U-Hack Med Gap Year-A Virtual Undergraduate Internship Program in Computer-Assisted Healthcare and Biomedical Research.

The COVID-19 healthcare crisis dramatically changed educational opportunities for undergraduate students. To overcome the lack of exposure to lab research and provide an alternative to cancelled classes and online lectures, the Lyda Hill Department of Bioinformatics at UT Southwestern Medical Center established an innovative, fully remote and paid "U-Hack Med Gap Year" internship program. At the core of the internship program were dedicated biomedical research projects spanning nine months in fields as diverse as computational microscopy, bioimage analysis, genome sequence analysis and establishment of a surgical skill analysis platform. To complement the project work, a biweekly Gap Year lab meeting was devised with opportunities to develop important skills in presenting, data sharing and analysis of new research. Despite a challenging year, all selected students completed the full internship period and over 30% will continue their project remotely after the end of the program.

Validity of criteria for dementia in older people with intellectual disability.

OBJECTIVE: Valid definitions of dementia should discriminate dementia from other forms of cognitive impairment such as intellectual disability (ID). We aimed to evaluate the usefulness of criteria for dementia and mild cognitive impairment (MCI) in ID, including predictive validity, and inter-rater reliability. METHOD: We assessed 222 participants in a survey of older adults with ID without Down syndrome at two time points for dementia (T1 and T2). Mean follow-up period was 2.9 years. Dementia diagnoses were made according to International Classification of Diseases, Tenth Revision, Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition), Diagnostic criteria for psychiatric disorders for use with adults with learning disabilities (DC-LD) criteria. At follow-up (T2), raters were blind to initial diagnosis. Predictive validity was determined by comparing odds ratios (ORs) of death, or of having a "poor outcome" (i.e., either dying or being diagnosed with dementia at T2). RESULTS: All dementia criteria showed substantial inter-rater reliability (κ > 0.68) and high specificity (~95%). Dementia cases at T1 were more likely to have died at T2 than those with no dementia (33.3% versus 14.9%; OR: 2.85; 95% confidence interval (95% CI): 1.12-7.22) and to have a "poor outcome" (77.8% versus 27.6%; OR: 9.18; 95% CI: 3.43-24.53). At least two dementia cases at T1 were false positives. Those with "MCI" at T1 were similar to "no dementia" cases in terms of poor outcomes at T2. CONCLUSION: Dementia diagnostic criteria show substantial reliability and satisfactory validity in ID. The diagnoses were, however, less stable than in the general population and some caution is advisable in those with more severe ID or additional sensory disability. MCI definitions require further consideration in the ID population.

Public health professionals as policy entrepreneurs: Arkansas's childhood obesity policy experience.

In response to a nationwide rise in obesity, several states have passed legislation to improve school health environments. Among these was Arkansas's Act 1220 of 2003, the most comprehensive school-based childhood obesity legislation at that time. We used the Multiple Streams Framework to analyze factors that brought childhood obesity to the forefront of the Arkansas legislative agenda and resulted in the passage of Act 1220. When 3 streams (problem, policy, and political) are combined, a policy window is opened and policy entrepreneurs may advance their goals. We documented factors that produced a policy window and allowed entrepreneurs to enact comprehensive legislation. This historical analysis and the Multiple Streams Framework may serve as a roadmap for leaders seeking to influence health policy.

Phenotypic and molecular evaluation of a chromosome 1q region with linkage and association to type 2 diabetes in humans.

OBJECTIVE: Linkage to type 2 diabetes (T2D) is well replicated on chromosome 1q21-q23. Within this region, T2D was associated with common single nucleotide polymorphisms that marked an extended linkage disequilibrium block, including the liver pyruvate kinase gene (PKLR), in several European-derived populations. In this study we sought to determine the molecular basis for the association and the phenotypic consequences of the risk haplotype. RESEARCH DESIGN AND METHODS: Genes surrounding PKLR were resequenced in European-American and African-American cases and controls, and association with T2D was tested. Copy number variants (CNVs) were tested for four regions with real-time PCR. Expression of genes in the region was tested in adipose and muscle from nondiabetic subjects with each genotype. Insulin secretion, insulin sensitivity, and hepatic glucose production were tested in nondiabetic individuals with each haplotype combination. RESULTS: No coding variant in the region was associated with T2D. CNVs were rare and not associated with T2D. PKLR was not expressed in available tissues, but expression of genes HCN3, CLK2, SCAMP3, and FDPS was not associated with haplotype combinations in adipose or muscle. Haplotype combinations were not associated with insulin secretion or peripheral insulin sensitivity, but homozygous carriers of the risk haplotype had increased hepatic glucose production during hyperinsulinemia. CONCLUSIONS: Noncoding variants in the PKLR region likely alter gene expression of one or more genes. Our extensive physiological and molecular studies suggest increased hepatic glucose production and reduced hepatic insulin sensitivity, thus pointing to PKLR itself as the most likely candidate gene in this population.

