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A new hybridization of berberine and benzimidazoles was performed to produce 13-(benzimidazolylmethyl)berberines (BMB) as potentially broad-spectrum antibacterial agents with the hope of confronting multidrug-resistant bacterial infections in the livestock industry. Some of the newly prepared hybrids showed obvious antibacterial effects against tested strains. Particularly, 13-((1-octyl-benzimidazolyl)methyl)berberine

Due to the heterogeneity of tumors, we do not understand the given effect of pyroptosis on hepatocellular carcinoma (HCC) fully, particularly its influences on prognosis. The paper aims at exploring the prognostic value of pyroptosis-associated genes and its role in immune status in HCC. A multigene prognostic signature is set up by utilizing the least absolute shrinkage and choosing operator Cox exploration. The comparison of survival between different risk groups is made with the Kaplan–Meier exploration and Cox regression. LASSO Cox regression analysis is adopted to set up a pyroptosis-associated gene signature (CEP55 and MMP1). By comparing with the group at low risks, the high-risk group displayed greatly decreased OS. The fatidic ability of the prognostic gene signature is confirmed by the receiver-running feature curve analysis. According to multivariate Cox exploration, the risk mark is an independent predicting agent for OS. A new signature established with two pyroptosis-associated genes can be adopted for prognostic forecast and influence the immune situation in HCC.

Concomitant mitral regurgitation (MR) is frequently seen in patients undergoing surgical aortic valve replacement (AVR) for severe aortic stenosis (AS). When the severity of MR is moderate or less, the decision to undertake simultaneous mitral valve intervention can be challenging.A systematic search of Medline, PubMed (NCBI), Embase and Cochrane Library was conducted to qualitatively assess the current evidence for concomitant mitral valve intervention for MR in patients with AS undergoing AVR. The primary outcome for this systematic review was the postoperative change in the severity of MR and other outcomes of interest included factors that predict improvement or persistence of MR and long-term impacts of residual MR.A total of 17 studies were included. The percentage of patients demonstrating improvement in MR severity following AVR ranged from 17.2% to 72%; the studies that exclusively included patients with moderate functional MR and reported longer term echocardiographic follow-up of greater than 12 months demonstrated an improvement in MR severity of 45% to 72%.This systematic review demonstrates that a proportion of patients can exhibit an improvement in MR following isolated surgical AVR, but whether this confers any long-term morbidity and mortality benefit remains unclear.

In patients with stable coronary artery disease, low DBP is associated with an increased risk of myocardial infarction and cardiovascular death, but its association with clinical outcomes in patients with acute myocardial infarction undergoing percutaneous coronary intervention (PCI) is unknown.Consecutive patients with ST-segment elevation myocardial infarction (STEMI) undergoing PCI from January 2010 to June 2016 were enrolled. The patients were divided into five groups according to the quintiles of DBP at admission. The primary outcome was in-hospital major adverse cardiovascular events (MACE) including all-cause death, stroke, target vessel revascularization, and recurrent myocardial infarction.A total of 2198 patients were enrolled, of whom 157 (7.1%) developed in-hospital MACE. Patients with DBP lower than 60 mmHg was associated with a higher rate of in-hospital MACE (14.8, 7.8, 5.6, 6.1, and 3.8%, P 0.001) and all-cause death (12.5, 6.4, 4.3, 3.9, and 1.9%, P 0.001) compared with those with DBP 60-69, 70-79, 80-89, and at least 90 mmHg. Multivariate logistic regression analysis demonstrated that DBP higher than 90 mmHg was a significant predictor of lower risk of in-hospital MACE (OR = 0.16, 95% CI = 0.04-0.61, P = 0.007). Cubic spline models for the association between DBP and MACE did not demonstrate a U-type relationship after adjusting for potential risk factors. During the follow-up, lower DBP was associated with a higher risk of all-cause death (P 0.0001).Lower DBP is independently associated with an elevated risk of in-hospital MACE and follow-up all-cause death.

Randall's plaques (RP) are well established as precursor lesions of idiopathic calcium oxalate (CaOx) stones, and the process of biomineralization driven by osteogenic-like cells has been highlighted in RP formation, but the mechanism is poorly understood. Given the inhibitory role of α-Klotho (KL), an aging suppressor protein with high expression in kidneys, in ectopic calcification and the close association between KL gene polymorphisms and urolithiasis susceptibility, we determined the potential role of KL in RP formation. This study found that both soluble KL (s-KL) and transmembrane KL (m-KL) were downregulated, and that s-KL but not m-KL was inversely correlated with upregulation of osteogenic markers in RP tissues. Additionally, s-KL expression was markedly suppressed in human renal interstitial fibroblasts (hRIFs) and slightly suppressed in HK-2 cells after osteogenic induction, intriguingly, which was echoed to the greater osteogenic capability of hRIFs than HK-2 cells. Further investigations showed the inhibitory effect of s-KL on hRIF osteogenic differentiation in vitro and in vivo. Moreover, coculture with recombinant human KL (r-KL) or HK-2 cells suppressed osteogenic differentiation of hRIFs, and this effect was abolished by coculture with KL-silenced HK-2 cells or the β-catenin agonist SKL2001. Mechanistically, s-KL inactivated the Wnt-β-catenin pathway by directly binding to Wnt2 and upregulating SFRP1. Further investigations identified activation of the Wnt-β-catenin pathway and downregulation of SFRP1 and DKK1 in RP tissues. In summary, this study identified s-KL deficiency as a pathological feature of RP and revealed that s-KL released from HK-2 cells inhibited osteogenic differentiation of hRIFs by inactivating the Wnt-β-catenin pathway, not only providing in-depth insight into the role of s-KL in renal interstitial biomineralization but also shedding new light on the interaction of renal tubular epithelial cells with interstitial cells to clarify RP formation.

Calcyphosine (CAPS) was initially identified from the canine thyroid. It also exists in many types of tumor, but its expression and function in glioma remain unknown. Here we explored the clinical significance and the functional mechanisms of CAPS in glioma. We found that CAPS was highly expressed in glioma and high expression of CAPS was correlated with poor survival, in glioma patients and public databases. Cox regression analysis showed that CAPS was an independent prognostic factor for glioma patients. Knockdown of CAPS suppressed the proliferation, whereas overexpression of CAPS promoted the proliferation of glioma both in vitro and in vivo. CAPS regulated the G2/M phase transition of the cell cycle, but had no obvious effect on apoptosis. CAPS affected PLK1 phosphorylation through interaction with MYPT1. CAPS knockdown decreased p-MYPT1 at S507 and p-PLK1 at S210. Expression of MYPT1 S507 phosphomimic rescued PLK1 phosphorylation and the phenotype caused by CAPS knockdown. The PLK1 inhibitor volasertib enhanced the therapeutic effect of temozolomide in glioma. Our data suggest that CAPS promotes the proliferation of glioma by regulating the cell cycle and the PLK1 inhibitor volasertib might be a chemosensitizer of glioma. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Background Dihydropyrimidinase like 2 (DPYSL2) has been linked to tumor metastasis. However, the function of DPSY2L in lung adenocarcinoma (LUAD) is yet to be explored. Methods Herein, we assessed DPYSL2 expression in various tumor types via online databases such as Oncomine and Tumor Immune Estimation Resource (TIMER). Further, we verified the low protein and mRNA expressions of DPYSL2 in LUAD via the ULCAN, The TCGA and GEPIA databases. We applied the ROC curve to examine the role of DPYSL2 in diagnosis. The prognostic significance of DPYSL2 was established through the Kaplan–Meier plotter and the Cox analyses (univariate and multivariate). TIMER was used to explore DPYSL2 expression and its connection to immune infiltrated cells. Through Gene Set Enrichment Analysis, the possible mechanism of DPYSL2 in LUAD was investigated. Results In this study, database analysis revealed lower DPYSL2 expression in LUAD than in normal tissues. The ROC curve suggested that expression of DPYSL2 had high diagnostic efficiency in LUAD. The DPYSL2 expression had an association with the survival time of LUAD patients in the Kaplan–Meier plotter and the Cox analyses. The results from TIMER depicted a markedly positive correlation of DPYSL2 expression with immune cells infiltrated in LUAD, such as macrophages, dendritic cells, CD4+ T cells, and neutrophils. Additionally, many gene markers for the immune system had similar positive correlations in the TIMER analysis. In Gene Set Enrichment Analysis, six immune-related signaling pathways were associated with DPYSL2. Conclusions In summary, DPYSL2 is a novel biomarker with diagnostic and prognostic potential for LUAD as well as an immunotherapy target. Highlights Expression of DPYSL2 was considerably lower in LUAD than in normal tissues. Investigation of multiple databases showed a high diagnostic value of DPYSL2 in LUAD. DPYSL2 can independently predict the LUAD outcomes. Immune-related mechanisms may be potential ways for DPYSL2 to play a role in LUAD.

