Exploring the Mediating Role of Multiple Organ Dysfunction in Sepsis-Induced Disseminated Intravascular Coagulation and Its Impact on Worsening Prognosis.

Disseminated intravascular coagulation (DIC) poses a high mortality risk, yet its exact impact remains contentious. This study investigates DIC's association with mortality in individuals with sepsis, emphasizing multiple organ function. Using data from the Peking University People's Hospital Investigation on Sepsis-Induced Coagulopathy database, we categorized patients into DIC and non-DIC groups based on DIC scores within 24 h of ICU admission (< 5 cutoff). ICU mortality was the main outcome. Initial data comparison preceded logistic regression analysis of mortality factors post-propensity score matching (PSM). Employing mediation analysis estimated direct and indirect associations. Of 549 participants, 131 were in the DIC group, with the remaining 418 in the non-DIC group. Following baseline characteristic presentation, PSM was conducted, revealing significantly higher nonplatelet sequential organ failure assessment (nonplt-SOFA) scores (6.3 ± 2.7 vs 5.0 ± 2.5, P < 0.001) and in-hospital mortality rates (47.3% vs 29.5%, P = 0.003) in the DIC group. A significant correlation between DIC and in-hospital mortality persisted (OR 2.15, 95% CI 1.29-3.59, P = 0.003), with nonplt-SOFA scores (OR 1.16, 95% CI 1.05-1.28, P = 0.004) and hemorrhage (OR 2.33, 95% CI 1.08-5.03, P = 0.032) as predictors. The overall effect size was 0.1786 (95% CI 0.0542-0.2886), comprising a direct effect size of 0.1423 (95% CI 0.0153-0.2551) and an indirect effect size of 0.0363 (95% CI 0.0034-0.0739), with approximately 20.3% of effects mediated. These findings underscore DIC's association with increased mortality risk in patients with sepsis, urging anticoagulation focus over bleeding management, with organ dysfunction assessment recommended for anticoagulant treatment efficacy.

Myeloproliferative neoplasm with eosinophilia and coexisting BCR::ABL1 and PDGFRB rearrangement: favorable and rapid response to imatinib.

Here, we present a rare case of myeloproliferative neoplasms (MPN) with eosinophilia harboring both BCR::ABL1 and PDGFRB rearrangements, posing a classification dilemma. The patient exhibited clinical and laboratory features suggestive of chronic myeloid leukemia (CML) and myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK), highlighting the diagnostic challenges associated with overlapping phenotypes. Despite the complexity, imatinib treatment swiftly achieved deep molecular remission, underscoring the therapeutic efficacy of tyrosine kinase inhibitors in such scenarios. Furthermore, the rapid attainment of deep remission by this patient in response to imatinib closely resembles that observed in MLN-TK patients with PDGFRB rearrangements. Further research is warranted to elucidate the underlying mechanisms driving the coexistence of multiple oncogenic rearrangements in MPNs and to optimize therapeutic strategies for these complex cases.

Trueness of different digital design methods for incisal guidance of maxillary anterior implant-supported single crowns / 北京大学学报(医学版)

