPDv = 2.177. Conclusions Based on the experimental findings, we propose that a combination of spectral pretreatment and multivariate statistical modeling is helpful for the non-destructive and rapid estimation of protein content in winter wheat. Graphical Abstract

Abstract Objective To investigate the effects of metabolic associated fatty liver disease (MAFLD) on chronic kidney disease (CKD) and abnormal albuminuria and the interaction between MAFLD and diabetes on abnormal albuminuria. Methods Data of participants in the American 2017–2018 National Health and Nutrition Examination Survey were analyzed. Hepatic steatosis was defined as median controlled attenuation parameter ≥248 dB/m, which was measured by ultrasound transient elastography. MAFLD was defined by evidence of hepatic steatosis on ultrasound in addition to any metabolic dysregulation. Hepatic fibrosis was detected by FibroScan and quantified by parameter of stiffness (E). Hepatic fibrosis was defined as E ≥ 9.7 kPa. As component of CKD, reduced estimated glomerular filtration rate (eGFR) was defined as

Background: Generalized convulsive status epilepticus (GCSE) is one of the most challenging life-threatening neurological emergencies. If GCSE becomes super-refractory, it is associated with significant mortality. Although aggressive management of prolonged status epilepticus was conducted, the mortality has not decreased since the late 1990s. Objectives: The present study aimed to explore the risk factors for progression to super-refractory in patients with generalized convulsive status epilepticus (GCSE). Moreover, we illustrated the risk factors for mortality in GCSE patients. Design: An observational retrospective cohort study. Methods: We conducted a retrospective study of patients with GCSE admitted to our neurocritical unit, in Guangzhou, China, from October 2010 to February 2021. The data of sociodemographic information, etiology, laboratory results, treatment, and prognosis were collected and analyzed. Results: A total of 106 patients were enrolled; 51 (48%) of them developed super-refractory status epilepticus (SRSE). Multivariate logistic regression analysis demonstrated that patients with autoimmune encephalitis ( p = 0.015) and intracranial infection ( p = 0.019) are likely to progress to SRSE. The in-hospital mortality was 11.8% and 9.1% for patients in the SRSE and non-SRSE groups, respectively ( p = 0.652). Multivariate logistic regression analysis showed that neutrophil-to-lymphocyte ratios (NLR) at admission were independently associated with in-hospital mortality. Up to 31.4% of SRSE patients and 29.1% of non-SRSE patients died within 6 months after discharge ( p = 0.798). Multivariate logistic regression analysis showed that plasma exchange (PE) was a protective factor for 6-month mortality. A high NLR at discharge was a risk factor for 6-month mortality. Conclusion: In the current study, about 48% of GCSE patients progressed to SRSE. Regarding etiology, autoimmune encephalitis or intracranial infection was prone to SRSE. No significant differences were observed in the in-hospital and 6-month mortality between SRSE and non-SRSE groups. Multivariate logistic regression analysis showed that NLR at admission and discharge was an independent predictor of in-hospital and 6-month mortality, respectively. Moreover, PE significantly reduced the 6-month mortality.

ObjectiveInsufficient thyroid hormone levels during pregnancy, especially in the first trimester, adversely affect maternal and fetal health. However, the impact of isolated hypothyroxinemia (IH) on adverse pregnancy outcomes remains controversial. Therefore, this study aimed to investigate the association between IH during the first trimester and adverse pregnancy outcomes.MethodsThis prospective cohort study included 1236 pregnant women. Thyroid-stimulating hormone and free thyroxine levels were measured before 13 weeks of gestation. Logistic regression analysis and the Cochran-Armitage trend test were used to assess the association between IH in the first trimester and adverse pregnancy outcomes.ResultsIH during the first trimester was associated with an increased risk of macrosomia. After adjusting for confounding factors, including age, body mass index, parity, abnormal pregnancy history, fasting blood glucose, and total cholesterol, multivariate logistic regression analysis showed that IH in the first trimester remained an independent risk factor for macrosomia. In addition, the risk of macrosomia increased with IH severity. However, no significant relationship was found between IH during the first trimester and gestational diabetes mellitus, hypertensive disorders of pregnancy, spontaneous abortion, premature rupture of membranes, placental abruption, oligohydramnios, premature delivery, fetal distress, or low birth weight.ConclusionIH during the first trimester did not increase the risk of adverse pregnancy outcomes, except for macrosomia.