Background Antibiotic-impregnated calcium sulfate has excellent curative efficacy in chronic osteomyelitis. However, its curative efficacy in pediatric hematogenous osteomyelitis has not been sufficiently studied. The purpose of this study was to evaluate the curative effects of antibiotic-impregnated calcium sulfate in the treatment of pediatric hematogenous osteomyelitis. Methods Overall, twenty-one pediatric patients with hematogenous osteomyelitis treated at our hospital between 2013 and 2018 were included for assessment. The clinical history, clinical manifestation, infection recurrence rate, sinus leakage, incision leakage, pathological fractures, bone growth and surgical procedures were analyzed. Results The infection recurrence rate was 0% (0/21) at a minimum of 31 months (range 31 to 91 months) of follow-up. Postoperative incision leakage was found in one pediatric patient. Osteolysis was found in one pediatric patient. Acceleration of bone growth occurred in one pediatric patient. Retardation of bone growth occurred in one pediatric patient. Genu valgus deformity occurred in one pediatric patient. Conclusions Although noninfectious complications occurred, the curative effect of antibiotic-impregnated calcium sulfate in pediatric hematogenous osteomyelitis was satisfactory.

Background Previous articles have focused on the diagnosis and treatment of acute hematogenous osteomyelitis. Here, we present a case of chronic hematogenous osteomyelitis in a 2-month-old girl. The diagnostic procedure was unusual and difficult due to negative culture results. Case presentation A girl aged 2 months and 23 days had fever and swelling in her right lower leg for 7 days. On the basis of her medical history, physical, and histological examination results; and radiologic and magnetic resonance imaging findings, a diagnosis of chronic osteomyelitis was made. The patient underwent surgical treatment and was discharged successfully. The patient showed good recovery and no sequelae at the 12-month follow-up. Conclusion Hematogenous osteomyelitis in babyhood is different from that at any other age. Hematogenous osteomyelitis-related bone destruction in babyhood is more serious and occurs faster. The transition from acute hematogenous osteomyelitis to chronic hematogenous osteomyelitis takes only 7 days. To the best of our knowledge, this chronic hematogenous osteomyelitis patient is the youngest ever reported.

Severe COVID-19 disease caused by SARS-CoV-2 is frequently accompanied by dysfunction of the lungs and extrapulmonary organs. However, the organotropism of SARS-CoV-2 and the port of virus entry for systemic dissemination remain largely unknown. We profiled 26 COVID-19 autopsy cases from four cohorts in Wuhan, China, and determined the systemic distribution of SARS-CoV-2. SARS-CoV-2 was detected in the lungs and multiple extrapulmonary organs of critically ill COVID-19 patients up to 67 days after symptom onset. Based on organotropism and pathological features of the patients, COVID-19 was divided into viral intrapulmonary and systemic subtypes. In patients with systemic viral distribution, SARS-CoV-2 was detected in monocytes, macrophages, and vascular endothelia at blood–air barrier, blood–testis barrier, and filtration barrier. Critically ill patients with long disease duration showed decreased pulmonary cell proliferation, reduced viral RNA, and marked fibrosis in the lungs. Permanent SARS-CoV-2 presence and tissue injuries in the lungs and extrapulmonary organs suggest direct viral invasion as a mechanism of pathogenicity in critically ill patients. SARS-CoV-2 may hijack monocytes, macrophages, and vascular endothelia at physiological barriers as the ports of entry for systemic dissemination. Our study thus delineates systemic pathological features of SARS-CoV-2 infection, which sheds light on the development of novel COVID-19 treatment.

Allergic diseases are caused by dysregulated Th2 immune responses involving multiple effector cells including basophils. Short chain fatty acids (SCFAs), mainly acetate, propionate and butyrate, exert immunomodulatory functions via activation of its receptors GPR41 and GPR43, and inhibition of the histone deacetylases (HDACs) activity. In allergic diseases, SCFAs suppress the activity of mast cells, eosinophils and type 2 innate lymphoid cells (ILC2) but enhance the function of Th2 cells. Here, we aimed to elucidate the function of SCFAs on human basophils. Human basophils were purified from healthy donors by flow cytometric sorting. The surface proteins, apoptosis and degranulation of basophils were analyzed by flow cytometric analysis. The mRNA expression was assayed using real-time PCR. Interleukin 4 (IL-4) and IL-13 were measured by ELISA. Histone acetylation was examined by western blot. GPR41 was expressed by basophils and was enhanced by IL-3. Acetate induced intracellular calcium influx in basophils which was suppressed by blocking GPR41. Propionate and butyrate, but not acetate, induced the expression of CD69 and IL-13. In addition, propionate and butyrate enhanced IgE-mediated basophil degranulation but inhibited basophil survival and IL-4 secretion. Propionate and butyrate induced histone acetylation of basophils and suppression of HDACs activity mimicked the effects of propionate and butyrate on human basophils. Our findings demonstrate that propionate and butyrate may play a complex role in regulating basophil apoptosis, activation and degranulation via inhibiting HDACs activity. The in vivo effects of SCFAs on the regulation of basophil-associated allergic diseases need to be further explored.

Moreau score has been used to differentiate chronic lymphocytic leukemia (CLL) from other mature B‐cell neoplasms. However, it showed limitations in Asian patients. Therefore, we conducted a new score system replacing CD5 and CD23 with CD43 and CD180 to evaluate its diagnostic value of CLL. 237 untreated samples diagnosed with mature B‐cell neoplasms were collected and were randomly divided into an exploratory and a validation cohort by a 2:1 ratio. The expression of CD5, CD19, CD20, CD23, CD43, CD79b, CD180, CD200, FMC7, and surface immunoglobulin (SmIg) were analyzed among all the samples. A proposed score was developed based on the logistic regression model. The sensitivity and specificity of the proposed score were calculated by ROC curves. CD43/CD180, CD200, FMC7, and CD79b were included in our new CLL score, which showed a sensitivity of 91.8% and a specificity of 83.1%. These results were confirmed in a validation cohort with a sensitivity of 90.5% (p = 0.808) and a specificity of 79.5% (p = 0.639). In CD5 negative or CD23 negative CLL group, the new CLL score displayed improved sensitivity of 79.4% compared to Moreau score and CLLflow score (41.2% and 47.1%, respectively). In atypical CLL group, the new CLL score showed improved sensitivity of 84.2% compared to Moreau score and CLLflow score (61.4% and 64.9%, respectively). This proposed atypical CLL score helped to offer an accurate differentiation of CLL from non‐CLL together with morphological and molecular methods, particularly in Chinese patients with atypical immunophenotype., This study demonstrated the diagnostic value of combination of CD43 and CD180 with CD200, FMC7 and CD79b in CD5‐ or CD23‐ CLL for the first time. How to differentiate atypical CLL from other mature B cell neoplasms poses a problem in the diagnosis of CLL. This study investigated the immunophenotyping data of patients with mature B‐cell malignancies, and developed a new combined score including CD43 and CD180 which could improve the diagnostic value of CLL versus non‐CLL, particularly in atypical CLL.

