Site-saturation mutagenesis of 500 human protein domains.

Missense variants that change the amino acid sequences of proteins cause one-third of human genetic diseases. Tens of millions of missense variants exist in the current human population, and the vast majority of these have unknown functional consequences. Here we present a large-scale experimental analysis of human missense variants across many different proteins.

MoCHI: neural networks to fit interpretable models and quantify energies, energetic couplings, epistasis, and allostery from deep mutational scanning data.

We present MoCHI, a tool to fit interpretable models using deep mutational scanning data. MoCHI infers free energy changes, as well as interaction terms (energetic couplings) for specified biophysical models, including from multimodal phenotypic data. When a user-specified model is unavailable, global nonlinearities (epistasis) can be estimated from the data.

The G4 resolvase Dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development.

Extensive genetic studies have elucidated cardiomyocyte differentiation and associated gene networks using single-cell RNA-seq, yet the intricate transcriptional mechanisms governing cardiac conduction system (CCS) development and working cardiomyocyte differentiation remain largely unexplored. Here we show that mice deleted for Dhx36 (encoding the Dhx36 helicase) in the embryonic or neonatal heart develop overt dilated cardiomyopathy, surface ECG alterations related to cardiac impulse propagation, and (in the embryonic heart) a lack of a ventricular conduction system (VCS). Heart snRNA-seq and snATAC-seq reveal the role of Dhx36 in CCS development and in the differentiation of working cardiomyocytes.

Massive experimental quantification of amyloid nucleation allows interpretable deep learning of protein aggregation.

Protein aggregation is a pathological hallmark of more than fifty human diseases and a major problem for biotechnology. Methods have been proposed to predict aggregation from sequence, but these have been trained and evaluated on small and biased experimental datasets. Here we directly address this data shortage by experimentally quantifying the amyloid nucleation of >100,000 protein sequences.

Comprehensive map of ribosomal 2'-O-methylation and C/D box snoRNAs in Drosophila melanogaster.

During their maturation, ribosomal RNAs (rRNAs) are decorated by hundreds of chemical modifications that participate in proper folding of rRNA secondary structures and therefore in ribosomal function. Along with pseudouridine, methylation of the 2'-hydroxyl ribose moiety (Nm) is the most abundant modification of rRNAs. The majority of Nm modifications in eukaryotes are placed by Fibrillarin, a conserved methyltransferase belonging to a ribonucleoprotein complex guided by C/D box small nucleolar RNAs (C/D box snoRNAs).

Biological basis of extensive pleiotropy between blood traits and cancer risk.

Background: The immune system has a central role in preventing carcinogenesis. Alteration of systemic immune cell levels may increase cancer risk. However, the extent to which common genetic variation influences blood traits and cancer risk remains largely undetermined.

The energetic and allosteric landscape for KRAS inhibition.

Thousands of proteins have been validated genetically as therapeutic targets for human diseases. However, very few have been successfully targeted, and many are considered 'undruggable'. This is particularly true for proteins that function via protein-protein interactions-direct inhibition of binding interfaces is difficult and requires the identification of allosteric sites.

Efficacy of Apremilast Gels in Mouse Model of Imiquimod-Induced Psoriasis Skin Inflammation.

Apremilast (APM) is a novel drug for the treatment of psoriasis and psoriatic arthritis. APM is a phosphodiesterase 4 (PDE4) inhibitor, raising intracellular cAMP levels and thereby decreasing the inflammatory response by modulating the expression of TNF-α, IL-17, IL-23, and other inflammatory cytokines. The goal of this study is to develop APM gels as a new pharmaceutical formulation for the treatment of topical psoriasis.

SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML.

KMT2A-rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical interrogation identified kinases as key drivers of survival and drug resistance in KMT2A-R leukemia. In contrast, the contribution and regulation of phosphatases is unknown.

MYC activation impairs cell-intrinsic IFNγ signaling and confers resistance to anti-PD1/PD-L1 therapy in lung cancer.

Elucidating the adaptive mechanisms that prevent host immune response in cancer will help predict efficacy of anti-programmed death-1 (PD1)/L1 therapies. Here, we study the cell-intrinsic response of lung cancer (LC) to interferon-γ (IFNγ), a cytokine that promotes immunoresponse and modulates programmed death-ligand 1 (PD-L1) levels. We report complete refractoriness to IFNγ in a subset of LCs as a result of JAK2 or IFNGR1 inactivation.

New insights on patterns of genetic admixture and phylogeographic history in Iberian high mountain populations of midwife toads.

Multiple Quaternary glacial refugia in the Iberian Peninsula, commonly known as "refugia within refugia", allowed diverging populations to come into contact and admix, potentially boosting substantial mito-nuclear discordances. In this study, we employ a comprehensive set of mitochondrial and nuclear markers to shed light onto the drivers of geographical differentiation in Iberian high mountain populations of the midwife toads Alytes obstetricans and A. almogavarii from the Pyrenees, Picos de Europa and Guadarrama Mountains.

Exposure to secondhand aerosol from electronic cigarettes at homes: A real-life study in four European countries.

Electronic cigarette (e-cigarette) use emits potentially hazardous compounds and deteriorates indoor air quality. Home is a place where e-cigarettes may frequently be used amid its increasing prohibition in public places. This study assessed the real-life scenario of bystanders' exposure to secondhand e-cigarette aerosol (SHA) at home.

