Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within ...resting CD4(+) T cells is the primary strategy to clear this reservoir. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4(+) T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4(+) cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.
Escherichia coli is one of the most-studied microorganisms worldwide but its characteristics are continually changing. Extraintestinal E. coli infections, such as urinary tract infections and ...neonatal sepsis, represent a huge public health problem. They are caused mainly by specialized extraintestinal pathogenic E. coli (ExPEC) strains that can innocuously colonize human hosts but can also cause disease upon entering a normally sterile body site. The virulence capability of such strains is determined by a combination of distinctive accessory traits, called virulence factors, in conjunction with their distinctive phylogenetic background. It is conceivable that by developing interventions against the most successful ExPEC lineages or their key virulence/colonization factors the associated burden of disease and health care costs could foreseeably be reduced in the future. On the other hand, one important problem worldwide is the increase of antimicrobial resistance shown by bacteria. As underscored in the last WHO global report, within a wide range of infectious agents including E. coli, antimicrobial resistance has reached an extremely worrisome situation that ‘threatens the achievements of modern medicine’. In the present review, an update of the knowledge about the pathogenicity, antimicrobial resistance and clinical aspects of this ‘old friend’ was presented.
New knowledgements about pathogenesis, antimicrobial resistance and clinical aspects of Escherichia coli.
Graphical Abstract Figure.
New knowledgements about pathogenesis, antimicrobial resistance and clinical aspects of Escherichia coli.
Coronaviruses (CoVs) have a remarkable potential to change tropism. This is particularly illustrated over the last 15 years by the emergence of two zoonotic CoVs, the severe acute respiratory ...syndrome (SARS)- and Middle East respiratory syndrome (MERS)-CoV. Due to their inherent genetic variability, it is inevitable that new cross-species transmission events of these enveloped, positive-stranded RNA viruses will occur. Research into these medical and veterinary important pathogens-sparked by the SARS and MERS outbreaks-revealed important principles of inter- and intraspecies tropism changes. The primary determinant of CoV tropism is the viral spike (S) entry protein. Trimers of the S glycoproteins on the virion surface accommodate binding to a cell surface receptor and fusion of the viral and cellular membrane. Recently, high-resolution structures of two CoV S proteins have been elucidated by single-particle cryo-electron microscopy. Using this new structural insight, we review the changes in the S protein that relate to changes in virus tropism. Different concepts underlie these tropism changes at the cellular, tissue, and host species level, including the promiscuity or adaptability of S proteins to orthologous receptors, alterations in the proteolytic cleavage activation as well as changes in the S protein metastability. A thorough understanding of the key role of the S protein in CoV entry is critical to further our understanding of virus cross-species transmission and pathogenesis and for development of intervention strategies.
The respiratory system reacts instantaneously to intrinsic and extrinsic inputs. This adaptability results in significant fluctuations in breathing parameters, such as respiratory rate, tidal volume, ...and inspiratory flow profiles. Breathing variability is influenced by several conditions, including sleep, various pulmonary diseases, hypoxia, and anxiety disorders. Recent studies have suggested that weaning failure during mechanical ventilation may be predicted by low respiratory variability. This review describes methods for quantifying breathing variability, summarises the conditions and comorbidities that affect breathing variability, and discusses the potential implications of breathing variability for anaesthesia and intensive care.
Planet Hunters IX. KIC 8462852 – where's the flux? Boyajian, T. S; LaCourse, D. M; Rappaport, S. A ...
Monthly notices of the Royal Astronomical Society,
04/2016, Letnik:
457, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Over the duration of the Kepler mission, KIC 8462852 was observed to undergo irregularly shaped, aperiodic dips in flux of up to ∼20 per cent. The dipping activity can last for between 5 and 80 d. We ...characterize the object with high-resolution spectroscopy, spectral energy distribution fitting, radial velocity measurements, high-resolution imaging, and Fourier analyses of the Kepler light curve. We determine that KIC 8462852 is a typical main-sequence F3 V star that exhibits no significant IR excess, and has no very close interacting companions. In this paper, we describe various scenarios to explain the dipping events observed in the Kepler light curve. We confirm that the dipping signals in the data are not caused by any instrumental or data processing artefact, and thus are astrophysical in origin. We construct scenario-independent constraints on the size and location of a body in the system that are needed to reproduce the observations. We deliberate over several assorted stellar and circumstellar astrophysical scenarios, most of which have problems explaining the data in hand. By considering the observational constraints on dust clumps in orbit around a normal main-sequence star, we conclude that the scenario most consistent with the data in hand is the passage of a family of exocomet or planetesimal fragments, all of which are associated with a single previous break-up event, possibly caused by tidal disruption or thermal processing. The minimum total mass associated with these fragments likely exceeds 10−6 M⊕, corresponding to an original rocky body of >100 km in diameter. We discuss the necessity of future observations to help interpret the system.