Unique coumarin aminophosphonates as new antibacterial agents were designed and synthesized to combat severely bacterial resistance. Bioactivity assessment identified that 3-hydroxylphenyl aminophosphonate 6f with low hemolytic activity not only exhibited excellent inhibition potency against Staphylococcus aureus at low concentration (0.5 μg/mL) in vitro but also showed considerable antibacterial potency in vivo. Meanwhile, the active compound 6f was capable of eradicating the S. aureus biofilm, thus alleviating the development of S. aureus resistance. Furthermore, the drug combination of compound 6f with norfloxacin could enhance the antibacterial efficacy. Mechanistic explorations manifested that molecule 6f was able to destroy the integrity of cell membrane, which resulted in the leakage of protein and metabolism inhibition. The cellular redox homeostasis was interfered through inducing the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), leading to the reduction of glutathione (GSH) activity and lipid peroxidation. Furthermore, compound 6f could intercalate into DNA base pair to hinder normal biological function. The above results provided powerful information for the further development of coumarin aminophosphonates as antibacterial agents.

Heat-induced labor loss is a major economic cost related to climate change. Here, we use hourly heat stress data modeled with a regional climate model to investigate the heat-induced labor loss in 231 Chinese cities. Results indicate that future urban heat stress is projected to cause an increase in labor losses exceeding 0.20% of the total account gross domestic product (GDP) per year by the 2050s relative to the 2010s. In this process, certain lower-paid sectors could be disproportionately impacted. The implementation of various urban adaptation strategies could offset 10% of the additional economic loss per year and help reduce the inequality-related impact on lower-paid sectors. So future urban warming can not only damage cities as a whole but can also contribute to income inequality. The implication of adaptation strategies should be considered in regard to not only cooling requirements but also environmental justice.

The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has been demonstrated to have comparable effectiveness or better to ATRA and chemotherapy (CHT) in non-high-risk acute promyelocytic leukemia (APL). However, the efficacy of ATRA-ATO compared to ATRA-ATO plus CHT in high-risk APL remains unknown. Here we performed a randomized multi-center non-inferiority phase III study to compare the efficacy of ATRA-ATO and ATRA-ATO plus CHT in newly diagnosed all-risk APL to address this question. Patients were assigned to receive ATRA-ATO for induction, consolidation, and maintenance or ATRA-ATO plus CHT for induction followed by three cycles of consolidation therapy, and maintenance therapy with ATRA-ATO. In the non-CHT group, hydroxyurea was used to control leukocytosis. A total of 128 patients were treated. The complete remission rate was 97% in both groups. The 2-year disease-free, event-free survival rates in the non-CHT group and CHT group in all-risk patients were 98% vs 97%, and 95% vs 92%, respectively (P = 0.62 and P = 0.39, respectively). And they were 94% vs 87%, and 85% vs 78% in the high-risk patients (P = 0.52 and P = 0.44, respectively). This study demonstrated that ATRA-ATO had the same efficacy as the ATRA-ATO plus CHT in the treatment of patients with all-risk APL.

BACKGROUND: Cervical cancer is a common gynecological cancer among women worldwide. OBJECTIVE: To determine the effects of 6 MV and 10 MV volumetric-modulated arc therapy (VMAT) photon beams on the target volume (TV) planning and critical organs in cases of cervical cancer. METHODS: Fifty patients with carcinoma of the cervix who underwent radiotherapy were selected. The transverse diameter (T) of the cross section of the upper edge of the sacroiliac joint on computerized tomography (CT) images of the patients was measured, and the mean value was calculated as 34 cm. All patients were divided into two groups: Group A (T < 34 cm) and Group B (T > 34 cm). The VMAT plans were generated using 6 MV and 10 MV plans separately. The prescription dose was 47.5 Gy, and the daily dose was 1.9 Gy. RESULTS: In Group A, the planning target volume (PTV) dose assessment parameters of 6 MV and 10 MV plans and their homogeneity and conformity indices were not statistically significantly different. A significant difference was observed between the 6 MV and 10 MV plans for the PTV dose assessment parameters and the homogeneity index of the plans for Group B. The monitor units (MUs) of the 10 MV plans were lower than in the 6 MV plans in both Groups A and B, and the difference was statistically significant. The assessment parameter V40 Gy of both the rectum and bladder in the 6 MV plans was smaller than the corresponding parameter in the 10 MV plans in Group A; in Group B, the assessment parameter V50 Gy of the rectum in the 10 MV plans was smaller than in the 6 MV plans. CONCLUSION: When T < 34 cm, 6 MV energy is more suitable for the external irradiation of cervical cancer. When T > 34 cm, 10 MV energy is more suitable for cervical cancer radiotherapy. Therefore, 10 MV should be considered for patients with a large abdominal size.

Substantial morbidity and mortality of fungal infections have aroused concerns all over the world, and common Candida spp. currently bring about severe systemic infections. A series of pyrimidinetrione-imidazole conjugates as potentially antifungal agents were developed. Bioassays manifested that 4-fluobenzyl pyrimidinetrione imidazole 5 f exerted favorable inhibition towards C. albicans (MIC=0.002 mM), being 6.5 folds more active than clinical antifungal drug fluconazole (MIC=0.013 mM). Preliminary mechanism research indicated that compound 5 f could not only depolarize membrane potential but also permeabilize the membrane of C. albicans. Molecular docking was operated to simulate the interaction mode between molecule 5 f and CYP51. In addition, hybrid 5 f might form 5 f-DNA supramolecular complex via intercalating into DNA. The interference of membrane and DNA might contribute to its fungicidal capacity with no obvious tendency to induce the resistance against C. albicans. Conjugate 5 f endowed good blood compatibility as well as low cytotoxicity towards HeLa and HEK-293T cells.

Vaccines based on live attenuated Chlamydia elementary bodies (EBs) can cause disease in vaccinated animals and the comparably safer inactivated whole EBs are only marginally protective. Recent studies show that a vaccine formulation comprising UV-inactivated EBs (EB) and appropriate mucosal delivery systems and/or adjuvants induced significant protective immunity. We tested the hypothesis that intranasal delivery of UV-inactivated C. psittaci EB formulated in Vibrio cholerae ghosts (VCG)-chitosan nanoparticles will induce protective immunity against intranasal challenge in SPF chickens. We first compared the impact of VCG and CpG adjuvants on protective immunity following IN mucosal and IM systemic delivery of EB formulated in chitosan hydrogel/microspheres. Immunologic analysis revealed that IN immunization in the presence of VCG induced higher levels of IFN-γ response than IM delivery or the CpG adjuvanted groups. Also, vaccine efficacy evaluation showed enhanced pharyngeal bacterial clearance and protection against lung lesions with the VCG adjuvanted vaccine formulation, thereby establishing the superior adjuvanticity of VCG over CpG. We next evaluated the impact of different concentrations of VCG on protective immunity following IN mucosal immunization. Interestingly, the adjuvanticity of VCG was concentration-dependent, since protective immunity induced following IN mucosal immunization showed dose-dependent immune responses and protection. These studies reveal that formulation of inactivated chlamydial antigens with adjuvants, such as VCG and chitosan increases their ability to induce protective immune responses against challenge.

