The Cryptococcus gattii species complex has often been referred to as a primary pathogen due to its high infection frequency among apparently immunocompetent patients. In order to scrutinize the ...immune status of patients and the lineages of etiologic agents, we analyzed patient histories and the molecular types of etiologic agents from 135 global C. gattii cases. Eighty-six of 135 patients had been diagnosed as immunocompetent, although some of them had underlying medical issues, and 49 were diagnosed as immunocompromised with risk factors similar to those seen in Cryptococcus neoformans infection. We focused on the 86 apparently immunocompetent patients and were able to obtain plasma from 32 (37%) to analyze for the presence of autoantibodies against the granulocyte-macrophage colony-stimulating factor (GM-CSF) since these antibodies have been reported as a hidden risk factor for C. gattii infection. Among the 32 patients, 25 were free from any known other health issues, and 7 had various medical conditions at the time of diagnosis for cryptococcosis. Importantly, plasma from 19 (76%) of 25 patients with no recognized underlying medical condition showed the presence of GM-CSF autoantibodies, supporting this antibody as a major hidden risk factor for C. gattii infection. These data indicate that seemingly immunocompetent people with C. gattii infection warrant detailed evaluation for unrecognized immunologic risks. There was no relationship between molecular type and underlying conditions of patients. Frequency of each molecular type was related to its geographic origin exemplified by the overrepresentation of VGIV in HIV-positive (HIV+) patients due to its prevalence in Africa.
The C. neoformans and C. gattii species complex causes cryptococcosis. The C. neoformans species complex is known as an opportunistic pathogen since it primarily infects immunocompromised patients. C. gattii species complex has been referred to as a primary pathogen due to its high infection frequency in apparently immunocompetent people. We analyzed 135 global cases of C. gattii infection with documented patient history. Eighty-six of 135 patients were originally diagnosed as immunocompetent and 49 as immunosuppressed with similar underlying conditions reported for C. neoformans infection. A significant number of C. gattii patients without known underlying conditions possessed autoantibodies against granulocytes-macrophage colony-stimulating factor (GM-CSF) in their plasma, supporting the presence of GM-CSF antibodies as a hidden risk factor for C. gattii infection. No relationship was found between C. gattii lineages and the underlying conditions except for overrepresentation of the molecular type VGIV among HIV+ patients due to the prevalence of VGIV in Africa.
In fibrotic liver, connective tissue growth factor (CTGF) is constantly expressed in activated hepatic stellate cells (HSCs) and acts downstream of TGF-β to modulate extracellular matrix production. ...Distinct from other cell types in which Smad signaling plays major role in regulating CTGF production, TGF-β stimulated CTGF expression in activated HSCs is only in part dependent on Smad3. Other signaling molecules like MAPKs and PI3Ks may also participate in this process, and the underlying mechanisms have yet to be clarified. In this study, we report involvement of Stat3 activation in modulating CTGF production upon TGF-β challenge in activated HSCs. Stat3 is phosphorylated via JAK1 and acts as a critical ALK5 (activin receptor-like kinase 5) downstream signaling molecule to mediate CTGF expression. This process requires de novo gene transcription and is additionally modulated by MEK1/2, JNK, and PI3K pathways. Cell-specific knockdown of Smad3 partially decreases CTGF production, whereas it has no significant influence on Stat3 activation. The total CTGF production induced by TGF-β in activated HSCs is therefore, to a large extent, dependent on the balance and integration of the canonical Smad3 and Stat3 signaling pathways.
Background: HSC-derived CTGF is an important mediator of liver fibrogenesis.
Results: Stat3 is an essential factor for TGF-β mediated CTGF expression in activated HSCs.
Conclusion: TGF-β is using a complex signaling network including Stat3 to trigger CTGF production in HSCs.
Significance: Stat3 is defined for the first time as crucial TGF-β downstream signaling mediator to regulate extracellular matrix production in liver.
The cervical spine of Australopithecus sediba Meyer, Marc R.; Williams, Scott A.; Schmid, Peter ...
Journal of human evolution,
March 2017, 2017-03-00, 20170301, Letnik:
104
Journal Article
Recenzirano
Cervical vertebrae are rare in the early hominin fossil record, presenting a challenge for understanding the evolution of the neck and head carriage in hominin evolution. Here, we examine the ...cervical vertebrae of Australopithecus sediba, which unlike other South African taxa is known from associated cervical vertebrae. The A. sediba cervical vertebrae exhibit human-like values for wedging, pedicle cross-sectional areas, and articular facet heights, indicating reduced ventral loading relative to African apes. These features combine with a pattern of vertebral body bone distribution and caudally progressive size expansion suggesting a mode of cervical lordosis, load mitigation, and head carriage similar to humans and distinct from the cantilevered mode of head carriage of the extant African great apes. Yet these derived features in A. sediba are accompanied by ape-like vertebral body and dorsal pillar sizes, articular facet orientation, and uncinate process morphology signaling reduced lateral and rotational coupled movements between vertebral elements and indicate a considerably stiffer neck than in humans. A primitively long and horizontally-oriented C7 spinous process is likely related to a prognathic viscerocranium, although the complimentary C3 spinous process is short, implying large moments emanating from scapular and shoulder elevators rather than large muscles of head stabilization. Cross-sectional spinous process shape and robust anterior tubercles similarly signal increased arm elevation consistent with climbing behavior in corroboration with arboreal signatures previously observed in the shoulder, arms, and hand of A. sediba. Spinal canal shape and size suggests that A. sediba lacked the cervical spinal cord enlargement of Homo that confers humans with enhanced motor control to the upper limbs. The cervical spine of A. sediba thus presents a mosaic of primitive and derived characters, with anatomical features relating to neck posture and head carriage mirroring humans juxtaposed with most other aspects of functional anatomy that resemble chimpanzees.
