PERFORMANCE AND STABILITY OF SOME BREAD WHEAT GENOTYPES FOR GRAIN YIELD, PROTEIN AND GLUTEN CONTENTS UNDER DIFFERENT ENVIRONMENTAL CONDITIONS

Seventeen genotypes (G) of bread wheat (14 promising lines and 3 commercial cultivars) were evaluated for mean performance and stability of grain yield/plant, grain protein content and dry gluten percentage under 16 environments (two locations (L), two sowing dates(D) and four fertilization treatments (F)). The resultsconfirmed the existence of considerable genetic variation among genotypes and their performance was significantly affected by different environments for the studied traits. Kalubia locations recorded the highest mean values for grain yield/plant while; Fayoum location recorded the highest mean values for the two quality traits. Yield and quality traits were significantly increased on early (recommended) sowing dates at Kalubia and Fayoum locations than on late sowing dates. Applying biofertilizer only gave the lowest mean performance in all traits, but adding mineral N besides biofertilizer markedly increased grain yield/plant and the two quality traits. However, insignificant differences existed between the rate of nitrogen recommended (80kg N/fed.) and the rate of (biofertilizer + 60kgN/fed.), indicating that biofertilizer could be efficient in reducing costs of the expensive mineral N and reducing environmental pollution. On an average highest values of grain yield/plant were recorded by the promising wheat lines no. 10 (24.57 g), no. 9 (22.50 g), and no. 11 (21.64 g) as compared to the best check cultivar Giza 168. Meantime, this cultivar surpassed the other genotypes in protein and dry gluten percentages. Concerning phenotypic stability, the three superior lines no. 10, 9 and 11 gave the highest mean values (x¯) of grain/plant coupled with significant regression coefficient (bi) values higher than unity and significant deviation from regression (S2di), thus they considered specifically adapted to favourable environments

Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial

Background: Once-daily oral semaglutide is an effective type 2 diabetes treatment. We aimed to investigate a new formulation of oral semaglutide at higher investigational doses versus the approved 14 mg dose in adults with inadequately controlled type 2 diabetes. Methods: This global, multicentre, randomised, double-blind, phase 3b trial, carried out at 177 sites in 14 countries, enrolled adults with type 2 diabetes, glycated haemoglobin (HbA1c) 8·0−10·5% (64−91 mmol/mol), a BMI of 25·0 kg/m2 or greater, receiving stable daily doses of one to three oral glucose-lowering drugs. Participants were randomly assigned (1:1:1), by means of an interactive web response system, to once-daily oral semaglutide 14 mg, 25 mg, or 50 mg for 68 weeks. Investigators, site personnel, trial participants, and trial sponsor staff were masked to dose assignment throughout the trial. The primary endpoint was change in HbA1c from baseline to week 52, evaluated with a treatment policy estimand in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of trial drug. This trial is registered with ClinicalTrials.gov, NCT04707469, and the European Clinical Trials register, EudraCT 2020-000299-39, and is complete. Findings: Between Jan 15 and Sept 29, 2021, of 2294 people screened, 1606 (n=936 [58·3%] male; n=670 [41·7%] female; mean [SD] age 58·2 [10·8] years) received oral semaglutide 14 mg (n=536), 25 mg (n=535), or 50 mg (n=535). At baseline, mean (SD) HbA1c was 9·0% (0·8; 74·4 mmol/L [SD 8·3]) and mean bodyweight was 96·4 kg (21·6). Mean changes (SE) in HbA1c at week 52 were −1·5 percentage points (SE 0·05) with oral semaglutide 14 mg, −1·8 percentage points (0·06) with 25 mg (estimated treatment difference [ETD] −0·27, 95% CI −0·42 to −0·12; p=0·0006), and −2·0 percentage points (0·06) with 50 mg (ETD −0·53, −0·68 to −0·38; p<0·0001). Adverse events were reported by 404 (76%) participants in the oral semaglutide 14 mg group, 422 (79%) in the 25 mg group, and 428 (80%) in the 50 mg group. Gastrointestinal disorders, which were mostly mild to moderate, occurred more frequently with oral semaglutide 25 mg and 50 mg than with 14 mg. Ten deaths occurred during the trial; none were judged to be treatment related. Interpretation: Oral semaglutide 25 mg and 50 mg were superior to 14 mg in reducing HbA1c and bodyweight in adults with inadequately controlled type 2 diabetes. No new safety concerns were identified. Funding: Novo Nordisk

Integrated Brain Atlas for Unbiased Mapping of Nervous System Effects Following Liraglutide Treatment

