Weekly Reading List

Nanopore sequencing, a third-generation sequencing technology, has revolutionized the gene sequencing industry with its advantages of long reads, fast speed, real-time sequencing and analysis, and potential in detecting base modifications. This technology allows researchers to sequence longer DNA fragments in a single read, providing more comprehensive genomic information compared to previous methods. Nanopore sequencing operates on electrical signals generated by a nanopore embedded in a membrane separating two electrolyte-filled chambers. When single-stranded DNA (ssDNA) passes through the nanopore, it creates variations in the current that correspond to different DNA bases. By analyzing these current fluctuations with machine learning algorithms, the DNA sequence can be determined. In this study, we introduced several improvements to nanopore sequencing, including nanopore local chemistry sequencing, novel motor and pore proteins, chip design, and basecalling algorithms. Our new nanopore sequencing platform, CycloneSEQ, demonstrated long-duration sequencing (107 hours) on a single chip with high yield (>50 Gb). In human genomic DNA sequencing, CycloneSEQ was able to produce long reads with N50 33.6 kb and modal identity 97.0%. Preliminary findings on human whole-genome de novo assembly, variant calling, metagenomics sequencing, and single-cell RNA sequencing have further highlighted CycloneSEQ’s potential across different areas of genomics. ### Competing Interest Statement All authors are employees of the BGI Group. The authors have submitted patent applications related to the methods or results presented in this manuscript.

The authors present a workflow integrating imaging mass cytometry and imaging mass spectrometry to deconvolute metabolic heterogeneity at the single-cell level.

US Office of Research Integrity report aligns with investigation by the University of Maryland, Baltimore

DNA polymerases are complex molecular machines able to replicate genetic material using a template-driven process. While the copying function of these enzymes is well established, their ability to perform untemplated DNA synthesis is less well characterized. Here, we explore the ability of DNA polymerases to synthesize DNA fragments in the absence of template. We use long-read nanopore sequencing and real-time PCR to observe the synthesis of pools of DNA products derived from a diverse set of natural and engineered DNA polymerases across varying temperatures and buffer compositions. We detail the features of the DNA fragments generated, enrichment of select sequence motifs, and demonstrate that the sequence composition of the synthesized DNA may be altered by modifying environmental conditions. This work provides an extensive data set to better discern the process of untemplated DNA polymerase activity and may support its potential repurposing as a technology for the guided synthesis of DNA sequences on the kilobase-scale and beyond. ### Competing Interest Statement A.W., G.L., B.T.R. and L.O. have been employees of Replay Holdings Inc. T.E.G., I.D.W.S., A.H. and P.H. have consulted for Replay Holdings Inc.

Gene-based rare variant analyses for 601 diseases across 748,879 individuals from three biobanks identify 363 significant associations and highlight important considerations for multi-ancestry and cross-biobank sequencing studies.

FDA explores AI’s potential in drug development—from biomarker strategies and data challenges to regulatory approaches for integrating AI in pharmaceutical innovation.

Here the authors provide a resource for ovarian cancer combining spatial transcriptomics, genomics, CRISPR Perturb-seq screens and in silico methods to focus on T cells and natural killer cells in the tumor and their role in immune evasion.

If H5N1 bird flu in cattle is confirmed at three dairy farms in California’s Central Valley, they would be the first cases in the state.

Nature talks with infectious disease specialists about whether vaccines will curb this outbreak and more.

Spiders produce nature’s toughest fiber using renewable components at ambient temperatures and with water as solvent, making it highly interesting to replicate for the materials industry. Despite this, much remains to be understood about the bioprocessing and composition of spider silk fibers. Here, we identify 18 proteins that make up the spiders’ strongest silk type, the major ampullate fiber. Single-cell RNA sequencing and spatial transcriptomics revealed that the secretory epithelium of the gland harbors six cell types.

Data from giant project show how withdrawn research propagates through the literature.

Exact Sciences said Tuesday that it enrolled the first patient into its multi-cancer early detection (MCED) Falcon Registry Real-World Evidence study.

