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RNAi therapy has huge potential but effective delivery to target location is a major issue. Here, the authors report on the delivery of RNAi to tumors using self-agglomerating nanohydrogels that can overcome the different delivery barriers and supply multiple RNAi payloads.

The distinct architecture of the Escherichia coli membrane transporter LetA mediates lipid trafficking across the bacterial envelope in partnership with the tunnel-like complex LetB.

Cocaine chemogenetics in rats is a selective approach for countering drug reinforcement by clamping dopamine release in the presence of cocaine.

Therapeutic options for patients with renal medullary carcinoma (RMC) are limited. Here the authors report the results of a phase II clinical trial of anti-PD1 nivolumab plus anti-CTLA4 ipilimumab in RMC, associating the activation of a myeloid mimicry program in tumor cells to the rapid disease progression and hyper-progression observed in treated patients.

The neurobiological mechanisms underlying the fast acting and long-lasting effects of these drugs are not fully understood. Here authors show that the psychedelic psilocin increases reactivity in the paraventricular nucleus of the hypothalamus (PVN) in male rats but does not change acute stress response. Male reactivity changes are driven by active threat responding, with clinical implications.

CaBLAM is a bioluminescent genetically encoded calcium indicator that delivers high-contrast signals as shown in cell culture, in the in vivo mouse brain and in zebrafish larvae.

Antibodies that block the Wnt inhibitors sclerostin and DKK- 1 enhance bone formation and fracture repair. Here the authors show these monospecific antibodies induce compensatory mechanisms that limit efficacy, and have designed a sclerostin/DKK-1 bispecific antibody that promotes superior fracture repair in rodents and bone formation in primates.

Selective activation of the hepatoportal nerve plexus via peripheral focused ultrasound stimulation improves glucose homoeostasis and enhances glucose tolerance and utilization in rodent models of diabetes and in swine.

The precise control of interfacial bonding between engineering materials and biological tissues is essential for in vivo uses but remains elusive. Here, the authors report an interface-enhanced strategy by spatial and temporal anchoring of magnetic nanostickers for controlled bioadhesive properties.

Artemisinin-resistantPlasmodium is an increasing problem. Here, using a medicinal chemistry programme, the authors identify a tetraoxane-based drug candidate that shows no cross-resistance with an artemisinin-resistant strain (PfK13-C580Y) and is efficient in Plasmodiummouse models.

Choroid plexus produces the cerebrospinal fluid (CSF) that serves as the brain dispersion route for nutrients and waste products. Here, the authors show that CSF secretion remains high in aging rats with intact choroid plexus morphology, gene expression, and high metabolic rate.

The enteric nervous system regulates gut function but is difficult to study due to sparse neuron distribution and gut motion. Here, the authors showcase a bioelectronic implant for electrophysiological monitoring of the enteric neural activity in freely-behaving animals.

The effects of SAP97 mutations associated with schizophrenia on synaptic function are unclear. Here, the authors show that schizophrenia-related SAP97 mutations enhance glutamatergic synapse strength in the dentate gyrus, impairing contextual episodic memory in rats.

Prabhakar et al. demonstrate in rats with mitomycin C-caused pulmonary veno-occlusive disease activation of protein kinase R (PKR) and the integrated stress response (ISR), leading to the depletion of VE-cadherin and RAD51 from endothelial junctions, endothelial barrier disruption and vascular remodeling. Inhibiting the PKR–ISR axis protects against mitomycin C-induced endothelial damage.

Photovoltaic devices attached to immune cells travel through the blood to inflamed brain regions.

The role of bile acid receptor TGR5 in feeding regulation remains elusive. Here, authors show that physiological and pharmacological activation of TGR5 in the nucleus of the solitary tract lowers feeding and enhances leptin signaling in rats.

Magnetic resonance imaging (MRI) is widely used to study the rat brain. Here, the authors provide standardized MRI brain templates and descriptive atlases for the rat, incorporating both structural and functional MRI data, along with associated resources.

