Water, sanitation, handwashing, and nutritional interventions can reduce child antibiotic use: evidence from Bangladesh and Kenya.

Antibiotics can trigger antimicrobial resistance and microbiome alterations. Reducing pathogen exposure and undernutrition can reduce infections and antibiotic use. We assess effects of water, sanitation, handwashing (WSH) and nutrition interventions on caregiver-reported antibiotic use in Bangladesh and Kenya, longitudinally measured at three timepoints among birth cohorts (ages 3-28 months) in a cluster-randomized trial.

Strength and durability of indirect protection against SARS-CoV-2 infection through vaccine and infection-acquired immunity.

Early investigation revealed that COVID-19 vaccines confer indirect protection to fully susceptible and unvaccinated persons, defined as a reduced risk of SARS-CoV-2 infection among social contacts of vaccinated individuals. However, indirect protection from infection-acquired immunity and its comparative strength and durability to vaccine-derived indirect protection in the current epidemiologic context of high levels of vaccination, prior infection, and novel variants are not well characterized. Here, we show that both infection-acquired and vaccine-derived immunity independently yield indirect protection to close social contacts with key differences in their strength and waning.

SuFEx Chemistry Enables Covalent Assembly of a 280-kDa 18-Subunit Pore-Forming Complex.

Proximity-enhanced chemical cross-linking is an invaluable tool for probing protein-protein interactions and enhancing the potency of potential peptide and protein drugs. Here, we extend this approach to covalently stabilize large macromolecular assemblies. We used SuFEx chemistry to covalently stabilize an 18-subunit pore-forming complex, CsgG:CsgF, consisting of nine CsgG membrane protein subunits that noncovalently associate with nine CsgF peptides.

design of peptides that bind specific conformers of α-synuclein.

Insoluble amyloids rich in cross-β fibrils are observed in a number of neurodegenerative diseases. Depending on the clinicopathology, the amyloids can adopt distinct supramolecular assemblies, termed conformational strains. However, rapid methods to study amyloids in a conformationally specific manner are lacking.

A cluster-randomized trial of water, sanitation, handwashing and nutritional interventions on stress and epigenetic programming.

A regulated stress response is essential for healthy child growth and development trajectories. We conducted a cluster-randomized trial in rural Bangladesh (funded by the Bill & Melinda Gates Foundation, ClinicalTrials.gov NCT01590095) to assess the effects of an integrated nutritional, water, sanitation, and handwashing intervention on child health.

De novo design of drug-binding proteins with predictable binding energy and specificity.

The de novo design of small molecule-binding proteins has seen exciting recent progress; however, high-affinity binding and tunable specificity typically require laborious screening and optimization after computational design. We developed a computational procedure to design a protein that recognizes a common pharmacophore in a series of poly(ADP-ribose) polymerase-1 inhibitors. One of three designed proteins bound different inhibitors with affinities ranging from <5 nM to low micromolar.

Stress biomarkers and child development in young children in Bangladesh.

Background: Hundreds of millions of children in low- and middle-income countries are exposed to chronic stressors, such as poverty, poor sanitation and hygiene, and sub-optimal nutrition. These stressors can have physiological consequences for children and may ultimately have detrimental effects on child development. This study explores associations between biological measures of chronic stress in early life and developmental outcomes in a large cohort of young children living in rural Bangladesh.

Comparing frequency of booster vaccination to prevent severe COVID-19 by risk group in the United States.

There is a public health need to understand how different frequencies of COVID-19 booster vaccines may mitigate the risk of severe COVID-19, while accounting for waning of protection and differential risk by age and immune status. By analyzing United States COVID-19 surveillance and seroprevalence data in a microsimulation model, here we show that more frequent COVID-19 booster vaccination (every 6-12 months) in older age groups and the immunocompromised population would effectively reduce the burden of severe COVID-19, while frequent boosters in the younger population may only provide modest benefit against severe disease. In persons 75+ years, the model estimated that annual boosters would reduce absolute annual risk of severe COVID-19 by 199 (uncertainty interval: 183-232) cases per 100,000 persons, compared to a one-time booster vaccination.

design of drug-binding proteins with predictable binding energy and specificity.