Microsatellite instability (MSI) has been associated with favourable survival in early stage colorectal cancer (CRC) compared to microsatellite stable (MSS) CRC. The BRAF V600E mutation has been ...associated with worse survival in MSS CRC. This mutation occurs in 40% of MSI CRC and it is unclear whether it confers worse survival in this setting. The prognostic value of KRAS mutations in both MSS and MSI CRC remains unclear. We examined the effect of BRAF and KRAS mutations on survival in stage II and III MSI colon cancer patients. BRAF exon 15 and KRAS exon 2–3 mutation status was assessed in 143 stage II (n = 85) and III (n = 58) MSI colon cancers by high resolution melting analysis and sequencing. The relation between mutation status and cancer‐specific (CSS) and overall survival (OS) was analyzed using Kaplan–Meier and Cox regression analysis. BRAF V600E mutations were observed in 51% (n = 73) and KRAS mutations in 16% of cases (n = 23). Patients with double wild‐type cancers (dWT; i.e., BRAF and KRAS wild‐type) had a highly favourable survival with 5‐year CSS of 93% (95% CI 84–100%), while patients with cancers harbouring mutations in either BRAF or KRAS, had 5‐year CSS of 76% (95% CI 67–85%). In the subgroup of stage II patients with dWT cancers no cancer‐specific deaths were observed. On multivariate analysis, mutation in either BRAF or KRAS vs. dWT remained significantly prognostic. Mutations in BRAF as well as KRAS should be analyzed when considering these genes as prognostic markers in MSI colon cancers.
What's new?
Mutations in the BRAF and KRAS genes are widely studied in patients with colorectal carcinomas (CRC), but their prognostic impact in cancers characterized by microsatellite instability due to impaired DNA mismatch repair remains unclear. Here the authors show that both mutations are associated with poor survival in patients afflicted with these genetically hypermutatable tumors as compared to patients carrying tumors with wildtype BRAF and KRAS genes, underscoring the prognostic value of determining combined or single mutations in these genes in this subset of CRC patients.
HAART suppresses HIV viral replication and restores immune function. The effects of HAART on neurological disease are less well understood. The aim of this study was to assess the prevalence and ...incidence of neurocognitive impairment in individuals who initiated HAART as part of an AIDS clinical trial.
A prospective cohort study of HIV-positive patients enrolled in randomized antiretroviral trials, the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) study.
We examined the association between baseline and demographic characteristics and neurocognitive impairment among 1160 subjects enrolled in the ALLRT study.
A history of immunosuppression (nadir CD4 cell count < 200 cells/microl) was associated with an increase in prevalent neurocognitive impairment. There were no significant virological and immunological predictors of incident neurocognitive impairment. Current immune status (low CD4 cell count) was associated with sustained prevalent impairment.
The association of previous advanced immunosuppression with prevalent and sustained impairment suggests that there is a non-reversible component of neural injury that tracks with a history of disease progression. The association of sustained impairment with worse current immune status (low CD4 cell count) suggests that restoring immunocompetence increases the likelihood of neurocognitive recovery. Finally, the lack of association between incident neurocognitive impairment and virological and immunological indicators implies that neural injury continues in some patients regardless of the success of antiretroviral therapy on these laboratory measures.
Chromosome 17q11-q21 is a region of the genome likely to harbor susceptibility to autism (MIM(209850)) based on earlier evidence of linkage to the disorder. This linkage is specific to multiplex ...pedigrees containing only male probands (MO) within the Autism Genetic Resource Exchange (AGRE). Earlier, Stone et al.(1) completed a high-density single nucleotide polymorphism association study of 13.7 Mb within this interval, but common variant association was not sufficient to account for the linkage signal. Here, we extend this single nucleotide polymorphism-based association study to complete the coverage of the two-LOD support interval around the chromosome 17q linkage peak by testing the majority of common alleles in 284 MO trios. Markers within an interval containing the gene, CACNA1G, were found to be associated with Autism Spectrum Disorder at a locally significant level (P=1.9 × 10(-5)). While establishing CACNA1G as a novel candidate gene for autism, these alleles do not contribute a sufficient genetic effect to explain the observed linkage, indicating that there is substantial genetic heterogeneity despite the clear linkage signal. The region thus likely harbors a combination of multiple common and rare alleles contributing to the genetic risk. These data, along with earlier studies of chromosomes 5 and 7q3, suggest few if any major common risk alleles account for Autism Spectrum Disorder risk under major linkage peaks in the AGRE sample. This provides important evidence for strategies to identify Autism Spectrum Disorder genes, suggesting that they should focus on identifying rare variants and common variants of small effect.
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