Monitoring Coxiella burnetii Infection in Naturally Infected Dairy Sheep Flocks Throughout Four Lambing Seasons and Investigation of Viable Bacteria.

Progression of Coxiella burnetii infection in four naturally infected sheep flocks, and in their farm environment, was monitored throughout four lambing seasons. Flocks with an active infection were selected based on the presence of C. burnetii DNA in bulk-tank milk (BTM) and a high seroprevalence in yearlings during the previous milking period (Spring 2015). During four consecutive lambing seasons (2015/16-2018/19), samples were collected within 1 week after each lambing period from animals (vaginal swabs, milk and feces from ewes, and yearlings) and the environment (dust indoor sheep premises). BTM samples and aerosols (outdoors and indoors) were monthly collected between lambing and the end of milking. Real-time PCR analyses showed different trends in C. burnetii shedding in the flocks, with a general progressive decrease in bacterial shedding throughout the years, interrupted in three flocks by peaks of reinfection associated with specific management practices. A significant relationship was found between C. burnetii fecal shedding and the bacterial burden detected in dust, whereas shedding by vaginal route affected the detection of C. burnetii in indoor aerosols. Three genotypes were identified: SNP8 (three flocks, 52.9% of the samples), SNP1 (two flocks, 44.8% samples), and SNP5 (one flock, two environmental samples). Coxiella burnetii viability in dust measured by culture in Vero cells was demonstrated in two of the flocks, even during the fourth lambing season. The results showed that infection can remain active for over 5 years if effective control and biosafety measures are not correctly implemented.This work was funded by INIA—Spanish National Institute for Agricultural and Food Research and Technology (RTA2017-00055-C02-00), the European Regional Development Funds (ERDF), and the Basque Government. RÁ-A is beneficiary of a Ph.D. contract funded by INIA (FPI-2015-014). The funders had no role in the study design, data collection and interpretation, or the decision to submit the work for publication.S

Plasmodium falciparum Apicomplexan-Specific Glucosamine-6-Phosphate <i>N</i>-Acetyltransferase Is Key for Amino Sugar Metabolism and Asexual Blood Stage Development.

--- - i: - N - N - O - N - Plasmodium falciparum - Cryptosporidium parvum - P. falciparum - N - N - P. falciparum - C. parvum b: - IMPORTANCE content: - UDP- - "-acetylglucosamine (UDP-GlcNAc), the main product of the hexosamine biosynthetic pathway, is an important metabolite in protozoan parasites since its sugar moiety is incorporated into glycosylphosphatidylinositol (GPI) glycolipids and " - "- and " - "-linked glycans. Apicomplexan parasites have a hexosamine pathway comparable to other eukaryotic organisms, with the exception of the glucosamine-phosphate " - "-acetyltransferase (GNA1) enzymatic step that has an independent evolutionary origin and significant differences from nonapicomplexan GNA1s. By using conditional genetic engineering, we demonstrate the requirement of GNA1 for the generation of a pool of UDP-GlcNAc and for the development of intraerythrocytic asexual " - " parasites. Furthermore, we present the 1.95\xE2\x80\x89\xC3\x85 resolution structure of the GNA1 ortholog from " - ", an apicomplexan parasite which is a leading cause of diarrhea in developing countries, as a surrogate for " - " GNA1. The in-depth analysis of the crystal shows the presence of specific residues relevant for GNA1 enzymatic activity that are further investigated by the creation of site-specific mutants. The experiments reveal distinct features in apicomplexan GNA1 enzymes that could be exploitable for the generation of selective inhibitors against these parasites, by targeting the hexosamine pathway. This work underscores the potential of apicomplexan GNA1 as a drug target against malaria." - " Apicomplexan parasites cause a major burden on global health and economy. The absence of treatments, the emergence of resistances against available therapies, and the parasite's ability to manipulate host cells and evade immune systems highlight the urgent need to characterize new drug targets to treat infections caused by these parasites. We demonstrate that glucosamine-6-phosphate " - -acetyltransferase (GNA1), required for the biosynthesis of UDP- - "-acetylglucosamine (UDP-GlcNAc), is essential for " - " asexual blood stage development and that the disruption of the gene encoding this enzyme quickly causes the death of the parasite within a life cycle. The high-resolution crystal structure of the GNA1 ortholog from the apicomplexan parasite " - ", used here as a surrogate, highlights significant differences from human GNA1. These divergences can be exploited for the design of specific inhibitors against the malaria parasite.

