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Accumulation of intermediates of haem biosynthesis, porphyrins, is harmful and usually inherited, but it is unclear how the same mutation may make some individuals more ill than others. Here, the authors show that a porphyrin transporter ABCB6 is a modulator of porphyria, and that patients with functionally defective ABCB6 show more severe symptoms.

The emergence of acquired resistance to standard platinum-etoposide chemotherapy in small cell lung cancer (SCLC) is a common event. Here, the authors using paired pre-treatment and post-chemotherapy circulating tumour cell patient-derived explant (CDX) models reveal a mechanism of drug resistance in SCLC mediated by Notch and nitric oxide activation of soluble guanylate cyclase signalling.

Mohammad et al. show that prenatal alcohol exposure increases Kcnn2 activity in the mouse cerebral cortex. Blockade of Kcnn2 improves learning deficits in a mouse model of fetal alcohol spectrum disorders.

A novel study led by scientists in Lübeck, Germany, shows that SARS-CoV-2-infected brain endothelial cells undergo cell death due to the cleavage of NEMO by the viral protease M^pro, potentially causing cerebral COVID-19 and ‘long COVID’ symptoms.

The regeneration dynamics following peripheral nerve injury differs among species. Here, the authors compared transcriptomic and lipid metabolism changes in murine and human Schwann cells in vivo and ex vivo sural nerves, underlying their switch from myelinating to repair state following injury.

Neuron types vulnerable to tau accumulation (excitatory neurons) in AD brain are intrinsically less able to maintain tau homeostasis than neuron types that are resistant (inhibitory neurons).

Systemically injected lipid–polymer nanoparticles encapsulating small interfering RNA for silencing genes in bone-marrow endothelial cells of mice improved the healing of the mice after myocardial infarction.

FXR1P is a RNA binding protein involved in muscle development. Here, the authors show that mutations in FXR1 exon 15, which is alternatively spliced in muscle, cause multi-minicore myopathy in humans and in mouse models.

Noninvasive cardiac radiotherapy may effectively manage ventricular tachycardia in refractory patients, but its radiobiologic mechanisms of action are unclear. Here, the authors show that photon radiation durably and favourably reprograms cardiac conduction in the absence of transmural fibrosis suggesting this could be the mechanism through which cardiac radiotherapy to modulates arrhythmia susceptibility.

Impaired adipocyte insulin signalling characterizes insulin resistance. Here the authors show that the hormone-sensitive lipase can sequester the glucose-responsive transcription factor ChREBP in the cytoplasm, which prevents transcription of its target ELOVL6, resulting in reduced insulin signalling.

Besnard et al. uncover functional heterogeneity of somatostatin interneurons (SST-INs) in the dorsolateral septum and reveal a role for a subpopulation of SST-INs as hippocampal relays that govern mobility to calibrate adaptive fear responses.

Loss of Trem2 function increases early amyloidogenesis by preventing microglial activation and clustering around amyloid seeds. As a consequence of reduced microglial ApoE production in the absence of Trem2 function, amyloid plaques contain less ApoE.

Genetic variants in ACTB and ACTG1 have been associated with Baraitser-Winter Cerebrofrontofacial syndrome. Here, the authors report of a syndromic thrombocytopenia caused by variants in ACTB exons 5 or 6 that compromise the organization and coupling of the cytoskeleton, leading to impaired platelet maturation.

Niemann–Pick disease is characterized by the cellular accumulation of sphingomyelin. Blumberg and colleagues use both mouse models and materials from patients with Niemann–Pick disease to show that sphingomyelin accumulation inhibits CD1d-restricted NKT cell activation and development.

Thermogenic adipose tissue has been suggested as a potential target to treat metabolic diseases. Here, Tran et al. show that a long noncoding RNA, LINC00473, is induced during activation of thermogenic adipocytes and regulates energy metabolism through interorganelle communication.

Oxidized host-derived phospholipids such as oxPAPC can play important roles in atherosclerosis. Zanoni and colleagues demonstrate that oxPAPC generates a distinctive metabolic and hyperinflammatory profile in macrophages that can drive atherosclerosis in mice.

Melanosomes traffic along F-actin in melanocytes. Here, the authors show that Rab27a coordinates SPIRE/FMN actin assembly and MyoVa motor proteins to generate a cell-wide actin/myosin network that links melanosomes and allows the collective activity of these force generators to drive their traffic.

Endurance exercise is associated with an increased risk of atrial fibrillation. Here, the authors show the adipokine TNFα is a crucial mediator of exercise-induced atrial fibrillation and irreversible atrial remodelling characterized by fibrosis and inflammation.

CAPZA2 deficiency impairs synaptic structure in the hippocampus and prefrontal cortex and disrupts synaptic protein expression, leading to cognitive and other behavioral abnormalities, revealing its critical role in brain development and function.

