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Despite the importance of osteoclast secretory lysosomes in bone digestion, the proteins that regulate them remain ill defined. Here, the authors identify Slc37a2 as a secretory lysosome sugar transporter that is required for maintenance of skeletal bone mass.

The authors used deep learning to derive a biological clock based on routine blood markers in mice that distinguishes slow-aging from fast-aging animals. Drawing on data from the NIH Study of Longitudinal Aging in Mice and a study of aging at The Jackson Laboratory, this clock reveals that platelets are key in predicting biological age.

Temporal multi-omic analysis of tissues from rats undergoing up to eight weeks of endurance exercise training reveals widespread shared, tissue-specific and sex-specific changes, including immune, metabolic, stress response and mitochondrial pathways.

Intravascularly infused extracellular matrix from ventricular myocardium binds to leaky vasculature and induces the regeneration of inflamed heart tissue, as shown in rats and pigs.

Sun et al. report human lifespan changes in the brain’s functional connectome in 33,250 individuals, which highlights critical growth milestones and distinct maturation patterns and offers a normative reference for development, aging and diseases.

A microfluidics- and electron-microscopy-based method enables the characterization of polyclonal antibody responses to infection and vaccination.

A plate-based assay called CRAFTseq has been developed that uses ‘multi-omic’ single-cell RNA sequencing and direct genotyping of CRISPR edits to test the functional effects of genetic variants on cell state and function.

Long-acting injectable drugs for viral suppression of HIV are not yet available in African settings. Here, the authors present a mathematical modelling and cost effectiveness study of a long-acting drug combination in adults living with HIV in East, Central, Southern and West Africa.

Loss of tumor suppressor function is one of the major causes of uncontrolled growth of cancer cells. Here authors show that inactivation of the tumor suppressors NF1, TSC1, and TGF-β RII also promotes a non-cell autonomous change in the tumor microenvironment, characterized by inflammatory features and LAG3+ T cell-mediated immune suppression, which are therapeutically targetable.

In a mouse model of Rett syndrome, intensive training during the presymptomatic period markedly improves the performance of motor and memory tasks and delays the onset of symptoms, providing a rationale for the genetic screening of newborn babies.

A millimetre-scale bioresorbable optoelectronic system with an onboard power supply and a wireless, optical control mechanism is developed for general applications in electrotherapy and specific uses in temporary cardiac pacing.

There are dynamic interactions between immune cells and β cells that lead to β cell destruction in the context of autoimmune diabetes. Here the authors show that TET2, a methylcytosine dioxygenase, can regulate this interaction and deletion of TET2 can prevent the autoimmune destruction of β cells in mice.

Dengue is a major public health concern in the Americas, and the Caribbean can be a source for reintroduction and spread. Here, the authors use travel surveillance data and genomic epidemiology to reconstruct Dengue epidemic dynamics in the Caribbean from 2009-2022.

We provide two procedures to cover distinct approaches for the initiation of lymph node metastases in mice: one for studying the metastatic cascade in tumorigenic cells and the other for studying the effect of metastatic formations in the host.

Immune checkpoint inhibitors (CPI) could effectively target cancers that are resistant to traditional therapy but may initiate immune related adverse effects, such as colitis. Here, authors characterise the gut immune microenvironment during CPI-colitis by bulk RNA sequencing, single-cell RNA sequencing and flow cytometry, and find that interleukin 23 plays an important role in promoting inflammation via cytotoxic polyfunctional IFNγ-producing lymphocytes.

Here Ramanan and colleagues provide an analysis of mammary T cells during late pregnancy and lactation. This revealed an increase in intraepithelial lymphocytes in the lactating mammary gland, which was driven by thymic and intestinal inputs and was sensitive to changes in the microbiota

The oncogenic splicing factor TRA2β is reported to be upregulated in human cancers partly by increased TRA2β poison exon (PE) skipping. Here the authors show that forced inclusion of this PE using antisense oligonucleotides depletes TRA2β protein levels and generates long non-coding RNAs that sequester nuclear proteins, leading to cancer toxicity.

The mechanisms underlying adaptive response to the stress elicited by radiotherapy in glioma cells remains unclear. Here, the authors show that therapeutic ionizing radiation induces rapid genome-wide chromatin reorganization to facilitate P-TEFb-mediated nascent transcriptional induction, which could be targeted to sensitize radiotherapy response in glioma.

Zhang et al. use human studies and mechanistic work in mouse models to describe how leucine serves as the key amino acid derived from dietary protein to drive deleterious macrophage mTORC1 signalling and promote cardiovascular disease.

Corticosteroid therapy is frequently used for chronic obstructive pulmonary disease (COPD) but its use is associated with increased risk of pneumonia. Here the authors show that corticosteroid use impairs innate and adaptive immunity to rhinovirus infection, which is restored by exogenous IFNβ.

Single-cell transcriptomic and proteomic data from synovial tissue from individuals with rheumatoid arthritis classify patients into groups based on abundance of cell states that can provide insights into pathology and predict individual treatment responses.

