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1.
Medicine (Baltimore) ; 98(35): e16903, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31464922

RESUMO

Staphylococcus aureus prosthetic valve endocarditis (SAPVE) has a poor prognosis. There are no large series that accurately describe this entity.This is a retrospective observational study on a prospective cohort from 3 Spanish reference hospitals for cardiac surgery, including 78 definitive episodes of left SAPVE between 1996 and 2016.Fifty percent had a Charlson Index score >5; 53% were health care-related. Twenty percent did not present fever. Complications at diagnosis included: severe heart failure (HF, 29%), septic shock (SS, 17.9%), central nervous system abnormalities (19%), septic metastasis (4%). Hemorrhagic stroke was not higher in anticoagulated patients. Twenty-seven percent were methicilin-resistant SA (MRSA). Fifteen of 31 had positive valve culture; it was related to surgery within first 24 hours. At diagnosis, 69% had vegetation (>10 mm in 75%), 21.8% perianular extension, and 20% prosthetic dehiscence. Forty-eight percent had persistent bacteremia, related to nonsurgical treatment. Perianular extension progressed in 18%. Surgery was performed in 35 episodes (12 with stroke). Eleven uncomplicated episodes were managed with medical therapy, 8 survived. In-hospital mortality was 55%, higher in episodes with hemorrhagic stroke (77.8% vs 52.2%, odds ratio 3.2 [0.62-16.55]). Early SAPVE was nosocomial (92%), presented as severe HF (54%), patients were diagnosed and operated on early, 38% died. In intermediate SAPVE (9 weeks-1 year) diagnosis was delayed (24%), patients presented with constitutional syndrome (18%), renal failure (41%), and underwent surgery >72 hours after indication; 53% died. Late SAPVE (>1 year) was related with health care, diagnosis delay, and 60% of deceases.Left SAPVE frequently affected patients with comorbidity and health care contact. Complications at diagnosis and absence of fever were frequent. Presence of MRSA was high. Positive valve culture was related to early surgery. Paravalvular extension was frequent; vegetations were large, but its absence at diagnosis was common. Some uncomplicated SAPVE episodes were safety treated with medical therapy. Surgery was feasible in patients with stroke. Mortality was high. There were differences in some clinical characteristics and in evolution according to the time elapsed from valve replacement. Prognosis was better in early SAPVE.

2.
Int J Mol Sci ; 20(16)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412584

RESUMO

Melatonin exerts oncostatic actions and sensitizes tumor cells to chemotherapeutics or radiation. In our study, we investigated the effects of docetaxel, vinorelbine, and radiation on human breast fibroblasts and its modulation by melatonin. Docetaxel or vinorelbine inhibits proliferation and stimulates the differentiation of breast preadipocytes, by increasing C/EBPα and PPARγ expression and by downregulating tumor necrosis factor α (TNFα), interleukin 6 (IL-6), and IL-11 expression. Radiation inhibits both proliferation and differentiation through the downregulation of C/EBPα and PPARγ and by stimulating TNFα expression. In addition, docetaxel and radiation decrease aromatase activity and expression by decreasing aromatase promoter II and cyclooxygenases 1 and 2 (COX-1 and COX-2) expression. Melatonin potentiates the stimulatory effect of docetaxel and vinorelbine on differentiation and their inhibitory effects on aromatase activity and expression, by increasing the stimulatory effect on C/EBPα and PPARγ expression and the downregulation of antiadipogenic cytokines and COX expression. Melatonin also counteracts the inhibitory effect of radiation on differentiation of preadipocytes, by increasing C/EBPα and PPARγ expression and by decreasing TNFα expression. Melatonin also potentiates the inhibitory effect exerted by radiation on aromatase activity and expression by increasing the downregulation of promoter II, and COX-1 and COX-2 expression. Our findings suggest that melatonin modulates regulatory effects induced by chemotherapeutic drugs or radiation on preadipocytes, which makes it a promising adjuvant for chemotherapy and radiotherapy sensibilization.

