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Oligodendrocytes are critical for brain myelination and repair. Here, the authors show that erythropoietin enhances oligodendrocyte lineage progression, promoting myelination through transcriptional regulation.

In this Protocol, three dual adeno-associated viral strategies for delivery of large transgenes are presented—by reconstitution at the genomic, transcript or protein level—together with instructions for the design, production and evaluation of dual adeno-associated viral vectors.

Large-footprint, low-sensitivity charge sensors hinder scaling semiconductor quantum dot arrays for quantum computation. Here the authors present a potentially scalable approach using multiplexed gate-based readout and operation in a foundry-fabricated quantum dot array, demonstrating single-electron occupancy.

Myelin is formed of proteins of long half-lives. The mechanisms of renewal of such a stable structure are unclear. Here, the authors show that myelin integrity requires continuous myelin synthesis at the inner tongue, contributing to the maintenance of a functional axon-myelin unit.

The involvement of cAMP-dependent regulation of HCN4 in the chronotropic heart rate response is a matter of debate. Here the authors use a knockin mouse model expressing cAMP-insensitive HCN4 channels to discover an inhibitory nonfiring cell pool in the sinoatrial node and a tonic and mutual interaction between firing and nonfiring pacemaker cells that is controlled by cAMP-dependent regulation of HCN4, with implications in chronotropic heart rate responses.

This study demonstrates that cryo nanoscale secondary ion mass spectrometry (CryoNanoSIMS) enables direct multi-elemental imaging at subcellular resolution of macro- and micronutrients or trace elements in plants and may provide insights into the in vivo roles of many transporters.

In vertebrate vision, the two types of photoreceptors, rods and cones, operate under low and bright light intensities, respectively. Here the authors show that under bright light conditions, when rods are not sensing light, they act as relay cells for cone-driven surround inhibition.

Direct interaction between the small GTPase Rab7a and the cation channel TPC2 has been reported but the functional regulation is less clear. Here, the authors show that Rab7a enhances the activity of TPC2 to promote melanoma progression through the GSK3β/β-Catenin/MITF axis.

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.

Mutations in the RyR1 channel cause core myopathies. Here the authors show that ER stress and the unfolded protein response underlie the pathology caused by a common RyR1 channel mutation, and show that treatment with a chemical chaperone restores muscle function in mice.

Bennu’s surface presents evidence of a variety of particle sizes, from fine regolith to metre-sized boulders. Its moderate thermal inertia suggests that the boulders are very porous or blanketed by thin dust. Bennu’s boulders exhibit high albedo variations, indicating different origins and/or ages.

Light increments and decrements are encoded in the retina by ON and OFF ganglion cells. The polarity of these cells' responses is thought to be fixed, but Tikidji-Hamburyan and colleagues now demonstrate in mouse and pig retina that they can change depending on ambient illuminance. For instance, an OFF cell can gain or lose an ON response at different light levels. Such changes in response polarity propagate to higher visual centers in vivo.

The interplay between amyloid and tau pathology in Alzheimer’s disease is still not well understood. Here, the authors show that amyloid-related increased in soluble p-tau is related to subsequent accumulation of tau aggregates and cognitive decline in early stage of the disease.

Two-pore channel 2 has been implicated in coupling changes in cellular energy status with endolysosomal function. Grimm et al.show that mice lacking this channel display defects in endolysosomal trafficking of LDL-cholesterol and are susceptible to hepatic cholesterol overload and fatty liver disease.

Mucolipidosis type IV is a lysosomal storage disorder caused by mutations in the endolysosomal cation channel TRPML1 and results in progressive neurodegeneration. Here, Chen et al. demonstrate that small molecules can be used to restore TRPML1 mutant channel function and rescue disease-associated symptoms.

An abnormal cardiac action potential underlies different types of cardiac arrhythmias. Here the authors show that microRNA-365 regulates the cardiac action potential by modulating key cardiac repolarizing channels.

Clinical multi-omics data are integrated and analyzed using a generative deep-learning model.

α-ketoglutarate (αKG) is an intermediate in the tricarboxylic acid cycle that is required in the nucleus for genomic DNA demethylation by Tet3. Here, the authors show that the enzyme glutamate dehydrogenase, which converts glutamate to αKG, is redirected from the mitochondria to the nucleus.

The direct measurement of the QCD dead cone in charm quark fragmentation is reported, using iterative declustering of jets tagged with a fully reconstructed charmed hadron.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known for their role in controlling the rhythmic activity of cardiac pacemaker cells and spontaneously firing neurons. They are now emerging as interesting targets not only for the development of drugs to lower heart rate but also for the treatment of diseases related to impaired neuronal activity, such as epilepsy and neuropathic pain.

Individuals with young onset sporadic Alzheimer’s disease show faster pathological and clinical progression. Here the authors report that earlier symptom onset in Alzheimer’s disease is associated with higher tau pathology in globally connected brain hubs, accelerated connectivity-mediated tau spreading and faster cognitive decline.

Large genes require dual adeno-associated viral (AAV) vectors for in vivo delivery/expression, but current methods have limitations. Here the authors develop and functionally evaluate REVeRT, an efficient and flexible dual AAV vector technology based on reconstitution via mRNA trans-splicing.

Calcium-sensing fluorescent proteins such as TN-XXL are valuable tools for studying cellular function but, when expressed in mice, may affect animal physiology and behaviour. The authors of this paper create transgenic mice expressing TN-XXL and show that long-term expression of TN-XXL is tolerated well.

Aggregation-prone forms of α-synuclein lead to degeneration of midbrain dopaminergic neurons, as seen in Parkinson’s disease, but less is known about the effects that the noxious protein has in other brain regions. Here, the authors investigate the effect of a pathological form of α-synuclein on the functional integration of new neurons into the olfactory bulb of adult mice.

A screening approach finds VH-domain antibodies that bind the SARS-CoV-2 Spike protein receptor-binding domain at its interface with host ACE2. Bi-paratopic and multivalent binders have high affinity and potency.

Early stellarator designs suffered from high particle losses, an issue that can be addressed by optimization of the coils. Here the authors measure the magnetic field lines in the Wendelstein 7-X stellarator, confirming that the complicated design of the superconducting coils has been realized successfully.

This protocol describes an in vivo and ex vivo electrophysiological study in the mouse heart to derive intracardiac electrograms, focusing on electrical stimulation protocols to characterize the cardiac conduction system and its vagal control and susceptibility to arrhythmia.

Shifts in the mixing regimes of lakes in a changing climate are projected to vary with altitude, with mid-altitude lakes particularly affected, according to simulations of 29 Swiss lakes with a physical lake model and downscaled climate projections.