Comprehensive histopathological analysis of gastric cancer in European and Latin America populations reveals differences in PDL1, HER2, p53 and MUC6 expression.

Introduction: Gastric cancer (GC) burden is currently evolving with regional differences associated with complex behavioural, environmental, and genetic risk factors. The LEGACy study is a Horizon 2020-funded multi-institutional research project conducted prospectively to provide comprehensive data on the tumour biological characteristics of gastroesophageal cancer from European and LATAM countries.

Material And Methods: Treatment-naïve advanced gastroesophageal adenocarcinoma patients were prospectively recruited in seven European and LATAM countries.

Analysis of multi-condition single-cell data with latent embedding multivariate regression.

Identifying gene expression differences in heterogeneous tissues across conditions is a fundamental biological task, enabled by multi-condition single-cell RNA sequencing (RNA-seq). Current data analysis approaches divide the constituent cells into clusters meant to represent cell types, but such discrete categorization tends to be an unsatisfactory model of the underlying biology. Here, we introduce latent embedding multivariate regression (LEMUR), a model that operates without, or before, commitment to discrete categorization.

Refining breast cancer genetic risk and biology through multi-ancestry fine-mapping analyses of 192 risk regions.

Genome-wide association studies have identified approximately 200 genetic risk loci for breast cancer, but the causal variants and target genes are mostly unknown. We sought to fine-map all known breast cancer risk loci using genome-wide association study data from 172,737 female breast cancer cases and 242,009 controls of African, Asian and European ancestry. We identified 332 independent association signals for breast cancer risk, including 131 signals not reported previously, and for 50 of them, we narrowed the credible causal variants down to a single variant.

Bacteria use exogenous peptidoglycan as a danger signal to trigger biofilm formation.

For any organism, survival is enhanced by the ability to sense and respond to threats in advance. For bacteria, danger sensing among kin cells has been observed, but the presence or impacts of general danger signals are poorly understood. Here we show that different bacterial species use exogenous peptidoglycan fragments, which are released by nearby kin or non-kin cell lysis, as a general danger signal.

Long-range organization of intestinal 2D-crypts using exogenous Wnt3a micropatterning.

Intestinal epithelial cells are segregated into proliferative crypts and differentiated regions. This organization relies on specific signals, including Wnt3a, which regulates cell proliferation within crypts, and Eph/Ephrin, which dictates cell positioning along the crypt-villus axis. However, studying how the spatial distributions of these signals influences crypt-villus organization is challenging both in vitro and in vivo.

Characterizing features affecting local ancestry inference performance in admixed populations.

In recent years, significant efforts have been made to improve methods for genomic studies of admixed populations using local ancestry inference (LAI). Accurate LAI is crucial to ensure that downstream analyses accurately reflect the genetic ancestry of research participants. Here, we test analytic strategies for LAI to provide guidelines for optimal accuracy, focusing on admixed populations reflective of Latin America's primary continental ancestries-African (AFR), Amerindigenous (AMR), and European (EUR).

4D structural biology-The 9 Murnau Conference on structural biology.

The data presented at the 9 International Murnau Conference on September 18-21, 2024, the largest recurring structural biology meeting in Central Europe, illustrated the thriving state of the structural biology community. This is largely attributed to the ground-breaking developments over the last decade, which were intensely discussed during the meeting.

Basic Science and Pathogenesis.

Background: Genome-wide association studies (GWAS) in Alzheimer's disease (AD) leveraging endophenotypes beyond case/control diagnosis, such as brain amyloid β pathology, have shown promise in identifying novel variants and understanding their potential functional impact. In this study, we leverage two brain amyloid β pathology measurement modalities, PET imaging and neuropathology, to address sample size limitations and to discover novel genetic drivers of disease.

Method: We conducted a meta-analysis on an amyloid PET imaging GWAS (N = 7,036, 35% amyloid positive, 53.

Basic Science and Pathogenesis.

Background: Although the rate of Alzheimer's disease (AD) in African-ancestry (AA) Americans is higher than that of persons from European-ancestry (EA) populations, AA participants have been underrepresented in AD neuropathological studies.

Method: Utilizing the AD Research Centers (ADRC) infrastructure, we obtained AA donor pre-frontal cortex (PFC) tissue from brain repositories of 12 ADRC and generated bulk RNA sequencing (RNA-seq) data for 179 samples that met QC and inclusion criteria. Previously generated PFC RNAseq data were obtained for 28 additional AA donors from the Columbia University ADRC.

Basic Science and Pathogenesis.

Background: Mosaic loss of the Y chromosome (LOY) is a somatic, age-related event that has been previously associated with a variety of diseases of aging. A prior study of European cohorts demonstrated an association between LOY and Alzheimer's Disease and more recent molecular studies have shown that LOY can also occur within microglia, suggesting a potential functional role in AD pathogenesis.

Method: In this study, we further validate the association between LOY in blood and AD via prospective analyses of 1,447 males.

PD-L1 and IFN-γ modulate Non-Small Cell Lung Cancer (NSCLC) cell plasticity associated to immune checkpoint inhibitor (ICI)-mediated hyperprogressive disease (HPD).

Background: Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer death worldwide. Although immune checkpoint inhibitors (ICIs) have shown remarkable clinical efficacy, they can also induce a paradoxical cancer acceleration, known as hyperprogressive disease (HPD), whose causative mechanisms are still unclear.

Methods: This study investigated the mechanisms of ICI resistance in an HPD-NSCLC model.

Efficiently accelerated bioimage analysis with NanoPyx, a Liquid Engine-powered Python framework.