Foveal avascular zone and choroidal thickness are decreased in subjects with hard drusen and without high genetic risk of developing Alzheimer’s disease

A family history (FH+) of Alzheimer’s disease (AD) and ɛ4 allele of the ApoE gene are the main genetic risk factors for developing AD, whereas ɛ4 allele plays a protective role in age-related macular degeneration. Ocular vascular changes have been reported in both pathologies. We analyzed the choroidal thickness using optical coherence tomography (OCT) and the foveal avascular zone (FAZ) using OCT-angiography and compared the results with ApoE gene expression, AD FH+, and the presence or absence of hard drusen (HD) in 184 cognitively healthy subjects. Choroidal thickness was statistically significantly different in the (FH−, ɛ4−, HD+) group compared with (i) both the (FH−, ɛ4−, HD−) and the (FH+, ɛ4+, HD+) groups in the superior and inferior points at 1500 μm, and (ii) the (FH+, ɛ4−, HD+) group in the superior point at 1500 μm. There were statistically significant differences in the superficial FAZ between the (FH+, ɛ4−, HD+) group and (i) the (FH+, ɛ4−, HD−) group and (ii) the (FH+, ɛ4+, HD−) group. In conclusion, ocular vascular changes are not yet evident in participants with a genetic risk of developing AD

Characterization of retinal drusen in subjects at high genetic risk of developing sporadic Alzheimer’s disease: An exploratory analysis

Having a family history (FH+) of Alzheimer’s disease (AD) and being a carrier of at least one ε4 allele of the ApoE gene are two of the main risk factors for the development of AD. AD and age-related macular degeneration (AMD) share one of the main risk factors, such as age, and characteristics including the presence of deposits (Aβ plaques in AD and drusen in AMD); however, the role of apolipoprotein E isoforms in both pathologies is controversial. We analyzed and characterized retinal drusen by optical coherence tomography (OCT) in subjects, classifying them by their AD FH (FH-or FH+) and their allelic characterization of ApoE ε4 (ApoE ε4-or ApoE ε4+) and considering cardiovascular risk factors (hypercholesterolemia, hypertension, and diabetes mellitus). In addition, we analyzed the choroidal thickness by OCT and the area of the foveal avascular zone with OCTA. We did not find a relationship between a family history of AD or any of the ApoE isoforms and the presence or absence of drusen. Subjects with drusen show choroidal thinning compared to patients without drusen, and thinning could trigger changes in choroidal perfusion that may give rise to the deposits that generate drusen

Tuning the Luminescence of Tin Oxide Low Dimensional Structures in the Near Infrared Range by In-Situ Doping During a Vapor-Solid Growth Process

Tin oxide low dimensional structures increasingly attract attention due to their wide application area. Indeed, by attaining new morphologies and properties the potential applications might increase the device portfolio. Furthermore, an adequate combination of doped SnO_2 nano- and micro-structures could enable multi-functionality and totally new applications. The latter might be the case of low dimensional tin oxide structures emitting in the near infrared range, which is below the energy of the common visible luminescence of tin oxide. The ability to obtain near infrared luminescence from tin oxide is tested by doping in-situ during a vapor-solid growth using Li, Cu, and Cr containing precursors in the initial mixture with tin oxide or metallic tin powders. Luminescence around 1.5eV is obtained for all the samples with morphologies varying from microtubes to rods and belts depending on the specific dopant and the Sn-based precursor

Development and validation of an UV-spectrophotometric method for the dissolution studies of sitagliptin tablets

A simple UV-spectrophotometric method was developed and validated for the analysis and dissolution studies of sitagliptin phosphate in tablets. Specificity test indicated an adequate UV detection at 267 nm. The method was validated regarding Specificity/accuracy/precision (RSD < 2 %), linearity (r2 = 0.9999), and partial robustness. Tablets uniformity was 102.52 % (RSD = 2.54 %). The method was applied for the determination of the drug in commercial tablet preparations and proved to be reliable for quantification It was also used for the comparison of dissolution profiles of sitagliptin tablets. After dissolution tests comparing eight different conditions through dissolution efficiency (DE), the chosen condition for posterior tests was USP apparatus 1 (basket) in 0.01M HCl pH 3.0, at a stirring rate of 50 rpm. The methodology was applied to two batches of sitagliptin phosphate tablets, giving similar dissolution profiles compared by the difference and similarity factor, obtaining values within the specified limits.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Somatic mTOR mutation in clonally expanded T lymphocytes associated with chronic graft versus host disease

