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"Williams, David A"
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Sport psychology : contemporary themes
\"This new edition of Sport Psychology combines theory, research, and empirical evidence to provide a comprehensive, introductory text, suitable for core use. All chapters have been updated, reflecting contemporary developments, and new content includes the latest research on metaimagery and self harm in sport, as well as new case examples throughout\"-- Provided by publisher.
Book
Modulating the stem cell niche for tissue regeneration
Manipulating the stem cell niche could provide new ways of coaxing stem cells to repair damaged tissues.
The field of regenerative medicine holds considerable promise for treating diseases that are currently intractable. Although many researchers are adopting the strategy of cell transplantation for tissue repair, an alternative approach to therapy is to manipulate the stem cell microenvironment, or niche, to facilitate repair by endogenous stem cells. The niche is highly dynamic, with multiple opportunities for intervention. These include administration of small molecules, biologics or biomaterials that target specific aspects of the niche, such as cell-cell and cell–extracellular matrix interactions, to stimulate expansion or differentiation of stem cells, or to cause reversion of differentiated cells to stem cells. Nevertheless, there are several challenges in targeting the niche therapeutically, not least that of achieving specificity of delivery and responses. We envisage that successful treatments in regenerative medicine will involve different combinations of factors to target stem cells and niche cells, applied at different times to effect recovery according to the dynamics of stem cell–niche interactions.
Journal Article
Highly efficient therapeutic gene editing of human hematopoietic stem cells
Re-expression of the paralogous γ-globin genes (
HBG1/2
) could be a universal strategy to ameliorate the severe β-globin disorders sickle cell disease (SCD) and β-thalassemia by induction of fetal hemoglobin (HbF, α
2
γ
2
)
1
. Previously, we and others have shown that core sequences at the
BCL11A
erythroid enhancer are required for repression of HbF in adult-stage erythroid cells but are dispensable in non-erythroid cells
2
–
6
. CRISPR–Cas9-mediated gene modification has demonstrated variable efficiency, specificity, and persistence in hematopoietic stem cells (HSCs). Here, we demonstrate that Cas9:sgRNA ribonucleoprotein (RNP)-mediated cleavage within a GATA1 binding site at the +58
BCL11A
erythroid enhancer results in highly penetrant disruption of this motif, reduction of BCL11A expression, and induction of fetal γ-globin. We optimize conditions for selection-free on-target editing in patient-derived HSCs as a nearly complete reaction lacking detectable genotoxicity or deleterious impact on stem cell function. HSCs preferentially undergo non-homologous compared with microhomology-mediated end joining repair. Erythroid progeny of edited engrafting SCD HSCs express therapeutic levels of HbF and resist sickling, while those from patients with β-thalassemia show restored globin chain balance. Non-homologous end joining repair-based
BCL11A
enhancer editing approaching complete allelic disruption in HSCs is a practicable therapeutic strategy to produce durable HbF induction.
Optimized conditions for ribonucleoprotein delivery of Cas9–sgRNA complexes enables precise and efficient gene editing to restore fetal hemoglobin expression in sickle cell disease patient-derived HSCs
Journal Article
The Changing Face of Adrenoleukodystrophy
Abstract
Adrenoleukodystrophy (ALD) is a rare X-linked disorder of peroxisomal oxidation due to mutations in ABCD1. It is a progressive condition with a variable clinical spectrum that includes primary adrenal insufficiency, myelopathy, and cerebral ALD. Adrenal insufficiency affects over 80% of ALD patients. Cerebral ALD affects one-third of boys under the age of 12 and progresses to total disability and death without treatment. Hematopoietic stem cell transplantation (HSCT) remains the only disease-modifying therapy if completed in the early stages of cerebral ALD, but it does not affect the course of adrenal insufficiency. It has significant associated morbidity and mortality. A recent gene therapy clinical trial for ALD reported short-term MRI and neurological outcomes comparable to historical patients treated with HSCT without the associated adverse side effects. In addition, over a dozen states have started newborn screening (NBS) for ALD, with the number of states expecting to double in 2020. Genetic testing of NBS-positive neonates has identified novel variants of unknown significance, providing further opportunity for genetic characterization but also uncertainty in the monitoring and therapy of subclinical and/or mild adrenal insufficiency or cerebral involvement. As more individuals with ALD are identified at birth, it remains uncertain if availability of matched donors, transplant (and, potentially, gene therapy) centers, and specialists may affect the timely treatment of these individuals. As these promising gene therapy trials and NBS transform the clinical management and outcomes of ALD, there will be an increasing need for the endocrine management of presymptomatic and subclinical adrenal insufficiency. (Endocrine Reviews 41: 1 – 17, 2020)
