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The diversity in genome resources is fundamental to designing genomic strategies for local breed improvement and utilisation. These resources also support gene discovery and enhance our understanding of the mechanisms of resilience with applications beyond local breeds. Here, we report the genome sequences of 555 cattle (208 of which comprise new data) and high-density (HD) array genotyping of 1,082 samples (537 new samples) from indigenous African cattle populations. The new sequences have an average genome coverage of ~30X, three times higher than the average (~10X) of the over 300 sequences already in the public domain. Following variant quality checks, we identified approximately 32.3 million sequence variants and 661,943 HD autosomal variants mapped to the Bos taurus reference genome (ARS-UCD1.2). The new datasets were generated as part of the Centre for Tropical Livestock Genetics and Health (CTLGH) Genomic Reference Resource for African Cattle (GRRFAC) initiative, which aspires to facilitate the generation of this livestock resource and hopes for its utilisation for complete indigenous breed characterisation and sustainable global livestock improvement.
Subject(s)
Genome , Cattle/genetics , Animals , Genomics , Africa , Breeding , Genetic VariationABSTRACT
Biomaterial-based approaches for bone regeneration seek to explore alternative strategies to repair non-healing fractures and critical-sized bone defects. Fracture non-union occurs due to a number of factors resulting in the formation of bone defects. Rigorous evaluation of the biomaterials in relevant models and assessment of their potential to translate towards clinical use is vital. Large animal experimentation can be used to model fracture non-union while scaling-up materials for clinical use. Growth factors modulate cell phenotype, behaviour and initiate signalling pathways leading to changes in matrix deposition and tissue formation. Bone morphogenetic protein-2 (BMP-2) is a potent osteogenic growth factor, with a rapid clearance time in vivo necessitating clinical use at a high dose, with potential deleterious side-effects. The current studies have examined the potential for Laponite® nanoclay coated poly(caprolactone) trimethacrylate (PCL-TMA900) scaffolds to bind BMP-2 for enhanced osteoinduction in a large animal critical-sized bone defect. An ovine femoral condyle defect model confirmed PCL-TMA900 scaffolds coated with Laponite®/BMP-2 produced significant bone formation compared to the uncoated PCL-TMA 900 scaffold in vivo, assessed by micro-computed tomography (µCT) and histology. This indicated the ability of Laponite® to deliver the bioactive BMP-2 on the PCL-TMA900 scaffold. Bone formed around the Laponite®/BMP-2 coated PCL-TMA900 scaffold, with no erroneous bone formation observed away from the scaffold material confirming localisation of BMP-2 delivery. The current studies demonstrate the ability of a nanoclay to localise and deliver bioactive BMP-2 within a tailored octet-truss scaffold for efficacious bone defect repair in a large animal model with significant implications for translation to the clinic.
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Protein misfolding is common to neurodegenerative diseases (NDs) including Alzheimer's disease (AD), which is partly characterized by the self-assembly and accumulation of amyloid-beta in the brain. Lysosomes are a critical component of the proteostasis network required to degrade and recycle material from outside and within the cell and impaired proteostatic mechanisms have been implicated in NDs. We have previously established that toxic amyloid-beta oligomers are endocytosed, accumulate in lysosomes, and disrupt the endo-lysosomal system in neurons. Here, we use pioneering correlative cryo-structured illumination microscopy and cryo-soft X-ray tomography imaging techniques to reconstruct 3D cellular architecture in the native state revealing reduced X-ray density in lysosomes and increased carbon dense vesicles in oligomer treated neurons compared with untreated cells. This work provides unprecedented visual information on the changes to neuronal lysosomes inflicted by amyloid beta oligomers using advanced methods in structural cell biology.
