Search

Background: Artificial intelligence (AI) conversational agents, or chatbots, are computer programs designed to simulate human conversations using natural language processing. They offer diverse functions and applications across an expanding range of healthcare domains. However, their roles in laboratory medicine remain unclear, as their accuracy, repeatability, and ability to interpret complex laboratory data have yet to be rigorously evaluated., Content: This review provides an overview of the history of chatbots, two major chatbot development approaches, and their respective advantages and limitations. We discuss the capabilities and potential applications of chatbots in healthcare, focusing on the laboratory medicine field. Recent evaluations of chatbot performance are presented, with a special emphasis on large language models such as the Chat Generative Pre-trained Transformer in response to laboratory medicine questions across different categories, such as medical knowledge, laboratory operations, regulations, and interpretation of laboratory results as related to clinical context. We analyze the causes of chatbots' limitations and suggest research directions for developing more accurate, reliable, and manageable chatbots for applications in laboratory medicine., Summary: Chatbots, which are rapidly evolving AI applications, hold tremendous potential to improve medical education, provide timely responses to clinical inquiries concerning laboratory tests, assist in interpreting laboratory results, and facilitate communication among patients, physicians, and laboratorians. Nevertheless, users should be vigilant of existing chatbots' limitations, such as misinformation, inconsistencies, and lack of human-like reasoning abilities. To be effectively used in laboratory medicine, chatbots must undergo extensive training on rigorously validated medical knowledge and be thoroughly evaluated against standard clinical practice., (© Association for Diagnostics & Laboratory Medicine 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

AbstractBackground Venetoclax monotherapy is an effective option for patients with acute myeloid leukemia (AML). Venetoclax has also been used in non-myeloablative conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk AML with a tolerable toxicity profile. However, the efficacy and safety of a venetoclax-containing myeloablative conditioning (MAC) allo-HSCT regimen for high-risk AML have not been evaluated.Objective To evaluate the safety and efficacy of a MAC regimen containing venetoclax for high-risk AML.Study design From 25 February 2021 to 4 September 2022, a total of 31 patients with high-risk AML who underwent allo-HSCT and a MAC regimen with venetoclax were analyzed.Results At the time of transplantation, 21 patients were in first complete remission (CR1), 4 were in a second complete remission (CR2), and 6 in non-remission (NR). Twenty-four patients (77.4%) were minimal residual disease (MRD)-positive before transplant. The FLT3-ITD gene mutation was present in 51.6% of patients. NUP98 rearrangement, MLL rearrangement or MLL-PTD and DEK::CAN fusion genes were found in 5 (16.1%), 7(22.6%) and 2 (6.5%) patients, respectively. Twenty-nine (93.6%) patients underwent haploidentical allo-HSCT. The median follow-up time was 278 days (range: 52–632 days). The 100-day cumulative incidence of grade 3 to 4 acute graft-versus-host disease (aGVHD) was 16.1% (95%CI, 7.2–36.0%). The 180-day cumulative incidence of moderate to severe chronic graft-versus-host disease (cGVHD) was 7.1% (95%CI, 1.9–26.9%). Cumulative incidence of 100-day cytomegalovirus (CMV) viraemia and 100-day Epstein-Barr virus (EBV) viraemia was 61.6% (95%CI, 46.5–81.4%) and 3.2% (95%CI, 0.4–22.2%), respectively. The 600-day overall survival (OS) and leukemia-free survival (LFS) were 80.9% (95%CI, 63.5–93.6%) and 81.3% (95%CI, 64.2–93.7%), respectively. The 600-day relapse incidence (RI) and non-relapse mortality (NRM) was 6.9% (95%CI, 1.8–26.3%) and 11.7% (95%CI, 3.9–35.0%).Conclusion Our study shows that the addition of venetoclax to a MAC allo-HSCT was feasible, safe and effective for high-risk AML patients.

Abstract Leucism, a widespread occurrence observed in Northern snakehead (Channa argus), bestows a striking white jade-like body coloration upon affected individuals and has gained substantial popularity in commercial breeding. While the visible manifestation of leucism in snakeheads is primarily limited to body coloration, it is crucial to explore the potential influence of leucism on organ development and elucidate the underlying molecular mechanisms. Through a comparative analysis of growth differences, our study revealed that at 150 days post-fertilization, the white variety exhibited an 8.5% higher liver index and intestinal index, but experienced a 20% and 38% decreased in spleen index and renal interstitial index, respectively, suggesting an enlarged digestive area but relatively smaller immune tissues. Nonetheless, no significant differences were observed in the intestinal flora between the two varieties, suggesting the exclusion of any exogenous impacts from symbiotic flora on the growth and development of the white variety. Importantly, transcriptome analysis demonstrated that the white variety exhibited higher expression levels of innate immune genes. Furthermore, annotation of the gene sets expressed in the liver and spleen revealed 76 and 35 genes respectively, with the white variety displaying lower expression in genes associated with “Viral protein interaction with cytokine and cytokine receptor”, “Protein processing in endoplasmic reticulum”, and “TNF signaling pathway”, while exhibiting higher expression in “Estrogen signaling pathway”. Notably, three genes, namely pcdhf 4, nlrc3 card 15-like, and a pol-like were identified in both the liver and spleen, indicating their potential involvement in altering the development and innate immunity of the white variety. This study reveals the systemic impact of leucism that extends beyond mere pigmentation alterations, highlighting the prominent characteristics of this phenotype and providing a foundation for future molecular breeding programs aimed at enhancing this variety.

Abstract TP53 mutation (TP53 mut) occurs in 10–20% of diffuse large B-cell lymphoma (DLBCL) cases and serves as an unfavorable biomarker of DLBCL progression. It confers resistance to immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation, and anti-CD19 chimeric antigen receptor T-cell therapy. Therapeutic targeting of TP53 mut remains a significant challenge in DLBCL treatment. Here we assessed TP53 mut in 667 patients with newly diagnosed DLBCL, including 576 patients treated with immunochemotherapy rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 91 patients with decitabine plus R-CHOP (DR-CHOP, NCT02951728 and NCT04025593). TP53 mut independently predicted an inferior prognosis in R-CHOP-treated DLBCL, although this could be mitigated by DR-CHOP treatment. In TP53 mut patients, multiple viral regulation pathways were repressed, resulting in the inhibition of immune modulation, as revealed by gene set enrichment analysis. TP53 mut DLBCL exhibited increased methyltransferase SUV39H1 expression and H3K9 trimethylation (H3K9me3), contributing to repression of endogenous retroviruses (ERVs) and immunosuppressive tumor microenvironment. In TP53 mut DLBCL cell lines, decitabine down-regulated SUV39H1, inhibited H3K9me3 occupancy on ERVs, and triggered ERV expression, thereby unleashing interferons program and CD4+T/CD8+T cell activation. Molecular silencing of SUV39H1 significantly abrogated decitabine-induced H3K9me3 inhibition and ERV expression. In TP53 mut patient-derived xenograft models and TP53 mut patients, the anti-tumor effect was improved upon the use of combined treatment of decitabine and doxorubicin via SUV39H1-H3K9me3-ERVs axis. Collectively, our findings highlight an ERV regulatory circuitry in TP53 mut DLBCL and the crucial roles ERVs for epigenetically reprogramming tumor microenvironment for treating TP53 mut-driven cancers.

