Accurate design of high-affinity protein binding macrocycles using deep learning.

The development of macrocyclic binders to therapeutic proteins typically relies on large-scale screening methods that are resource-intensive and provide little control over binding mode. Despite considerable progress in physics-based methods for peptide design and deep-learning methods for protein design, there are currently no robust approaches for design of protein-binding macrocycles. Here, we introduce RFpeptides, a denoising diffusion-based pipeline for designing macrocyclic peptide binders against protein targets of interest.

Risankizumab for Ulcerative Colitis: Two Randomized Clinical Trials.

Importance: The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown.

Objective: To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis.

Design, Setting, And Participants: Two phase 3 randomized clinical trials were conducted.

UK research priority setting for childhood neurological conditions.

Aim: To identify research priorities regarding the effectiveness of interventions for children and young people (CYP) with childhood neurological conditions (CNCs). These include common conditions such as epilepsies and cerebral palsy, as well as many rare conditions.

Method: The National Institute for Health and Care Research (NIHR) and the James Lind Alliance (JLA) champion and facilitate priority setting partnerships (PSPs) between patients, caregivers, and clinicians (stakeholders) to identify the most important unanswered questions for research (uncertainties).

De novo design of buttressed loops for sculpting protein functions.

In natural proteins, structured loops have central roles in molecular recognition, signal transduction and enzyme catalysis. However, because of the intrinsic flexibility and irregularity of loop regions, organizing multiple structured loops at protein functional sites has been very difficult to achieve by de novo protein design. Here we describe a solution to this problem that designs tandem repeat proteins with structured loops (9-14 residues) buttressed by extensive hydrogen bonding interactions.

Computational Design of Cyclic Peptide Inhibitors of a Bacterial Membrane Lipoprotein Peptidase.

There remains a critical need for new antibiotics against multi-drug-resistant Gram-negative bacteria, a major global threat that continues to impact mortality rates. Lipoprotein signal peptidase II is an essential enzyme in the lipoprotein biosynthetic pathway of Gram-negative bacteria, making it an attractive target for antibacterial drug discovery. Although natural inhibitors of LspA have been identified, such as the cyclic depsipeptide globomycin, poor stability and production difficulties limit their use in a clinical setting.

Expansive discovery of chemically diverse structured macrocyclic oligoamides.

Small macrocycles with four or fewer amino acids are among the most potent natural products known, but there is currently no way to systematically generate such compounds. We describe a computational method for identifying ordered macrocycles composed of alpha, beta, gamma, and 17 other amino acid backbone chemistries, which we used to predict 14.9 million closed cycles composed of >42,000 monomer combinations.

Inflammatory breast cancer: Epidemiologic data and therapeutic results.

Since the early description more than a century ago, inflammatory breast cancer (IBC) remains an aggressive disease, with a different geographic repartition, with the highest ones incidence reported in the North of Africa (Tunisia, Algeria, Morocco, and Egypt), and the lowest incidence in Western countries (USA, Europe…). In this study, we reviewed the literature using the Surveillance, Epidemiology, and End Results (SEER) database compared to other published series. We observed that in the high incidence areas (North of Africa) when compared to "classical" breast cancer, IBC was associated to younger age (less than 50 years) with rapid evolution of signs and symptoms (in less than 3 up to 6 months), and more aggressive clinical and histopathological-molecular parameters, due to the predominance of triple-negative and HER2+ subtypes in around 60% of cases.

Design of amyloidogenic peptide traps.

Segments of proteins with high β-strand propensity can self-associate to form amyloid fibrils implicated in many diseases. We describe a general approach to bind such segments in β-strand and β-hairpin conformations using de novo designed scaffolds that contain deep peptide-binding clefts. The designs bind their cognate peptides in vitro with nanomolar affinities.

Backbone Modification Provides a Long-Acting Inverse Agonist of Pathogenic, Constitutively Active PTH1R Variants.

Parathyroid hormone 1 receptor (PTH1R) plays a key role in mediating calcium homeostasis and bone development, and aberrant PTH1R activity underlies several human diseases. Peptidic PTH1R antagonists and inverse agonists have therapeutic potential in treating these diseases, but their poor pharmacokinetics and pharmacodynamics undermine their in vivo efficacy. Herein, we report the use of a backbone-modification strategy to design a peptidic PTH1R inhibitor that displays prolonged activity as an antagonist of wild-type PTH1R and an inverse agonist of the constitutively active PTH1R-H223R mutant both in vitro and in vivo.

Climate stress and anxiety, environmental context, and civic engagement: A nationally representative study.

