is the anaerobic protozoan parasite responsible for human amoebiasis, the third most deadly parasitic disease worldwide. This highly motile eukaryotic cell invades human tissues and constitutes an ...excellent experimental model of cell motility and cell shape deformation. The absence of extranuclear microtubules in
means that the actin-rich cytoskeleton takes on a crucial role in not only amoebic motility but also other processes sustaining pathogenesis, such as the phagocytosis of human cells and the parasite's resistance of host immune responses. Actin is highly conserved among eukaryotes, although diverse isoforms exist in almost all organisms studied to date. However,
has a single actin protein, the structure of which differs significantly from those of its human homologs. Here, we studied the expression, structure and dynamics of actin in
. We used molecular and cellular approaches to evaluate actin gene expression during intestinal invasion by
trophozoites. Based on a three-dimensional structural bioinformatics analysis, we characterized protein domains differences between amoebic actin and human actin. Fine-tuned molecular dynamics simulations enabled us to examine protein motion and refine the three-dimensional structures of both actins, including elements potentially accounting for differences changes in the affinity properties of amoebic actin and deoxyribonuclease I. The dynamic, multifunctional nature of the amoebic cytoskeleton prompted us to examine the pleiotropic forms of actin structures within live
cells; we observed the cortical cytoskeleton, stress fibers, "dot-like" structures, adhesion plates, and macropinosomes. In line with these data, a proteomics study of actin-binding proteins highlighted the Arp2/3 protein complex as a crucial element for the development of macropinosomes and adhesion plaques.
Candida auris is an emerging multidrug-resistant fungus that causes hospital-associated outbreaks of invasive infections with high death rates. During 2015-2016, health authorities in Colombia ...detected an outbreak of C. auris. We conducted an investigation to characterize the epidemiology, transmission mechanisms, and reservoirs of this organism. We investigated 4 hospitals with confirmed cases of C. auris candidemia in 3 cities in Colombia. We abstracted medical records and collected swabs from contemporaneously hospitalized patients to assess for skin colonization. We identified 40 cases; median patient age was 23 years (IQR 4 months-56 years). Twelve (30%) patients were <1 year of age, and 24 (60%) were male. The 30-day mortality was 43%. Cases clustered in time and location; axilla and groin were the most commonly colonized sites. Temporal and spatial clustering of cases and skin colonization suggest person-to-person transmission of C. auris. These cases highlight the importance of adherence to infection control recommendations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type 2 diabetes (T2D). Although the molecular mechanisms linking ...these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes. However, no direct connection between the obesity-associated variants and FTO expression or function has been made. Here we show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with the homeobox gene IRX3. The obesity-associated FTO region directly interacts with the promoters of IRX3 as well as FTO in the human, mouse and zebrafish genomes. Furthermore, long-range enhancers within this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval belongs to the regulatory landscape of IRX3. Consistent with this, obesity-associated single nucleotide polymorphisms are associated with expression of IRX3, but not FTO, in human brains. A direct link between IRX3 expression and regulation of body mass and composition is demonstrated by a reduction in body weight of 25 to 30% in Irx3-deficient mice, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Finally, hypothalamic expression of a dominant-negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data suggest that IRX3 is a functional long-range target of obesity-associated variants within FTO and represents a novel determinant of body mass and composition.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Bats are distinctive among mammals due to their ability to fly, use laryngeal echolocation, and tolerate viruses. However, there are currently no reliable cellular models for studying bat biology or ...their response to viral infections. Here, we created induced pluripotent stem cells (iPSCs) from two species of bats: the wild greater horseshoe bat (Rhinolophus ferrumequinum) and the greater mouse-eared bat (Myotis myotis). The iPSCs from both bat species showed similar characteristics and had a gene expression profile resembling that of cells attacked by viruses. They also had a high number of endogenous viral sequences, particularly retroviruses. These results suggest that bats have evolved mechanisms to tolerate a large load of viral sequences and may have a more intertwined relationship with viruses than previously thought. Further study of bat iPSCs and their differentiated progeny will provide insights into bat biology, virus host relationships, and the molecular basis of bats’ special traits.