Abstract Objectives The clinical features of aseptic meningitis associated with amoxicillin are unknown. The main objective of this study was to investigate the clinical characteristics of amoxicillin-induced aseptic meningitis (AIAM) and provide a reference for clinical diagnosis and treatment. Methods AIAM-related studies were collected by searching the relevant databases from inception to October 31, 2022. Results AIAM usually occurred 3 h to 7 days after amoxicillin administration in 13 males and 9 females. Twenty-one patients (95.5%) had recurrent AIAM with a total of 62 episodes. Fever (19 cases, 86.4%) and headache (18 cases, 81.8%) were the most common symptoms. Typical cerebrospinal fluid (CSF) findings were leukocytosis (100%) with lymphocytic predominance (14 cases, 63.6%), elevated protein (20 cases, 90.1%), normal glucose (21 cases, 95.5%) and negative culture (21 cases, 100%). Brain magnetic resonance imaging showed mild meningeal enhancement in one patient. The symptoms resolved mainly within 1–4 days after drug discontinuation in all patients. Conclusion Clinical attention should be given to the adverse effects of AIAM. The medication history of patients with suspected meningitis should be investigated to avoid unnecessary examination and antibiotic treatment.

General anesthesia leads to a loss of consciousness and an unrousable state in patients. Although general anesthetics are widely used in clinical practice, their underlying mechanisms remain elusive. The potential involvement of nonneuronal cells is unknown. Microglia are important immune cells in the central nervous system (CNS) that play critical roles in CNS function and dysfunction. We unintentionally observed delayed anesthesia induction and early anesthesia emergence in microglia-depleted mice. We found that microglial depletion differentially regulates neuronal activities by suppressing the neuronal network of anesthesia-activated brain regions and activating emergence-activated brain regions. Thus, microglia facilitate and stabilize the anesthesia status. This influence is not mediated by dendritic spine plasticity. Instead, it relies on the activation of microglial P2Y12 and subsequent calcium influx, which facilitates the general anesthesia response. Together, we elucidate the regulatory role of microglia in general anesthesia, extending our knowledge of how nonneuronal cells modulate neuronal activities.

Background Lung adenocarcinoma (LUAD) is still the most prevalent type of respiratory cancer. Intermittent hypoxia can increase the mortality and morbidity associated with lung cancer. Long non-coding RNAs (lncRNAs) are crucial in lung adenocarcinoma. However, the effects of intermittent hypoxia-related long non-coding RNAs (IHRLs) on lung adenocarcinoma are still unknown. Method In the current research, eight IHRLs were selected to create a prognostic model. The risk score of the prognostic model was evaluated using multivariate and univariate analyses, and its accuracy and reliability were validated using a nomogram and ROC. Additionally, we investigated the relationships between IHRLs and the immune microenvironment. Result Our analysis identified GSEC, AC099850.3, and AL391001.1 as risk lncRNAs, while AC010615.2, AC010654.1, AL513550.1, LINC00996, and LINC01150 were categorized as protective lncRNAs. We observed variances in the expression of seven immune cells and 15 immune-correlated pathways between the two risk groups. Furthermore, our results confirmed the ceRNA network associated with the intermittent hypoxia-related lncRNA GSEC/miR-873-3p/EGLN3 regulatory pathway. GSEC showed pronounced expression in lung adenocarcinoma tissues and specific cell lines, and its inhibition resulted in reduced proliferation and migration in A549 and PC9 cells. Intriguingly, GSEC manifested oncogenic properties by sponging miR-873-3p and demonstrated a tendency to modulate EGLN3 expression favorably. Conclusion GSEC acts as an oncogenic lncRNA by interacting with miR-873-3p, modulating EGLN3 expression. This observation underscores the potential of GSEC as a diagnostic and therapeutic target for LUAD.

Abstract Background Chimeric antigen receptor macrophage (CAR-M) therapy is a novel cancer immunotherapy approach that integrates CAR structure and macrophage functions. CAR-M therapy has shown unique and impressive antitumor effects in immunotherapy for solid tumors. However, the polarization state of macrophages can affect the antitumor effect of CAR-M. We hypothesized that the antitumor activity of CAR-Ms may be further improved after inducing M1-type polarization. Methods In this report, we constructed a novel HER2-targeting CAR-M, which was composed of humanized anti-HER2 scFv, CD28 hinge region and FcγRI transmembrane domain and intracellular domain. Phagocytosis, tumor-killing capacities, and cytokine release of CAR-Ms were detected with or without M1-polarization pretreatment. Several syngeneic tumor models were used to monitor the in vivo antitumor activity of M1-polarized CAR-Ms. Results After polarization with LPS combined with interferon-γ in vitro, we found that the phagocytic and tumor-killing capacities of CAR-Ms against target cells were significantly enhanced. The expression of costimulatory molecules and proinflammatory cytokines was also significantly increased after polarization. By establishing several syngeneic tumor models in vivo, we also demonstrated that infusing polarized M1-type CAR-Ms could effectively suppress tumor progression and prolong the survival of tumor-bearing mice with enhanced cytotoxicity. Conclusions We demonstrated that our novel CAR-M can effectively eliminate HER2-positive tumor cells both in vitro and in vivo, and M1 polarization significantly enhanced the antitumor ability of CAR-M, resulting in a stronger therapeutic effect in solid cancer immunotherapy.

Glucose is the basic fuel essential for maintenance of viability and functionality of all cells. However, some neurons — namely, glucose-inhibited (GI) neurons — paradoxically increase their firing activity in low-glucose conditions and decrease that activity in high-glucose conditions. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here, we showed that currents mediated by the anoctamin 4 (Ano4) channel are only detected in GI neurons in the ventromedial hypothalamic nucleus (VMH) and are functionally required for their activation in response to low glucose. Genetic disruption of the Ano4 gene in VMH neurons reduced blood glucose and impaired counterregulatory responses during hypoglycemia in mice. Activation of VMHAno4 neurons increased food intake and blood glucose, while chronic inhibition of VMHAno4 neurons ameliorated hyperglycemia in a type 1 diabetic mouse model. Finally, we showed that VMHAno4 neurons represent a unique orexigenic VMH population and transmit a positive valence, while stimulation of neurons that do not express Ano4 in the VMH (VMHnon-Ano4) suppress feeding and transmit a negative valence. Together, our results indicate that the Ano4 channel and VMHAno4 neurons are potential therapeutic targets for human diseases with abnormal feeding behavior or glucose imbalance.

Abstract Light initiated multi-gate semiconductor switch (LIMS) is a kind of power electronic device which has many differences from traditional thyristor triggered by electric pulse. LIMS is triggered by laser, the turn-on time is smaller, and the anti-electromagnetic interferences is strong. The opening mode of LIMS is obviously different to traditional thyristor. After the laser into the gate area, a large number of electrons and holes will appear in P-base region, holes gather in the area of P-base in PN junction J2, and electrons gather in N-drift region around the PN junction J2. PN junction J2 will open first, then PN junction J3 opens. The delay time of the NPN and PNP thyristors is close to zero when the laser pulse is narrow and the peak power is high, so the turn-on velocity is fast. To optimize the characteristics of the LIMS at high temperatures, we propose a new structure of the LIMS with the optimization of the n+ layer, circular light gate, and the new-style edge termination. The diameter of the LIMS is 23 mm. The experiment results show that the leakage current of the proposed LIMS has been decreased from more than 1 mA to 500 μA at 125 °C, the output current of the LIMS is 10.2 kA with a voltage of 4 kV at 85 °C, and the output current of the LIMS is 12.1 kA with a voltage of 4 kV at − 55 °C. Additionally, di/dt is larger than 30 kA/μs.

