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Abstract Background Gastroesophageal reflux disease (GERD) is among the most common complications of bariatric surgery. This study aimed to analyse the risk factors affecting the worsening of GERD symptoms after laparoscopic sleeve gastrectomy (LSG), and to establish and validate a related nomogram model. Methods The study recruited 236 participants and randomly divided them into training and validation sets in a ratio of 7:3. LASSO regression technique was used to select the optimal predictive features, and multivariate logistic regression was used to construct the column line graphs. The performance of the nomogram was evaluated and validated by analyzing the area under the receiver operating characteristic (ROC) curve, calibration curve, and decision curve. Results In this study, Lasso-logistic regression was applied to select 5 predictors from the relevant variables, which were body mass index (BMI), diabetes, hiatal hernia, GERD, and triglyceride levels. These 5 predictor variables constructed a model with moderate predictive power, with an area under the ROC curve of 0.779 for the training set and 0.796 for the validation set. Decision curve analysis showed that in external validation, if the risk thresholds were between 4 and 98% and 14–95%, then the nomogram can be applied to the clinic. Conclusions We have developed and validated a nomogram that effectively predicts the risk of worsening gastroesophageal reflux symptoms following LSG.

Abstract Neoadjuvant chemotherapy (NACT) is a viable therapeutic option for women diagnosed locally advanced cervical cancer (LACC). However, the factors influencing pathological response are still controversial. We collected pair specimens of 185 LACC patients before and after receiving NACT and conducted histological evaluation. 8 fresh tissues pre-treatment were selected from the entire cohort to conducted immune gene expression profiling. A novel pathological grading system was established by comprehensively assessing the percentages of viable tumor, inflammatory stroma, fibrotic stroma, and necrosis in the tumor bed. Then, 185 patients were categorized into either the good pathological response (GPR) group or the poor pathological response (PPR) group post-NACT, with 134 patients (72.4%, 134/185) achieving GPR. Increasing tumor-infiltrating lymphocytes (TILs) and tumor-infiltrating lymphocytes volume (TILV) pre-treatment were correlated with GPR, with TILV emerging as an independent predictive factor for GPR. Additionally, CIBERSORT analysis revealed noteworthy differences in the expression of immune makers between cPR and non-cPR group. Furthermore, a significantly heightened density of CD8 + T cells and a reduced density of FOXP3 + T cells were observed in GPR than PPR. Importantly, patients exhibiting GPR or inflammatory type demonstrated improved overall survival and disease-free survival. Notably, stromal type was an independent prognostic factor in multivariate analysis. Our study indicates the elevated TILV in pre-treatment specimens may predict a favorable response to NACT, while identifying stromal type in post-treatment specimens as an independent prognostic factor. Moreover, we proposed this pathological grading system in NACT patients, which may offer a more comprehensive understanding of treatment response and prognosis.

Abstract The Asian ladybeetle, Coccinella septempunctata, is an important insect of predatory natural enemy, which has a strong control effect and application prospects for aphids, whiteflies, mealybugs, and other small-sized pests of agriculture and forestry crops. Gut microbiota composition posed impacts on development of insects. In order to clarify the effect of artificial feed feeding on the intestinal microbial species and structure of C. septempunctata, we compared the intestinal microbial flora of C. septempunctata reared on bean aphids and artificial food for 15 days. Results show that Proteobacteria was the dominant component in all groups at phylum level, Rhodobacter, Methylovigula, Burkholderia, and Bradyrhizobium were the dominant bacteria among all groups at genus level. As to the differences in bacterial community structure and diversity, there is no significant difference between Shannon index and Simpson index, the principal components analysis of the bacterial communities, and the samples were roughly distributed in different regions. After 15 days of feeding, artificial diet did not significantly reduce the microbial diversity of the gut of C. septempunctata compared to the aphid group, and there was no significant effect on the abundance of dominant flora in the gut of C. septempunctata, C. septempunctata gut has a similar core microbiota. This study clarifies the effects in intestinal microbial diversity and composition structure of the C. septempunctata with artificial diet, and provides a theoretical basis for understanding the intestinal microorganisms and optimizating the artificial diet of C. septempunctata.

Abstract This study aimed to develop and validate prognostic nomograms that can estimate the probability of 1-, 3- and 5-year overall survival (OS) as well as cancer-specific survival (CSS) for Intrahepatic cholangiocarcinoma (ICCA) patients. Clinical data of 1446 patients diagnosed with ICCA between 2010 and 2017 from the Surveillance, Epidemiology, and End Results (SEER) database were analyzed. In both the OS and the CSS group, the training cohort and validation cohort were divided into a 7:3 ratio. Age, sex, AJCC T stage, AJCC N stage, AJCC M stage, surgical status, and tumor grade were selected as independent prognostic risk factors to build the nomograms. To compare the efficacy of predicting 1-, 3-, and 5-year OS and CSS rates of the nomogram with the 8th edition of the American Joint Committee on Cancer (AJCC) staging system, we evaluated the Harrell’s index of concordance (C-index), area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA) in both cohorts. The results showed the nomogram for 1-, 3-, and 5-year OS and CSS prediction performed better than the AJCC staging system. In the subgroup analysis for patients could not receive surgery as the primary treatment. We developed two nomograms for predicting the 1-, and 2-year OS and CSS rates following the same analysis procedure. Results indicate that the performance of both nomograms, which contained sex, AJCC T stage, AJCC M stage, chemotherapy, and tumor grade and prognostic factors, was also superior to the AJCC staging system. Meanwhile, four dynamic network-based nomograms were published. The survival analysis showed the survival rate of patients classified as high-risk based on the nomogram score was significantly lower compared to those categorized as low-risk (P

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease with no cure. Receptor-interacting protein kinase 1 (RIPK1) has been proposed to mediate pathogenesis of ALS. Primidone has been identified as an old drug that can also inhibit RIPK1 kinase. We conducted a drug-repurposing biomarker study of primidone as a RIPK1 inhibitor using SOD1G93A mice and ALS patients. SOD1G93A mice treated with primidone showed significant delay of symptomatic onset and improved motor performance. One-hundred-sixty-two ALS participants dosed daily with primidone (62.5 mg) completed 24-week follow-up. A significant reduction was showed in serum levels of RIPK1 and IL-8, which were significantly higher in ALS patients than that of healthy controls (P

Biomaterials are natural, synthetic, or hybrid materials, which are used in medical devices or implants that are placed in contact with the human biological system to compensate for or restore diminished functions of the body. The field of biomaterials has rapidly developed to meet the ever-expanding needs in healthcare and medicine practices. Advancements in science and technology have enabled the fabrication and reengineering of biomaterials into useful medical devices or implants, such as heart valves, bone plates, hip joints, and cardiac pacemakers. Because biomaterials are placed in continuous close contact with the recipient’s body fluids or tissues, the classification of available biomaterials is crucial for selecting safer and highly biocompatible materials. This review focuses on biomaterial classification, namely bioceramic, polymeric, and metallic biomaterials. Their medical applications, advantages, and disadvantages are discussed. Current trends in biomaterials involved in disease treatments, such as controlled drug delivery and cancer therapy, are additionally explored.

