Tailoring industrial enzymes for thermostability and activity evolution by the machine learning-based iCASE strategy.

The pursuit of obtaining enzymes with high activity and stability remains a grail in enzyme evolution due to the stability-activity trade-off. Here, we develop an isothermal compressibility-assisted dynamic squeezing index perturbation engineering (iCASE) strategy to construct hierarchical modular networks for enzymes of varying complexity. Molecular mechanism analysis elucidates that the peak of adaptive evolution is reached through a structural response mechanism among variants.

Comparative Pharmacokinetics and Safety Assessment of 1st- and 2nd-Generation Zinpentraxin Alfa Drug Products in Healthy Volunteers: A Randomized Crossover Study.

Zinpentraxin alfa is a recombinant form of the human pentraxin-2 that was studied in idiopathic pulmonary fibrosis (IPF). To improve the purity and yield of the drug material, a 2nd-generation drug product was developed. To characterize and compare the pharmacokinetic (PK) properties of the 1st- and 2nd-generation zinpentraxin alfa, PK studies were conducted in healthy volunteers (HVs).

Idiopathic pulmonary fibrosis therapy development: a clinical pharmacology perspective.

Drug development for idiopathic pulmonary fibrosis (IPF) has been challenging due to poorly understood disease etiology, unpredictable disease progression, highly heterogeneous patient populations, and a lack of robust pharmacodynamic biomarkers. Moreover, because lung biopsy is invasive and dangerous, making the extent of fibrosis as a direct longitudinal measurement of IPF disease progression unfeasible, most clinical trials studying IPF can only assess progression of fibrosis indirectly through surrogate measures. This review discusses current state-of-art practices, identifies knowledge gaps, and brainstorms development opportunities for preclinical to clinical translation, clinical populations, pharmacodynamic endpoints, and dose optimization strategies.

Safety, Tolerability, and Pharmacokinetics of Benralizumab: A Phase 1, Randomized, Single-Blind Study of Healthy Chinese Participants.

Purpose: Biological therapies targeting eosinophils have been shown to be effective in treating patients with severe eosinophilic asthma. Benralizumab (Fasenra, AstraZeneca) is a humanized monoclonal antibody binding to the alpha subunit of the interleukin-5 receptor, which rapidly depletes eosinophils via antibody-dependent cellular cytotoxicity. The aim of this Phase 1 study was to assess the safety, tolerability, and pharmacokinetics of benralizumab in healthy Chinese individuals.

Plasma Biomarkers and Fractional Exhaled Nitric Oxide in the Diagnosis of Eosinophilic Esophagitis.

Objectives: Eosinophilic esophagitis (EoE) is a chronic disease which requires endoscopy with biopsies for diagnosis and monitoring. We aimed to identify a panel of non-invasive markers that could help identify patients with active EoE.

Methods: In this prospective cohort study, we enrolled 128 children aged 5-18 years old, scheduled for endoscopy for suspected esophageal or peptic disease.

Aerodigestive Approach to Pediatric Chronic Cough.

Chronic cough is defined as cough lasting more than 4 weeks in children aged 14 years or older. Normal children, without pathophysiology, can cough up to more than 30 times a day. When cough occurs pathologically, it is often more often and can be divided into specific and nonspecific cough types.

Growing Up in Québec: the experience of a pilot study.

Growing Up in Québec, also known as the Québec Longitudinal Study of Child Development, 2nd edition (QLSCD 2), is a prospective cohort that began in spring 2021. Its goal is to follow the development of Québec children from the age of five months to adulthood in about 4,500 families. It is conducted by the Institut de la statistique du Québec and is based on the Québec Longitudinal Study of Child Development, 1st edition (QLSCD 1), which began in 1998 and is still ongoing.

Nonlinear Population Pharmacokinetics of Anifrolumab in Healthy Volunteers and Patients With Systemic Lupus Erythematosus.

We characterized the population pharmacokinetics of anifrolumab, a type I interferon receptor-blocking antibody. Pharmacokinetic data were analyzed from the anifrolumab (intravenous [IV], every 4 weeks) arms from 5 clinical trials in patients with systemic lupus erythematosus (SLE) (n = 664) and healthy volunteers (n = 6). Population pharmacokinetic modeling was performed using a 2-compartment model with parallel linear and nonlinear elimination pathways.