The hormone leptin is known to robustly suppress food intake by acting upon the leptin receptor (LepR) signaling system residing within the agouti-related protein (AgRP) neurons of the hypothalamus. However, clinical studies indicate that leptin is undesirable as a therapeutic regiment for obesity, which is at least partly attributed to the poorly understood complex secondary structure and key signaling mechanism of the leptin-responsive neural circuit. Here, we show that the LepR-expressing portal neurons send GABAergic projections to a cohort of α3-GABAA receptor expressing neurons within the dorsomedial hypothalamic nucleus (DMH) for the control of leptin-mediated obesity phenotype. We identified the DMH as a key brain region that contributes to the regulation of leptin-mediated feeding. Acute activation of the GABAergic AgRP-DMH circuit promoted food intake and glucose intolerance, while activation of post-synaptic MC4R neurons in the DMH elicited exactly opposite phenotypes. Rapid deletion of LepR from AgRP neurons caused an obesity phenotype which can be rescued by blockage of GABAA receptor in the DMH. Consistent with behavioral results, these DMH neurons displayed suppressed neural activities in response to hunger or hyperglycemia. Furthermore, we identified that α3-GABAA receptor signaling within the DMH exerts potent bi-directional regulation of the central effects of leptin on feeding and body weight. Together, our results demonstrate a novel GABAergic neural circuit governing leptin-mediated feeding and energy balance via a unique α3-GABAA signaling within the secondary leptin-responsive neural circuit, constituting a new avenue for therapeutic interventions in the treatment of obesity and associated comorbidities.

Abstract. Background:. Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by complex and various clinical manifestations. The study aimed to analyze clinical features and cerebral magnetic resonance imaging (MRI) changes of hyperintense white matter (WM) lesions in SLE patients. Methods:. This was a retrospective study based on a consecutive cohort of 1191 SLE patients; 273 patients for whom cerebral MRI data were available were enrolled to assess hyperintense WM lesions associated with SLE. Patients were assigned to two groups, i.e., with or without hyperintense WM lesions. The MRI assessment showed that the hyperintense WM lesions could be classified into three categories: type A, periventricular hyperintense WM lesions; type B, subcortical hyperintense WM lesions; and type C, multiple discrete hyperintense WM lesions. The clinical and MRI characteristics were analyzed. Factors related to hyperintense WM lesions were identified by multivariate logistic regression analysis. Results:. Among the 273 SLE patients with available cerebral MRI scans, 35.9% (98/273) had hyperintense WM lesions associated with SLE. The proportions of types A, B, and C were 54.1% (53/98), 11.2% (11/98), and 92.9% (91/98), respectively. Fifty-one percents of the patients showed an overlap of two or three types. Type C was the most common subgroup to be combined with other types. Compared with those without hyperintense WM lesions, the patients with hyperintense WM lesions were associated with neuropsychiatric SLE (NPSLE), lupus nephritis (LN), hypertension, and hyperuricemia (P = 0.002, P = 0.018, P = 0.045, and P = 0.036, respectively). Significantly higher rates of polyserous effusions and cardiac involvement were found in the patients with hyperintense WM lesions (P = 0.029 and P = 0.027, respectively), and these patients were more likely to present with disease damage (P

Transmembrane proteins have exhibited a significant correlation with glioblastoma multiforme (GBM). The current study elucidates the roles of transmembrane protein 150A (TMEM150A) in GBM. Data on patients with GBM were collected from The Cancer Genome Atlas and Xena databases. The objective was to identify the expression levels of TMEM150A in patients with GBM, and evaluate its diagnostic and prognostic values, accomplished using the receiver operating characteristic and survival analyses. On a cellular level, Cell Counting Kit-8, Wound healing, and Transwell experiments were performed to gauge the impact of TMEM150A on cell growth and migration. The study further investigated the correlation between TMEM150A expression and immune status, along with ribonucleic acid (RNA) modifications in GBM. The findings demonstrated TMEM150A overexpression in the cancerous tissues of patients with GBM, with an area under the curve value of 0.95. TMEM150A overexpression was significantly correlated with poor prognostic indicators. TMEM150A overexpression and isocitrate dehydrogenase (IDH) mutation status were predictive of poor survival time among patients with GBM. In vitro experiments indicated that suppressing TMEM150A expression could inhibit GBM cell proliferation, migration, and invasion. Moreover, TMEM150A overexpression was associated with stromal, immune, and estimate scores, immune cells (such as the T helper (Th) 17 cells, Th2 cells, and regulatory T cells), cell markers, and RNA modifications. Therefore, TMEM150A overexpression might serve as a promising biomarker for predicting poor prognosis in patients with GBM. Inhibiting TMEM150A expression holds the potential for improving the survival time of patients with GBM.

Fatty acid metabolism (FAM) is an important factor in tumorigenesis and development. However, whether fatty acid metabolism (FAM)-related genes are associated with prostate cancer (PCa) prognosis is not known. Therefore, we established a novel prognostic model based on FAM-related genes to predict biochemical recurrence in PCa patients. First, PCa sequencing data were acquired from TCGA as the training cohort and GSE21032 as the validation cohort. Second, a prostate cancer prognostic model containing 10 FAM-related genes was constructed using univariate Cox and LASSO. Principal component analysis and t-distributed stochastic neighbour embedding analysis showed that the model was highly effective. Third, PCa patients were divided into high- and low-risk groups according to the model risk score. Survival analysis, ROC curve analysis, and independent prognostic analysis showed that the high-risk group had short recurrence-free survival (RFS), and the risk score was an independent diagnostic factor with diagnostic value in PCa patients. External validation using GSE21032 also showed that the prognostic model had high reliability. A nomogram based on a prognostic model was constructed for clinical use. Fourth, tumor immune correlation analyses, such as the ESTIMATE, CIBERSORT algorithm, and ssGSEA, showed that the high-risk group had higher immune cell infiltration, lower tumour purity, and worse RFS. Various immune checkpoints were expressed at higher levels in high-risk patients. In summary, this prognostic model is a promising prognostic biomarker for PCa that should improve the prognosis of PCa patients. These data provide new ideas for antitumour immunotherapy and have good potential value for the development of targeted drugs.

Abstract Background To identify the critical genes in the onset and progression of Immunoglobulin A nephropathy (IgAN) and to explore its immune cell infiltration feature. Methods Differentially expressed genes (DEGs) were firstly screened from 1 blood-derived dataset GSE73953 and a glomerulus derived dataset GSE93798 through limma analysis, overlap genes omitting and weighted gene correlation network analysis (WGCNA) and further reduced according to expression pattern and correlation with the clinical features: eGFR and proteinuria, followed by external validation using the GSE37460 dataset and an IgAN cohort. In addition, the CIBERSORT tool for immune cell infiltration analysis, ceRNA network construction and Connectivity Map (CMAP) were also performed. Results A total of 195 DEGs were found, and among them, 3 upregulated (ORMDL2, NRP1, and COL4A1) and 3 downregulated genes (ST13, HSPA8 and PKP4) are verified to correlate clinically, and finally ORMDL2, NRP1 and COL4A1 were validated in patient cohort and with the ability of IgAN discrimination (highest AUC was COL4A1: 97.14%). The immune cell infiltration results revealed that significant differences could be found on resting memory CD4 T cells, activated NK cells, and M2 macrophages between control and IgAN. Conclusions Our results demonstrated here that significantly upregulated DEGs: ORMDL2, NRP1 and COL4A1, could be served as the diagnostic marker for IgAN, and dysregulated immune cell infiltration hinted possible the immune system intervention point in the setting of IgAN.

