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The differentiation of naive T cells to immune suppressing induced regulatory T (iTreg) cells requires TGF-beta-1 and downregulation of mTORC1 activity, which inhibits mRNA translation. Here the authors show that iTreg cell differentiation uses an alternate mRNA translation mechanism involving translation factors DAP5 and eIF3d.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

SIRT1-driven deacetylation of the MED1 subunit of the Mediator complex under stress modifies gene expression by enhancing RNA polymerase II action, promoting survival and growth of estrogen-receptor-positive breast cancer cells.

Pluripotent stem cells depend on specialized nuclear organization for their function. Here, the authors show that DDX18 regulates nucleolar phase separation and chromatin architecture to preserve human embryonic stem cell pluripotency.

It remains critical to understand the genomic events in response to treatment of oesophageal adenocarcinoma (OAC). Here, the authors perform a multi-omics analysis of OAC patients from the DOCTOR phase II clinical trial, finding genomic features and immune clusters associated with survival.

Current therapeutic strategies for vitamin D-induced hypercalcemia are poorly efficient. Here the authors identify a new interaction between the vitamin D receptor (VDR) and WBP4 controlling the subcellular localization of VDR and show that ZK168281, a VDR antagonist, enhances the interaction between VDR and WBP4 blunting VDR signalling and normalizing calcium levels in vitamin D-intoxicated mice.

In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

Nipah virus is a WHO priority pathogen, and there is currently no approved drug for clinical therapy. Here, the authors identified potent human neutralizing antibodies that block receptor binding and provide protection against NiV infection in vivo.

Activation of the PPARγ/RXRα pathway in luminal bladder cancers has mainly been linked to PPARG gene amplifications and activating point mutations in RXRα. Here, the authors identify recurrent PPARγ mutations with similar effects and elucidate the structural basis for this mutational PPARγ activation.

The covid pandemic has highlighted the need for rapid antibody development. Here, authors develop an approach called SLISY, which uses NGS with phage display to simultaneously assess millions of clones to rapidly isolate specific antibodies against SARS-CoV-2 and its evolving variants.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

SARS-CoV-2 variants of concern continue to emerge, reducing vaccine efficacy and limiting therapeutic options. Here, Chen and colleagues describe the identification and design of shark nanobodies with pansarbecovirus activity.

The role of interferon-γ (IFNγ) in anti-viral immunity has been unclear. Here the authors show that bacterial-induced or intranasally administered IFNγ effectively restricts SARS-CoV-2 infection in mice through effects on non-hematopoietic cells.

Loss or over-expression of Grainyhead-like transcription factors (Grhl) prevents closure of the neural tube but the mechanism underlying this is unclear. Here, the authors show that Grhl2 regulates murine posterior-neuropore closure via changes in the identity and biomechanics of the non-neural, surface ectoderm cells.

Analysis of whole genomes of four fox species shows that introgression facilitated adaptation to the hot arid environment of the Sahara Desert and suggests renal water homeostasis as a mechanism of adaptation in the extreme desert specialist species.

Excess macrophage elastase MMP-12 is a major driver of chronic obstructive pulmonary disease. Here the authors show that the endolysosomal ion channel TRPML3 is a regulator of the cellular reuptake of MMP-12, thus neutralizing harmful MMP-12 in the lung.

Here, the authors characterize the microbiome and resistome in a longitudinal cohort of 159 international students visiting the Andean city of Cusco, Peru. They find that international travel associates with spread of antimicrobial resistance, and that travelers’ diarrhea increases a persons’ risk for acquiring antimicrobial-resistant pathogens, while a diverse, “healthy” microbiome can be protective against diarrhea.

TASL is an adaptor molecule bridging Toll-like receptor signalling and transcription activation by IRF5. Here the authors show that TASL deficiency impacts TLR7/9 responses, and that a TASL paralogue, Gm6377/TASL2, also contributes to IRF5 activation, as dual TASL/TASL2 deficiency dampens both protective and pathogenic inflammatory responses in mice.