Objective:To compare the trueness of incisal guidance of implant-supported single crowns designed by patient-specific motion(PSM)with that designed by average-value virtual articulator(AVA).Methods:The study had recruited 12 participants with complete dentition and stable incisal guidance.An intraoral scanner was used to scan digital casts and record two types of patient-specific mo-tion(data only including protrusive movement,and data including protrusive movement and lateral pro-trusive movement).The lingual surfaces of the maxillary incisors which guided the protrusive movement was selected and elevated to create a reference cast.A maxillary central incisor of original casts was vir-tually extracted and implanted to generate a working cast.The Dental system software program was used to design implant-supported single crowns with the anatomical coping design method.The incisal guidance was designed by different methods.The incisal guidance in control group was designed by the average-value virtual articulator.The incisal guidance in experiment groups was designed by the patient-specific motion only including protrusive movement(PSM1)and with the patient-specific motion including protru-sive movement and lateral protrusive movement(PSM2).The incisal guidance of prosthesis designed by these 3 methods were compared with the original incisal guidance in Geomagic Control 2015(3DSystem,America).The measurements included:Average of positive values,ratio of positive area and maximum value reflecting supra-occlusion;average of negative values,ratio of negative area and minimum value re-flecting over-correction;and root mean square reflecting overall deviation.Results:Statistical data were collected using the median(interquartile range)method.The average of positive values,ratio of positive area and average of negative values of the PSM2 group were smaller than those of the control group[8.0(18.8)μm vs.37.5(47.5)μm;0vs.7.2％(38.1％);-109.0(63.8)μm vs.-66.5(64.5)μm],and the ratio of negative area of PSM2 group was larger than those of the control group[52.9％(47.8％)vs.17.3％(45.3％)],with significant differences(P all＜0.05).The ratio of positive area[0.1％(7.0％)]and average of negative values[-97.0(61.5)μm]of PSM1 group,were smaller than those of the control group,and the ratio of negative area[40.7％(39.2％)]of the PSM1 group was larger than that of the control group,with significant differences(P＜0.05).The average of positive values[20.0(42.0)μm]and ratio of positive area of PSM1 group was larger than that of the PSM2 group with significant differences(P＜0.05).Conclusion:To establish the incisor guidance of implant-supported single crowns,compared with the average-value virtual articulator and the patient-specific motion only including protrusive movement,the patient-specific motion including protrusive movement and lateral protrusive movement is more conducive to reducing the protrusive interference of prosthesis and improving the occlusal fit.

Tooth number abnormality: from bench to bedside / 国际口腔科学杂志·英文版

Tooth number abnormality is one of the most common dental developmental diseases, which includes both tooth agenesis and supernumerary teeth. Tooth development is regulated by numerous developmental signals, such as the well-known Wnt, BMP, FGF, Shh and Eda pathways, which mediate the ongoing complex interactions between epithelium and mesenchyme. Abnormal expression of these crutial signalling during this process may eventually lead to the development of anomalies in tooth number; however, the underlying mechanisms remain elusive. In this review, we summarized the major process of tooth development, the latest progress of mechanism studies and newly reported clinical investigations of tooth number abnormality. In addition, potential treatment approaches for tooth number abnormality based on developmental biology are also discussed. This review not only provides a reference for the diagnosis and treatment of tooth number abnormality in clinical practice but also facilitates the translation of basic research to the clinical application.

Analysis of work stress and its influencing factors among nursing staff in Tianjin City / 中华劳动卫生职业病杂志

Objective: To explore the current situation of work stress among nursing staff in Tianjin City and analyze its influencing factors. Methods: From August to October 2020, 26002 nursing staff from tertiary hospitals, secondary public hospitals, secondary private hospitals, primary hospitals, and other medical institutions in Tianjin City were selected as objects, and their general situation and working stress situation were surveyed by the general information questionnaire and the Nurse's Work Stressor Scale. Single factor analysis and multiple linear regression analysis were used to explore the influencing factors of work stress among nursing staff. Results: The average age of 26002 nursing staff was (33.86±8.28) years old, and the average working years were (11.84±9.12) years. There were 24874 women (95.66%) and 1128 men (4.34%). The total score of work stress was (79.82±21.69), and the average score of workload and time allocation dimension was the highest (2.55±0.79). The results of multiple linear regression analysis showed that marital status (β=-0.015, P=0.014), employment form as contract system (β=0.022, P=0.001), post as clinical nursing (β=0.048, P<0.001), education level (β=0.024, P<0.001), age (β=0.050, P<0.001), working years (β=0.075, P<0.001), and professional title (β=0.036, P<0.001) were the influencing factors of work stress, which explained 22.8% of the total variation in work stress of nursing staff (F=24.25, P<0.001) . Conclusion: The work stress among nursing staff in Tianjin City is high, the corresponding departments and nursing managers should adopt scientific management methods to reduce the workload of nursing staff according to the influencing factors of work stress, so as to create a good atmosphere for further promoting the healthy development of nursing career and nursing industry in the new era.