Abstract. Background:. Intensive phototherapy (IPT) and exchange transfusion (ET) are the main treatments for extreme hyperbilirubinemia. However, there is no reliable evidence on determining the thresholds for these treatments. This multicenter study compared the effectiveness and complications of IPT and ET in the treatment of extreme hyperbilirubinemia. Methods:. This retrospective cohort study was conducted in seven centers from January 2015 to January 2018. Patients with extreme hyperbilirubinemia that met the criteria of ET were included. Patients were divided into three subgroups (low-, medium-, and high- risk) according to gestational week and risk factors. Propensity score matching (PSM) was performed to balance the data before treatment. Study outcomes included the development of bilirubin encephalopathy, duration of hospitalization, expenses, and complications. Mortality, auditory complications, seizures, enamel dysplasia, ocular motility disorders, athetosis, motor, and language development were evaluated during follow-up at age of 3 years. Results:. A total of 1164 patients were included in this study. After PSM, 296 patients in the IPT only group and 296 patients in the IPT plus ET group were further divided into the low-, medium-, and high-risk subgroups with 188, 364, and 40 matched patients, respectively. No significant differences were found between the IPT only and IPT plus ET groups in terms of morbidity, complications, and sequelae. Hospitalization duration and expenses were lower in the low- and medium-risk subgroups in the IPT only group. Conclusions:. In this study, our results suggest that IPT is a safe and effective treatment for extreme hyperbilirubinemia. The indication of ET for patients with hyperbilirubinemia could be stricter. However, it is necessary to have a contingency plan for emergency ET as soon as IPT is commenced especially for infants with risk factors. If IPT can be guaranteed and proved to be therapeutic, ET should be avoided as much as possible.

With the development and progress of medical technology, the survival rate of premature and low-birth-weight infants has increased, as has the incidence of a variety of neonatal diseases, such as hypoxic–ischemic encephalopathy, intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, and retinopathy of prematurity. These diseases cause severe health conditions with poor prognoses, and existing control methods are ineffective for such diseases. Stem cells are a special type of cells with self-renewal and differentiation potential, and their mechanisms mainly include anti-inflammatory and anti-apoptotic properties, reducing oxidative stress, and boosting regeneration. Their paracrine effects can affect the microenvironment in which they survive, thereby affecting the biological characteristics of other cells. Due to their unique abilities, stem cells have been used in treating various diseases. Therefore, stem cell therapy may open up the possibility of treating such neonatal diseases. This review summarizes the research progress on stem cells and exosomes derived from stem cells in neonatal refractory diseases to provide new insights for most researchers and clinicians regarding future treatments. In addition, the current challenges and perspectives in stem cell therapy are discussed.

The threat of bacterial septicemia caused by Aeromonas hydrophila infection to aquaculture growth can be prevented through vaccination, but differences among A. hydrophila strains may affect the effectiveness of non-conserved subunit vaccines or non-inactivated A. hydrophila vaccines, making the identification and development of conserved antigens crucial. In this study, a bioinformatics analysis of 4268 protein sequences encoded by the A. hydrophila J-1 strain whole genome was performed based on reverse vaccinology. The specific analysis included signal peptide prediction, transmembrane helical structure prediction, subcellular localization prediction, and antigenicity and adhesion evaluation, as well as interspecific and intraspecific homology comparison, thereby screening the 39 conserved proteins as candidate antigens for A. hydrophila vaccine. The 9 isolated A. hydrophila strains from diseased fish were categorized into 6 different molecular subtypes via enterobacterial repetitive intergenic consensus (ERIC)-PCR technology, and the coding regions of 39 identified candidate proteins were amplified via PCR and sequenced to verify their conservation in different subtypes of A. hydrophila and other Aeromonas species. In this way, conserved proteins were screened out according to the comparison results. Briefly, 16 proteins were highly conserved in different A. hydrophila subtypes, of which 2 proteins were highly conserved in Aeromonas species, which could be selected as candidate antigens for vaccines development, including type IV pilus secretin PilQ (AJE35401.1) and TolC family outer membrane protein (AJE35877.1). The present study screened the conserved antigens of A. hydrophila by using reverse vaccinology, which provided basic foundations for developing broad-spectrum protective vaccines of A. hydrophila.

Abstract Background A novel and improved methodology is still required for the diagnosis of diabetic kidney disease (DKD). The aim of the present study was to identify novel biomarkers using extracellular vesicle (EV)-derived mRNA based on kidney tissue microarray data. Methods Candidate genes were identified by intersecting the differentially expressed genes (DEGs) and eGFR-correlated genes using the GEO datasets GSE30528 and GSE96804, followed by clinical parameter correlation and diagnostic efficacy assessment. Results Fifteen intersecting genes, including 8 positively correlated genes, B3GALT2, CDH10, MIR3916, NELL1, OCLM, PRKAR2B, TREM1 and USP46, and 7 negatively correlated genes, AEBP1, CDH6, HSD17B2, LUM, MS4A4A, PTN and RASSF9, were confirmed. The expression level assessment results revealed significantly increased levels of AEBP1 in DKD-derived EVs compared to those in T2DM and control EVs. Correlation analysis revealed that AEBP1 levels were positively correlated with Cr, 24-h urine protein and serum CYC and negatively correlated with eGFR and LDL, and good diagnostic efficacy for DKD was also found using AEBP1 levels to differentiate DKD patients from T2DM patients or controls. Conclusions Our results confirmed that the AEBP1 level from plasma EVs could differentiate DKD patients from T2DM patients and control subjects and was a good indication of the function of multiple critical clinical parameters. The AEBP1 level of EVs may serve as a novel and efficacious biomarker for DKD diagnosis.

Abstract The CDK4/6‐Rb axis is a crucial target of cancer therapy and several selective inhibitors of it have been approved for clinical application. However, current therapeutic efficacy evaluation mostly relies on anatomical imaging, which cannot directly reflect changes in drug targets, leading to a delay in the selection of optimal treatment. In this study, we constructed a novel fluorescent probe, CPP30‐Lipo/CDKACT4, for real‐time monitoring of CDK4 activity and the therapeutic efficacy of its inhibitor in HR+/HER2– breast cancer. CPP30‐Lipo/CDKACT4 exhibited good optical stability and targetability. The signal of the probe in living cells decreased after CDK4 knockdown or palbociclib treatment. Moreover, the fluorescence intensity of the tumors after 7 days of palbociclib treatment was significantly lower than that before treatment, while no significant change in tumor diameter was observed under magnetic resonance imaging. Overall, we developed an innovative fluorescent probe that can monitor CDK4 activity and the early therapeutic response to CDK4 inhibitors in living cells and in vivo. It may provide a new strategy for evaluating antitumor therapeutic efficacy in a clinical context and for drug development.

