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Yanan Xu,1,* Ying Jing,2,* Lingfei Hu,2 Qiaoxiang Cheng,1 Huixia Gao,3 Zhi Zhang,3 Huiying Yang,2 Yuee Zhao,2 Dongsheng Zhou,2 Zhe Yin,2 Erhei Dai1,3 1Department of Clinical Laboratory Medicine, Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China; 2State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, People’s Republic of China; 3Department of Laboratory Medicine, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, Hebei, 050021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Erhei Dai; Zhe Yin, Tel +86-311-85814612 ; +86-10-66948557, Email daieh2008@126.com; jerry9yin@163.comPurpose: To establish a typing scheme for IncFIB replicon and to dissect genomic features of IncFIB-4.1/4.2 single-replicon plasmids.Methods: A total of 146 representative fully sequenced IncFIB-replicon-containing plasmids were selected to construct a phylogenetic tree of repBIncFIB sequences. A collection of nine IncFIB-4.1/4.2 single-replicon plasmids from China were fully sequenced here and compared with the first sequenced IncFIB-4.1/4.2 single-replicon plasmids from GenBank to dissect their genomic diversity.Results: In this study, a repB sequence-based scheme was proposed for grouping IncFIB replicon into seven primary types and further into 70 subtypes. A collection of nine IncFIB-4.1/4.2 single-replicon plasmids were fully sequenced here and compared with the first sequenced IncFIB-4.1/4.2 single-replicon plasmids from GenBank. These 11 plasmids had small backbones and shared only three key backbone markers repB together with its iterons, parABC, and stbD. Each plasmid contained one large accessory region (LAR) inserted into the backbone, and these 11 LARs had significantly distinct profiles of mobile genetic elements (MGEs) and resistance/metabolism gene loci. Antibiotic resistance regions (ARRs; the antibiotic resistance gene-containing genetic elements) were found in seven of these 11 LARs. Besides resistance genes, ARRs carried unit or composite transposons, integrons, and putative resistance units. IncFIB-4.1/4.2 single-replicon plasmids were important vectors of drug resistance genes. This was the first report of three novel MGEs: In1776, Tn 6755, and Tn 6857.Conclusion: Data presented here provided a deeper insight into diversity and evolution of IncFIB replicon and IncFIB-4.1/4.2 single-replicon plasmids.Keywords: IncFIB, IncFIB-4 single-replicon plasmids, large accessory regions, antibiotic resistance regions, In1776, Tn 6755, Tn 6857

Shujie Wang1,*, Erhei Dai2,*, Xiaoyuan Jiang3, Lijun Zeng3, Qiaoxiang Cheng2,3, Ying Jing3, Lingfei Hu3, Zhe Yin3, Bo Gao3, Jinglin Wang3, Guixin Duan4, Xuehui Cai1, Dongsheng Zhou3 1State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, People’s Republic of China; 2Department of Laboratory Medicine, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, Hebei 050021, People’s Republic of China; 3State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, People’s Republic of China; 4Animal Science and Technology College, Heilongjiang Bayi Agricultural University, Daqing 163000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongsheng ZhouState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, No. 20 Dongdajie Street, Fengtai District, Beijing 100071, People’s Republic of ChinaTel +86 106 694 8503Email dongshengzhou1977@gmail.comXuehui CaiState Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, No. 678 Haping Road, Xiangfang District, Harbin 150069, People’s Republic of ChinaTel +86 4 515 105 1766Email aci139@sina.comBackground: Multiple incompatibility (Inc) groups of plasmids have been identified in Enterobacteriaceae species, but there are still quite a few sequenced plasmids that could not be assigned to any known Inc groups.Methods: One IncFIIpKF727591β plasmid p205880-qnrS and two IncpKPHS1 plasmids p11219-CTXM and p205880-NR1 were fully sequenced in this work. Detailed genomic comparison was applied to all available sequenced plasmids of IncFIIpKF727591 or IncpKPHS1 group.Results: p205880-qnrS carried a novel transposon Tn6396, which was an ISKpn19-compsite transposon and represented a prototype transposable element carrying a minimum core qnrS1 module. p11219-CTXM harbored a novel transposon Tn6559, which was generated from integration of a truncated IS903D–blaCTX-M-14–ISEcp1 unit into the Tn3-family cryptic unit transposon Tn1722. Two Inc groups, IncFIIpKF727591 and IncpKPHS1, of plasmids from Enterobacteriaceae species were proposed, and IncFIIpKF727591 was further grouped into two subgroups IncFIIpKF727591α and IncFIIpKF727591β. Each of the 11 IncFIIpKF727591 plasmids carried multiple accessory modules including at least one resistance module, and the relatively small IncFIIpKF727591 backbones could acquire a wealth of foreign genetic contents. The modular structures of plasmid backbones were conserved within each of IncFIIpKF727591α and IncFIIpKF727591β subgroups but dramatically different, although with similar gene organizations, between these two subgroups. The IncpKPHS1 backbones were conserved with respect to modular structures, and only four of the 14 IncpKPHS1 plasmids carried accessory modules, two of which contained resistance genes.Conclusion: A genomic comparison of sequenced IncpKPHS1 or IncFIIpKF727591 plasmids provides insights into modular differences and genetic diversification of these plasmids, some of which carries antimicrobial resistance genes.Keywords: plasmids, IncFIIpKF727591, IncpKPHS1, Tn6396, Tn6559

The synthesis, structure determination by single-crystal X-ray diffraction, and physical properties are reported and compared for superconducting molecular charge-transfer salts with stoichiometry (BEDT-TTF)(sub 4)[A(super I)M(super III)(C2O4)(sub 3)].PhCN, where A(super I) = H3O, NH4, K; M(super III) = Cr, Fe, Co, Al; BEDT-TTF = bis(ethylenedithio)tetrathisfulvalene. The findings indicate that this difference is responsible for the two different BEDT-TTF packing motifs.