Light Sheet Fluorescence Microscopy (LSFM) of whole organs, in particular the brain, offers a plethora of biological data imaged in 3D. This technique is however often hindered by cumbersome non-Automated analysis methods. Here we describe an approach to fully automate the analysis by integrating with data from the Allen Institute of Brain Science (AIBS), to provide precise assessment of the distribution and action of peptide-based pharmaceuticals in the brain. To illustrate this approach, we examined the acute central nervous system effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide. Peripherally administered liraglutide accessed the hypothalamus and brainstem, and led to activation in several brain regions of which most were intersected

New perspectives on pathology in Huntington's disease - characterization of hypothalamic changes

Huntington’s disease (HD) is a neurodegenerative disorder caused by an expansion of the CAG repeat in the huntingtin gene. Non-motor symptoms and signs such as psychiatric disturbances and metabolic dysfunction are also part of the disease manifestation. These symptoms often precede the motor symptoms by decades. The hypothalamus is an area in the brain involved in the regulation of emotions and metabolism. So far, there has been limited assessment of the extent of hypothalamic pathology in HD. We hypothesized that several of the non-motor features may be linked to hypothalamic dysfunction and pathol- ogy. Therefore, the aim of the work in this thesis was to investigate how the hypothala- mus is affected in clinical HD using neuropathological, neuroimaging and gene expression analyses. In the Paper I and II included in this thesis, we quantified selective neuropeptide-ex- pressing hypothalamic populations known to regulate metabolism and emotion in patients with HD compared to healthy controls. We showed that both oxytocin- and vasopressin- expressing neurons were decreased in HD cases. These reductions were suggested to ap- pear at an early disease stage before striatal pathology has occurred. Also in the first study, we demonstrated that the number of cocaine- and amphetamine-regulated transcript (CART)-expressing neurons was increased in HD cases. We also demonstrated that the both oxytocin- and vasopressin-expressing neurons reductions were accompanied with cell loss in the paraventricular nucleus in the hypothalamus of HD cases. In study three, we developed a robust method to measure the hypothalamic volume in magnetic resonance imaging (MRI) in order to determine whether the hypothalamic dysfunction in HD is associated with the volume of this region. We performed hypotha- lamic volumetric analyses on prodromal HD, symptomatic HD and control participants who underwent MRI scanning at baseline and 18 months follow-up as a part of the IM- AGE-HD study. We found no evidence of cross-sectional or longitudinal changes between groups in hypothalamic volume, suggesting that hypothalamic pathology in HD is not associated with volume changes. In our forth study, we investigated whether transcriptional dysfunction in emotion and metabolism regulating factors in hypothalamic nuclei were present in HD. We found that an array of genes involved in the neuropeptide expression, autophagy, neurotropic factors, neurogenesis and receptor signaling were altered in selective hypothalamic nuclei in the HD cases. Taken together, the results from this thesis demonstrate that hypothalamic dysfunction is a part of HD pathology, which could contribute to the pathogenesis of several non- motor symptoms of the disease. These findings might have the potential to give rise to new and more effective therapeutic interventions

The Role of Hypothalamic Pathology for Non-Motor Features of Huntington's Disease

Huntington's disease (HD) is a fatal genetic neurodegenerative disorder. It has mainly been considered a movement disorder with cognitive symptoms and these features have been associated with pathology of the striatum and cerebral cortex. Importantly, individuals with the mutant huntingtin gene suffer from a spectrum of non-motor features often decades before the motor disorder manifests. These symptoms and signs include a range of psychiatric symptoms, sleep problems and metabolic changes with weight loss particularly in later stages. A higher body mass index at diagnosis is associated with slower disease progression. The common psychiatric symptom of apathy progresses with the disease. The fact that non-motor features are present early in the disease and that they show an association to disease progression suggest that unravelling the underlying neurobiological mechanisms may uncover novel targets for early disease intervention and better symptomatic treatment. The hypothalamus and the limbic system are important brain regions that regulate emotion, social cognition, sleep and metabolism. A number of studies using neuroimaging, postmortem human tissue and genetic manipulation in animal models of the disease has collectively shown that the hypothalamus and the limbic system are affected in HD. These findings include the loss of neuropeptide-expressing neurons such as orexin (hypocretin), oxytocin, vasopressin, somatostatin and VIP, and increased levels of SIRT1 in distinct nuclei of the hypothalamus. This review provides a summary of the results obtained so far and highlights the potential importance of these changes for the understanding of non-motor features in HD