The de novo design of small-molecule-binding proteins has seen exciting recent progress; however, the ability to achieve exquisite affinity for binding small molecules while tuning specificity has not yet been demonstrated directly from computation. Here, we develop a computational procedure that results in the highest affinity binders to date with predetermined relative affinities, targeting a series of PARP1 inhibitors. Two of four designed proteins bound with affinities ranging from < 5 nM to low μM, in a predictable manner.

Design of Peptides that Bind Specific Conformers of α-Synuclein.

Insoluble amyloids rich in cross-β fibrils are observed in a number of neurodegenerative diseases. Depending on the clinicopathology, the amyloids can adopt distinct supramolecular assemblies, termed conformational strains. However, rapid methods to study amyloid in a conformationally specific manner are lacking.

Stress Biomarkers and Child Development in Young Children in Bangladesh.

Background: Hundreds of millions of children in low- and middle-income countries are exposed to chronic stressors, such as poverty, poor sanitation and hygiene, and sub-optimal nutrition. These stressors can have physiological consequences for children and may ultimately have detrimental effects on child development. This study explores associations between biological measures of chronic stress in early life and developmental outcomes in a large cohort of young children living in rural Bangladesh.

Predicting the Public Health Impact of Bivalent Vaccines and Nirmatrelvir-Ritonavir Against Coronavirus Disease 2019.

Background: Uptake of coronavirus disease 2019 (COVID-19) bivalent vaccines and the oral medication nirmatrelvir-ritonavir (Paxlovid) has remained low across the United States. Assessing the public health impact of increasing uptake of these interventions in key risk groups can guide further public health resources and policy and determine what proportion of severe COVID-19 is avertable with these interventions.

Methods: This modeling study used person-level data from the California Department of Public Health on COVID-19 cases, hospitalizations, deaths, and vaccine administration from 23 July 2022 to 23 January 2023.

Micronutrient status during pregnancy is associated with child immune status in rural Bangladesh.

Background: Poor immune function increases children's risk of infection and mortality. Several maternal factors during pregnancy may affect infant immune function during the postnatal period.

Objectives: We aimed to evaluate whether maternal micronutrients, stress, estriol, and immune status during the first or second trimester of pregnancy were associated with child immune status in the first two years after birth.

Predicting the public health impact of bivalent vaccines and nirmatrelvir-ritonavir against COVID-19.

Background: Uptake of COVID-19 bivalent vaccines and oral medication nirmatrelvir-ritonavir (Paxlovid) has remained low across the United States. Assessing the public health impact of increasing uptake of these interventions in key risk groups can guide further public health resources and policy.

Methods: This modeling study used person-level data from the California Department of Public Health on COVID-19 cases, hospitalizations, deaths, and vaccine administration from July 23, 2022 to January 23, 2023.

Stacked binding of a PET ligand to Alzheimer's tau paired helical filaments.

Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer's disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease-specific cross-β amyloid conformations that self-propagate and are implicated in neuronal loss. Development of molecular diagnostics and therapeutics is of critical importance.

Attenuation of Lipopolysaccharide-Induced Inflammatory Responses through Inhibition of the NF-κB Pathway and the Increased NRF2 Level by a Flavonol-Enriched -Butanol Fraction from .

Pathologic hyperreactive inflammatory responses occur when there is excessive activation of a proinflammatory NF-κB pathway and a reduced cytoprotective NRF2 cascade. The noncytotoxic, highly selective COX-2 inhibitory flavonol-enriched butanol fraction (UaB) from () was investigated for its inflammatory modulating potential by targeting NF-κB activation and NRF2 activity. Enzyme-linked immunosorbent assay was initially performed to measure levels of proinflammatory mediators [nitric oxide (NO), prostaglandin E, and reactive oxygen species (ROS)] and cytokines [tumor necrosis factor-alpha (TNF-α), IL-1β, and IL-6], followed by reverse transcription-polymerase chain reaction and western blotting to determine mRNA and protein expression, respectively.