Short-term efficacy of camrelizumab combined with induction chemotherapy followed by concurrent chemoradiotherapy for patients with locally advanced nasopharyngeal carcinoma / 中华放射医学与防护杂志

Objective:To investigate the clinical effect and safety of camrelizumab combined with induction chemotherapy followed by concurrent chemoradiotherapy for patients with locally advanced nasopharyngeal carcinoma (NPC).Methods:A total of 24 patients with stage Ⅲ-IV A NPC were recruited prospectively to receive two cycles of camrelizumab combined with induction chemotherapy (docetaxel 75 mg/m 2+ cisplatin 25 mg/m 2 for three consecutive days) followed by concurrent chemoradiotherapy (prescription doses: 6 996 cGy in 33 fractions for PGTV and PGTV nd, 6 006 cGy in 33 fractions for PTV 1, 5 096 cGy in 28 fractions for PTV 2, and concurrent cisplatin chemotherapy with a dose of 75 mg/m 2). The short-term efficacy and adverse reactions were evaluated. Results:After induction therapy, nasopharyngeal lesions showed an objective response rate (ORR) of 91.6%, including 45.8% of complete response (CR) and 45.8% of partial response (PR); cervical lymph nodes showed an ORR of 95.8% (CR: 4.2%; PR: 91.6%). Seventeen patients accepted a reexamination under a nasopharyngoscope, and the biting biopsy result indicated that 13 patients among them had complete pathologic response. After concurrent chemoradiotherapy, nasopharyngeal lesions and cervical lymph nodes showed CR rates of 83.3% and 91.7% and PR rates of 16.7% and 8.3%, respectively. After the induction therapy, 13 patients with stage IV A NPC had ORR (PR) rates of 92.4% and 92.4%, respectively, at nasopharyngeal lesions and cervical lymph nodes. After concurrent chemoradiotherapy, the patients with stage IV A NPC had CR rates of 84.6% and 92.3% and PR rates of 15.4% and 7.7%, respectively, at nasopharyngeal lesions and cervical lymph nodes. Major adverse reactions include leukopenia, granulopenia, anemia, radioactive acute oropharyngeal mucositis and dermatitis, digestive tract reaction, fatigue, hypothyroidism, aminotransferase elevation, and reactive capillary hyperplasia. Conclusions:Camrelizumab combined with induction chemotherapy followed by concurrent chemoradiotherapy can achieve high short-term efficacy for patients with locally advanced nasopharyngeal carcinoma, without increasing the incidence of adverse reactions. Its long-term efficacy deserves further research.

Analysis of Related Factors Affecting the Risk Assessment of Death during Hospitalization of Extremely Low Birth Weight Infants / 中山大学学报(医学科学版)