Relationship Between Anifrolumab Pharmacokinetics, Pharmacodynamics, and Efficacy in Patients With Moderate to Severe Systemic Lupus Erythematosus.

This study aimed to elucidate the pharmacokinetic/pharmacodynamic and pharmacodynamic/efficacy relationships of anifrolumab, a type I interferon receptor antibody, in patients with moderate to severe systemic lupus erythematosus. Data were pooled from the randomized, 52-week, placebo-controlled TULIP-1 and TULIP-2 trials of intravenous anifrolumab (150 mg/300 mg, every 4 weeks for 48 weeks). Pharmacodynamic neutralization was measured with a 21-gene type I interferon gene signature (21-IFNGS) in patients with high IFNGS.

Perceived effects of COVID-19 restrictions on smallholder farmers: Evidence from seven lower- and middle-income countries.

Context: The COVID-19 pandemic caused unprecedented global disruption and continues to wreak havoc. Dire predictions were made about the risks to smallholder farmers in lower- and middle- income, but hard data have been lacking. We present the results from 9201 interviews with smallholder farmers from seven countries.

Human Breast Milk Promotes the Immunomodulatory Function of Probiotic DSM 17938 in the Neonatal Rat Intestine.

Background And Objective: Breast milk has many growth-promoting and immune-active components, including transforming growth factor-β, lactoferrin, lysozyme, immunoglobulin A, and prebiotics such as the human milk oligosaccharides. Treatment with DSM 17938 (LR), a probiotic with immunomodulatory functions, significantly increases regulatory T cells (Tregs) in the intestinal mucosa of newborn suckling rats. In humans, treatment with LR of infants with colic reduces crying optimally if the infants are breast-fed.

One-year results with selective bladder denervation in women with refractory overactive bladder.

Aims: To report 1-year results with selective bladder denervation (SBD) of the trigone in women with refractory overactive bladder (OAB).

Methods: In this prospective, international, multicenter case series, women with refractory OAB underwent a single SBD treatment of the bladder subtrigone region using temperature-controlled radiofrequency. Patients were followed for 1 year and evaluated for changes in OAB symptoms and adverse events.

Human Breast Milk Promotes the Secretion of Potentially Beneficial Metabolites by Probiotic DSM 17938.

Human breast milk (HBM) may have beneficial effects on DSM 17938 (LR 17938) -mediated immunomodulation. We aimed to determine the effects of HBM on proliferation of LR 17938 in vitro and its associated proteins and metabolites in culture, in order to provide mechanistic insights into the health benefits of LR 17938. LR 17938 was cultured anaerobically in MRS bacterial culture media, HBM (from 6 mothers), and 2 types of cow-milk formula.

Infantile Colic: New Insights into an Old Problem.

Infant colic is a characteristic group of behaviors seen in young infants. The most prominent feature is prolonged crying. Additional characteristics, including clenching of the fists and flexion of the hips, have led to the suggestion that these behaviors are related to abdominal discomfort.

Linguistic mortality gradients in Quebec and the role of migrant composition.

Objective: Anglophones and Allophones in Quebec (Canada) have lower mortality than Francophones, despite being linguistic minorities. This study assesses whether (1) language is a risk factor for mortality after accounting for migrant composition and (2) interprovincial migrants differ in mortality with respect to Quebec-born individuals.

Methods: We analyzed death records between 2004 and 2008 from Quebec (all-cause and main causes) and population data from the 2006 census to estimate age-adjusted mortality rates according to language and migrant status.

The era of immunogenomics/immunopharmacogenomics.

Although germline alterations and somatic mutations in disease cells have been extensively analyzed, molecular changes in immune cells associated with disease conditions have not been characterized in depth. It is clear that our immune system has a critical role in various biological and pathological conditions, such as infectious diseases, autoimmune diseases, drug-induced skin and liver toxicity, food allergy, and rejection of transplanted organs. The recent development of cancer immunotherapies, particularly drugs modulating the immune checkpoint molecules, has clearly demonstrated the importance of host immune cells in cancer treatments.

Characterization of the B-cell receptor repertoires in peanut allergic subjects undergoing oral immunotherapy.

B-cell receptors (BCRs) play a critical role in adaptive immunity as they generate highly diverse immunoglobulin repertoires to recognize a wide variety of antigens. To better understand immune responses, it is critically important to establish a quantitative and rapid method to analyze BCR repertoire comprehensively. Here, we developed "Bcrip", a novel approach to characterize BCR repertoire by sequencing millions of BCR cDNA using next-generation sequencer.

