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关键词： cell death   cell size   Escherichia coli   experimental evolution   natural selection   organismal fitness  

摘要： Bacteria adopt a wide variety of sizes and shapes, with many species exhibiting stereotypical morphologies. How morphology changes, and over what timescales, is less clear. Previous work examining cell morphology in an experiment with Escherichia coli showed that populations evolved larger cells and, in some cases, cells that were less rod-like. That experiment has now run for over two more decades. Meanwhile, genome sequence data are available for these populations, and new computational methods enable high-throughput microscopic analyses. In this study, we measured stationary-phase cell volumes for the ancestor and 12 populations at 2,000, 10,000, and 50,000 generations, including measurements during exponential growth at the last time point. We measured the distribution of cell volumes for each sample using a Coulter counter and microscopy, the latter of which also provided data on cell shape. Our data confirm the trend toward larger cells while also revealing substantial variation in size and shape across replicate populations. Most populations first evolved wider cells but later reverted to the ancestral length-to-width ratio. All but one population evolved mutations in rod shape maintenance genes. We also observed many ghost-like cells in the only population that evolved the novel ability to grow on citrate, supporting the hypothesis that this lineage struggles with maintaining balanced growth. Lastly, we show that cell size and fitness remain correlated across 50,000 generations. Our results suggest that larger cells are beneficial in the experimental environment, while the reversion toward ancestral length-to-width ratios suggests partial compensation for the less favorable surface area-to-volume ratios of the evolved cells. IMPORTANCE Bacteria exhibit great morphological diversity, yet we have only a limited understanding of how their cell sizes and shapes evolve and of how these features affect organismal fitness. This knowledge gap reflects, in part, the

关键词： RSAD2   Primary Sjogren's syndrome   B cell   NF-kappa b  

摘要： Primary Sjogren's syndrome (pSS) is a chronic autoimmune disease that is mainly characterized as abnormal activation of B cells. It is reported that radical s-adenosyl methionine domain-containing 2 (RSAD2) is overexpressed in CD19+ B cells of pSS patients, but its role in pSS B cells remains unknown. Herein, RSAD2 expression was upregulated in CD19+ B cells of pSS patients and positively correlated with the expression of interleukin-10 (IL-10) in serum. After CD40L stimulation, knockdown of RSAD2 significantly attenuated cell viability, the production levels of immunoglobins and the expression of IL-10, while promoted cell apoptosis of pSS CD19+ B cells. Mechanistically, knockdown of RSAD2 negatively regulated nuclear factor kappa-b (NF-kappa b) signaling pathway. In addition, overexpression of p65 prominently alleviated the inhibitory effect of RSAD2 knockdown on proliferation, immunoglobin production and IL-10 expression in CD40L-induced CD19+ B cells. Our study indicated that silencing RSAD2 attenuated pSS B cell hyperactivity via suppressing NF-kappa b signaling pathway, which might provide a potential therapeutic target for pSS treatment.

关键词： Autoantibody   Antiphospholipid syndrome   B cell   Tolerance   Autoimmunity   Thrombosis  

摘要： It is now widely accepted that antiphospholipid antibodies (aPL) have direct pathogenic effects and that B cells, notably through aPL production, play a key role in the development of antiphospholipid syndrome (APS). Recent findings strengthened the implication of B cells with the description of specific B cell phenotype abnormalities and inborn errors of immunity involving B cell signaling in APS patients. In addition, it has been shown in preclinical models that cross-reactivity between APS autoantigens and mimotopes expressed by human gut commensals can lead to B cell tolerance breakdown and are sufficient for APS development. However, B cell targeting therapies are surprisingly not as effective as expected in APS compared to other autoimmune diseases. Elucidation of the B cell tolerance breakdown mechanisms in APS patients may help to develop and guide the use of novel therapeutic agents that target B cells or specific immune pathway.

关键词： pure red cell aplasia   HSC transplantation   ABO mismatch  

摘要： Pure red cell aplasia (PRCA) following allogeneic haematopoietic stem cell transplantation (aHSCT) with major ABO incompatibility is responsible for transfusion dependent anaemia, impaired quality of life and iron overload. We conducted a retrospective study, over a 10-year period, which included all consecutive patients who received a major ABO mismatched aHSCT, to assess the impact of specific treatment on PRCA. We did not observe any PRCA in the 57 aHSCT issued from cord blood. Among the remaining 631 patients, cumulative incidence of PRCA was 10 center dot 5% [range 8 center dot 2-13.0]. The median duration of resolved PRCA was 171 days [IQR 116;261]. Pre-transplant high isohaemagglutinins titre was associated with an increased risk of PRCA (P < 10(-4)). PRCA did not affect overall survival (P = 0 center dot 95). Twenty-two patients (33 center dot 3%) received at least one specific treatment. The most commonly used treatments were rituximab (17 patients) and donor lymphocyte infusion (DLI;seven patients). Regarding PRCA resolution, we did not observe a significant difference between treated or untreated subjects (HR = 0 center dot 93, 95% confidence interval (CI) 0 center dot 48- 1 center dot 80;P = 0 center dot 82). Similar results were observed with erythropoietin treatment (22 patients, HR = 0 center dot 86 95% CI: [0 center dot 47-1 center dot 57] P = 0 center dot 62). Our data do not support the use of erythropoietin, rituximab or DLI for the treatment of PRCA.