Strand asymmetry influences mismatch resolution during a single-strand annealing.

Background: Biases of DNA repair can shape the nucleotide landscape of genomes at evolutionary timescales. The molecular mechanisms of those biases are still poorly understood because it is difficult to isolate the contributions of DNA repair from those of DNA damage.

Results: Here, we develop a genome-wide assay whereby the same DNA lesion is repaired in different genomic contexts.

Involving society in science: Reflections on meaningful and impactful stakeholder engagement in fundamental research.

Open Science calls for transparent science and involvement of various stakeholders. Here are examples of and advice for meaningful stakeholder engagement.

The Built Environment and Health in Low- and Middle-Income Countries: a Review on Quantitative Health Impact Assessments.

Purpose Of Review: Features and attributes of the built environment (BE) impact positively and negatively on health, especially in cities facing unprecedented urban population growth and mass motorization. A common approach to assess the health impacts of built environment is health impact assessment (HIA), but it is rarely used in low- and middle-income countries (LMICs) where urbanization rates are fastest. This article reviews selected HIA case studies from LMICs and reports the methods and tools used to support further implementation of quantitative HIAs in cities of LMICs.

CHD4 ensures stem cell lineage fidelity during skeletal muscle regeneration.

Regeneration of skeletal muscle requires resident stem cells called satellite cells. Here, we report that the chromatin remodeler CHD4, a member of the nucleosome remodeling and deacetylase (NuRD) repressive complex, is essential for the expansion and regenerative functions of satellite cells. We show that conditional deletion of the Chd4 gene in satellite cells results in failure to regenerate muscle after injury.

Cell survival and DNA damage repair are promoted in the human blood thanatotranscriptome shortly after death.

RNA analysis of post-mortem tissues, or thanatotranscriptomics, has become a topic of interest in forensic science due to the essential information it can provide in forensic investigations. Several studies have previously investigated the effect of death on gene transcription, but it has never been conducted with samples of the same individual. For the first time, a longitudinal mRNA expression analysis study was performed with post-mortem human blood samples from individuals with a known time of death.

Reduced expansion of CD94/NKG2C NK cells in chronic lymphocytic leukemia and CLL-like monoclonal B-cell lymphocytosis is not related to increased human cytomegalovirus seronegativity or NKG2C deletions.

Introduction: Dysregulated NK cell-mediated immune responses contribute to tumor evasion in chronic lymphocytic leukemia (CLL), although the NK cell compartment in CLL-like monoclonal B-cell lymphocytosis (MBL) is poorly understood. In healthy individuals, human cytomegalovirus (HCMV) induces the expansion of NK cells expressing high levels of CD94/NKG2C NK cell receptor (NKR) specific for HLA-E.

Methods: We analyzed the expression of NKG2A, NKG2C, ILT2, KIR, CD161, and CD57 in 24 MBL and 37 CLL.

Subcellular relocalization and nuclear redistribution of the RNA methyltransferases TRMT1 and TRMT1L upon neuronal activation.

RNA modifications are dynamic chemical entities that expand the RNA lexicon and regulate RNA fate. The most abundant modification present in mRNAs, N6-methyladenosine (mA), has been implicated in neurogenesis and memory formation. However, whether additional RNA modifications may be playing a role in neuronal functions and in response to environmental queues is largely unknown.

Data for a city-level health impact assessment of urban transport in Mauritius.

Participatory quantitative Health Impact Assessments (HIAs) in developing countries are rare partly due to data scarcity. This paper reports on primary data collected in the city of Port Louis to complete a HIA of urban transport planning in Mauritius. We conducted a full-chain participatory HIA to assess health impacts on the basis of a transport mode shift in Port Louis, Mauritius [1].

Apremilast Microemulsion as Topical Therapy for Local Inflammation: Design, Characterization and Efficacy Evaluation.

Apremilast (APR) is a selective phosphodiesterase 4 inhibitor administered orally in the treatment of moderate-to-severe plaque psoriasis and active psoriatic arthritis. The low solubility and permeability of this drug hinder its dermal administration. The purpose of this study was to design and characterize an apremilast-loaded microemulsion (APR-ME) as topical therapy for local skin inflammation.

RNA-binding proteins in human genetic disease.

RNA-binding proteins (RBPs) are critical effectors of gene expression, and as such their malfunction underlies the origin of many diseases. RBPs can recognize hundreds of transcripts and form extensive regulatory networks that help to maintain cell homeostasis. System-wide unbiased identification of RBPs has increased the number of recognized RBPs into the four-digit range and revealed new paradigms: from the prevalence of structurally disordered RNA-binding regions with roles in the formation of membraneless organelles to unsuspected and potentially pervasive connections between intermediary metabolism and RNA regulation.

Framework for Participatory Quantitative Health Impact Assessment in Low- and Middle-Income Countries.

Background: Conducting health impact assessments (HIAs) is a growing practice in various organizations and countries, yet scholarly interest in HIAs has primarily focused on the synergies between exposure and health outcomes. This limits our understanding of what factors influence HIAs and the uptake of their outcomes. This paper presents a framework for conducting participatory quantitative HIA (PQHIA) in low- and middle-income countries (LMICs), including integrating the outcomes back into society after an HIA is conducted.