Summary: Background: Routine whole genome sequencing of Mycobacterium tuberculosis has been implemented with increasing frequency. However, its value for tuberculosis (TB) control programs beyond individual case management and enhanced drug resistance detection has not yet been explored. Methods: We analysed routine sequencing data of culture-confirmed TB cases notified between 1st January 2017 and 31st December 2021 in New South Wales (NSW), Australia. Genomic surveillance included evidence of local TB transmission, defined by single nucleotide polymorphism (SNP) clustering over a variable (0–25) SNP threshold, and drug resistance conferring mutations. Findings: M. tuberculosis sequences from 1831 patients were examined, representing 64.8% of all notified TB cases and 96.2% of culture-confirmed cases. Applying a traditional 5-SNP cluster threshold identified 62 transmission clusters with 183 clustered cases; 101/183 (55.2%) had 0 SNP differences. Cluster assessment over a 5-year period, using a 5-SNP threshold, provided a comprehensive overview of likely recent transmission within NSW, Australia, as an indicator of local TB control. Genotypic drug susceptibility testing (DST) was highly concordant with phenotypic DST and provided a 6.8% increase in antimycobacterial resistance detection. Importantly, it detected mutations missed by routine molecular tests. Lineage 2 strains were more likely to be drug resistant (p

Background Psoriasis is a chronic skin disease, and topical sequential therapy with a combination of calcipotriol and calcipotriol betamethasone is currently approved topical treatment. However, the exact mechanism by which this treatment regimen relieves psoriasis is unknown. Method We assembled a cohort of 65 psoriasis patients and divided post-treatment cohort into responder group and non-responder group according to the Psoriasis Area Severity Index (PASI) score after 12-week treatment. We measured the expression levels of proteins in collected 130 serum samples using our in-depth proteomics platform with a data-independent acquisition mass spectrometer and antibody microarray. We performed bioinformatics analyses of the biologic processes and signaling pathways that were changed in the responder group and constructed a proteomics landscape of psoriasis pathogenesis response to treatment. We then validated the biomarkers of disease severity in an independent cohort of 88 samples using an enzyme-linked immunosorbent assay. Results We first identified 174 differentially expressed proteins (DEPs) for comparative analysis of proteins between responders and non-responders at baseline (p

AbstractObjective This study aims to explore the correlation between central and peripheral thyroid resistance indices and diabetic retinopathy(DR) in patients with type 2 diabetes mellitus (T2DM), so as to provide a clinical basis for the prevention and treatment of diabetic retinopathy.Methods This study retrospectively analyzed 1249 euthyroid patients with T2DM hospitalized in the Department of Endocrinology, Peking University International Hospital from January 2017 to June 2022, including 852 males and 397 females, with an average age of 54.73 ± 13.40 years. According to the degree of DR, the patients were divided into three groups including the no diabetic retinopathy (NDR) group, non-proliferative diabetic retinopathy (NPDR) group and proliferative diabetic retinopathy (PDR) group.Results Free thymidine (FT4), thyroid stimulating hormone (TSH), thyroid feedback quantile index (TFQI), thyrotropin-T4 resistance index (TT4RI), thyroid stimulating hormone index (TSHI) and free triiodothyronine/free thyroxine (FT3/FT4) levels among the three groups were significantly different, with the NDR group having lowest TSH, TFQI, TT4QI, TSHI and the highest in the PDR group (all p

