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A bivalent biparatopic nanobody penetrates the brain, binds to and potentiates the activity of homodimeric metabotropic glutamate receptor 2, correcting cognitive deficits in two preclinical mouse models with endophenotypes resulting from NMDA receptor hypofunction.

The discovery of 510-million-year-old skeletal fragments that are thought to belong to an early armoured fish — probably one of the earliest-known vertebrates — may change accepted ideas about the evolution of the vertebrate skeleton.

Imaging of a Devonian jawless fish reveals advanced features previously thought to be exclusive to jawed vertebrates, challenging the idea that jaws were the primary driver for the evolution of derived traits in the vertebrate body plan.

High-throughput screening and hit optimization have led to the development of a small molecule, CIM-834, that targets the SARS-CoV-2 membrane protein and blocks assembly of the virus.

Drugs of abuse exert both motivational and emotional effects. Here, the authors show that nicotine and ethanol activate a VTA–NAc loop that inhibits dopamine neurons projecting to the amygdala, thereby inducing anxiety-like behavior and linking the reward and emotional circuits.

Opioid therapy is limited by analgesic tolerance and hyperalgesia. Here, the authors show that FLT3 in primary sensory neurons drives morphine tolerance and hyperalgesia while its inhibition improves morphine analgesia optimizing pain treatment.

Therapeutic administration of angiopoietin-like 4 prevents shock during Neisseria meningitidis infection or lipopolysaccharide-induced sepsis in mice.

Fossil data shed light on a debate about when vertebrate dental tissues arose by assigning an early sensory structure to arthropods rather than to vertebrates.

The presence of a pulmonary system in fossil coelacanths has only recently been identified, with little known about homologues in living species. Here, Cupello et al. confirm the presence of a lung in the extant species Latimeria chalumnaeand report its growth during different stages of development.

Using nanobodies labeled with FRET fluorophores, the authors show the presence and activation of GPCR mGlu2 and mGlu4 dimers in mouse brain samples and reveal that mGlu2–mGlu4 is the major form of mGlu4-containing dimers outside the cerebellum.

Phenothiazines inhibit Type IV pili function in Neisseria meningitidis and protect against bacterial colonization of blood vessels and lethality during infection.

G protein-coupled receptors are considered promising therapeutic targets. Here, the authors have identified nanobodies, or single-domain llama antibodies, that specifically enhance agonist-induced activity of a type of G protein-coupled receptor, the mGlu2 receptor.

The muscle-secreted, exercise-induced peptide hormone apelin decreases with aging and sarcopenia, and its repletion in aged mice with recombinant protein improves muscle mass and function.

Mice evolved a new shape in the upper, but not in the lower molar. In addition to developmental changes specific to the upper molar, this occurred through shared changes with the lower molar, the development of which has drifted to support upper molar adaptation.

This study identifies a novel immune checkpoint in senescent cells that is linked to the ganglioside GD3 and that contributes to the evasion of immune clearance by these cells and to aging and age-related diseases.

After myocardial infarction, inflammatory cells are rapidly recruited to the heart and strongly affect the course of recovery. Ziad Mallat and his colleagues uncover a pathogenic role for B cells after myocardial infarction, showing that infarction triggers B cell secretion of the chemokine Ccl7, which mobilizes monocytes from the bone marrow, increases their recruitment to the heart and impairs heart function.

Mice lacking the metabotropic glutamate receptor mGluR7 are hypersensitive to convulsant drugs. But how does mGluR7 act to prevent seizures? Here the authors show that interfering with the interaction between mGluR7 and the intracellular adaptor protein PICK1 causes a phenotype in mice and rats that is reminiscent of human absence epilepsy.

It is hypothesised that exposure to bovine spongiform encephalopathy through contaminated food could have resulted in a large proportion of latent variant Creutzfeldt-Jakob disease cases in humans. Here the authors demonstrate that inoculation with blood from non-symptomatic, vCJD infected humans, results in a unique prion-like disorder in mice and macaques.

Evolutionary biologists have floundered when trying to explain how the asymmetrical head of flatfishes came about. 'Gradually' is the answer arising from exquisite studies of 45-million-year-old fossil specimens.

Delval, Hantute-Ghesquier, Sencio and colleagues demonstrate that depletion of age-associated senescent cells decreases pulmonary viral load and ameliorates early and late lung COVID-19 in a hamster model of aging.