Graphical Abstract
Graphical Abstract
Journal Article
Impacts of Voids, Line-of-sight Interactions, and Local Emission Environment on the Detectability of Gamma-Ray Active Galactic Nuclei
Cosmic voids may have novel effects on the propagation of high-energy photons. We consider the fraction of the line of sight that intersect voids (termed “voidiness”). A previous study showed that active galactic nuclei (AGN) detected by the Fermi Large Area Telescope (LAT) lie along voidier lines of sight than redshift-matched populations of Sloan Digital Sky Survey (SDSS) optically detected quasars in the redshift range from 0.4 ≤ z < 0.7. We explore this difference and various astrophysical explanations for it. Weaker intergalactic magnetic fields in voids would naturally enhance the gamma-ray cascading flux within the Fermi-LAT point-spread function. We find that line-of-sight interactions increasing the flux in the Fermi-LAT energy band by ∼0.1% Mpc–1 of void traversed may be sufficient to result in the observed difference in voidiness distributions. Voidiness comparisons between SDSS QSOs and AGN detected by imaging atmospheric Cherenkov telescopes at very high energies (VHEs) do not yield any conclusive statement, likely because of the limited VHE sample size, and therefore are inconclusive about the role of possibly weaker extragalactic background light within voids. Finally, we measure that 28% ± 3% of gamma-ray-detected sources exist within a void (consistent with random mock populations) compared to 19.1% ± 0.3% of SDSS quasars. We do not find any significant local void effect for gamma-ray sources that would explain the voidiness difference between Fermi-LAT gamma-ray and SDSS QSO sources. These results suggest that the observed difference in voidiness distributions may be due to line-of-sight interactions rather than the local emission environment of gamma-ray AGN.
Journal Article
Fecal microbiome composition and diversity of cryopreserved canine stool at different duration and storage conditions
Fresh-frozen stool banks intended for humans with gastrointestinal and metabolic disorders have been recently established and there are ongoing efforts to establish the first veterinary fresh-frozen stool bank. Fresh frozen stored feces provide an advantage of increased availability and accessibility to high-quality optimal donor fecal material. The stability of frozen canine feces regarding fecal microbiome composition and diversity has not been reported in dogs, providing the basis for this study. We hypothesized that fecal microbial composition and diversity of healthy dogs would remain stable when stored at -20°C and -80°C for up to 12 months compared to baseline samples evaluated before freezing. Stool samples were collected from 20 apparently healthy dogs, manually homogenized, cryopreserved in 20% glycerol and aliquoted, frozen in liquid nitrogen and stored at -20°C or -80°C for 3, 6, 9, and 12 months. At baseline and after period of storage, aliquots were thawed and treated with propidium monoazide before fecal DNA extraction. Following long-read 16S-rRNA amplicon sequencing, bacterial community composition and diversity were compared among treatment groups. We demonstrated that fresh-frozen canine stools collected from 20 apparently healthy dogs could be stored for up to 12 months at -80°C with minimal change in microbial community composition and diversity and that storage at -80°C is superior to storage at -20°C. We also found that differences between dogs had the largest effect on community composition and diversity. Relative abundances of certain bacterial taxa, including those known to be short-chain fatty acid producers, varied significantly with specific storage temperatures and duration. Further work is required to ascertain whether fecal donor material that differs in bacterial community composition and diversity across storage conditions and duration could lead to differences in clinical efficacy for specific clinical indications of fecal microbiota transplantation.
Journal Article
Two Phase 3 Trials of Adalimumab for Hidradenitis Suppurativa
Hidradenitis suppurativa is a painful, chronic inflammatory skin disease. In two double-blind, placebo-controlled trials, treatment with adalimumab resulted in significantly increased rates of clinical response at week 12. Rates of serious adverse events were similar between groups.