Subject(s)
Amyloid beta-Peptides , Lysosomes , Neurons , Lysosomes/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/chemistry , Neurons/metabolism , Tomography, X-Ray/methods , Animals , Humans , Cryoelectron Microscopy/methodsABSTRACT
African science has substantial potential, yet it grapples with significant challenges. Here we describe the establishment of the Biomedical Science Research and Training Centre (BioRTC) in Yobe State, Northeast Nigeria, as a case study of a hub fostering on-continent research and describe strategies to overcome current barriers. We detail the steps taken to establish BioRTC, emphasising the critical importance of stakeholder engagement, community involvement, resource optimisation and collaborations. With its state-of-the-art facilities and commitment to training African scientists, BioRTC is poised to significantly advance neuroscience research and training in the region. Although we are in the early stages of our journey, our model, emphasizing open access and inclusivity, offers a replicable blueprint for neuroscience research development in similar resource-limited settings, promising to enrich the global neuroscience community. We invite the support and collaboration of those who share our vision and believe in our potential.
Subject(s)
Biomedical Research , Neurosciences , Nigeria , Neurosciences/educationABSTRACT
Background: People with chronic obstructive pulmonary disease have high levels of anxiety and depression, which is associated with increased morbidity and poor uptake of effective treatments, such as pulmonary rehabilitation. Cognitive-behavioural therapy improves mental health of people with long-term conditions and could potentially increase uptake of pulmonary rehabilitation, enabling synergies that could enhance the mental health of people with chronic obstructive pulmonary disease. Aim: Our aim was to develop and evaluate the clinical effectiveness and cost effectiveness of a tailored cognitive-behavioural approach intervention, which links into, and optimises the benefits of, routine pulmonary rehabilitation. Design: We carried out a pragmatic multicentre randomised controlled trial using a 1.25 : 1 ratio (intervention : control) with a parallel process evaluation, including assessment of fidelity. Setting: Twelve NHS trusts and five Clinical Commissioning Groups in England were recruited into the study. The intervention was delivered in participant's own home or at a local NHS facility, and by telephone. Participants: Between July 2017 and March 2020 we recruited adults with moderate/very severe chronic obstructive pulmonary disease and mild/moderate anxiety and/or depression, meeting eligibility criteria for assessment for pulmonary rehabilitation. Carers of participants were invited to participate. Intervention: The cognitive-behavioural approach intervention (i.e. six to eight 40- to 60-minute sessions plus telephone support throughout pulmonary rehabilitation) was delivered by 31 trained respiratory healthcare professionals to participants prior to commencing pulmonary rehabilitation. Usual care included routine pulmonary rehabilitation referral. Main outcome measures: Co-primary outcomes were Hospital Anxiety and Depression Scale - anxiety and Hospital Anxiety and Depression Scale - depression at 6 months post randomisation. Secondary outcomes at 6 and 12 months included health-related quality of life, smoking status, uptake of pulmonary rehabilitation and healthcare use. Results: We analysed results from 423 randomised participants (intervention, n = 242; control, n = 181). Forty-three carers participated. Follow-up at 6 and 12 months was 93% and 82%, respectively. Despite good fidelity for intervention delivery, mean between-group differences in Hospital Anxiety and Depression Scale at 6 months ruled out clinically important effects (Hospital Anxiety and Depression Scale - anxiety mean difference -0.60, 95% confidence interval -1.40 to 0.21; Hospital Anxiety and Depression Scale - depression mean difference -0.66, 95% confidence interval -1.39 to 0.07), with similar results at 12 months. There were no between-group differences in any of the secondary outcomes. Sensitivity analyses did not alter these conclusions. More adverse events were reported for intervention participants than for control participants, but none related to the trial. The intervention did not generate quality-of-life improvements to justify the additional cost (adjusted mean difference £770.24, 95% confidence interval -£27.91 to £1568.39) to the NHS. The intervention was well received and many participants described positive affects on their quality of life. Facilitators highlighted the complexity of participants' lives and considered the intervention to be of potential valuable; however, the intervention would be difficult to integrate within routine clinical services. Our well-powered trial delivered a theoretically designed intervention with good fidelity. The respiratory-experienced facilitators were trained to deliver a low-intensity cognitive-behavioural approach intervention, but high-intensity cognitive-behavioural therapy might have been more effective. Our broad inclusion criteria specified objectively assessed anxiety and/or depression, but participants were likely to favour talking therapies. Randomisation was concealed and blinding of outcome assessment was breached in only 15 participants. Conclusions: The tailored cognitive-behavioural approach intervention delivered with fidelity by trained respiratory healthcare professionals to people with chronic obstructive pulmonary disease was neither clinically effective nor cost-effective. Alternative approaches that are integrated with routine long-term condition care are needed to address the unmet, complex clinical and psychosocial needs of this group of patients. Trial registration: This trial is registered as ISRCTN59537391. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/146/02) and is published in full in Health Technology Assessment; Vol. 28, No. 1. See the NIHR Funding and Awards website for further award information.