There is increasing recognition that people are experiencing stress and anxiety around climate change, and that this climate stress/anxiety may be associated with more pro-environmental behavior. However, less is known about whether people's own environmental exposures affect climate stress/anxiety or the relationship between climate stress/anxiety and civic engagement. Using three waves of survey data (2020-2022) from the nationally representative Tufts Equity in Health, Wealth, and Civic Engagement Study of US adults (n = 1071), we assessed relationships among environmental exposures (county-level air pollution, greenness, number of toxic release inventory sites, and heatwaves), self-reported climate stress/anxiety, and civic engagement measures (canvasing behavior, collaborating to solve community problems, personal efficacy to solve community problems, group efficacy to solve community problems, voting behavior).

design of buttressed loops for sculpting protein functions.

In natural proteins, structured loops play central roles in molecular recognition, signal transduction and enzyme catalysis. However, because of the intrinsic flexibility and irregularity of loop regions, organizing multiple structured loops at protein functional sites has been very difficult to achieve by protein design. Here we describe a solution to this problem that generates structured loops buttressed by extensive hydrogen bonding interactions with two neighboring loops and with secondary structure elements.

Boredom at the border of philosophy: conceptual and ethical issues.

Boredom is a topic in philosophy. Philosophers have offered close descriptions of the experience of boredom that should inform measurement and analysis of empirical results. Notable historical authors include Seneca, Martin Heidegger, and Theodor Adorno; current philosophers have also contributed to the literature.

Environmental equity and COVID-19 experiences in the United States: Results from three survey waves of a nationally representative study conducted between 2020-2022.

Certain environmental exposures, such as air pollution, are associated with COVID-19 incidence and mortality. To determine whether environmental context is associated with other COVID-19 experiences, we used data from the nationally representative Tufts Equity in Health, Wealth, and Civic Engagement Study data (n=1785; three survey waves 2020-2022). Environmental context was assessed using self-reported climate stress and county-level air pollution, greenness, toxic release inventory site, and heatwave data.

Computational design of non-porous, pH-responsive antibody nanoparticles.

Programming protein nanomaterials to respond to changes in environmental conditions is a current challenge for protein design and important for targeted delivery of biologics. We describe the design of octahedral non-porous nanoparticles with the three symmetry axes (four-fold, three-fold, and two-fold) occupied by three distinct protein homooligomers: a designed tetramer, an antibody of interest, and a designed trimer programmed to disassemble below a tunable pH transition point. The nanoparticles assemble cooperatively from independently purified components, and a cryo-EM density map reveals that the structure is very close to the computational design model.

Exploration of Structured Symmetric Cyclic Peptides as Ligands for Metal-Organic Frameworks.

Despite remarkable advances in the assembly of highly structured coordination polymers and metal-organic frameworks, the rational design of such materials using more conformationally flexible organic ligands such as peptides remains challenging. In an effort to make the design of such materials fully programmable, we first developed a computational design method for generating metal-mediated 3D frameworks using rigid and symmetric peptide macrocycles with metal-coordinating sidechains. We solved the structures of six crystalline networks involving conformationally constrained 6 to 12 residue cyclic peptides with C2, C3, and S2 internal symmetry and three different types of metals (Zn, Co, or Cu) by single-crystal X-ray diffraction, which reveals how the peptide sequences, backbone symmetries, and metal coordination preferences drive the assembly of the resulting structures.

Cyclic Peptide Screening Methods for Preclinical Drug Discovery.

Cyclic peptides are among the most diverse architectures for current drug discovery efforts. Their size, stability, and ease of synthesis provide attractive scaffolds to engage and modulate some of the most challenging targets, including protein-protein interactions and those considered to be "undruggable". With a variety of sophisticated screening technologies to produce libraries of cyclic peptides, including phage display, mRNA display, split intein circular ligation of peptides, and screening, a new era of cyclic peptide drug discovery is at the forefront of modern medicine.

Experiences with and impacts of the COVID-19 pandemic by substance use disorder in the early phase of pandemic in the United States: A cross-sectional survey, 2020.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic could disproportionately affect individuals who have a substance use disorder (SUD). However, little information exists on COVID-19-related experiences among individuals with a SUD. We examined whether individuals with a SUD differ from other individuals with regard to COVID-19 testing, susceptibility, and employment-related vulnerability.

Generation of Potent and Stable GLP-1 Analogues Via "Serine Ligation".

Peptide and protein bioconjugation technologies have revolutionized our ability to site-specifically or chemoselectively install a variety of functional groups for applications in chemical biology and medicine, including the enhancement of bioavailability. Here, we introduce a site-specific bioconjugation strategy inspired by chemical ligation at serine that relies on a noncanonical amino acid containing a 1-amino-2-hydroxy functional group and a salicylaldehyde ester. More specifically, we harness this technology to generate analogues of glucagon-like peptide-1 that resemble Semaglutide, a long-lasting blockbuster drug currently used in the clinic to regulate glucose levels in the blood.