Abstract To identify a gemcitabine resistance-associated gene signature for risk stratification and prognosis prediction in pancreatic cancer. Pearson correlation analysis was performed with gemcitabine half maximal inhibitory concentration (IC50) data of 17 primary pancreatic cancer lines from Genomics of Drug Sensitivity in Cancer (GDSC) and the transcriptomic data from GDSC and Broad Institute Cancer Cell Line Encyclopedia, followed by risk stratification, expression evaluation, overall survival (OS) prediction, clinical data validation and nomogram establishment. Our biomarker discovery effort identified a 14-gene signature, most of which featured differential expression. The 14-gene signature was associated with poor OS in E-MTAB-6134 (HR 2.37; 95% CI 1.75–3.2; p

Abstract. Background:. Previously, we developed a novel Coronary Artery Tree description and Lesion EvaluaTion (CatLet©) angiographic scoring system, which was capable of accounting for the variability in the coronary anatomy and assisting in the risk-stratification of patients with acute myocardial infarction (AMI). Our preliminary study revealed that the CatLet score better predicted clinical outcomes for AMI patients than the Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery score. However, the reproducibility of the CatLet score in both inter- and intra-observer remains to be evaluated. Methods:. A total of 30 consecutive AMI patients, admitted in September of 2015, were independently assessed by two experienced interventional cardiologists to evaluate the inter-observer reproducibility of the CatLet score. Another set of 49 consecutive AMI patients, admitted between September and October in 2014, were assessed by one of the two interventional cardiologists on two occasions 3 months apart to evaluate the intra-observer reproducibility of the CatLet score. The weighted kappa was used to express the degree of agreement. Results:. The weighted kappa values (95% confidence interval) for the intra- and inter-observer reproducibility of the CatLet Score were 0.82 (0.59–1.00, Z = 7.23, P 22). Regarding the adverse characteristics pertinent to lesions and dominance parameters, the kappa values for the inter-observer variability were 0.80 (0.56–1.00, Z = 6.47, P

Objective: The study aimed to discuss the treatment of acute thromboembolic event (TE) during endovascular embolization of intracranial aneurysms. Methods: Between April 2013 and April 2019, 158 patients with 167 intracranial aneurysms were treated with endovascular embolization in our hospital, in which 9 cases of acute TEs occurred during the embolization procedures. The clinical data, radiological findings and treatments of the 9 patients were reviewed and analyzed. Results: The TEs occurred at the aneurysmal neck in 3 patients, at distal part of the parent artery in 3, in the stent in 2, and at the proximal part of the parent artery in 1. Intra-arterial (IA) infusion of tirofiban were performed in 6 patients, mechanical thromboectomy (MT) with a stent in 2 patients, and combined use of the two methods in 1 patients. According to the modified Thrombolysis In Cerebral Infarction (mTICI) score, 7 patients had recanalization of 2b/3a, 1 patients had recanalization of 1, and 1 patients had recanalization of 0. At discharge, the mRS score was 0 in 3 patients, 1 in 3 patients, and 2, 3, 4 in 1 patient each. 6 months after the endovascular treatment, the mRS score was 0 in 5 patients, 1 in 2 patients, and 3 in 1 patient. Conclusions: IA tirofiban and MT are effective remedies for the acute TE during endovascular embolization of intracranial aneurysm, reasonable selection of which may improve the prognosis of patients.

The current COVID-19 epidemic situation is grim, and the government has realized the importance of biosafety. This paper summarizes the situation and experience of biosafety management and education in pathogenic biology teaching laboratory from the aspects of management system, hardware construction and software construction. And through the questionnaire survey of the eight-year clinical students in Shanghai Jiao Tong University School of Medicine, we have a preliminary understanding of the students' views on the way of learning biosafety knowledge and the situation of mastering biosafety knowledge. It is expected that through the consideration of biosafety education, the curriculum design of biosafety education of pathogenic biology will be discussed to improve the knowledge level of biosafety of medical students.

Altered cell-derived microparticles (MPs) have been reported in multiple autoimmune diseases. However, the roles of megakaryocyte- and platelet-derived MPs (MKMPs and PMPs) in immune thrombocytopenia (ITP) have not been investigated. In this study, we examined plasma MKMP and PMP levels in patients with ITP and evaluated their potential diagnostic values. Plasma MKMP and PMP levels were analyzed by flow cytometry in a discovery set of ITP patients (n = 78), non-immune thrombocytopenia (TP) patients (n = 69), and age- and gender-matched healthy controls (n = 88). Samples from a therapy set of ITP patients (n = 21) were used to assess the response to thrombopoietin receptor agonist (TPO-RA) treatment. Spearman correlation analysis was performed between MP levels and disease parameters. Receiver operator characteristic (ROC) curves were generated to evaluate the diagnostic values of the MPs. We found that plasma MKMP and PMP levels were significantly lower in ITP patients than those in healthy controls (p values < 0.0001) but higher than in those in TP patients (p < 0.002 and p < 0.0002, respectively). After normalization to platelet counts, PMP/Platelet ratios in ITP patients were higher than those in TP patients and healthy controls (p values < 0.001). PMP/Platelet ratios had a diagnostic value for ITP (area under the curve = 0.808, p < 0.0001) with 73.1% sensitivity and 77.3% specificity. MKMP levels can be used to discriminate ITP from TP with a cut-off value of 112.5 MPs/μL and a sensitivity of 74.4%. Moreover, both MKMP and PMP levels were elevated in ITP patients who responded to TPO-RA treatment. Plasma PMP levels positively correlated with platelet counts in the responders (r = 0.558, p < 0.01). Our results indicate that plasma MKMP and PMP levels are decreased in ITP patients and that plasma MKMP and PMP levels may serve as biomarkers for ITP diagnosis and prediction of TPO-RA treatment response.

Introduction The full-endoscopic spinal surgery (FESS) procedure is widely accepted and welcomed in China. With the continuous development of minimally invasive surgery, the further expansion of indications and the greater diversity of techniques, spinal endoscopic surgery currently accounts for more than 10% of spinal surgery in China, ranking among the top in the world. However, the admission system and standardised training system for spinal endoscopic surgery are not perfect, which presents a challenge and disadvantage for novices.Methods and analysis Exploratory mixed methods are applied for designing this study. First, we will collect questions from novices by allowing them to openly list their concerns to those who have completed FESS. These qualitative questions will be categorised using NVivo software. To produce the qualitative results, a questionnaire for the sequential two-round Delphi approach will be developed to identify the 20 most important questions from novices. This study is planned to be started at April 2021, and completed at March 2022.Ethics and dissemination The Research Ethics Committee of Peking University Third Hospital provided a waiver for this Delphi protocol. We expect that the findings will be published in a clinical journal and presented at conferences. Furthermore, we hope that the results can contribute to answering the questions raised by novices of spinal endoscopy in the form of books and to improving the training system for spinal endoscopy surgery.

Background: Recently, we discovered a new glucogenic and centrally acting orexigenic hormone – asprosin. Asprosin is elevated in metabolic syndrome (MS) patients, and its genetic loss results in reduced appetite, leanness, and blood glucose burden, leading to protection from MS. Methods: We generated three independent monoclonal antibodies (mAbs) that recognize unique asprosin epitopes and investigated their preclinical efficacy and tolerability in the treatment of MS. Results: Anti-asprosin mAbs from three distinct species lowered appetite and body weight, and reduced blood glucose in a dose-dependent and epitope-agnostic fashion in three independent MS mouse models, with an IC50 of ~1.5 mg/kg. The mAbs displayed a half-life of over 3days in vivo, with equilibrium dissociation-constants in picomolar to low nanomolar range. Conclusions: We demonstrate that anti-asprosin mAbs are dual-effect pharmacologic therapy that targets two key pillars of MS – over-nutrition and hyperglycemia. This evidence paves the way for further development towards an investigational new drug application and subsequent human trials for treatment of MS, a defining physical ailment of our time. Funding: DK118290 and DK125403 (R01; National Institute of Diabetes and Digestive and Kidney Diseases), DK102529 (K08; National Institute of Diabetes and Digestive and Kidney Diseases), Caroline Wiess Law Scholarship (Baylor College of Medicine, Harrington Investigatorship Harrington Discovery Institute at University Hospitals, Cleveland); Chao Physician Scientist Award (Baylor College of Medicine); RP150551 and RP190561 (Cancer Prevention and Research Institute of Texas [CPRIT]).