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•Understanding of bat biology has been limited by lack of cellular models•Induced pluripotent stem cells are produced from two evolutionarily distant bat species•The core pluripotency expression profile resembles that of cells attacked by viruses•Bat stem cells accommodate a substantial load of endogenous viral sequences
Generation of induced pluripotent stem cells from two diverse bat species opens the door to functional studies of bat cell biology, including the question of why they are distinctively able to harbor viruses of importance to human health.
Increasingly, colleges across the world are contending with rising rates of mental disorders, and in many cases, the demand for services on campus far exceeds the available resources. The present ...study reports initial results from the first stage of the WHO World Mental Health International College Student project, in which a series of surveys in 19 colleges across 8 countries (Australia, Belgium, Germany, Mexico, Northern Ireland, South Africa, Spain, United States) were carried out with the aim of estimating prevalence and basic sociodemographic correlates of common mental disorders among first-year college students. Web-based self-report questionnaires administered to incoming first-year students (45.5% pooled response rate) screened for six common lifetime and 12-month DSM-IV mental disorders: major depression, mania/hypomania, generalized anxiety disorder, panic disorder, alcohol use disorder, and substance use disorder. We focus on the 13,984 respondents who were full-time students: 35% of whom screened positive for at least one of the common lifetime disorders assessed and 31% screened positive for at least one 12-month disorder. Syndromes typically had onsets in early to middle adolescence and persisted into the year of the survey. Although relatively modest, the strongest correlates of screening positive were older age, female sex, unmarried-deceased parents, no religious affiliation, nonheterosexual identification and behavior, low secondary school ranking, and extrinsic motivation for college enrollment. The weakness of these associations means that the syndromes considered are widely distributed with respect to these variables in the student population. Although the extent to which cost-effective treatment would reduce these risks is unclear, the high level of need for mental health services implied by these results represents a major challenge to institutions of higher education and governments.
General Scientific Summary
Roughly 1/3 of first-year students in 19 colleges across 8 countries who participated in a self-report survey screened positive for at least 1 common DSM-IV anxiety, mood, or substance disorder (35.3% lifetime, 31.4% 12 months). Basic sociodemographic correlates were modest, showing that the syndromes were widely distributed rather than concentrated in 1 small segment of the student population.
Objective
In gout, hyperuricemia promotes urate crystal deposition, which stimulates the NLRP3 inflammasome and interleukin‐1β (IL‐1β)–mediated arthritis. Incident gout without background ...hyperuricemia is rarely reported. To identify hyperuricemia‐independent mechanisms driving gout incidence and progression, we characterized erosive urate crystalline inflammatory arthritis in a young female patient with normouricemia diagnosed as having sufficient and weighted classification criteria for gout according to the American College of Rheumatology (ACR)/EULAR gout classification criteria (the proband).
Methods
We conducted whole‐genome sequencing, quantitative proteomics, whole‐blood RNA‐sequencing analysis using serum samples from the proband. We used a mouse model of IL‐1β–induced knee synovitis to characterize proband candidate genes, biomarkers, and pathogenic mechanisms of gout.
Results
Lubricin level was attenuated in human proband serum and associated with elevated acute‐phase reactants and inflammatory whole‐blood transcripts and transcriptional pathways. The proband had predicted damaging gene variants of NLRP3 and of inter‐α trypsin inhibitor heavy chain 3, an inhibitor of lubricin‐degrading cathepsin G. Changes in the proband's serum protein interactome network supported enhanced lubricin degradation, with cathepsin G activity increased relative to its inhibitors, SERPINB6 and thrombospondin 1. Activation of Toll‐like receptor 2 (TLR‐2) suppressed levels of lubricin mRNA and lubricin release in cultured human synovial fibroblasts (P < 0.01). Lubricin blunted urate crystal precipitation and IL‐1β induction of xanthine oxidase and urate in cultured macrophages (P < 0.001). In lubricin‐deficient mice, injection of IL‐1β in knees increased xanthine oxidase–positive synovial resident M1 macrophages (P < 0.05).
