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Abstract Genome-wide association studies of primary sclerosing cholangitis have identified 23 susceptibility loci. The majority of these loci reside in non-coding regions of the genome and are thought to exert their effect by perturbing the regulation of nearby genes. Here, we aim to identify these genes to improve the biological understanding of primary sclerosing cholangitis, and nominate potential drug targets. We first build an eQTL map for six primary sclerosing cholangitis-relevant T-cell subsets obtained from the peripheral blood of primary sclerosing cholangitis and ulcerative colitis patients. These maps identify 10,459 unique eGenes, 87% of which are shared across all six primary sclerosing cholangitis T-cell types. We then search for colocalisations between primary sclerosing cholangitis loci and eQTLs and undertake Bayesian fine-mapping to identify disease-causing variants. In this work, colocalisation analyses nominate likely primary sclerosing cholangitis effector genes and biological mechanisms at five non-coding (UBASH3A, PRKD2, ETS2 and AP003774.1/CCDC88B) and one coding (SH2B3) primary sclerosing cholangitis loci. Through fine-mapping we identify likely causal variants for a third of all primary sclerosing cholangitis-associated loci, including two to single variant resolution.

Abstract The uptake and elimination of beta-lactam antibiotics in the human body are facilitated by the proton-coupled peptide transporters PepT1 (SLC15A1) and PepT2 (SLC15A2). The mechanism by which SLC15 family transporters recognize and discriminate between different drug classes and dietary peptides remains unclear, hampering efforts to improve antibiotic pharmacokinetics through targeted drug design and delivery. Here, we present cryo-EM structures of the proton-coupled peptide transporter, PepT2 from Rattus norvegicus, in complex with the widely used beta-lactam antibiotics cefadroxil, amoxicillin and cloxacillin. Our structures, combined with pharmacophore mapping, molecular dynamics simulations and biochemical assays, establish the mechanism of beta-lactam antibiotic recognition and the important role of protonation in drug binding and transport.

Abstract Determining the genetic architecture of Alzheimer’s disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

Abstract Inherited retinopathies are devastating diseases that in most cases lack treatment options. Disease-modifying therapies that mitigate pathophysiology regardless of the underlying genetic lesion are desirable due to the diversity of mutations found in such diseases. We tested a systems pharmacology-based strategy that suppresses intracellular cAMP and Ca2+ activity via G protein-coupled receptor (GPCR) modulation using tamsulosin, metoprolol, and bromocriptine coadministration. The treatment improves cone photoreceptor function and slows degeneration in Pde6βrd10 and RhoP23H/WT retinitis pigmentosa mice. Cone degeneration is modestly mitigated after a 7-month-long drug infusion in PDE6A-/- dogs. The treatment also improves rod pathway function in an Rpe65-/- mouse model of Leber congenital amaurosis but does not protect from cone degeneration. RNA-sequencing analyses indicate improved metabolic function in drug-treated Rpe65-/- and rd10 mice. Our data show that catecholaminergic GPCR drug combinations that modify second messenger levels via multiple receptor actions provide a potential disease-modifying therapy against retinal degeneration.

Abstract Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer’s Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% of the mass of diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related functions of Aβ aggregates throughout the course of aggregation. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.

Abstract Proline-rich antimicrobial peptides (PrAMPs) inhibit bacterial protein biosynthesis by binding to the polypeptide exit tunnel (PET) near the peptidyl transferase center. Api137, an optimized derivative of honeybee PrAMP apidaecin, inhibits protein expression by trapping release factors (RFs), which interact with stop codons on ribosomes to terminate translation. This study uses cryo-EM, functional assays and molecular dynamic (MD) simulations to show that Api137 additionally occupies a second binding site near the exit of the PET and can repress translation independently of RF-trapping. Api88, a C-terminally amidated (-CONH2) analog of Api137 (-COOH), binds to the same sites, occupies a third binding pocket and interferes with the translation process presumably without RF-trapping. In conclusion, apidaecin-derived PrAMPs inhibit bacterial ribosomes by multimodal mechanisms caused by minor structural changes and thus represent a promising pool for drug development efforts.