Abstract Background As the complexity and diversity of the tumor immune microenvironment (TIME) are becoming better understood, burgeoning research has progressed in this field. However, there is a scarcity of literature specifically focused on the bibliometric analysis of this topic. This study sought to investigate the development pattern of TIME-related research from 2006 to September 14, 2022, from a bibliometric perspective. Methods We acquired both articles and reviews related to TIME from the Web of Science Core Collection (WoSCC) (retrieved on September 14, 2022). R package “Bibliometrix” was used to calculate the basic bibliometric features, present the collaborative conditions of countries and authors, and generate a three-field plot to show the relationships among authors, affiliations, and keywords. VOSviewer was utilized for co-authorship analysis of country and institution and keyword co-occurrence analysis. CiteSpace was used for citation burst analysis of keywords and cited references. In addition, Microsoft Office Excel 2019 was used to develop an exponential model to fit the cumulative publication numbers. Results A total of 2545 publications on TIME were included, and the annual publication trend exhibited a significant increase over time. China and Fudan University were the most productive country and institution, with the highest number of publications of 1495 and 396, respectively. Frontiers in Oncology held the highest number of publications. A number of authors were recognized as the main contributors in this field. The clustering analysis revealed six clusters of keywords that highlighted the research hot spots in the fields of basic medical research, immunotherapy, and various cancer types separately. Conclusions This research analyzed 16 years of TIME-related research and sketched out a basic knowledge framework that includes publications, countries, journals, authors, institutions, and keywords. The finding revealed that the current research hot spots of the TIME domain lie in “TIME and cancer prognosis”, “cancer immunotherapy”, and “immune checkpoint”. Our researchers identified the following areas: “immune checkpoint-based immunotherapy”, “precise immunotherapy” and “immunocyte pattern”, which may emerge as frontiers and focal points in the upcoming years, offering valuable avenues for further exploration.

Abstract Background As a life-threatening and serious condition, aortic dissection (AD) is divided into type A and B according to its association with the ascending or descending aorta. Type A AD is often accompanied by aortic regurgitation, while type B dissections are rarely accompanied by severe aortic regurgitation. Case presentation We present a 71 year-old Chinese man with a rare case of type B AD with severe aortic insufficiency, who self-healed after 1 year of an aortic valve replacement. He complained of chest tightness and abdominal pain. Due to poor cardiac function, he underwent aortic valve replacement before intervening on the dissection. The operation was successful, and the dissection was treated conservatively. During the 1-year follow-up, his chest tightness improved, and the type B dissection was healed. His general condition is considerably improved. Conclusions In type B AD combined with severe aortic insufficiency, aortic valve replacement should be prioritized. This is potentially explained by the aortic root activity and pulse pressure difference.

ObjectiveTo survey the development status and actual needs of virtual autopsy technology in China and to clarify the applicability of forensic virtual autopsy laboratory accreditation.MethodsThe questionnaire was set up included three aspects： （1） the current status of virtual autopsy technology development; （2） the accreditation elements such as personnel, equipment, entrustment and acceptance, methods, environmental facilities; （3） the needs and suggestions of practicing institutions. A total of 130 forensic pathology institutions were surveyed by online participation through the Questionnaire Star platform.ResultsAmong the 130 institutions, 43.08% were familiar with the characteristics of virtual autopsy technology, 35.38% conducted or received training in virtual autopsy, and 70.77% have establishment needs （including maintenance）. Relevant elements were suitable for laboratory accreditation.ConclusionVirtual autopsy identification has gained social recognition. There is a demand for accreditation of forensic virtual autopsy laboratory. After the preliminary assessment, considering the characteristics and current situation of this technology, China National Accreditation Service for Conformity Assessment （CNAS） can first carry out the accreditation pilot of virtual autopsy project at large comprehensive forensic institutions with higher identification capability, and then CNAS can popularize the accreditation in a wide range when the conditions are suitable.

Abstract Background Mentoring relationships play a critical but poorly understood role in mentoring’s overall success. To overcome these knowledge gaps, a study of mentee experiences in the Palliative Medicine Initiative, a structured research-based mentoring program, is proposed. The program’s clearly described mentoring approach, competency-based mentoring stages and curated mentoring environment ensure a consistent mentoring experience. It provides a unique platform to study mentoring relationships longitudinally and its implications on professional identity formation. Methodology The Tool Design Systematic Evidence-Based Approach methodology is used to map and employ current understanding. A review of recent reviews on mentoring processes, mentoring’s effects, professional identity formation and professional identity formation assessment tools lay the foundation for the design of semi-structured interviews and mentoring diaries to evaluate the characteristics of successful mentoring relationships and mentoring’s impact on professional identity formation. The data accrued from these tools were evaluated using this methodology whilst changes in professional identity formation were assessed using the Ring Theory of Personhood. Results The semi-structured interviews revealed four themes: stakeholders, mentoring stages, mentoring relationships and professional identity formation whilst the mentoring diaries revealed two: mentoring processes and mentoring relationships. Two final domains emerged – mentoring relationships and professional identity formation. Conclusions The Palliative Medicine Initiative’s structured stage-based mentoring approach, trained stakeholders, curated environment, assessment-directed and personalized mentoring support reveal seven developmental stages of mentoring relationships. These culminate in changes to the values, beliefs and principles that shape how mentees see, feel and act as professionals. These findings suggest that mentoring programs may help to further develop and fine-tune their professional identity formation.

Abstract An ongoing randomized, double-blind, controlled phase 2 trial was conducted to evaluate the safety and immunogenicity of a mosaic-type recombinant vaccine candidate, named NVSI-06-09, as a booster dose in subjects aged 18 years and older from the United Arab Emirates (UAE), who had administered two or three doses of inactivated vaccine BBIBP-CorV at least 6 months prior to enrollment. The participants were randomly assigned with 1:1 to receive a booster dose of NVSI-06-09 or BBIBP-CorV. The primary outcomes were immunogenicity and safety against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, and the exploratory outcome was cross-immunogenicity against other circulating strains. Between May 25 and 30, 2022, 516 adults received booster vaccination with 260 in NVSI-06-09 group and 256 in BBIBP-CorV group. Interim results showed a similar safety profile between two booster groups, with low incidence of adverse reactions of grade 1 or 2. For immunogenicity, by day 14 post-booster, the fold rises in neutralizing antibody geometric mean titers (GMTs) from baseline elicited by NVSI-06-09 were remarkably higher than those by BBIBP-CorV against the prototype strain (19.67 vs 4.47-fold), Omicron BA.1.1 (42.35 vs 3.78-fold), BA.2 (25.09 vs 2.91-fold), BA.4 (22.42 vs 2.69-fold), and BA.5 variants (27.06 vs 4.73-fold). Similarly, the neutralizing GMTs boosted by NVSI-06-09 against Beta and Delta variants were also 6.60-fold and 7.17-fold higher than those by BBIBP-CorV. Our findings indicated that a booster dose of NVSI-06-09 was well-tolerated and elicited broad-spectrum neutralizing responses against divergent SARS-CoV-2 variants, including Omicron and its sub-lineages.

Acute myeloid leukemia （AML） is a malignant clonal disease originating from hematopoietic stem/progenitor cells. Chemotherapy is the main treatment. If not effectively treated after 2 courses of standard treatment， these patients can be diagnosed with refractory AML. In this article， a case of refractory AML complicated with disseminated Fusarium infection receiving combined treatment of venetoclax and azacitidine was reported. The patient was diagnosed with AML （M5a） with DNMT3A， IDH2 and BCOR mutations， classified in the moderate group. Standard dose of IA regimen （deoxydaunorubicin + cytarabine） was ineffective， and additional homoharringtonine induction therapy remained ineffective. Subsequently， combined use of venetoclax and azacitidine was adopted and the severity of disease was alleviated. Complete remission was achieved after three cycles of venetoclax combined with azacitidine consolidation therapy. After the first chemotherapy， the patient presented with recurrent fever， purple induration with central necrosis in the upper and lower limbs， and visible subcutaneous liquid mass. Pathological examination suggested Fusarium infection. After amphotericin B combined with voriconazole as antifungal therapy， disseminated Fusarium infection was effectively controlled. This case prompts that combined use of venetoclax and azacitidine yields high remission rate in the treatment of refractory AML. Disseminated Fusarium infection is a rare fatal complication in AML patients after chemotherapy. Early diagnosis and effective antifungal treatment are effective interventions to improve the survival rate of patients.

