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Vaccines induce beneficial immunity for COVID-19, but immune waning prompts boosting vaccination. Here, the authors show that a third, boosting dose of COVID-19 mRNA vaccine induces transient CD8 + T effector cell response while conserving the CD8 memory T cell pool, thereby permitting reactivation of spike-specific CD8 + T cells upon breakthrough infection or 4th vaccination.

A follow-up analysis of a clinical trial that evaluated anti-PD-1 therapy in patients with cancer who are living with HIV provides mechanistic insights into transcriptomic, cellular and cytokine changes related to immune checkpoint inhibitor treatment and identifies a signature associated with clinical response.

Archaeogenetic study of ancient DNA from medieval northwestern Europeans reveals substantial increase of continental northern European ancestry in Britain, suggesting mass migration across the North Sea during the Early Middle Ages.

Nuclear protein homeostasis relies on proteasome import into the nucleus. Here the authors identify how assembled human proteasomes are transported across the nuclear pore complex and reveal a mechanism enabling the large complex to bypass pore size limitations.

KRAS mutations are keenly associated with pancreatic ductal adenocarcinoma and represent a potential therapeutic target. Here the authors present the findings from a phase I clinical trial testing pooled KRAS mutant peptides in combination with immune checkpoint blockade in patients with resected pancreatic ductal adenocarcinoma.

Trimodal single-cell analysis reveals gene-regulatory architecture in complex tissues.

The contribution of ether lipid species in cancer cell fate has not been fully understood yet. Here the authors show that malignant cancer cells employ ether lipids to modulate membrane biophysical properties, enhancing iron endocytosis and ferroptosis susceptibility.

Additive manufacturing of metals is now widely available, but the interaction of the metal powder with the laser remains unclear. Here, the authors use X-rays to image melt features and pore behaviour during laser melting of powders.

Multi-template PCR enables parallel DNA amplification but suffers from sequence-specific biases. Here, the authors develop a 1D-CNN model predicting amplification efficiency directly from the DNA sequence and discover adapter-mediated self-priming as a key cause of uneven amplification during PCR.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

Baarlink et al. identify a transient pool of nuclear F-actin, the dynamics of which are controlled by cofilin-1 that accumulates after mitosis and is important for chromatin reorganization in G1.

Transcriptomic and clinical data analyses from multiple cohorts of patients with cancer receiving immunotherapy find that PD-1 blockade potentiates tumor-specific IgG1 plasma cell responses that complement cellular immunity and contribute to clinical benefit.

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.

Cancers arising from the gastric squamous-columnar junction have high incidence and are characterized by a poor prognosis. Here, the authors use genetic mouse models to show that loss of p53 and Rb1 expression results in preferential tumour development at the gastric squamous-columnar junction that contains a large pool of osteopontin responsive Lgr5-CD44+ cells.

Bioactive sesquiterpenes accumulating in petunia stigmas are synthesized in the floral tube and then transported to the pistil via natural fumigation within the internal airspace of the developing flower.

An alternative mating system, termed parasex, produces progeny with high levels of genotypic diversity and is able to fulfil the roles of meiosis when it is absent in the fungal pathobiont Candida albicans.

How cellular metabolism influences tissue-resident macrophage survival is currently unknown. The authors here demonstrate that SerpinB2 regulates mitochondrial function to promote tissue-resident macrophage survival.

Hepatic glycogenolysis is essential for protein glycosylation and rhythmic secretion by the liver. Disruptions to hepatic glycogenolysis, caused by congenital diseases or physiological factors such as obesity, caloric restriction and changes to meal timing, alter hepatic protein secretion.

In order to find a general treatment for cancer, this study found that MTH1 activity is essential for the survival of transformed cells, and isolated two small-molecule inhibitors of MTH1, TH287 and TH588 — in the presence of these inhibitors, damaged nucleotides are incorporated into DNA only in cancer cells, causing cytotoxicity and eliciting a beneficial response in patient-derived mouse xenograft models.

A study examines the effects of mutations that occur naturally in T cell cancers, reporting that such mutations can potentially be exploited to increase the potency of T cell therapies.