Conclusion
Our findings linked normouricemic erosive gout to attenuated lubricin, with impaired control of cathepsin G activity, compounded by deleterious NLRP3 variants. Lubricin suppressed monosodium urate crystallization and blunted IL‐1β–induced increases in xanthine oxidase and urate in macrophages. The collective activities of articular lubricin that could limit incident and erosive gouty arthritis independently of hyperuricemia are subject to disruption by inflammation, activated cathepsin G, and synovial fibroblast TLR‐2 signaling.
Objectives
Mental disorders and suicidal thoughts and behaviors (STB) are common and burdensome among college students. Although available evidence suggests that only a small proportion of the ...students with these conditions receive treatment, broad‐based data on patterns of treatment are lacking. The aim of this study is to examine the receipt of mental health treatment among college students cross‐nationally.
Methods
Web‐based self‐report surveys were obtained from 13,984 first year students from 19 colleges in eight countries across the world as part of the World Health Organization's World Mental Health–International College Student Initiative. The survey assessed lifetime and 12‐month common mental disorders/STB and treatment of these conditions.
Results
Lifetime and 12‐month treatment rates were very low, with estimates of 25.3–36.3% for mental disorders and 29.5–36.1% for STB. Treatment was positively associated with STB severity. However, even among severe cases, lifetime and 12‐month treatment rates were never higher than 60.0% and 45.1%, respectively.
Conclusions
High unmet need for treatment of mental disorders and STB exists among college students. In order to resolve the problem of high unmet need, a reallocation of resources may focus on innovative, low‐threshold, inexpensive, and scalable interventions.
The oxidation of aqueous solutions containing Allura Red AC (AR–AC) using bicarbonate-activated peroxide (BAP) and cobalt-impregnated pillared clay (Co/Al–PILC) as the catalyst was investigated. ...Using the CCD-RMS approach (central composite design–response surface methodology), the effects of dye, H2O2, and NaHCO3 concentrations on AR–AC degradation were studied. The decolorization, total nitrogen (TN), and total carbon (TC) removals were the analyzed responses, and the experimental data were fitted to empirical quadratic equations for these responses, obtaining coefficients of determination R2 and adjusted-R2 higher than 0.9528. The multi-objective optimization conditions were dye = 21.25 mg/L, H2O2 = 2.59 mM, NaHCO3 = 1.25 mM, and a catalyst loading of 2 g/L. Under these conditions, a decolorization greater than 99.43% was obtained, as well as TN and TC removals of 72.82 and 18.74%, respectively, with the added advantage of showing cobalt leaching below 0.01 mg/L. Chromatographic analyses (GC–MS and HPLC) were used to identify some reaction intermediates and by-products. This research showed that wastewater containing azo dyes may be treated using the cobalt-catalyzed BAP system in heterogeneous media.
CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ...ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCRαβ+CD4-CD8- T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4-CD8- αβ T cells exhibit intact responses to HLA class II-restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei.
Identification of the emerging multidrug-resistant yeast
Candida auris
is challenging. Here, we describe the role of the Mexico national reference laboratory Instituto de Diagnóstico y Referencia ...Epidemiológicos Dr. Manuel Martínez Báez (InDRE) and the Mexican national laboratory network in the identification of
C. auris
. Reference identification of six suspected isolates was done based on phenotypic and molecular laboratory methods, including growth in special media, evaluation of isolate micromorphology, and species-specific PCR and pan-fungal PCR and sequencing. The four
C. auris
isolates identified were able to grow on modified Sabouraud agar with 10% NaCl incubated at 42 °C. With one exception, isolates of
C. auris
were spherical to ovoid yeast-like cells and blastoconidia, with no hyphae or pseudohyphae on cornmeal agar.
C. auris
isolates were resistant to fluconazole. Species-specific and pan-fungal PCR confirmed isolates as
C. auris
. Sequence analysis revealed the presence of two different
C. auris
clades in Mexico, clade I (South Asia) and clade IV (South America).
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