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The practical rules for the early non-invasive diagnosis of cirrhosis in NAFLD are not well defined. Here, the authors develop and validate two diagnostic tools: a stepwise stratification algorithm including a cirrhosis group, and a risk prediction chart providing a personalized assessment of the individual probability of cirrhosis.

Variants in the PSMC5 gene impair proteasome function and cellular homeostasis, altering brain development in children. This study reveals underlying molecular mechanisms contributing to this neurodevelopmental phenotype, and suggests therapeutic leads for neurodevelopmental proteasomopathies.

A multi-ancestry genome-wide association meta-analysis of kidney cancer identifies 63 regions associated with disease susceptibility including one locus that was associated with increased risk in individuals with African ancestry.

To consider the impact of sex on adaptation to space, the European Space Agency initiated VIVALDI dry immersion microgravity simulation in female subjects. Here, the authors show marked deconditioning with 5-day exposure, and propose comprehensive multi-system physiological assessment in 18 healthy women.

The authors identify pathogenic variants in the SMARCA1 gene as the cause of a variable neurodevelopmental disorder. Mouse studies suggest diverse genetic mechanisms related to NURF complex composition mediate the phenotype.

Combined hepatocellular-cholangiocarcinomas (cHCC-CCA) are challenging to diagnose, as they exhibit features of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICCA). Here, the authors use deep learning to re-classify cHCC-CCA tumours into HCC or ICCA based on histopathology images.

Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca²⁺ transport and AMPAR currents.”

Polycyclic aromatic hydrocarbons such as [4]helicenes are important interstellar molecules. Here, the authors show their evolution of chiral clusters upon aggregation through coincidence spectroscopy and quantum chemical calculations.

Marginal liver grafts are associated with a higher risk of graft failure due to their increased susceptibility to ischemia-reperfusion injury. Here, the authors show the regulatory mechanism of fibroblast growth factor 21 and offer insights into its clinical application in early liver graft injury.

As remote sensing technology improves, it is now possible to map fine-scale variation in plant functional traits. Schneider et al. remotely sense tree functional diversity, validate with field data, and reveal patterns of plant adaptation to the environment previously not retrievable from plot data

Analysis of snRNA genes in individuals with rare disorders identifies de novo and recurrent variants in RNU5B-1 and RNU5A-1, in addition to previously unreported cases with pathogenic or likely pathogenic variants in RNU4-2.

Disruptions to the ER-Golgi network can lead to neurodevelopmental disorders, though our understanding of these Golgipathies remains incomplete. Here Lauri, Tartaglia and colleagues show that ARF3 mutations cause a rare pediatric neurological disorder and perform detailed molecular characterization in fish.

Loss-of-function variants in thyroid hormone transporter MCT8 cause a neurodevelopmental and metabolic disorder. Here the authors identify genotype-phenotype relationships, advance insights in MCT8 (dys)function and create a pathogenicity-severity variant classifier.

A geological, petrographic and geochemical survey of distinctive mudstone and conglomerate outcrops of the Bright Angel formation on Mars reveals textures, chemical and mineral characteristics, and organic signatures that warrant consideration as potential biosignatures.

APOGEE 2 is a machine-learning tool for assessing the fragility of the mitochondrial genome, evaluating genetic variant pathogenicity and ultimately enhancing our understanding of the clinical heterogeneity of mitochondrial genetic diseases.

A high-quality reference genome of rose is generated by sequencing a doubled haploid line. The researchers analysed the genome structure and uncovered candidate genes associated with major ornamental traits through integrated genetic and genomic analyses.

Literature produced inconsistent findings regarding the links between extreme weather events and climate policy support across regions, populations and events. This global study offers a holistic assessment of these relationships and highlights the role of subjective attribution.

Anaplastic oligodendrogliomas are rare and incurable primary brain tumours with few treatment options. Here Labrecheet al. perform whole-exome sequencing and identify recurring mutations in transcription factor TCF12, which are associated with aggressive tumours.

