Insights into Spt6: a histone chaperone that functions in transcription, DNA replication, and genome stability.

Transcription elongation requires elaborate coordination between the transcriptional machinery and chromatin regulatory factors to successfully produce RNA while preserving the epigenetic landscape. Recent structural and genomic studies have highlighted that suppressor of Ty 6 (Spt6), a conserved histone chaperone and transcription elongation factor, sits at the crux of the transcription elongation process. Other recent studies have revealed that Spt6 also promotes DNA replication and genome integrity. Here, we review recent studies of Spt6 that have provided new insights into the mechanisms by which Spt6 controls transcription and have revealed the breadth of Spt6 functions in eukaryotic cells.

Genetic modifiers of muscular dystrophy act on sarcolemmal resealing and recovery from injury.

Genetic disruption of the dystrophin complex produces muscular dystrophy characterized by a fragile muscle plasma membrane leading to excessive muscle degeneration. Two genetic modifiers of Duchenne Muscular Dystrophy implicate the transforming growth factor ß (TGFß) pathway, osteopontin encoded by the SPP1 gene and latent TGFß binding protein 4 (LTBP4). We now evaluated the functional effect of these modifiers in the context of muscle injury and repair to elucidate their mechanisms of action. We found that excess osteopontin exacerbated sarcolemmal injury, and correspondingly, that loss of osteopontin reduced injury extent both in isolated myofibers and in muscle in vivo. We found that ablation of osteopontin was associated with reduced expression of TGFß and TGFß-associated pathways. We identified that increased TGFß resulted in reduced expression of Anxa1 and Anxa6, genes encoding key components of the muscle sarcolemma resealing process. Genetic manipulation of Ltbp4 in dystrophic muscle also directly modulated sarcolemmal resealing, and Ltbp4 alleles acted in concert with Anxa6, a distinct modifier of muscular dystrophy. These data provide a model in which a feed forward loop of TGFß and osteopontin directly impacts the capacity of muscle to recover from injury, and identifies an intersection of genetic modifiers on muscular dystrophy.

Intermittent Glucocorticoid Dosing Improves Muscle Repair and Function in Mice with Limb-Girdle Muscular Dystrophy.

The muscular dystrophies are genetically diverse. Shared pathological features among muscular dystrophies include breakdown, or loss of muscle, and accompanying fibrotic replacement. Novel strategies are needed to enhance muscle repair and function and to slow this pathological remodeling. Glucocorticoid steroids, like prednisone, are known to delay loss of ambulation in patients with Duchenne muscular dystrophy but are accompanied by prominent adverse effects. However, less is known about the effects of steroid administration in other types of muscular dystrophies, including limb-girdle muscular dystrophies (LGMDs). LGMD 2B is caused by loss of dysferlin, a membrane repair protein, and LGMD 2C is caused by loss of the dystrophin-associated protein, γ-sarcoglycan. Herein, we assessed the efficacy of steroid dosing on sarcolemmal repair, muscle function, histopathology, and the regenerative capacity of primary muscle cells. We found that in murine models of LGMD 2B and 2C, daily prednisone dosing reduced muscle damage and fibroinflammatory infiltration. However, daily prednisone dosing also correlated with increased muscle adipogenesis and atrophic remodeling. Conversely, intermittent dosing of prednisone, provided once weekly, enhanced muscle repair and did not induce atrophy or adipogenesis, and was associated with improved muscle function. These data indicate that dosing frequency of glucocorticoid steroids affects muscle remodeling in non-Duchenne muscular dystrophies, suggesting a positive outcome associated with intermittent steroid dosing in LGMD 2B and 2C muscle.

Enhanced Muscular Dystrophy from Loss of Dysferlin Is Accompanied by Impaired Annexin A6 Translocation after Sarcolemmal Disruption.