Graft versus host disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GvHD (cGvHD) carrying persistent CD4(+) T cell clonal expansion harboring somatic mTOR, NFKB2, and TLR2 mutations. In the screening cohort (n=134), we detect the mTOR P2229R kinase domain mutation in two additional cGvHD patients, but not in healthy or HSCT patients without cGvHD. Functional analyses of the mTOR mutation indicate a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways, leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements support increased cytotoxicity of mutated CD4(+) T cells. High throughput drug-sensitivity testing suggests that mutations induce resistance to mTOR inhibitors, but increase sensitivity for HSP90 inhibitors. Our findings imply that somatic mutations may contribute to aberrant T cell proliferations and persistent immune activation in cGvHD, thereby paving the way for targeted therapies. Chronic graft versus host disease (cGvHD) is a major cause of morbidity and mortality in allogeneic bone marrow transplantation. Here the authors identify a recurrent activating mTOR mutation in expanded donor T-cell clones of 3 cGvHD patients, which suggests somatic mutations may contribute to GvHD pathogenesis and opens avenues to targeted therapies.Peer reviewe

Glaucoma: from pathogenic mechanisms to retinal glial cell response to damage

Glaucoma is a neurodegenerative disease of the retina characterized by the irreversible loss of retinal ganglion cells (RGCs) leading to visual loss. Degeneration of RGCs and loss of their axons, as well as damage and remodeling of the lamina cribrosa are the main events in the pathogenesis of glaucoma. Different molecular pathways are involved in RGC death, which are triggered and exacerbated as a consequence of a number of risk factors such as elevated intraocular pressure (IOP), age, ocular biomechanics, or low ocular perfusion pressure. Increased IOP is one of the most important risk factors associated with this pathology and the only one for which treatment is currently available, nevertheless, on many cases the progression of the disease continues, despite IOP control. Thus, the IOP elevation is not the only trigger of glaucomatous damage, showing the evidence that other factors can induce RGCs death in this pathology, would be involved in the advance of glaucomatous neurodegeneration. The underlying mechanisms driving the neurodegenerative process in glaucoma include ischemia/hypoxia, mitochondrial dysfunction, oxidative stress and neuroinflammation. In glaucoma, like as other neurodegenerative disorders, the immune system is involved and immunoregulation is conducted mainly by glial cells, microglia, astrocytes, and Müller cells. The increase in IOP produces the activation of glial cells in the retinal tissue. Chronic activation of glial cells in glaucoma may provoke a proinflammatory state at the retinal level inducing blood retinal barrier disruption and RGCs death. The modulation of the immune response in glaucoma as well as the activation of glial cells constitute an interesting new approach in the treatment of glaucoma

Projections of Excess Mortality Related to Diurnal Temperature Range Under Climate Change Scenarios: a multi-country modelling study

Various retrospective studies have reported on the increase of mortality risk due to higher diurnal temperature range (DTR). This study projects the effect of DTR on future mortality across 445 communities in 20 countries and regions

Ambient Particulate Air Pollution and Daily Mortality in 652 Cities.

BACKGROUND: The systematic evaluation of the results of time-series studies of air pollution is challenged by differences in model specification and publication bias. METHODS: We evaluated the associations of inhalable particulate matter (PM) with an aerodynamic diameter of 10 μm or less (PM10) and fine PM with an aerodynamic diameter of 2.5 μm or less (PM2.5) with daily all-cause, cardiovascular, and respiratory mortality across multiple countries or regions. Daily data on mortality and air pollution were collected from 652 cities in 24 countries or regions. We used overdispersed generalized additive models with random-effects meta-analysis to investigate the associations. Two-pollutant models were fitted to test the robustness of the associations. Concentration-response curves from each city were pooled to allow global estimates to be derived. RESULTS: On average, an increase of 10 μg per cubic meter in the 2-day moving average of PM10 concentration, which represents the average over the current and previous day, was associated with increases of 0.44% (95% confidence interval [CI], 0.39 to 0.50) in daily all-cause mortality, 0.36% (95% CI, 0.30 to 0.43) in daily cardiovascular mortality, and 0.47% (95% CI, 0.35 to 0.58) in daily respiratory mortality. The corresponding increases in daily mortality for the same change in PM2.5 concentration were 0.68% (95% CI, 0.59 to 0.77), 0.55% (95% CI, 0.45 to 0.66), and 0.74% (95% CI, 0.53 to 0.95). These associations remained significant after adjustment for gaseous pollutants. Associations were stronger in locations with lower annual mean PM concentrations and higher annual mean temperatures. The pooled concentration-response curves showed a consistent increase in daily mortality with increasing PM concentration, with steeper slopes at lower PM concentrations. CONCLUSIONS: Our data show independent associations between short-term exposure to PM10 and PM2.5 and daily all-cause, cardiovascular, and respiratory mortality in more than 600 cities across the globe. These data reinforce the evidence of a link between mortality and PM concentration established in regional and local studies. (Funded by the National Natural Science Foundation of China and others.)