Genome-wide association analysis of an improved telomere length score, calculated from quantitative PCR and whole-genome sequencing measurements in 462,666 individuals in the UK Biobank, identifies novel genes and variants underlying this trait.

The NVIDIA NIM Agent Blueprint for generative AI-based virtual screening will help reduce the time and cost of developing life-saving drugs.

Made-to-order gene could be so toxic that cells only assemble it in emergencies

Here, Wong et al investigate the cell-free DNA landscape of individuals with Li-Fraumeni syndrome (LFS), a cancer predisposition, and find altered composition compared to non-LFS individuals which can be used to detect and track cancer development.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder. During the last two decades, substantial efforts from pharmaceutical companies have targeted amyloid peptides as disease-modifying therapies. The elevated Aβ42/Aβ40 ratio in familial AD patients carrying PSEN mutations has been taken as crucial evidence for a causal role of Aβ in the pathogenesis. The current genetic study using APP deficiency to remove Aβ completely in various Psen mutant mice provides compelling experimental evidence for the lack of a causal role of Aβ in the age-dependent neurodegeneration and elevated apoptotic cell death in the cerebral cortex caused by Psen mutations.

Tumor immunoediting occurs early during tumorigenesis and is thereby difficult to study. Here the authors overcome this issue using an aggressive breast cancer model that enables them to compare and contrast the trancriptomic state of early versus late tumors.

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS), resulting in neurological disability that worsens over time. While progress has been made in defining the immune system’s role in MS pathophysiology, the contribution of intrinsic CNS cell dysfunction remains unclear. Here, we generated a collection of induced pluripotent stem cell (iPSC) lines from people with MS spanning diverse clinical subtypes and differentiated them into glia-enriched cultures. Using single-cell transcriptomic profiling and orthogonal analyses, we observed several distinguishing characteristics of MS cultures pointing to glia-intrinsic disease mechanisms. We found that primary progressive MS-derived cultures contained fewer oligodendrocytes.

Although immune checkpoint blockade is a standard treatment for patients with malignant mesothelioma, only a minority of patients exhibit radiological response. In a phase II clinical trial (MIST4) investigating the efficacy, safety and molecular correlates of response following treatment with atezolizumab and bevacizumab, the authors demonstrate that the gut microbiota may modulate responsiveness to treatment.

Pathoplexus is starting with sequences for Ebola strains and two other risky viruses

A maxim from the great but fictional advertising executive Don Draper: “if you don’t like what people are saying, change the conversation”.…

Merck on Thursday said it is discontinuing the Phase III KEYNOTE-630 trial of Keytruda (pembrolizumab) as adjuvant therapy in patients with high-risk, locally advanced cutaneous squamous cell carcinoma, in which researchers are looking at PD-L1 expression levels.

Here the authors provide a resource for ovarian cancer combining spatial transcriptomics, genomics, CRISPR Perturb-seq screens and in silico methods to focus on T cells and natural killer cells in the tumor and their role in immune evasion.

Irreversibility, in which a transient perturbation leaves a system in a new state, is an emergent property in systems of interacting entities. This property has well-established implications in statistical physics but remains underexplored in biological networks, especially for bacteria and other prokaryotes whose regulation of gene expression occurs predominantly at the transcriptional level. Focusing on the reconstructed regulatory network of Escherichia coli, we examine network responses to transient single-gene perturbations.

This analysis presents a systematic comparison of 11 sequencing-based spatial transcriptomics methods using well-characterized references, which offers insights into performance variations in spatial transcriptomic techniques.

Researchers identify gene responsible for the arachnids’ signature hourglass shape

A pair of studies from two independent research teams showcases how scientists are using data from the UK Biobank (UKB) Pharma Proteomics Project (PPP) to identify biomarkers linked to disease and other biological processes.

September 1, 2024 Hey There! Thanks for spending part of your Sunday with Omic.ly! I’m pretty surprised no one made fun of me for getting the date wrong on the last issue. Maybe you’ve all just made peace with my typos. I’m still not there yet. This Week’s Headlines