Infectiousness of SARS-CoV-2 breakthrough infections and reinfections during the Omicron wave.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infections in vaccinated individuals and reinfections in previously infected individuals have become increasingly common. Such infections highlight a broader need to understand the contribution of vaccination, including booster doses, and natural immunity to the infectiousness of individuals with SARS-CoV-2 infections, especially in high-risk populations with intense transmission, such as in prisons. Here we show that both vaccine-derived and naturally acquired immunity independently reduce the infectiousness of persons with Omicron variant SARS-CoV-2 infections in a prison setting.

Infectiousness of SARS-CoV-2 breakthrough infections and reinfections during the Omicron wave.

SARS-CoV-2 breakthrough infections in vaccinated individuals and reinfections among previously infected individuals have become increasingly common. Such infections highlight a broader need to understand the contribution of vaccination, including booster doses, and natural immunity to the infectiousness of persons with SARS-CoV-2 infections, especially in high-risk populations with intense transmission such as prisons. Here, we show that both vaccine-derived and naturally acquired immunity independently reduce the infectiousness of persons with Omicron variant SARS-CoV-2 infections in a prison setting.

COVID-19 Vaccination and Estimated Public Health Impact in California.

Importance: Despite widespread vaccination against COVID-19 in the United States, there are limited empirical data quantifying their public health impact in the population.

Objective: To estimate the number of COVID-19 cases, hospitalizations, and deaths directly averted because of COVID-19 vaccination in California.

Design, Setting, And Participants: This modeling study used person-level data provided by the California Department of Public Health (CDPH) on COVID-19 cases, hospitalizations, and deaths as well as COVID-19 vaccine administration from January 1, 2020, to October 16, 2021.

Polyphenolic Natural Products Active Against SARS-CoV-2 Spike Receptor Binding Domains and Non-structural Proteins - A Review.

The ongoing Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has been proven to be more severe than the previous coronavirus outbreaks due to the virus' high transmissibility. With the emergence of new variants, this global phenomenon took a more dramatic turn, with many countries recently experiencing higher surges of confirmed cases and deaths. On top of this, the inadequacy of effective treatment options for COVID-19 aggravated the problem.

Telomere length is associated with growth in children in rural Bangladesh.

Background: Previously, we demonstrated that a water, sanitation, handwashing, and nutritional intervention improved linear growth and was unexpectedly associated with shortened childhood telomere length (TL) (Lin et al., 2017). Here, we assessed the association between TL and growth.

Elucidation of the molecular interactions that enable stable assembly and structural diversity in multicomponent immune receptors.

Multicomponent immune receptors are essential complexes in which distinct ligand-recognition and signaling subunits are held together by interactions between acidic and basic residues of their transmembrane helices. A 2:1 acidic-to-basic motif in the transmembrane domains of the subunits is necessary and sufficient to assemble these receptor complexes. Here, we study a prototype for these receptors, a DAP12-NKG2C 2:1 heterotrimeric complex, in which the two DAP12 subunits each contribute a single transmembrane Asp residue, and the NKG2C subunit contributes a Lys to form the complex.

Acyl Transfer Catalytic Activity in De Novo Designed Protein with N-Terminus of α-Helix As Oxyanion-Binding Site.

The design of catalytic proteins with functional sites capable of specific chemistry is gaining momentum and a number of artificial enzymes have recently been reported, including hydrolases, oxidoreductases, retro-aldolases, and others. Our goal is to develop a peptide ligase for robust catalysis of amide bond formation that possesses no stringent restrictions to the amino acid composition at the ligation junction. We report here the successful completion of the first step in this long-term project by building a completely de novo protein with predefined acyl transfer catalytic activity.

Modulating Integrin αIIbβ3 Activity through Mutagenesis of Allosterically Regulated Intersubunit Contacts.

Integrin αIIbβ3, a transmembrane heterodimer, mediates platelet aggregation when it switches from an inactive to an active ligand-binding conformation following platelet stimulation. Central to regulating αIIbβ3 activity is the interaction between the αIIb and β3 extracellular stalks, which form a tight heterodimer in the inactive state and dissociate in the active state. Here, we demonstrate that alanine replacements of sensitive positions in the heterodimer stalk interface destabilize the inactive conformation sufficiently to cause constitutive αIIbβ3 activation.