Robust immune responses are essential for eliminating pathogens but must be metered to avoid prolonged immune activation and potential host damage. Upon recognition of microbial DNA, the cytosolic ...DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) produces the second messenger cGAMP to initiate the stimulator of interferon genes (STING) pathway and subsequent interferon (IFN) production. We report that the direct interaction between cGAS and the Beclin-1 autophagy protein not only suppresses cGAMP synthesis to halt IFN production upon double-stranded DNA (dsDNA) stimulation or herpes simplex virus-1 infection, but also enhances autophagy-mediated degradation of cytosolic pathogen DNA to prevent excessive cGAS activation and persistent immune stimulation. Specifically, this interaction releases Rubicon, a negative autophagy regulator, from the Beclin-1 complex, activating phosphatidylinositol 3-kinase class III activity and thereby inducing autophagy to remove cytosolic pathogen DNA. Thus, the cGAS-Beclin-1 interaction shapes innate immune responses by regulating both cGAMP production and autophagy, resulting in well-balanced antimicrobial immune responses.
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•DNA sensor cGAS binds Beclin-1 autophagy protein upon HSV infection or DNA exposure•Beclin-1 binding deregulates cGAS activity to block cGAMP and IFN production•cGAS binding to Beclin-1 releases Rubicon, inducing autophagy of cytosolic DNA
Antimicrobial responses limit infection but require regulation to prevent host damage. Liang et al. show that crosstalk between the DNA sensor cGAS and Beclin-1 autophagy protein not only suppresses cGAS to halt cGAMP and subsequent interferon production, but also enhances autophagy-mediated degradation of microbial DNA to avoid persistent immune stimulation.
The aim of this review paper is to summarize recent developments in the field of wearable sensors and systems that are relevant to the field of rehabilitation. The growing body of work focused on the ...application of wearable technology to monitor older adults and subjects with chronic conditions in the home and community settings justifies the emphasis of this review paper on summarizing clinical applications of wearable technology currently undergoing assessment rather than describing the development of new wearable sensors and systems. A short description of key enabling technologies (i.e. sensor technology, communication technology, and data analysis techniques) that have allowed researchers to implement wearable systems is followed by a detailed description of major areas of application of wearable technology. Applications described in this review paper include those that focus on health and wellness, safety, home rehabilitation, assessment of treatment efficacy, and early detection of disorders. The integration of wearable and ambient sensors is discussed in the context of achieving home monitoring of older adults and subjects with chronic conditions. Future work required to advance the field toward clinical deployment of wearable sensors and systems is discussed.
Linear ubiquitination is a newly discovered posttranslational modification that is currently restricted to a small number of known protein substrates. The linear ubiquitination assembly complex ...(LUBAC), consisting of HOIL-1L, HOIP, and Sharpin, has been reported to activate NF-κB-mediated transcription in response to receptor signaling by ligating linear ubiquitin chains to Nemo and Rip1. Despite recent advances, the detailed roles of LUBAC in immune cells remain elusive. We demonstrate a novel HOIL-1L function as an essential regulator of the activation of the NLRP3/ASC inflammasome in primary bone marrow-derived macrophages (BMDMs) independently of NF-κB activation. Mechanistically, HOIL-1L is required for assembly of the NLRP3/ASC inflammasome and the linear ubiquitination of ASC, which we identify as a novel LUBAC substrate. Consequently, we find that HOIL-1L(-/-) mice have reduced IL-1β secretion in response to in vivo NLRP3 stimulation and survive lethal challenge with LPS. Together, these data demonstrate that linear ubiquitination is required for NLRP3 inflammasome activation, defining the molecular events of NLRP3 inflammasome activation and expanding the role of LUBAC as an innate immune regulator. Furthermore, our observation is clinically relevant because patients lacking HOIL-1L expression suffer from pyogenic bacterial immunodeficiency, providing a potential new therapeutic target for enhancing inflammation in immunodeficient patients.
Recent trends in assistive technology for mobility Cowan, Rachel E; Fregly, Benjamin J; Boninger, Michael L ...
Journal of neuroengineering and rehabilitation,
04/2012, Letnik:
9, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Loss of physical mobility makes maximal participation in desired activities more difficult and in the worst case fully prevents participation. This paper surveys recent work in assistive technology ...to improve mobility for persons with a disability, drawing on examples observed during a tour of academic and industrial research sites in Europe. The underlying theme of this recent work is a more seamless integration of the capabilities of the user and the assistive technology. This improved integration spans diverse technologies, including powered wheelchairs, prosthetic limbs, functional electrical stimulation, and wearable exoskeletons. Improved integration is being accomplished in three ways: 1) improving the assistive technology mechanics; 2) improving the user-technology physical interface; and 3) sharing of control between the user and the technology. We provide an overview of these improvements in user-technology integration and discuss whether such improvements have the potential to be transformative for people with mobility impairments.