People with long-standing lung problems, such as chronic obstructive pulmonary disease, often also have anxiety and depression, which further reduces their quality of life. Two existing treatments could help. Pulmonary rehabilitation (a programme of exercise and education) improves both the physical and mental health of people with chronic obstructive pulmonary disease. Cognitivebehavioural therapy (a talking therapy) may reduce anxiety and depression. The TANDEM [Tailored intervention for Anxiety and Depression Management in chronic obstructive pulmonary disease (COPD)] intervention linked these two treatments by providing talking therapy based on cognitivebehavioural therapy during the waiting time following referral for pulmonary rehabilitation. The TANDEM treatment was delivered by respiratory healthcare professionals (e.g. nurses or physiotherapists) trained to deliver the talking therapy in six to eight weekly sessions. The sessions were conducted in the participant's home (or another convenient location), with brief telephone support during the pulmonary rehabilitation. Of 423 participants recruited to the study, 242 participants received TANDEM talking therapy and 181 participants received usual care (including a referral to pulmonary rehabilitation). We measured mental health, quality of life, social life, attendance at pulmonary rehabilitation and healthcare use in both groups at 6 and 12 months. Forty-three carers joined the study and we assessed their mental well-being. We interviewed patients, carers and health professionals to find out their views and experience of the TANDEM treatment. We also examined whether or not the TANDEM treatment was good value for money. The TANDEM treatment did not improve the mental or the physical health of people with chronic obstructive pulmonary disease. In addition, the TANDEM treatment cost the NHS an extra £770 per patient, which was not good value for money. The TANDEM treatment was well received, and many participants told us how it had helped them. Heath-care professionals noted how participants did not just have chronic obstructive pulmonary disease, but were coping with many physical, mental and social problems. The TANDEM intervention was not effective and, therefore, other strategies will be needed to help people with chronic obstructive pulmonary disease and mental health problems live with their condition.
Subject(s)
Depression , Pulmonary Disease, Chronic Obstructive , Adult , Humans , Depression/therapy , Quality of Life , Psychosocial Intervention , Anxiety/therapy , Pulmonary Disease, Chronic Obstructive/therapy , Cost-Benefit AnalysisSubject(s)
Cognitive Behavioral Therapy , Pulmonary Disease, Chronic Obstructive , Humans , Depression/therapy , Depression/psychology , Psychosocial Intervention , Anxiety/therapy , Anxiety/psychology , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/therapy , Pulmonary Disease, Chronic Obstructive/psychologyABSTRACT
BACKGROUND: The genomes of indigenous African cattle are composed of components with Middle Eastern (taurine) and South Asian (indicine) origins, providing a valuable model to study hybridization and to identify genetic barriers to gene flow. In this study, we analysed indigenous African cattle breeds as models of hybrid zones, considering taurine and indicine samples as ancestors. In a genomic cline analysis of whole-genome sequence data, we considered over 8 million variants from 144 animals, which allows for fine-mapping of potential genomic incompatibilities at high resolution across the genome. RESULTS: We identified several thousand variants that had significantly steep clines ('SCV') across the whole genome, indicating restricted introgression. Some of the SCV were clustered into extended regions, with the longest on chromosome 7, spanning 725 kb and including 27 genes. We found that variants with a high phenotypic impact (e.g. indels, intra-genic and missense variants) likely represent greater genetic barriers to gene flow. Furthermore, our findings provide evidence that a large proportion of breed differentiation in African cattle could be linked to genomic incompatibilities and reproductive isolation. Functional evaluation of genes with SCV suggest that mitonuclear incompatibilities and genes associated with fitness (e.g. resistance to paratuberculosis) could account for restricted gene flow in indigenous African cattle. CONCLUSIONS: To our knowledge, this is the first time genomic cline analysis has been applied to identify restricted introgression in the genomes of indigenous African cattle and the results provide extended insights into mechanisms (e.g. genomic incompatibilities) contributing to hybrid differentiation. These results have important implications for our understanding of genetic incompatibilities and reproductive isolation and provide important insights into the impact of cross-breeding cattle with the aim of producing offspring that are both hardy and productive.