Background: Parathyroid hormone related protein (PTHrP) triggers white adipose tissue (WAT) browning and cachexia in lung cancer mouse models. It remains unknown whether excessive PTH secretion affects WAT browning and to what extent it contributes to body weight change in primary hyperparathyroidism (PHPT). Methods: Using the adeno-associated virus injection, Pth gene over-expressed mice mimicking PHPT were firstly established to observe their WAT browning and body weight alteration. The association between PTH and body weight was investigated in 496 PHPT patients. The adipose browning activities of 20 PHPT and 60 control subjects were measured with PET/CT scanning. Findings: Elevated plasma PTH triggered adipose tissue browning, leading to increased energy expenditure, reduced fat content, and finally decreased body weight in PHPT mice. Higher circulating PTH levels were associated with lower body weight (β = −0.048, P = .0003) independent of renal function, serum calcium, phosphorus,and albumin levels in PHPT patients. PHPT patients exhibited both higher prevalence of detectable brown/beige adipose tissue (20% vs 3.3%, P = .03) and increased browning activities (SUV in cervical adipose was 0.77 vs 0.49,P = .02) compared with control subjects. Interpretation: Elevated serum PTH drove WAT browning program, which contributed in part to body weight loss in both PHPT mice and patients. These results give insights into the novel pathological effect of PTH and are of importance in understanding the metabolic changes of PHPT. Fund: This research is supported by the National Key Research and Development Program of China and National Natural Science Foundation of China. Keywords: Primary hyperparathyroidism, Parathyroid hormone, Adipose tissue browning, Body weight

BackgroundOvarian cancer (OC) is a leading cause of death in gynecological malignancies worldwide. Multitudinous studies have suggested the potential of circulating tumor DNA (ctDNA), circulating microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) as novel diagnostic molecular biomarkers for OC. Here, we include three updated meta-analysis methods using different molecular biomarkers to evaluate their discriminative value in OC diagnosis.MethodsWe conducted three meta-analyses after searching different databases, and 23 eligible articles, including 8 concerning ctDNA, 11 concerning miRNAs, and 4 concerning lncRNAs, were found. Further, we pooled data concerning the sensitivity, specificity, and other indicators of accuracy for ctDNA/miRNAs/lncRNAs in the diagnosis of OC. The heterogeneity was further explored by meta-regressions and subgroup analyses, and Deeks' funnel plots were used to measure the publication bias of these three meta-analyses.ResultsIn all, this meta-analysis included 1732 OC patients and 3958 controls. The sensitivity of ctDNA for OC diagnosis was superior to that of lncRNA and miRNA (84% vs. 81% vs. 78%). Moreover, the specificity and area under the receiver-operating characteristic (ROC) curve (AUC) of ctDNA were 91% and 94%, which were significantly higher than those of miRNA and lncRNAs (78% and 85%; 78% and 86%, respectively). No significant difference was observed among the two meta-analyses of ctDNA and lncRNA (P > 0.05) with regard to publication bias, while the meta-analysis of miRNA observed a significantly small publication bias (P < 0.05).ConclusionctDNA/miRNAs/lncRNAs may be promising molecular biomarkers for OC diagnosis. Further large-scale studies are needed to verify the potential applicability of ctDNA/miRNAs/lncRNAs molecular signatures alone or in combination as diagnostic molecular biomarkers for OC.

The pressure upon local governments to redeem their debt could affect government fiscal ability. It could consequently affect their fiscal policies on corporations, which might distort corporate innovation. Based on the data of Chinese Shanghai and Shenzhen A-share listed companies and the local government implicit short-term debt financed by local government financing vehicles (LGFVs) in 31 provinces, this paper shows that local government debt (LGD) negatively affects corporate R&D investment in China, thereby suggesting a strong crowding-out effect. The crowding-out effect is more pronounced when the firm is a non-state-owned enterprise (NSOE), the firm’s size is small, the firm’s age is young, or the firm is in the lower market competition. This paper provide evidence by interacting the terms that local government actions, such as consumption of fiscal resources, strengthening tax collection efforts, or consumption of credit resources, might partially account for the crowding-out effect. This study illustrates the innovation costs of local government debt.

Objective Hyperbilirubinemia is one of the most common clinical symptoms in newborns. To improve patient outcomes, evidence-based and implementable guidelines are required. However, clinical guidelines may vary in quality, criteria and recommendations among regions and countries. In this study, we aimed to systematically assess the quality of guidelines using the Appraisal of Guidelines for Research & Evaluation (AGREE)-II instrument and summarise the specific recommendations for neonatal hyperbilirubinemia in order to provide suggestions for future guideline development.Design Systematic review.Interventions We searched the PubMed, Embase, Medline and guideline databases for relevant articles on 10 April 2020. The studies were screened by two independent reviewers according to our inclusion criteria. Two reviewers independently extracted the descriptive data. Four appraisers assessed the guidelines using the AGREE-II instrument.Results Our systematic review appraised 12 clinical practice guidelines for the diagnosis and management of neonatal hyperbilirubinemia. The 12 guidelines achieved an average score of 36%–89%. The guidelines received the highest scores for clarity of presentation and lowest scores for rigour of development. Most recommendations for diagnosis were relatively consistent, but recommendations regarding risk factors, the initiating threshold of treatment and pharmacotherapy varied.Conclusions Our study revealed that current guidelines vary in the quality of the developing process and are inconsistent with regards to recommendations. Future guidelines should afford more attention to the quality of methodologies in guideline development, and more qualified evidence is needed to standardise the initiating threshold of treatment for neonatal hyperbilirubinemia.

Hepatitis B is a leading cause of death worldwide. Here, we performed a large, population-based, cross-sectional study in Chongqing, China from 2011 to 2016 to assess the prevalence of HBsAg among couples of reproductive age, to predict subsequent trends, and to provide evidence for the WHO goal of "the elimination of viral hepatitis as a public health threat by 2030". A total of 386,286 couples aged 20 to 49 years were enrolled in the study. Approximately 14.35% of couples were HBsAg positive, including 95.00% with discordant HBsAg positivity. HBsAg prevalence was higher in men than in women. Among different occupations, the two categories of “houseworker” (female 6.73%, male 9.99%) and “unemployed” (female 6.64%, male 9.94%) showed the highest HBsAg positivity. In different regions, the lowest prevalence appeared in southeastern Chongqing (female 4.87%, male 7.71%). In 2030, the HBsAg positivity rate is expected to be 2.79%, 7.27% and 5.13% in females, males, and the whole population, respectively. According to the trends, this rate would drop to less than 2% in 2034, 2078 and 2051. In conclusion, the HBsAg prevalence in Chongqing is still relatively high compared with that in other parts of western China, especially among reproductive-age men. HBsAg-positive couples should be taken as an important unit of care. Vaccination is necessary before pregnancy if no antibody is found. More attention should be given to people without stable jobs. HBsAg-positive rate will decrease perceptibly by 2030 and will reach the level of low in epidemic areas by 2050.