3.
Sci Rep ; 9(1): 12236, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439886

RESUMO

Lignocellulosic ethanol production requires high substrate concentrations for its cost-competitiveness. This implies the presence of high concentrations of insoluble solids (IS) at the initial stages of the process, which may limit the fermentation performance of the corresponding microorganism. The presence of 40-60% IS (w/w) resulted in lower glucose consumption rates and reduced ethanol volumetric productivities of Saccharomyces cerevisiae F12. Yeast cells exposed to IS exhibited a wrinkled cell surface and a reduced mean cell size due to cavity formation. In addition, the intracellular levels of reactive oxygen species (ROS) increased up to 40%. These ROS levels increased up to 70% when both lignocellulose-derived inhibitors and IS were simultaneously present. The general stress response mechanisms (e.g. DDR2, TPS1 or ZWF1 genes, trehalose and glycogen biosynthesis, and DNA repair mechanisms) were found repressed, and ROS formation could not be counteracted by the induction of the genes involved in repairing the oxidative damage such as glutathione, thioredoxin and methionine scavenging systems (e.g. CTA1, GRX4, MXR1, and TSA1; and the repression of cell cycle progression, CLN3). Overall, these results clearly show the role of IS as an important microbial stress factor that affect yeast cells at physical, physiological, and molecular levels.

4.
Brain Connect ; 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31244329

RESUMO

The prognostic capacity of the diffusion tensor imaging measures fractional anisotropy (FA) and mean diffusivity (MD) to detect mild cognitive impairment (MCI) progression to Alzheimer's disease (AD) was assessed in 135 MCI patients and 72 healthy subjects over a median follow-up of 40 months. Forty-nine MCI patients (36.3%) developed AD. The factors MD left hippocampus, FA left cingulate, and FA left hippocampus emerged as predictors of progression. Age (hazard ratio [HR] 1.21), delayed text recall (HR 0.89), FA left uncinate (HR 1.90), FA left hippocampus (HR 2.21), and carrying at least one ApoE4 allele (HR 2.86) were associated with a high conversion rate. FA measures revealed the greatest discriminative capacity (Harrell's C = 0.73 versus 0.65 without FA; p = 0.034). The inclusion of FA structural connectivity data in our model improved discrimination between subjects with MCI progressing or not to dementia.

5.
Talanta ; 203: 9-15, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31202354

RESUMO

Biosensors are rising technologies in the pharmaceutical field for medicine discovery, development and Quality Control (QC) stages. Surface acoustic wave (SAW) biosensor employs acoustic waves generated by oscillating a piezoelectric crystal quartz plate to meas. mass and viscosity, and allows to detect and quantify binding events between the analyte and an immobilized interacting ligand. We present here a SAW biosensor based approach for the functional quantification of Escherichia colil-asparaginase (E. colil-ASNase), using polyclonal antibody (pAb) as the interaction partner immobilized on the chip. Different immobilization strategies of pAb were initially evaluated, resulting in the BS3 activated amide coupling via protein G strategy as the final immobilization method. The method was validated by evaluating the selectivity, linearity, as well as accuracy (a recovery of 102.4%) and precision (RSD of 8.5%). The application of the validated method on different samples encompassing different lots of E. colil-ASNase, deamidated E. colil-ASNase and dry-heated E. colil-ASNase (80 °C, 10 min) indicated the suitability of the developed SAW method to quantify E. colil-ASNase. We suggest this SAW method can be adopted as a pharmaceutical QC method.

6.
Bioresour Technol ; 288: 121540, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31174085

RESUMO

Since xylose is the second most abundant sugar in lignocellulose, using microorganisms able to metabolize it into bio-based chemicals like lactic acid is an attractive approach. In this study, Lactobacillus pentosus CECT4023T was evolved to improve its xylose fermentation capacity even at acid pH by adaptive laboratory evolution in repeated anaerobic batch cultures at increasing xylose concentration. The resulting strain (named MAX2) presented between 1.5 and 2-fold more xylose consumption and lactic acid production than the parental strain in 20 g L-1 xylose defined media independently of the initial pH value. When the pH was controlled in bioreactor, lactic acid productivity at 16 h increased 1.4-fold when MAX2 was grown both in xylose defined media and in wheat straw hydrolysate. These results demonstrated the potential of this new strain to produce lactic acid from hemicellulosic substrates at low pH, reducing the need of using neutralizing agents in the process.