关键词： Clinical inertia   Insulin initiation   Insulin titration   Type    2 diabetes  

摘要： Therapeutic inertia related to insulin treatment, i.e. delays in initiation, especially titration of basal insulin, is a significant problem in daily practice in Southeast European countries. This phenomenon can be traced back to several patient-, physician- and health system-related factors. In recognition of the issue of inadequate insulin titration, 11 leading experts from countries in this region held a consensus-seeking meeting to review the current status of insulin initiation after non-insulin treatment and the potential barriers to insulin titration to provide an algorithm and tools for outpatient physicians and for patients aimed at optimizing basal insulin titration. The experts reached a consensus on the majority of the topics and proposed recommendations on how clinical inertia can be overcome. The outcomes of the meeting have been summarized in this paper.

关键词： Aerobic plate count   Dairy goats   Somatic cell counts   Indicator microorganisms   Mastitis  

摘要： The objective of this study was to identify on-farm risk factors associated with microbiological traits and somatic cell counts of goat bulk milk. A cross-sectional study was carried out on 160 goat dairy herds. Bulk tank milk samples were collected aseptically for qualitative (Salmonella enterica) and quantitative (aerobic mesophilic bacteria, total coliforms, E. coli, Staphylococcus spp. and Staphylococcus aureus) microbiological analyses. Additionally, information on various herd characteristics, general management practices, and milking procedures was collected by means of a questionnaire. A model for risk factors associated with the investigated traits was built by means of logistic regression after selection of putative variables by univariable analysis. Absence of pre-dipping, non-discharge of foremilk before milking and confirmed mastitis cases in the herds were identified as major risk factors for high aerobic plate counts. Low milk yield ( 25 kg / milk / day) was identified as a major risk factor for high somatic cell counts (SCC) in goat milk. Other variables such as long-term establishment of the herds ( 7 years), the use of ponds as water source, long lactation periods (> 210 days), practice of milking in late pregnancy and non-discharge of foremilk before milking were also identified as risk factors for high SCC. The information generated by this study can support intervention measures targeting the improvement of goat milk quality, which is of paramount importance for the continuous development of the goat dairy industry.

关键词： acute myeloid leukemia   treatment   chemosensitivity   all-trans retinoic acid   valproic acid   histone deacetylase   mass spectrometry   proteomics   phosphoproteomics  

摘要： Simple Summary Acute myeloid leukemia (AML) is an aggressive hematological malignancy, and the only possibility of cure is intensive antileukemic treatment. Such treatment is only possible for relatively young and fit patients, but there is a large subset of elderly/unfit patients above 65-70 years of age who cannot receive intensive treatment. The low-toxicity combination of valproic acid (VP) plus all-trans retinoic acid (ATRA) has an AML-stabilizing effect for a subset of patients, even those with chemoresistant relapse. This response may be an indirect effect due to the modulation of the metabolic environment, but in this article, we describe that the in vivo treatment with ATRA/VP also has direct effects on the fundamental functions of human AML cells. Furthermore, new and less intensive antileukemic therapies are now available (i.e., venetoclax, azacitidine, decitabine), and the combination of these new agents with ATRA/VP may represent a new therapeutic strategy in AML. All-trans retinoic acid (ATRA) and valproic acid (VP) have been tried in the treatment of non-promyelocytic variants of acute myeloid leukemia (AML). Non-randomized studies suggest that the two drugs can stabilize AML and improve normal peripheral blood cell counts. In this context, we used a proteomic/phosphoproteomic strategy to investigate the in vivo effects of ATRA/VP on human AML cells. Before starting the combined treatment, AML responders showed increased levels of several proteins, especially those involved in neutrophil degranulation/differentiation, M phase regulation and the interconversion of nucleotide di- and triphosphates (i.e., DNA synthesis and binding). Several among the differentially regulated phosphorylation sites reflected differences in the regulation of RNA metabolism and apoptotic events at the same time point. These effects were mainly caused by increased cyclin dependent kinase 1 and 2 (CDK1/2), LIM domain kinase 1 and 2 (LIMK1/2), mitogen-activated protein kinase 7