There is ongoing debate about the effective combination of strategies for COIVD-19 control. Here, the authors use an agent-based model to quantify and compare several intervention strategies, and identify minimal levels of social distancing compliance required to control the epidemic in Australia.

The RNA-induced silencing complex (RISC) represses gene expression via micro-RNA guided mRNA silencing. Here, the authors show that RISC component Argonaute 2 in the liver regulates energy metabolism by inducing microRNAs that cause metabolic disruption and by suppressing protein translation linked to AMPK activation.

Pak et al. show that prolonged fasting is required for the effects of calorie restriction on insulin sensitivity, fuel utilization and ageing in mice.

Our quest to bring a child into our family led us to confront academic working practices, say Tony Ly and Nathan W. Bailey.

In a multicenter, single-arm, open-label phase 2 study of patients with previously treated metastatic uveal melanoma, treatment with tebentafusp, a soluble TCR bispecific (gp100xCD3) showed promising clinical activity with an acceptable safety profile.

Dengue is endemic in the Dominican Republic, and causes regular outbreaks, whereas Zika and chikungunya are emerging infections in the area. Here, the authors show that outbreaks of the emerging infections could not be predicted by seasonal dengue dynamics.

Mutations in the NRF2-KEAP1 pathway is found to be related with therapeutic resistance and poor outcomes of non-small cell lung cancer (NSCLC). Here this group reports that cystine/glutamate antiporter system xc−, controlled by NRF2, can be non-invasively imaged by positron emission tomography thereby providing a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC.

Selvakumar, Clayton et al. use a porcine model of myocardial infarction and PSC-CM transplantation and identify atrial and pacemaker-like cardiomyocytes as the cause of engraftment arrhythmias and surface marker signatures to distinguish between arrhythmogenic and non-arrhythmogenic cardiomyocytes.

Zhang et al. show that in mice, an adipocyte population with high expression of the transcription factor JunB in the brown adipose tissue shows reduced thermogenic capacity. Depletion of JunB increases the fraction of adipocytes with high thermogenic capacity and ameliorates diet-induced insulin resistance.

A bedside-to-bench analysis identifies single-chain variable fragment linker length as an important component of chimeric antigen receptor (CAR) structure and suggests that, in contrast to CD28-based CAR T cells, tonic signaling can be beneficial for 4-1BB-based CAR T cell function.

Orthologous therapeutic proteins can elude the adaptive immune system and allow for effective repeated dosing, as shown for CRISPR gene editing with orthologues of adeno-associated viral capsids and of the Cas9 protein.

Why joints are highly responsive to systemic inflammation is unknown. Hasegawa et al. sought to address this question, developing a whole-mount imaging system of the entire synovium to profile the vascular, neuronal and immune components.

A connectome of the right optic lobe from a male fruitfly is presented together with an extensive collection of genetic drivers matched to a comprehensive neuron-type catalogue.

The mechanisms of intratumoral subtype heterogeneity in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, the authors analyse PDAC tumours and preclinical models using multi-omics and imaging; they demonstrate that AP1 dichotomy influences tumor plasticity, heterogeneity, and immune response, with potential therapeutic implications.

This is a post hoc 18-month follow-up analysis of the CRB-401 trial, testing idecabtagene vicleucel (ide-cel, bb2121) in relapsed and refractory multiple myeloma, and reports sustained safety and clinical efficacy, which correlates with T cell phenotypes.

Analysis of 4,041 single-nucleotide variants (SNVs) linked to 13 cancers performed in primary human cell types identifies 380 potentially regulatory SNVs and their putative target genes. Editing one SNV, rs10411210, revealed that the risk allele increases RHPN2 expression and stimulus-responsive RhoA activation.

Siliciano and colleagues describe the generation of bispecific antibodies that target the HIV-1 envelope protein (Env) on the surface of HIV-1-infected cells and the receptor CD16 on the surface of NK cells to induce the NK cell-mediated lysis of HIV-1-infected cells and reduce the viral reservoir.

Many of the factors underlying malaria pathogenesis are not well understood, including protection from the development of febrile symptoms. Here, Van Den Ham et al. show that susceptibility to febrile malaria is associated with the composition of the gut microbiome prior to the malaria season in 10-year-old Malian children, but not in younger children.

Fas drives apoptosis and mutations in this receptor can cause autoimmunity through failure of cell death. Here, the authors uselpr/lprmice with palmitoylation-defective mutant Fas to provide evidence that Fas might limit spontaneous autoimmunity through a non-apoptotic mechanism.

Here the authors show that Omicron neutralizing antibody titers decline over time in mice immunized with a wild-type (WT) lipid nanoparticle (LNP)-mRNA vaccine and are robustly increased by WT or Omicron LNP-mRNA and that Omicron boosters elicit higher BA.1-neutralizing titer than WT boosters.

Removal of senescent cells rejuvenates lungs of aged mice. Here the authors show that elimination of senescent cells using either genetic or pharmacological means improves lung function and physical health in a mouse model of idiopathic pulmonary fibrosis (IPF), suggesting potential therapy for treatment of human IPF.