Retinol binding protein 4 as a candidate gene for type 2 diabetes and prediabetic intermediate traits.

Serum retinol binding protein 4 (RBP4) was recently described as a new adipokine that reduced peripheral and hepatic insulin sensitivity and increased hepatic gluconeogenesis. The RBP4 gene maps to 10q23-24, near a region linked to T2DM in Caucasian and Mexican American populations. Hence, sequence variants that alter RBP4 expression or function could increase T2DM susceptibility and reduce insulin sensitivity. We screened the 6 exons, flanking intronic sequence, and 5' and 3' flanking sequences in 48 Caucasian and 48 African American subjects. We identified 21 SNPs, of which 8 were unique to the African American population. Additional public database SNPs were chosen for regions not screened. We selected SNPs for typing based on frequency, linkage disequilibrium, and location in a putative functional or conserved region. We typed 10 SNPs in 191 Caucasians with T2DM and a family history of T2DM, and 188 euglycemic controls with no family history of diabetes. We similarly typed 14 variants in 182 controls and 353 diabetic individuals of African American ancestry. No single variant was associated with type 2 diabetes in either population (p>0.15 in African Americans, p>0.09 in Caucasians), but a haplotype of 8 common SNPs in Caucasians was significantly increased in type 2 diabetics compared with controls (0.137 vs. 0.076, p=0.008). Furthermore, SNPs -804 and +9476 were associated with reduced insulin secretion, (p=0.01 and 0.001, respectively), and SNP +390 with reduced insulin sensitivity (p=0.0005) in Caucasians. Our data suggest that noncoding SNPs may increase diabetes susceptibility in Caucasians and may contribute to insulin resistance and reduced insulin secretion.

Polymorphisms in the glucokinase-associated, dual-specificity phosphatase 12 (DUSP12) gene under chromosome 1q21 linkage peak are associated with type 2 diabetes.

Linkage of type 2 diabetes to chromosome 1q21-q23 is well replicated across populations. In an initial 50-kb marker map (580 markers) across the linked region, one of the two strongest associations observed in Utah Caucasians was at marker rs1503814 (P < 0.00001 in pools, P < 0.004 in individuals). Based on this association, we typed additional markers and screened for sequence variation in the nearby DUSP12 gene. The strongest associations mapped to a highly conserved nongenic sequence just telomeric to rs1503814 and extended 10 kb telomeric through the DUSP12 gene and into the 5' end of the adjacent ATF6 gene. No coding variant could explain the association in the DUSP12 gene. An extended haplotype encompassing markers from -8,379 to +10,309 bp relative to the ATG start was more common in Caucasian case (0.381) than control subjects (0.285, P = 0.005) and was uniquely tagged by a 194-bp allele at either of two simple tandem repeat variants or by the T allele at marker +7,580. Markers -8,379 and +7,580 were nominally associated with type 2 diabetes in African-American subjects (P < 0.05), but with different alleles. Marker rs1503814 was strongly associated with postchallenge insulin levels among family members (P = 0.000002), but sequence variation in this region was not associated with type 2 diabetes in three other populations of European ancestry. Our data suggest that sequences in or upstream of DUSP12 may contribute to type 2 diabetes susceptibility, but the lack of replication suggests a small effect size.

Analysis of FOXO1A as a candidate gene for type 2 diabetes.