Subject(s)
Genome , Genomics , Animals , Cattle/genetics , Hybridization, Genetic , Gene Flow , Polymorphism, Single NucleotideABSTRACT
[This corrects the article DOI: 10.3389/fmolb.2021.779240.].
ABSTRACT
Several factors, including breed, lead to divergent performance of pigs for production and reproduction traits in different environments. A recent genomics study showed that Modern European (ME) pig breeds contribute to the ancestry of smallholder pigs in the Hoima and Kamuli districts, Uganda. These pigs were also involved in a longitudinal study with several traits recorded, including 540 body weights (WT) of 374 growing pigs, 195 records of total number of piglets born alive (TBA) of 157 sows, and 110 total number weaned (TNW) records of 94 sows. Linear mixed-effects models were used to test for the significance of environmental effects, including housing system, geographic location, and the season when the events occurred as well as animal-specific effects like age, sex, parity, and farrow-to-weaning interval. Stepwise model reduction starting from models with all main effects and pairwise interactions was applied. The final models were then expanded to include proportions of Modern European (ME) ancestry for the subset of animals genotyped, following genomic ancestry analysis based on a Porcine 50K SNP Chip. ME ancestry proportions ranged from 0.02 to 0.50 and were categorized into three classes (low/medium/high ME) based on 33.3% quantiles. The effects of ME classes on WT and TBA were not significant. ME showed a significant effect on TNW. Sows with a high proportion of ME weaned 2.4 piglets more than the low group, the medium ME group being intermediate. This study used genomic data to investigate the effects of genetic ancestry on the performance of smallholder pigs in Uganda. The proportion of Modern European ancestry did not exceed 0.50, therefore not allowing for the comparison of local versus pure "exotic" types of pigs. For the range of ancestries observed, which is the relevant one for current smallholder systems in Uganda, differences were small for the body weight of growing pigs and the number of piglets born alive, while higher proportions of ME ancestry resulted in significantly more piglets weaned. The availability of genotypes of a higher number of growing pigs would have been beneficial for drawing conclusions on the effect of ME ancestry on the growth rates of smallholder pigs in Uganda.