Transplantation of neural stem cells (NSCs) has been proved to promote functional rehabilitation of brain lesions including ischemic stroke. However, the therapeutic effects of NSC transplantation are limited by the low survival and differentiation rates of NSCs due to the harsh environment in the brain after ischemic stroke. Here, we employed NSCs derived from human induced pluripotent stem cells together with exosomes extracted from NSCs to treat cerebral ischemia induced by middle cerebral artery occlusion/reperfusion in mice. The results showed that NSC-derived exosomes significantly reduced the inflammatory response, alleviated oxidative stress after NSC transplantation, and facilitated NSCs differentiation in vivo. The combination of NSCs with exosomes ameliorated the injury of brain tissue including cerebral infarction, neuronal death, and glial scarring, and promoted the recovery of motor function. To explore the underlying mechanisms, we analyzed the miRNA profiles of NSC-derived exosomes and the potential downstream genes. Our study provided the rationale for the clinical application of NSC-derived exosomes as a supportive adjuvant for NSC transplantation after stroke.

Abstract Background Tuberous sclerosis complex (TSC) results in neurodevelopmental phenotypes, benign tumors, and cysts throughout the body. Recent studies show numerous rare findings in TSC. Guidelines suggest routine abdominal and chest imaging to monitor these thoracoabdominal findings, but imaging is not uniformly done across centers. Thus, the prevalence of many findings is unknown. To answer this, we categorized the clinical reads of 1398 thoracoabdominal scans from 649 patients of all ages in the Cincinnati Children’s Hospital TSC Repository Database. Results Typical TSC findings were present in many patients: kidney cysts (72%), kidney fat-containing angiomyolipomas (51%), kidney lipid-poor angiomyolipomas (27%), liver angiomyolipomas (19%), and lung nodules thought to represent multifocal micronodular pneumocyte hyperplasia (MMPH) (18%). While many features were more common in TSC2 patients, TSC1 patients had a higher prevalence of MMPH than TSC2 patients (24% versus 13%, p = 0.05). Many rare findings (e.g., lymphatic malformations and liver masses) are more common in TSC than in the general population. Additionally, most thoracoabdominal imaging findings increased with age except kidney cysts which decreased, with the 0–10 years age group having the highest percentage (69% 0–10 years, 49% 10–21 years, 48% 21 + years, p

Abstract Bystander cardiopulmonary resuscitation (BCPR), early defibrillation and timely treatment by emergency medical services (EMS) can double the chance of survival from out-of-hospital sudden cardiac arrest (OHCA). We investigated the effect of the COVID-19 pandemic on the pre-hospital chain of survival. We searched five bibliographical databases for articles that compared prehospital OHCA care processes during and before the COVID-19 pandemic. Random effects meta-analyses were conducted, and meta-regression with mixed-effect models and subgroup analyses were conducted where appropriate. The search yielded 966 articles; 20 articles were included in our analysis. OHCA at home was more common during the pandemic (OR 1.38, 95% CI 1.11–1.71, p = 0.0069). BCPR did not differ during and before the COVID-19 pandemic (OR 0.94, 95% CI 0.80–1.11, p = 0.4631), although bystander defibrillation was significantly lower during the COVID-19 pandemic (OR 0.65, 95% CI 0.48–0.88, p = 0.0107). EMS call-to-arrival time was significantly higher during the COVID-19 pandemic (SMD 0.27, 95% CI 0.13–0.40, p = 0.0006). Resuscitation duration did not differ significantly between pandemic and pre-pandemic timeframes. The COVID-19 pandemic significantly affected prehospital processes for OHCA. These findings may inform future interventions, particularly to consider interventions to increase BCPR and improve the pre-hospital chain of survival.

BackgroundAdherence to the delirium bundle intervention is sub-optimal in routine practice, and inappropriate use of the instructional design of interventions may result in higher cognitive load among nurses. It remains unclear whether the Clinical Decision Support System (CDSS) Assisted Prevention and Management for Delirium (CDSS-AntiDelirium) results in the improvement of adherence to delirium intervention and the reduction of extraneous cognitive load, as well as improving adherence to delirium intervention, among nurses in the intensive care unit (ICU).MethodsThis study (named the CDSSD-ICU) is a multicentre, prospective, cluster randomized controlled clinical trial. A total of six ICUs in two hospitals will be randomized in a 1:1 ratio to receive either the CDSS-AntiDelirium group or the delirium guidelines group. The CDSS-AntiDelirium consists of four modules: delirium assessment tools, risk factor assessment, a nursing care plan, and a nursing checklist module. Each day, nurses will assess ICU patients with the assistance of the CDSS-AntiDelirium. A total of 78 ICU nurses are needed to ensure statistical power. Outcome assessments will be conducted by investigators who are blinded to group assignments. The primary endpoint will be adherence to delirium intervention, the secondary endpoint will be nurses' cognitive load measured using an instrument to assess different types of cognitive load. Repeated measures analysis of variance will be used to detect group differences. A structural equation model will be used to clarify the mechanism of improvement in adherence.DiscussionAlthough the CDSS has been widely used in hospitals for disease assessment, management, and recording, the applications thereof in the area of delirium are still in infancy. This study could provide scientific evidence regarding the impact of a CDSS on nurses' adherence and cognitive load and promote its further development in future studies.Clinical trial registrationChiCTR1900023711 (Chinese Clinical Trial Registry).

OBJECTIVES/GOALS: Glioblastoma (GBM) is the most common and aggressive adult primary brain malignancy. Clinically, GBM is refractory to T cell immune checkpoint blockade (ICB), in part due to its dense immune suppressive myeloid stroma. Here we show that myeloid-targeting STING agonists can repolarize the GBM microenvironment to cure ICB-refractory GBM models. METHODS/STUDY POPULATION: Using the synthetic cyclic di-nucleotide STING agonist IACS-8803 (8803) we treated orthotopic ICB-refractory QPP8 orthotopic murine GBM tumors intratumorally. We then analyzed survival and performed high parameter flow cytometry profiling of the tumor immune microenvironment following STING agonist treatment. To assess the contribution of adaptive immunity to STING agonist therapeutic efficacy, we treated orthotopic QPP8 tumors implanted in RAG1 KO mice and monitored survival. RESULTS/ANTICIPATED RESULTS: We found that STING agonist therapy cured murine orthotopic QPP8 tumors, in contrast to ICB that showed no survival benefit. In RAG1-/- mice bearing QPP8 tumors STING agonist therapy extended survival, however, the curative effect observed in wild-type mice was lost in the absence of adaptive immunity. STING agonist-treated QPP8 tumors displayed increased counts of CD8 T cells and NK cells, and decreased CD8 T cell PD1 expression. Infiltration of STING-treated gliomas by Ly6C+ F4/80+ Mono-MDSC substantially increased; however, these cells expressed reduced CD206 and CD163, suggestive of reduced immuno-suppression. Finally, in the cervical LN of QPP8-treated mice the frequency and CD80/CD86 expression of cDC1 cells increased.​ DISCUSSION/SIGNIFICANCE: ICB has failed in GBM, and the suppressive myeloid stroma remains a major barrier to generating anti-GBM T cell responses. Our work shows that STING activation, which primarily targets innate immunity myeloid cells 'upstream' of T cells in the antitumor immunity cycle, can cure ICB-refractory GBM tumors in an adaptive immunity-dependent manner.

