Defensins couple dysbiosis to primary immunodeficiency in Crohn's disease

Antimicrobial peptides,including defensins,are essential effectors in host defence and in the maintenance of immune homeostasis.Clinical studies have linked the defective expression of both α-and β-defensin to the reduced killing of certain microorganisms by the intestinal mucosa of patients suffering from ileal and colonic Crohn's disease(CD),respectively.Only recently have the events leading to defective expression of defensins in CD been further elucidated,and are discussed herein.These events may account for CD-associated alterations in the microbiome and may subsequently precipitate the development of granulomatous inflammatory lesions in genetically-predisposed patients.We also address how these discoveries may pave the way for the development of a molecular medicine aimed at restoring gut barrier function in CD.

Correlation between in vitro and in vivo immunomodulatory properties of lactic acid bacteria

AIM: To investigate the correlation between in vitro and in vivo immunomodulation potential of the probiotic strain and its ability to prevent experimental colitis in mice. METHODS: In vitro immunomodulation was assessed by measuring interleukin (IL)-12p70, IL-10, tumor necrosis factor alpha (TNFa) and interferon g (IFNg) release by human peripheral blood mononuclear cells (PBMCs) after 24 h stimulation with 13 live bacterial strains. A murine model of acute TNBS-colitis was next used to evaluate the prophylactic protective capacity of the same set of strains. RESULTS: A strain-specific in vivo protection was observed. The strains displaying an in vitro potential to induce higher levels of the anti-inflammatory cytokine IL-10 and lower levels of the inflammatory cytokine IL-12, offered the best protection in the in vivo colitis model. In contrast, strains leading to a low IL-10/IL-12 cytokine ratio could not significantly attenuate colitis symptoms. CONCLUSION: These results show that we could predict the in vivo protective capacity of the studied lactic acid bacteria (LAB) based on the cytokine profile we established in vitro. The PBMC-based assay we used may thus serve as a useful primary indicator to narrow down the number of candidate strains to be tested inmurine models for their anti-inflammatory potential.

Hepatitis C virus proteins

Hepatitis C virus (HCV) encodes a single polyprotein, which is processed by cellular and viral proteases to generate 10 polypeptides. The HCV genome also contains an overlapping +1 reading frame that may lead to the synthesis of an additional protein. Until recently, studies of HCV have been hampered by the lack of a productive cell culture system. Since the identification of HCV genome approximately 17 years ago, structural, biochemical and biological information on HCV proteins has mainly been obtained with proteins produced by heterologous expression systems. In addition, some functional studies have also been confirmed with replicon systems or with retroviral particles pseudotyped with HCV envelope glycoproteins. The data that have accumulated on HCV proteins begin to provide a framework for understanding the molecular mechanisms involved in the major steps of HCV life cycle. Moreover, the knowledge accumulated on HCV proteins is also leading to the development of antiviral drugs among which some are showing promising results in early- phase clinical trials. This review summarizes the current knowledge on the functions and biochemical features of HCV proteins.

Microbiological Contamination of Bed Linen and Staff Uniforms in a Hospital

Hospital linen is clearly recognized as a potential reservoir for microorganisms and could be a vector of disease transmission. The aim of this study was to isolate, count and identify fungi and bacteria from different kinds of clean and dirty linen in a hospital. Microbiological samples have been collected on clean bed linen (n = 200), dirty bed linen (n = 192) and staff uniforms (n = 192) by using contact plates. 55% of samples from clean bed linen were contaminated before contact with the patient, with a mean count of 3 cfu/25 cm2 (range: 1-117 cfu) when contaminated. Virtually all samples from dirty bed linen carried microorganisms, with a mean count of 23 cfu/25 cm2 (range 1-191 cfu). In addition, staff hospital uniforms showed the highest contamination rates in the study, with an average of 45 cfu/25 cm2 (range: 1-218 cfu). Microbial species were mostly bacteria commonly found in the environment or on human skin, such as staphylococci or micrococci. Nevertheless, 57% of the identified species may be opportunistic pathogens for humans, representing a risk for people with a deficient or weakened immune system, especially in cases of superinfection. Since contamination of linen seems to occur after washing, actively antimicrobial textiles would represent a valuable measure to prevent textiles from being a vehicle for transfer of microorganisms.

HCV-specific immune responses induced by CIGB-230 in combination with IFN-α plus ribavirin