Abstract Membrane-camouflaged nanomedicines often suffer from reduced efficacy caused by membrane protein disintegration and spatial disorder caused by separation and reassembly of membrane fragments during the coating process. Here we show that intracellularly gelated macrophages (GMs) preserve cell membrane structures, including protein content, integration and fluidity, as well as the membrane lipid order. Consequently, in our testing GMs act as cellular sponges to efficiently neutralize various inflammatory cytokines via receptor-ligand interactions, and serve as immune cell-like carriers to selectively bind inflammatory cells in culture medium, even under a flow condition. In a rat model of collagen-induced arthritis, GMs alleviate the joint injury, and suppress the overall arthritis severity. Upon intravenous injection, GMs efficiently accumulate in the inflammatory lungs of acute pneumonia mice for anti-inflammatory therapy. Conveniently, GMs are amenable to lyophilization and can be stored at ambient temperatures for at least 1 month without loss of integrity and bio-activity. This intracellular gelation technology provides a universal platform for targeted inflammation neutralization treatment.

Abstract Target deconvolution of small molecule hits from phenotypic screens presents a major challenge. Many screens have been conducted to find inhibitors for the Hedgehog signaling pathway – a developmental pathway with many implications in health and disease – yielding many hits but only few identified cellular targets. We here present a strategy for target identification based on Proteolysis-Targeting Chimeras (PROTACs), combined with label-free quantitative proteomics. We develop a PROTAC based on Hedgehog Pathway Inhibitor-1 (HPI-1), a phenotypic screen hit with unknown cellular target. Using this Hedgehog Pathway PROTAC (HPP) we identify and validate BET bromodomains as the cellular targets of HPI-1. Furthermore, we find that HPP-9 is a long-acting Hedgehog pathway inhibitor through prolonged BET bromodomain degradation. Collectively, we provide a powerful PROTAC-based approach for target deconvolution, that answers the longstanding question of the cellular target of HPI-1 and yields a PROTAC that acts on the Hedgehog pathway.

‘The induction and coordination of immune cells in response to SARS-CoV-2 infection are critical in the immunopathology of COVID-19. Here the authors use a rhesus macaque model of SARS-CoV-2 infection and show key populations of macrophage drive the inflammatory cytokine production in the alveolar space’.

The brain-expressed receptor GPR10 is involved in energy homeostasis in mice. Here the authors identify rare loss of function variants in GPR10 in people with severe obesity and showed that one of these variants causes obesity when modelled in mice, suggesting that future studies could explore GPR10 as a potential target for weight-loss therapy.

Long noncoding RNA molecules are RNA transcripts long thought to remain untranslated. In this study, the authors demonstrate that certain lncRNA can be translated into peptides that are immunogenic to CD8+ T cells and promote anti-tumour responses when delivered as vaccine vectors in mice.

The genetic basis of primary sclerosing cholangitis has only been partially uncovered. Here, the authors perform a multitrait genome-wide association study to provide insight into the genetic etiology of primary sclerosing cholangitis risk and possible therapeutic drug targets.

The production of ribosomes is a precisely orchestrated energy consuming cellular process of highest priority. Here, the authors use cryo-EM to show that bacterial ribosomal subunits, self-assembled from their purified RNA and protein components, mature along parallel pathways.

SARS-CoV-2 variants have accumulated multiple defining mutations within their spike glycoproteins. Here, the authors report a structural basis for broad neutralization of several variants by a heavy chain antibody fragment and provide a mutational analysis focusing on antibody evasion, receptor engagement, and spike protein structure.

The highest tensile strength biomaterial known exists in limpet teeth and replicating this material is of interest. Here, the authors report on the ex vivo growth of teeth and use of isolated limpet tissue and cells providing foundations for the development of this high-tensile biomaterial.

Dysregulation of lipid metabolism is associated with coronary artery disease (CAD). Here, the authors perform GWAS of the serum lipidome to identify variants associated with lipid species that are putatively in the mechanistic pathway to CAD.

Cell migration is essential for many physiological processes. Its deregulation causes cancer metastasis and it is not well understood how it is tightly controlled. We identify NHSL1 as a negative regulator of actin nucleating Scar/WAVE-Arp2/3 complexes, cell protrusion stability, and cell migration.

The functional relevance of epigenetic modifications on transcription regulation has been an important question since their discovery. Here, the authors investigate the effect of DNA methylation on Pioneer Transcription Factor (PF) binding and distinguish between PFs that protect their binding sites from methylation and those that bind to methylated DNA and induce DNA demethylation.

