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Although normally dormant, hair follicle stem cells (HFSCs) quickly become activated to divide during a new hair cycle. The quiescence of HFSCs is known to be regulated by a number of intrinsic and extrinsic mechanisms. Here we provide several lines of evidence to demonstrate that HFSCs utilize glycolytic metabolism and produce significantly more lactate than other cells in the epidermis. Furthermore, lactate generation appears to be critical for the activation of HFSCs as deletion of lactate dehydrogenase (Ldha) prevented their activation. Conversely, genetically promoting lactate production in HFSCs through mitochondrial pyruvate carrier 1 (Mpc1) deletion accelerated their activation and the hair cycle. Finally, we identify small molecules that increase lactate production by stimulating Myc levels or inhibiting Mpc1 carrier activity and can topically induce the hair cycle. These data suggest that HFSCs maintain a metabolic state that allows them to remain dormant and yet quickly respond to appropriate proliferative stimuli. Flores et al. show that hair follicle stem cells rely on the production of lactate via the LDHA enzyme to become activated. Inducing Ldha through Mpc1 inhibition or Myc activation successfully reactivates the hair cycle in quiescent follicles.

The amygdala processes positive and negative valence and contributes to addiction, but the cell-type-specific gene regulatory programs involved are unknown. We generated an atlas of single-nucleus gene expression and chromatin accessibility in the amygdala of outbred rats with high and low cocaine addiction-like behaviors following prolonged abstinence. Differentially expressed genes between the high and low groups were enriched for energy metabolism across cell types. Rats with high addiction index (AI) showed increased relapse-like behaviors and GABAergic transmission in the amygdala. Both phenotypes were reversed by pharmacological inhibition of the glyoxalase 1 enzyme, which metabolizes methylglyoxal—a GABA A receptor agonist produced by glycolysis. Differences in chromatin accessibility between high and low AI rats implicated pioneer transcription factors in the basic helix-loop-helix, FOX, SOX and activator protein 1 families. We observed opposite regulation of chromatin accessibility across many cell types. Most notably, excitatory neurons had greater accessibility in high AI rats and inhibitory neurons had greater accessibility in low AI rats. Using single-cell genomics, addiction-like behaviors in outbred rats are associated with persistent cell-type-specific molecular signatures in the amygdala, implicating a pivotal role of energy metabolism in cocaine addiction.

The amygdala processes positive and negative valence and contributes to the development of addiction, but the underlying cell type-specific gene regulatory programs are unknown. We generated an atlas of single nucleus gene expression and chromatin accessibility in the amygdala of outbred rats with low and high cocaine addiction-like behaviors following prolonged abstinence. Between rats with different addiction indexes, we identified thousands of cell type-specific differentially expressed genes enriched for energy metabolism-related pathways that are known to affect synaptic transmission and action potentials. Rats with high addiction-like behaviors showed enhanced GABAergic transmission in the amygdala, which, along with relapse-like behaviors, were reversed by inhibition of Glyoxalase 1, which metabolizes the GABAA receptor agonist methylglyoxal. Finally, we identified thousands of cell type-specific chromatin accessible sites and transcription factor (TF) motifs where accessibility was associated with addiction index, most notably at motifs for pioneer TFs in the Fox, Sox, helix-loop-helix, and AP1 families.

In vivo calcium imaging through microendoscopic lenses enables imaging of previously inaccessible neuronal populations deep within the brains of freely moving animals. However, it is computationally challenging to extract single-neuronal activity from microendoscopic data, because of the very large background fluctuations and high spatial overlaps intrinsic to this recording modality. Here, we describe a new constrained matrix factorization approach to accurately separate the background and then demix and denoise the neuronal signals of interest. We compared the proposed method against previous independent components analysis and constrained nonnegative matrix factorization approaches. On both simulated and experimental data recorded from mice, our method substantially improved the quality of extracted cellular signals and detected more well-isolated neural signals, especially in noisy data regimes. These advances can in turn significantly enhance the statistical power of downstream analyses, and ultimately improve scientific conclusions derived from microendoscopic data.

Mobile element insertions (MEIs) are repetitive genomic sequences that contribute to genetic variation and can lead to genetic disorders. Targeted and whole-genome approaches using short-read sequencing have been developed to identify reference and non-reference MEIs; however, the read length hampers detection of these elements in complex genomic regions. Here, we pair Cas9-targeted nanopore sequencing with computational methodologies to capture active MEIs in human genomes. We demonstrate parallel enrichment for distinct classes of MEIs, averaging 44% of reads on-targeted signals and exhibiting a 13.4-54x enrichment over whole-genome approaches. We show an individual flow cell can recover most MEIs (97% L1Hs, 93% Alu Yb, 51% Alu Ya, 99% SVA_F, and 65% SVA_E). We identify seventeen non-reference MEIs in GM12878 overlooked by modern, long-read analysis pipelines, primarily in repetitive genomic regions. This work introduces the utility of nanopore sequencing for MEI enrichment and lays the foundation for rapid discovery of elusive, repetitive genetic elements. Mobile element insertions (MEIs) are a source of repetitive genetic variation and can lead to genetic disorders. Here the authors use Cas9-targeted nanopore sequencing to efficiently saturate enrichment for known and non-reference MEIs.