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Introduction: Patients with COPD who exhibit elevated levels of anxiety and/or depression are typically less able to improve symptoms and physical activity levels following a programme of pulmonary rehabilitation (PR). The objective of the present study was to provide proof of concept that offering an intervention comprising cognitive behavioural therapy (CBT) alongside physical activity behavioural modification strategies (BPA) during PR is more effective in improving physical activity outcomes compared to PR and CBT alone. Methods: 32 patients with COPD (mean±sd forced expiratory volume in 1â s 42±14% predicted) were assigned 1:1 to receive PR+CBT+BPA or PR+CBT. BPA comprised motivational interviews, step-count monitoring, feedback using a pedometer and goal setting. Assessments included accelerometer-derived steps per day, movement intensity, 6-min walk distance (6MWD) and Hospital Anxiety and Depression Scale (HADS) scores. Results: The magnitude of improvement across physical activity outcomes was greater for the PR+CBT+BPA compared to the PR+CBT intervention (by 829 steps per day (p=0.029) and by 80±39 vector magnitude units (p=0.042), respectively). Compared to PR and CBT alone, the PR+CBT+BPA intervention induced greater clinically meaningful improvements in HADS anxiety scores (by -2â units, 95% CI -4-1â units) and 6MWD (by 33±20â m). Conclusions: Providing anxious and/or depressed patients with COPD with a combined intervention of CBT and BPA during PR presents more favourable improvements in physical activity outcome measures compared to CBT alone during PR.
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BACKGROUND: The TANDEM multicentre, pragmatic, randomised controlled trial evaluated whether a tailored psychological intervention based on a cognitive behavioural approach for people with COPD and symptoms of anxiety and/or depression improved anxiety or depression compared with usual care (control). METHODS: People with COPD and moderate to very severe airways obstruction and Hospital Anxiety and Depression Scale subscale scores indicating mild to moderate anxiety (HADS-A) and/or depression (HADS-D) were randomised 1.25:1 (242 intervention and 181 control). Respiratory health professionals delivered the intervention face-to-face over 6-8â weeks. Co-primary outcomes were HADS-A and HADS-D measured 6â months post-randomisation. Secondary outcomes at 6 and 12â months included: HADS-A and HADS-D (12â months), Beck Depression Inventory II, Beck Anxiety Inventory, St George's Respiratory Questionnaire, social engagement, the EuroQol instrument five-level version (EQ-5D-5L), smoking status, completion of pulmonary rehabilitation, and health and social care resource use. RESULTS: The intervention did not improve anxiety (HADS-A mean difference -0.60, 95% CI -1.40-0.21) or depression (HADS-D mean difference -0.66, 95% CI -1.39-0.07) at 6â months. The intervention did not improve any secondary outcomes at either time-point, nor did it influence completion of pulmonary rehabilitation or healthcare resource use. Deaths in the intervention arm (13/242; 5%) exceeded those in the control arm (3/181; 2%), but none were associated with the intervention. Health economic analysis found the intervention highly unlikely to be cost-effective. CONCLUSION: This trial has shown, beyond reasonable doubt, that this cognitive behavioural intervention delivered by trained and supervised respiratory health professionals does not improve psychological comorbidity in people with advanced COPD and depression or anxiety.
Subject(s)
Depression , Pulmonary Disease, Chronic Obstructive , Humans , Depression/therapy , Psychosocial Intervention , Anxiety/therapy , Anxiety Disorders , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/therapy , Quality of LifeABSTRACT
Pig keeping is important to the livelihoods of many rural Ugandans. Pigs are typically sold based on live weight or a carcass weight derived from this; however this weight is commonly estimated due to the lack of access to scales. Here, we explore the development of a weigh band for more accurate weight determination and potentially increased farmer bargaining power on sale price. Pig weights and varied body measurements (heart girth, height, and length) were collected on 764 pigs of different ages, sex, and breed types, from 157 smallholder pig keeping households in Central and Western Uganda. Mixed-effects linear regression analyses, with household as a random effect and the varied body measurements as a fixed effect, were performed to determine the best single predictor for cube root of weight (transformation of weight for normality), for 749 pigs ranging between 0 and 125 kg. The most predictive single body measurement was heart girth, where weight in kg = (0.4011 + heart girth in cm × 0.0381)3. This model was found to be most suitable for pigs between 5 and 110 kg, notably more accurate than farmers' estimates, but still with somewhat broad confidence intervals (for example, ±11.5 kg for pigs with a predicted weight of 51.3 kg). We intend to pilot test a weigh band based on this model before deciding on whether it is suitable for wider scaling.