ObjectiveTo explore the influencing factors of different scores on predicting death risk of extremely low birth weight infants （ELBWI）. MethodsA total of 186 cases of ELBWI admitted by the Children's Hospital affiliated to Nanjing Medical University and the Lishui Branch of the Affiliated Zhongda Hospital of Southeast University were admitted from January 1， 2019 to January 1， 2021， and 125 ELBWIs were finally included after screening by inclusion and exclusion criteria. There were 47 cases in the death group and 78 cases in the survival group. General data and the items of score for neonatal acute physiology version Ⅱ （SNAP-Ⅱ）， simplified version of the score for neonatal acute physiology perinatal extension （SNAPPE-Ⅱ）， clinical risk index for babies （CRIB）， clinical risk index for babies Ⅱ （CRIB-Ⅱ） and the national critical illness score （NCIS） were collected. Univariate and multivariate analysis was performed and nomogram was evaluated using receiver operating characteristic curve （ROC）. ResultsIt was found that systolic blood pressure， maximum inhaled oxygen concentration， BE value and birth weight were important factors in ELBWI mortality risk assessment ［systolic blood pressure OR： 0.968， 95%CI： 0.938-0.999， P=0.043； maximum inhaled oxygen concentration OR： 1.020， 95%CI： 1.006-1.034， P=0.006； BE OR： 0.868， 95%CI： 0.786-0.959， P=0.005； birth weight OR： 0.994， 95%CI： 0.991-0.997， P=0.000］. ROC showed that the area under the curve of the above four variables is 0.71， and the 95% confidence interval is 0.610-0.799， which is better than CRIB score. ConclusionLower systolic blood pressure， higher inhaled oxygen concentration， higher BE and lower birthweight are important influencing factors to predict the death risk of ELBWI. The above four items should be included in the newly developed score assessment to obtain a more effective ELBWI prediction system.

Efficacy and Safety of Allogeneic Hematopoietic Stem Cell Transplantation with Decitabine-containing Regimen in Myelodysplastic Syndromes and Myelodysplastic Syndromes Transformed Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with decitabine (Dec)-conditioning regimen in the treatment of myelodysplastic syndrome (MDS) and MDS transformed acute myeloid leukemia (MDS-AML).@*METHODS@#The characteristics and efficacy data of 93 patients with MDS and MDS-AML who received allo-HSCT in our center from April 2013 to November 2021 were retrospectively analyzed. All patients were administered by myeloablative conditioning regimen containing Dec (25 mg/m2 /d×3 d).@*RESULTS@#Among the 93 patients, 63 males and 30 females, were diagnosed as MDS（n ＝77）, MDS-AML（n ＝16）. The incidence of I/II grade regimen-related toxicity (RRT) was 39.8%, and III grade RRT was only found in 1 patient (1%). Neutrophil engraftment was successful in 91 (97.8%) patients after a median neutrophil engraftment time of 14 (9-27) days; Successful platelet engraftment was achieved in 87 (93.5%) patients, with a median engraftment time of 18 (9-290) days. The incidence of acute graft versus host disease（aGVHD） and grade III-IV aGVHD was 44.2% and 16.2%, respectively. The incidence of chronic graft versus host disease（cGVHD） and moderate-to-severe cGVHD was 59.5% and 37.1%, respectively. Of the 93 patients, 54 (58%) developed posttransplant infections, among which lung infection (32.3%) and bloodstream infection (12.9%) were the most common. The median follow-up after transplantation was 45 (0.1-108) months. The 5-year overall survival (OS) rate, disease-free survival (DFS) rate, treatment-related mortality, and cumulative incidence of relapse were 72.7%, 68.4%, 25.1%, and 6.5%, respectively. And the 1-year graft-versus-host disease/relapse-free survival rate was 49.3%. The patients in different group of relative high-risk prognostic scoring or low-risk prognostic scoring, with or without poor-risk mutation(s), with mutations number ≥3 or <3 had similar 5-year OS rate (more than 70%). Multivariate analysis showed that the incidence of grade III-IV aGVHD was the independent risk factor affecting OS（P =0.008）and DFS (P =0.019).@*CONCLUSION@#Allo-HSCT with Dec-conditioning regimen is feasible and effective in the treatment of patients with MDS and MDS-AML, especially those in high prognostic risk and with poor-risk mutations.