Tumour-associated macrophages (TAMs) abundantly infiltrate high-grade gliomas and orchestrate immune response, but their diversity in isocitrate dehydrogenase (IDH)-differential grade 4 gliomas remains largely unknown. This study aimed to dissect the transcriptional states, spatial distribution, and clinicopathological significance of distinct monocyte-derived TAM (Mo-TAM) and microglia-derived TAM (Mg-TAM) clusters across glioblastoma-IDH-wild type and astrocytoma-IDH-mutant-grade 4 (Astro-IDH-mut-G4). Single-cell RNA sequencing was performed on four cases of human glioblastoma and three cases of Astro-IDH-mut-G4. Cell clustering, single-cell regulatory network inference, and gene set enrichment analysis were performed to characterize the functional states of myeloid clusters. The spatial distribution of TAM subsets was determined in human glioma tissues using multiplex immunostaining. The prognostic value of different TAM-cluster specific gene sets was evaluated in the TCGA glioma cohort. Profiling and unbiased clustering of 24,227 myeloid cells from glioblastoma and Astro-IDH-mut-G4 identified nine myeloid cell clusters including monocytes, six Mo/Mg-TAM subsets, dendritic cells, and proliferative myeloid clusters. Different Mo/Mg-TAM clusters manifest functional and transcriptional diversity controlled by specific regulons. Multiplex immunostaining of subset-specific markers identified spatial enrichment of distinct TAM clusters at peri-vascular/necrotic areas in tumour parenchyma or at the tumour-brain interface. Glioblastoma harboured a substantially higher number of monocytes and Mo-TAM-inflammatory clusters, whereas Astro-IDH-mut-G4 had a higher proportion of TAM subsets mediating antigen presentation. Glioblastomas with a higher proportion of monocytes exhibited a mesenchymal signature, increased angiogenesis, and worse patient outcome. Our findings provide insight into myeloid cell diversity and its clinical relevance in IDH-differential grade 4 gliomas, and may serve as a resource for immunotherapy development. © 2022 The Pathological Society of Great Britain and Ireland.

SARS-CoV-2, a novel Corona virus strain, was first detected in Wuhan, China, in December 2019. As of December 16, 2021, almost 4,822,472 people had died and over 236,132,082 were infected with this lethal viral infection. It is believed that the human immune system is thought to play a critical role in the initial phase of infection when the viruses invade the host cells. Although some effective vaccines have already been on the market, researchers and many bio-pharmaceuticals are still working hard to develop a fully functional vaccine or more effective therapeutic agent against the COVID-19. Other efforts, in addition to functional vaccines, can help strengthen the immune system to defeat the corona virus infection. Herein, we have reviewed some of those proven measures, following which a more efficient immune system can be better prepared to fight viral infection. Among these, dietary supplements like- fresh vegetables and fruits offer a plentiful of vitamins and antioxidants, enabling to build of a healthy immune system. While the pharmacologically active components of medicinal plants directly aid in fighting against viral infection, supplementary supplements combined with a healthy diet will assist to regulate the immune system and will prevent viral infection. In addition, some personal habits, like- regular physical exercise, intermittent fasting, and adequate sleep, had also been proven to aid the immune system in becoming an efficient one. Maintaining each of these will strengthen the immune system, allowing innate immunity to become a more defensive and active antagonistic mechanism against corona-virus infection. However, because dietary treatments take longer to produce beneficial effects in adaptive maturation, personalized nutrition cannot be expected to have an immediate impact on the global outbreak.

We explored the therapeutic effects of Adipose-derived mesenchymal stem cells (ADMSCs) and Synovial-derived mesenchymal stem cells (SDMSCs) on osteoarthritis (OA).SDMSCs and ADMSCs were co-cultured with chondrocytes and stimulated with interleukin (IL)-1β. An OA model was established on rats by intra-articular injection with ADMSCs and SDMSCs. After 8 weeks, the joint diameter difference was detected, and histological staining was used to observe the pathological changes in cartilage tissue. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expressions of IL-6, tumor necrosis factor (TNF)-α and IL-1β in joint fluid. The expressions of COL2A1, Aggrecan, Matrix metalloproteinase (MMP)-13, SOX9, IL-6, TNF-α and IL-1β were detected by qRT-PCR and Western blotting in cartilage tissue. Reactive oxygen species (ROS) content in cells and cartilage tissues was detected by ROS kit.SDMSCs and ADMSCs co-cultured with chondrocytes could reduce MMP-13 expression, increase the expressions of COL2A1, Aggrecan and SOX9, as well as reverse the effects of IL-1β on promoting ROS content and inflammatory factors levels. After the OA model was established, the injection of ADMSCs and SDMSCs reduced the differences in joint diameter and tissue lesions in OA rats. The OA model led to increased levels of IL-6, TNF-α and IL-1β in joint fluid and cartilage tissue, while the injection of ADMSCs and SDMSCs inhibited the inflammatory factor levels in OA rats, and increased the expressions of COL2A1, Aggrecan and SOX9 in OA rats.ADMSCs and SDMSCs improve osteoarthritis in rats by reducing chondrocyte ROS and inhibiting inflammatory response.

In this study, we studied the effect and possible mechanism of TGF-β1 on vascular calcification. We found that the serum levels of TGF-β1 and cycloxygenase-2 (COX-2) were significantly increased in patients with chronic kidney disease. Phosphate up regulated TGF-β1 in vascular smooth muscle cells (VSMCs). TGF-β1 decreased the markers of VSMCs, but increased osteogenic markers and calcification in aortic segments. The phosphate-induced osteogenic markers were reduced by the TGFβR I inhibitor (LY364947), which also attenuated the potential of phosphate to reduce VSMC markers in VSMCs. Both phosphate and TGF-β1 increased the protein level of β-catenin, which was partially mitigated by LY364947. TGF-β1 decreased sclerostin, and exogenous sclerostin decreased the mineralization induced by TGF-β1. LY364947 reduced the phosphate and TGF-β1 induced COX-2. Meanwhile, the effects of TGF-β1 on osteogenic markers, β-catenin, and sclerostin, were partially reversed by the COX-2 inhibitor. Mechanistically, we found that p-Smad2/3 and p-CREB were both enriched at the promoter regions of sclerostin and β-catenin. TGF-β1 and COX-2 were significantly elevated in serum and aorta of rats undergoing renal failure. Therapeutic administration of meloxicam effectively ameliorated the renal lesion. Our results suggested that COX-2 may mediate the effect of TGF-β1 on vascular calcification through down-regulating sclerostin in VMSCs.

BackgroundToxoplasma gondiiis an opportunistic protozoan infecting almost one-third of the world’s population.Toxoplasma gondiirhoptry protein 18 (TgROP18) is a key virulence factor determining the parasite’s acute virulence and is secreted into host cells during infection. We previously identified the interaction ofTgROP18 and host cell immune-related receptor protein IL20RB, and observed the activation of STAT3 in human keratinocytes (HaCaT) cells infected by therop16knockout RH strain, thoughTgROP16 is regarded as being responsible for host STAT3 activation duringT. gondiiinvasion. Therefore, we hypothesizeTgROP18 can activate host STAT3 through binding to IL20RB.MethodsCRISPR-CAS9 technology was used to generate the ROP16 and ROP18 double knockout RH strain, RH-∆rop16∆rop18. SDS-PAGE and western blot were used to detect STAT3 activation in different HaCaT cells with high endogenous IL20RB expression treated withT. gondiitachyzoites infection, recombinant ROP18, or IL-20. FRET and co-immunoprecipitation (Co-IP) was used to detect the protein-protein interaction.ResultsWe observed thatTgROP18 was involved in a synergic activation of the host JAK/STAT3 pathway together withTgROP16 in human HaCaT cells infected withT. gondiior treated with recombinantTgROP18 protein, stimulating host proinflammatory immune responses such as expression of TNF-α. The effect of recombinant ROP18 on STAT3 phosphorylation was presented in a dose-dependent manner. Additionally,TgROP18 was identified to target IL20RB on its extracellular domain. When we treated different cell lines with the recombinant ROP18, STAT3 phosphorylation could only be observed in the cells with endogenous IL20RB expression, such as HaCaT cells.ConclusionsThese findings indicate thatTgROP18-IL20RB interaction uponT. gondiiinvasion was involved in STAT3 activation, which is associated with host cell defense.

