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Tryptase is the most abundant secretory granule protein in human lung mast cells and plays an important role in asthma pathogenesis. MTPS9579A is a novel monoclonal antibody that selectively inhibits tryptase activity by dissociating active tetramers into inactive monomers. The safety, tolerability, pharmacokinetics (PKs), and systemic and airway pharmacodynamics (PDs) of MTPS9579A were assessed in healthy participants. In this phase I single‐center, randomized, observer‐blinded, and placebo‐controlled study, single and multiple ascending doses of MTPS9579A were administered subcutaneously (s.c.) or intravenously (i.v.) in healthy participants. In addition to monitoring safety and tolerability, the concentrations of MTPS9579A, total tryptase, and active tryptase were quantified. This study included 106 healthy participants (82 on active treatment). Overall, MTPS9579A was well‐tolerated with no serious or severe adverse events. Serum MTPS9579A showed a dose‐proportional increase in maximum serum concentration (Cmax) values at high doses, and a nonlinear increase in area under the curve (AUC) values at low concentrations consistent with target‐mediated clearance were observed. Rapid and dose‐dependent reduction in nasosorption active tryptase was observed postdose, confirming activity and the PK/PD relationship of MTPS9579A in the airway. A novel biomarker assay was used to demonstrate for the first time that an investigative antibody therapeutic (MTPS9579A) can inhibit tryptase activity in the upper airway. A favorable safety and tolerability profile supports further assessment of MTPS9579A in asthma. Understanding the exposure‐response relationships using the novel PD biomarker will help inform clinical development, such as dose selection or defining patient subgroups.

Background: Most patients with diabetic kidney disease (DKD) experience disease progression despite receiving standard care therapy. Oxidative stress is associated with DKD severity and risk of progression, but currently approved therapies do not directly attenuate the pathologic consequences of oxidative stress. GS-4997 is a once daily, oral molecule that inhibits Apoptosis Signal-regulating Kinase 1 (ASK1), which is a key mediator of the deleterious effects of oxidative stress. Methods: We describe the rationale and design of a Phase 2 placebo-controlled clinical trial investigating the effects of GS-4997 in patients with T2DM and stage 3/4 DKD receiving standard of care therapy. Approximately, 300 subjects will be randomized in a stratified manner, based on the estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio, to one of four arms in this dose-ranging study. The primary endpoint is change in eGFR at 48 weeks, and the key secondary endpoint is change in albuminuria. Conclusion: Guided by the biology of oxidative stress signaling through ASK1, the biology of DKD pathogenesis, and solid statistical methods, the decisions made for this Phase 2 study regarding delineating study population, efficacy outcomes, treatment period and statistical methods represent innovative attempts to resolve challenges specific to DKD study design.

Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection worldwide 1 . The only available vaccine, BCG (Bacillus Calmette–Guérin), is given intradermally and has variable efficacy against pulmonary tuberculosis, the major cause of mortality and disease transmission 1 , 2 . Here we show that intravenous administration of BCG profoundly alters the protective outcome of Mtb challenge in non-human primates ( Macaca mulatta ). Compared with intradermal or aerosol delivery, intravenous immunization induced substantially more antigen-responsive CD4 and CD8 T cell responses in blood, spleen, bronchoalveolar lavage and lung lymph nodes. Moreover, intravenous immunization induced a high frequency of antigen-responsive T cells across all lung parenchymal tissues. Six months after BCG vaccination, macaques were challenged with virulent Mtb. Notably, nine out of ten macaques that received intravenous BCG vaccination were highly protected, with six macaques showing no detectable levels of infection, as determined by positron emission tomography–computed tomography imaging, mycobacterial growth, pathology and granuloma formation. The finding that intravenous BCG prevents or substantially limits Mtb infection in highly susceptible rhesus macaques has important implications for vaccine delivery and clinical development, and provides a model for defining immune correlates and mechanisms of vaccine-elicited protection against tuberculosis. The delivery route and dose of the BCG vaccine profoundly alters the protective outcome after Mycobacterium tuberculosis challenge in non-human primates.