It is unclear if multiple sclerosis (MS) genetic susceptibility can be mediated through perturbations of CNS-intrinsic pathways. Authors show that the rs7665090 risk variant is associated with astrocyte responses that enhance lymphocyte recruitment, and with increased lymphocyte infiltration and lesion sizes in MS lesions.

A microfluidic assay predicts the metastatic potential of breast cancer specimens by quantifying the abundance and proliferative index of the migratory cells within them.

The lack of animal models for some human diseases precludes our understanding of disease mechanisms and our ability to test new therapies in vivo. Here the authors present a tissue bioengineering strategy for the study of a rare kidney tumor called angiomyolipoma, in vitro and in vivo, using patient-derived hiPSCs.

Biomarkers to indicate potential response to biologic therapeutics are needed for patients with psoriasis. Here the authors show that phosphorylation of NFκBp65 in cDC2 before therapy is an indication of non-response to the anti-TNF therapy adalimumab in patients with psoriasis.

Molecular mechanisms controlling axonal growth cone behaviour are only partially understood. Here the authors reveal a role of an adaptor protein GIPC1 in Plexin-D1 receptor recycling, and show that this process is required for axon track formation and vascular patterning in mice.

Hypoxic brain damage associated with premature birth causes lasting neurological impairments. Here, the authors use environmental enrichment to rescue white matter dysmaturation following hypoxia, while identifying a critical window of intervention and oligodendrocyte-specific changes in gene expression.

The mechanism of force production by invadopodia is unclear. Here, the authors show that cell surface MT1-MMP when in contact with collagen, induces Arp2/3 branched actin polymerisation on the concave side of invadopodia, which generates a pushing force along with collagen cleavage by MT1-MMP to invade.

Parvalbumin and somatostatin expressing interneurons mediate lateral inhibition between cortical neurons. Here the authors report the mechanisms by which acetylcholine from the basal forebrain selectively augments lateral inhibition via Martinotti cells and show that this is conserved in humans.

The mechanism underlying endothelial cell responses to BMP signals is unknown. Here, the authors show that the endothelial response to pro-angiogenic BMP ligands is regulated by Notch via its effect on SMAD6, a known inhibitor of BMP intracellular signaling cascade.

Ascorbate depletion in mice increased haematopoietic stem-cell frequency and promoted leukaemogenesis, partly by reducing the function of the Tet2 tumour suppressor enzyme.

Th17 cells are involved in the pathogenesis of several inflammatory diseases. Here, the authors show that inhibitors of the pro-inflammatory cytokine TNF, used in patients undergoing anti-inflammatory treatment, might mediate the acquisition of anti-inflammatory properties by these typically pathogenic cells.

Metabolic pathways are increasingly recognized as crucial determinants of T cell function. Here the authors show that the balance between IFNγ and IL-10 production in human CD4 T cells is modulated by the cholesterol biosynthetic pathway.

Barak et al. show that deletion of Gtf2i, a gene deleted in Williams syndrome, from the excitatory neurons of the forebrain reduced myelin thickness and axonal conduction. Rescuing myelination with a US Food and Drug Administration-approved drug restored normal behavior.

The cytokine oncostatin M drives intestinal inflammation in mice, and its abundance in the intestine of patients with inflammatory bowel disease predicts response to tumor necrosis factor–neutralizing therapy.

Complement, while serving to remove pathogens in the circulation, is also important for synergizing with inflammasomes to modulate CD4 T cell activation. Here the authors show that CD46, a complement receptor expressed only in humans, is essential for inducing optimal activation and effector functions of human CD8 T cells.

Glucocorticoids (GC) are reported to block cancer cell proliferation, but the mode of action is unclear. Here the authors show that glucocorticoid receptor activation induces cancer cell dormancy in lung cancer by regulating CDKN1C expression through a distal enhancer, and these dormant cells are addicted to IGF-1R signalling pathway.

Z-lock is introduced as a new method to control protein activity with light. It relies on a steric block placed over important regions of the target protein that can be released reversibly. Z-lock was applied to regulate cofilin and αTAT activity.

ABCC9 encodes the SUR2 subunit of K_ATP channels and dominant genetic variants in ABCC9 have been associated with cardiac phenotypes. Here, the authors report recessive ABCC9 mutations in individuals with mild intellectual disability, myopathy and cardiac systolic dysfunction which is associated with loss of K_ATP channel function.

During red blood cell infection, malaria parasites export hundreds of proteins that remodel the host cell surface. Cowman and colleagues identify a putative protein translocator complex spatially associated with exported proteins, revealing the cellular domains involved in protein export.

The clinical benefit of anti-PD-1 antibody treatment is dependent on the extent to which exhausted CD8 T cells are reinvigorated in relation to the tumour burden of the patient.

Immunological stressors are linked to the transformation of preleukemic B cells to B-cell acute lymphoblastic leukemia. Here the authors show a dysregulation of innate immune signaling in preleukemic precursor B cells and link to the development of B-cell acute lymphoblastic leukemia in a murine model.