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Genomic and transcriptomic analysis of samples from patients with multiple myeloma, followed by in vitro validation, indicate mechanisms of antigen escape in response to GPRC5D T cell-engager talquetamab, including biallelic deletions, small nucleotide variants, insertion-deletions and chromatin silencing.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

The factors that govern hydrogel-dependent bacterial growth are complex. Here, bacteria proliferation in two agarose hydrogels is investigated for 120 different growth conditions, finding that growth decreased with increasing hydrogel stiffness and with water loss.

A synthesizer that combines a fixed low-noise photonic oscillator and a direct digital synthesizer—and is based on components that can all be integrated on chip—can create microwave signals that are tunable with low noise.

Dramatic change to environments and climates across the Pleistocene/Holocene boundary is often cited as driving human subsistence change, but at Kiowa, New Guinea, environments and human lifeways remained consistent, stable isotope analysis reveals.

A spatially resolved optical polarimetry technique is used to identify a three-state Potts-nematic order parameter in a triangular lattice antiferromagnetic material.

Typical quantum error correcting codes assign fixed roles to the underlying physical qubits. Now the performance benefits of alternative, dynamic error correction schemes have been demonstrated on a superconducting quantum processor.

Concentrated water infiltration was detected in 46% of Australian groundwater bores across arid and wet climates, suggesting that conventional diffuse-only recharge estimates may significantly underestimate total recharge, according to Tritium data from more than 1,700 samples.

Experimental measurements of high-order out-of-time-order correlators on a superconducting quantum processor show that these correlators remain highly sensitive to the quantum many-body dynamics in quantum computers at long timescales.

Jayavelu, Samaha et al., apply machine learning models on hospital admission data, including antibody titers and viral load, to identify patients at high risk for Long COVID. Low antibody levels, high viral loads, chronic diseases, and female sex are key predictors, supporting early, targeted interventions.

Lipid nanoparticles (LNPs) are a versatile class of clinically approved drug delivery vehicles, particularly for nucleic acid cargoes, but they often suffer from instability issues. Here, the authors report that the room temperature stability of small interfering RNA LNPs formulated with unsaturated ionizable lipids can be improved by inclusion of mildly acidic, antioxidant-containing buffers.

Transcriptome-wide association studies (TWAS) have identified colorectal cancer (CRC) susceptibility genes. Here, the authors combine two multi-tissue TWAS methods, Mendelian randomisation, and genetic colocalization to identify 37 likely causal CRC susceptibility genes.

Li et al. discovered that the cytotoxic synthetic small molecule BRD1732 is directly ubiquitinated in cells. Ubiquitination of BRD1732 is E3 ligase dependent and leads to inhibition of proteasomal degradation.

Gene activation may involve the formation of a DNA loop that connects enhancer-bound transcription factors with the transcription apparatus at the core promoter. But this process is not well understood. Here, two proteins, mediator and cohesin, are shown to connect the enhancers and core promoters of active genes in embryonic stem cells. These proteins seem to generate cell-type-specific DNA loops linked to the gene expression program of each cell.

A COVID-19 test implemented in an automated microfluidic device and leveraging isothermal RNA amplification followed by T7 transcription and Cas13-mediated cleavage of a quenched fluorophore rapidly detects SARS-CoV-2 RNA in saliva samples.

Inspired by many examples in nature where organisms change shape to concur environments, there is much interest in designing robots that are capable of shape change. Shah et al. demonstrate a method for automatically discovering shape and gait changes for soft robots that can adapt to different terrains.

An atlas study of adipose tissue in people with obesity undergoing weight loss and their lean counterparts reveals that weight loss reduces cell senescence but cannot reverse all the metabolic problems caused by obesity.

We present the complete 62,460,029-base-pair sequence of a human Y chromosome from the HG002 genome (T2T-Y) that corrects multiple errors in GRCh38-Y and adds over 30 million base pairs of sequence to the reference.

The mechanisms of pathological astrocyte responses during multiple sclerosis remain unclear. Kadowaki et al. found in MS mouse models that CLEC16A suppresses astrocyte pathogenic activities related to mitochondria by boosting mitophagy.

As large-scale neurodevelopmental MRI studies gain prominence, the authors identify tradeoffs between sample size and quality control that can dramatically affect results, and they evaluate a range of approaches to mitigate risk for error.

Large language models show potential in suggesting common functions for a gene set.