Animals rely on a multitude of resistance and tolerance mechanisms to resist harmful gut microbes. Here, the authors explore the genetic, molecular and physiological basis underlying the remarkable phenotypic variation in resistance to enteric bacterial infection inDrosophila melanogaster.

Jeremy Manry, Quentin Vincent et al. report a genome-wide association study for susceptibility to Buruli ulcer in a rural population from the West African country of Benin. They identify two independently associated variants within LncRNA genes and confirm the protective effect of a missense variant in the bacterial autophagy gene ATG16L1.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

Mandibuloacral dysplasias (MADs) are rare progeroid syndromes characterized by nuclear morphological and functional abnormalities. Here the authors report that loss of mitochondrial membrane protein MTX2 causes a progeroid MAD sharing clinical features with lamin-associated progeroid syndromes.

SuFu is a tumour suppressor in medulloblastoma and regulates Gli proteins in the Sonic Hedgehog pathway; however, the molecular mechanisms behind this regulation are unclear. Here, the authors show that the Itch/β-arrestin2 complex binds and ubiquitylates SuFu, facilitating the interaction with Gli3 and its conversion into the repressive form, thus counteracting medulloblastoma formation.

Jamel Chelly, Nicholas Cowan and colleagues report mutations in TUBG1, DYNC1H1, KIF2A and KIF5C in individuals with malformations of cortical development and microcephaly. Their findings emphasize the importance of centrosomal and microtubule-related proteins for normal brain development.

Rational antibody engineering can greatly improve the clinical value of therapeutic antibodies. Here authors describe ISB 1442, a fully human bispecific antibody, consisting of two targeting modules against two different epitopes on CD38, combined with a targeting module blocking CD47 and engineered effector properties, to enhance complement dependent cytotoxicity, antibody dependent cells cytotoxicity and antibody dependent cell phagocytosis to combat multiple myeloma.

Perro and colleagues develop a CD3⁺ T cell engager co-targeting BCMA and CD38 to improve immunotherapy for multiple myeloma, demonstrate cytotoxicity in patient-derived samples and murine models and develop a quantitative systems pharmacology model.

Recent work indicates that drug delivery to the brain can be improved through disruption of the blood brain barrier using low intensity pulsed ultrasound. Here, the authors report a phase I/II clinical trial investigating the combination of a nine-emitter implantable ultrasound device and carboplatin in patients with recurrent glioblastoma.

The WNT/β-catenin signaling pathway regulates key physiological processes. Here, the authors show that FZD-LRP6 association alone is insufficient to activate β-catenin signaling, as seen with WNT−16B, but effective signaling instead requires higher-order receptor clustering to trigger the pathway.

Vitamin E metabolites are proposed to have signalling capacity, but how they may regulate immune responses is still unclear. Here the authors show that a vitamin E metabolite, α-T-13′-COOH, can inhibit 5-lipoxygenase and thereby suppress the synthesis of lipid mediators of immune activation and inflammatory responses.

Immunomagnetic cell sorting implemented in a microfluidic chip can perform loss-of-function CRISPR–Cas9-mediated phenotypic screening at higher throughput than fluorescence-activated cell sorting.

In a pooled analysis of six international studies involving about 17,900 female survivors of childhood cancer, the use of doxorubicin was associated with a dose-dependent risk of subsequent breast cancer, irrespective of prior chest radiotherapy exposure.

Impact-induced acoustic and seismic wave events on Mars recorded by the InSight lander’s seismometer have been traced to fresh craters observed in spacecraft imagery.

In this Primer, Loomba and colleagues discuss the epidemiology, current understanding of pathophysiology, diagnosis and management of metabolic dysfunction-associated steatotic liver disease, the most common chronic liver disease worldwide, affecting 30% of the adult population.

Van Haute et al describe autosomal recessive TEFM variants that impair mitochondrial transcription elongation and reduce the levels of promoter distal mitochondrial RNA transcripts, leading to heterogeneous mitochondrial diseases with a treatable neuromuscular transmission defect.