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\"This book explores the possibilities that exist within educational spaces for Black male students when teachers care for these students while also acknowledging the intersectionality of Black male identity and the potential oppression and resilience that they experience as the result\"-- Provided by author.

The mammalian skeleton performs a diverse range of vital functions, requiring mechanisms of regeneration that restore functional skeletal cell populations after injury. We hypothesized that the Wnt pathway specifies distinct functional subsets of skeletal cell types, and that lineage tracing of Wnt-responding cells (WRCs) using the Axin2 gene in mice identifies a population of long-lived skeletal cells on the periosteum of long bone. Ablation of these WRCs disrupts healing after injury, and three-dimensional finite element modeling of the regenerate delineates their essential role in functional bone regeneration. These progenitor cells in the periosteum are activated upon injury and give rise to both cartilage and bone. Indeed, our findings suggest that WRCs may serve as a therapeutic target in the setting of impaired skeletal regeneration.

Cranial sutures are major growth centers for the calvarial vault, and their premature fusion leads to a pathologic condition called craniosynostosis. This study investigates whether skeletal stem/progenitor cells are resident in the cranial sutures. Prospective isolation by FACS identifies this population with a significant difference in spatio-temporal representation between fusing versus patent sutures. Transcriptomic analysis highlights a distinct signature in cells derived from the physiological closing PF suture, and scRNA sequencing identifies transcriptional heterogeneity among sutures. Wnt-signaling activation increases skeletal stem/progenitor cells in sutures, whereas its inhibition decreases. Crossing Axin2 LacZ/+ mouse, endowing enhanced Wnt activation, to a Twist1 +/− mouse model of coronal craniosynostosis enriches skeletal stem/progenitor cells in sutures restoring patency. Co-transplantation of these cells with Wnt3a prevents resynostosis following suturectomy in Twist1 +/− mice. Our study reveals that decrease and/or imbalance of skeletal stem/progenitor cells representation within sutures may underlie craniosynostosis. These findings have translational implications toward therapeutic approaches for craniosynostosis. Cranial sutures are major growth centers for the skull vault and premature fusion leads to pathological fusion, craniosynostosis. Here the authors isolate Wnt responsive skeletal stem and progenitor cells from sutures, that can be transplanted together with Wnt3a protein to repair craniosynostosis in a mouse model.

Background The National Institutes of Health (NIH) Research Task Force (RTF) on Research Standards for Chronic Low Back Pain impact score is a composite measure of Patient Reported Outcomes Measurement Information System (PROMIS) pain intensity, pain interference and physical function. PROMIS surveys are available in short-form and computer adaptive testing (CAT) formats. Minimal important change (MIC) can be estimated to determine if between-group differences are large enough to be important. To date, three anchor-based estimates of impact score MIC ranging from 3 to 7.5 have been published, and all were based on data collected using PROMIS short-form surveys. None used CAT versions of PROMIS surveys. Methods Secondary analysis of data collected during the conduct of two randomized clinical trials of 6-week courses of nonpharmacological pain therapies. Research subjects were US active-duty service members referred to an interdisciplinary pain management center. Impact score was assessed at the beginning and end of treatment. The Patient Global Impression of Change (PGIC) questionnaire was administered at the end of treatment and asked respondents to report their status compared to the start of treatment using a 7-item categorical scale ranging from very much improved to very much worse. A PGIC response of “much” or “very much” improved defined important improvement. Receiver operating characteristic (ROC) curve analysis and predictive logistic regression models were used to estimate MIC for the full combined sample and stratified by study sample and baseline impact score. Measures of individual statistical change were also computed. Results Overall, a decrease of 3 points in impact score was the estimated MIC (2.5 for ROC analysis and 3.4 for predictive modeling approach). Larger decreases in impact score were needed for participants with moderate and severe baseline pain impact to report important improvement. Thresholds for individual statistically significant change ranged from 6 to 14. Conclusions Using data collected with CAT surveys, we calculated an MIC of 3 points for the NIH RTF impact score, and estimates ranged from 1.3 to 7.2 depending on the baseline impact score and statistical approach used. These findings are consistent with previous MIC estimates that were based on non-adaptive short form surveys and have implications for improving the accuracy of pain treatment response assessment. Registry information Trial registration. ClinicalTrials.gov. Registry numbers: NCT03297905 (registered 9/29/17) and NCT04656340 (registered 11/30/20). Link to full applications: https://classic.clinicaltrials.gov/ct2/show/NCT03297905?titles=Determinants+of+Optimal+Dosage%26cntry=US%26draw=2%26rank=1 ; https://classic.clinicaltrials.gov/ct2/show/results/NCT04656340?titles=Complementary+and+Integrative+pain+therapies+and+functional+restoration+%28IMPPPORT%29%26draw=2%26rank=1 . Patient enrollment dates: SMART: 17 March 2021, prospectively registered; IMPPPORT: 9 December 2015, retrospectively registered.