Hidradenitis suppurativa, also known as acne inversa, is a painful, chronic inflammatory skin disease
1
–
3
characterized by multifocal, recurrent nodules, abscesses, and fistulas, predominantly affecting the axillary, inguinal, breast-fold, and anogenital regions.
4
The prevalence of self-reported disease is 1% in Western Europe.
1
,
5
The average interval from the onset of symptoms to diagnosis is 7.2 years.
6
Women are affected 2 to 5 times as frequently as men, and the disease may be more common in blacks than in whites.
1
,
7
Disease severity ranges from mild (localized lesions) to severe (multiple areas of widely dispersed lesions, including interconnected sinus tracts and . . .
Journal Article
Cardiovascular post-acute sequelae of SARS-CoV-2 in children and adolescents: cohort study using electronic health records
The risk of cardiovascular outcomes following SARS-CoV-2 infection has been reported in adults, but evidence in children and adolescents is limited. This paper assessed the risk of a multitude of cardiac signs, symptoms, and conditions 28-179 days after infection, with outcomes stratified by the presence of congenital heart defects (CHDs), using electronic health records (EHR) data from 19 children’s hospitals and health institutions from the United States within the RECOVER consortium between March 2020 and September 2023. The cohort included 297,920 SARS-CoV-2-positive individuals and 915,402 SARS-CoV-2-negative controls. Every individual had at least a six-month follow-up after cohort entry. Here we show that children and adolescents with prior SARS-CoV-2 infection are at a statistically significant increased risk of various cardiovascular outcomes, including hypertension, ventricular arrhythmias, myocarditis, heart failure, cardiomyopathy, cardiac arrest, thromboembolism, chest pain, and palpitations, compared to uninfected controls. These findings were consistent among patients with and without CHDs. Awareness of the heightened risk of cardiovascular disorders after SARS-CoV-2 infection can lead to timely referrals, diagnostic evaluations, and management to mitigate long-term cardiovascular complications in children and adolescents.
Post-acute sequelae of SARS-CoV-2 infection affecting the cardiovascular system have been reported, but evidence in young people is limited. Here, the authors quantify the incidence of a range of outcomes in children and adolescents using electronic health records from the United States.
Journal Article
One dog’s waste is another dog’s wealth : a pilot study of fecal microbiota transplantation in dogs with acute hemorrhagic diarrhea syndrome
Canine acute hemorrhagic diarrhea syndrome (AHDS) has been associated in some studies with Clostridioides perfringens overgrowth and toxin-mediated necrosis of the intestinal mucosa. We aimed to determine the effect of a single fecal microbiota transplantation (FMT) on clinical scores and fecal microbiomes of 1 and 7 dogs with AHDS from New Zealand and South Africa. We hypothesized that FMT would improve AHDS clinical scores and increase microbiota alpha-diversity and short-chain fatty acid (SCFA)-producing microbial communities’ abundances in dogs with AHDS after FMT. We sequenced the V3-V4 region of the 16S-rRNA gene in the feces of AHDS FMT-recipients and sham-treated control dogs, and their healthy donors at admission, discharge, and 30 days post-discharge. There were no significant differences in median AHDS clinical scores between FMT-recipients and sham-treated controls at admission or discharge (P = 0.22, P = 0.41). At admission, the Shannon diversity index (SDI) was lower in AHDS dogs than healthy donors (P = 0.002). The SDI did not change from admission to 30 days in sham-treated dogs yet increased in FMT-recipients from admission to discharge (P = 0.04) to levels not different than donors (P = 0.33) but significantly higher than sham-treated controls (P = 0.002). At 30 days, the SDI did not differ between FMT recipients, sham-treated controls, and donors (P = 0.88). Principal coordinate analysis of the Bray-Curtis index separated post-FMT and donor dogs from pre-FMT and sham-treated dogs (P = 0.009) because of increased SCFA-producing genera’s abundances after FMT. A single co-abundance subnetwork contained many of the same OTUs found to be differentially abundant in FMT-recipients, and the abundance of this module was increased in FMT-recipients at discharge and 30 days, compared to shamtreated controls. We conclude in this small pilot study FMT did not have any clinical benefit.
Journal Article