Subject(s)
Commerce , Farmers , Swine , Animals , Humans , Uganda , HeartABSTRACT
Alzheimer's disease is linked to increased levels of amyloid beta (Aß) in the brain, but the mechanisms underlying neuronal dysfunction and neurodegeneration remain enigmatic. Here, we investigate whether organizational characteristics of functional presynaptic vesicle pools, key determinants of information transmission in the central nervous system, are targets for elevated Aß. Using an optical readout method in cultured hippocampal neurons, we show that acute Aß42 treatment significantly enlarges the fraction of functional vesicles at individual terminals. We observe the same effect in a chronically elevated Aß transgenic model (APPSw,Ind) using an ultrastructure-function approach that provides detailed information on nanoscale vesicle pool positioning. Strikingly, elevated Aß is correlated with excessive accumulation of recycled vesicles near putative endocytic sites, which is consistent with deficits in vesicle retrieval pathways. Using the glutamate reporter, iGluSnFR, we show that there are parallel functional consequences, where ongoing information signaling capacity is constrained. Treatment with levetiracetam, an antiepileptic that dampens synaptic hyperactivity, partially rescues these transmission defects. Our findings implicate organizational and dynamic features of functional vesicle pools as targets in Aß-driven synaptic impairment, suggesting that interventions to relieve the overloading of vesicle retrieval pathways might have promising therapeutic value.
Subject(s)
Amyloid beta-Peptides , Synaptic Vesicles , Synaptic Vesicles/physiology , Amyloid beta-Peptides/metabolism , Presynaptic Terminals/physiology , Neurons/metabolism , Hippocampus/physiology , Synaptic Transmission/physiologyABSTRACT
Tau is a natively unfolded protein that contributes to the stability of microtubules. Under pathological conditions such as Alzheimer's disease (AD), tau protein misfolds and self-assembles to form paired helical filaments (PHFs) and straight filaments (SFs). Full-length tau protein assembles poorly and its self-assembly is enhanced with polyanions such as heparin and RNA in vitro, but a role for heparin or other polyanions in vivo remains unclear. Recently, a truncated form of tau (297-391) has been shown to self-assemble in the absence of additives which provides an alternative in vitro PHF model system. Here we describe methods to prepare in vitro PHFs and SFs from tau (297-391) named dGAE. We also discuss the range of biophysical/biochemical techniques used to monitor tau filament assembly and structure.
Subject(s)
Alzheimer Disease , tau Proteins , Humans , tau Proteins/metabolism , Neurofibrillary Tangles/metabolism , Alzheimer Disease/metabolism , Heparin/metabolismABSTRACT
Background: The COVID-19 pandemic confirmed that respiratory nurses are critical healthcare providers. Limited knowledge is available about appropriate education to prepare nurses to deliver high-quality respiratory care. A survey was developed by the International Coalition for Respiratory Nursing (ICRN) group to identify the need for a respiratory nursing core curriculum. Method: A 39-item survey was distributed to 33 respiratory nursing experts in 27 countries. Questions asked about current roles, perception of need, expectations for a core curriculum project and respiratory content in nursing education in their countries. Results: 30 responses from 25 countries were analysed; participants predominantly worked in academia (53.3%, 16/30) and clinical practice (40%, 12/30). In total, 97% (29/30) confirmed a need for a core respiratory nursing curriculum. Post-registration nursing programmes at bachelor (83.3%, 25/30) and masters (63.3%, 19/30) levels include internal/medical nursing care; less than half identified separate respiratory nursing content. The core educational programme developed should include knowledge (70%, 21/30), skills (60%, 18/30), and competencies (50%, 15/30), with separate paediatric and adult content. Conclusion: Survey results confirm a wide variation in nursing education and respiratory nursing education across the world, with many countries lacking any formal educational programmes to prepare nurses capable of providing enhanced quality respiratory care. These findings support the need for a core respiratory curriculum. To advance this significant work the ICRN group plans to conduct a Delphi study to identify core curriculum requirements for respiratory nursing education at pre-registration and advanced educational levels to flexibly meet each country's specific educational requirements for recognition of respiratory nursing speciality practice.