Objective To observe the influence of dapagliflozin on ERS of myocardial tissues from rats with heart failure, and explore the its relationship with myocardial remodeling. Methods The rats were divided into the control group, model group (with aortic coarctation, TAC) and Dapagliflozin intervention group (with Dapagliflozin 0.5 and 1.0 mg/kg given by gavage once daily). Non-invasive rat tail artery manometer was used to detect mean arterial pressure. Weigh body weight, whole heart weight and left ventricular weight were recorded to calculate the rat myocardial hypertrophy index HWI and LVWI. Small animal ultrasound was used to detect rat heart function. The morphological changes of cardiomyocytes was microscopied with HE staining. Immuno-histochemistry and Western blot were used to detect GRP78 and CHOP expression in rat myocardial tissue. Results Compared with the control group, MAP, HWI and LVWI in the model group were significantly increased (P＜0.01), EF and FS decreased significantly (P＜0.01). Compared with the model group, HWI and LVWI were reduced (P＜0.05), EF and FS were increased (P＜0.05) in dapagliflozin group. HE staining showed that the myocardial fibers in control group were neatly arranged and morphologically regular; in model group, the myocardial fibers were excluded from the disorder, the morphology was irregular, and the tissue was evacuated; the myocardial fibers in dapagliflozin group were better than that of model group. Compared with control group, the expression of GRP78 and CHOP in the myocardium of model group was significantly increased(P＜0.01);compared with model group, the expression of GRP78 and CHOP in dapagliflozin group was reduced (P＜0.05). Conclusions Dapagliflozin obviously inhibits ERS, down-regulates the expression of GRP78 and CHOP, protects cardiomyocytes, more effectively relieves ventricular remodeling and improves cardiac function. ERS may be one of the molecular biological mechanisms of Dapagliflozin.

Abstract Thyroid Carcinoma (THCA) is the most common endocrine tumor that is mainly treated using surgery and radiotherapy. In addition, immunotherapy is a recently developed treatment option that has played an essential role in the management of several types of tumors. However, few reports exist on the use of immunotherapy to treat THCA. The study downloaded the miRNA, mRNA and lncRNA data for THCA patients from the TCGA database ( https://portal.gdc.cancer.gov/ ). Thereafter, the tumor samples were divided into cold and hot tumors, based on the immune score of the tumor microenvironment. Moreover, the differentially expressed lncRNAs and miRNAs were obtained. Finally, the study jointly constructed a ceRNA network through differential analysis of the mRNA data for cold and hot tumors. The study first assessed the level of immune infiltration in the THCA tumor microenvironment then divided the samples into cold and hot tumors, based on the immune score. Additionally, a total of 568 up-regulated and 412 down-regulated DEGs were screened by analyzing the differences between hot and cold tumors. Thereafter, the study examined the differentially expressed genes for lncRNA and miRNA. The results revealed 629 differentially expressed genes related to lncRNA and 114 associated with miRNA. Finally, a ceRNA network of the differentially expressed genes was constructed. The results showed a five-miRNA hubnet, i.e., hsa-mir-204, hsa-mir-128, hsa-mir-214, hsa-mir-150 and hsa-mir-338. The present study identified the immune-related mRNA, lncRNA and miRNA in THCA then constructed a ceRNA network. These results are therefore important as they provide more insights on the immune mechanisms in THCA. The findings also provides additional information for possible THCA immunotherapy.

Large-scale populations in the world have been vaccinated with COVID-19 vaccines, however, breakthrough infections of SARS-CoV-2 are still growing rapidly due to the emergence of immune-evasive variants, especially Omicron. It is urgent to develop effective broad-spectrum vaccines to better control the pandemic of these variants. Here, we present a mosaic-type trimeric form of spike receptor-binding domain (mos-tri-RBD) as a broad-spectrum vaccine candidate, which carries the key mutations from Omicron and other circulating variants. Tests in rats showed that the designed mos-tri-RBD, whether used alone or as a booster shot, elicited potent cross-neutralizing antibodies against not only Omicron but also other immune-evasive variants. Neutralizing antibody ID50 titers induced by mos-tri-RBD were substantially higher than those elicited by homo-tri-RBD (containing homologous RBDs from prototype strain) or the BIBP inactivated COVID-19 vaccine (BBIBP-CorV). Our study indicates that mos-tri-RBD is highly immunogenic, which may serve as a broad-spectrum vaccine candidate in combating SARS-CoV-2 variants including Omicron.

Abstract Background Colorectal cancer is the third most common diagnosis. Oxaliplatin is used as first-line treatment of colon cancer. However, oxaliplatin resistance greatly reduces its therapeutic effect. SRPK1 involves in pre-mRNA splicing and tumorigenesis. How SRPK1 mediates drug resistance in colon cancer is unknown. Methods The expression of SRPK1 was analyzed in the TCGA and the CPTAC pan-cancer samples and detected in colon cancer cell lines and tissues by IHC and western blot. The MTT and TUNEL assay were used to verify the anti-apoptosis ability of colon cancer cell. The activation of NF-κB was determined by luciferase assay and qRT-PCR. AKT, IKK, IκB and their phosphorylation level were verified by western blot. Results We found that SRPK1 expression was the second highest in TCGA and the CPTAC pan-cancer samples. The mRNA and protein levels of SRPK1 were increased in tissues from patients with colon cancer. SRPK1 was associated with clinical stage and TNM classifications in 148 cases of colon cancer patients. High SRPK1 levels correlated with poor prognosis (p

Abstract Magnolia sieboldii K. Koch (M. sieboldii) is a deciduous Chinese tree species of the Magnoliaceae family with high ornamental, medicinal, and economic benefits. The germination of M. sieboldii seeds under natural conditions is extremely difficult, thereby hindering the cultivation and breeding of this important species. The molecular mechanisms underlying M. sieboldii seed germination remain unclear due to the lack of genomic and transcriptomic resources. Here, we integrated both mRNA and miRNA sequencing to identify the genes and pathways related to M. sieboldii germination. A comprehensive full-length transcriptome containing 158,083 high-quality unigenes was obtained by single-molecule real-time (SMRT) sequencing technology. We identified a total of 13,877 genes that were differentially expressed between non-germinated and germinated seeds. These genes were mainly involved in plant hormone signal transduction and diverse metabolic pathways such as those involving lipids, sugars, and amino acids. Our results also identified a complex regulatory network between miRNAs and their target genes. Taken together, we present the first transcriptome of M. sieboldii and provide key genes and pathways associated with seed germination for further characterization. Future studies of the molecular basis of seed germination will facilitate the genetic improvement M. sieboldii.

Abstract Tenofovir and entecavir are currently designated as the preferred oral antiviral drugs for chronic hepatitis B. However, only less than 40% of patients can achieve HBeAg seroconversion. We aim at investigating the role of intestinal microbiome in HBeAg seroconversion induced by oral antiviral therapy and describe multi-omics characteristics of HBeAg seroconversion associated intestinal flora. In this study, we prospectively collected fecal samples at baseline from the patients with HBeAg positive chronic hepatitis B who would have oral antiviral therapy. 16S rDNA sequencing and metabolomics were performed. We identified HBeAg seroconversion-related microbial signature and constructed prediction model for HBeAg seroconversion. Thirty-seven of these subjects achieved HBeAg seroconversion within 156 weeks after the initiation of oral antiviral therapy, while 41 subjects remained HBeAg positive even after over 156 weeks of therapy. A computational statistical and machine learning approach allowed us to identify a microbial signature for HBeAg seroconversion. Using random forest method, we further constructed a classifier based on the microbial signature, with area under curve being 0.749 for the test set. Patients who achieved HBeAg seroconversion tended to have lower abundance of certain fecal metabolites such as essential amino acids, and several dipeptides. By analyzing the fecal microbiota from the patients with and without HBeAg seroconversion, we showed intestinal microbiome play a critical role in HBeAg seroconversion induced by oral antiviral therapy. We also identified intestinal microbial signature that is associated with HBeAg seroconversion after oral antiviral therapy.

