Opportunities, barriers, and recommendations in down syndrome research

Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community. The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan. NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS. This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade. This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy

Incorporating different proportions of exotic maize germplasm into two adapted populations

Maize breeders frequently wish to use exotic germplasm in their breeding programs without losing specific characteristics of their adapted material. The objective of this study was to determine the optimal proportions of exotic germplasm to incorporate into adapted populations (F2 = 50% exotic, BC1 = 25% exotic, BC2 = 12.5% exotic and BC3 = 6.25% exotic) to form the initial foundation population and to determine the heterosis between adapted x exotics. We used six exotic populations of different origins and two adapted populations representing a Brazilian heterotic pattern. In 1993-94 and 1994-95, the parents, F1, F2, BC1, BC2, BC3 and four checks were evaluated in six environments in central Brazil using an 8 x 9 simple rectangular lattice design. Higher mean values for yield were obtained as the proportion of exotic germplasm decreased. Some backcrosses produced more than the adapted populations BR 105 (7.59 ton/ha) and BR 106 (8.43 ton/ha). The best results were obtained when incorporating 6.25 or 12.5% of exotic genes. This trend was true for root lodging, stalk lodging and ear diseases but not for plant and ear height. The midparent heterosis for yield varied from -16.1 to 40.3%. Midparent heterosis with positive and negative values were also found for the other traits. The results indicate the potential of exotic germplasm for developing good hybrids. After choosing the best exotic source, some recurrent selection might be appropriate in order to adapt and improve the exotic populations.<br>Os melhoristas de milho que utilizam germoplasmas exóticos nos programas de melhoramento têm a preocupação de não perder as características desejáveis dos materiais adaptados. Buscando atender esta demanda, o presente trabalho teve por objetivo determinar a proporção ideal de germoplasma exótico que deve ser incorporado em populações melhoradas (F2 = 50% exótico; RC1 = 25% exótico; RC2 = 12,5% exótico; RC3 = 6,25% exótico), para formar as populações base para seleção e determinar a heterose entre os germoplasmas exóticos e adaptados. Em 1993/94 e 1994/95, os parentais, F1, F2, RC1, RC2, RC3 e quatro testemunhas foram avaliados em seis ambientes da região central do Brasil, utilizando-se o delineamento em látice simples 8 x 9. De um modo geral, à medida que a proporção de germoplasma exótico decresceu, valores médios mais altos foram obtidos para o caráter peso de espigas. Alguns retrocruzamentos produziram mais que as populações melhoradas BR 105 (7.500 kg/ha) e BR 106 (8.430 kg/ha). Os melhores resultados foram obtidos quando houve a incorporação de 6,25 ou 12,5% de genes exóticos. Esta tendência foi observada para acamamento, quebramento e espigas doentes, mas não para altura de planta e de espiga. A heterose média para peso de espiga variou de -16,1 a 40,3%. Heteroses médias com valores positivos e negativos também foram encontradas para outros caracteres. Os resultados obtidos mostraram o potencial em se utilizar germoplasmas exóticos para a obtenção de híbridos. Sugere-se, após a escolha dos germoplasma, algum esquema de seleção recorrente para adaptar e melhorar as populações exóticas

Design of an Insulin Analog with Enhanced Receptor Binding Selectivity: RATIONALE, STRUCTURE, AND THERAPEUTIC IMPLICATIONS*

Insulin binds with high affinity to the insulin receptor (IR) and with low affinity to the type 1 insulin-like growth factor (IGF) receptor (IGFR). Such cross-binding, which reflects homologies within the insulin-IGF signaling system, is of clinical interest in relation to the association between hyperinsulinemia and colorectal cancer. Here, we employ nonstandard mutagenesis to design an insulin analog with enhanced affinity for the IR but reduced affinity for the IGFR. Unnatural amino acids were introduced by chemical synthesis at the N- and C-capping positions of a recognition α-helix (residues A1 and A8). These sites adjoin the hormone-receptor interface as indicated by photocross-linking studies. Specificity is enhanced more than 3-fold on the following: (i) substitution of GlyA1 by d-Ala or d-Leu, and (ii) substitution of ThrA8 by diaminobutyric acid (Dab). The crystal structure of [d-AlaA1,DabA8]insulin, as determined within a T6 zinc hexamer to a resolution of 1.35 Å, is essentially identical to that of human insulin. The nonstandard side chains project into solvent at the edge of a conserved receptor-binding surface shared by insulin and IGF-I. Our results demonstrate that modifications at this edge discriminate between IR and IGFR. Because hyperinsulinemia is typically characterized by a 3-fold increase in integrated postprandial insulin concentrations, we envisage that such insulin analogs may facilitate studies of the initiation and progression of cancer in animal models. Future development of clinical analogs lacking significant IGFR cross-binding may enhance the safety of insulin replacement therapy in patients with type 2 diabetes mellitus at increased risk of colorectal cancer

Opportunities, barriers, and recommendations in down syndrome research.

BackgroundRecent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community.ObjectiveThe National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan.MethodsNDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS.ResultsThis review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade.ConclusionsThis review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy

Time to Peak Glucose and Peak C-Peptide During the Progression to Type 1 Diabetes in the Diabetes Prevention Trial and TrialNet Cohorts

OBJECTIVE To assess the progression of type 1 diabetes using time to peak glucose or C-peptide during oral glucose tolerance tests (OGTTs) in autoantibody-positive relatives of people with type 1 diabetes. RESEARCH DESIGN AND METHODS We examined 2-h OGTTs of participants in the Diabetes Prevention Trial Type 1 (DPT-1) and TrialNet Pathway to Prevention (PTP) studies. We included 706 DPT-1 participants (mean ± SD age, 13.84 ± 9.53 years; BMI Z-score, 0.33 ± 1.07; 56.1% male) and 3,720 PTP participants (age, 16.01 ± 12.33 years; BMI Z-score, 0.66 ± 1.3; 49.7% male). Log-rank testing and Cox regression analyses with adjustments (age, sex, race, BMI Z-score, HOMA-insulin resistance, and peak glucose/C-peptide levels, respectively) were performed. RESULTS In each of DPT-1 and PTP, higher 5-year diabetes progression risk was seen in those with time to peak glucose >30 min and time to peak C-peptide >60 min (P < 0.001 for all groups), before and after adjustments. In models examining strength of association with diabetes development, associations were greater for time to peak C-peptide versus peak C-peptide value (DPT-1: χ2 = 25.76 vs. χ2 = 8.62; PTP: χ2 = 149.19 vs. χ2 = 79.98; all P < 0.001). Changes in the percentage of individuals with delayed glucose and/or C-peptide peaks were noted over time. CONCLUSIONS In two independent at-risk populations, we show that those with delayed OGTT peak times for glucose or C-peptide are at higher risk of diabetes development within 5 years, independent of peak levels. Moreover, time to peak C-peptide appears more predictive than the peak level, suggesting its potential use as a specific biomarker for diabetes progression