To date, there has been relatively little published research on the mental health impacts of COVID-19 for the general public at the beginning of the U.S.’ experience of the pandemic, or the factors associated with stress, anxiety, depression, and post-traumatic growth during this time. The current study provides a longitudinal examination of the predictors of self-reported stress, anxiety, depression, and post-traumatic growth for U.S. residents between April and May, 2020, including the influence of demographic, psychosocial, and behavioral factors on these outcomes. The findings indicate that, generally, the early months of the U.S. COVID-19 experience were characterized by a modest negative impact on mental health. Younger adults, people with pre-existing health conditions, and those experiencing greater perceived risk, higher levels of rumination, higher levels of co-rumination, greater social strain, or less social support reported worse mental health. Positive mental health was associated with the adoption of coping strategies, especially those that were forward-looking, and with greater adherence to national health-protection guidelines. The findings are discussed with regard to the current status of health-protective measures and mental health in the U.S., especially as these impact future management of the on-going pandemic.

Phylogenetic relationships among subgroups of cockroaches and termites are still matters of debate. Their divergence times and major phenotypic transitions during evolution are also not yet settled. We addressed these points by combining the first nuclear phylogenomic study of termites and cockroaches with a thorough approach to divergence time analysis, identification of endosymbionts, and reconstruction of ancestral morphological traits and behaviour. Analyses of the phylogenetic relationships within Blattodea robustly confirm previously uncertain hypotheses such as the sister-group relationship between Blaberoidea and remaining Blattodea, and Lamproblatta being the closest relative to the social and wood-feeding Cryptocercus and termites. Consequently, we propose new names for various clades in Blattodea: Cryptocercus + termites = Tutricablattae; Lamproblattidae + Tutricablattae = Kittrickea; and Blattoidea + Corydioidea = Solumblattodea. Our inferred divergence times contradict previous studies by showing that most subgroups of Blattodea evolved in the Cretaceous, reducing the gap between molecular estimates of divergence times and the fossil record. On a phenotypic level, the blattodean ground-plan is for egg packages to be laid directly in a hole while other forms of oviposition, including ovovivipary and vivipary, arose later. Finally, other changes in egg care strategy may have allowed for the adaptation of nest building and other novelties.

While SARS-CoV-2 continues to adapt for human infection and transmission, genetic variation outside of the spike gene remains largely unexplored. This study investigates a highly variable region at residues 203–205 in the SARS-CoV-2 nucleocapsid protein. Recreating a mutation found in the alpha and omicron variants in an early pandemic (WA-1) background, we find that the R203K+G204R mutation is sufficient to enhance replication, fitness, and pathogenesis of SARS-CoV-2. The R203K+G204R mutant corresponds with increased viral RNA and protein both in vitro and in vivo . Importantly, the R203K+G204R mutation increases nucleocapsid phosphorylation and confers resistance to inhibition of the GSK-3 kinase, providing a molecular basis for increased virus replication. Notably, analogous alanine substitutions at positions 203+204 also increase SARS-CoV-2 replication and augment phosphorylation, suggesting that infection is enhanced through ablation of the ancestral ‘RG’ motif. Overall, these results demonstrate that variant mutations outside spike are key components in SARS-CoV-2’s continued adaptation to human infection.

Restoration of human brain function after injury is a signal challenge for translational neuroscience. Rodent stroke recovery studies identify an optimal or sensitive period for intensive motor training after stroke: near-full recovery is attained if task-specific motor training occurs during this sensitive window. We extended these findings to adult humans with stroke in a randomized controlled trial applying the essential elements of rodent motor training paradigms to humans. Stroke patients were adaptively randomized to begin 20 extra hours of self-selected, task-specific motor therapy at ≤30 d (acute), 2 to 3 mo (subacute), or ≥6 mo (chronic) after stroke, compared with controls receiving standard motor rehabilitation. Upper extremity (UE) impairment assessed by the Action Research Arm Test (ARAT) was measured at up to five time points. The primary outcome measure was ARAT recovery over 1 y after stroke. By 1 y we found significantly increased UE motor function in the subacute group compared with controls (ARAT difference = +6.87 ± 2.63, P = 0.009). The acute group compared with controls showed smaller but significant improvement (ARAT difference = +5.25 ± 2.59 points, P = 0.043). The chronic group showed no significant improvement compared with controls (ARAT = +2.41 ± 2.25, P = 0.29). Thus task-specific motor intervention was most effective within the first 2 to 3 mo after stroke. The similarity to rodentmodel treatment outcomes suggests that other rodent findings may be translatable to human brain recovery. These results provide empirical evidence of a sensitive period for motor recovery in humans.