Solid organ transplant recipients are at increased risk of infectious disease and have unique molecular pathophysiology. Here the authors use host-microbe profiling to assess SARS-CoV-2 infection and immunity in solid organ transplant recipients, showing enhanced viral abundance, impaired clearance, and increased expression of innate immunity genes.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Here, the authors describe 3D hubs as regulatory subunits of gene expression in the three essential lineages of embryogenesis. They develop a computational model that can predict novel enhancers and they validate such enhancers in the context of specific lineages.

The authors associate a novel genomic risk score with a broad set of psychiatric symptoms in children. They trace the impact of associated genes on cerebellar developmental processes that originate in fetal life and endure through early adolescence.

A multi-ancestry transcriptome-wide association study using an optimal linear combination of association statistics provides insights into tobacco use biology and suggests opportunities for drug repurposing.

Regulated cholesterol transport is essential for the maintenance of cellular cholesterol distribution and homeostasis, but tools to monitor this process are limited. Here, the authors develop a genetically encoded cholesterol biosensor and demonstrate its use for visualising cellular cholesterol distribution in various live cells in real time.

Maps of protein-protein interactions (PPIs) help identify new components of pathways, complexes, and processes. In this work, state-of-the-art methods are used to identify binary Drosophila PPIs, generating broadly useful physical and data resources.

A cell-sorting method leveraging leucine zippers allows for the generation of T cells displaying multiple chimaeric antigen receptors as well as receptors converting inhibitory signals into stimulatory signals.

A model-based correction (MBC) algorithm offers fast and accurate correction of multiple-blinking artifacts in PALM data. MBC outperforms other algorithms in both speed and accuracy and improves quantitative downstream image analysis.

In a randomized control trial, individuals who received dietitian-led counseling in the supermarket, together with web-based tools, had improved dietary quality in comparison to a control group, as assessed by adherence to the heart-healthy DASH diet plan.

Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease.

The results obtained by seventy different teams analysing the same functional magnetic resonance imaging dataset show substantial variation, highlighting the influence of analytical choices and the importance of sharing workflows publicly and performing multiple analyses.

RMC-7977, a compound that exhibits potent inhibition of the active states of mutant and wild-type KRAS, NRAS and HRAS variants has a strong anti-tumour effect on RAS-addicted tumours and is well tolerated in preclinical models.

Pharmacotyping analyses of large cohorts of pediatric acute lymphoblastic leukemia identify correlations between drug sensitivities and clinical outcomes across different genomic subtypes.

Previous studies identified an association between the 2q35 locus and breast cancer. Here, the authors show that a SNP at 2q35, rs4442975, is associated with oestrogen receptor positive disease and suggest that this effect is mediated through the downregulation of a known breast cancer gene, IGFBP5.

A fabricated transparent ribcage facilitates real-time analysis of whole-lung function down to cellular resolution.

Microglia mediate aberrant synapse engulfment in Alzheimer’s disease (AD), but the underlying mechanisms are poorly understood. Here the authors show a perivascular cells-to-microglia crosstalk that induces microglia phagocytic state resulting in synapse engulfment in two mouse models of AD.

T cells derived from stem cells can be harnessed for regenerative medicine and cancer immunotherapy, but current technologies limit production and translation. Here, the authors present a serum-free, stromal-cell free DLL4-coated microbead method for the scalable production of T-lineage cells from multiple sources of stem cells.

Oncolytic viruses (OVs) represent a treatment option for patients with cancer. Here the authors propose a tumour-agnostic dual-virus strategy for cancer therapy by generating a vesicular stomatitis virus encoding a truncated version of HER2, combined with a vaccinia virus as a delivery platform for a HER2-targeted T-cell engager.

Esophageal adenocarcinoma is characterised by frequent amplifications in oncogenes. Here, the authors use short- and long-read sequencing approaches to analyze primary tumor samples and tumour-derived organoids and to investigate the mechanisms underlying complex amplifications.

The molecular mechanisms responsible for cellular cholesterol distribution remain unclear. Here, the authors identify a key role of lipid transfer proteins ORP9, OSBP, and GRAMD1s in maintaining cholesterol levels in the Golgi and plasma membrane.

This study finds that decision markets can be a useful tool for selecting studies for replication. For a sample of 26 online experiments published in PNAS selected by a decision market, the authors find replication rates ranging between 54% and 62%.

Using high-resolution ex vivo MRI and serial histology, Ravikumar et al. characterise 3D tau spread across histologically defined medial temporal lobe subregions thus providing a postmortem reference for in vivo studies on early Alzheimer’s disease.