AIM:To analyze hepatitis C virus(HCV)-specific immune responses in chronically infected patients under triple therapy with interferon-α(IFN-α)plus ribavirin and CIGB-230.METHODS:CIGB-230 was administered in different schedules with respect to IFN-αplus ribavirin therapy.Paired serum and peripheral blood mononuclear cells(PBMC)samples from baseline and end of treatment were analyzed.The HCV-specific humoral response was tested by enzyme-linked immunosorbent assay,neutralizing antibodies were evaluated by cell culture HCV neutralization assays,PBMC proliferation was assayed by carboxyfluorescein succinimidyl ester staining and IFN-γsecretion was assessed by enzyme-linked immunospot.Data on virological and histological response and their association with immune variables are also provided.RESULTS:From week 12 to week 48,all groups of patients showed a significant reduction in mean leukocyte counts.Statistically significant reductions in antibody titers were frequent,but only individuals immunized with CIGB-230 as early add-on treatment sustained the core-IgG response,and the neutralizing antibody response was enhanced only in patients receiving CIGB-230.Cell-mediated immune responses also tended to decline,but significant reductions in IFN-γsecretion and total absence of core-specific lymphoproliferation were exclusive of the control group.Only CIGB-230-immunized individuals showed de novo induced lymphoproliferative responses against the structural antigens.Importantly,it was demonstrated that thequality of the CIGB-230-induced immune response depended on the number of doses and timing of administration in relation to the antiviral therapy.Specifically,the administration of 6 doses of CIGB-230 as late addon to therapy increased the neutralizing antibody activity and the de novo core-specific IFN-γsecretion,both of which were associated with the sustained virological response.CONCLUSION:CIGB-230,combined with IFN-α-based therapy,modifies the immune response in chronic patients.The study provides evidence for the design of more effective therapeutic vaccine interventions against HCV.

Non-Invasive Second Harmonic Generation (SHG) in Macroscopy (MacroSHG) as Bio-Diagnosis to Image Collagen Network Organization in Extracellular Matrix

In this work, we have considered a new multimodality imaging for macroscopy based on Second Harmonic Generation (SHG) method to monitor invasivelessly the matrix collagen. As the triple helicoidally structure of collagen molecules appearing as not centrosymetric, very organized and spatially oriented, collagen fibrils give rise to a very strong SHG signal and can be imaged without any exogenous dye. To integrate a multidimensional scale with a large field of view (non-sliced samples), we have adapted and validated an instrumental coupling between a two photon excitation laser and a macroscope to collect cartography of SHG signal. We introduced an index (F-SHG) based on decay time response measured by TCSPC for respectively Fluorescence (F) and Second Harmonic Generation (SHG) values. For various sample where protein collagen is the major component of extracellular matrix (vessel, skin, carotide vessel, rat femoral head cartilage, mouse tumor, human wharton’s jelly and rat tendon) or not (nacre), we compared the index distribution obtained with MacroSHG. In this work, we showed for the first time that multiscale large field imaging (Macroscopy) combined to Multimodality approaches (SHG-TCSPC) could be an innovative and non-invasive technique to detect and identify some biological interest molecules (collagen) in biomedical topics.

卡介苗的理论和方法学两个方面的情况综述——从Calmette和Guérin的发现到分子生物学

卡介苗自从1921年以来用于预防结核病,60年代以来又用于肿瘤的免疫刺激。预防性和免疫刺激性两种作用都曾有人对之作出评价并加以报道,但却得出互相矛盾的正反两方面结论。为了客观地评价并解释卡介苗保护作用的功效、有效性和效率,必须考虑以下事实:(1)一些从事生产的实验室业已开发了数种卡介苗次代株,它们的残余毒力各不相同,而后者对免疫原性和反应原性起着决定作用;(2)用了各种液体的和冷冻干燥的卡介苗生产方法,结果使一次剂量所含卡介苗活菌单位各异(3)定量的生物测定方法尚未被用于本疫苗的统计学的质量控制;(4)卡介苗产品被用于各种人口统计的、流行病学的、以及社会经济的情况,其接种制度均不相同;(5)不适当的生物统计学模式常被用于效能、有效性和不良反应的分析。同样的情况也影响对卡介苗在肿瘤形成中免疫刺激作用的准确评价。重组DNA技术将会改进生产方法,并在分子水平上解释卡介苗在结核病中起到的保护作用,和在肿瘤形成中产生免疫刺激的机理。建立在概率逻辑和归纳推理基础上的高水平实验室技术和生物统计学方法,使适当实验设计的制订和实验资料与接种制度所得结果的正确分析得到保证。这些将会导致对卡介苗保护作用的评价,以减少在卡介苗问题上的意见分歧。

阿尔茨海默病APOE基因表达和脑内淀粉样蛋白沉积之间是否相关

Background: It has been proposed that, independent of the 4 allele, APOE prom oter polymorphisms (- 491 A/T and 219 G/T) may be risks factor for Alzheimer’ s disease by modulating APOE expression. Objective: To measure the level of APOE expression in Alzheimer’ s disease. Methods: Brains were obtained at necropsy from 114 patients with early and late onset sporadic Alzheimer’ s disease in Gr eater Manchester (UK) during years 1986 to 2001. Total RNA was extracted from 84 brains. Purified lymphocytes were obtained from fresh blood from 16 probable Al zheimer cases from Lille (France). APOE and β - actin gene expression was dete rmined by reverse transcriptase polymerase chain reaction in brain and lymphocyt es. Results: An inverse correlation between APOE expression level and Aβ loads was observed. As previously described and extended to 114 cases here, an associ ation between the - 219 TT genotype and a higher level of parenchymal Aβ .depo sition was found, irrespective of APOE  4 allele status. This effect was more pronounced in older individuals, whereas higher Aβ load appeared more closely related to 4inthe younger age group (cut off point at the median age at death (7 2.5 years). The - 219 TT genotype was associated with a decrease in APOE expres sion. There was a 60% decrease in APOE expression in lymphocytes from probable Alzheimer cases v controls (p=0.01). Conclusions: In the oldest individuals, re duced APOE expression, modulated in part by - 219 G/T polymorphism, may influen ce risk and constitute a determinant Aβ load in Alzheimer’ s disease.