Primary cilia support cartilage regeneration after injury / 国际口腔科学杂志·英文版

In growing children, growth plate cartilage has limited self-repair ability upon fracture injury always leading to limb growth arrest. Interestingly, one type of fracture injuries within the growth plate achieve amazing self-healing, however, the mechanism is unclear. Using this type of fracture mouse model, we discovered the activation of Hedgehog (Hh) signaling in the injured growth plate, which could activate chondrocytes in growth plate and promote cartilage repair. Primary cilia are the central transduction mediator of Hh signaling. Notably, ciliary Hh-Smo-Gli signaling pathways were enriched in the growth plate during development. Moreover, chondrocytes in resting and proliferating zone were dynamically ciliated during growth plate repair. Furthermore, conditional deletion of the ciliary core gene Ift140 in cartilage disrupted cilia-mediated Hh signaling in growth plate. More importantly, activating ciliary Hh signaling by Smoothened agonist (SAG) significantly accelerated growth plate repair after injury. In sum, primary cilia mediate Hh signaling induced the activation of stem/progenitor chondrocytes and growth plate repair after fracture injury.

Evaluating coronary artery calcification with low-dose chest CT reconstructed by different kernels.

PURPOSE: To understand the reliability of low-dose chest computed tomography (LDCT) in coronary artery calcification (CAC) assessment and evaluate the performance of different reconstruction kernels against the standard cardiac computed tomography (CaCT) as reference. MATERIALS AND METHODS: Patients from the NELCIN-B3 screening program who underwent CaCT and LDCT scans were analyzed retrospectively. LDCT were reconstructed with smooth, standard, and sharp kernels (Group B1, B2 and B3) to compare against standard CaCT (Group A). The image quality was evaluated by noise value, signal-to-noise ratio (SNR), and contrast to noise ratio (CNR); moreover, radiation dose was recorded for both scans. Coronary artery calcification scores (CACS) were measured with volume, mass and Agatston standards. Agatston score was divided into four cardiovascular risk categories (0, 1-99, 100-399, and >400). The agreement in CACS and risk classification between LDCT and CaCT was analyzed by intra-group correlation coefficient (ICC) and Kappa test. RESULTS: The sensitivity of diagnosing CAC with LDCT was 98.5% (330/335) regardless of reconstruction kernels. Group B1 demonstrated the highest agreement in raw CACS (ICC volume 0.932; mass 0.904; Agatston 0.906; all p < 0.001) and risk classification (kappa 0.757, 95% CI 0.70-0.82). Smooth-kernel reconstruction achieved lower image noise, better SNR and CNR than other kernels. The effective radiation dose in of LDCT was 41.2% lower than that of the calcium scan (p < 0.001). CONCLUSION: Reconstructing LDCT with a smooth kernel in LDCT could provide a reliable imaging method to detect and quantitatively evaluate CAC, potentially expanding the application of LDCT lung screening to incidental findings of cardiovascular disease.

Tracing PRX1+ cells during molar formation and periodontal ligament reconstruction / 国际口腔科学杂志·英文版

Neural crest-derived mesenchymal stem cells (MSCs) are known to play an essential function during tooth and skeletal development. PRX1+ cells constitute an important MSC subtype that is implicated in osteogenesis. However, their potential function in tooth development and regeneration remains elusive. In the present study, we first assessed the cell fate of PRX1+ cells during molar development and periodontal ligament (PDL) formation in mice. Furthermore, single-cell RNA sequencing analysis was performed to study the distribution of PRX1+ cells in PDL cells. The behavior of PRX1+ cells during PDL reconstruction was investigated using an allogeneic transplanted tooth model. Although PRX1+ cells are spatial specific and can differentiate into almost all types of mesenchymal cells in first molars, their distribution in third molars is highly limited. The PDL formation is associated with a high number of PRX1+ cells; during transplanted teeth PDL reconstruction, PRX1+ cells from the recipient alveolar bone participate in angiogenesis as pericytes. Overall, PRX1+ cells are a key subtype of dental MSCs involved in the formation of mouse molar and PDL and participate in angiogenesis as pericytes during PDL reconstruction after tooth transplantation.

Case Report: Combination Therapy With PD-1 Blockade for Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation Resulted in Fatal GVHD.