Abstract In East Asia, genetic divergence is usually considered to be correlated to different floristic regions, however, subtropical-tropical divergence is largely ignored, compared to widely explored temperate-subtropical divergence. Lindera aggregata (Lauraceae), a dominant species in South-East China was selected to address this issue. Fifteen low-copy nuclear genes (LCGs) and four chloroplast DNA (cpDNA) fragments were used to detect its evolutionary history. In LCGs, STRUCTURE and dated Bayesian phylogeny analyses detect distinct subtropical-tropical divergence since late Pleistocene. Approximate Bayesian calculation (ABC) further supports the distinct subtropical-tropical divergence, and close related Taiwan and South China populations are diverged at the last interglacial. Isolation by distance, isolation by environment and isolation by resistance analyses suggest the current climatic difference rather than geographical distance contributes to the genetic differentiation. Principle component analysis shows populations of tropical cluster occur in warmer area with higher precipitation. Ancestral area reconstruction based on Bayesian phylogeny indicates that ancestral L. aggregata populations are distributed in tropical region. In cpDNA, although unique haplotypes are found in tropical region, distinct subtropical-tropical divergence is absent. In conclusion, distinct late Pleistocene subtropical-tropical divergence of L. aggregata is triggered by climate. It is likely that L. aggregata is originated in Southwest-South China and experienced hierarchical dispersal from south to north. The South China Sea land bridge has dual role in connecting or isolating Taiwan and mainland populations since the last glaciation.

Abstract Sulforaphane (SFN) extracted from broccoli sprout has previously been investigated for its potential properties in cancers, however, the underlying mechanisms of the anticancer activity of SFN remain not fully understood. In the present study, we investigate the effects of SFN on cell proliferation, cell cycle, cell apoptosis, and also the expression of several cell cycle and apoptosis-related genes by MTT assay, flow cytometry and western blot analysis in gastric cancer (GC) cells. The results showed that SFN could impair the colony-forming ability in BGC-823 and MGC-803 cell lines compared with the control. In addition, SFN significantly suppressed cell proliferation by arresting the cell cycle at the S phase and enhancing cell apoptosis in GC cells in a dose-dependent manner. Western blot results showed that SFN treatment significantly increased the expression levels of p53, p21 and decreased CDK2 expression, which directly regulated the S phase transition. The Bax and cleaved-caspase-3 genes involved in apoptosis executive functions were significantly increased in a dose-dependent manner in BGC-823 and MGC-803 cells. These results suggested that SFN-induced S phase cell cycle arrest and apoptosis through p53-dependent manner in GC cells, which suggested that SFN has a potential therapeutic application in the treatment and prevention of GC.

Objective To explore the expression and function of hsa-miR-4483 in breast cancer cells. Methods Using TargetScan to find out how can-miR-4483 act on the c-Myc gene, and RT-qPCR verified the expression of hsa-miR-4483. Transfected MCF-7 and MDA-MB-231 and set up NC-negative controls, Western blot was used to detect the expression of the hsa-miR-4483 gene, MTT assay and Transwell chamber experiment were applied to verify the proliferation and migration of breast cancer cells. Results The expression of hsa-miR-4483 was significantly lower (P＜0.001, P＜0.01) in MCF-7 and MDA-MB-231(P＜0.001, P＜0.01) The up-regulation of c-myc in MCF-7 and MDA-MB-231 promoted cell proliferation and migration (P＜0.001). Conclusions hsa-miR-4483 can promote the proliferation and migration of breast cancer cell lines, which plays a regulatory role in the development of breast cancer and its prognosis.

In May 2019, we investigated monkeypox in a traveler from Nigeria to Singapore. The public health response included rapid identification of contacts, use of quarantine, and postexposure smallpox vaccination. No secondary cases were identified. Countries should develop surveillance systems to detect emerging infectious diseases globally.

Objective To establish an analysis method for simultaneous determination of 13 sedative substances and their metabolites in blood by liquid-liquid extraction and liquid chromatography-tandem mass spectrometry （LC-MS/MS） technology and to apply the method to actual cases. Methods The samples were extracted with ethyl acetate after an internal standard was added. The extract was condensed until it was nearly dry and then its residues were dissolved with methanol, filtered through 0.22 μm filter and finally determined. The 13 sedative substances and their metabolites were separated through the C18 chromatographic column, then gradient elution was performed on them with methanol and 20 mmol/L ammonium formate （containing 0.1% formic acid） solution. After that, they were determined in the electrospray positive ion mode and quantified by internal standard method. Results The 13 sedative substances and their metabolites in blood showed good linearity in the range of 5-200 μg/L with correlation coefficients ranging from 0.990 3 to 0.999 8. The detection limits were 0.1-1.0 μg/L. Recovery rates of sedative substances were in the range of 71.2%-93.4% when solutions with concentrations of 10, 50 and 200 μg/L were added. The deviations of intra-day and inter-day relative standard deviations （RSD） were not more than 8.6%. Accuracies （bias） were within ±9.8%. Conclusion This method is rapid, simple, effective and sensitive, and can be applied to analysis of 13 sedative substances and their metabolites in blood in forensic toxicology.

BackgroundPost-acute coronary syndrome (ACS) depression is a common but not well understood complication experienced by ACS patients. Research on the effectiveness of various therapies remains limited. Hence, we sought to conduct a network meta-analysis to assess the efficacy of different interventions for post-ACS depression in improving patient outcomes.Methods and findingsThree electronic databases were searched for randomised controlled trials describing different depression treatment modalities in post-ACS patients. Each article was screened based on inclusion criteria and relevant data were extracted. A bivariate analysis and a network meta-analysis was performed using risk ratios (RR) and standardized mean differences (SMD) for binary and continuous outcomes, respectively. A total of 30 articles were included in our analysis. Compared to standard care, psychosocial therapy was associated with the greatest reduction in depression scores (SMD:-1.21, 95% CI: -1.81 to -0.61, pConclusionThis network meta-analysis found that the treatment effect of the various psychological modalities on depression severity were similar. Future trials on psychological interventions assessing clinical outcomes and improvement in adherence to ACS-specific interventions are needed.

A previously well 32-year-old Chinese male presented with acute bilateral upper and lower limb paralysis upon waking, ten days after the onset of COVID-19 infection. Examination revealed areflexia over all four limbs, associated with reduced muscle strength, but no sensory or cranial nerve deficit. Initial concern was Guillain-Barre syndrome given the acute flaccid paralysis following COVID-19 infection. However, investigations revealed severe hypokalaemia (1.7 mmol/L) and primary hyperthyroidism. He was treated for thyrotoxic periodic paralysis (TPP) with β-blockers, antithyroid medications, and intravenous potassium chloride (KCl). Despite frequent monitoring of potassium, rebound hyperkalaemia occurred with prompt resolution of paralysis.