Quantitative analysis and clonal characterization of T-cell receptor β repertoires in patients with advanced non-small cell lung cancer treated with cancer vaccine.

With the development of cancer immunotherapy that may activate T cells, a practical and quantitative method to improve monitoring and/or prediction of immunological response of patients as a predictive biomarker is of importance. To examine possible biomarkers for a therapeutic cancer vaccine containing a mixture of three epitope peptides derived from cell division-associated 1, lymphocyte antigen 6 complex locus K and insulin-like growth factor-II mRNA-binding protein 3, T-cell receptor β (TCRβ) repertoires of blood samples from 24 patients with human leukocyte antigen-A*2402-positive non-small cell lung cancer were characterized prior to and following 8 weeks of the cancer vaccine treatment, by applying a next-generation sequencing method. It was identified that 14 patients with overall survival (OS) times of ≥12 months had significantly lower TCRβ diversity indexes in samples prior to treatment, compared with 10 patients who succumbed within 1 year (P=0.

Hepatic and renal mechanisms underlying the osmopressor response.

Increased blood pressure (BP) is observed in patients with impaired baroreflexes after water drinking. The stimulus for this effect is low blood osmolality, and it has been termed the osmopressor response (OPR). The BP increase is associated with activation of the sympathetic nervous system and a requirement for transient receptor potential vanilloid 4 (TRPV4) channels.

Comparison of exome-based HLA class I genotyping tools: identification of platform-specific genotyping errors.

Accurate human leukocyte antigen (HLA) genotyping is critical in studies involving the immune system. Several algorithms to estimate HLA genotypes from whole-exome data were developed. We compared the accuracy of seven algorithms, including Optitype, Polysolver and PHLAT, as well as investigated patterns and possible causes of miscalls using 12 clinical samples and 961 individuals from the 1000 Genomes Project.

Systematic review of the association between chronic social stress and telomere length: A life course perspective.

Our aim was to examine whether chronic social stress is associated with telomere length throughout the life course, following our protocol published in 2014. Structured searches were conducted in MEDLINE (PubMed interface), EMBASE (OVID interface), Cochrane Central (OVID interface) and grey from their start date onwards. Reference lists of retrieved citations were hand searched for relevant studies.

Early life adversity and C-reactive protein in diverse populations of older adults: a cross-sectional analysis from the International Mobility in Aging Study (IMIAS).

Background: Recent studies suggest potential associations between childhood adversity and chronic inflammation at older ages. Our aim is to compare associations between childhood health, social and economic adversity and high sensitivity C-reactive protein (hsCRP) in populations of older adults living in different countries.

Methods: We used the 2012 baseline data (n = 1340) from the International Mobility in Aging Study (IMIAS) of community-dwelling people aged 65-74 years in Natal (Brazil), Manizales (Colombia) and Canada (Kingston, Ontario; Saint-Hyacinthe, Quebec).

The role of the residential neighborhood in linking youths' family poverty trajectory to decreased feelings of safety at school.

Although disadvantaged youth are more likely to be victimized at school, victimization only partly explains their decreased feelings of safety at school. We applied a socioecological approach to test the hypotheses that the experience of poverty is associated with decreased feelings of safety at school, and that residential neighborhood features partly mediate the relationship between poverty and feeling less safe at school. This study draws on the Québec Longitudinal Study of Child Development (QLSCD) which began in 1998 with a representative population-based cohort of 2,120 5-month old infants (49.

Protocol for a systematic review of the association between chronic stress during the life course and telomere length.

Background: The effects of stress on ill health have become evident in recent years. Under acute stress situations, a cascade of physiological events helps the body mount an appropriate adaptive response. However, under chronic stress situations, this physiological response may lead to wear and tear on the body that accelerates the decline in physiological functioning and increases the risk of chronic conditions.

Calcitonin gene-related peptide (CGRP) in autonomic cardiovascular regulation and vascular structure.

Calcitonin gene-related peptide (CGRP) is reported to play important roles in cardiovascular regulation in human and animal models. In spite of this, its role remains controversial. We aim to clarify this by studying the autonomic cardiovascular function and vascular structure in CGRP knockout (CGRP(-/-)) mice.