Therapeutic exercise attenuates neutrophilic lung injury and skeletal muscle wasting

Early mobilization of critically ill patients with the acute respiratory distress syndrome (ARDS) has emerged as a therapeutic strategy that improves patient outcomes, such as the duration of mechanical ventilation and muscle strength. Despite the apparent efficacy of early mobility programs, their use in clinical practice is limited outside of specialized centers and clinical trials. To evaluate the mechanisms underlying mobility therapy, we exercised acute lung injury (ALI) mice for 2 days after the instillation of lipopolysaccharides into their lungs. We found that a short duration of moderate intensity exercise in ALI mice attenuated muscle ring finger 1 (MuRF1)?mediated atrophy of the limb and respiratory muscles and improved limb muscle force generation. Exercise also limited the influx of neutrophils into the alveolar space through modulation of a coordinated systemic neutrophil chemokine response. Granulocyte colony-stimulating factor (G-CSF) concentrations were systemically reduced by exercise in ALI mice, and in vivo blockade of the G-CSF receptor recapitulated the lung exercise phenotype in ALI mice. Additionally, plasma G-CSF concentrations in humans with acute respiratory failure (ARF) undergoing early mobility therapy showed greater decrements over time compared to control ARF patients. Together, these data provide a mechanism whereby early mobility therapy attenuates muscle wasting and limits ongoing alveolar neutrophilia through modulation of systemic neutrophil chemokines in lung-injured mice and humans.Fil: Files, D. Clark. School Of Medicine; Estados UnidosFil: Liu, Chun. School Of Medicine; Estados UnidosFil: Pereyra, Andrea Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Wang, Zhong Min. University Wake Forest; Estados Unidos. School Of Medicine; Estados UnidosFil: Aggarwal, Neil. Johns Hopkins Asthma And Allergy Center; Estados UnidosFil: D´Alessio, Franco. Johns Hopkins Asthma And Allergy Center; Estados UnidosFil: Garibaldi, Brian T.. Johns Hopkins Asthma and Allergy Center; Estados UnidosFil: Mock, Jason R.. Johns Hopkins Asthma and Allergy Center; Estados UnidosFil: Singer, Benjamin D.. Johns Hopkins Asthma and Allergy Center; Estados UnidosFil: Feng, Xin. Wake Forest School of Medicine; Estados UnidosFil: Yammani, Raghunatha R.. Wake Forest School of Medicine; Estados UnidosFil: Zhang, Tan. Wake Forest School of Medicine; Estados UnidosFil: Lee, Amy L.. Wake Forest School of Medicine; Estados UnidosFil: Philpott, Sydney. Wake Forest School of Medicine; Estados UnidosFil: Lussier, Stephanie. Wake Forest School of Medicine; Estados UnidosFil: Purcell, Lina. Wake Forest School of Medicine; Estados UnidosFil: Chou, Jeff. Wake Forest School of Medicine; Estados UnidosFil: Seeds, Michael. Wake Forest School of Medicine; Estados UnidosFil: King, Landon S.. Johns Hopkins Asthma and Allergy Center; Estados UnidosFil: Morris, Peter E.. Wake Forest School of Medicine; Estados UnidosFil: Delbono, Osvaldo. School Of Medicine; Estados Unido

SARS-CoV-2 surveillance in households with and without asthmatic/allergic children: The Human Epidemiology and Response to SARS-CoV-2 study (HEROS)

Rationale: Whether children and people with asthma and allergic diseases are at increased risk for SARS-CoV-2 infection is not known. Neither is their role in household transmission. Methods: Biweekly nasal sample collections and weekly surveys were conducted to identify incident SARS-CoV-2 infections among children (\u3c13 \u3eyears) and teenagers (13-21 years) enrolled in asthma/allergic disease focused cohorts, and their household members, from May 2020-February 2021. Probability of subject/household infections and household transmissions were calculated using time-to-event analyses, and factors associated with infection and transmission risk using regression analyses. Results: Household (N=1,394) and subject (N=4,142) SARS-CoV-2 infection probability was 25.8% and 14.0%, respectively, and was similar for children (14.0%,CI:8.0-19.6%), teenagers (12.1%,CI:8.2-15.9%), and adults (14.0%,CI:9.5-18.4%). Infections were symptomatic in 24.5% of children, 41.2% of teenagers, and 62.5% of adults. Exposure to both symptomatic (aHR=87.39,CI:58.02-131.63) and asymptomatic (aHR=27.80,CI:17.16–45.03) infected household members was a risk factor for infection. Food allergy was associated with decreased infection risk (aHR=0.50,CI:0.32-0.81), but asthma was not (aHR=1.04,CI:0.73-1.46). Household infection risk was associated with attending in-person school (aHR=1.67,CI:1.09-2.57). Household secondary attack rate was 57.7%. Decreased risk of household transmission was associated with teen age, lower BMI, and lower viral load. Conclusions: Asthma does not increase risk of SARS-CoV-2 infection, while food allergy is protective. SARS-CoV-2 infection risk in children is similar to that of teenagers and adults. SARS-CoV-2 transmission risk and secondary attack rate is much higher than previously estimated in households with children, likely driven by the high frequency of asymptomatic childhood infections