The intravenous injection of oxygen via polymeric microbubbles that are stable in storage yet quickly dissolve following intravenous injection led to the maintenance of critical oxygenation and to improved survival in swine with profound hypoxaemia.

Antiretroviral therapy (ART) for the treatment of HIV-1 requires life-long daily adherence to supress viral replication, and nucleoside reverse transcriptase inhibitors that are commonly used in ART have not been converted into long-acting agents. Here, the authors report two lipophilic tenofovir (TVF) ProTide nanoformulations, NM1TFV and NM2TFV, which sustain drug levels above therapeutic concentrations for two months after a single intramuscular dose in rats.

[¹⁸F]OXD-2314 is a brain penetrant positron emission tomography radiotracer with high affinity for tau aggregates in Alzheimer’s disease (AD) and non-AD tauopathies based on in vitro and in vivo studies, and is suitable for first-in-human use.

Many genetic variants have been associated with body size, but the contribution of copy number of rDNA is unknown. Here, the authors explore the association between rDNA copy number and body size in both rats and humans, finding that lower rDNA CN is associated with higher weight and BMI.

The p3 peptide, Aβ(17-40/42), rapidly forms amyloid fibrils by secondary nucleation which cross-seeds with full-length Aβ peptide. Furthermore, p3 annular and oligomer structures are cytotoxic, disrupt membrane integrity and form ion-channel pores.

Nanoscale membrane lipid domains are emerging as important regulators of ion channel function. This study highlights their role in modulating pacemaker HCN channels in sensory neurons, revealing a mechanism that may contribute to neuropathic pain.

MIPS521, a positive allosteric modulator of the adenosine A₁ receptor, has analgesic properties in a rat model of neuropathic pain through a mechanism by which MIPS521 stabilizes the complex between adenosine, receptor and G protein.

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.

Sequential drinks of crosslinker and polymer solutions form a tough hydrogel in the stomach, enabling delivery of drugs and biologics in this harsh chemical environment.

Here, the authors investigate the proteome trajectory of human iPSCs differentiating into hepatic stellate cells (diHSCs) and identify RORA as a key transcription factor that governs metabolic reprogramming essential for diHSCs’ commitment, identity, and quiescent phenotype.

The brain is sensitive to oxygen deprivation. Here, the authors show in experimental animals that sensitivity to hypoxia is inversely related to the level of sulfide:quinone oxidoreductast (SQOR) and the capacity to catabolize sulfide in the brain.

Acoustically activatable nanocarriers made by incorporating 5% sucrose into liposomes release drug with low-intensity ultrasound, providing a readily clinically translatable system for both central and peripheral noninvasive neuromodulation.

Implanting an electrode into the cortex activates microglia, triggers the foreign body response, and impedes intracortical brain-computer interface. Here, the authors apply low-intensity pulsed ultrasound stimulation (LIPUS) after probe insertion to reduce microglia-mediated neuroinflammation.

Acute bronchoconstriction is the leading cause of asthmatic sudden death following allergen exposure. The authors show that the systemic increase of LPA following inhaled allergen or bradykinin challenge activates the carotid bodies through TRPV1 and LPA-specific receptors and that systemic TRPV1 and LPA-specific receptor antagonists ameliorate acute bronchoconstriction.

Tools for imaging and manipulating proteins in their native environments are critical to understand their function. Here, the authors develop antibody-based probes to visualize and manipulate AMPA-type glutamate receptors in neurons.

The ability to encode and recall information about food is critical for survival. We reveal that ventral hippocampus projections to the lateral hypothalamus encode meal-related memories, and that disruption of this circuit promotes excessive eating.

A small molecule identified from high-throughput screening and optimization specifically stabilizes a disease-linked CLRN1 protein, delivering it to its site of action at the plasma membrane and preserving hearing in a new mouse model for Usher syndrome type III.