7.
Nat Commun ; 10(1): 2423, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160559

RESUMO

The germinal center (GC) reaction in Peyer's patches (PP) requires continuous access to antigens, but how this is achieved is not known. Here we show that activated antigen-specific CCR6+CCR1+GL7- B cells make close contact with M cells in the subepithelial dome (SED). Using in situ photoactivation analysis of antigen-specific SED B cells, we find migration of cells towards the GC. Following antigen injection into ligated intestinal loops containing PPs, 40% of antigen-specific SED B cells bind antigen within 2 h, whereas unspecifc cells do not, indicating B cell-receptor involvment. Antigen-loading is not observed in M cell-deficient mice, but is unperturbed in mice depleted of classical dendritic cells (DC). Thus, we report a M cell-B cell antigen-specific transporting pathway in PP that is independent of DC. We propose that this antigen transporting pathway has a critical role in gut IgA responses, and should be taken into account when developing mucosal vaccines.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Antígenos/imunologia , Linfócitos B/imunologia , Células Epiteliais/imunologia , Nódulos Linfáticos Agregados/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Animais , Células Dendríticas/imunologia , Centro Germinativo/imunologia , Imunoglobulina A/imunologia , Ativação Linfocitária , Camundongos
9.
Infect Dis Ther ; 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31127539

RESUMO

INTRODUCTION: We evaluated the diagnostic reliability of serum polymerase chain reaction (PCR) versus blood culture, abdominal fluid or both (composite measure) in patients receiving empirical antifungal treatment for suspected invasive candidiasis. METHODS: This observational, prospective, non-interventional, multicentre study in Spain enrolled 176 critically ill patients admitted to the intensive care unit. Separate blood samples for culture and serum PCR were taken before the start of antifungal therapy. Patient assessment was performed according to each site's usual clinical practice. The primary end point was concordance between serum PCR and blood culture. Secondary end points were concordance between serum PCR and a positive abdominal fluid sample or the composite measure. Quality indices included sensitivity, specificity, positive/negative predictive values (PPV/NPV) and kappa indices. RESULTS: Among 175 evaluable patients, rates of Candida detection were similar for serum PCR (n = 16/175, 9.1%) versus blood culture (n = 14/175, 8.0%). Quality indices for serum PCR relative to blood culture were: sensitivity 21.4%; specificity 91.9%; PPV 18.8%; NPV 93.1%; kappa index 0.125. Thirty-two abdominal fluid samples were positive. Quality indices for serum PCR versus abdominal fluid were: sensitivity 31.3%; specificity 83.0%; PPV 15.6%; NPV 92.3%; kappa index 0.100. Quality indices for serum PCR versus the composite measure were: sensitivity 15.8%; specificity 92.7%; PPV 37.5%; NPV 79.9%; kappa index 0.107. CONCLUSION: The sensitivity of serum PCR for Candida detection was low and the rate of concordance was low between serum PCR and the other diagnostic techniques used to identify Candida infections. Hospital-based diagnostic tests need optimising to improve outcomes in patients with suspected invasive candidiasis. FUNDING: Astellas Pharma Inc.

11.
Biopolymers ; : e23284, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31059131

RESUMO

The static light scattering and sedimentation equilibrium of solutions of Dextran 70 were measured as functions of concentration up to 100 g/L in pH 7.4 phosphate-buffered saline at temperatures between 5 and 37 °C. The concentration dependence of scattering intensity and the apparent molar mass obtained from sedimentation equilibrium were found to be nearly independent of temperature over this range to within the uncertainty of measurement. Global analysis of the concentration dependence of both properties yielded a reliable estimate of the concentration-dependent thermodynamic activity coefficient, a quantitative measure of the free energy of self-interaction. The self-interaction between Dextran molecules is compared with that of a globular protein (BSA) and a highly crosslinked polymer of similar molar mass (Ficoll 70). The observed concentration dependence of the free energy of Dextran self-interaction may be quantitatively accounted for by a semi-empirical model in which the polymer molecule is represented by a compressible sphere.

12.
Med Clin (Barc) ; 2019 May 03.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31060878

RESUMO

BACKGROUND AND OBJECTIVES: Influenza vaccine is recommended for patients with autoimmune inflammatory rheumatic diseases who receive biological therapy. To evaluate if biological therapy impairs immunization after seasonal influenza vaccine. MATERIAL AND METHODS: Patients with inflammatory arthopathies, psoriasis, inflammatory bowel disease or connective tissue diseases who were receiving or were going to initiate biological therapy were included and vaccinated during 2014-2015 influenza season. ELISA was used to measure influenza antigen A and B antibodies, before and after vaccination. Demographic parameters, diagnosis and kind of treatment were recorded and their influence on the final serological status against influenza was studied. RESULTS: 253 subjects were analyzed. After vaccination, 77% of participants presented detectable antibodies against antigen A and 50.6% of them had detectable antibodies against antigen B. Final seropositivity rate against antigen B antibodies increased from baseline (50.6% vs 43.5%, p<0.001). Anti-TNF drugs were associated with better response and rituximab with the worst (79.2% vs 55.0% for final seropositivity against antigen A, p=0.020). Vaccine response in the rituximab group tended to improve when the interval between the drug administration and the vaccination was at least 12 weeks (seropositivity rate 80.0% in those with the longer interval vs 25.0% in the other group, p=0.054). CONCLUSIONS: Among the patients on biological therapy vaccinated against influenza, anti-TNF therapy was identified as a predictive factor of final seropositivity. Rituximab presented a lower rate of final seropositivity, which could be increased with an accurate administration schedule.