Dysferlin is a membrane-associated protein implicated in membrane resealing; loss of dysferlin leads to muscular dystrophy. We examined the same loss-of-function Dysf mutation in two different mouse strains, 129T2/SvEmsJ (Dysf(129)) and C57BL/6J (Dysf(B6)). Although there are many genetic differences between these two strains, we focused on polymorphisms in Anxa6 because these variants were previously associated with modifying a pathologically distinct form of muscular dystrophy and increased the production of a truncated annexin A6 protein. Dysferlin deficiency in the C57BL/6J background was associated with increased Evan's Blue dye uptake into muscle and increased serum creatine kinase compared to the 129T2/SvEmsJ background. In the C57BL/6J background, dysferlin loss was associated with enhanced pathologic severity, characterized by decreased mean fiber cross-sectional area, increased internalized nuclei, and increased fibrosis, compared to that in Dysf(129) mice. Macrophage infiltrate was also increased in Dysf(B6) muscle. High-resolution imaging of live myofibers demonstrated that fibers from Dysf(B6) mice displayed reduced translocation of full-length annexin A6 to the site of laser-induced sarcolemmal disruption compared to Dysf(129) myofibers, and impaired translocation of annexin A6 associated with impaired resealing of the sarcolemma. These results provide one mechanism by which the C57BL/6J background intensifies dysferlinopathy, giving rise to a more severe form of muscular dystrophy in the Dysf(B6) mouse model through increased membrane leak and inflammation.

Comparison of service utilisation and costs of working age adults and older adults receiving treatment for psychosis and severe non-psychotic conditions in England: implications for commissioning.

OBJECTIVE: Current plans in the English National Health Service are to replace block contracts for mental health providers with a single tariff for each 'cluster' of conditions. A single tariff will not take into account the potential additional complexity and costs inherent in caring for older people. To examine the basis for a uniform tariff, differences in service utilisation and costs between working age adults and older adults in two populous clusters (non-psychotic, psychotic) were investigated across five mental health healthcare providers in and around London. METHODS: Retrospective review of records over 3 months assessing service utilisation and costs using the Client Services Receipt Inventory. RESULTS: Records of 362 patients were reviewed, 179 older adults (90 non-psychotic, 89 psychotic) and 183 adults of working age (83 non-psychotic, 100 psychotic). Older adults in both clusters had more tests, assessments and home visits. Overall costs of care of older adults were significantly higher in the non-psychotic cluster (£5634, vs £4405 psychotic, p = 0.044). CONCLUSIONS: An appropriate age-related tariff is required for each cluster. Copyright © 2016 John Wiley & Sons, Ltd.

Ethiopian wheat yield and yield gap estimation: A spatially explicit small area integrated data approach.

Despite the routine collection of annual agricultural surveys and significant advances in GIS and remote sensing products, little econometric research has integrated these data sources in estimating developing nations' agricultural yields. In this paper, we explore the determinants of wheat output per hectare in Ethiopia during the 2011-2013 principal Meher crop seasons at the kebele administrative area. Using a panel data approach, combining national agricultural field surveys with relevant GIS and remote sensing products, the model explains nearly 40% of the total variation in wheat output per hectare across the country. Reflecting on the high interannual variability in output per hectare, we explore whether these changes can be explained by weather, shocks to, and management of rain-fed agricultural systems. The model identifies specific contributors to wheat yields that include farm management techniques (e.g. area planted, improved seed, fertilizer, and irrigation), weather (e.g. rainfall), water availability (e.g. vegetation and moisture deficit indexes) and policy intervention. Our findings suggest that woredas produce between 9.8 and 86.5% of their locally attainable wheat yields given their altitude, weather conditions, terrain, and plant health. In conclusion, we believe the combination of field surveys with spatial data can be used to identify management priorities for improving production at a variety of administrative levels.

Cost-effectiveness of exercise as a therapy for behavioural and psychological symptoms of dementia within the EVIDEM-E randomised controlled trial.

OBJECTIVE: Although available evidence is modest, exercise could be beneficial in reducing behavioural and psychological symptoms of dementia. We aim to evaluate the cost-effectiveness of a dyadic exercise regimen for individuals with dementia and their main carer as therapy for behavioural and psychological symptoms of dementia. METHODS: Cost-effectiveness analysis within a two-arm, pragmatic, randomised, controlled, single-blind, parallel-group trial of a dyadic exercise regimen (individually tailored, for 20-30 min at least five times per week). The study randomised 131 community-dwelling individuals with dementia and clinically significant behavioural and psychological symptoms with a carer willing and able to participate in the exercise regimen; 52 dyads provided sufficient cost data for analyses. RESULTS: Mean intervention cost was £284 per dyad. For the subsample of 52 dyads, the intervention group had significantly higher mean cost from a societal perspective (mean difference £2728.60, p = 0.05), but costs were not significantly different from a health and social care perspective. The exercise intervention was more cost-effective than treatment as usual from both societal and health and social care perspectives for the measure of behavioural and psychological symptoms (Neuropsychiatric Inventory). It does not appear cost-effective in terms of cost per quality-adjusted life year gain. CONCLUSIONS: The exercise intervention has the potential to be seen as cost-effective when considering behavioural and psychological symptoms but did not appear cost-effective when considering quality-adjusted life year gains.