The role of mutations within long noncoding RNAs (lncRNAs) exons on tumour cell fitness remains to be explored. Here, the authors investigate the landscape of driver lncRNAs in primary and metastatic samples and validate the functional significance of single nucleotide variants in the NEAT1 oncogene in vitro and in vivo.

Until today, genetic tools have been lacking to enable manipulation of amoebal giant viruses (GVs) by CRISPR/Cas9 technology. Here, Bisio et al. apply S. pyogenes Cas9 together with pU6- driven guide RNAs to investigate the replication of pandoravirus, a GV replication in the nucleus. Using this tool, they provide evidence for stepwise evolution and genetic expansion of viral gigantism.

SARS-CoV-2 vaccination has shown reduced efficacy in patients with haematological malignancies. Here, the authors show that a third vaccine is able to enhance SARS-CoV-2 antibody responses in most cases in a cohort of 381 patients with haematological malignancies.

Creative experiences such as dance, music, drawing, and strategy video games might preserve brain health. The authors show that regular practice or short training in these activities is linked to brains that look younger and work more efficiently.

FHL1A is a crucial host factor for alphavirus infection but its impact on pathogenesis is unclear. Here, the authors use a FHL1−/− knockout mouse model to show that the FHL1 splice variant impacts arthritis and myositis after chikungunya or o’nyong-nyong infections but not Ross River or mayaro virus infection.

Antibodies play a crucial role in protection from influenza virus infection, but functional details, particularly in older adults, are incomplete. Here the authors show that NK cell-activating antibodies are associated with protection from influenza infection in vaccinated older adults.

Oral immunotherapy (OIT) clinical trials have helped a subset of participants achieve sustained unresponsiveness (SU) to the cognate allergen. Here the authors analyse immune cells from participants from one peanut OIT trial and show that CD8⁺ T cell differentiation status at baseline may help to predict the likelihood of achieving SU.

GEMIN5, an RNA-binding protein, is required for formation of small nuclear ribonucleoproteins. Here, the authors identify loss of function mutations in GEMIN5 that are associated with a human neurodevelopmental disorder.

Invasive non-typhoidal Salmonella (iNTS) infections are dominated by antibiotic resistant isolates of the sequence type (ST) 313. Here, the authors identify the ST313 sublineage II.1 in the Democratic Republic of the Congo exhibiting extensive drug resistance and genetic signatures potentially associated with host adaptation.

Genomic surveillance has been important for tracking the evolution and spread of SARS-CoV-2. Here, the authors analyse ~300,000 SARS-CoV-2 genomes from two years of sequencing in the Latin America and Caribbean regions and describe the emergence and spread of different lineages over time.

DNA methylation turnover is an essential epigenetic process during development. Here, the authors look at the changes in DNA methylation during the differentiation of post-mitotic human monocytes (MO), and find that EGR2 interacts with TET2 and is required for DNA demethylation at its binding sites; revealing EGR2 as an epigenetic pioneer factor in human MO.

This work integrates duplex sequencing with cost-effective Ultima sequencing to enhance the accuracy of whole-genome circulating cell-free DNA profiling.

Neuromuscular junctions (NMJs) are denervated in amyotrophic lateral sclerosis (ALS) through unknown mechanisms. Here, the authors show immune cells infiltrating muscle of ALS patients and mouse models, driven by CCL2-CCR2, which can be blocked to protect NMJs.

The IRE1α-XBP1 arm of the unfolded protein response (UPR) has been associated with immunosuppression and cancer progression. Here the authors show that IRE1α-XBP1 activation is associated with poor overall survival in patients with non-small cell lung cancer and that IRE1α loss in cancer cells promotes anti-tumor immune responses in lung cancer preclinical models.

Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

The activity of PD-1 blockade in patients with sarcoma has been modest so far. Here, the authors report the results of a pilot clinical trial to assess the efficacy and safety of bempegaldesleukin, a CD122-preferential interleukin-2 (IL-2) pathway agonist, in combination with the PD1 blockade (nivolumab) in patients with locally advanced or metastatic high-grade sarcoma.