Background Management of chronic calcaneal osteomyelitis is challenging. At present, there is still no widely accepted, simple, and effective surgical method to eradicate the infection and prevent osteomyelitis recurrence. The objective of this study was to assess the outcomes of one-stage treatment of chronic calcaneal osteomyelitis with a shape-preserving debridement technique combined with antibiotic-loaded calcium sulphate. Methods Between 2012 and 2018, 33 patients (33 limbs) with chronic calcaneal osteomyelitis were treated with a novel debridement technique, named “eggshell-like debridement”, plus antibiotic-impregnated calcium sulphate. The infection remission rate, recurrence rate, and amputation rate were analyzed. The American Orthopedic Foot and Ankle Society (AOFAS) ankle and hindfoot score was used to assess postoperative hindfoot function. Results 26 patients (81.8%) achieved infection remission without recurrence. In the patients with osteomyelitis remission, pain, limitation of movement, sinus tracts, and typical redness and swelling were generally eliminated. Most of the patients could tolerate full weight-bearing without pain. The average AOFAS ankle and hindfoot score was 88 points (range, 67–100 points), implying the foot function was mostly restored. 6 patients (18.2%) had osteomyelitis recurrence but no amputation was required to elimilate the infection. Conclusions Eggshell-like debridement combined with antibiotic-loaded calcium sulphate is an effective method for one-stage management of chronic calcaneal osteomyelitis. With the application of this technique, secondary autogenous bone or muscle flap grafts are unnecessary. The surgical procedure can be simplified whlie the hindfoot function is well preserved.

Aims: The present study was designed to survey the associations between polymorphisms of the common single nucleotide polymorphism (SNP) rs4938723 in the miR-34b/c gene, as well as the rs3746444 SN...

Introduction To improve the standard treatment paradigm for glioblastoma (GBM), efforts have been made to explore the efficacy of epigenetic agents as chemosensitizers. Recent data suggest possible synergy between decitabine (DAC), a DNA hypomethylating agent, and temozolomide (TMZ) in GBM, but the mechanism remains unclear. The objective of this study was to determine the effects of DAC on TMZ sensitization in a consecutively derived set of primary GBM cultures, with a focus on mismatch repair (MMR) proteins. Methods Half maximal inhibitory concentrations (IC50) of TMZ were calculated in eleven consecutive patient-derived GBM cell lines before and after preconditioning with DAC. MMR protein expression changes were determined by quantitative immunoblots and qPCR arrays. Single-molecule real-time (SMRT) sequencing of bisulfite (BS)-converted PCR amplicons of the MLH1 promoter was performed to determine methylation status. Results TMZ IC50 significantly changed in 6 of 11 GBM lines of varying MGMT promoter methylation status in response to DAC preconditioning. Knockdown of MLH1 after preconditioning reversed TMZ sensitization. SMRT-BS sequencing of the MLH1 promoter region revealed higher levels of baseline methylation at proximal CpGs in desensitized lines compared to sensitized lines. Conclusions DAC enhances TMZ cytotoxicity in a subset of GBM cell lines, comprising lines both MGMT methylated and unmethylated tumors. This effect may be driven by levels of MLH1 via E2F1 transcription factor binding. Using unbiased long-range next-generation bisulfite-sequencing, we identified a region of the proximal MLH1 promoter with differential methylation patterns that has potential utility as a clinical biomarker for TMZ sensitization.

The design of novel agents that specifically target DNA and interrupt its normal biological processes is an attractive goal in drug design. Among the promising metallodrugs, metal-directed self-assembled metallohelices with defined three-dimensional stereochemical structures display unique structure-inherent and unprecedented noncovalent targeting abilities towards DNA, resulting in excellent anticancer or antibiotic activities. A newly burgeoning hotspot is focusing on lighting them up by embedding luminescent metal ions as the vertices. The photoactive metallohelices that combine strong interactions toward DNA targets and efficient 1O2 quantum yield may provide new motivation in diagnostic and photodynamic therapy (PDT) areas. This perspective focuses on research progress on metallohelices as DNA binders and chemotherapeutic agents, and highlights recent advances in fabricating luminescent examples for PDT. The relative assembly strategies are also discussed and compared. Finally, perspectives on the future development of the lit-up metallohelices are presented.

OBJECTIVE: To study the feasibility of tracheal intubation for meconium suction immediately after birth of nonvigorous neonates born through meconium-stained amniotic fluid (MSAF). METHODS: A retrospective cohort study was performed on nonvigorous neonates born through MSAF who were admitted to the Department of Neonatology, Zhecheng People's Hospital. The neonates without meconium suction who were admitted from July 1, 2017 to June 30, 2018 were enrolled as the control group. The neonates who underwent meconium suction from July 1, 2018 to June 30, 2019 were enrolled as the suction group. The two groups were compared in terms of the mortality rate and the incidence rates of neonatal meconium aspiration syndrome (MAS), persistent pulmonary hypertension of the newborn, pneumothorax, and pulmonary hemorrhage. RESULTS: There were 80 neonates in the control group and 71 in the suction group. There were no significant differences between the two groups in the incidence rates of MAS (11% vs 7%), persistent pulmonary hypertension of the newborn (5% vs 4%), pneumothorax (3% vs 1%), and death (0% vs 1%). Compared with the control group, the suction group had a significantly lower proportion of neonates requiring oxygen inhalation (16% vs 33%, P

Direct myocardial and vascular injuries due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-driven inflammation is the leading cause of acute cardiac injury associated with coronavirus disease 2019 (COVID-19). However, in-depth knowledge of the injury characteristics of the heart affected by inflammation is lacking. In this study, using a quantitative spatial proteomics strategy that combines comparative anatomy, laser-capture microdissection, and histological examination, we establish a region-resolved proteome map of the myocardia and microvessels with obvious inflammatory cells from hearts of patients with COVID-19. A series of molecular dysfunctions of myocardia and microvessels is observed in different cardiac regions. The myocardia and microvessels of the left atrial are the most susceptible to virus infection and inflammatory storm, suggesting more attention should be paid to the lesion and treatment of these two parts. These results can guide in improving clinical treatments for cardiovascular diseases associated with COVID-19.

The understanding at a molecular level of ambient secondary organic aerosol (SOA) formation is hampered by poorly constrained formation mechanisms and insufficient analytical methods. Especially in developing countries, SOA related haze is a great concern due to its significant effects on climate and human health. We present simultaneous measurements of gas-phase volatile organic compounds (VOCs), oxygenated organic molecules (OOMs), and particle-phase SOA in Beijing. We show that condensation of the measured OOMs explains 26-39% of the organic aerosol mass growth, with the contribution of OOMs to SOA enhanced during severe haze episodes. Our novel results provide a quantitative molecular connection from anthropogenic emissions to condensable organic oxidation product vapors, their concentration in particle-phase SOA, and ultimately to haze formation.

Osteoporosis is a common systemic bone disease caused by the imbalance between osteogenic activity and osteoclastic activity. Aged women are at higher risk of osteoporosis, partly because of estrogen deficiency. However, the underlying mechanism of how estrogen deficiency affects osteoclast activity has not yet been well elucidated. In this study, GSE2208 and GSE56815 datasets were downloaded from GEO database with 25 PreH BMD women and 25 PostL BMD women in total. The RRA algorithm determined 38 downregulated DEGs and 30 upregulated DEGs. Through GO analysis, we found that downregulated DEGs were mainly enriched in myeloid cell differentiation, cytokine-related functions while upregulated DEGs enriched in immune-related biological processes; pathways like Notch signaling and MAPK activation were found in KEGG/Rectome pathway database; a PPI network which contains 66 nodes and 91 edges was constructed and three Modules were obtained by Mcode; Correlation analysis helped us to find highly correlated genes in each module. Moreover, three hub genes FOS, PTPN6, and CTSD were captured by Cytohubba. Finally, the hub genes were further confirmed in blood monocytes of ovariectomy (OVX) rats by real-time PCR assay. In conclusion, the integrative bioinformatics analysis and real-time PCR analysis were utilized to offer fresh light into the role of monocytes in premenopausal osteoporosis and identified FOS, PTPN6, and CTSD as potential biomarkers for postmenopausal osteoporosis.