Methyl-CpG-binding protein 2 (MeCP2) encoded by the MECP2 gene is a transcriptional regulator whose mutations cause Rett syndrome (RTT). Mecp2-deficient mice show fear regulation impairment; however, the cellular and molecular mechanisms underlying this abnormal behavior are largely uncharacterized. Here, we showed that Mecp2 gene deficiency in cholinergic interneurons of the nucleus accumbens (NAc) dramatically impaired fear learning. We further found that spontaneous activity of cholinergic interneurons in Mecp2-deficient mice decreased, mediated by enhanced inhibitory transmission via α2-containing GABAA receptors. With MeCP2 restoration, opto- and chemo-genetic activation, and RNA interference in ChAT-expressing interneurons of the NAc, impaired fear retrieval was rescued. Taken together, these results reveal a previously unknown role of MeCP2 in NAc cholinergic interneurons in fear regulation, suggesting that modulation of neurons in the NAc may ameliorate fear-related disorders.

BackgroundExtreme pre-pregnancy body mass index (BMI) values have been associated with reduced fecundability and prolonged time to pregnancy in previous studies. However, the effect in fertile couples is unclear.ObjectivesThis study aimed to evaluate the association between pre-pregnancy BMI and fecundability, measured as time to pregnancy (TTP), among couples that achieved pregnancy within 1 year.MethodsThis was a retrospective cohort study of 50,927 couples wishing to conceive, enrolled in the National Free Preconception Health Examination Project (NFPHEP) in Chongqing, China, during 2012-2016. Participants' weight and height were measured by NFPHEP-trained preconception guidance physicians. TTP measured in months was used to determine subfecundity (TTP >6 months). The strength of association between BMI and TTP/subfecundity was measured with fecundability odds ratios (FOR)/odds ratios (OR) and their corresponding 95% confidence intervals (CI), calculated with Cox and logistic regression analysis. We used restricted cubic spline regression (RCS) to test the observed FOR trends.ResultsCompared to women with normal BMI, women with pre-pregnancy overweight/obesity had longer TTP (FOR = 0.96, 95% CI: 0.94-0.99) and increased risk of subfecundity (OR = 1.08, 95% CI: 1.00-1.17). There was no association between TTP and male BMI. RCS trends varied when data were stratified by male pre-pregnancy BMI, with the greatest change detected in pre-pregnancy underweight men.ConclusionsPre-pregnancy overweight/obesity was associated with longer TTP and subfecundity among women who became pregnant within 1 year; this effect was likely mediated by their partners' pre-pregnancy BMI. These findings indicate that BMI could affect fecundability, independently of affecting the risk of sterility. Advice on weight management and maintaining healthy weight should be included in couples' preconception guidance.

Growing evidence showed that alternative splicing (AS) event is significantly related to tumor occurrence and progress. This study was performed to make a systematic analysis of AS events and constructed a robust prediction model of hepatocellular carcinoma (HCC). The clinical information and the genes expression profile data of 335 HCC patients were collected from The Cancer Genome Atlas (TCGA). Information of seven types AS events were collected from the TCGA SpliceSeq database. Overall survival (OS) related AS events and splicing factors (SFs) were identified using univariate Cox regression analysis. The corresponding genes of OS-related AS events were sent for gene network analysis and functional enrichment analysis. Optimal OS-related AS events were selected by LASSO regression to construct prediction model using multivariate Cox regression analysis. Prognostic value of the prediction models were assessed by receiver operating characteristic (ROC) curve and KaplanMeir survival analysis. The relationship between the Percent Spliced In (PSI) value of OS-related AS events and SFs expression were analyzed using Spearman correlation analysis. And the regulation network was generated by Cytoscape. A total of 34,163 AS events were identified, which consist of 3,482 OS-related AS events. UBB, UBE2D3, SF3A1 were the hub genes in the gene network of the top 800 OS-related AS events. The area under the curve (AUC) of the final prediction model based on seven types OS-related AS events was 0.878, 0.843, 0.821 in 1, 3, 5 years, respectively. Upon multivariate analysis, risk score (All) served as the risk factor to independently predict OS for HCC patients. SFs HNRNPH3 and HNRNPL were overexpressed in tumor samples and were signifcantly associated with the OS of HCC patients. The regulation network showed prominent correlation between the expression of SFs and OS-related AS events in HCC patients. The final prediction model performs well in predicting the prognosis of HCC patients. And the findings in this study improve our understanding of the association between AS events and HCC.

Objective This study aimed to identify several potentially key genes associated with the pathogenesis of Takayasu’s arteritis (TA). This identification may lead to a deeper mechanistic understanding of TA etiology and pave the way for potential therapeutic approaches. Materials and Methods In this experimental study, the microarray dataset GSE33910, which includes expression data for peripheral blood mononuclear cell (PBMC) samples isolated from TA patients and normal volunteers, was downloaded from the publicly accessible Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified in PBMCs of TA patients compared with normal controls. Gene ontology (GO) enrichment analysis of DEGs and analysis of protein-protein interaction (PPI) network were carried out. Several hub proteins were extracted from the PPI network based on node degrees and random walk algorithm. Additionally, transcription factors (TFs) were predicted and the corresponding regulatory network was constructed. Results A total of 932 DEGs (372 up- and 560 down-regulated genes) were identified in PBMCs from TA patients. Interestingly, up-regulated and down-regulated genes were involved in different GO terms and pathways. A PPI network of proteins encoded by DEGs was constructed and RHOA, FOS, EGR1, and GNB1 were considered to be hub proteins with both higher random walk score and node degree. A total of 13 TFs were predicted to be differentially expressed. A total of 49 DEGs had been reported to be associated with TA in the Comparative Toxicogenomics Database (CTD). The only TA marker gene in the CTD database was NOS2, confirmed by three studies. However, NOS2 was not significantly altered in the analyzed microarray dataset. Nevertheless,NOS3 was a significantly down-regulated gene and was involved in the platelet activation pathway. Conclusion RHOA, FOS, and EGR1 are potential candidate genes for the diagnosis and therapy of TA.

Abstract Background Platelet autoantibody detection is critical for immune thrombocytopenia (ITP) diagnosis and prognosis. Therefore, we aimed to establish a quantitative flow cytometric immunobead assay (FCIA) for ITP platelet autoantibodies evaluation. Methods Capture microbeads coupled with anti-GPIX, -GPIb, -GPIIb, -GPIIIa and P-selectin antibodies were used to bind the platelet-bound autoantibodies complex generated from plasma samples of 250 ITP patients, 163 non-ITP patients and 243 healthy controls, a fluorescein isothiocyanate (FITC)-conjugated secondary antibody was the detector reagent and mean fluorescence intensity (MFI) signals were recorded by flow cytometry. Intra- and inter-assay variations of the quantitative FCIA assay were assessed. Comparisons of the specificity, sensitivity and accuracy between quantitative and qualitative FCIA or monoclonal antibody immobilization of platelet antigen (MAIPA) assay were performed. Finally, treatment process was monitored by our quantitative FCIA in 8 newly diagnosed ITPs. Results The coefficient of variations (CV) of the quantitative FCIA assay were respectively 9.4, 3.8, 5.4, 5.1 and 5.8% for anti-GPIX, -GPIb, -GPIIIa, -GPIIb and -P-selectin autoantibodies. Elevated levels of autoantibodies against platelet glycoproteins GPIX, GPIb, GPIIIa, GPIIb and P-selectin were detected by our quantitative FCIA in ITP patients compared to non-ITP patients or healthy controls. The sensitivity, specificity and accuracy of our quantitative assay were respectively 73.13, 81.98 and 78.65% when combining all 5 autoantibodies, while the sensitivity, specificity and accuracy of MAIPA assay were respectively 41.46, 90.41 and 72.81%. Conclusions A quantitative FCIA assay was established. Reduced levels of platelet autoantibodies could be confirmed by our quantitative FCIA in ITP patients after corticosteroid treatment. Our quantitative assay is not only good for ITP diagnosis but also for ITP treatment monitoring.