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Self-management, as a strategy to support those living with chronic respiratory conditions such as asthma and COPD, has been widely advocated in guidelines and adopted in practice. However, there can be a disconnect between the goals of patients and healthcare professionals. Goals and barriers to self-management are often compounded by the complex social, emotional and medical needs of patients. People living with chronic respiratory conditions also often have symptoms of anxiety and depression, which can impact on self-management. Self-management therefore requires patients and healthcare professionals to work together and it is essential to involve patients when designing, implementing and evaluating self-management interventions. Patient preferences are clearly important and goal setting needs an individual, flexible and responsive approach from healthcare professionals, which aligns to a more personalised approach to management of treatable traits and the burden of disease. To achieve these goals, healthcare professionals need education to support patients in self-management and behaviour change. This approach should lead to shared decision-making and partnership working that puts the patient right at the centre of their care.
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BACKGROUND: Despite improvements in pulmonary function following lung transplantation (LTx), physical activity levels remain significantly lower than the general population. To date, there is little research investigating interventions to improve daily physical activity in LTx recipients. This study assessed the feasibility and acceptability of a novel, 12-weeks physical activity tele-coaching (TC) intervention in LTx recipients. METHODS: Lung transplant recipients within 2 months of hospital discharge were recruited and randomised (1:1) to TC or usual care (UC). TC consists of a pedometer and smartphone app, allowing transmission of activity data to a platform that provides feedback, activity goals, education, and contact with the researcher as required. Recruitment and retention, occurrence of adverse events, intervention acceptability and usage were used to assess feasibility. RESULTS: Key criteria for progressing to a larger study were met. Of the 15 patients eligible, 14 were recruited and randomised to TC or UC and 12 completed (67% male; mean ± SD age; 58 ± 7 years; COPD n = 4, ILD n = 6, CF n = 1, PH n = 1): TC (n = 7) and UC (n = 5). TC was well accepted by patients, with 86% indicating that they enjoyed taking part. Usage of the pedometer was excellent, with all patients wearing it for over 90% of days and rating the pedometer and telephone contact as the most vital aspects. There were no adverse events related to the intervention. After 12 weeks, only TC displayed improvements in accelerometry steps/day (by 3475 ± 3422; p = .036) and movement intensity (by 153 ± 166 VMU; p = .019), whereas both TC and UC groups exhibited clinically important changes in physical SF-36 scores (by 11 ± 14 and 7 ± 9 points, respectively). CONCLUSION: TC appears to be a feasible, safe, and well-accepted intervention in LTx.
Subject(s)
Mentoring , Female , Humans , Male , Exercise , Feasibility Studies , Lung , Transplant RecipientsABSTRACT
BACKGROUND: In cattle, genome-wide association studies (GWAS) have largely focused on European or Asian breeds, using genotyping arrays that were primarily designed for European cattle. Because there is growing interest in performing GWAS in African breeds, we have assessed the performance of 23 commercial bovine genotyping arrays for capturing the diversity across African breeds and performing imputation. We used 409 whole-genome sequences (WGS) spanning global cattle breeds, and a real cohort of 2481 individuals (including African breeds) that were genotyped with the Illumina high-density (HD) array and the GeneSeek bovine 50 k array. RESULTS: We found that commercially available arrays were not effective in capturing variants that segregate among African indicine animals. Only 6% of these variants in high linkage disequilibrium (LD) (r2 > 0.8) were on the best performing arrays, which contrasts with the 17% and 25% in African and European taurine cattle, respectively. However, imputation from available HD arrays can successfully capture most variants (accuracies up to 0.93), mainly when using a global, not continent-specific, reference panel, which partially reflects the unusually high levels of admixture on the continent. When considering functional variants, the GGPF250 array performed best for tagging WGS variants and imputation. Finally, we show that imputation from low-density arrays can perform almost as well as HD arrays, if a two-stage imputation approach is adopted, i.e. first imputing to HD and then to WGS, which can potentially reduce the costs of GWAS. CONCLUSIONS: Our results show that the choice of an array should be based on a balance between the objective of the study and the breed/population considered, with the HD and BOS1 arrays being the best choice for both taurine and indicine breeds when performing GWAS, and the GGPF250 being preferable for fine-mapping studies. Moreover, our results suggest that there is no advantage to using the indicus-specific arrays for indicus breeds, regardless of the objective. Finally, we show that using a reference panel that better represents global bovine diversity improves imputation accuracy, particularly for non-European taurine populations.