RBPJ mutations identified in two families affected by Adams-Oliver syndrome.

Through exome resequencing, we identified two unique mutations in recombination signal binding protein for immunoglobulin kappa J (RBPJ) in two independent families affected by Adams-Oliver syndrome (AOS), a rare multiple-malformation disorder consisting primarily of aplasia cutis congenita of the vertex scalp and transverse terminal limb defects. These identified mutations link RBPJ, the primary transcriptional regulator for the Notch pathway, with AOS, a human genetic disorder. Functional assays confirmed impaired DNA binding of mutated RBPJ, placing it among other notch-pathway proteins altered in human genetic syndromes.

Old age psychiatry in the modern age.

Old age psychiatry services globally are under threat. The discipline enjoyed its heyday in the two decades bridging the millennium. More recently there has been a move to integrate old age services with those of working age adults, to create 'ageless' services. Evidence is beginning to accumulate that this is a bad idea.

Kinetic Stability of MOF-5 in Humid Environments: Impact of Powder Densification, Humidity Level, and Exposure Time.

Metal-organic frameworks (MOFs) are an emerging class of microporous, crystalline materials with potential applications in the capture, storage, and separation of gases. Of the many known MOFs, MOF-5 has attracted considerable attention because of its ability to store gaseous fuels at low pressure with high densities. Nevertheless, MOF-5 and several other MOFs exhibit limited stability upon exposure to reactive species such as water. The present study quantifies the impact of humid air exposure on the properties of MOF-5 as a function of exposure time, humidity level, and morphology (i.e., powders vs pellets). Properties examined include hydrogen storage capacity, surface area, and crystallinity. Water adsorption/desorption isotherms are measured using a gravimetric technique; the first uptake exhibits a type V isotherm with a sudden increase in uptake at ∼50% relative humidity. For humidity levels below this threshold only minor degradation is observed for exposure times up to several hours, suggesting that MOF-5 is more stable than generally assumed under moderately humid conditions. In contrast, irreversible degradation occurs in a matter of minutes for exposures above the 50% threshold. Fourier transform infrared spectroscopy indicates that molecular and/or dissociated water is inserted into the skeletal framework after long exposure times. Densification into pellets can slow the degradation of MOF-5 significantly, and may present a pathway to enhance the stability of some MOFs.

Stochastic reduced order models for inverse problems under uncertainty.

This work presents a novel methodology for solving inverse problems under uncertainty using stochastic reduced order models (SROMs). Given statistical information about an observed state variable in a system, unknown parameters are estimated probabilistically through the solution of a model-constrained, stochastic optimization problem. The point of departure and crux of the proposed framework is the representation of a random quantity using a SROM - a low dimensional, discrete approximation to a continuous random element that permits e cient and non-intrusive stochastic computations. Characterizing the uncertainties with SROMs transforms the stochastic optimization problem into a deterministic one. The non-intrusive nature of SROMs facilitates e cient gradient computations for random vector unknowns and relies entirely on calls to existing deterministic solvers. Furthermore, the method is naturally extended to handle multiple sources of uncertainty in cases where state variable data, system parameters, and boundary conditions are all considered random. The new and widely-applicable SROM framework is formulated for a general stochastic optimization problem in terms of an abstract objective function and constraining model. For demonstration purposes, however, we study its performance in the specific case of inverse identification of random material parameters in elastodynamics. We demonstrate the ability to efficiently recover random shear moduli given material displacement statistics as input data. We also show that the approach remains effective for the case where the loading in the problem is random as well.

The effect of exercise on behavioural and psychological symptoms of dementia: the EVIDEM-E randomised controlled clinical trial.

