Fragmenstein: predicting protein-ligand structures of compounds derived from known crystallographic fragment hits using a strict conserved-binding-based methodology.

Current strategies centred on either merging or linking initial hits from fragment-based drug design (FBDD) crystallographic screens generally do not fully leaverage 3D structural information. We show that an algorithmic approach (Fragmenstein) that 'stitches' the ligand atoms from this structural information together can provide more accurate and reliable predictions for protein-ligand complex conformation than general methods such as pharmacophore-constrained docking. This approach works under the assumption of conserved binding: when a larger molecule is designed containing the initial fragment hit, the common substructure between the two will adopt the same binding mode.

The false evidence rate: An approach to frequentist error rate control conditioning on the observed value.

A value is conventionally interpreted either as a) the probability by chance of obtaining more extreme results than those observed or b) a tool for declaring significance at a prespecified level. Both approaches carry difficulties: b) does not allow users to make inferences based on the data in hand, and is not rigorously followed by researchers in practice, while (a) is not meaningful as an error rate. Although values retain an important role, these shortcomings are likely to have contributed significantly to the scientific reproducibility crisis.

A scalable variational inference approach for increased mixed-model association power.

The rapid growth of modern biobanks is creating new opportunities for large-scale genome-wide association studies (GWASs) and the analysis of complex traits. However, performing GWASs on millions of samples often leads to trade-offs between computational efficiency and statistical power, reducing the benefits of large-scale data collection efforts. We developed Quickdraws, a method that increases association power in quantitative and binary traits without sacrificing computational efficiency, leveraging a spike-and-slab prior on variant effects, stochastic variational inference and graphics processing unit acceleration.

Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma.

Human tumors are diverse in their natural history and response to treatment, which in part results from genetic and transcriptomic heterogeneity. In clinical practice, single-site needle biopsies are used to sample this diversity, but cancer biomarkers may be confounded by spatiogenomic heterogeneity within individual tumors. Here we investigate clonally expressed genes as a solution to the sampling bias problem by analyzing multiregion whole-exome and RNA sequencing data for 450 tumor regions from 184 patients with lung adenocarcinoma in the TRACERx study.

Mapping mitochondrial morphology and function: COX-SBFSEM reveals patterns in mitochondrial disease.

Mitochondria play a crucial role in maintaining cellular health. It is interesting that the shape of mitochondria can vary depending on the type of cell, mitochondrial function, and other cellular conditions. However, there are limited studies that link functional assessment with mitochondrial morphology evaluation at high magnification, even fewer that do so in situ and none in human muscle biopsies.

The NE/AAT/CBG axis regulates adipose tissue glucocorticoid exposure.

Corticosteroid binding globulin (CBG; SERPINA6) binds >85% of circulating glucocorticoids but its influence on their metabolic actions is unproven. Targeted proteolytic cleavage of CBG by neutrophil elastase (NE; ELANE) significantly reduces CBG binding affinity, potentially increasing 'free' glucocorticoid levels at sites of inflammation. NE is inhibited by alpha-1-antitrypsin (AAT; SERPINA1).

Computational pathology applied to clinical colorectal cancer cohorts identifies immune and endothelial cell spatial patterns predictive of outcome.

Colorectal cancer (CRC) is a histologically heterogeneous disease with variable clinical outcome. The role the tumour microenvironment (TME) plays in determining tumour progression is complex and not fully understood. To improve our understanding, it is critical that the TME is studied systematically within clinically annotated patient cohorts with long-term follow-up.

Towards a 'people and nature' paradigm for biodiversity and infectious disease.

Zoonotic and vector-borne infectious diseases are among the most direct human health consequences of biodiversity change. The COVID-19 pandemic increased health policymakers' attention on the links between ecological degradation and disease, and sparked discussions around nature-based interventions to mitigate zoonotic emergence and epidemics. Yet, although disease ecology provides an increasingly granular knowledge of wildlife disease in changing ecosystems, we still have a poor understanding of the net consequences for human disease.

Dual-targeting CRISPR-CasRx reduces C9orf72 ALS/FTD sense and antisense repeat RNAs in vitro and in vivo.