Subject(s)
Genome-Wide Association Study , Polymorphism, Single Nucleotide , Animals , Cattle/genetics , Genotype , Linkage DisequilibriumABSTRACT
A characteristic hallmark of Alzheimer's Disease (AD) is the pathological aggregation and deposition of tau into paired helical filaments (PHF) in neurofibrillary tangles (NFTs). Oxidative stress is an early event during AD pathogenesis and is associated with tau-mediated AD pathology. Oxidative environments can result in the formation of covalent dityrosine crosslinks that can increase protein stability and insolubility. Dityrosine cross-linking has been shown in Aß plaques in AD and α-synuclein aggregates in Lewy bodies in ex vivo tissue sections, and this modification may increase the insolubility of these aggregates and their resistance to degradation. Using the PHF-core tau fragment (residues 297 - 391) as a model, we have previously demonstrated that dityrosine formation traps tau assemblies to reduce further elongation. However, it is unknown whether dityrosine crosslinks are found in tau deposits in vivo in AD and its relevance to disease mechanism is unclear. Here, using transmission electron microscope (TEM) double immunogold-labelling, we reveal that neurofibrillary NFTs in AD are heavily decorated with dityrosine crosslinks alongside tau. Single immunogold-labelling TEM and fluorescence spectroscopy revealed the presence of dityrosine on AD brain-derived tau oligomers and fibrils. Using the tau (297-391) PHF-core fragment as a model, we further showed that prefibrillar tau species are more amenable to dityrosine crosslinking than tau fibrils. Dityrosine formation results in heat and SDS stability of oxidised prefibrillar and fibrillar tau assemblies. This finding has implications for understanding the mechanism governing the insolubility and toxicity of tau assemblies in vivo.
Subject(s)
Alzheimer Disease , Neurofibrillary Tangles , Tyrosine , tau Proteins , Alzheimer Disease/metabolism , Humans , Neurofibrillary Tangles/chemistry , Protein Conformation, alpha-Helical , Tyrosine/analogs & derivatives , Tyrosine/chemistry , alpha-Synuclein/chemistry , tau Proteins/chemistryABSTRACT
BACKGROUND: Indigenous Sudanese cattle are mainly indicine/zebu (humped) type. They thrive in the harshest dryland environments characterised by high temperatures, long seasonal dry periods, nutritional shortages, and vector disease challenges. Here, we sequenced 60 indigenous Sudanese cattle from six indigenous breeds and analysed the data using three genomic scan approaches to unravel cattle adaptation to the African dryland region. RESULTS: We identified a set of gene-rich selective sweep regions, detected mostly on chromosomes 5, 7 and 19, shared across African and Gir zebu. These include genes involved in immune response, body size and conformation, and heat stress response. We also identified selective sweep regions unique to Sudanese zebu. Of these, a 250 kb selective sweep on chromosome 16 spans seven genes, including PLCH2, PEX10, PRKCZ, and SKI, which are involved in alternative adaptive metabolic strategies of insulin signalling, glucose homeostasis, and fat metabolism. CONCLUSIONS: Our results suggest that environmental adaptation may involve recent and ancient selection at gene-rich regions, which might be under a common regulatory genetic control, in zebu cattle.