Hypericum kouytchense Lévl is a semi-evergreen plant of the Hypericaceae family. Its roots and seeds have been used in a number of traditional remedies for antipyretic, detoxification, anti-inflammatory, antimicrobial and antiviral functions. However, to date, no bioactivity compounds have been characterized from the insect gall of H. kouytchens. In this study, we evaluated the antiviral activities of different extracts from the insect gall of H. kouytchen against cathepsin L, HIV-1 and renin proteases and identified the active ingredients using UPLC–HRMS. Four different polar extracts (HW, H30, H60 and H85) of the H. kouytchense insect gall exhibited antiviral activities with IC50 values of 10.0, 4.0, 3.2 and 17.0 µg/mL against HIV-1 protease; 210.0, 34.0, 24.0 and 30.0 µg/mL against cathepsin L protease; and 180.0, 65.0, 44.0 and 39.0 µg/mL against human renin, respectively. Ten compounds were identified and quantified in the H. kouytchense insect gall extracts. Epicatechin, eriodictyol and naringenin chalcone were major ingredients in the extracts with contents ranging from 3.9 to 479.2 µg/mg. For HIV-1 protease, seven compounds showed more than 65% inhibition at a concentration of 1000.0 µg/mL, especially for hypericin and naringenin chalcone with IC50 values of 1.8 and 33.0 µg/mL, respectively. However, only hypericin was active against cathepsin L protease with an IC50 value of 17100.0 µg/mL, and its contents were from 0.99 to 11.65 µg/mg. Furthermore, we attempted to pinpoint the interactions between the active compounds and the proteases using molecular docking analysis. Our current results imply that the extracts and active ingredients could be further formulated and/or developed for potential prevention and treatment of HIV or SARS-CoV-2 infections.

Abstract Background The distant metastasis of cancer cells is a risk factor for tumor lethality and poor prognosis in non-small-cell lung carcinoma (NSCLC). Increased SOX9 expression has been associated with clinical stage and poor prognosis in NSCLC, but the molecular mechanisms by which SOX9 promotes metastasis in NSCLC are still unknown. Methods The relationship between SOX9 expression and T, N, M classification was assessed using the χ2 test and Spearman’s analysis in 142 immunohistochemically diagnosed specimens of NSCLC. We also generated SOX9-overexpression and SOX9-knockdown cells lines and their corresponding control cell lines by transfection with lentiviral constructs. In vivo assay, SOX9-overexpressing and SOX9-knockdown NSCLC cells were injected in zebrafish to examine distance metastasis. Gene set enrichment analysis (GSEA) was applied to analysis the correlation between SOX9 overexpression and Wnt/β-catenin pathway. Luciferase assay was used to check transcriptional activity of TCF/LEF and western blot and immunofluorescence was employed to detect β-catenin translocation in SOX9-overexpression, SOX9-knockdown and their corresponding control cell lines. Results We found that SOX9 overexpression correlates with the T, N and M stage significantly (p = 0.03, 0.000, and 0.032 respectively) in 142 immunohistochemically diagnosed specimens of NSCLC. SOX9 overexpression was found to decrease the expression of the epithelial cell markers E-cadherin and γ-catenin and increase the expression of the mesenchymal cell markers N-cadherin and vimentin. An in vivo assay showed distant metastasis of the SOX9-overexpressing cells, which was not observed in the SOX9-knockdown cells. These findings indicate that SOX9 promotes distant metastasis by promoting EMT in NSCLC cells. GSEA showed that SOX9 overexpression was significantly correlated with the Wnt/β-catenin pathway which was corroborated by the expression of EMT-associated proteins in this pathway and its downstream target genes. SOX9 overexpression was also found to enhance the transcriptional activity of TCF/LEF, promote the nuclear translocation of β-catenin and increase the phosphorylation of GSK3β at Ser9. Further, inhibition of β-catenin suppressed the metastasis-promoting effects of SOX9 overexpression. Conclusions This study is the first to report that SOX9 is associated with clinical TNM stage and indicates that SOX9 promotes migration, invasion and the EMT process through the Wnt/β-catenin pathway.

Kidney renal clear cell carcinoma (KIRC) is the most common and aggressive type of renal cell carcinoma. Due to high mortality rate, high metastasis rate and chemical resistance, the prognosis of KIRC patients is poor. Therefore, it is necessary to study the mechanisms of KIRC development and to develop more effective prognostic molecular biomarkers to help clinical patients. In our study, we used The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to investigate that the expression of nuclear factor I B (NFIB) is significantly higher in KIRC than in adjacent tissues. Moreover, NFIB expression levels are associated with multiple clinical pathological parameters of KIRC, and KIRC patients with high NFIB expression have poor prognosis, suggesting that NFIB may play vital roles in the malignant development of KIRC. Further studies demonstrated that NFIB could promote the progression and metastasis of KIRC and participate in the regulation of PTEN induced kinase 1 (PINK1). Furthermore, we used chromatin immunoprecipitation (ChIP) experiments to confirm that NFIB binds to the PINK1 promoter and regulates its expression at the transcriptional level. Further experiments also confirmed the important roles of PINK1 in promoting the development of tumors by NFIB. Hence, our data provide a new NFIB-mediated regulatory mechanism for the tumor progression of KIRC and suggest that NFIB can be applied as a new predictor and therapeutic target for KIRC.

In order to prioritize available immune therapeutics, immune profiling across glioma grades was conducted, followed by preclinical determinations of therapeutic effect in immune-competent mice harboring gliomas. T cells and myeloid cells were isolated from the blood of healthy donors and the blood and tumors from patients with glioma and profiled for the expression of immunomodulatory targets with an available therapeutic. Murine glioma models were used to assess therapeutic efficacy of agents targeting the most frequently expressed immune targets. In patients with glioma, the A2aR/CD73/CD39 pathway was most frequently expressed, followed by the PD-1 pathway. CD73 expression was upregulated on immune cells by 2-hydroxyglutarate in IDH1 mutant glioma patients. In murine glioma models, adenosine receptor inhibitors demonstrated a modest therapeutic response; however, the addition of other inhibitors of the adenosine pathway did not further enhance this therapeutic effect. Although adenosine receptor inhibitors could recover immunological effector functions in T cells, immune recovery was impaired in the presence of gliomas, indicating that irreversible immune exhaustion limits the effectiveness of adenosine pathway inhibitors in patients with glioma. This study illustrates vetting steps that should be considered before clinical trial implementation for immunotherapy-resistant cancers, including testing an agent’s ability to restore immunological function in the context of intended use.

ObjectivePulmonary tuberculosis (TB) is a severe infectious respiratory disease, the burden of which remains high in China. To provide scientific evidence for developing more targeted prevention and control strategies, this study aimed to determine the incidence trends and explore the epidemiological characteristics of pulmonary TB in Anhui Province, Eastern China between 2013 and 2018.MethodsThe retrospective study analyzed information regarding pulmonary TB cases reported by the National Infectious Disease Reporting System and census data collected from the Anhui Provincial Bureau of Statistics.ResultsOverall, 211,892 cases of TB patients were reported in Anhui Province, China between 2013 and 2018, with an average annual reported incidence rate of 57.7 per 100,000 persons. A significant decrease in the incidence rate of pulmonary TB (p < 0.001) was observed during the study period. Men had a higher incidence rate of pulmonary TB than women (p < 0.001). The highest annual average reported incidence rate was 204.2 per 100,000 persons in those aged 70-74 years. The number of farmers with pulmonary TB, i.e., 155,415, accounted for 73.4% of all cases. Moreover, the peak period of reported cases was from January to March. Four cities along the Yangtze River-Anqing, Tongling, Chizhou, and Wuhu-reported significantly higher incidence rates of pulmonary TB than other cities (p < 0.001).ConclusionsFrom 2013 to 2018, there was a significant decline in the incidence rate of pulmonary TB in Anhui Province, with peaks occurring from January to March. Prevention and control strategies targeting men, people aged 70-74 years, farmers, and the four cities along the Yangtze River should be strengthened.