Therapeutic exercise attenuates neutrophilic lung injury and skeletal muscle wasting

Early mobilization of critically ill patients with the acute respiratory distress syndrome (ARDS) has emerged as a therapeutic strategy that improves patient outcomes, such as the duration of mechanical ventilation and muscle strength. Despite the apparent efficacy of early mobility programs, their use in clinical practice is limited outside of specialized centers and clinical trials. To evaluate the mechanisms underlying mobility therapy, we exercised acute lung injury (ALI) mice for 2 days after the instillation of lipopolysaccharides into their lungs. We found that a short duration of moderate intensity exercise in ALI mice attenuated muscle ring finger 1 (MuRF1)–mediated atrophy of the limb and respiratory muscles and improved limb muscle force generation. Exercise also limited the influx of neutrophils into the alveolar space through modulation of a coordinated systemic neutrophil chemokine response. Granulocyte colony-stimulating factor (G-CSF) concentrations were systemically reduced by exercise in ALI mice, and in vivo blockade of the G-CSF receptor recapitulated the lung exercise phenotype in ALI mice. Additionally, plasma G-CSF concentrations in humans with acute respiratory failure (ARF) undergoing early mobility therapy showed greater decrements over time compared to control ARF patients. Together, these data provide a mechanism whereby early mobility therapy attenuates muscle wasting and limits ongoing alveolar neutrophilia through modulation of systemic neutrophil chemokines in lung-injured mice and humans.Facultad de Ciencias Médica

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Lower influenza-specific cell-mediated immune responses in individuals with atopic dermatitis compared with healthy controls

In a sub-study of a clinical trial (NCT01737710) investigating the immunogenicity of trivalent inactivated influenza vaccine (IIV3) administered intradermally or intramuscularly to individuals with atopic dermatitis (AD), we assessed T cell and antigen-presenting cell (APC) responses to influenza B in AD and Non-AD controls. The comparison of IFN-γ ELISpot in 58 AD and 31 Non-AD showed lower responses in AD pre-vaccination. Pre-vaccination, AD also had lower Th2 responses and less inflammatory cytokine production by APC measured by flow cytometry and cytokine levels in culture supernatants. AD also had lower Th1 and Th2 responses to nonspecific anti-CD3/anti-CD28-stimulation, but these were not significantly correlated with the influenza-specific responses, suggesting a primary role for the APC in the decreased influenza-specific T cell responses. Multivariate modeling of influenza-specific responses pre-vaccination with influenza-specific antibody titers and IFN-γ ELISpot as outcome measures identified several T cell and APC subsets that negatively or positively predicted protective responses to the vaccine. However, none of the functional differences between AD and Non-AD had high predictive value on adaptive responses to influenza vaccine, which was in agreement with the overall similar responses to the vaccine in the parent clinical trial

Correlation of telomere length in brain tissue with peripheral tissues in living human subjects

Telomeres are important to chromosomal stability, and changes in their length correlate with disease, potentially relevant to brain disorders. Assessing telomere length in human brain is invasive, but whether peripheral tissue telomere length correlates with that in brain is not known. Saliva, buccal, blood, and brain samples were collected at time points before, during, and after subjects undergoing neurosurgery (n = 35) for intractable epilepsy. DNA was isolated from samples and average telomere length assessed by qPCR. Correlations of telomere length between tissue samples were calculated across subjects. When data were stratified by sex, saliva telomere length correlated with brain telomere length in males only. Buccal telomere length correlated with brain telomere length when males and females were combined. These findings indicate that in living subjects, telomere length in peripheral tissues variably correlates with that in brain and may be dependent on sex. Peripheral tissue telomere length may provide insight into brain telomere length, relevant to assessment of brain disorder pathophysiology