Cas12a3 nucleases constitute a distinct clade of type V CRISPR–Cas bacterial immune systems that preferentially cleave the 3′ tails of tRNAs after recognition of target RNA to induce growth arrest and block phage dissemination.

The authors show that the SNARE protein VAMP4 acts to maintain calcium-dependent asynchronous synaptic vesicle release. These findings suggest that VAMP4 is functionally distinct from synaptobrevin2, which primarily drives fast, synchronous release.

Physical unclonable functions provide algorithm-independent cryptography based on non-distributable unique tokens. Here, the authors introduce unclonable functions based on random DNA pools, enabling secure decentralized authentication.

Ubiquitin chains direct post-ER membrane proteins toward different degradation routes. Here, the authors show that K63 chains promote lysosomal sorting, whereas K48 chains trigger “CUTUP”, a protein shearing pathway mediated by two ubiquitin-dependent proteases, Ddi1 and Rbd2, and the proteasome.

Rare cells are often biologically and clinically important, but their low abundance makes them challenging to study using single-cell transcriptomics. Here, the authors develop PURE-seq which integrates FACS and PIP-seq to directly sequence ultra-rare cells. It captures cells at 1 in 1,000,000 rarity, which the authors demonstrate by profiling circulating tumor cells and identifying Egr1 as a regulator of mouse hematopoietic stem cell aging.

Elevated triglyceride-rich lipoproteins (TRLs), long linked to cardiovascular disease, were thought to be harmful mainly in their remnant form. Here, the authors show that intact TRLs, not just their remnants, promote atherosclerosis and vascular inflammation in a mouse model.

Here the authors show that mitochondrial RNA leaks into the cytosol of senescent cells through sublethal apoptosis, driving inflammation. Blocking this pathway improves outcomes in Metabolic Dysfunction-Associated Steatohepatitis.

Understanding what happens to the liquid in melt pools during welding and metal-based additive manufacturing remains a challenge. Here, the authors directly image internal melt pool dynamics using synchrotron radiation to show surface tension affects flow speed, orientation and surface turbulence.

Giles et al. developed a method for noninvasive absorbance measurement of mitochondrial hemes to monitor the mitochondrial membrane potential in the perfused heart. They then applied this approach to show how the mitochondrial membrane potential changed during cardiac ischemia.

Plant-pollinator interactions are vital for food security and ecosystem stability but threatened by climate change. This study shows how warming and drying limit floral diversity, interaction resistance, and resilience for honey bees across Europe.

Dihydroorotate dehydrogenase (DHODH) is the only core de novo pyrimidine enzyme in the mitochondrial inner membrane, coupling nucleotide production to electron transport. Curtabbi et al. show that a cytosolic, fumarate-dependent DHODH orthologue can bypass this dependence, sustaining pyrimidine synthesis and supporting cell growth during respiration failure.

Temperature sensitivity of bulk soil carbon stocks is controlled by the compositional distribution between mineral-associated and particulate carbon, according to analyses of global soil carbon pools.

EGFR inhibitors are standard of care in patients with EGFR-mutant non-small cell lung cancer (NSCLC) but resistance often develops. Here the authors report that the evolution of EGFR inhibitor resistance in EGFR-mutant NSCLC results in a sensitivity to the compound, MCB-613, and investigate the underlying mechanism of action.

Researchers studied the blood-based metabolome of over 23,000 people from ten ethnically diverse cohorts. They identified 235 metabolites associated with future risk of type 2 diabetes (T2D). By integrating genetic and modifiable lifestyle factors, their findings provide insights into T2D mechanisms and could improve risk prediction and inform precision prevention.

It is not fully understood why genomic loci show asynchronous DNA replication. Here, the authors show that two imprinted gene domains replicate asynchronously between the parental chromosomes due to differential DNA methylation and non-coding RNA, leading to allelic differences.

In this study, authors employ fragment-based lead discovery to identify WRN inhibitors. The fragment hits reveal an additional allosteric pocket and uncover a previously uncharacterized structural conformation of the WRN helicase domain with unique orientations of the ATPase domains

A comparison of alpha diversity (number of plant species) and dark diversity (species that are currently absent from a site despite being ecologically suitable) demonstrates the negative effects of regional-scale anthropogenic activity on plant diversity.