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Abstract:  Several scientific studies have shown contradictory results regarding the effect of probiotic supplementation on the inhibition of pro-inflammatory cytokines and the improvement of the clinical nutritional profile in people with cardiometabolic diseases. This research aimed to analyze the relationship between the intake of probiotic foods and supplements with probiotics and inflammation markers in cardiometabolic diseases in adults, through a systematic review, during the period between 2015 and 2020. The systematic review was carried out according to the Cochrane recommendations and the GRADE guidelines; different databases such as Pubmed, Oxford and BVS were used. Three reviewers participated in this process. Papers that did not meet the quality of evidence criteria were excluded: risk of bias, imprecise results, inconsistent results, problems of applicability of the evidence, and the existence of publication bias. To control bias, the checklist proposed by Downs and Black was used. Of the 859 articles identified, 17 met the inclusion requirements. Controlled trials and randomized clinical trials were considered among the eligibility criteria. Of all the studies that analyzed the effect of probiotics (bifidobacterium, lactobacillus, lactococcus, acetobacter) on the biomarkers of inflammation in cardiometabolic diseases, a decrease in interleukin concentrations (IL-1, IL-6, IL- 8 and IL-12) in eight of them and the same happened with TNFα; in the case of INFγ, it was decreased in one of the three studies that analyzed it; while, the consumption of probiotics caused a decrease in the concentration of hsCRP, an effect that was observed in three of six studies. According to the checklist proposed by Downs and Black, 88% of the included studies correspond to high quality and 12% to intermediate quality. The intake of probiotics presented diverse results, being necessary more studies to identify the effect of the strains, doses and duration, in order to implement more consistent nutritional clinical treatments with the aim of improving the levels of inflammation biomarkers and risk factors in people with cardiometabolic diseases.Resumen:  Diversos estudios científicos han demostrado resultados contradictorios en cuanto al efecto que tiene la suplementación con probióticos sobre la inhibición de citoquinas proinflamatorias y la mejora del perfil clínico nutricional en personas con enfermedades cardiometabólicas.  Esta investigación tuvo como objetivo analizar la relación entre la ingesta de alimentos probióticos y suplementos con probióticos y marcadores de inflamación en enfermedades cardiometabólicas en personas adultas, a través de una revisión sistemática, durante el período comprendido entre 2015 y 2020. La revisión sistemática se realizó de acuerdo a las recomendaciones Cochrane y las guías GRADE; se utilizaron diferentes bases de datos como Pubmed, Oxford y BVS. Participaron de este proceso tres revisores. Se excluyeron los trabajos que no cumplian con los criterios de calidad de la evidencia: riesgo de sesgo, resultados imprecisos, resultados inconsistentes, problemas de aplicabilidad de la evidencia y la existencia de sesgo de publicación. Para el control del sesgo se utilizó la lista de verificación propuesta por Downs y Black. De los 859 artículos identificados, 17 cumplieron los requisitos de inclusión. Entre los criterios de elegibilidad se consideraron los ensayos controlados y ensayos clínicos aleatorizados. Del total de los estudios que analizaron el efecto de los probióticos (bifidobacterium, lactobacillus, lactococcus, acetobacter) sobre los biomarcadores de inflamación en enfermedades cardiometabólicas, se evidenció una disminución de las concentraciones de interleucinas (IL-1, IL-6, IL-8 e IL-12) en ocho de ellos, lo mismo sucedió con el FNTα; en el caso del IFNγ se vio disminuido en uno de tres estudios que lo analizaron; mientras que, el consumo de probióticos provocó el descenso de la concentración de PCRus, efecto que se observó en tres de seis estudios. Según la lista de verificación propuesta por Downs y Black, el 88% de los estudios incluidos corresponde a calidad alta y el 12% a calidad intermedia.  La ingesta de probióticos presentó resultados diversos, siendo necesarios más estudios para identificar el efecto de las cepas, dosis y duración, a fin de poder implementar tratamientos clínicos nutricionales más consistentes con el objetivo de mejorar los niveles de biomarcadores de inflamación y los factores de riesgo en personas con enfermedades cardiometabólicas.

Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome

A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP-deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR-deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR-SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR-ATRIP Seckel Syndrome to be define

Surface Localization of Glucosylceramide during Cryptococcus neoformans Infection Allows Targeting as a Potential Antifungal

Cryptococcus neoformans (Cn) is a significant human pathogen that, despite current treatments, continues to have a high morbidity rate especially in sub-Saharan Africa. The need for more tolerable and specific therapies has been clearly shown. In the search for novel drug targets, the gene for glucosylceramide synthase (GCS1) was deleted in Cn, resulting in a strain (Δgcs1) that does not produce glucosylceramide (GlcCer) and is avirulent in mouse models of infection. To understand the biology behind the connection between virulence and GlcCer, the production and localization of GlcCer must be characterized in conditions that are prohibitive to the growth of Δgcs1 (neutral pH and high CO2). These prohibitive conditions are physiologically similar to those found in the extracellular spaces of the lung during infection. Here, using immunofluorescence, we have shown that GlcCer localization to the cell surface is significantly increased during growth in these conditions and during infection. We further seek to exploit this localization by treatment with Cerezyme (Cz), a recombinant enzyme that metabolizes GlcCer, as a potential treatment for Cn. Cz treatment was found to reduce the amount of GlcCer in vitro, in cultures, and in Cn cells inhabiting the mouse lung. Treatment with Cz induced a membrane integrity defect in wild type Cn cells similar to Δgcs1. Cz treatment also reduced the in vitro growth of Cn in a dose and condition dependent manner. Finally, Cz treatment was shown to have a protective effect on survival in mice infected with Cn. Taken together, these studies have established the legitimacy of targeting the GlcCer and other related sphingolipid systems in the development of novel therapeutics