Background: Azacitidine is commonly used in the treatment of relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the effectiveness of this monotherapy is still very low. A possible mechanism of resistance to hypomethylating agents (HMAs) is the upregulation of the expression of inhibitory checkpoint receptors and their ligands, making the combination of HMAs and immune checkpoint blockade therapy a rational approach. Although the safety of anti-programmed cell death protein (PD)-1 antibodies for patients with post-allo-HSCT remains a complicated issue, the preliminary clinical result of combining azacitidine with anti-PD-1 antibodies is encouraging; however, the safety and efficacy of this approach need further investigation. Case Presentation: We reported a case of treated secondary (ts)-AML in a patient who received tislelizumab (an anti-PD-1 antibody) in combination with azacitidine. The patient relapsed after allo-HSCT and was previously exposed to HMAs-based therapy. The patient received tislelizumab for compassionate use. After the combination treatment, the patient achieved complete remission with incomplete hematologic recovery, negative minimal residual disease (MRD) by flow cytometry (FCM), and negative Wilms' tumor protein 1 (WT1). However, the patient successively developed serious immune-related adverse events (irAEs) and graft vs. host disease (GVHD) and eventually died from complications of GVHD. Conclusion: To our knowledge, this is the first case to report the combined use of tislelizumab and azacitidine to treat relapsed AML posttransplantation. This report highlights the safety concerns of using an anti-PD-1 antibody in combination with azacitidine after allo-HSCT, especially the risk of GVHD, and provides a basis for future studies.

Primary cilia in hard tissue development and diseases / 医学前沿

Bone and teeth are hard tissues. Hard tissue diseases have a serious effect on human survival and quality of life. Primary cilia are protrusions on the surfaces of cells. As antennas, they are distributed on the membrane surfaces of almost all mammalian cell types and participate in the development of organs and the maintenance of homeostasis. Mutations in cilium-related genes result in a variety of developmental and even lethal diseases. Patients with multiple ciliary gene mutations present overt changes in the skeletal system, suggesting that primary cilia are involved in hard tissue development and reconstruction. Furthermore, primary cilia act as sensors of external stimuli and regulate bone homeostasis. Specifically, substances are trafficked through primary cilia by intraflagellar transport, which affects key signaling pathways during hard tissue development. In this review, we summarize the roles of primary cilia in long bone development and remodeling from two perspectives: primary cilia signaling and sensory mechanisms. In addition, the cilium-related diseases of hard tissue and the manifestations of mutant cilia in the skeleton and teeth are described. We believe that all the findings will help with the intervention and treatment of related hard tissue genetic diseases.

Progress in clinical research of congenital membranous cataract / 国际眼科杂志(Guoji Yanke Zazhi)

@#Congenital cataract is one of the leading causes of childhood blindness and congenital membranous cataract is a rare and special type of congenital cataract. The lens fibre of congenital membranous cataract is degenerative and its cortex is absorbed gradually. Congenital membranous cataract also has another name, pseudoaphakia, due to the similar phenotype with posterior capsule opacification after cataract surgery, but without intraocular refractive power. There are few reports on congenital membranous cataract at home and abroad, and the research on the pathogenesis of congenital membranous cataract is even less. Clarifying the pathogenesis of congenital membranous cataract, especially the genetics, is very helpful for us to understand the pathogenesis of congenital cataract and the molecular mechanism of lens development.

Selection of an artificial paraquat-specific binding protein from a ribosome display library based on a lipocalin scaffold.