The use of automated tools to reconstruct lipid metabolic pathways is not warranted in plants. Here, the authors construct Plant Lipid Module for Arabidopsis rosette using constraint-based modeling, demonstrate its integration in other plant metabolic models, and use it to dissect the genetic architecture of lipid metabolism.

Antibodies against SARS-CoV-2 can be used to treat infections but there is a risk of driving viral resistance to antibodies. Here the authors characterise SARS-CoV-2 escape mutants from an immunocompromised patient treated with anti-SARS-CoV-2 antibodies using mouse protection studies and structural prediction.

Anaplastic lymphoma kinase (ALK) inhibitors are currently being considered in neuroblastoma (NB), but its acquired resistance is reported in non-small cell lung cancers. Here, the authors have found PIM1 overexpression decreases sensitivity to ALK inhibitors in NB and combined ALK and PIM1 inhibition enhances anti-tumour efficacy in vitro and in PDX models.

The TGFβ signaling pathway has been shown to regulate transcription by regulating enhancer activity. Here, the authors perform a comprehensive analysis of enhancers in normal mammary epithelial gland cells to elucidate how TGFβ-dependent enhancers control gene transcription in these cells.

p62 is a signaling hub protein that contributes to the control of energy expenditure. Here the authors investigate the relative roles of p62 and a similar protein, NBR1, and show that NBR1 is required for the repression of thermogenesis in adipocytes occurring in the absence of p62.

Cytotoxic T lymphocytes (CTLs) eliminate virus-infected and cancerous cells by secreting the pore-forming protein (perforin) and pro-apoptotic serine proteases (granzymes). Here authors show that two mechanisms protect the membranes of CTLs from disruption by perforin and granzymes.

Here, the authors show in a cohort of people with HIV, COVID mRNA vaccination is followed by a transient boost in a particular profile of HIV-specific T-cell responses and a corresponding decrease in residual HIV RNA – suggesting productive immune engagement with infected cells.

Protein level information enables the identification of potential biomarkers and therapeutic targets for breast cancer. Here, the authors perform proteomic analysis of 2 cohorts of breast cancer surgical specimens and identify distinct subtypes, immune features and survival outcomes.

Obesity encompasses numerous interconnected pathological mechanisms. Here, the authors show that integrating multi-omics data uncovers distinct molecular profiles and prenatal factors linked to childhood obesity and metabolic dysfunction, providing insights for early prevention and intervention strategies.

The dynamics of DNA replication factors is crucial for cell cycle progression. Arabidopsis encode two origin recognition complex 1 proteins, ORC1a and ORC1b, with distinct roles in DNA replication and deposition of heterochromatic H3K27me1, respectively.

Neutrophil-mediated drug delivery has been investigated as a therapeutic approach for brain tumors. Here the authors report the anti-tumor activity of chlorotoxin-directed CAR neutrophils delivering chemodrug-loaded nanoparticles in preclinical glioblastoma models.

A chemical probe BI-9321 for the PWWP1 domain of NSD3 and its inactive analog were identified. BI-9321 binds to the methyl-lysine binding site, reduces the association of NSD3 with chromatin and inhibits proliferation of acute myeloid leukemia cells.

Finding positive meaning in past negative events is associated with enhanced mental health. Here the authors show this adaptively updates memory, leading to enhanced positive emotion and content at future retrieval, which remains two months later.

Cystathionine beta-synthase is a conserved essential enzyme of one-carbon metabolism. Here, the authors show that the enzyme oligomerises to form filaments that undergo conformational and morphological changes in response to its activator S-adenosyl-L-methionine, the global methyl donor.

There are no approved interventions for Hendra or Nipah viruses. Here, the authors isolate a G glycoprotein-specific antibody with cross-neutralizing and in vivo protective activities, and structurally resolve its binding pattern to the G protein.