While the role of specific posttranslational modifications (PTMs) is increasingly well understood for core histones, this is not the case for linker histone H1. Here the authors show that site-specific ubiquitylation of H1 results in distinct interactomes, regulates phase separation, and modulates assembly of chromatosomes.

The onset and pathology of Alzheimer’s disease (AD) is associated with changes to lipid metabolism. Here, the authors analysed 569 lipids from 32 classes and subclasses in two independent patient cohorts to identify key lipid pathways to link the plasma lipidome with AD and the future onset of AD.

2D materials are foreseen as an opportunity to tailor spintronics devices interfaces, a.k.a spinterfaces. Here, using state-of-the-art large-scale integration in spin-valves, authors demonstrate that hybridization of graphene with a metallic spin source results in strong spin filtering effects.

The human ICF 4 syndrome is caused by mutation of the chromatin remodeller LSH. Here, the authors show that LSH depletion disrupts the ability of histone variant macroH2A to insert into chromatin and silence transcription.

Despite the identification of genetic risk loci for late-onset Alzheimer’s disease (LOAD), the genetic architecture and prediction remains unclear. Here, the authors use genetic risk scores for prediction of LOAD across three datasets and show evidence suggesting oligogenic variant architecture for this disease.

Due to poor specificity, the current pharmacotherapy of atherosclerosis has limited therapeutic efficacy. Here, the authors show that a macrophage-biomimetic nanomedicine effectively alleviates atherosclerosis via targeted pharmacotherapy and sequestration of proinflammatory cytokines and chemokines.

Marine woodborers can digest woody biomass without the help of gut microbiota but the mechanism has remained unclear. Here, the authors provide evidence that the woodborer’s respiratory protein hemocyanin plays a central role in wood digestion and may offer a route toward biorefining of woody plant biomass.

Loss of the transcription factor Myogenin in mice reduces skeletal myogenesis and leads to perinatal death but how Myogenin regulates muscle formation is unclear. Here, the authors show that zebrafish Myogenin enhances Myomaker expression, muscle cell fusion and myotome size, yet decreases fast muscle fibre number.

Paraquat is a widely used herbicide that is highly toxic to humans upon acute ingestion or chronic exposure. Here, the authors generate a photosensitive formulation that releases paraquat upon exposure to UV light or sunlight, which shows an improved safety profile in zebrafish and mouse models, while maintaining substantial herbicidal activity.

The peripheral nervous system has been implicated in wound healing. Here, Parfejevs and colleagues report that cutaneous wounding in mice induces the de-differentiation and proliferation of Schwann cells, which disseminate into the wound bed, secrete soluble factors, and promote wound healing.

Myosin VI (MVI) is known to interact with RNA Polymerase II and to play non-cytoplasmic roles in cells. Here, the authors provide evidence that the transcription co-activator NDP52 regulates MVI binding to DNA and that MVI interacts with nuclear receptors to drive gene expression.

Understanding the link between epigenetic marks and gene regulation requires the development of new tools to directly manipulate chromatin. Here the authors demonstrate a Cas9-based system to recruit chromatin remodelers to loci of interest, allowing rapid, reversible manipulation of epigenetic states.

Inherited retinopathies are devastating diseases that in most cases lack treatment options. Disease-modifying therapies that mitigate pathophysiology regardless of the underlying genetic lesion are desirable due to the diversity of mutations found in such diseases. We tested a systems pharmacology-based strategy that suppresses intracellular cAMP and Ca2+ activity via G protein-coupled receptor (GPCR) modulation using tamsulosin, metoprolol, and bromocriptine coadministration. The treatment improves cone photoreceptor function and slows degeneration in Pde6βrd10 and RhoP23H/WT retinitis pigmentosa mice. Cone degeneration is modestly mitigated after a 7-month-long drug infusion in PDE6A-/- dogs. The treatment also improves rod pathway function in an Rpe65-/- mouse model of Leber congenital amaurosis but does not protect from cone degeneration. RNA-sequencing analyses indicate improved metabolic function in drug-treated Rpe65-/- and rd10 mice. Our data show that catecholaminergic GPCR drug combinations that modify second messenger levels via multiple receptor actions provide a potential disease-modifying therapy against retinal degeneration.