Objective To characterize the absolute risks for older patients of readmission to hospital and death in the year after hospitalization for heart failure, acute myocardial infarction, or pneumonia.Design Retrospective cohort study.Setting 4767 hospitals caring for Medicare fee for service beneficiaries in the United States, 2008-10.Participants More than 3 million Medicare fee for service beneficiaries, aged 65 years or more, surviving hospitalization for heart failure, acute myocardial infarction, or pneumonia.Main outcome measures Daily absolute risks of first readmission to hospital and death for one year after discharge. To illustrate risk trajectories, we identified the time required for risks of readmission to hospital and death to decline 50% from maximum values after discharge; the time required for risks to approach plateau periods of minimal day to day change, defined as 95% reductions in daily changes in risk from maximum daily declines after discharge; and the extent to which risks are higher among patients recently discharged from hospital compared with the general elderly population.Results Within one year of hospital discharge, readmission to hospital and death, respectively, occurred following 67.4% and 35.8% of hospitalizations for heart failure, 49.9% and 25.1% for acute myocardial infarction, and 55.6% and 31.1% for pneumonia. Risk of first readmission had declined 50% by day 38 after hospitalization for heart failure, day 13 after hospitalization for acute myocardial infarction, and day 25 after hospitalization for pneumonia; risk of death declined 50% by day 11, 6, and 10, respectively. Daily change in risk of first readmission to hospital declined 95% by day 45, 38, and 45; daily change in risk of death declined 95% by day 21, 19, and 21. After hospitalization for heart failure, acute myocardial infarction, or pneumonia, the magnitude of the relative risk for hospital admission over the first 90 days was 8, 6, and 6 times greater than that of the general older population; the relative risk of death was 11, 8, and 10 times greater.Conclusions Risk declines slowly for older patients after hospitalization for heart failure, acute myocardial infarction, or pneumonia and is increased for months. Specific risk trajectories vary by discharge diagnosis and outcome. Patients should remain vigilant for deterioration in health for an extended time after discharge. Health providers can use knowledge of absolute risks and their changes over time to better align interventions designed to reduce adverse outcomes after discharge with the highest risk periods for patients.

Technologically critical rare-earth elements are notoriously difficult to separate, owing to their subtle differences in ionic radius and coordination number 1 – 3 . The natural lanthanide-binding protein lanmodulin (LanM) 4 , 5 is a sustainable alternative to conventional solvent-extraction-based separation 6 . Here we characterize a new LanM, from Hansschlegelia quercus ( Hans -LanM), with an oligomeric state sensitive to rare-earth ionic radius, the lanthanum(III)-induced dimer being >100-fold tighter than the dysprosium(III)-induced dimer. X-ray crystal structures illustrate how picometre-scale differences in radius between lanthanum(III) and dysprosium(III) are propagated to Hans -LanM’s quaternary structure through a carboxylate shift that rearranges a second-sphere hydrogen-bonding network. Comparison to the prototypal LanM from Methylorubrum extorquens reveals distinct metal coordination strategies, rationalizing Hans -LanM’s greater selectivity within the rare-earth elements. Finally, structure-guided mutagenesis of a key residue at the Hans- LanM dimer interface modulates dimerization in solution and enables single-stage, column-based separation of a neodymium(III)/dysprosium(III) mixture to >98% individual element purities. This work showcases the natural diversity of selective lanthanide recognition motifs, and it reveals rare-earth-sensitive dimerization as a biological principle by which to tune the performance of biomolecule-based separation processes. A study biochemically and structurally characterizes a lanmodulin from Hansschlegelia quercus with an oligomeric state sensitive to rare-earth ionic radius.