Ganglioside GM3 Has an Essential Role in the Pathogenesis and Progression of Rheumatoid Arthritis

Rheumatoid arthritis (RA), a chronic systemic inflammatory disorder that principally attacks synovial joints, afflicts over 2 million people in the United States. Interleukin (IL)-17 is considered to be a master cytokine in chronic, destructive arthritis. Levels of the ganglioside GM3, one of the most primitive glycosphingolipids containing a sialic acid in the structure, are remarkably decreased in the synovium of patients with RA. Based on the increased cytokine secretions observed in in vitro experiments, GM3 might have an immunologic role. Here, to clarify the association between RA and GM3, we established a collagen-induced arthritis mouse model using the null mutation of the ganglioside GM3 synthase gene. GM3 deficiency exacerbated inflammatory arthritis in the mouse model of RA. In addition, disrupting GM3 induced T cell activation in vivo and promoted overproduction of the cytokines involved in RA. In contrast, the amount of the GM3 synthase gene transcript in the synovium was higher in patients with RA than in those with osteoarthritis. These findings indicate a crucial role for GM3 in the pathogenesis and progression of RA. Control of glycosphingolipids such as GM3 might therefore provide a novel therapeutic strategy for RA

Control of magnetic anisotropy by orbital hybridization in (La0.67Sr0.33MnO3)n/(SrTiO3)n superlattice

The asymmetry of chemical nature at the hetero-structural interface offers an unique opportunity to design desirable electronic structure by controlling charge transfer and orbital hybridization across the interface. However, the control of hetero-interface remains a daunting task. Here, we report the modulation of interfacial coupling of (La0.67Sr0.33MnO3)n/(SrTiO3)n superlattices by manipulating the periodic thickness with n unit cells of SrTiO3 and n unit cells La0.67Sr0.33MnO3. The easy axis of magnetic anisotropy rotates from in-plane (n = 10) to out-of-plane (n = 2) orientation at 150 K. Transmission electron microscopy reveals enlarged tetragonal ratio > 1 with breaking of volume conservation around the (La0.67Sr0.33MnO3)n/(SrTiO3)n interface, and electronic charge transfer from Mn to Ti 3d orbitals across the interface. Orbital hybridization accompanying the charge transfer results in preferred occupancy of 3d3z2-r2 orbital at the interface, which induces a stronger electronic hopping integral along the out-of-plane direction and corresponding out-of-plane magnetic easy axis for n = 2. We demonstrate that interfacial orbital hybridization in superlattices of strongly correlated oxides may be a promising approach to tailor electronic and magnetic properties in device applications

A New Approach for Adipose Tissue Treatment and Body Contouring Using Radiofrequency-Assisted Liposuction

A new liposuction technology for adipocyte lipolysis and uniform three-dimensional tissue heating and contraction is presented. The technology is based on bipolar radiofrequency energy applied to the subcutaneous adipose tissue and subdermal skin surface. Preliminary clinical results, thermal monitoring, and histologic biopsies of the treated tissue demonstrate rapid preaspiration liquefaction of adipose tissue, coagulation of subcutaneous blood vessels, and uniform sustained heating of tissue

From product recommendation to cyber-attack prediction: generating attack graphs and predicting future attacks

Modern information society depends on reliable functionality of information systems infrastructure, while at the same time the number of cyber-attacks has been increasing over the years and damages have been caused. Furthermore, graphs can be used to show paths than can be exploited by attackers to intrude into systems and gain unauthorized access through vulnerability exploitation. This paper presents a method that builds attack graphs using data supplied from the maritime supply chain infrastructure. The method delivers all possible paths that can be exploited to gain access. Then, a recommendation system is utilized to make predictions about future attack steps within the network. We show that recommender systems can be used in cyber defense by predicting attacks. The goal of this paper is to identify attack paths and show how a recommendation method can be used to classify future cyber-attacks in terms of risk management. The proposed method has been experimentally evaluated and validated, with the results showing that it is both practical and effective

SREB, a GATA Transcription Factor That Directs Disparate Fates in Blastomyces dermatitidis Including Morphogenesis and Siderophore Biosynthesis

Blastomyces dermatitidis belongs to a group of human pathogenic fungi that exhibit thermal dimorphism. At 22°C, these fungi grow as mold that produce conidia or infectious particles, whereas at 37°C they convert to budding yeast. The ability to switch between these forms is essential for virulence in mammals and may enable these organisms to survive in the soil. To identify genes that regulate this phase transition, we used Agrobacterium tumefaciens to mutagenize B. dermatitidis conidia and screened transformants for defects in morphogenesis. We found that the GATA transcription factor SREB governs multiple fates in B. dermatitidis: phase transition from yeast to mold, cell growth at 22°C, and biosynthesis of siderophores under iron-replete conditions. Insertional and null mutants fail to convert to mold, do not accumulate significant biomass at 22°C, and are unable to suppress siderophore biosynthesis under iron-replete conditions. The defect in morphogenesis in the SREB mutant was independent of exogenous iron concentration, suggesting that SREB promotes the phase transition by altering the expression of genes that are unrelated to siderophore biosynthesis. Using bioinformatic and gene expression analyses, we identified candidate genes with upstream GATA sites whose expression is altered in the null mutant that may be direct or indirect targets of SREB and promote the phase transition. We conclude that SREB functions as a transcription factor that promotes morphogenesis and regulates siderophore biosynthesis. To our knowledge, this is the first gene identified that promotes the conversion from yeast to mold in the dimorphic fungi, and may shed light on environmental persistence of these pathogens