Search

Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

Congenital heart disease (CHD) is a disorder that occurs in ∼1% of live births. Here the authors describe a genome-wide allele-specific expression analyses in CHD patients, identifying five new genes involved in CHD and showing that paternally-expressed imprinted genes are monoallelic, while maternally-expressed imprinted genes are biallelic.

Results of the TRACERx study shed new light into the association between body composition and body weight with survival in individuals with non-small cell lung cancer, and delineate potential biological processes and mediators contributing to the development of cancer-associated cachexia.

In a mouse model of Huntington's disease, synaptic activation of NMDA receptors induces the formation of huntingtin-containing inclusions, rendering neurons more resistant to death in vivo and in vitro. In contrast, stimulation of extrasynaptic NMDA receptors increases neuronal vulnerability by preventing inclusion formation.

Nonlinearity enhancement in different materials is relevant for many scientific applications. Here the authors demonstrate pulse modulation in the UV regime due to polariton-based nonlinearity in an AlInGaN waveguide structure, including at room temperature.

The heterogeneity of androgen receptor (AR) gene alterations across metastases in prostate cancer remains unresolved. Here, the authors characterise AR genomic complexity across spatially separated lethal metastases from 10 prostate cancer patients and investigate how AR alterations evolve.

Using a Streptococcus pneumoniae human challenge model, the authors here show that baseline nasal microbiota profiles are associated with pneumococcal acquisition and density, independent of live-attenuated influenza vaccine (LAIV) administration, and with mucosal cytokine responses to LAIV.

There is a functional link between SNPs and epigenetic variations when they are in close range, but the long-range effect is unclear. Here, by analysing methylation quantitative trait loci, the authors demonstrate that methylation levels at CpG sites in lymphocytes are correlated with distal SNPs.

A phase I clinical trial of an adjuvant personalized mRNA neoantigen vaccine, autogene cevumeran, in patients with pancreatic ductal carcinoma demonstrates that the vaccine can induce T cell activity that may correlate with delayed recurrence of disease.

The authors uncover a new role for the RNA-binding protein Msi2 in the regulation of hematopoietic stem cell homeostasis and leukemogenesis. Msi2 is required for the maintenance of the balance between progenitor renewal and differentiation, and its overexpression cooperates with oncogenic events to induce aggressive leukemia. Msi2 expression is also elevated in human myeloid leukemias and may be a new prognostic marker and therapeutic target in acute myeloid leukemia.

Comparative genomics of 70 lethal, non-lethal symptomatic and asymptomatic enteropathogenic Escherichia coli (EPEC) isolates identifies the virulence-associated genes that are significantly more prevalent in symptomatic and lethal infections.

For homeostatic plasticity, neuronal circuits rely on poorly understood retrograde signals. Here, the authors identify a visual activity-dependent feedback loop mediated by the secreted Allnighter pseudokinase with effects on brain-wide proteostasis and sleep.

A stack of longitudinal 2D light sheets provides 3D holographic images with improved depth perception.

Activation of the signalling molecule SHP2 is implicated in driving several cancers. In a newly described class of bone-progenitor cells, however, it seems that the protein acts as a tumour suppressor. See Letter p.491

Diabetic eye disease is a cause of preventable blindness and accurate and timely referral of patients with diabetic macular edema is important to start treatment. Here the authors present a deep learning model that can predict the presence of diabetic macular edema from color fundus photographs with superior specificity and positive predictive value compared to retinal specialists.

Mechanisms underlying bone formation induced by divalent metal cations remain largely unknown. Here the authors show that these cations can activate the skeleton interoceptive circuit through the immune-neural axis to initiate new bone formation.

CAR T cells administered intracerebroventricularly or intratumorally exhibit more rapid kinetics, reduced systemic toxicity and greater therapeutic potency as compared to intravenously delivered CAR T cells in atypical teratoid/rhabdoid tumor xenograft mouse models.

Machine-learning algorithms trained with retinal fundus images, with subject metadata or with both data types, predict haemoglobin concentration with mean absolute errors lower than 0.75 g dl^–1 and anaemia with areas under the curve in the range of 0.74–0.89.

This study shows that scavenger receptor type I knockout mice (Scarb1-/-) have high adrenocorticotropic hormone (ACTH) levels but are osteopenic. Bone differentiation of Scarb1-/- mesenchymal stem cells at normal ACTH concentrations is reduced. However, 0–10 nM ACTH increases, but 100–1000 nM ACTH reduces wild-type osteoblast differentiation. Therefore, ACTH and the high-density lipoprotein receptor Scarb1 play independent roles in osteoblast differentiation.

Circulating haematopoetic stem cells and their progenitors exhibit robust circadian fluctuations, peaking 5 hours after the initiation of light and reaching a nadir 5 hours after darkness. Circadian oscillations are markedly altered when mice are subjected to continuous light or to a 'jet lag' (defined as a shift of 12 h). Data also suggests that circadian, neurally driven haematopoetic stem cells release during the animal's resting period may promote regeneration of the stem cell niche, and possibly of other tissues.

Recent evidence indicates that gene bookmarking — the combination of mitotic retention of transcription factors at promoters, histone modifications and DNA methylation — is a novel epigenetic mechanism that sustains cellular identity after mitosis. This Opinion article discusses the importance of bookmarking in biological control and disease.

Exome sequencing of patients with congenital heart disease (CHD) and their unaffected parents reveals an excess of strong-effect, protein-altering de novo mutations in genes expressed in the developing heart, many of which regulate chromatin modification in key developmental genes; collectively, these mutations are predicted to account for approximately 10% of severe CHD cases.

Matthew Hurles and colleagues report exome sequencing of 1,891 individuals with syndromic or nonsyndromic congenital heart defects (CHD). They found that nonsyndromic CHD patients were enriched for protein-truncating variants in CHD-associated genes inherited from unaffected parents and identified three new syndromic CHD disorders caused by de novo mutations.

Olivier Delattre and colleagues show that a Ewing sarcoma susceptibility variant at 10q21.3 influences EGR2 expression by altering the activity of an enhancer bound by EWSR1-FLI1. They further show that EGR2 knockdown inhibits growth of Ewing sarcoma cells in vitro and induces complete regression of xenografts in vivo, establishing a critical role for EGR2 in Ewing sarcomagenesis.

By sequencing the exomes of 10,503 individuals living in Pakistan, the authors identify rare predicted loss-of-function mutations that are estimated to knock out genes and correlate these mutations with a broad range of phenotypes, providing a framework for a human knockout project.

Ultraviolet (UV) exposure has been implicated in melanoma formation. Here it is shown, in a mouse model, that UVB induces the recruitment of macrophages which produce interferon-γ to promote melanomagenesis. The study suggests that in melanomas, interferon-γ could be targeted therapeutically.

This study of a cohort of over 3,500 pregnant women in six different populations worldwide identifies specific fetal cranial growth trajectories, measured by serial ultrasound scans early in gestation, that are related to postnatal growth and neurodevelopment up to the key milestone age of 2 years.

Nucleic acids and regulatory proteins are compartmentalized in microenvironments within the nucleus. These precise arrangements can be distrupted in cancer cells. How can we measure these changes and what might they tell us about cancer development and treatment?