13.
Opt Lett ; 44(7): 1762-1765, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30933141

RESUMO

Light scattering and spin-orbit angular momentum coupling phenomena from subwavelength objects, with electric and magnetic dipolar responses, are receiving an increasing interest. Under illumination by circularly polarized light, spin-orbit coupling effects have been shown to lead to significant shifts between the measured and actual position of particles. Here we show that the remarkable angular dependence of these "optical mirages" and those of the intensity, degree of circular polarization (DoCP), and spin and orbital angular momentum of scattered photons are all linked, and fully determined, by the dimensionless "asymmetry parameter" g, being independent of the specific optical properties of the scatterer. Interestingly, for g≠0, the maxima of the optical mirage and angular momentum exchange take place at different scattering angles. We further show that the g parameter is exactly half of the DoCP at a right-angle scattering, which opens the possibility to infer the whole angular properties of the scattered fields by a single far-field polarization measurement.

14.
Cell Death Dis ; 10(5): 347, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31024001

RESUMO

The primordium of the limb contains a number of progenitors far superior to those necessary to form the skeletal components of this appendage. During the course of development, precursors that do not follow the skeletogenic program are removed by cell senescence and apoptosis. The formation of the digits provides the most representative example of embryonic remodeling via cell degeneration. In the hand/foot regions of the embryonic vertebrate limb (autopod), the interdigital tissue and the zones of interphalangeal joint formation undergo massive degeneration that accounts for jointed and free digit morphology. Developmental senescence and caspase-dependent apoptosis are considered responsible for these remodeling processes. Our study uncovers a new upstream level of regulation of remodeling by the epigenetic regulators Uhrf1 and Uhrf2 genes. These genes are spatially and temporally expressed in the pre-apoptotic regions. UHRF1 and UHRF2 showed a nuclear localization associated with foci of methylated cytosine. Interestingly, nuclear labeling increased in cells progressing through the stages of degeneration prior to TUNEL positivity. Functional analysis in cultured limb skeletal progenitors via the overexpression of either UHRF1 or UHRF2 inhibited chondrogenesis and induced cell senescence and apoptosis accompanied with changes in global and regional DNA methylation. Uhrfs modulated canonical cell differentiation factors, such as Sox9 and Scleraxis, promoted apoptosis via up-regulation of Bak1, and induced cell senescence, by arresting progenitors at the S phase and upregulating the expression of p21. Expression of Uhrf genes in vivo was positively modulated by FGF signaling. In the micromass culture assay Uhrf1 was down-regulated as the progenitors lost stemness and differentiated into cartilage. Together, our findings emphasize the importance of tuning the balance between cell differentiation and cell stemness as a central step in the initiation of the so-called "embryonic programmed cell death" and suggest that the structural organization of the chromatin, via epigenetic modifications, may be a precocious and critical factor in these regulatory events.

15.
Trials ; 20(1): 179, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894206

RESUMO

BACKGROUND: Early mother-child skin-to-skin contact (SSC) in the first 2 h postpartum is highly beneficial for both mother and child. However, cases have been reported of newborns who have experienced apparently life-threatening events (ALTEs) or sudden death during this procedure. The causes of these events are unknown. Newborn's prone position could influence the onset of these events but there is very little evidence to support any recommendation. We hypothesize that newborns' breathing obstruction episodes increase as mothers lie more horizontally. The main objective of this study is to compare the occurrence of desaturation and bradycardia episodes as a function of mother's bed incline. The study is designed as a randomized, controlled, assessor blind, multicenter, superiority trial with two parallel groups and 1:1 allocation ratio. METHODS: The study participants will be full-term healthy mother-newborn dyads from ten hospitals in Spain. Participants will be randomly assigned to one of two study arms defined by mother's bed inclination (45° or 15°). The planned sample size is 5866. Centralized permuted blocks randomization and assessor blinding will be implemented. The newborns will be monitored remotely with pulse oximetry, from 10 min to 2 h after delivery. We established SO2 and heart rate (HR) limit alarms, as well as an action protocol in the event of alarm activation. The primary outcome is the number of healthy newborns who undergo episodes of SO2 ≤ 90%. Secondary outcomes are the mean SO2 level, the number of newborns who experience episodes of SO2 ≤ 85%, the time to SSC discontinuation due to abnormal SO2 or HR, and episodes of HR < 111 beats per minute (bpm) or > 180 bpm. Subgroups and pooled analysis will be performed to identify if breast-feeding and mother and child positions favor the occurrence of desaturation or bradycardia episodes. DISCUSSION: A simple intervention such as modifying mother's bed angle of inclination while in SSC with her child during the first 2 h postpartum could favor newborn's hemodynamic and respiratory stabilization and thus contribute to reducing the onset of ALTEs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02585492 . Registered on 22nd October 2015. PROTOCOL VERSION: 2 (30th June 2015).