SAR442257, a CD38/CD28/CD3 trispecific antibody, potentiates CAR T-cell activity against large B-cell lymphoma The CD38/CD28xCD3 trispecific antibody SAR442257 boosted CART-cell activity through recognition of CD38 on the tumor, costimulation of CART-cells, and induced fratricide of CD38+ T-cells. CART cell therapy has significantly improved outcomes of patients with relapsed/refractory large B cell lymphoma (rrLBCL), but many do not experience long term benefit. [Extracted from the article]

Objective To implement complex, PINCER (pharmacist led information technology intervention) prescribing indicators, on a national scale with general practice data to describe the impact of the covid-19 pandemic on safe prescribing.Design Population based, retrospective cohort study using federated analytics.Setting Electronic general practice health record data from 56.8 million NHS patients by use of the OpenSAFELY platform, with the approval of the National Health Service (NHS) England.Participants NHS patients (aged 18-120 years) who were alive and registered at a general practice that used TPP or EMIS computer systems and were recorded as at risk of at least one potentially hazardous PINCER indicator.Main outcome measure Between 1 September 2019 and 1 September 2021, monthly trends and between practice variation for compliance with 13 PINCER indicators, as calculated on the first of every month, were reported. Prescriptions that do not adhere to these indicators are potentially hazardous and can cause gastrointestinal bleeds; are cautioned against in specific conditions (specifically heart failure, asthma, and chronic renal failure); or require blood test monitoring. The percentage for each indicator is formed of a numerator of patients deemed to be at risk of a potentially hazardous prescribing event and the denominator is of patients for which assessment of the indicator is clinically meaningful. Higher indicator percentages represent potentially poorer performance on medication safety.Results The PINCER indicators were successfully implemented across general practice data for 56.8 million patient records from 6367 practices in OpenSAFELY. Hazardous prescribing remained largely unchanged during the covid-19 pandemic, with no evidence of increases in indicators of harm as captured by the PINCER indicators. The percentage of patients at risk of potentially hazardous prescribing, as defined by each PINCER indicator, at mean quarter 1 (Q1) 2020 (representing before the pandemic) ranged from 1.11% (age ≥65 years and non-steroidal anti-inflammatory drugs) to 36.20% (amiodarone and no thyroid function test), while Q1 2021 (representing after the pandemic) percentages ranged from 0.75% (age ≥65 years and non-steroidal anti-inflammatory drugs) to 39.23% (amiodarone and no thyroid function test). Transient delays occurred in blood test monitoring for some medications, particularly angiotensin-converting enzyme inhibitors (where blood monitoring worsened from a mean of 5.16% in Q1 2020 to 12.14% in Q1 2021, and began to recover in June 2021). All indicators substantially recovered by September 2021. We identified 1 813 058 patients (3.1%) at risk of at least one potentially hazardous prescribing event.Conclusion NHS data from general practices can be analysed at national scale to generate insights into service delivery. Potentially hazardous prescribing was largely unaffected by the covid-19 pandemic in primary care health records in England.

Abdominal aortic aneurysms are often fatal due to atherosclerosis, thromboembolism, rupture, and hemorrhage, however, treatment is limited to expectant monitoring and surgical intervention. Inflammation is detected in aneurysms and in plaque with associated increased apoptosis, chemokines, cytokines, hemorrhage, and thrombosis. We compared treatment with three different myxomavirus-derived anti-inflammatory proteins targeting apoptosis, thrombosis, and chemokine pathways. The effect of each protein on aortic dilatation and plaque growth was assessed after angioplasty in Apolipoprotein Enull mice. Four myxomavirus-derived proteins were studied; Serp-1 a serine protease inhibitor (serpin) targeting thrombotic and thrombolytic proteases, Serp-2 a cross-class serpin inhibiting granzyme B and caspases 1 and 8, M-T7 a broad spectrum C, CC, and CXC chemokine inhibitor, and R171E, an inactive M-T7 mutant. Cell invasion, elastin breaks, plaque progression, and aortic dilatation were significantly reduced by Serp-1, Serp-2, or M-T7 protein treatment, but not by R171E. PCR array analysis detected altered expression of a group of shared 40 apoptotic genes in monocytes after treatment with each active protein, but not R171E. Interference with inflammatory cell responses, through highly divergent inflammatory response pathways, produces similar reductions in monocyte invasion, arterial dilatation, and plaque growth potentially through modified expression of apoptotic genes. [ABSTRACT FROM AUTHOR]

The clinical efficacy for treating of celastrol rheumatoid arthritis (RA) has been well-documented, but its mechanism of action remains unclear. Here we explored through what proteins and processes celastrol may act in activated fibroblast-like synoviocytes (FLS) from RA patients. Differential expression of genes and proteins after celastrol treatment of FLS was examined using RNA sequencing, label-free relatively quantitative proteomics and molecular docking. In this paper, expression of 26,565 genes and 3,372 proteins was analyzed. Celastrol was associated with significant changes in genes that respond to oxidative stress and oxygen levels, as well as genes that stabilize or synthesize components of the extracellular matrix. These results identify several potential mechanisms through which celastrol may inhibit inflammation in RA.