代谢综合征与双亲早发心血管疾病史之间的关系

Aims: The goal of this study is to assess the association between the metabolic syndrome(MS) and parental history of cardiovascular disease(CVD). Methods and results: Participants were recruited in a population survey of 3441 men and women, aged 35-64. MS was defined with NCEP-III guidelines. Familial history of myocardial infarction(MI), angina, and stroke was assessed with a standardized questionnaire. Parental premature CVD was defined if CVD occurred before 55/65 years in the father/mother. A total of 390 men and 281 women had MS. Positive parental CVD was associated with MS in women(43.0 vs. 36.8% , P< 0.001) but not in men(36.9 vs. 31.8% , P=0.06). Similarly, parental premature CVD was associated with MS in women(19.2 vs. 11.8% , P< 0.0007) but not in men(11.1 vs. 11.1% , ns). In women with MS, the age, centre, and educational level adjusted odds ratios [OR(95% CI)] of having a positive parental premature stroke was 1.84(1.0-3.38), P=0.049. This OR was 1.76(1.23-2.76), P=0.007 for combined parental premature MI and stroke and 1.67(1.17-2.38), P=0.004 for combined premature MI, stroke, and angina. After further adjustment on personal coronary heart disease and CVD risk factors, the ORs of having a positive parental history of combined premature MI and stroke [1.75(1.11-2.76), P=0.016] or MI, stroke, and angina [1.79(1.21-2.63), P=0.003], remained statistically significant, in women with MS. Conclusion: The MS is associated with parental premature CVD independently of classical CV risk factors, suggesting that MS is a contributor to the familial aggregation of premature CVD.

Science:研究人员利用小分子SMARt-420逆转结核分枝杆菌的抗生素耐药性

在一项新的研究中，来自瑞典、法国、比利时和瑞士的一个研究团队发现一种方法逆转对一种用于治疗肺结核的抗生素药物产生的耐药性。在他们发表在Science期刊上的论文中．该团队描述了他们如何筛选激活用于活化ethionaide的不同通路的化合物。Ethionaide是一种被用来治疗肺结核的前体分子。在体内经过代谢后产生一种真正有疗效的药物。

COVID-19 and flu:conserved or specific immune signature?

Respiratory viruses are a major cause of infectious disease and mortality worldwide.Among respiratory viruses,emerging and well-known coronaviruses and influenza viruses cause seasonal epidemics and pandemics and rank as very important pathogens.The clinical signs of viral respiratory infections range from asymptomatic forms to life-threatening acute respiratory distress syndrome(ARDS,associated with a high mortality rate).Another reported cause of mortality is multiple organ dysfunction.The ongoing pandemic of coronavirus disease 19(COVID-19,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2))is a serious public health problem.SARS-CoV-2 infection induces to a clinical signature distinct from that associated with other types of pneumonia,and SARS-CoV-2 differs from influenza viruses with regard to target cells and replicative properties.The morbidity and mortality rates are higher for COVID-19 than for seasonal influenza.

Neuroendocrine control of natural killer cell function through the checkpoint molecule PD-1

Host defense strategies encompass resistance to reduce pathogen burden,and disease tolerance to preserve host fitness.1 Immunedriven resistance mechanisms have inevitably a negative impact on host fitness and can lead to immunopathology.Disease tolerance limit immunopathology and therefore disease severity by preventing tissue damage or ameliorating tissue function without interfering with pathogen load.Several pathways cooperate to protect the host.These pathways include metabolic and oxidative stress responses,2 and the interaction between neuroendocrine system and the immune system3 to favor resolution of inflammation and to prevent tissue damage.

Proposed nomenclature for Pseudallescheria,Scedosporium and related genera

As a result of fundamental changes in the International Code of Nomenclature on the use of separate names for sexual and asexual stages of fungi,generic names of many groups should be reconsidered.Members of the ECMM/ISHAM working group on Pseudallescheria/Scedosporium infections herein advocate a novel nomenclature for genera and species in Pseudallescheria,Scedosporium and allied taxa.The generic names Parascedosporium,Lomentospora,Petriella,Petriellopsis,and Scedosporium are proposed for a lineage within Microascaceae with mostly Scedosporium anamorphs producing slimy,annellidic conidia.Considering that Scedosporium has priority over Pseudallescheria and that Scedosporium prolificans is phylogenetically distinct from the other Scedosporium species,some name changes are proposed.Pseudallescheria minutispora and Petriellidium desertorum are renamed as Scedosporium minutisporum and S.desertorum,respectively.Scedosporium prolificans is renamed as Lomentospora prolificans.