AbstractThe aim of this study is to demonstrate a method for improving the solubility and relative bioavailability of artemisinin using a self-emulsifying drug delivery system (SEDDS). The self-emulsifying drug load, solubility, and emulsifying time were used as the evaluation indices, based on a solubility test and a ternary phase diagram. Optimal Mixture Design in Design-Expert software was used to optimize the prescription of the artemisinin SEDDS. By determining the water distribution coefficient in vitro, combined with the drug concentration–time curve in vivo, a comparison was made of the relative oral bioavailability of the artemisinin SEDDS and the crude drug. The optimal prescription ratio of oleic acid polyethylene glycol glyceride, polyoxyethylene hydrogenated castor oil, and diethylene glycol monoethyl ether in the artemisinin SEDDS was 0.5:0.2:0.3 (wt/wt/wt), with a drug loading capacity of 41.556 mg/g, a solubility of 1.997 mg/mL, and a self-emulsification time of 214 s. The optimal prescription was transparent, slightly yellow, and oil-like. The average loading capacity of artemisinin was 41.912 mg/g, the emulsification time was 231 s, the average particle size was 128.0 nm, the average Zeta potential was –4.29 mV, and the solubility of artemisinin SEDDS in water was 1.997 mg mL–1. It is 33.85 times of the solubility of artemisinin in water, which achieves the purpose of increasing the solubility of artemisinin. The comparison of the oil/water distribution coefficient of the artemisinin SEDDS with that of the crude drug in vitro showed that SEDDS could improve the permeability of artemisinin and promote the absorption in vivo, and the relative bioavailability of the SEDDS agent was at least 1.47 times higher than that of the crude drug. The artemisinin SEDDS could significantly improve the solubility and relative bioavailability of artemisinin.

Abstract Papillary thyroid cancer (PTC) is the most frequent subtype of thyroid cancer, but 20% of cases are indeterminate (i.e., cannot be accurately diagnosed) based on preoperative cytology, which might lead to surgical removal of a normal thyroid gland. To address this concern, we performed an in-depth analysis of the serum proteomes of 26 PTC patients and 23 healthy controls using antibody microarrays and data-independent acquisition mass spectrometry (DIA-MS). We identified a total of 1091 serum proteins spanning 10–12 orders of magnitude. 166 differentially expressed proteins were identified that participate in complement activation, coagulation cascades, and platelet degranulation pathways. Furthermore, the analysis of serum proteomes before and after surgery indicated that the expression of proteins such as lactate dehydrogenase A and olfactory receptor family 52 subfamily B member 4, which participate in fibrin clot formation and extracellular matrix-receptor interaction pathways, were changed. Further analysis of the proteomes of PTC and neighboring tissues revealed integrin-mediated pathways with possible crosstalk between the tissue and circulating compartments. Among these cross-talk proteins, circulating fibronectin 1 (FN1), gelsolin (GSN) and UDP-glucose 4-epimerase (GALE) were indicated as promising biomarkers for PTC identification and validated in an independent cohort. In differentiating between patients with benign nodules or PTC, FN1 produced the best ELISA result (sensitivity = 96.89%, specificity = 91.67%). Overall, our results present proteomic landscapes of PTC before and after surgery as well as the crosstalk between tissue and the circulatory system, which is valuable to understand PTC pathology and improve PTC diagnostics in the future.

Coal is not only important energy resource, but also potential source of materials. As energy resource, coal has these physical properties which are important for comprehensive applications and transformations. For example, the pore structure of coal is crucial for the reservoir, adsorption, and migration and desorption of coal bed methane. As feedstock of materials, coal can provide good raw material for special technological fields, such as graphite and graphene from coal. Macerals are the main components of coal, which are significant for properties and applications of coal. Taking coal sample (XJH) from No. 2 coal seam of Xiaojihan coal mine, Yuheng mining area as the object of this study, macerals were observed by atomic force microscope (AFM). Micro morphology and pore structure of vitrinite, semifusinite and fusinite are analyzed to provide fundamentals for clean and comprehensive application of coal in this area. Results show that the micro morphology is featured by granular structure with randomly distributed granules. Vitrinite has the largest Ds value, indicating a complex micro morphological structure. Granules accumulate densely and fluctuate in large extent. Semifusinite has a medium Ds value. Fusinite has the smallest Ds value, and granules accumulate dispersedly and fluctuate in small extent. As for pore structure, vitrinite has the lowest value of mean pore size and volume, but has the largest pore number. It results from the micro pores sized below 2 nm. The pore structure of vitrinite is beneficial to reservoir and adsorption of coal bed methane. Inertinite has larger pore size and volume than vitrinite, but the pore number is less. This is mainly contributed by pores sized in 2～50 nm. The pore structure of inertinite can provide beneficial space for the diffusion of coal bed methane. Inertinite is dominated in pores sized in 2～50 nm, but fractal dimension of pores (D) of semifusinite is larger than fusinite, indicating pores in semifusinite has larger irregular degree than fusinite.