Abstract Twelve Holstein bulls were used in a 4 × 4 Latin square design to investigate the effects of using whole-crop wheat hay (WCWH) as a substitute for Leymus chinensis (LC) on apparent digestibility, plasma parameters, ruminal fermentation, and microbial communities. Experimental treatments were four proportions of WCWH, 0, 33, 67, and 100%, as a substitute for LC (WCWH0, WCWH33, WCWH67, and WCWH100, respectively). The WCWH100 group showed a higher nutritional intake of crude protein (CP) and higher apparent digestibility of organic matter (OM), CP, and ether extract (EE) than the WCWH0 group (P

Background: As a traditional Chinese medicine, Cordyceps sinensis (CS) possesses a variety of immunoregulatory properties. This study aimed to explore the therapeutic potential of CS in a mice model of multiple sclerosis (MS)-experimental autoimmune encephalomyelitis (EAE). Methods: Female C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein35–55to induce EAE, followed by an instant intragastric feeding with a low dosage of CS (low-CS group, n = 5), high dosage of CS (high-CS group, n = 5), or the same volume of normal saline (control group, n = 5). All the mice were observed for clinical assessment. Over the 30 days of CS treatment, flow cytometry was used to detect the frequency of helper T-cell (Th) subsets, Th1 and Th17, and CD4+ CD25+ regulatory T cells in the spleen and lymph nodes. Meanwhile, pathological changes in brain were determined using both hematoxylin-eosin and luxol fast blue staining. Data were analyzed using the one-way analysis of variance (ANOVA). Results: Over the 15 and 30 days of CS treatment, the clinical assessment for EAE demonstrated that both high-CS group (2.51 ± 0.31 and 2.26 ± 0.39 scores, respectively) and low-CS group (2.99 ± 0.40 and 2.69 ± 0.46, respectively) had lower disease severity scores than those of control group (3.57 ± 0.53 and 3.29 ± 0.53, all P < 0.01, respectively). Meanwhile, after 15 and 30 days, the high-CS group (19.18 ± 1.34 g and 20.41 ± 1.56 g, respectively) and low-CS group (18.07 ± 1.18 g and 19.48 ± 1.69 g, respectively) had a lower body weight, as compared with control group (16.85 ± 1.15 g and 18.22 ± 1.63 g, all P < 0.01, respectively). At 30 days post-CS treatment, there was a lower Th1 frequency in the lymph nodes (2.85 ± 1.54% and 2.77 ± 1.07% vs. 5.35 ± 1.34%, respectively; P < 0.05) and spleens (3.96 ± 1.09% and 3.09 ± 0.84% vs. 5.07 ± 1.50%, respectively; P < 0.05) and less inflammatory infiltration and demyelination in the brain of CS-treated mice than that of control group. Conclusions: Our preliminary study demonstrated that CS efficiently alleviated EAE severity and EAE-related pathology damage and decreased the number of Th1s in the periphery, indicating its effectiveness in the treatment of murine EAE. Thus, our findings strongly support the therapeutic potential of this agent as a new traditional Chinese medicine approach in MS treatment.

Background The medicinal plants of Radix et Rhizoma Nardostachyos include Nardostachys jatamansi and N. chinensis. Traditionally, the two plants have been used to treat many diseases. Because of their special aroma, they are also commonly used in the food and cosmetics industry. Recently, N. jatamansi and N. chinensis have been overexploited due to their economic importance, resulting in a sharp decline in their wild resources. Predicting potential distributions of the genus Nardostachys under different climate scenarios and understanding its preferred habitat are of great significance for their conservation, artificial cultivation, and assessment of their value. Methods The Maxent model was used to predict the potential geographical distributions of the genus Nardostachys under current and future climatic conditions based on two representative concentration pathways (RCP2.6 and RCP8.5) for the 2050s and 2070s. These data were used to study the effects of climate variables. Results The results show that the potential distribution of the two species will increase, thus more suitable habitats will be present in China. The suitable habitat for N. chinensis presents a relatively stable growth compared to N. jatamansi. In addition, precipitation plays a crucial role in modeling the effects of climate change on the genus Nardostachys. This study provides theoretical guidance for the cultivation of N. chinensis.

Background: Urine output (UO) is an essential criterion of the Kidney Disease Improving Global Outcomes (KDIGO) definition and classification system for acute kidney injury (AKI), of which the diagnostic value has not been extensively studied. We aimed to determine whether AKI based on KDIGO UO criteria (KDIGOUO) could improve the diagnostic and prognostic accuracy, compared with KDIGO serum creatinine criteria (KDIGOSCr). Methods: We conducted a secondary analysis of the database of a previous study conducted by China Critical Care Clinical Trial Group (CCCCTG), which was a 2-month prospective cohort study (July 1, 2009 to August 31, 2009) involving 3063 patients in 22 tertiary Intensive Care Units in Mainland of China. AKI was diagnosed and classified separately based on KDIGOUOand KDIGOSCr. Hospital mortality of patients with more severe AKI classification based on KDIGOUOwas compared with other patients by univariate and multivariate regression analyses. Results: The prevalence of AKI increased from 52.4% based on KDIGOSCrto 55.4% based on KDIGOSCrcombined with KDIGOUO. KDIGOUOalso resulted in an upgrade of AKI classification in 7.3% of patients, representing those with more severe AKI classification based on KDIGOUO. Compared with non-AKI patients or those with maximum AKI classification by KDIGOSCr, those with maximum AKI classification by KDIGOUOhad a significantly higher hospital mortality of 58.4% (odds ratio [OR]: 7.580, 95% confidence interval [CI]: 4.141–13.873, P< 0.001). In a multivariate logistic regression analysis, AKI based on KDIGOUO (OR: 2.891, 95% CI: 1.964–4.254, P< 0.001), but not based on KDIGOSCr (OR: 1.322, 95% CI: 0.902–1.939, P = 0.152), was an independent risk factor for hospital mortality. Conclusion: UO was a criterion with additional value beyond creatinine criterion for AKI diagnosis and classification, which can help identify a group of patients with high risk of death.

Dysfunction of the noradrenergic (NE) neurons is implicated in the pathogenesis of bipolar disorder (BPD). ErbB4 is highly expressed in NE neurons, and its genetic variation has been linked to BPD; however, how ErbB4 regulates NE neuronal function and contributes to BPD pathogenesis is unclear. Here we find that conditional deletion of ErbB4 in locus coeruleus (LC) NE neurons increases neuronal spontaneous firing through NMDA receptor hyperfunction, and elevates catecholamines in the cerebrospinal fluid (CSF). Furthermore, Erbb4-deficient mice present mania-like behaviors, including hyperactivity, reduced anxiety and depression, and increased sucrose preference. These behaviors are completely rescued by the anti-manic drug lithium or antagonists of catecholaminergic receptors. Our study demonstrates the critical role of ErbB4 signaling in regulating LC-NE neuronal function, reinforcing the view that dysfunction of the NE system may contribute to the pathogenesis of mania-associated disorder.