Preclinical data suggest the combination of an anti-programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib ...alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with
V600-mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti-programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with
V600-mutant unresectable or metastatic melanoma.
Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic
V600-mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692).
At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 95% CI, 0.66 to 1.03;
= .042 one-sided; nonsignificant). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm.
The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.
Xanthomonas oryzae pv. oryzae causes bacterial blight of rice (Oryza sativa L.), a major disease that constrains production of this staple crop in many parts of the world. We report here on the ...complete genome sequence of strain PXO99A and its comparison to two previously sequenced strains, KACC10331 and MAFF311018, which are highly similar to one another.
The PXO99A genome is a single circular chromosome of 5,240,075 bp, considerably longer than the genomes of the other strains (4,941,439 bp and 4,940,217 bp, respectively), and it contains 5083 protein-coding genes, including 87 not found in KACC10331 or MAFF311018. PXO99A contains a greater number of virulence-associated transcription activator-like effector genes and has at least ten major chromosomal rearrangements relative to KACC10331 and MAFF311018. PXO99A contains numerous copies of diverse insertion sequence elements, members of which are associated with 7 out of 10 of the major rearrangements. A rapidly-evolving CRISPR (clustered regularly interspersed short palindromic repeats) region contains evidence of dozens of phage infections unique to the PXO99A lineage. PXO99A also contains a unique, near-perfect tandem repeat of 212 kilobases close to the replication terminus.
Our results provide striking evidence of genome plasticity and rapid evolution within Xanthomonas oryzae pv. oryzae. The comparisons point to sources of genomic variation and candidates for strain-specific adaptations of this pathogen that help to explain the extraordinary diversity of Xanthomonas oryzae pv. oryzae genotypes and races that have been isolated from around the world.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: The human leukocyte antigen (HLA) class II molecules are constitutively expressed in some melanoma, but the underlying molecular mechanisms have not yet been characterized. Methods: The ...expression of HLA class II antigen processing machinery (APM) components was determined in melanoma samples by qPCR, Western blot, flow cytometry and immunohistochemistry. Immunohistochemical and TCGA datasets were used for correlation of HLA class II expression to tumor grading, T-cell infiltration and patients’ survival. Results: The heterogeneous HLA class II expression in melanoma samples allowed us to characterize four distinct phenotypes. Phenotype I totally lacks constitutive HLA class II surface expression, which is inducible by interferon-gamma (IFN-γ); phenotype II expresses low basal surface HLA class II that is further upregulated by IFN-γ; phenotype III lacks constitutive and IFN-γ controlled HLA class II expression, but could be induced by epigenetic drugs; and in phenotype IV, lack of HLA class II expression is not recovered by any drug tested. High levels of HLA class II APM component expression were associated with an increased intra-tumoral CD4+ T-cell density and increased patients’ survival. Conclusions: The heterogeneous basal expression of HLA class II antigens and/or APM components in melanoma cells is caused by distinct molecular mechanisms and has clinical relevance.
Traumatic brain injury (TBI) disrupts brain communication and increases risk for post-traumatic stress disorder (PTSD). However, mechanisms by which TBI-related disruption of brain communication ...confers PTSD risk have not been successfully elucidated in humans. This may be in part because functional MRI (fMRI), the most common technique for measuring functional brain communication, is unreliable for characterizing individual patients. However, this unreliability can be overcome with sufficient within-individual data. Here, we examined whether relationships could be observed among TBI, structural and functional brain connectivity, and PTSD severity by collecting ∼3.5 hours of resting-state fMRI and diffusion tensor imaging (DTI) data in each of 26 United States military veterans. We observed that a TBI history was associated with decreased whole-brain resting-state functional connectivity (RSFC), while the number of lifetime TBIs was associated with reduced whole-brain fractional anisotropy (FA). Both RSFC and FA explained independent variance in PTSD severity, with RSFC mediating the TBI-PTSD relationship. Finally, we showed that large amounts of per-individual data produced highly reliable RSFC measures, and that relationships among TBI, RSFC/FA, and PTSD could not be observed with typical data quantities. These results demonstrate links among TBI, brain connectivity, and PTSD severity, and illustrate the need for precise characterization of individual patients using high-data fMRI scanning.