The therapeutic potential of Wnt proteins has long been recognized but challenges associated with in vivo stability and delivery have hindered their development as drug candidates. By exploiting the hydrophobic nature of the protein we provide evidence that exogenous Wnt3a can be delivered in vivo if it is associated with a lipid vesicle. Recombinant Wnt3a associates with the external surface of the lipid membrane; this association stabilizes the protein and leads to prolonged activation of the Wnt pathway in primary cells. We demonstrate the consequences of Wnt pathway activation in vivo using a bone marrow engraftment assay. These data provide validation for the development of WNT3A as a therapeutic protein.

The Xist lncRNA mediates X chromosome inactivation (XCI). Here we show that Spen, an Xist-binding repressor protein essential for XCI , binds to ancient retroviral RNA, performing a surveillance role to recruit chromatin silencing machinery to these parasitic loci. Spen loss activates a subset of endogenous retroviral (ERV) elements in mouse embryonic stem cells, with gain of chromatin accessibility, active histone modifications, and ERV RNA transcription. Spen binds directly to ERV RNAs that show structural similarity to the A-repeat of Xist, a region critical for Xist-mediated gene silencing. ERV RNA and Xist A-repeat bind the RRM domains of Spen in a competitive manner. Insertion of an ERV into an A-repeat deficient Xist rescues binding of Xist RNA to Spen and results in strictly local gene silencing in cis. These results suggest that Xist may coopt transposable element RNA-protein interactions to repurpose powerful antiviral chromatin silencing machinery for sex chromosome dosage compensation. The genetic material inside cells is often packaged into thread-like structures called chromosomes. In humans, mice and other mammals, a pair of sex chromosomes determines the genetic or chromosomal sex of each individual. Those who inherit two “X” chromosomes are said to be chromosomally female, while chromosomal males have one “X” and one “Y” chromosome. This means females have twice as many copies of genes on the X chromosome as a male does, which turns out to be double the number that the body needs. To solve this problem, mammals have developed a strategy known as dosage compensation. The second X chromosome in females becomes “silent”: its DNA remains unchanged, but none of the genes are active. A long noncoding RNA molecule called Xist is responsible for switching off the extra X genes in female cells. It does this by coating the entirety of the second X chromosome. Normally, RNA molecules transmit the coded instructions in genes to the cellular machinery that manufactures proteins. “Noncoding” RNAs like Xist, however, are RNAs that have taken on different jobs inside the cell. Researchers believe that the ancestral Xist gene may have once encoded a protein but changed over time to produce only a noncoding RNA. Carter, Xu et al. therefore set out to find out how exactly this might have happened, and also how Xist might have acquired its ability to switch genes off. Initial experiments used mouse cells grown in the laboratory, in which a protein called Spen was deleted. Spen is known to help Xist silence the X chromosome. In female cells lacking Spen, the second X chromosome remained active. Other chromosomes in male and female cells also had stretches of DNA that became active upon Spen’s removal. These DNA sequences, termed endogenous retroviruses, were remnants of ancestral viral infections. In other words, Spen normally acted as an antiviral defense. Analysis of genetic sequences showed that Spen recognized endogenous retrovirus sequences resembling a key region in Xist, a region which was needed for Xist to work properly. Inserting fragments of endogenous retroviruses into a defective version of Xist lacking this region also partially restored its ability to inactivate genes, suggesting that X chromosome silencing might work by hijacking cellular defenses against viruses. That is, female cells essentially ‘pretend’ there is a viral infection on the second X chromosome by coating it with Xist (which mimics endogenous retroviruses), thus directing Spen to shut it down. This research is an important step towards understanding how female cells carry out dosage compensation in mammals. More broadly, it sheds new light on how ancient viruses may have shaped the evolution of noncoding RNAs in the human genome.