The human forkhead box O1A (FOXO1A) gene on chromosome 13q14.1 is a key transcription factor in insulin signaling in liver and adipose tissue and plays a central role in the regulation of key pancreatic beta-cell genes including IPF1. We hypothesized that sequence variants of FOXO1A contribute to the observed defects in hepatic and peripheral insulin action and altered beta-cell compensation that characterize type 2 diabetes (T2DM). To test this hypothesis, we screened the three exons, 3' untranslated region, and 5' flanking region for sequence variants in Caucasian and African-American individuals with early onset (<45 years) T2DM. We identified only six variants; none altered the coding sequence, and except for one variant in the 3' untranslated region, they were rare or absent in Caucasians. To increase coverage of the gene, we selected seven additional variants in the large first intron and 5' flanking region, thus providing 13 variants that spanned 116.4kb. Based on frequency and linkage disequilibrium patterns in a subset of individuals, we selected eight SNPs to type in a Caucasian population comprising 192 unrelated nondiabetic control individuals and 192 individuals with T2DM, and 10 SNPs to type in 182 controls and 352 diabetic individuals of African-American ancestry. No variant was associated with T2DM (African-Americans, p>0.08; Caucasians, p>0.09). Of the 8 Caucasian SNPs, six comprised a single haplotype block spanning over 100kb and including most of the large first intron. In contrast, no block was observed among SNPs typed in African-Americans. No haplotype was associated with T2DM. FOXO1A variation is rare and is unlikely to contribute to T2DM in either Caucasian or African-American populations.

Adiponectin receptor 1 gene (ADIPOR1) as a candidate for type 2 diabetes and insulin resistance.

Considerable data support adiponectin as an important adipose-derived insulin sensitizer that enhances fatty acid oxidation and alters hepatic gluconeogenesis. Adiponectin acts by way of two receptors, ADIPOR1 and ADIPOR2. ADIPOR1 is widely expressed in tissues, including muscle, liver, and pancreas, and binds the globular form of adiponectin with high affinity. To test the hypothesis that sequence variations in or near the ADIPOR1 gene contribute to the risk of developing type 2 diabetes and the metabolic syndrome, we screened the eight exons (including the untranslated exon 1) of the ADIPOR1 gene with flanking intronic sequences and the 5' and 3' flanking sequences. We identified 22 single nucleotide polymorphisms (SNPs) in Caucasian and African-American subjects, of which a single nonsynonymous SNP (N44K) in exon 2 was present only in African-American subjects. We typed 14 sequence variants that had minor allele frequencies >5%. No SNP was associated with type 2 diabetes in Caucasians or African Americans, and no SNP was a determinant of insulin sensitivity or insulin secretion among nondiabetic members of high-risk Caucasian families. However, the two alleles of a SNP in the 3' untranslated region were expressed unequally, and ADIPOR1 mRNA levels were significantly lower among transformed lymphocytes from diabetic African-American individuals than among control cell lines. This altered gene expression might suggest a role for ADIPOR1 in the metabolic syndrome.

Alpha-endosulfine, a positional and functional candidate gene for type 2 diabetes: molecular screening, association studies, and role in reduced insulin secretion.

Impaired glucose stimulated insulin secretion is a prominent, early defect in type 2 diabetes. Insulin secretion is coupled to glucose metabolism by effects of the intracellular ATP/ADP ratio on the multimeric beta-cell potassium channel. The sulfonylurea receptor (SUR1 or ABCC8), the regulatory subunit of that channel, binds sulfonylurea agents and thus closes the channel and stimulates exocytosis of insulin-containing granules. alpha-Endosulfine (ENSA), has been proposed as the endogenous ligand for SUR1. We mapped ENSA in silico to chromosome 1q21 near a confirmed type 2 diabetes susceptibility locus, and derived the genomic structure of four exons and three introns. We identified four single nucleotide polymorphisms (SNP) and one insertion deletion polymorphism among 16 Caucasian and 16 African-American diabetic individuals. Only one SNP was common to both ethnic groups, and no SNP altered the coding sequence. No variant was associated with type 2 diabetes in Caucasian or African-American studies, but a single SNP in intron 3 (SNP 17) was associated with a reduced disposition index (insulin sensitivity x acute insulin response to glucose) in interaction with family membership in 126 members of 26 Caucasian families. Individuals homozygous for the rare allele showed a 70% reduction in insulin secretion (disposition index) relative to all other genotypes. Our data do not suggest that ENSA could explain the linkage of T2DM to this region, but ENSA SNP 17 may have an important role in reducing the ability of the beta-cell to compensate for reduced insulin sensitivity, which in turn would increase the susceptibility to T2DM.