No prospective cohort study of high-risk children has used rigorous exposure assessment and optimal diagnostic procedures to examine the perinatal antecedents of autism spectrum disorder separately ...among those with and without cognitive impairment.
We sought to identify perinatal factors associated with increased risk for autism spectrum disorder with and without intellectual disability (intelligence quotient <70) in children born extremely preterm.
This prospective multicenter (14 institutions in 5 states) birth cohort study included children born at 23-27 weeks’ gestation in 2002 through 2004 who were evaluated for autism spectrum disorder and intellectual disability at age 10 years. Pregnancy information was obtained from medical records and by structured maternal interview. Cervical-vaginal “infection” refers to maternal report of bacterial infection (n = 4), bacterial vaginosis (n = 30), yeast infection (n = 62), mixed infection (n = 4), or other/unspecified infection (n = 43; eg, chlamydia, trichomonas, or herpes). We do not know the extent to which infection per se was confirmed by microbial colonization. We use the terms “fetal growth restriction” and “small for gestational age” interchangeably in light of the ongoing challenge to discern pathologically from constitutionally small newborns. Severe fetal growth restriction was defined as a birthweight Z-score for gestational age at delivery <–2 (ie, ≥2 SD below the median birthweight in a referent sample that excluded pregnancies delivered for preeclampsia or fetal indications). Participants were classified into 4 groups based on whether or not they met rigorous diagnostic criteria for autism spectrum disorder and intellectual disability (autism spectrum disorder+/intellectual disability–, autism spectrum disorder+/intellectual disability+, autism spectrum disorder–/intellectual disability+, and autism spectrum disorder–/intellectual disability–). Temporally ordered multinomial logistic regression models were used to examine the information conveyed by perinatal factors about increased risk for autism spectrum disorder and/or intellectual disability (autism spectrum disorder+/intellectual disability–, autism spectrum disorder+/intellectual disability+, and autism spectrum disorder–/intellectual disability+).
In all, 889 of 966 (92%) children recruited were assessed at age 10 years, of whom 857 (96%) were assessed for autism spectrum disorder; of these, 840 (98%) children were assessed for intellectual disability. Autism spectrum disorder+/intellectual disability– was diagnosed in 3.2% (27/840), autism spectrum disorder+/intellectual disability+ in 3.8% (32/840), and autism spectrum disorder–/intellectual disability+ in 8.5% (71/840). Maternal report of presumed cervical-vaginal infection during pregnancy was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.7; 95% confidence interval, 1.2–6.4). The lowest gestational age category (23-24 weeks) was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.3–6.6) and autism spectrum disorder+/intellectual disability– (odds ratio, 4.4; 95% confidence interval, 1.7–11). Severe fetal growth restriction was strongly associated with increased risk for autism spectrum disorder+/intellectual disability– (odds ratio, 9.9; 95% confidence interval, 3.3–30), whereas peripartum maternal fever was uniquely associated with increased risk of autism spectrum disorder–/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.2–6.7).
Our study confirms that low gestational age is associated with increased risk for autism spectrum disorder irrespective of intellectual ability, whereas severe fetal growth restriction is strongly associated with autism spectrum disorder without intellectual disability. Maternal report of cervical-vaginal infection is associated with increased risk of autism spectrum disorder with intellectual disability, and peripartum maternal fever is associated with increased risk for intellectual disability without autism spectrum disorder.
The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single ...cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease. Our analysis revealed an enrichment of innate immune cells in skin during the first trimester and clonal expansion of disease-associated lymphocytes in atopic dermatitis and psoriasis. We uncovered and validated in situ a reemergence of prenatal vascular endothelial cell and macrophage cellular programs in atopic dermatitis and psoriasis lesional skin. These data illustrate the dynamism of cutaneous immunity and provide opportunities for targeting pathological developmental programs in inflammatory skin diseases.
There are well-documented associations of glaucoma with high-dose radiation exposure, but only a single study suggesting risk of glaucoma, and less conclusively macular degeneration, associated with ...moderate-dose exposure. We assessed risk of glaucoma and macular degeneration associated with occupational eye-lens radiation dose, using participants from the US Radiologic Technologists Study, followed from the date of surveys in 1994-1998, 2003-2005 to the earliest of diagnosis of glaucoma or macular degeneration, cancer other than non-melanoma skin cancer, or date of last survey (2012-2014). We excluded those with baseline disease or previous radiotherapy history. Cox proportional hazards models with age as timescale were used. There were 1631 cases of newly self-reported doctor-diagnosed cases of glaucoma and 1331 of macular degeneration among 69,568 and 69,969 eligible subjects, respectively. Estimated mean cumulative eye-lens absorbed dose from occupational radiation exposures was 0.058 Gy. The excess relative risk/Gy for glaucoma was -0.57 (95% CI -1.46, 0.60, p = 0.304) and for macular degeneration was 0.32 (95% CI -0.32, 1.27, p = 0.381), suggesting that there is no appreciable risk for either endpoint associated with low-dose and low dose-rate radiation exposure. Since this is the first examination of glaucoma and macular degeneration associated with low-dose radiation exposure, this result needs to be replicated in other low-dose studies.
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