The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is an intronic GC repeat expansion in C9orf72. The repeats undergo bidirectional transcription to produce sense and antisense repeat RNA species, which are translated into dipeptide repeat proteins (DPRs). As toxicity has been associated with both sense and antisense repeat-derived RNA and DPRs, targeting both strands may provide the most effective therapeutic strategy.

COA5 has an essential role in the early stage of mitochondrial complex IV assembly.

Pathogenic variants in cytochrome oxidase assembly factor 5 (COA5), a proposed complex IV (CIV) assembly factor, have been shown to cause clinical mitochondrial disease with two siblings affected by neonatal hypertrophic cardiomyopathy manifesting a rare, homozygous missense variant (NM_001008215.3: c.157G>C, p.

Investigating the origins of the mutational signatures in cancer.

Most of the risk factors associated with chronic and complex diseases, such as cancer, stem from exogenous and endogenous exposures experienced throughout an individual's life, collectively known as the exposome. These exposures can modify DNA, which can subsequently lead to the somatic mutations found in all normal and tumor tissues. Understanding the precise origins of specific somatic mutations has been challenging due to multitude of DNA adducts (i.

Deep analysis of the major histocompatibility complex genetic associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDS.

Introduction: We have reanalyzed the genomic data from the International Collaboration for the Genomics of HIV (ICGH), focusing on HIV-1 Elite Controllers (EC).

Methods: A genome-wide association study (GWAS) was performed, comparing 543 HIV-1 EC individuals with 3,272 uninfected controls (CTR) of European ancestry. 8 million single nucleotide polymorphisms (SNPs) and HLA class I and class II gene alleles were imputed to compare EC and CTR.

Transcriptome and DNA methylation profiling during the NSN to SN transition in mouse oocytes.

Background: During the latter stages of their development, mammalian oocytes under dramatic chromatin reconfiguration, transitioning from a non-surrounded nucleolus (NSN) to a surrounded nucleolus (SN) stage, and concomitant transcriptional silencing. Although the NSN-SN transition is known to be essential for developmental competence of the oocyte, less is known about the accompanying molecular changes. Here we examine the changes in the transcriptome and DNA methylation during the NSN to SN transition in mouse oocytes.

Cardiac conduction system regeneration prevents arrhythmias after myocardial infarction.

Arrhythmias are a hallmark of myocardial infarction (MI) and increase patient mortality. How insult to the cardiac conduction system causes arrhythmias following MI is poorly understood. Here, we demonstrate conduction system restoration during neonatal mouse heart regeneration versus pathological remodeling at non-regenerative stages.

Bayesian Effect Size Ranking to Prioritise Genetic Risk Variants in Common Diseases for Follow-Up Studies.

Biological datasets often consist of thousands or millions of variables, e.g. genetic variants or biomarkers, and when sample sizes are large it is common to find many associated with an outcome of interest, for example, disease risk in a GWAS, at high levels of statistical significance, but with very small effects.

DSIF factor Spt5 coordinates transcription, maturation and exoribonucleolysis of RNA polymerase II transcripts.

Precursor messenger RNA (pre-mRNA) is processed into its functional form during RNA polymerase II (Pol II) transcription. Although functional coupling between transcription and pre-mRNA processing is established, the underlying mechanisms are not fully understood. We show that the key transcription termination factor, RNA exonuclease Xrn2 engages with Pol II forming a stable complex.

A new class of natural anthelmintics targeting lipid metabolism.

Parasitic helminths are a major global health threat, infecting nearly one-fifth of the human population and causing significant losses in livestock and crops. Resistance to the few anthelmintic drugs is increasing. Here, we report a set of avocado fatty alcohols/acetates (AFAs) that exhibit nematocidal activity against four veterinary parasitic nematode species: Brugia pahangi, Teladorsagia circumcincta and Heligmosomoides polygyrus, as well as a multidrug resistant strain (UGA) of Haemonchus contortus.

Genome-wide characterization of 54 urinary metabolites reveals molecular impact of kidney function.