OBJECTIVE: The objective of this study is to evaluate the effectiveness of a simple dyadic (person with dementia and their main carer) exercise regimen as a therapy for the behavioural and psychological symptoms of dementia. METHOD: A two arm, pragmatic, randomised, controlled, single-blind, parallel-group trial of a dyadic exercise regimen (individually tailored walking regimen designed to become progressively intensive and last between 20-30 min, at least five times per week).Community-dwelling individuals with ICD-10 confirmed dementia with the following: clinically significant behavioural and psychological symptoms, a carer willing and able to co-participate in the exercise regimen, and no physical conditions or symptoms that would preclude exercise participation were invited by mental health or primary care services into the study. RESULTS: One hundred and thirty-one dyads were recruited to this study. There was no significant difference in Behavioural and Psychological Symptoms as measured by the Neuropsychiatric Inventory at week 12 between the group receiving the dyadic exercise regimen and those that did not (adjusted difference in means (intervention minus control) = -1.53, p = 0.6, 95% CI [-7.37, 4.32]). There was a significant between-group difference in caregiver's burden as measured by the Zarit Caregiver Burden Inventory at week 12 (OR = 0.18, p = 0.01, CI [0.05, 0.69]) favouring the exercise group. CONCLUSIONS: This study found that regular simple exercise does not appear to improve the behavioural and psychological symptoms of dementia, but did seem to attenuate caregiver burden. Further study to improve exercise uptake are needed.

SMIM1 absence is associated with reduced energy expenditure and excess weight.

BACKGROUND: Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments. METHODS: We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in the small integral membrane protein 1 (SMIM1) and the general population, leveraging data from five cohorts. Metabolic characterization of SMIM1-/- individuals was performed using plasma biochemistry, calorimetric chamber, and DXA scan. FINDINGS: We found that individuals homozygous for a loss-of-function genetic variant in SMIM1 gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin to adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure. CONCLUSION: This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them. FUNDING: This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.

Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550).

Inhibitors of the JAK family of nonreceptor tyrosine kinases have demonstrated clinical efficacy in rheumatoid arthritis and other inflammatory disorders; however, the precise mechanisms by which JAK inhibition improves inflammatory immune responses remain unclear. In this study, we examined the mode of action of tofacitinib (CP-690,550) on JAK/STAT signaling pathways involved in adaptive and innate immune responses. To determine the extent of inhibition of specific JAK/STAT-dependent pathways, we analyzed cytokine stimulation of mouse and human T cells in vitro. We also investigated the consequences of CP-690,550 treatment on Th cell differentiation of naive murine CD4(+) T cells. CP-690,550 inhibited IL-4-dependent Th2 cell differentiation and interestingly also interfered with Th17 cell differentiation. Expression of IL-23 receptor and the Th17 cytokines IL-17A, IL-17F, and IL-22 were blocked when naive Th cells were stimulated with IL-6 and IL-23. In contrast, IL-17A production was enhanced when Th17 cells were differentiated in the presence of TGF-ß. Moreover, CP-690,550 also prevented the activation of STAT1, induction of T-bet, and subsequent generation of Th1 cells. In a model of established arthritis, CP-690,550 rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. Furthermore, efficacy in this disease model correlated with the inhibition of both JAK1 and JAK3 signaling pathways. CP-690,550 also modulated innate responses to LPS in vivo through a mechanism likely involving the inhibition of STAT1 signaling. Thus, CP-690,550 may improve autoimmune diseases and prevent transplant rejection by suppressing the differentiation of pathogenic Th1 and Th17 cells as well as innate immune cell signaling.

Estimating acid soil effects on selected cereal crop productivities in Ethiopia: Comparing economic cost-effectiveness of lime and fertilizer applications.

Acid soils are a major constraint to agricultural productivity in many parts of sub-Saharan Africa, including Ethiopia. Restoring soil pH to optimal ranges for agriculture can have a significant impact on yields, particularly for acid intolerant crops like wheat and barley. The application of agricultural lime is the standard corrective, although the large application requirements, lack of farmer awareness, and weak or non-existent lime supply chains make this a complex problem to address at scale. To date, no large-scale farmer trials of lime application have been undertaken in Ethiopia. This leaves open the question to local policy makers as to the economic benefits given the enormous capital and logistics investments required. To help address this we leverage existing spatial edaphic data and longitudinal crop surveys to simulate the productivity impact of varying lime and fertilizer applications. Our estimates find the impact of moving pH from 5.5 to 6.5, modeled as a lime soil remediation strategy, increases yields by 22% and 19% for wheat and barley, respectively. In addition, at lower pH levels our models indicate that commonly used nitrogen-based fertilizers are less cost-effective. For wheat in highly acidic soils, we find that fertilizers cost over two times as much as a single application of lime over a five-year period. The cost savings of the use of lime reaches as high as 121% of average one-year agricultural household income for wheat; with barley these savings are lower but still substantial at 24%. In general, we advocate for an integrated soil fertility management strategy that applies appropriate levels of fertilizer on pH balanced soil. If successful, Ethiopia's acid soil reclamation could become a modest version of Brazil's successful "cerrado miracle" and serve as an example for Africa.