How nicotine impacts the adolescent development of neural circuitry is not fully understood. Here authors show that early adolescent nicotine exposure in male mice blocked the maturation of nicotine-evoked dopamine signaling, causing an immature, vulnerable behavioral response in adult mice. Restoring their adult-like nicotine-evoked signaling unmasks a mature behavioral response in male mice.

Perro and colleagues develop a CD3⁺ T cell engager co-targeting BCMA and CD38 to improve immunotherapy for multiple myeloma, demonstrate cytotoxicity in patient-derived samples and murine models and develop a quantitative systems pharmacology model.

A current challenge in genome editing is delivering Cas9 and sgRNA into target cells. Here the authors engineer a delivery system based on murine leukemia virus-like particles loaded with Cas9-sgRNA ribonucleoproteins to induce efficient genome editing in both cell culture and in vivo in mouse.

How aging influences peripheral immune cell infiltration and the role of these cells following traumatic injury of the CNS is unclear. Here, the authors show that aging transforms CNS-associated macrophages into regulators of immune cell trafficking after ischemic stroke, modulating neurological outcomes.

Tuz et al. report that stroke and myocardial infarction induce the release of neutrophil extracellular traps (NETs), triggering the loss of B cells and a decrease in immunoglobulin A secretion, and that inhibition of NETs prevents the loss of immunoglobulin A in mice and in patients with stroke.

Gut microbiome dysbiosis has been shown to alter the immune response to lung infection. Authors utilise a murine model to investigate if gut colonisation with carbapenemase-producing Enterobacterales altered the outcomes of Pseudomonas aeruginosa lung infection.

Sensitisation of dorsal root ganglia neurons contributes to neuropathic pain. Here the authors demonstrate the cytokine FL contributes to sensitisation of DRGs via its receptor FLT3 expressed on neurons, and identify a novel FLT3 inhibitor that attenuates neuropathic pain in mice.

Currently licensed COVID-19 vaccines are based on antigen sequences of early SARS-CoV-2 isolates, despite the prevalence of variants of concerns escaping vaccine-mediated protection. Using their updated yellow fever 17D vectored candidate, here, authors assess neutralising antibody responses against variants of concern, and demonstrate protection and reduced transmission in a hamster model.

Disease tolerance mechanisms counter the negative effects of infection without decreasing the pathogen load. Here, the authors show that in mouse models of malaria, such disease tolerance can be conferred by adrenal hormones, by preventing excessive inflammation and hypoglycemia.

Glucocorticoids reprogram the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and, as a consequence, inhibition of the inflammatory response.

Adipose tissue is composed of a variety of cell types, including adipocyte precursor populations, that contribute to adipose tissue function upon differentiation. Here, using scRNA-sequencing of adolescent and adult mouse subcutaneous adipose tissue, the authors identify an Asc-1 positive preadipocyte population that is enriched in adolescent subcutaneous fat and demonstrate that loss of Asc-1 triggers spontaneous beige adipocyte differentiation.

Deoxycytidine kinase is the rate-limiting enzyme of the salvage pathway and it has recently emerged as a target for antiproliferative therapies for cancers where it is essential. Here, the authors develop a potent inhibitor applying an iterative multidisciplinary approach, which relies on computational design coupled with experimental evaluations.

RUFY proteins are known to regulate autophagy, cytoskeletal dynamics, migration and endosomal trafficking. Here, Char et al. show that iRUFY3 plays a role in perinuclear positioning, phagocyte migration and antigen presentation during Salmonella infection.

For more than a century, scientists have pondered over mysterious fossils of an aquatic vertebrate, and argued about the type of creature this species represents. Newly analysed specimens might help to solve this puzzle.

Tissue-nonspecific alkaline phosphatase (TNAP) – a protein previously linked to atherosclerotic plaque calcification – is shown to dephosphorylate phosphocholine in the bloodstream and at the hepatocyte membrane to enable choline uptake by hepatocytes.

GnRH neurons control their own connectivity and function as well as the sexual maturation of the individual by using prostaglandin D₂ DP1 signaling to recruit and stably associate with newborn astrocytes in the preoptic region during infancy in rodents.

Chronic nicotine exposure impacts various components of decision-making processes, such as exploratory behaviors. Here, the authors identify the cellular mechanism and show that chronic nicotine exposure increases the tonic activity of VTA dopaminergic neurons and reduces exploration in mice.

Immune cells contribute to adverse remodeling following myocardial infarction. Here the authors show in mice and pigs that CD8⁺ lymphocytes release Granzyme B in the infarcted heart leading to cardiomyocyte death, enhanced inflammation and deterioration of cardiac function.