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High-throughput monitoring of neurotransmitter release at single-vesicle resolution remains a challenge. Here, the authors present a silicon-based electrode array with 1024 on-chip electrodes that measures neurochemical signal in 0.1 millisecond intervals to capture the modulation of exocytosis due to Parkinson’s disease treatment within 30 total minutes of recording.

Abstract Uneven access to water and wastewater infrastructure is shaped by local governance. A substantial number of U.S. households lack adequate access and the U.S. is one of the few countries with large populations living outside of city bounds, in unincorporated areas. Few studies address how infrastructure services and local governance are intertwined at a regional scale. We examine the connection between incorporation status and access to centralized infrastructure, using negative binomial regression. A novel dataset informs this analysis, comprised of 31,383 Census block groups located in nine states representing over 25% of the national population. We find evidence that inequities in access are associated with unincorporated status and poverty rates. Sewer coverage rates are significantly lower for unincorporated communities in close proximity to municipal boundaries. Infrastructure equity could be improved by targeting high-poverty unincorporated communities, addressing challenges with noncontiguous service areas, and strengthening regional water planning and participatory governance.

Abstract Snow is a major, climate-sensitive feature of the Earth’s surface and catalyst of fundamentally important ecosystem processes. Understanding how snow influences sentinel species in rapidly changing mountain ecosystems is particularly critical. Whereas effects of snow on food availability, energy expenditure, and predation are well documented, we report how avalanches exert major impacts on an ecologically significant mountain ungulate - the coastal Alaskan mountain goat (Oreamnos americanus). Using long-term GPS data and field observations across four populations (421 individuals over 17 years), we show that avalanches caused 23−65% of all mortality, depending on area. Deaths varied seasonally and were directly linked to spatial movement patterns and avalanche terrain use. Population-level avalanche mortality, 61% of which comprised reproductively important prime-aged individuals, averaged 8% annually and exceeded 22% when avalanche conditions were severe. Our findings reveal a widespread but previously undescribed pathway by which snow can elicit major population-level impacts and shape demographic characteristics of slow-growing populations of mountain-adapted animals.

Abstract The advent of SARS-CoV-2 variants with defined mutations that augment pathogenicity and/or increase immune evasiveness continues to stimulate global efforts to improve vaccine formulation and efficacy. The extraordinary advantages of lipid nanoparticles (LNPs), including versatile design, scalability, and reproducibility, make them ideal candidates for developing next-generation mRNA vaccines against circulating SARS-CoV-2 variants. Here, we assess the efficacy of LNP-encapsulated mRNA booster vaccines encoding the spike protein of SARS-CoV-2 for variants of concern (Delta, Omicron) and using a predecessor (YN2016C isolated from bats) strain spike protein to elicit durable cross-protective neutralizing antibody responses. The mRNA-LNP vaccines have desirable physicochemical characteristics, such as small size (~78 nm), low polydispersity index (90%). We employ in vivo bioluminescence imaging to illustrate the capacity of our LNPs to induce robust mRNA expression in secondary lymphoid organs. In a BALB/c mouse model, a three-dose subcutaneous immunization of mRNA-LNPs vaccines achieved remarkably high levels of cross-neutralization against the Omicron B1.1.529 and BA.2 variants for extended periods of time (28 weeks) with good safety profiles for all constructs when used in a booster regime, including the YN2016C bat virus sequences. These findings have important implications for the design of mRNA-LNP vaccines that aim to trigger durable cross-protective immunity against the current and newly emerging variants.

Breast cancer heterogeneity and tumour evolutionary trajectories remain largely unknown among women of African ancestry. Here, the authors perform whole genome and transcriptome sequencing of Nigerian breast cancer patients and identify unique evolutionary phenomena.

Abstract Liquid biopsy is a valuable precision oncology tool that is increasingly used as a non-invasive approach to identify biomarkers, detect resistance mutations, monitor disease burden, and identify early recurrence. The Tempus xF liquid biopsy assay is a 105-gene, hybrid-capture, next-generation sequencing (NGS) assay that detects single-nucleotide variants, insertions/deletions, copy number variants, and chromosomal rearrangements. Here, we present extensive validation studies of the xF assay using reference standards, cell lines, and patient samples that establish high sensitivity, specificity, and accuracy in variant detection. The Tempus xF assay is highly concordant with orthogonal methods, including ddPCR, tumor tissue-based NGS assays, and another commercial plasma-based NGS assay. Using matched samples, we developed a dynamic filtering method to account for germline mutations and clonal hematopoiesis, while significantly decreasing the number of false-positive variants reported. Additionally, we calculated accurate circulating tumor fraction estimates (ctFEs) using the Off-Target Tumor Estimation Routine (OTTER) algorithm for targeted-panel sequencing. In a cohort of 1,000 randomly selected cancer patients who underwent xF testing, we found that ctFEs correlated with disease burden and clinical outcomes. These results highlight the potential of serial testing to monitor treatment efficacy and disease course, providing strong support for incorporating liquid biopsy in the management of patients with advanced disease.

The use of organoids in personalized medicine is promising but high throughput platforms are needed. Here the authors develop an automated, high-throughput, microfluidic 3D organoid culture system that allows combinatorial and dynamic drug treatments and real-time analysis of organoids.

Despite recent progress to advance cardiac cell-based therapy for patients, heart failure mortality rivals most cancers. Here, the authors describe an approach to control and pattern 3 distinct human cardiac cell populations to promote superior repair and regeneration after myocardial infarction.

ENCODE is a resource comprising thousands of functional genomic datasets. Here, the authors present custom annotation within ENCODE for cancer, highlighting a workflow that can help prioritise key elements in oncogenesis.

Research on racial and ethnic influence on breast cancer mortality is stymied by a lack of genomic studies in diverse populations. Here, the authors genomically interrogate 194 Nigerian breast cancers, unveiling molecular features that could explain the high mortality rate from breast cancer in an indigenous African population.

Chromatin accessibility may be altered in disease states. Here the authors carry out ATAC-seq on a large number of samples of dorsolateral prefrontal cortex from individuals with schizophrenia, and healthy controls.

The oligometastasis hypothesis suggests certain metastases are limited in extent and curable with focal therapies. Here they identify three integrated molecular subtypes of colorectal cancer liver metastasis, which complement clinical risk stratification to distinguish the subset of oligometastatic patients.

Homozygous deletions are rare in cancers and often target tumour suppressor genes. Here, the authors conduct pan-cancer analyses and apply statistical modelling to identify 27 candidate tumour suppressors, including MAFTRR, KIAA1551, and IGF2BP2.

The original version of this Article contained an error in the author affiliations. The affiliation of Kevin P. White with Tempus Labs, Inc. Chicago, IL, USA was inadvertently omitted. This has now been corrected in both the PDF and HTML versions of the Article.

The original version of this Article omitted a declaration from the competing interests statement, which should have included the following: ‘K.P.W. is President of Tempus Lab, Inc., Chicago, IL, USA’. This has now been corrected in both the PDF and HTML versions of the Article.

The original version of this Article contained an error in the author affiliations. The affiliation of Kevin P. White with Tempus Labs, Inc., Chicago, IL, USA was inadvertently omitted.This has now been corrected in both the PDF and HTML versions of the Article.