The expanding scale and complexity of microscopy image datasets require accelerated analytical workflows. NanoPyx meets this need through an adaptive framework enhanced for high-speed analysis. At the core of NanoPyx, the Liquid Engine dynamically generates optimized central processing unit and graphics processing unit code variations, learning and predicting the fastest based on input data and hardware.

DGCR2 targeting affibody molecules for delivery of drugs and imaging reagents to human beta cells.

A distinctive feature of both type 1 and type 2 diabetes is the waning of insulin-secreting beta cells in the pancreas. New methods for direct and specific targeting of the beta cells could provide platforms for delivery of pharmaceutical reagents. Imaging techniques such as Positron Emission Tomography (PET) rely on the efficient and specific delivery of imaging reagents, and could greatly improve our understanding of diabetes etiology as well as providing biomarkers for viable beta-cell mass in tissue, in both pancreas and in islet grafts.

Structural insights into distinct mechanisms of RNA polymerase II and III recruitment to snRNA promoters.

RNA polymerase III (Pol III) transcribes short, essential RNAs, including the U6 small nuclear RNA (snRNA). At U6 snRNA genes, Pol III is recruited by the snRNA Activating Protein Complex (SNAPc) and a Brf2-containing TFIIIB complex, forming a pre-initiation complex (PIC). Uniquely, SNAPc also recruits Pol II at the remaining splicesosomal snRNA genes (U1, 2, 4 and 5).

TransLeish: Identification of membrane transporters essential for survival of intracellular Leishmania parasites in a systematic gene deletion screen.

For the protozoan parasite Leishmania, completion of its life cycle requires sequential adaptation of cellular physiology and nutrient scavenging mechanisms to the different environments of a sand fly alimentary tract and the acidic mammalian host cell phagolysosome. Transmembrane transporters are the gatekeepers of intracellular environments, controlling the flux of solutes and ions across membranes. To discover which transporters are vital for survival as intracellular amastigote forms, we carried out a systematic loss-of-function screen of the L.

A new effLuc/Kate dual reporter allele for tumour imaging in mice.

Genetically engineered mouse models (GEMMs) are instrumental for modelling local and systemic features of complex diseases such as cancer. Non-invasive, longitudinal cell detection and monitoring in tumors, metastases and/or the micro-environment is paramount to achieve a better spatiotemporal understanding of cancer progression and to evaluate therapies in preclinical studies. Bioluminescent and fluorescent reporters marking tumor cells or their microenvironment are valuable for non-invasive cell detection and monitoring in vivo.

Gliomagenesis mimics an injury response orchestrated by neural crest-like cells.

Glioblastoma is an incurable brain malignancy. By the time of clinical diagnosis, these tumours exhibit a degree of genetic and cellular heterogeneity that provides few clues to the mechanisms that initiate and drive gliomagenesis. Here, to explore the early steps in gliomagenesis, we utilized conditional gene deletion and lineage tracing in tumour mouse models, coupled with serial magnetic resonance imaging, to initiate and then closely track tumour formation.

A Multiyear Longitudinal Harmonization Study of Quality Controls in Mass Spectrometry Proteomics Core Facilities.

Quality control procedures play a pivotal role in ensuring the reliability and consistency of data generated in mass spectrometry-based proteomics laboratories. However, the lack of standardized quality control practices across laboratories poses challenges for data comparability and reproducibility. In response, we conducted a harmonization study within proteomics laboratories of the Core for Life alliance with the aim of establishing a common quality control framework, which facilitates comprehensive quality assessment and identification of potential sources of performance drift.

Open problems in synthetic multicellularity.

Multicellularity is one of the major evolutionary transitions, and its rise provided the ingredients for the emergence of a biosphere inhabited by complex organisms. Over the last decades, the potential for bioengineering multicellular systems has been instrumental in interrogating nature and exploring novel paths to regeneration, disease, cognition, and behaviour. Here, we provide a list of open problems that encapsulate many of the ongoing and future challenges in the field and suggest conceptual approaches that may facilitate progress.

Ultrastructural Remodeling of Cardiomyocytes in Postinfarction Myocardium of Rats in the Late Stages of the Disease.

Identifying factors that contribute to the transition to the dilated phase in cardiac ischemia is a critical challenge in heart failure treatment. Currently, no effective therapies exist for this ischemic complication, and the mechanisms driving left ventricular dilatation during chronic post-infarction remodeling remain poorly understood. One potential pathological process leading to ventricular dilatation involves specific compensatory rearrangements in the border zone adjacent to the infarct, which isolates the intact myocardium from inflammation at the scar edge.

TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling.

Chromosomal instability (CIN) is common in solid tumours and fuels evolutionary adaptation and poor prognosis by increasing intratumour heterogeneity. Systematic characterization of driver events in the TRACERx non-small-cell lung cancer (NSCLC) cohort identified that genetic alterations in six genes, including FAT1, result in homologous recombination (HR) repair deficiencies and CIN. Using orthogonal genetic and experimental approaches, we demonstrate that FAT1 alterations are positively selected before genome doubling and associated with HR deficiency.

Alleviating batch effects in cell type deconvolution with SCCAF-D.

Cell type deconvolution methods can impute cell proportions from bulk transcriptomics data, revealing changes in disease progression or organ development. But benchmarking studies often use simulated bulk data from the same source as the reference, which limits its application scenarios. This study examines batch effects in deconvolution and introduces SCCAF-D, a computational workflow that ensures a Pearson Correlation Coefficient above 0.

Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction.

Background: The 313-variant polygenic risk score (PRS) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS across different European populations which could influence risk estimation has not been performed.

Methods: We explored the distribution of PRS across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank.