Excessive concentrations of kinase inhibitors in translational studies impede effective drug repurposing.

Drug repositioning seeks to leverage existing clinical knowledge to identify alternative clinical settings for approved drugs. However, repositioning efforts fail to demonstrate improved success rates in late-stage clinical trials. Focusing on 11 approved kinase inhibitors that have been evaluated in 139 repositioning hypotheses, we use data mining to characterize the state of clinical repurposing.

Deciphering the Mechanistic Basis for Perfluoroalkyl-Protein Interactions.

Although rarely used in nature, fluorine has emerged as an important elemental ingredient in the design of proteins with altered folding, stability, oligomerization propensities, and bioactivity. Adding to the molecular modification toolbox, here we report the ability of privileged perfluorinated amphiphiles to noncovalently decorate proteins to alter their conformational plasticity and potentiate their dispersion into fluorous phases. Employing a complementary suite of biophysical, in-silico and in-vitro approaches, we establish structure-activity relationships defining these phenomena and investigate their impact on protein structural dynamics and intracellular trafficking.

Agent-Based Models Help Interpret Patterns of Clinical Drug Resistance by Contextualizing Competition Between Distinct Drug Failure Modes.

Introduction: Modern targeted cancer therapies are carefully crafted small molecules. These exquisite technologies exhibit an astonishing diversity of observed failure modes (drug resistance mechanisms) in the clinic. This diversity is surprising because back of the envelope calculations and classic modeling results in evolutionary dynamics suggest that the diversity in the modes of clinical drug resistance should be considerably smaller than what is observed.

SARS-CoV-2 Attack Rate and Population Immunity in Southern New England, March 2020 to May 2021.

Importance: In emergency epidemic and pandemic settings, public health agencies need to be able to measure the population-level attack rate, defined as the total percentage of the population infected thus far. During vaccination campaigns in such settings, public health agencies need to be able to assess how much the vaccination campaign is contributing to population immunity; specifically, the proportion of vaccines being administered to individuals who are already seropositive must be estimated.

Objective: To estimate population-level immunity to SARS-CoV-2 through May 31, 2021, in Rhode Island, Massachusetts, and Connecticut.

A pan-CRISPR analysis of mammalian cell specificity identifies ultra-compact sgRNA subsets for genome-scale experiments.

A genetic knockout can be lethal to one human cell type while increasing growth rate in another. This context specificity confounds genetic analysis and prevents reproducible genome engineering. Genome-wide CRISPR compendia across most common human cell lines offer the largest opportunity to understand the biology of cell specificity.

SARS-CoV-2 epidemic after social and economic reopening in three U.S. states reveals shifts in age structure and clinical characteristics.

State-level reopenings in late spring 2020 facilitated the resurgence of severe acute respiratory syndrome coronavirus 2 transmission. Here, we analyze age-structured case, hospitalization, and death time series from three states-Rhode Island, Massachusetts, and Pennsylvania-that had successful reopenings in May 2020 without summer waves of infection. Using 11 daily data streams, we show that from spring to summer, the epidemic shifted from an older to a younger age profile and that elderly individuals were less able to reduce contacts during the lockdown period when compared to younger individuals.

SARS-CoV-2 attack rate and population immunity in southern New England, March 2020 - May 2021.

Estimating an infectious disease attack rate requires inference on the number of reported symptomatic cases of a disease, the number of unreported symptomatic cases, and the number of asymptomatic infections. Population-level immunity can then be estimated as the attack rate plus the number of vaccine recipients who had not been previously infected; this requires an estimate of the fraction of vaccines that were distributed to seropositive individuals. To estimate attack rates and population immunity in southern New England, we fit a validated dynamic epidemiological model to case, clinical, and death data streams reported by Rhode Island, Massachusetts, and Connecticut for the first 15 months of the COVID-19 pandemic, from March 1 2020 to May 31 2021.

SARS-CoV-2 epidemic after social and economic reopening in three US states reveals shifts in age structure and clinical characteristics.

In the United States, state-level re-openings in spring 2020 presented an opportunity for the resurgence of SARS-CoV-2 transmission. One important question during this time was whether human contact and mixing patterns could increase gradually without increasing viral transmission, the rationale being that new mixing patterns would likely be associated with improved distancing, masking, and hygiene practices. A second key question to follow during this time was whether clinical characteristics of the epidemic would improve after the initial surge of cases.

Optimal SARS-CoV-2 vaccine allocation using real-time attack-rate estimates in Rhode Island and Massachusetts.

Background: When three SARS-CoV-2 vaccines came to market in Europe and North America in the winter of 2020-2021, distribution networks were in a race against a major epidemiological wave of SARS-CoV-2 that began in autumn 2020. Rapid and optimized vaccine allocation was critical during this time. With 95% efficacy reported for two of the vaccines, near-term public health needs likely require that distribution is prioritized to the elderly, health care workers, teachers, essential workers, and individuals with comorbidities putting them at risk of severe clinical progression.

Optimal SARS-CoV-2 vaccine allocation using real-time seroprevalence estimates in Rhode Island and Massachusetts.

As three SARS-CoV-2 vaccines come to market in Europe and North America in the winter of 2020-2021, distribution networks will be in a race against a major epidemiological wave of SARS-CoV-2 that began in autumn 2020. Rapid and optimized vaccine allocation is critical during this time. With 95% efficacy reported for two of the vaccines, near-term public health needs require that distribution is prioritized to the elderly, health-care workers, teachers, essential workers, and individuals with co-morbidities putting them at risk of severe clinical progression.

Multi-scale Predictions of Drug Resistance Epidemiology Identify Design Principles for Rational Drug Design.

Rationally designing drugs that last longer in the face of biological evolution is a critical objective of drug discovery. However, this goal is thwarted by the diversity and stochasticity of evolutionary trajectories that drive uncertainty in the clinic. Although biophysical models can qualitatively predict whether a mutation causes resistance, they cannot quantitatively predict the relative abundance of resistance mutations in patient populations.

Single-Molecule Sequencing Reveals Patterns of Preexisting Drug Resistance That Suggest Treatment Strategies in Philadelphia-Positive Leukemias.

Sequential treatment with targeted therapies can result in complex combinations of resistance mutations in drug targets. This mutational complexity has spurred the development of pan-target inhibitors, i.e.