Dissecting the genetic mechanisms underlying urinary metabolite concentrations can provide molecular insights into kidney function and open possibilities for causal assessment of urinary metabolites with risk factors and disease outcomes. Proton nuclear magnetic resonance metabolomics provides a high-throughput means for urinary metabolite profiling, as widely applied for blood biomarker studies. Here we report a genome-wide association study meta-analysed for 3 European cohorts comprising 8,011 individuals, covering both people with type 1 diabetes and general population settings.

The molecular reach of antibodies crucially underpins their viral neutralisation capacity.

Key functions of antibodies, such as viral neutralisation, depend on high-affinity binding. However, viral neutralisation poorly correlates with antigen affinity for reasons that have been unclear. Here, we use a new mechanistic model of bivalent binding to study  >45 patient-isolated IgG1 antibodies interacting with SARS-CoV-2 RBD surfaces.

Remodelling of the immune landscape by IFNγ counteracts IFNγ-dependent tumour escape in mouse tumour models.

Loss of IFNγ-sensitivity by tumours is thought to be a mechanism enabling evasion, but recent studies suggest that IFNγ-resistant tumours can be sensitised for immunotherapy, yet the underlying mechanism remains unclear. Here, we show that IFNγ receptor-deficient B16-F10 mouse melanoma tumours are controlled as efficiently as WT tumours despite their lower MHC class I expression. Mechanistically, IFNγ receptor deletion in B16-F10 tumours increases IFNγ availability, triggering a remodelling of the immune landscape characterised by inflammatory monocyte infiltration and the generation of 'mono-macs'.

Demonstration of Enhancement of Tumor Intravasation by Dicarbonyl Stress Using a Microfluidic Organ-on-chip.

Cancer metastasis involves cell migration from their primary organ foci into vascular channels, followed by dissemination to prospective colonization sites. Vascular entry of tumor cells or intravasation involves their breaching stromal and endothelial extracellular matrix (ECM) and the endothelial barriers. How the kinetics of this breach are confounded by chronic inflammatory stresses seen in diabetes and aging remains ill-investigated.

High-resolution genomic history of early medieval Europe.

Many known and unknown historical events have remained below detection thresholds of genetic studies because subtle ancestry changes are challenging to reconstruct. Methods based on shared haplotypes and rare variants improve power but are not explicitly temporal and have not been possible to adopt in unbiased ancestry models. Here we develop Twigstats, an approach of time-stratified ancestry analysis that can improve statistical power by an order of magnitude by focusing on coalescences in recent times, while remaining unbiased by population-specific drift.

Loss of Mfn1 but not Mfn2 enhances adipogenesis.

Objective: A biallelic missense mutation in mitofusin 2 (MFN2) causes multiple symmetric lipomatosis and partial lipodystrophy, implicating disruption of mitochondrial fusion or interaction with other organelles in adipocyte differentiation, growth and/or survival. In this study, we aimed to document the impact of loss of mitofusin 1 (Mfn1) or 2 (Mfn2) on adipogenesis in cultured cells.

Methods: We characterised adipocyte differentiation of wildtype (WT), Mfn1-/- and Mfn2-/- mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes in which Mfn1 or 2 levels were reduced using siRNA.

Integrative Approaches to Study Virus Structures.

A virus particle must work as a strongroom to protect its genome, but at the same time it must undergo dramatic conformational changes to infect the cell in order to replicate and assemble progeny. Thus, viruses are miniaturized wonders whose structural complexity requires investigation by a combination of different techniques that can tackle both static and dynamic processes. In this chapter, we will illustrate how major structural techniques such as X-ray crystallography and electron microscopy can be combined with other techniques to determine the structure of complex viruses.

Detection of fungal sequences in human brain: rDNA locus amplification and deep sequencing.

The aetiology of Alzheimer's disease (AD) and Parkinson's disease (PD) are unknown and tend to manifest at a late stage in life; even though these neurodegenerative diseases are caused by different affected proteins, they are both characterized by neuroinflammation. Links between bacterial and viral infection and AD/PD has been suggested in several studies, however, few have attempted to establish a link between fungal infection and AD/PD. In this study we adopted a nanopore-based sequencing approach to characterise the presence or absence of fungal genera in both human brain tissue and cerebrospinal fluid (CSF).