Abstract Colorectal cancer (CRC) has high incidence and mortality rates and is one of the most common cancers of the digestive tract worldwide. Metastasis and drug resistance are the main causes of cancer treatment failure. Studies have recently suggested extracellular vesicles (EVs) as a novel mechanism for intercellular communication. They are vesicular particles, which are secreted and released into biological fluids, such as blood, urine, milk, etc., by a variety of cells and carry numerous biologically active molecules, including proteins, nucleic acids, lipids, metabolites, etc. EVs play a crucial part in the metastasis and drug resistance of CRC by delivering cargo to recipient cells and modulating their behavior. An in-depth exploration of EVs might facilitate a comprehensive understanding of the biological behavior of CRC metastasis and drug resistance, which might provide a basis for developing therapeutic strategies. Therefore, considering the specific biological properties of EVs, researchers have attempted to explore their potential as next-generation delivery systems. On the other hand, EVs have also been demonstrated as biomarkers for the prediction, diagnosis, and presumed prognosis of CRC. This review focuses on the role of EVs in regulating the metastasis and chemoresistance of CRC. Moreover, the clinical applications of EVs are also discussed. Graphical Abstract

Abstract Depression is a common mental illness, which is related to monoamine neurotransmitters and the dysfunction of the cholinergic, immune, glutamatergic, and neuroendocrine systems. The hypothesis of monoamine neurotransmitters is one of the commonly recognized pathogenic mechanisms of depression; however, the drugs designed based on this hypothesis have not achieved good clinical results. A recent study demonstrated that depression and inflammation were strongly correlated, and the activation of alpha7 nicotinic acetylcholine receptor (α7 nAChR)-mediated cholinergic anti-inflammatory pathway (CAP) in the cholinergic system exhibited good therapeutic effects against depression. Therefore, anti-inflammation might be a potential direction for the treatment of depression. Moreover, it is also necessary to further reveal the key role of inflammation and α7 nAChR in the pathogenesis of depression. This review focused on the correlations between inflammation and depression as well-discussed the crucial role of α7 nAChR in the CAP.

Abstract Background Blau syndrome is a rare autoinflammatory disease caused by autosomal dominant mutations in the CARD15/NOD2 gene. Vascular involvement is a rare phenotype in Blau syndrome patients. In this study, we aimed to describe a 20-year- old Chinese girl with Blau syndrome complicated by renal arteritis. In addition, we summarized a literature review of published cases of vascular involvement in patients with Blau syndrome. Case presentation We describe a 20-year-old girl who was initially misdiagnosed with juvenile idiopathic arthritis (JIA) almost 15 years prior. In October 2019, she developed renal arteritis at the age of 17 years and was eventually diagnosed with Blau syndrome. A de-novo M513T mutation was found in her gene testing. A review of the literature on patients with Blau syndrome and vasculitis showed that a total of 18 cases were reported in the past 40 years. The vast majority of them were predominantly involved medium and large vessel arteritis. Of the 18 patients included in our literature review, 14 patients had aorto-arteritis, and 4 of them had renal artery involvement. Two patients presented with renal artery stenosis, 1with a sinus of Valsalva aneurysm, and 1 with retinal vasculitis. Conclusion A detailed medical history inquiry and a careful physical examination are helpful for the early identification of Blau syndrome, especially for infant onset refractory JIA. Medium-and large-vessel arteritis is a rare clinical manifestation in Blau syndrome patients. Careful examination of the peripheral pulse and measurement of blood pressure at every regular visit may be helpful in the early identification of Blau syndrome-arteritis. Early diagnosis and appropriate treatment may prevent or delay the occurrence of severe symptoms in patients to improve the patient’s quality of life.

