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.

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.

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.

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.

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.

Recombinant annexin A6 promotes membrane repair and protects against muscle injury.

Membrane repair is essential to cell survival. In skeletal muscle, injury often associates with plasma membrane disruption. Additionally, muscular dystrophy is linked to mutations in genes that produce fragile membranes or reduce membrane repair. Methods to enhance repair and reduce susceptibility to injury could benefit muscle in both acute and chronic injury settings. Annexins are a family of membrane-associated Ca2+-binding proteins implicated in repair, and annexin A6 was previously identified as a genetic modifier of muscle injury and disease. Annexin A6 forms the repair cap over the site of membrane disruption. To elucidate how annexins facilitate repair, we visualized annexin cap formation during injury. We found that annexin cap size positively correlated with increasing Ca2+ concentrations. We also found that annexin overexpression promoted external blebs enriched in Ca2+ and correlated with a reduction of intracellular Ca2+ at the injury site. Annexin A6 overexpression reduced membrane injury, consistent with enhanced repair. Treatment with recombinant annexin A6 protected against acute muscle injury in vitro and in vivo. Moreover, administration of recombinant annexin A6 in a model of muscular dystrophy reduced serum creatinine kinase, a biomarker of disease. These data identify annexins as mediators of membrane-associated Ca2+ release during membrane repair and annexin A6 as a therapeutic target to enhance membrane repair capacity.

Mental health liaison in a regional burns unit-Past, present and future.

OBJECTIVE: To describe the epidemiology of patients assessed by a Psychiatric Liaison Team (PLT) on a Regional Burns Unit in London, UK. METHOD: A case note review of all patients assessed by the PLT over a 4-year period was carried out. Data were extracted regarding whether the burn was sustained intentionally or non-intentionally, ICD-10 psychiatric diagnosis, alcohol use at the time of injury and mechanism of injury. The independent t-test and chi-squared test were used for data analysis. RESULTS: The PLT assessed 81 patients in total, 45 (55.6%) of burns were non-intentional, 32 (39.5%) were deliberate, and 4 patients (4.9%) were victims of an assault. The overall ratio of males to females was approximately equal. The mean age of patients with deliberate burns was younger, as compared to non-intentional burns, this difference was statistically significant (p < 0.01). Of the patients in the sample, 95% had a psychiatric diagnosis. We identified a difference in type of psychiatric diagnosis in the non-intentional and intentional burns groups. Alcohol use was linked to 38 (48%) of all patients assessed. Flame injuries were the most common mechanism of injury. Chemical burns, were significantly associated with a diagnosis of personality disorder (p < 0.05, chi-square test). CONCLUSION: Well-resourced psychiatric liaison teams working collaboratively with burns units are essential to meet the needs of this diverse and complex group of patients.

Deletion of Sulfonylurea Receptor 2 in the Adult Myocardium Enhances Cardiac Glucose Uptake and Is Cardioprotective.

The adult myocardium relies on oxidative metabolism. In ischemic myocardium, such as the embryonic heart, glycolysis contributes more prominently as a fuel source. The sulfonylurea receptor 2 (SUR2) was previously implicated in the normal myocardial transition from glycolytic to oxidative metabolism that occurs during adaptation to postnatal life. This receptor was now selectively deleted in adult mouse myocardium resulting in protection from ischemia reperfusion injury. SUR2-deleted cardiomyocytes had enhanced glucose uptake, and SUR2 forms a complex with the major glucose transporter. These data identify the SUR2 receptor as a target to shift cardiac metabolism to protect against myocardial injury.

HZETRN radiation transport validation using balloon-based experimental data.

The deterministic radiation transport code HZETRN (High charge (Z) and Energy TRaNsport) was developed by NASA to study the effects of cosmic radiation on astronauts and instrumentation shielded by various materials. This work presents an analysis of computed differential flux from HZETRN compared with measurement data from three balloon-based experiments over a range of atmospheric depths, particle types, and energies. Model uncertainties were quantified using an interval-based validation metric that takes into account measurement uncertainty both in the flux and the energy at which it was measured. Average uncertainty metrics were computed for the entire dataset as well as subsets of the measurements (by experiment, particle type, energy, etc.) to reveal any specific trends of systematic over- or under-prediction by HZETRN. The distribution of individual model uncertainties was also investigated to study the range and dispersion of errors beyond just single scalar and interval metrics. The differential fluxes from HZETRN were generally well-correlated with balloon-based measurements; the median relative model difference across the entire dataset was determined to be 30%. The distribution of model uncertainties, however, revealed that the range of errors was relatively broad, with approximately 30% of the uncertainties exceeding  ±â€¯40%. The distribution also indicated that HZETRN systematically under-predicts the measurement dataset as a whole, with approximately 80% of the relative uncertainties having negative values. Instances of systematic bias for subsets of the data were also observed, including a significant underestimation of alpha particles and protons for energies below 2.5  GeV/u. Muons were found to be systematically over-predicted at atmospheric depths deeper than 50 g/cm2 but under-predicted for shallower depths. Furthermore, a systematic under-prediction of alpha particles and protons was observed below the geomagnetic cutoff, suggesting that improvements to the light ion production cross sections in HZETRN should be investigated.