Emergency medicine (EM) resident physicians face unique challenges in adhering to the principles of sleep hygiene due to the nature of EM shift work. They are at higher risk for sleep disorders, sleep-related errors and accidents, and impaired performance due to constantly changing schedules. Military residents also perceive a stigma against seeking mental health care and taking sleeping medications. This mixed-methods study investigated sleep quality and barriers to seeking care among EM residents at a single center, three-year, Active-Duty military EM residency program. A survey was made available to all 36 EM residents assessing daytime sleepiness using the Epworth Sleepiness Scale (ESS) with a target response rate of 66.7 %. The purpose of using the ESS was to identify at least 9 EM residents with excessive daytime sleepiness to participate in semi-structured interviews about their sleeping experiences. Excessive daytime sleepiness is defined as ≥11 on the ESS. These interviews were coded using a phenomenological approach to data analysis. Of the 36 EM residents in the program, 24 (66.7 %) completed the survey. Of these, 11 scored ≥11 on the ESS. Of these, nine EM residents participated in semi-structured interviews. Thematic saturation was achieved, and four themes emerged from interviews: 1) challenges with sleep hygiene; 2) less satisfied with sleep since starting residency; 3) normalization of poor sleep; and 4) taking medication for sleep is stigmatized. Results revealed significant difficulties adhering to the principles of sleep hygiene due to inconsistent sleep-wake times. Participants identified difficulty avoiding caffeine, alcohol, and large meals before bed, and felt their sleep had worsened since starting residency. Though residents often discussed sleep difficulties with colleagues, these conversations normalized sleeping problems and reduced help-seeking behavior. Participants perceived a stigma against using prescription medication for sleep. This study highlights significant sleep disturbances experienced by EM residents in this study and an inability to adhere to the principles of sleep hygiene. Normalization of sleep disturbances in residency seems to impede residents from seeking professional help. Further research should focus on targeted interventions to improve resident sleep hygiene, promote help-seeking behavior, and reduce the stigma associated with prescription drug use, when necessary. Additional studies are needed to examine the generalizability of these results to other training programs.

Maintaining nutrient availability in organic orchards presents challenges. Diverse litter sources may increase nutrient cycling and the efficiency by which microbes utilize carbon (C). Two tree-row treatments: ‘straw-mulch’ ( Triticum aestivum L.) and ‘living-mulch’ ( Lobularia maritima (L.) Desv.), and two alleyway groundcovers: ‘grass’ ( Festuca rubra with Lolium perenne L.) and a legume, ‘Birdsfoot trefoil’ ( Lotus corniculatus L.) were compared to an industry standard, tillage with a grass alleyway. Tree-row deposited trefoil biomass contributed 0.2 kg additional total nitrogen (N) per tree annually. Soil from tree-rows with trefoil alleyways had 23% greater organic C (+ 3.1 g kg −1 ), 17% greater total N (+ 0.3 g kg −1 ), up to 53% greater microbial biomass (+ 204 mg CO 2 –C kg −1 ), 32, 34 and 31% greater dehydrogenase (+ 2.3 µg TPF g −1 ), alkaline (+ 55.9 µg p-nitrophenol g −1 ) and acid (+ 106.7 µg p-nitrophenol g −1 ) phosphomonoesterase enzyme activity, 62% greater soil NO 3 − N (+ 2.05 µg NO 3 −1  g −1 ), and 51% higher nitrification rates (+ 0.22 µg NO 2 − –N + NO 3 − –N g −1 soil h −1 ) than tree-row soils adjacent to grass alleyways. Straw-mulch and living-mulch soils did not differ. Metabolic CO 2 quotient (qCO 2 ) values were lowest in trefoil (0.0032) and living-mulch with grass treatments (0.0036), indicating greater microbial growth efficiency. Tillage and straw-mulch with grass alleyway treatments had the highest qCO 2 (0.0053 and 0.0048) and the lowest microbial biomass (246.3 and 297.6 mg CO 2 –C kg −1 soil). Higher potential biochemical activity, and total C and N, suggests orchards with trefoil alleyways cut and deposited into tree-rows, enhances soil organic matter and promotes balanced nutrient cycling and retentive processes.

Intersectional Care for Black Boys in an Alternative School is an exploration of the possibilities that exist within educational spaces for Black male students when teachers care for these students while also acknowledging the intersectionality of Black male identity and the potential oppression and resilience that they experience as the result.

Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of articular cartilage 1 . The etiology of OA is complex and involves a variety of factors, including genetic predisposition, acute injury and chronic inflammation 2 – 4 . Here we investigate the ability of resident skeletal stem-cell (SSC) populations to regenerate cartilage in relation to age, a possible contributor to the development of osteoarthritis 5 – 7 . We demonstrate that aging is associated with progressive loss of SSCs and diminished chondrogenesis in the joints of both mice and humans. However, a local expansion of SSCs could still be triggered in the chondral surface of adult limb joints in mice by stimulating a regenerative response using microfracture (MF) surgery. Although MF-activated SSCs tended to form fibrous tissues, localized co-delivery of BMP2 and soluble VEGFR1 (sVEGFR1), a VEGF receptor antagonist, in a hydrogel skewed differentiation of MF-activated SSCs toward articular cartilage. These data indicate that following MF, a resident stem-cell population can be induced to generate cartilage for treatment of localized chondral disease in OA. Endogenous skeletal stem cells are recruited to form cartilage in mice when stimulated by microfracture surgery together with localized delivery of growth factors, pointing to a new approach for treating cartilage defects.