BACKGROUND:The full spectrum of HIV-1 diversity can be found in Central Africa, including 2 divergent HIV-1 strains collected in 1983 and 1990 in Democratic Republic of Congo (DRC) that were ...preliminarily classified as group M subtype L. However, a third epidemiologically distinct subtype L genome must be identified to designate L as a true subtype.
METHODS:Specimen CG-0018a-01 was collected in 2001 in DRC as part of an HIV diversity study. Previous subgenomic HIV-1 sequences from this specimen branched closely with proposed subtype L references. Metagenomic next-generation sequencing (mNGS) and HIV-specific target-enriched (HIV-xGen) libraries were combined for NGS to extend genome coverage. mNGS reads were analyzed for the presence of other coinfections with the sequence-based ultrarapid pathogen identification bioinformatics pipeline.
RESULTS:A complete HIV-1 genome was generated with an average coverage depth of 47,783×. After bioinformatic analysis also identified hepatitis B virus reads, a complete hepatitis B virus genotype A genome was assembled with an average coverage depth of 73,830×. The CG-0018a-01 HIV-1 genome branched basal to the 2 previous putative subtype L strains with strong bootstrap support of 100. With no evidence of recombination present, the strain was classified as subtype L.
CONCLUSIONS:The CG-0018a-01 HIV-1 genome establishes subtype L and confirms ongoing transmission in DRC as recently as 2001. Since CG-0018a-01 is more closely related to an ancestral strain than to isolates from 1983 to 1990, additional strains are likely circulating in DRC and possibly elsewhere.
The clinical and public health utility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serologic testing requires a better understanding of the dynamics of the humoral response to ...infection. To track seroconversion of IgG and IgM antibodies in patients with SARS-CoV-2 infection and its association with patient and clinical factors and outcomes. Residual patient specimens were analyzed on the Abbott ARCHITECT i2000 instrument using the Abbott SARS-CoV-2 IgG assay and prototype SARS-CoV-2 IgM assay. Age, sex, comorbidities, symptom onset date, mortality, and specimen collection date were obtained from electronic medical records. Three hundred fifty-nine longitudinal samples were collected from 89 hospitalized patients 0 to 82 days postsymptom onset. Of all, 51.7% of the patients developed IgG and IgM antibodies simultaneously; 32.8% seroconverted for IgM before IgG. On average, patients seroconverted for IgG by 8 days and for IgM by 7 days postsymptom onset. All patients achieved IgG seropositivity by 19 days and IgM seropositivity by 17 days. Median time to IgG and IgM seroconversion was prolonged and initial levels of IgG were lower in immunocompromised patients and patients <65 years of age compared to immune competent patients and those ≥65 years of age. Immunocompromised patients also had persistently lower levels of IgM that peaked on day 17.6 and decreased thereafter compared to immune competent patients. IgM seroconversion in patients who died reached significantly higher levels later after symptom onset than in those who recovered. SARS-CoV-2 infected patients have similar time to seroconversion for IgG and IgM. However, differences in immune status and age alter time to seroconversion. These results may help guide serologic testing application in COVID-19 management.
Acute postoperative myocardial ischemia (PMI) after cardiac surgery is an infrequent event that can evolve rapidly and become a potentially life-threatening complication. Multiple factors are ...associated with acute PMI after cardiac surgery and may vary by the type of surgical procedure performed. Although the criteria defining nonprocedural myocardial ischemia are well established, there are no universally accepted criteria for the diagnosis of acute PMI. In addition, current evidence on the management of acute PMI after cardiac surgery is sparse and generally of low methodological quality. Once acute PMI is suspected, prompt diagnosis and treatment are imperative, and options range from conservative strategies to percutaneous coronary intervention and redo coronary artery bypass grafting. In this document, a multidisciplinary group including experts in cardiac surgery, cardiology, anesthesiology, and postoperative care summarizes the existing evidence on diagnosis and treatment of acute PMI and provides clinical guidance.