Climate is critically affected by aerosols, which alter cloud lifecycles and precipitation distribution through radiative and microphysical effects. In this study, aerosol and cloud property datasets from MODIS (Moderate Resolution Imaging Spectroradiometer), onboard the Aqua satellite, and surface observations, including aerosol concentrations, raindrop size distribution, and meteorological parameters, were used to statistically quantify the effects of aerosols on low-level warm-cloud microphysics and drizzle over northern Taiwan during multiple fall seasons (from 15 October to 30 November of 2005–2017). Our results indicated that northwestern Taiwan, which has several densely populated cities, is dominated by low-level clouds (e.g., warm, thin, and broken clouds) during the fall season. The observed effects of aerosols on warm clouds indicated aerosol indirect effects (i.e., increased aerosol loading caused a decrease in cloud effective radius (CER)), an increase in cloud optical thickness, an increase in cloud fraction, and a decrease in cloud-top temperature under a fixed cloud water path. Quantitatively, aerosol–cloud interactions (ACI=-∂ln⁡CER∂ln⁡α|CWP, changes in CER relative to changes in aerosol amounts) were 0.07 for our research domain and varied between 0.09 and 0.06 in the surrounding remote (i.e., ocean) and polluted (i.e., land) areas, respectively, indicating aerosol indirect effects were stronger in the remote area. From the raindrop size distribution analysis, high aerosol loading resulted in a decreased frequency of drizzle events, redistribution of cloud water to more numerous and smaller droplets, and reduced collision–coalescence rates. However, during light rain (≤1 mm h−1), high aerosol concentrations drove raindrops towards smaller droplet sizes and increased the appearance of drizzle drops. This study used long-term surface and satellite data to determine aerosol variations in northern Taiwan, effects on clouds and precipitation, and observational strategies for future research on aerosol–cloud–precipitation interactions.

The quantum-mechanical motion of electrons in molecules and solids occurs on the sub-femtosecond timescale. Consequently, the study of ultrafast electronic phenomena requires the generation of laser pulses shorter than 1 fs and of sufficient intensity to interact with their target with high probability. Probing these dynamics with atomic-site specificity requires the extension of sub-femtosecond pulses to the soft X-ray spectral region. Here, we report the generation of isolated soft X-ray attosecond pulses with an X-ray free-electron laser. Our source has a pulse energy that is millions of times larger than any other source of isolated attosecond pulses in the soft X-ray spectral region, with a peak power exceeding 100 GW. This unique combination of high intensity, high photon energy and short pulse duration enables the investigation of electron dynamics with X-ray nonlinear spectroscopy and single-particle imaging, unlocking a path towards a new era of attosecond science.

Background Epithelial-to-mesenchymal transition (EMT) has, in recent years, emerged as an important tumor cell behavior associated with high metastatic potential and drug resistance. Interestingly, protein SUMOylation and hepatocyte growth factor could respectively reduce the effect of small molecule inhibitors on tyrosine kinase activity of mutated epidermal growth factor receptor of lung adenocarcinomas (LADC). The actual mechanism is yet to be resolved. Methods Immunohistochemistry was used to stain proteins in LADC specimens. Protein expression was confirmed by Western blotting. In vitro, expression of proteins was determined by Western blotting and immunocytochemistry. Levels of circular RNA were determined by reverse transcription-polymerase chain reaction. Results SAE2 and cirRNA CCDC66 were highly expressed in LADC. Expression of SAE2 was mainly regulated by EGFR; however, expression of cirRNA CCDC66 was positively regulated by FAK and c-Met but negatively modulated by nAchR7α. EGFR-resistant H1975 also highly expressed cirRNA CCDC66. Immediate response of hypoxia increased phosphorylated c-Met, SAE2, and epithelial-to-mesenchymal transition. Either activation of FAK or silencing of nAchR7α increased cirRNA CCDC66. Conclusions HGF/c-Met regulates expression of SAE2 and cirRNA CCDC66 to increase EMT and drug resistance of LADC cells. Multimodality drugs concurrently aiming at these targets would probably provide more benefits for cancer patients.