Biofortification in Ethiopia: Opportunities and Challenges.

BACKGROUND: Children younger than 5 years and women of reproductive age often suffer from micronutrient deficiencies. Biofortification, which involves enriching staple crops with micronutrients, is a nutritional intervention focused on addressing micronutrient deficiencies. It is equitable, sustainable, and costs less than other nutritional interventions. OBJECTIVE: This study investigates biofortification in Ethiopia, considering 6 globally biofortified crops, 5 of which are currently being biofortified in Ethiopia. However, only 2 of these crops are important in the consumption baskets of most Ethiopians. Therefore, efforts to mainstream biofortification should begin with studies to identify crops that have larger impacts in reducing local micronutrient deficiencies and their cost-effectiveness. METHODS: Literature was searched between July and December 2021 using Google Scholar to provide insights into the state of biofortification in Ethiopia. Key-informant interviews were conducted to gain insights into the state of biofortification in Ethiopia and to identify bottlenecks for scaling up the production and consumption of biofortified foods. Furthermore, Annual Agriculture Sample Survey and 2015/16 Ethiopian Household Consumption and Expenditure Survey data were used to describe the area under production of biofortifiable crops and their importance in total consumption, respectively. RESULTS: Mainstreaming biofortification in Ethiopia faces several challenges. Policy documents appear to be inconsistent, regressive, and vague regarding biofortification. Critically, there is no specific institution to oversee and/or coordinate biofortification-related activities. CONCLUSION: Overall, the success of biofortification depends upon a strong coordination body with clear mandates from detailed policies; adequate funding for research and development; and robust monitoring and evaluation of the identified production, adoption, and consumption issues.

Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice.

OBJECTIVES: Obesity in humans and mice is associated with elevated levels of two hormones responsive to cellular stress, namely GDF15 and FGF21. Over-expression of each of these is associated with weight loss and beneficial metabolic changes but where they are secreted from and what they are required for physiologically in the context of overfeeding remains unclear. METHODS: Here we used tissue selective knockout mouse models and human transcriptomics to determine the source of circulating GDF15 in obesity. We then generated and characterized the metabolic phenotypes of GDF15/FGF21 double knockout mice. RESULTS: Circulating GDF15 and FGF21 are both largely derived from the liver, rather than adipose tissue or skeletal muscle, in obese states. Combined whole body deletion of FGF21 and GDF15 does not result in any additional weight gain in response to high fat feeding but it does result in significantly greater hepatic steatosis and insulin resistance than that seen in GDF15 single knockout mice. CONCLUSIONS: Collectively the data suggest that overfeeding activates a stress response in the liver which is the major source of systemic rises in GDF15 and FGF21. These hormones then activate pathways which reduce this metabolic stress.

Empowerment in older psychiatric inpatients: development of the empowerment questionnaire for inpatients (EQuIP).

OBJECTIVE: To develop a questionnaire that measures levels of empowerment experienced by older adults admitted to a psychiatric ward. DESIGN: Diverse views were sought to inform the questionnaire through a triangulation method; opinions of researchers were collected through a Delphi survey, clinical staff from different disciplines completed questionnaires, and patients participated in two focus group sessions. Once the questionnaire was developed, the authors asked patients to complete it alongside other instruments. SETTINGS: Eight psychiatric wards of seven hospitals in and around London for people aged more than 65 years with a range of organic and functional mental health problems. PARTICIPANTS: Eighty-seven patients with a functional psychiatric diagnosis participated in the psychometric evaluation of the instrument; 28 completed the scale twice for test-retest reliability. MEASURES: Measures of quality of life (World Health Organisation Quality of Life - Abbreviated Version), degree of dependency (Care Dependency Scale), satisfaction with care (Psychiatric Care Satisfaction Questionnaire [PCSQ]), and psychosocial functioning (GAF) were used to evaluate psychometric properties of the empowerment questionnaire for inpatients (EQuIP). RESULTS: The EQuIP is a measure of empowerment, which computes the subjective importance of the different aspects of psychiatric care for the individual patient. It had high internal consistency (Cronbach's alpha = 0.88) and reasonable concurrent validity (correlation with PCSQ as a measure of satisfaction with care, r(85) = 0.65, p = 0.01). High test-retest variability may signify fluidity of the construct of empowerment. CONCLUSION: The EQuIP may be used to assess empowerment in older psychiatric inpatients.