In this study, an anticalin that could specifically bind paraquat (PQ), a quaternary nitrogen herbicide, as a new set of engineered receptor protein with antibody-like properties was generated to detect PQ concentration. To this end, a native and random library was constructed and engineered to allow in vitro transcription and translation using an Escherichia coli lysate system. Meanwhile, a PQ derivative that carries an active aliphatic carboxylate group at the end of an aliphatic spacer arm was synthesized. Then, this compound was coupled covalently to the carrier protein bovine serum albumin/ovalbumin and amino-functionalized paramagnetic beads. Alternating selection in solution and immobilization in microtiter wells were used to pan mRNA-ribosome-antibody complexes. After several rounds of ribosome display, three variants were selected from a random library of the bilin-binding protein. The variants that could bind complex PQ with high affinity and exhibit IC50 values as low as 14.039 ± 0.970 ng/mL were identified. Moreover, the limits of detection reached 0.083 ± 0.011 ng/mL. Our data suggest that the generation of anticalins may provide a promising alternative to recombinant antibody fragments to create a stable receptor protein against hapten with bioanalytical relevance.

Double Lock of a Potent Human Monoclonal Antibody against SARS-CoV-2

Receptor recognition and subsequent membrane fusion are essential for the establishment of successful infection by SARS-CoV-2. Halting these steps can cure COVID-19. Here we have identified and characterized a potent human monoclonal antibody, HB27, that blocks SARS-CoV-2 attachment to its cellular receptor at sub-nM concentrations. Remarkably, HB27 can also prevent SARS-CoV-2 membrane fusion. Consequently, a single dose of HB27 conferred effective protection against SARS-CoV-2 in two established mouse models. Rhesus macaques showed no obvious adverse events when administrated with 10-fold of effective dose of HB27. Cryo-EM studies on complex of SARS-CoV-2 trimeric S with HB27 Fab reveal that three Fab fragments work synergistically to occlude SARS-CoV-2 from binding to ACE2 receptor. Binding of the antibody also restrains any further conformational changes of the RBD, possibly interfering with progression from the prefusion to the postfusion stage. These results suggest that HB27 is a promising candidate for immuno-therapies against COVID-19. HighlightsO_LISARS-CoV-2 specific antibody, HB27, blocks viral receptor binding and membrane fusion C_LIO_LIHB27 confers prophylactic and therapeutic protection against SARS-CoV-2 in mice models C_LIO_LIRhesus macaques showed no adverse side effects when administered with HB27 C_LIO_LICryo-EM studies suggest that HB27 sterically occludes SARS-CoV-2 from its receptor C_LI

Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody

The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in an unprecedented public health crisis. There are no approved vaccines or therapeutics for treating COVID-19. Here we reported a humanized monoclonal antibody, H014, efficiently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nM level by engaging the S receptor binding domain (RBD). Importantly, H014 administration reduced SARS-CoV-2 titers in the infected lungs and prevented pulmonary pathology in hACE2 mouse model. Cryo-EM characterization of the SARS-CoV-2 S trimer in complex with the H014 Fab fragment unveiled a novel conformational epitope, which is only accessible when the RBD is in open conformation. Biochemical, cellular, virological and structural studies demonstrated that H014 prevents attachment of SARS-CoV-2 to its host cell receptors. Epitope analysis of available neutralizing antibodies against SARS-CoV and SARS-CoV-2 uncover broad cross-protective epitopes. Our results highlight a key role for antibody-based therapeutic interventions in the treatment of COVID-19. One sentence summaryA potent neutralizing antibody conferred protection against SARS-CoV-2 in an hACE2 humanized mouse model by sterically blocking the interaction of the virus with its receptor.

Molecular epidemiology and virulence characteristics of polymyxin-resistant Klebsiella pneumonia / 中华传染病杂志