Staghorn calculi remain a treatment challenge for urologists. The aim of the study was to compare the treatment outcomes of suctioning minimally invasive percutaneous nephrolithotomy (MPCNL) and traditional MPCNL for renal staghorn stones.Between April 2018 and June 2019, we included patients suffering from renal staghorn stones who were treated with modified MPCNL with a suctioning system. The outcomes of these patients were compared with those of a cohort of patients undergoing traditional MPCNL (between January 2017 and March 2018) using a 1:1 scenario matched-pair analysis. Cases were matched sequentially according to stone burden, stone branches, and stone hardness as well as age and sex.A total of 512 patients were included in this study (256 patients in each group). The baseline characteristics were equally distributed between the two groups. The suctioning MPCNL group achieved a significantly higher stone-free rate (SFR) (78.5% vs 69.1%; P = 0.016) after a single procedure and had a significantly shorter operative time (106.2 ± 18.4 vs. 132.1 ± 22.2 min; P 0.001) than the traditional MPCNL group. The traditional MPCNL group experienced a significantly higher rate of overall complications than the suctioning MPCNL group (27.3% vs. 16.8%; P = 0.004). Regarding individual complications, a significantly higher rate of fever (13.7% vs. 7.4%; P = 0.021) and urosepsis requiring only additional antibiotics (8.2% vs. 3.5%; P = 0.024) was observed in the traditional MPCNL group than in the suctioning MPCNL group; there was a trend that the suctioning MPCNL group conferred a decreased risk of urosepsis shock (1.2% vs. 2.3%), but this trend failed to achieve statistical significance (P = 0.313). There was no significant difference between the two groups regarding the incidence of severe hemorrhage, the mean number of tracts used during a single procedure and the postoperative hospital stay.The use of suctioning MPCNL for staghorn calculi had advantages over the use of traditional MPCNL in terms of a higher SFR after a single procedure and fewer postoperative infectious complications. Further well-designed studies are needed to confirm the results.

Natural berberine-derived azolyl ethanols as new structural antibacterial agents were designed and synthesized for fighting with dreadful bacterial resistance. Partial target molecules exhibited potent activity against the tested strains, particularly, nitroimidazole derivative

Stroke is a leading cause of death and disability in East Asia. Owing to the aging population and high prevalence of stroke, East Asia might suffer a disproportionately heavy burden of stroke under the changing climate. However, the evidence relevant is still limited in this area.To evaluate the stroke mortality risk due to heat exposure in East Asia and predict its burden under various future climate change scenarios.We conducted a multi-center observational study and collected data from 22 representative cities in three main East Asian countries (i.e., China, Japan, and South Korea) from 1972 to 2015. The two-stage time-series analyses were applied to estimate the effects of heat on stroke mortality at the regional and country level. We further projected the burden of heat-related stroke mortality using 10 global climate models (GCMs) under four shared socioeconomic pathway and representative concentration pathway (SSP-RCP) scenarios, including SSP1-RCP1.9, SSP1-RCP2.6, SSP2-RCP4.5, and SSP5-RCP8.5 scenarios.In the present study, a total of 287,579 stroke deaths were collected during the warm season. Heat was significantly associated with an increased risk of stroke mortality. Overall, compared with the 2010 s, the heat-related attributable fraction (AF) was projected to increase in the 2090 s, with increments ranging from 0.8 % to 7.5 % across various climate change scenarios. The heat-related AF was projected to reach 11.9 % (95 % empirical confidence interval [eCI]: 6.1 %, 17.5 %) in the 2090 s under the SSP5-RCP8.5 scenario in China, while the corresponding estimates were 6.6 % (95 % eCI: 2.5 %, 11.0 %) and 5.1 % (95 % eCI: 1.2 %, 9.1 %) for Japan and South Korea, respectively.Climate change will exacerbate the burden of heat-related stroke mortality but with considerable geographical heterogeneity in East Asia.

Background: Chronic osteomyelitis of calcaneus is not rare but is very hard to treat. Irrigation-suction and antibiotic-impregnated calcium sulfate following debridement are commonly used in managing chronic osteomyelitis, but their effects have rarely been compared. We aimed to compare the effectiveness of antibiotic-impregnated calcium sulfate with irrigation-suction in the treatment of patients with chronic calcaneal osteomyelitis. Methods: From January 2011 to June 2018, adult patients at our institute with chronic osteomyelitis receiving treatment of either antibiotic-impregnated calcium sulfate (CS group) or irrigation-suction (IS group) following thorough debridement were screened and selected according to the inclusion and exclusion criteria. The clinical presentation, laboratory tests, complications, and the ultimate single-staged cure rate and recurrence were compared. Results: A total of 61 patients, including 41 in the CS group and 20 in the IS group, were included in our study. Of the patients, 85.4% in the CS group and 60.0% in the IS group ( P = .006) were successfully cured in the single stage, respectively, without infection recurrence. Lower infection recurrence rates with shorter hospital stay were found in the CS group than the IS group. Inflammatory biomarkers after surgery with both treatments were slightly decreased and not significantly different from preoperative or between-groups postoperative. Exudate from incision was found primarily in the CS group. Conclusion: This study demonstrates that both antibiotic-impregnated calcium sulfate and irrigation-suction after careful and thorough surgical debridement are generally effective in treating chronic calcaneal osteomyelitis. Antibiotic-impregnated calcium sulfate achieved a higher single-staged cure rate but was associated with an increased postoperative wound exudate. Level of Evidence: Level III, retrospective cohort study.

Glioblastoma is a lethal primary brain tumor with abundant immune-suppressive glioblastoma-associated macrophage (GAM) infiltration. Skewing immune suppressive GAMs towards an immune-activating phenotype represents a promising immunotherapeutic strategy against glioblastoma. Herein, we reported that genetic deletion of miRNA-processing enzyme Dicer in macrophages inhibited the growth of GL261 murine glioblastoma xenografts and prolonged survival of tumor-bearing mice. Single cell RNA sequencing (scRNA-seq) of the tumor-infiltrating immune cells revealed that Dicer deletion in macrophages reduced the proportion of cell-cycling GAM cluster and reprogramed the remaining GAMs towards a proinflammatory activation state (enhanced phagocytotic and IFN-producing signature). Dicer-deficient GAMs showed reduced level of cyclin-dependent kinases (CDK1 and CDK2) and increased expression of CDK inhibitor p27 Kip1, thus manifesting impaired proliferation. Dicer knockout enhanced phagocytotic activity of GAMs to eliminate GL261 tumor cells. Increased proinflammatory GAM clusters in macrophage Dicer-deficient mice actively interacted with tumor-infiltrating T cells and NK cells through TNF paracrine signaling to create a pro-inflammatory immune microenvironment for tumor cell elimination. Our work identifies the role of Dicer deletion in macrophages in generating an immune-activating microenvironment, which could be further developed as a potential immunotherapeutic strategy against glioblastoma.