Assuntos
Relações Mãe-Filho , Oxigênio/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Leitos , Interpretação Estatística de Dados , Feminino , Frequência Cardíaca , Humanos , Recém-Nascido , Avaliação de Resultados (Cuidados de Saúde) , Projetos de Pesquisa
16.
J Steroid Biochem Mol Biol ; 190: 104-114, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30878503

RESUMO

Alzheimer's disease (AD) is the most common form of dementia and it is characterized by the deposition of amyloid-ß (Aß) plaques and neurofibrillary tangles in the brain. However, the complete pathogenesis of the disease is still unknown. High level of serum cholesterol has been found to positively correlate with an increased risk of dementia and some studies have reported a decreased prevalence of AD in patients taking cholesterol-lowering drugs. Years of research have shown a strong correlation between blood hypercholesterolemia and AD, however cholesterol is not able to cross the Blood Brain Barrier (BBB) into the brain. Cholesterol lowering therapies have shown mixed results in cognitive performance in AD patients, raising questions of whether brain cholesterol metabolism in the brain should be studied separately from peripheral cholesterol metabolism and what their relationship is. Unlike cholesterol, oxidized cholesterol metabolites known as oxysterols are able to cross the BBB from the circulation into the brain and vice-versa. The main oxysterols present in the circulation are 24S-hydroxycholesterol and 27-hydroxycholesterol. These oxysterols and their catalysing enzymes have been found to be altered in AD brains and there is evidence indicating their influence in the progression of the disease. This review gives a broad perspective on the relationship between hypercholesterolemia and AD, cholesterol lowering therapies for AD patients and the role of oxysterols in pathological and non-pathological conditions. Also, we propose cholesterol metabolites as valuable targets for prevention and alternative AD treatments.

17.
J Anat ; 234(6): 815-829, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30875434

RESUMO

During embryonic development, organ morphogenesis requires major tissue rearrangements that are tightly regulated at the genetic level. A large number of studies performed in recent decades assigned a central role to programmed cell death for such morphogenetic tissue rearrangements that often sculpt the shape of embryonic organs. However, accumulating evidence indicates that far from being the only factor responsible for sculpting organ morphology, programmed cell death is accompanied by other tissue remodeling events that ensure the outcome of morphogenesis. In this regard, cell senescence has been recently associated with morphogenetic degenerative embryonic processes as an early tissue remodeling event in development of the limbs, kidney and inner ear. Here, we have explored cell senescence by monitoring ß-galactosidase activity during embryonic heart development where programmed cell death is believed to exert an important morphogenetic function. We report the occurrence of extensive cell senescence foci during heart morphogenesis. These foci overlap spatially and temporally with the areas of programmed cell death that are associated with remodeling of the outflow tract to build the roots of the great arteries and with the septation of cardiac cavities. qPCR analysis allowed us to identify a gene expression profile characteristic of the so-called senescence secretory associated phenotype in the remodeling outflow tract of the embryonic heart. In addition, we confirmed local upregulation of numerous tumor suppressor genes including p21, p53, p63, p73 and Btg2. Interestingly, the areas of cell senescence were also accompanied by intense lysosomal activation and non-apoptotic DNA damage revealed by γH2AX immunolabeling. Considering the importance of sustained DNA damage as a triggering factor for cell senescence and apoptosis, we propose the coordinated contribution of DNA damage, senescence and apoptotic cell death to assure tissue remodeling in the developing vertebrate heart.