Defining genetic diversity of viral infections directly from patient specimens is the ultimate goal of surveillance. Simple tools that can provide full-length sequence information on blood borne ...viral hepatitis viruses: hepatitis C, hepatitis B and hepatitis D viruses (HCV, HBV and HDV) remain elusive. Here, an unbiased metagenomic next generation sequencing approach (mNGS) was used for molecular characterization of HCV infections (n = 99) from Israel which yielded full-length HCV sequences in 89% of samples, with 7 partial sequences sufficient for classification. HCV genotypes were primarily 1b (68%) and 1a (19%), with minor representation of genotypes 2c (1%) and 3a (8%). HBV/HDV coinfections were characterized by suppressed HBV viral loads, resulting in sparse mNGS coverage. A probe-based enrichment approach (xGen) aiming to increase HBV and HDV coverage was validated on a panel of diverse genotypes, geography and titers. The method extended HBV genome coverage a median 61% (range 8-84%) and provided orders of magnitude boosts in reads and sequence depth for both viruses. When HBV-xGen was applied to Israeli samples, coverage was improved by 28-73% in 4 samples and identified HBV genotype A1, A2, D1 specimens and a dual B/D infection. Abundant HDV reads in mNGS libraries yielded 18/26 (69%) full genomes and 8 partial sequences, with HDV-xGen only providing minimal extension (3-11%) of what were all genotype 1 genomes. Advanced molecular approaches coupled to virus-specific capture probes promise to enhance surveillance of viral infections and aid in monitoring the spread of local subtypes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The beneficial effects of physical activity (PA) are well documented, yet the mechanisms by which PA prevents disease and improves health outcomes are poorly understood. To identify major gaps in ...knowledge and potential strategies for catalyzing progress in the field, the NIH convened a workshop in late October 2014 entitled “Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits.” Presentations and discussions emphasized the challenges imposed by the integrative and intermittent nature of PA, the tremendous discovery potential of applying “-omics” technologies to understand interorgan crosstalk and biological networking systems during PA, and the need to establish an infrastructure of clinical trial sites with sufficient expertise to incorporate mechanistic outcome measures into adequately sized human PA trials. Identification of the mechanisms that underlie the link between PA and improved health holds extraordinary promise for discovery of novel therapeutic targets and development of personalized exercise medicine.
This Perspective reports on the NIH October 2014 workshop “Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits,” where major gaps in knowledge, as well as potential strategies for catalyzing progress in the field of physical activity, were discussed and the outcome consensus points reached.
Abstract Patterson SL, Forrester LW, Rodgers MM, Ryan AS, Ivey FM, Sorkin JD, Macko RF. Determinants of walking function after stroke: differences by deficit severity. Objectives To investigate the ...relationship of cardiovascular fitness (V o2 peak), neurologic deficits in balance and leg strength, and body composition to ambulatory function after stroke and to determine whether these relationships differ between those with milder versus more severe gait deficits. Design Cross-sectional correlation study. Setting Outpatient clinic of an academic medical center. Participants Seventy-four people (43 men, 31 women; mean age ± standard deviation, 64±10y) with chronic hemiparetic stroke. Interventions Not applicable. Main Outcome Measures Thirty-foot (9.1-m) walk velocity, 6-minute walk distance, V o2 peak, Berg Balance Scale score, bilateral quadriceps eccentric torque, total and regional lean mass, and percentage of fat mass. Results Short-distance walking correlated significantly with cardiovascular fitness, balance, paretic leg strength, nonparetic leg strength, percentage of body fat, and paretic lean mass but not with nonparetic lean mass. Long-distance walking correlated significantly with cardiovascular fitness, balance, paretic leg strength, nonparetic leg strength, and paretic lean mass but not with percentage of body fat or nonparetic lean mass. Stepwise regression showed that cardiovascular fitness, balance, and paretic leg strength were independently associated with long-distance walking ( r2 =.60, P <.001). Variance in long-distance walking was largely explained by balance for those who walked more slowly (<.48m/s) for short distances ( r2 =.42, P <.001) and by cardiovascular fitness for those who walked more quickly (>.48m/s) for short distances ( r2 =.26, P =.003). Conclusions Short-distance walking after stroke is related to balance, cardiovascular fitness, and paretic leg strength. Long-distance walking ability differs by gait deficit severity, with balance more important in those who walk more slowly and cardiovascular fitness playing a greater role in those who walk more quickly. Improved understanding of the factors that predict ambulatory function may assist the design of individualized rehabilitation strategies across the spectrum of gait deficit severity in those with hemiparetic stroke.
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