A method for simultaneous screening of 90 pesticide residues in blueberries by ultra-high pressure liquid chromatography high resolution mass spectrometry was developed. Target residues in blueberries were extracted by an improved QuEChERS protocol. Ultra-high pressure liquid chromatography coupled to quadrupole/orbitrap high-resolution mass spectrometry was employed for screening analysis with full mass scanning trigged data dependent fragment ion acquisition in positive and negative mode. The analytes were quantified by representative matrix-matched standard curve. The results showed that the optimized ratio of PSA vs C18 was 1:1 with amount of 150 mg respectively in the improved QuEChERS protocol. The limits of detection and limits of quantitation of the method were 0.1~18.7 μg/kg and 0.2~20.2 μg/kg as well. The linearities for 90 pesticides were fitted by regression calculation at the range of 0.005~0.1 mg/kg with determination coefficient R2≥0.992. With calibration of the representative matrix-matched standard curve, recoveries were calculated ranging from 50.1% to 130.9% and relative standard deviations were varied in the scope of 1.0%~14.9% at the three spiking levels of 0.01, 0.05 and 0.1 mg/kg. Five pesticides were detected in the real-life blueberry samples purchased in the market, evidencing the applicability of the developed method. The proposed approach is applicable for routine pesticide monitoring in blueberries with simple sample preparation, broad analyte coverage and powerful capability of quantification and qualification.

Data outsourcing has become more and more popular due to its low cost and flexibility. However, there is a problem that the cloud server used to store data is partially trusted. Searchable encryption is an efficient technology that is devoted to helping people conduct accurate searches without leaking information. Nonetheless, most existing schemes cannot support dynamic updates or meet the privacy requirements of all users. There have been some experiments to solve these issues by implementing a dynamically searchable asymmetric encryption scheme. This paper proposes an efficient searchable encryption scheme based on the Authenticator Bloom Filter (ABF). The solution can support dynamic updates and multiple users and meet forward and backward security. This paper uses an ABF to improve the efficiency of searches and updates while playing a significant role in dynamic updates. This paper designs a new token encryption scheme and file set encryption scheme, which not only helps users reduce time in searches and updates but also supports multi-user modes. Experiments show that the proposed scheme takes less time in searching and updating algorithms, especially when the keyword does not exist. The solution also takes into account the problem of history storage when updating, which reduces the unnecessary consumption of memory and avoids multiple storage states for the same file.

BackgroundTo explore the association between thyroid hormones and gestational diabetes mellitus in euthyroid pregnant women, with the aim of preventing the occurrence of gestational diabetes mellitus.MethodsIn this prospective study, a total of 1222 euthyroid pregnant women in their first trimester were recruited at Peking University International Hospital between December 2017 and March 2019. These participants underwent an oral glucose tolerance test during the 24-28 weeks of gestation.ResultsDuring early pregnancy, the gestational diabetes mellitus group displayed lower levels of free thyroxine when compared to the non-gestational diabetes mellitus group. Additionally, the ratio of free triiodothyronine to free thyroxine in the gestational diabetes mellitus group during early pregnancy was significantly higher (p