18.
PLoS One ; 14(3): e0213441, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30897111

RESUMO

INTRODUCTION: The relation between TV viewing and posttraumatic stress disorder (PTSD) is controversial; prior work focused exclusively on whether TV viewing of disaster events constitutes a traumatic stressor that causes PTSD. This study evaluates a possible bidirectional relation between PTSD and TV viewing in community-dwelling women. METHODS: Data are from the PTSD subsample of the Nurses' Health II study, an ongoing prospective study of women aged 24-42 years at enrollment and who have been followed biennially (N = 50,020). Trauma exposure and PTSD symptoms (including date of onset) were assessed via the Brief Trauma Questionnaire and the Short Screening Scale for DSM-IV PTSD. Average TV viewing was reported at 5 times over 18 years of follow-up. Linear mixed models assessed differences in TV viewing patterns by trauma/PTSD status. Among women with trauma/PTSD onset during follow-up (N = 14,374), linear spline mixed models assessed differences in TV viewing patterns before and after PTSD onset. RESULTS: Women with high PTSD symptoms reported more TV viewing (hours/wk) compared to trauma-unexposed women at all follow-up assessments (ß = 0.14, SE = 0.01, p < .001). Among the women who experienced trauma during follow-up, significant increases in TV viewing (hours/day) prior to onset of high PTSD symptom levels were evident (ß = 0.15, SE = 0.02, p < .001). CONCLUSIONS: TV viewing following trauma exposure may be a marker of vulnerability for developing PTSD and also a consequence of having PTSD. High TV viewing levels may be linked with ineffective coping strategies or social isolation, which increase risk of developing PTSD.

19.
Vet Microbiol ; 231: 264-270, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30853132

RESUMO

Chlamydiosis, caused by Chlamydia pecorum, is regarded as an important threat to koala populations. Across the koala's geographical range, disease severity associated with C. pecorum infection varies, with pathogen diversity and strain pathogenicity being likely important factors. To examine C. pecorum diversity on a sub-population level a Multi-Locus Sequence Typing (MLST) scheme, containing the housekeeping genes; gatA, oppA_3, hflX, gidA, enoA, hemN and fumC, was used to type strains from two sub-populations of koalas from the Liverpool Plains, NSW, Australia, with different disease expressions. Typing of samples from 2015 to 2017, revealed a significant association between sequence type ST 69 and clinical disease and a significant difference in sequence type frequencies between sub-populations. Sequence type ST 69 has previously been identified in both subclinical and clinically diseased koalas indicating that these markers alone are not illustrative of pathogenicity. However, recent emergence of this sequence type in a naïve population may explain the differing disease expressions. Sequence types ST 73 and ST 69 have been described in koalas across a broad geographic range, indicating multiple introduction events and/or a limited veracity of the MLST loci to explore fine scale epidemiological investigations, particularly those examining the interface between pathogenic strain and disease outcome.


Assuntos
Infecções por Chlamydia/veterinária , Chlamydia/genética , Phascolarctidae/microbiologia , Animais , Austrália/epidemiologia , Técnicas de Tipagem Bacteriana , Chlamydia/classificação , Infecções por Chlamydia/epidemiologia , Tipagem de Sequências Multilocus , Filogenia , Reação em Cadeia da Polimerase
20.
Cell Death Differ ; 26(9): 1545-1565, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30770874

RESUMO

In the presence of aggregation-prone proteins, the cytosol and endoplasmic reticulum (ER) undergo a dramatic shift in their respective redox status, with the cytosol becoming more oxidized and the ER more reducing. However, whether and how changes in the cellular redox status may affect protein aggregation is unknown. Here, we show that C. elegans loss-of-function mutants for the glutathione reductase gsr-1 gene enhance the deleterious phenotypes of heterologous human, as well as endogenous worm aggregation-prone proteins. These effects are phenocopied by the GSH-depleting agent diethyl maleate. Additionally, gsr-1 mutants abolish the nuclear translocation of HLH-30/TFEB transcription factor, a key inducer of autophagy, and strongly impair the degradation of the autophagy substrate p62/SQST-1::GFP, revealing glutathione reductase may have a role in the clearance of protein aggregates by autophagy. Blocking autophagy in gsr-1 worms expressing aggregation-prone proteins results in strong synthetic developmental phenotypes and lethality, supporting the physiological importance of glutathione reductase in the regulation of misfolded protein clearance. Furthermore, impairing redox homeostasis in both yeast and mammalian cells induces toxicity phenotypes associated with protein aggregation. Together, our data reveal that glutathione redox homeostasis may be central to proteostasis maintenance through autophagy regulation.

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