Abstract. Human immunodeficiency virus (HIV)-infected individuals exhibit remarkable transcriptomic variation. Transcriptome analyses of antiretroviral therapy (ART)-free chronically infected HIV-1 patients with different clinical outcomes are likely to aid the development of vaccine and immune therapies. Here, we performed microarray analyses on whole-blood derived RNA from 89 ART-free HIV-1-infected individuals from 2 cohorts. The differentially expressed genes were analyzed between long-term non-progressors, viremic non-progressors and typical progressors, and between elite controllers and non-elite controllers among the long-term non-progressors. Several genes related to T-cell growth, proliferation and differentiation and antiapoptosis were upregulated, whereas interferon-stimulated genes and inflammatory genes were significantly downregulated in long-term non-progressors and viremic non-progressors. The observations above were further confirmed in the set of 261 genes that correlated with disease progression during a 5-year follow-up, which included 51 genes significantly associated with slower disease progression, and 210 genes associated with aggressive disease progression. Overall, our data suggest that it is vital to maintain the homeostasis of the immune system when mounting antiviral immune responses. Immune therapeutics able to reconstruct immune homeostasis are likely to be required for immune reconstitution in the context of ART, such as the administration of interleukin-7, healthy allogenic CD4+ T cells (providing CD4+ T-cell growth factors), or Tregs.

Abstract Animal mitochondrial genomes usually exhibit conserved gene arrangement across major lineages, while those in the Hymenoptera are known to possess frequent rearrangements, as are those of several other orders of insects. Here, we sequenced two complete mitochondrial genomes of Trichogramma japonicum and Trichogramma ostriniae (Hymenoptera: Chalcidoidea: Trichogrammatidae). In total, 37 mitochondrial genes were identified in both species. The same gene arrangement pattern was found in the two species, with extensive gene rearrangement compared with the ancestral insect mitochondrial genome. Most tRNA genes and all protein-coding genes were encoded on the minority strand. In total, 15 tRNA genes and seven protein-coding genes were rearranged. The rearrangements of cox1 and nad2 as well as most tRNA genes were novel. Phylogenetic analysis based on nucleotide sequences of protein-coding genes and on gene arrangement patterns produced identical topologies that support the relationship of (Agaonidae + Pteromalidae) + Trichogrammatidae in Chalcidoidea. CREx analysis revealed eight rearrangement operations occurred from presumed ancestral gene order of Chalcidoidea to form the derived gene order of Trichogramma. Our study shows that gene rearrangement information in Chalcidoidea can potentially contribute to the phylogeny of Chalcidoidea when more mitochondrial genome sequences are available.

Abstract Evaporative drying (ED) is an alternative technique for long-term preservation of mammalian sperm, which does not require liquid nitrogen or freeze-drying equipment, but offers advantages for storage and shipping at ambient temperature and low cost. However, the development of zygotes generated from these sperms was poor. Here, we demonstrated that the supplementation of tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, during embryo culture improved the developmental competency of embryos derived from in vitro matured pig oocytes injected intracytoplasmically with boar ED spermatozoa by reducing the production of reactive oxygen species, the DNA degradation and fragmentation, and the expression of apoptosis-related gene Bax and Bak, and by increasing the transcription of anti-apoptosis gene Bcl-XL and Bcl-2. Furthermore, TUDCA treatment promoted the blastocyst quality manifested by the total cell numbers and the ratio of inner cell mass. Taken together, our data suggest that evaporative drying would be a potentially useful method for the routine preservation of boar sperm in combination with further optimization of subsequently embryo culture conditions.

Abstract Differentiated thyroid cancer (DTC) patients with negative serum thyroglobulin (Tg), negative 131I whole–body scintigraphy (131I-WBS) at first post-ablation and progressively increased TgAb level are a relatively rare entity in the follow-up after total thyroidectomy and radioactive iodine therapy. The value of 18F-FDG PET/CT in detecting the recurrence of disease in these patients has only been reported in a small case series. The goal of this study was to investigate the diagnostic accuracy of 18F-FDG PET/CT in detecting recurrent disease in these specific PTC patients and to identify risk factors for patients with positive 18F-FDG PET/CT results. Eighty-two PTC patients who had 18F-FDG PET/CT scans with negative Tg, negative 131I-WBS at first post-ablation and progressively increased TgAb levels were included. We found that the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 18F-FDG PET/CT in this patient group were determined as 84%, 72%, 92%, 57% and 82%, respectively. 18F-FDG PET/CT scan had a good diagnostic performance and should be performed routinely in PTC patients with negative Tg, negative 131I-WBS at first postablation and progressively increased TgAb level, especially when span for progressively increased TgAb level ≥ 3 years and/or progressively increased TgAb value up to 150 IU/mL.

Abstract Skin fibrosis in systemic sclerosis (SSc) is accompanied by attrition of dermal white adipose tissue (dWAT) and reduced levels of circulating adiponectin. Since adiponectin has potent regulatory effects on fibroblasts, we sought to assess adiponectin signaling in SSc skin biopsies, and evaluate fibrosis in mice with adiponectin gain- and loss-of-function mutations. Furthermore, we investigated the effects and mechanism of action of agonist peptides targeting adiponectin receptors in vitro and in vivo. We found that adiponectin pathway activity was significantly reduced in a subset of SSc skin biopsies. Mice lacking adiponectin mounted an exaggerated dermal fibrotic response, while transgenic mice with constitutively elevated adiponectin showed selective dWAT expansion and protection from skin and peritoneal fibrosis. Adiponectin receptor agonists abrogated ex vivo fibrotic responses in explanted normal and SSc fibroblasts and in 3D human skin equivalents, in part by attenuating focal adhesion complex assembly, and prevented and reversed experimentally-induced organ fibrosis in mice. These results implicate aberrant adiponectin pathway activity in skin fibrosis, identifying a novel function for this pleiotropic adipokine in regulation of tissue remodeling. Restoring adiponectin signaling in SSc patients therefore might represent an innovative pharmacological strategy for intractable organ fibrosis.

Background: Orthotopic liver transplantation (OLT) improves the prognosis of patients with hepatocellular carcinoma (HCC). Moreover, the complement system is a powerful immune effector that can affect liver function and process of liver cirrhosis. However, studies correlating the complement system with tacrolimus metabolism after OLT are scarce. In this study, the role of single nucleotide polymorphisms (SNPs) associated with the sixth complement component (C6) in tacrolimus metabolism was investigated during the early stages of liver transplantation. Methods: The study enrolled 135 adult patients treated with OLT for HCC between August 2011 and October 2013. Ten SNPs in C6 gene and rs776746 in cytochrome P450 3A5 (CYP3A5) gene were investigated. The tacrolimus levels were monitored daily during 4 weeks after transplantation. Results: Both donor and recipient CYP3A5 rs776746 allele A were correlated with decreased concentration/dose (C/D) ratios. Recipient C6 rs9200 allele G and donor C6 rs10052999 homozygotes were correlated with lower C/D ratios. Recipient CYP3A5 rs776746 allele A (yielded median tacrolimus C/D ratios of 225.90 at week 1 and 123.61 at week 2), C6 rs9200 allele G (exhibited median tacrolimus C/D ratios of 211.31 at week 1, 110.23 at week 2, and 99.88 at week 3), and donor CYP3A5 rs776746 allele A (exhibited median C/D ratios of 210.82 at week 1, 111.06 at week 2, 77.49 at week 3, and 85.60 at week 4) and C6 rs10052999 homozygote (exhibited median C/D ratios of 167.59 at week 2, 157.99 at week 3, and 155.36 at week 4) were associated with rapid tacrolimus metabolism. With increasing number of these alleles, patients were found to have lower tacrolimus C/D ratios at various time points during the 4 weeks after transplantation. In multiple linear regression analysis, recipient C6 rs9200 group (AA vs. GG/GA) was found to be related to tacrolimus metabolism at weeks 1, 2, and 3 (P = 0.005, P = 0.045, and P = 0.033, respectively), whereas donor C6 rs10052999 group (CC/TT vs. TC) was demonstrated to be correlated with tacrolimus metabolism only at week 4 (P = 0.001). Conclusions: Recipient C6 gene rs9200 polymorphism and donor C6 gene rs10052999 polymorphism are new genetic loci that affect tacrolimus metabolism in patients with HCC after OLT.