Schizandrin A (SchA) can be extracted from the vine plant Schisandra chinensis and has been reported to confer various biologically active properties. However, its potential biological effects on non‑small cell lung cancer (NSCLC) remain unknown. Therefore, the present study aims to address this issue. NSCLC and normal lung epithelial cell lines were first treated with SchA. Cell viability and proliferation were measured using CellTiter‑Glo Assay and colony formation assays, respectively. PI staining was used to measure cell cycle distribution. Cell cycle‑related proteins p53, p21, cyclin D1, CDK4, CDK6, cyclin E1, cyclin E2, CDK2 and DNA damage‑related protein SOX4 were detected by western blot analysis. Annexin V‑FITC/PI staining, DNA electrophoresis and Hoechst 33342/PI dual staining were used to detect apoptosis. JC‑1 and DCFH‑DA fluorescent dyes were used to measure the mitochondrial membrane potential and reactive oxygen species concentrations, respectively. Apoptosis‑related proteins caspase‑3, cleaved caspase‑3, poly(ADP‑ribose) polymerase (PARP), cleaved PARP, BimEL, BimL, BimS, Bcl2, Bax, caspase‑9 and cleaved caspas‑9 were measured by western blot analysis. Dansylcadaverine was used to detect the presence of the acidic lysosomal vesicles. The expression levels of the autophagy‑related proteins LC3‑I/II, p62/SQSTM and AMPKα activation were measured using western blot analysis. In addition, the autophagy inhibitor 3‑methyladenine was used to inhibit autophagy. SchA treatment was found to reduce NSCLC cell viability whilst inhibiting cell proliferation. Low concentrations of SchA (10‑20 µM) mainly induced G1/S‑phase cell cycle arrest. By contrast, as the concentration of SchA used increases (20‑50 µM), cells underwent apoptosis and G2/M‑phase cell cycle a13rrest. As the treatment concentration of SchA increased from 0 to 50 µM, the expression of p53 and SOX4 protein also concomitantly increased, but the expression of p21 protein was increased by 10 µM SchA and decreased by higher concentrations (20‑50 µM). In addition, the mRNA and protein expression levels of Bcl‑like 11 (Bim)EL, BimL and BimS increased following SchA application. SchA induced the accumulation of acidic vesicles and induced a marked increase in the expression of LC3‑II protein, suggsting that SchA activated the autophagy pathway. However, the expression of the p62 protein was found to be increased by SchA, suggesting that p62 was not degraded during the autophagic flux. The 3‑methyladenine exerted no notable effects on SchA‑induced apoptosis. Taken together, results from the present study suggest that SchA exerted inhibitory effects on NSCLC physiology by inducing cell cycle arrest and apoptosis. In addition, SchA partially induced autophagy, which did not result in any cytoprotective effects.

As a multikinase inhibitor, sorafenib is commonly used to treat patients with advanced hepatocellular carcinoma (HCC), however, acquired resistance to sorafenib is a major obstacle to the effectiveness of this treatment. Thus, in this study, we investigated the mechanisms underlying sorafenib resistance as well as approaches devised to increase the sensitivity of HCC to sorafenib. We demonstrated that miR-124-3p.1 downregulation is associated with early recurrence in HCC patients who underwent curative surgery and sorafenib resistance in HCC cell lines. Regarding the mechanism of this phenomenon, we identified FOXO3a, an important cellular stress transcriptional factor, as the key factor in the function of miR-124-3p.1 in HCC. We showed that miR-124-3p.1 binds directly to AKT2 and SIRT1 to reduce the levels of these proteins. Furthermore, we showed that AKT2 and SIRT1 phosphorylate and deacetylate FOXO3a. We also found that miR-124-3p.1 maintains the dephosphorylation and acetylation of FOXO3a, leading to the nuclear location of FOXO3a and enhanced sorafenib-induced apoptosis. Moreover, the combination of miR-124-3p.1 mimics and sorafenib significantly enhanced the curative efficacy of sorafenib in a nude mouse HCC xenograft model. Collectively, our data reveal that miR-124-3p.1 represents a predictive indicator of early recurrence and sorafenib sensitivity in HCC. Furthermore, we demonstrate that miR-124-3p.1 enhances the curative efficacy of sorafenib through dual effects on FOXO3a. Thus, the miR-124-3p.1-FOXO3a axis is implicated as a potential target for the diagnosis and treatment of HCC.

Antibiotics are frequently used in aquaculture as feed additives and finally enter the marine environment that can pose potential threat to humans. In this study, magnetic molecularly imprinted nanocomposites were prepared by surface imprinting and applied as selective sorbents for specific capture of doxycycline. A multivariate approach based on response surface methodology with Box-Behnken design was adopted to optimize the dispersive solid-phase extraction of doxycycline from marine sediment. Three key parameters, including adsorbent amount and type of washing/eluting solvent, were screened. Under optimum conditions, the limit of detection was 0.03 μg g

Glioma stem cells (GSCs) are self-renewing tumor cells with multi-lineage differentiation potential and the capacity of construct glioblastoma (GBM) heterogenicity. Mitochondrial morphology is associated with the metabolic plasticity of GBM cells. Previous studies have revealed distinct mitochondrial morphologies and metabolic phenotypes between GSCs and non-stem tumor cells (NSTCs), whereas the molecules regulating mitochondrial dynamics in GBM cells are largely unknown. Herein, we report that carnitine palmitoyltransferase 1A (CPT1A) is preferentially expressed in NSTCs, and governs mitochondrial dynamics and GSC differentiation. Expressions of CPT1A and GSC marker CD133 were mutually exclusive in human GBMs. Overexpression of CPT1A inhibited GSC self-renewal but promoted mitochondrial fusion. In contrast, disruption of CPT1A in NSTCs promoted mitochondrial fission and reprogrammed NSTCs toward GSC feature. Mechanistically, CPT1A overexpression increased the phosphorylation of dynamin-related protein 1 at Ser-637 to promote mitochondrial fusion. In vivo, CPT1A overexpression decreased the percentage of GSCs, impaired GSC-derived xenograft growth and prolonged tumor-bearing mice survival. Our work identified CPT1A as a critical regulator of mitochondrial dynamics and GSC differentiation, indicating that CPT1A could be developed as a molecular target for GBM cell-differentiation strategy.

Human basophils are terminally differentiated granulocytes that are least abundant in the peripheral blood but play important roles in allergic diseases. Studies on human basophils are limited by the high cost on the isolation of human basophils by magnetic-activated cell sorting (MACS) for negative depletion of non-basophils, followed by CD123-based positive selection of basophils. Moreover, such CD123-based purification of basophils may be limited by blocking of the binding of IL-3/anti-CD123 to the surface CD123. Here we identified SSClow CD4- CD127- HLA-DR- CRTH2high as unique markers for the identification of human basophils through stringent flow cytometric analysis of leukocytes from buffy coat. We established an efficient and cost-effective method for isolating human basophils from buffy coat based on positive magnetic selection of CRTH2+ cells followed by flow cytometric sorting of SSClow CD4- CD127- HLA-DR- CRTH2high cells. Approximately 1 to 1.5 million basophils were isolated from one buffy coat with a purity of >97%. Basophils purified by this method were viable and efficiently responded to key regulators of basophils including IL-3 and anti-IgE. This method can be used for purifying human basophils for subsequent functional studies.

To explore the value of red cell distribution width (RDW), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and hemoglobin (Hb) A2 combined determination scheme for screening thalassemia.The RDW levels of thalassemia group and healthy control group were detected and compared. The efficiency of RDW for screening thalassemia was evaluated by receiver operating characteristic (ROC) curve. The diagnostic cut-off value of RDW was also acquired by Youden index. Then, 3 groups for thalassemia screening scheme were set, including MCV+MCH+HBAThe RDW level in thalassemia group was significantly higher than that in healthy control group (P0.05). The diagnostic cut-off value for screening thalassemia was RDW15.15, when the Youden index was the biggest among all data. The sensitivity, specificity, positive predictive value, negative predictive value, false negative rate and consistency rate of MCV+MCH+RDW(15.15)+HBAThe diagnostic cut-off value of RDW for thalassemia screening has been established. The group of MCV(82.0 fl)+MCH(27.0 pg)+HBARDW筛查地中海贫血诊断界值的建立及其与MCV、MCH、HBA探讨红细胞分布宽度（RDW）与红细胞平均体积（MCV）、平均红细胞血红蛋白含量（MCH）、血红蛋白（Hb）A2联合筛查方案在地中海贫血（简称地贫）筛查中的应用价值.检测地贫患者和体检健康者（健康对照组）的RDW水平，比较两组RDW水平变化。绘制受试者工作曲线（ROC），计算约登指数，评价RDW的诊断性能，建立RDW筛查地贫诊断界值。另外选取621例疑似地贫患者，设置3组筛查方案，分别为MCV+MCH+HBA地贫患者RDW水平明显高于体检健康者（健康对照组），差异具有统计学意义（P0.05）。选用RDW15.15作为筛查地贫的诊断界值。MCV+MCH+RDW（15.15）+HBA建立了RDW筛查地贫的诊断界值，在MCV（82.0 fl）+MCH（27.0 pg）+HBA