Can we improve the outcome of hydrodilatation for adhesive capsulitis?

BACKGROUND: Hydrodilatation (HD) has been shown to improve pain and function in patients with adhesive capsulitis (AC). There is no consensus concerning how HD should be performed or what volume should be injected. It has distinct advantages compared to surgery; however, it is a painful procedure and is often poorly tolerated. METHODS: We retrospectively reviewed all patients referred for HD over a 2.5-year period aiming to assess whether volume injected influences outcome. RESULTS: There were 107 patients treated with HD; of these, 76 (43 female, 32 male) had full data for analysis. The majority were classified as primary AC (n = 57) with an average age of 55.5 years. The mean improvement in Oxford Shoulder Score (OSS) was 12.1, with females (13.9) and post-traumatic cases of AC (14.1) demonstrating the best outcome. No complications were observed during the HD process. There was a negative correlation observed between volume injected and OSS improvement. Only two patients experienced a poor outcome and required further treatment with manipulation +/- arthroscopic arthrolysis. CONCLUSIONS: The present study supports the use of HD as a first line treatment for AC regardless of the underlying cause, and also demonstrates that the volume injected does appear to influence the outcome.

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.

STING-associated vasculopathy develops independently of IRF3 in mice.

Patients with stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) develop systemic inflammation characterized by vasculopathy, interstitial lung disease, ulcerative skin lesions, and premature death. Autosomal dominant mutations in STING are thought to trigger activation of IRF3 and subsequent up-regulation of interferon (IFN)-stimulated genes (ISGs) in patients with SAVI. We generated heterozygous STING N153S knock-in mice as a model of SAVI. These mice spontaneously developed inflammation within the lung, hypercytokinemia, T cell cytopenia, skin ulcerations, and premature death. Cytometry by time-of-flight (CyTOF) analysis revealed that the STING N153S mutation caused myeloid cell expansion, T cell cytopenia, and dysregulation of immune cell signaling. Unexpectedly, we observed only mild up-regulation of ISGs in STING N153S fibroblasts and splenocytes and STING N154S SAVI patient fibroblasts. STING N153S mice lacking IRF3 also developed lung disease, myeloid cell expansion, and T cell cytopenia. Thus, the SAVI-associated STING N153S mutation triggers IRF3-independent immune cell dysregulation and lung disease in mice.

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.

Intermittent glucocorticoid steroid dosing enhances muscle repair without eliciting muscle atrophy.

Glucocorticoid steroids such as prednisone are prescribed for chronic muscle conditions such as Duchenne muscular dystrophy, where their use is associated with prolonged ambulation. The positive effects of chronic steroid treatment in muscular dystrophy are paradoxical because these steroids are also known to trigger muscle atrophy. Chronic steroid use usually involves once-daily dosing, although weekly dosing in children has been suggested for its reduced side effects on behavior. In this work, we tested steroid dosing in mice and found that a single pulse of glucocorticoid steroids improved sarcolemmal repair through increased expression of annexins A1 and A6, which mediate myofiber repair. This increased expression was dependent on glucocorticoid response elements upstream of annexins and was reinforced by the expression of forkhead box O1 (FOXO1). We compared weekly versus daily steroid treatment in mouse models of acute muscle injury and in muscular dystrophy and determined that both regimens provided comparable benefits in terms of annexin gene expression and muscle repair. However, daily dosing activated atrophic pathways, including F-box protein 32 (Fbxo32), which encodes atrogin-1. Conversely, weekly steroid treatment in mdx mice improved muscle function and histopathology and concomitantly induced the ergogenic transcription factor Krüppel-like factor 15 (Klf15) while decreasing Fbxo32. These findings suggest that intermittent, rather than daily, glucocorticoid steroid regimen promotes sarcolemmal repair and muscle recovery from injury while limiting atrophic remodeling.

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.

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.

A Computationally-Efficient Probabilistic Approach to Model-Based Damage Diagnosis.

This work presents a computationally-efficient, probabilistic approach to model-based damage diagnosis. Given measurement data, probability distributions of unknown damage parameters are estimated using Bayesian inference and Markov chain Monte Carlo (MCMC) sampling. Substantial computational speedup is obtained by replacing a three-dimensional finite element (FE) model with an efficient surrogate model. While the formulation is general for arbitrary component geometry, damage type, and sensor data, it is applied to the problem of strain-based crack characterization and experimentally validated using full-field strain data from digital image correlation (DIC). Access to full-field DIC data facilitates the study of the effectiveness of strain-based diagnosis as the distance between the location of damage and strain measurements is varied. The ability of the framework to accurately estimate the crack parameters and effectively capture the uncertainty due to measurement proximity and experimental error is demonstrated. Furthermore, surrogate modeling is shown to enable diagnoses on the order of seconds and minutes rather than several days required with the FE model.

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.