Objective To evaluate the accuracy of cone beam CT (CBCT) in calculating the volume of the bone defect in alveolar cleft. Methods 14 patients with unilateral alveolar cleft were included in this study. Their image data were collected by CBCT scan and imported in the Mimics 10.01 software. The volume of the bone defect in alveolar cleft was calculated by Mimics 10.01 software. The real bone volumes transplanted during operation were measured by sterile syringes and were compared with preoperative CBCT data. Results The volume of bone defect from CBCT calculation was (2.78±0.70) mL, while the real volume obtained in operation was (2.88±0.70) mL. There was no significant difference between the CBCT data and the real bone defect (P>0.05). The accuracy of CBCT in predicting bone defect volume was (95.09±2.56)%. Conclusion The combination of CBCT data and Mimics software can evaluate the bone defect volume in alveolar cleft accurately.

Background The spruce forests are dominant communities in northwest China, and play a key role in national carbon budgets. However, the patterns of carbon stock distribution and accumulation potential across stand ages are poorly documented. Methods We investigated the carbon stocks in biomass and soil in the natural spruce forests in the region by surveys on 39 plots. Biomass of tree components were estimated using allometric equations previously established based on tree height and diameter at breast height, while biomass in understory (shrub and herb) and forest floor were determined by total harvesting method. Fine root biomass was estimated by soil coring technique. Carbon stocks in various biomass components and soil (0–100 cm) were estimated by analyzing the carbon content of each component. Results The results showed that carbon stock in these forest ecosystems can be as high as 510.1 t ha−1, with an average of 449.4 t ha−1. Carbon stock ranged from 28.1 to 93.9 t ha−1 and from 0.6 to 8.7 t ha−1 with stand ages in trees and deadwoods, respectively. The proportion of shrubs, herbs, fine roots, litter and deadwoods ranged from 0.1% to 1% of the total ecosystem carbon, and was age-independent. Fine roots and deadwood which contribute to about 2% of the biomass carbon should be attached considerable weight in the investigation of natural forests. Soil carbon stock did not show a changing trend with stand age, ranging from 254.2 to 420.0 t ha−1 with an average of 358.7 t ha−1. The average value of carbon sequestration potential for these forests was estimated as 29.4 t ha−1, with the lower aged ones being the dominant contributor. The maximum carbon sequestration rate was 2.47 t ha−1 year−1 appearing in the growth stage of 37–56 years. Conclusion The carbon stock in biomass was the major contributor to the increment of carbon stock in ecosystems. Stand age is not a good predictor of soil carbon stocks and accurate evaluation of the soil carbon dynamics thus requires long-term monitoring in situ. The results not only revealed carbon stock status and dynamics in these natural forests but were helpful to understand the role of Natural Forest Protection project in forest carbon sequestration as well.

Phylogeny of hard ticks (Ixodidae) remains unresolved. Mitochondrial genomes (mitogenomes) are increasingly used to resolve phylogenetic controversies, but remain unavailable for the entire large Hyalomma genus. Hyalomma asiaticum is a parasitic tick distributed throughout the Asia. As a result of great morphological variability, two subspecies have been recognised historically; until a morphological data-based synonymization was proposed. However, this hypothesis was never tested using molecular data. Therefore, objectives of this study were to: 1. sequence the first Hyalomma mitogenome; 2. scrutinise the proposed synonymization using molecular data, i.e. complete mitogenomes of both subspecies: H. a. asiaticum and kozlovi; 3. conduct phylogenomic and comparative analyses of all available Ixodidae mitogenomes. Results corroborate the proposed synonymization: the two mitogenomes are almost identical (99.6%). Genomic features of both mitogenomes are standard for Metastriata; which includes the presence of two control regions and all three "Tick-Box" motifs. Gene order and strand distribution are perfectly conserved for the entire Metastriata group. Suspecting compositional biases, we conducted phylogenetic analyses (29 almost complete mitogenomes) using homogeneous and heterogeneous (CAT) models of substitution. The results were congruent, apart from the deep-level topology of prostriate ticks (Ixodes): the homogeneous model produced a monophyletic Ixodes, but the CAT model produced a paraphyletic Ixodes (and thereby Prostriata), divided into Australasian and non-Australasian clades. This topology implies that all metastriate ticks have evolved from the ancestor of the non-Australian branch of prostriate ticks. Metastriata was divided into three clades: 1. Amblyomminae and Rhipicephalinae (Rhipicephalus, Hyalomma, Dermacentor); 2. Haemaphysalinae and Bothriocrotoninae, plus Amblyomma sphenodonti; 3. Amblyomma elaphense, basal to all Metastriata. We conclude that mitogenomes have the potential to resolve the long-standing debate about the evolutionary history of ticks, but heterogeneous evolutionary models should be used to alleviate the effects of compositional heterogeneity on deep-level relationships.

This study was conducted to investigate the effects of replacing dietary fish oil (FO) with palm oil (PO) in juvenile Nile tilapia, Oreochromis niloticus (9.34± 0.02g initial weight) with emphasis on growth performance, digestive enzyme activities as well as serum biochemical parameters. Also, lysozyme activity (LYZ), respiratory burst (RB), superoxide dismutase (SOD), catalase (CAT) and resistance to Streptococcus iniae were investigated. Fish were stocked in 15 rectangular fiber glass tanks (150× 60× 40 cm) at 40 fish per tank with water maintained at 210 litres. Fish were fed five isonitrogenous (33% crude protein) and isolipidic (10% lipid) diets with PO included at 0% (0% PO), 25% (25% PO), 50% (50%PO), 75% (75% PO) and 100% (100% PO) for 8 weeks. The findings demonstrated that growth, and feed utilization was not compromised when PO was used in place of FO either partially or totally. Except for protease activity which was not significantly altered, lipase and amylase activities were significantly altered when FO was replaced with PO. There were no significant differences among treatments for CAT, SOD and LYZ. Serum malondialdehyde (MDA) in fish fed 100% PO was significantly lower than all other groups whiles total antioxidant capacity (TAC) of fish fed 0% PO was significantly higher than all other groups. Fish fed 0% PO, 25% PO and 50% PO had glutathione reductase (GR) significantly higher than fish fed 75% PO and 100% PO. RB in fish fed 0% PO were significantly lower than fish fed 75% PO and 100% PO. Also, fish fed 0% PO had significantly lower total protein (TP) compared with groups fed 50% PO and 75% PO. Fish fed diets with PO had similar resistance ability to Streptococcus iniae as those fed diets with FO. However, the liver function was likely to be compromised due to the increase in aspartate amino transferase (AST) and alkaline phosphatas (ALP) along increasing PO inclusion levels. AST, total protein, triacylglycerol (TAG) and low-density lipoprotein cholesterol (LDL-C) were significantly higher (p