To observe the clinical efficacy of allogeneic peripheral blood stem cell transplantation（allo-HSCT） on the treatment of adult acute leukemia patients, moreover, to establish and evaluate a Logistic model to predict the risk of relapse in adult acute leukemia patients after allo-HSCT.The clinical data of 145 adult acute leukemia patients treated by peripheral blood stem cell transplantation in the First Affiliated Hospital of Xi'an Jiaotong University from January 2010 to December 2019 was enrolled and analyzed retrospectively. Complications and survival of patients were observed. The relationship between patients' age, diagnosis, leukocyte count at onset, risk stratification, time of diagnosis to transplantation, HCT-CI, minimal residual disease pre-transplantation, donor-recipient sex relationship, HLA match degree, prophylaxis of graft versus host disease(GVHD), donor age, number of transfused mononuclear cells, CD34 positive cells, engraftment time, acute and chronic GVHD, CMV, EBV infection, and hemorrhagic cystitis and recurrence after transplantation were analyzed by logistic regression. Relapse prediction model was established and evaluated according to the results.Among 145 acute leukemia patients, 81 with acute myeloid leukemia, 64 with acute lymphocytic leukemia, 18 with EBV infection, 2 with post-transplant lymphoproliferative disorder(PTLD), 85 with CMV, 26 with hemorrhagic cystitis, 65 patients developed acute GVHD, 51 patients developed chronic GVHD and 45 patients relapsed. The overall survival （OS） rates in one and three years were 86.4% and 61.8%, and the progress-free survival （PFS） rates in one and three years were 67.5% and 62.4%, respectively. There were significant differences in OS and PFS between relapsed and non-relapsed patients, as well as AML and ALL patients. Univariate analysis revealed that patient's age, risk stratification, time to transplantation, HCT-CI index, ATG based GVHD prophylaxis, minimal residual disease pre-transplantation, GVHD prophylaxis, and acute and chronic GVHD were associated with the relapse of disease, multivariate logistic regression analysis showed that pre-transplantation minimal residual disease showed positively correlation with relapse of the disease, while chronic GVHD showed negatively correlation.The relapse rate of adult acute leukemia patients treated with allo-HSCT in our hospital is 31.0%, and OS of AML patients is better than ALL patients'. OS of relapsed patients is significantly lower than non-relapsed patients'. Pre-transplantation minimal residual disease is a risk factor of relapse. The risk of relapse is reduced in patients with chronic GVHD.异基因外周血造血干细胞移植治疗成人急性白血病疗效及移植后复发风险预测模型的建立.观察成人急性白血病异基因外周血造血干细胞移植的临床疗效，并建立预测急性白血病移植后复发风险的Logistics模型.选取西安交通大学第一附属医院2010年1月至2019年12月收治的行异基因外周血造血干细胞移植的成人急性白血病患者145例及其供者的临床资料，观察移植后并发症及生存情况；通过多因素Logistics回归分析患者年龄、诊断、起病时白细胞数、危险度分层、移植前微小残留病灶、诊断到移植的时间、HCT-CI、供受者性别关系、HLA配型相合程度、移植物抗宿主病（GVHD）预防方案、供者年龄、输注单个核细胞及CD34+细胞数、造血重建时间、有无急慢性GVHD、CMV及EBV感染、出血性膀胱炎与移植后复发的关系；依据多因素分析的结果建立预测成人急性白血病移植后复发风险的模型，并进行评价.145例急性白血病患者中，急性髓系白血病（AML）81例,急性淋巴细胞白血病（ALL）64例，18例合并有EBV感染，其中2例合并移植后淋巴细胞增殖性疾病，85例合并CMV血症，26例合并出血性膀胱炎症，65例并发急性GVHD，51例并发慢性GVHD，共计45例复发。移植后1、3年OS率分别为86.4%和61.8%，移植后1、3年PFS率分别为67.5%和62.4%。急性髓系白血病与急性淋巴细胞白血病患者移植后OS及PFS存在统计学差异。未复发患者与复发患者OS及PFS存在统计学差异。单因素分析结果显示，患者年龄、危险度分层、诊断到移植的时间、HCT-CI指数、移植前微小残留病灶、GVHD预防方案中是否含有抗人胸腺细胞免疫球蛋白、移植后急慢性GVHD与移植后复发相关，纳入多因素Logistics回归分析，结果显示，移植前残留病灶与复发呈正相关，移植后慢性GVHD与复发呈负相关.成人急性白血病异基因外周血造血干细胞移植后复发率为31.0%，AML患者移植后长期生存率优于ALL患者,移植后复发患者长期生存率显著低于未复发患者。移植前微小残留病灶阳性是移植后复发的高危因素，移植后合并慢性GVHD的患者复发风险降低.

This work did a new exploration towards aminothiazolquinolone oximes as potentially multi-targeting antimicrobial agents. A class of novel hybrids of quinolone, aminothiazole, piperazine and oxime fragments were designed for the first time, conveniently synthesized as well as characterized by 1H NMR, 13C NMR and HRMS spectra. Biological activity showed that some of the synthesized compounds exhibited good antimicrobial activities in comparison with the reference drugs. Especially, O-methyl oxime derivative 10b displayed excellent inhibitory efficacy against MRSA and S. aureus 25923 with MIC values of 0.009 and 0.017 mM, respectively. Further studies indicated that the highly active compound 10b showed low toxicity toward BEAS-2B and A549 cell lines and no obvious propensity to trigger the development of bacterial resistance. Quantum chemical studies have also been conducted and rationally explained the structural features essential for activity. The preliminarily mechanism exploration revealed that compound 10b could not only exert efficient membrane permeability by interfering with the integrity of cells, bind with topoisomerase IV–DNA complex through hydrogen bonds and π-π stacking, but also form a steady biosupramolecular complex by intercalating into DNA to exert the efficient antibacterial activity. The supramolecular interaction between compound 10b and human serum albumin (HSA) was a static quenching, and the binding process was spontaneous, where hydrogen bonds and van der Waals force played vital roles in the supramolecular transportation of the active compound 10b by HSA.

Direct conversion of readily available non-neural cells from patients into induced neurons holds great promise for neurological disease modeling and cell-based therapy. Olfactory ensheathing cells (OECs) is a unique population of glia in olfactory nervous system. Based on the regeneration-promoting properties and the relative clinical accessibility, OECs are attracting increasing attention from neuroscientists as potential therapeutic agents for use in neural repair. Here, we report that OECs can be directly, rapidly and efficiently reprogrammed into neuronal cells by the single transcription factor Neurogenin 2 (NGN2). These induced cells exhibit typical neuronal morphologies, express multiple neuron-specific markers, produce action potentials, and form functional synapses. Genome-wide RNA-sequencing analysis shows that the transcriptome profile of OECs is effectively reprogrammed towards that of neuronal lineage. Importantly, these OEC-derived induced neurons survive and mature after transplantation into adult mouse spinal cords. Taken together, our study provides a direct and efficient strategy to quickly obtain neuronal cells from adult OECs, suggestive of promising potential for personalized disease modeling and cell replacement-mediated therapeutic approaches to neurological disorders.

The detection of circulating tumor cells (CTCs) is crucial to early cancer diagnosis and the evaluation of cancer metastasis. However, it remains challenging due to the scarcity of CTCs in the blood. Herein, we report an ultrasensitive platform for the direct detection of CTCs using luminescent lanthanide nanoprobes. These were designed to recognize the epithelial cell adhesion molecules on cancer cells, allowing signal amplification through dissolution-enhanced time-resolved photoluminescence (TRPL) and the elimination of short-lived autofluorescence interference. This enabled the direct detection of blood breast-cancer cells with a limit of detection down to 1 cell/well of a 96-well plate. Moreover, blood CTCs (≥10 cells mL-1 ) can be detected in cancer patients with a detection rate of 93.9 % (14/15 patients). We envision that this ultrasensitive detection platform with excellent practicality may provide an effective strategy for early cancer diagnosis and prognosis evaluation.