BackgroundMaturity-onset diabetes of the young type 5 (MODY5) is an uncommon, underrecognized condition that can be encountered in several clinical contexts. It is challenging to diagnose because it is considered rare and therefore overlooked in the differential diagnosis. Moreover, no typical clinical features or routine laboratory tests can immediately inform the diagnosis.Case presentationWe report a 28-year-old man who was once misdiagnosed with type 1 diabetes due to decreased islet function and recurrent diabetic ketosis or ketoacidosis. However, he had intermittent nausea, vomiting, abdominal distension, and abdominal pain 6 months prior. Further examinations revealed agenesis of the dorsal pancreas, complex renal cyst, kidney stone, prostate cyst, hypomagnesaemia, and delayed gastric emptying. Accordingly, whole-exon gene detection was performed, and a heterozygous deletion mutation was identified at [GRCh37 (hg19)] chr17:34842526-36347106 (1.5 Mb, including HNF1B gene). The patient was eventually diagnosed with 17q12 deletion syndrome with gastroparesis.ConclusionWe report a novel case of diabetes mellitus type MODY5 as a feature of 17q12 deletion syndrome caused by a new 17q12 deletion mutation, which will further broaden the genetic mutation spectrum of this condition. With the help of gene detection technology, these findings can assist endocrinologists in making the correct diagnosis of MODY5 or 17q12 deletion syndrome. Additionally, they can formulate an appropriate therapy and conduct genetic screening counseling for their family members to guide and optimize fertility.

Abstract The profile of antibodies against antigenic epitopes of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) during neutralizing antibody (NAb) decay has not been clarified. Using a SARS‐CoV‐2 proteome microarray that contained viral antigenic peptides, we analyzed the characteristics of the humoral response in patients with coronavirus disease 19 (COVID‐19) in a longitudinal study. A total of 89 patients were recruited, and 226 plasma samples were serially collected in 2020. In the antigenic peptide microarray, the level of immunoglobulin G (IgG) antibodies against peptides within the S2 subunit (S‐82) and a conserved gene region in variants of interest, open reading frame protein 10 (ORF10‐3), were closely associated with the presence of SARS‐CoV‐2 NAbs. In an independent evaluation cohort of 232 plasma samples collected from 116 COVID‐19 cases in 2020, S82‐IgG titers were higher in NAbs‐positive samples (p = 0.002) than in NAbs‐negative samples using enzyme‐linked immunosorbent assay. We further collected 66 plasma samples from another cohort infected by Omicron BA.1 virus in 2022. Compared with the samples with lower S82‐IgG titers, NAb titers were significantly higher in the samples with higher S82‐IgG titers (p = 0.04). Our findings provide insights into the understanding of the decay‐associated signatures of SARS‐CoV‐2 NAbs.

Abstract Background Large tumor suppressor kinase 1 (LATS1), one of the predominant components of the Hippo pathway, has been characterized as a key player controlling the proliferation and invasion of cancer cells, including gastric cancer (GC) cells. However, the mechanism by which the functional stability of LATS1 is modulated has yet to be elucidated. Methods Online prediction tools, immunohistochemistry and western blotting assays were used to explore the expression of WW domain-containing E3 ubiquitin ligase 2 (WWP2) in GC cells and tissues. Gain- and loss-of-function assays, as well as rescue experiments were performed to determine the role of the WWP2-LATS1 axis in cell proliferation and invasion. Additionally, the mechanisms involving WWP2 and LATS1 were assessed by coimmunoprecipitation (Co-IP), immunofluorescence, cycloheximide and in vivo ubiquitination assays. Results Our results demonstrate a specific interaction between LATS1 and WWP2. WWP2 was markedly upregulated and correlated with disease progression and a poor prognosis in GC patients. Moreover, ectopic WWP2 expression facilitated the proliferation, migration and invasion of GC cells. Mechanistically, WWP2 interacts with LATS1, resulting in its ubiquitination and subsequent degradation, leading to increased transcriptional activity of YAP1. Importantly, LATS1 depletion abolished the suppressive effects of WWP2 knockdown on GC cells. Furthermore, WWP2 silencing attenuated tumor growth by regulating the Hippo-YAP1 pathway in vivo. Conclusions Our results define the WWP2-LATS1 axis as a critical regulatory mechanism of the Hippo-YAP1 pathway that promotes GC development and progression. Video Abstract