Objective:To analyze the molecular epidemiology and virulence characteristics of polymyxin-resistant Klebsiella pneumoniae ( K. pneumoniae). Methods:From 2011 to 2016, 1 376 strains of K. pneumoniae were isolated from various clinical specimens of hospitalized patients in First Affiliated Hospital of Wenzhou Medical University. Agar dilution method was used to screen out the polymyxin-resistant strains.Polymerase chain reaction (PCR) was used to detect the genes related to polymyxin resistance, and real-time fluorescence quantitative PCR was used to detect the relative mRNA expression level of drug resistant genes. Pulsed-field gel electrophoresis, multilocus sequence typing and Galleria mellonella larvae infection model were performed to analyze the molecular epidemiological and virulent characteristics. Results:A total of 14 strains (1.02%) of polymyxin-resistant K. pneumoniae were detected among 1 376 K. pneumoniae isolates. Subsequent sequencing identified mutations leading to amino-acid changes (K2E, F28C) in MgrB of 10 isolates and D150G in PhoQ of nine isolates, and genes such as mcr and crrB were not detected in all drug-resistant strains. Compared with standard strains, the relative expression levels of pmrH and pmrD mRNA of these drug resistant strains were increased. Analysis of the molecular epidemiology indicated that the 14 drug-resistant strains were divided into nine clones. Galleria mellonella larvae infection model revealed polymyxin-resistant K. pneumoniae isolates had higher virulence. Conclusions:Polymyxin-resistant K. pneumoniae has mutations in mgrB and phoQ genes, and mgrB mutation may play a key role in the change of virulence profiles. The homology among the polymyxin-resistant K. pneumoniae stains in this study is low.

Prevalence and characteristics of clinical Aeromonas isolates carrying mcr-3 gene / 中华微生物学和免疫学杂志

Objective:To investigate the prevalence and characteristics of mcr genes in clinical isolates of Aeromonas spp. in our hospital, and provide reference for clinical analysis of the prevalence and expression of colistin resistance genes. Methods:Polymerase chain reaction (PCR) was used to detect mcr genes in 183 Aeromonas spp. strains. The minimum inhibitory concentrations (MICs) of colistin and polymyxin against mcr-positive Aeromonas spp. were detected by micro broth dilution method. Broth conjugation and filter mating conjugation were performed. Whole genome sequencing was used to analyze the genetic environment of mcr-3 gene in Aeromonas spp.. A recombinant Escherichia coli ( E. coli) DH5α-pGEM-T: : p mcr-3 strain was constructed to verify the expression of mcr-3 gene. Results:The positive rate of mcr-3 gene in 183 strains of Aeromonas spp. was 2.19% (4/183). No mcr-1 or mcr-2 gene was detected among these isolates. Antimicrobial susceptibility test showed that four mcr-3-carrying Aeromonas hydrophilia ( A. hydrophilia) strains were sensitive to colistin and polymyxin (MIC<2 μg/ml). Conjugation experiments indicated that mcr-3 gene could not be transferred between strains. Whole-genome sequencing analysis suggested that the mcr-3 genes carried by the A. hydrophilia isolates belonged to mcr-3.2 and mcr-3-like variants, and no adjacent transfer element was detected upstream and downstream. The recombinant E. coli DH5α-pGEM-T: : p mcr-3 strain was sensitive to colistin (MIC=2 μg/ml). Conclusions:The clinical isolates of A. hydrophilia in our hospital carried mcr-3 gene, but does not exhibit colistin resistance, and no evidence supported the transfer of mcr-3 gene for the time being.

Research progress in regulatory effect of sulforaphane on diabetes and fatty liver disease / 中国药理学与毒理学杂志

The intervention of sulforaphane can reduce the risk of diabetes and its complications. It is mainly achieved by regulating nuclear factor erythroid-2-related factor 2 (Nrf2) to inhibit endothelial cell activation and improve high density lipoprotein levels. In addition, sulforaphane can bring about a marked improvement on fatty liver disease by regulating lipid metabolism. Its important pathways include the regulation of peroxisome proliferators-activated receptors y (PPARy), hormone-sensitive triglyceride lipase (HSL) and AMP-activated protein kinase (AMPK) regulation promotes lipolysis. In summary, further exploration of the mechanism of action of plant-derived functional ingredients of sulforaphane may be the key to preventing and treating diabetes and fatty liver disease.