Basal Temporal Language Area: Evidence from Cortical Stimulation and Surgical Ablation

TB

Mitochondrial Genetic Background Modulates Bioenergetics and Susceptibility to Acute Cardiac Volume Overload

Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mtDNA sequence variation contributes to disease susceptibility. In the present study we show a novel animal model of mtDNA polymorphisms, the MNX (mitochondrial–nuclear exchange) mouse, in which the mtDNA from the C3H/HeN mouse has been inserted on to the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harbouring the C57/BL6J mtDNA generate more ROS (reactive oxygen species) and have a higher mitochondrial membrane potential relative to those with C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the ‘mitochondrial paradigm’ for the development of disease susceptibility, and show that the mtDNA modulates cellular bioenergetics, mitochondrial ROS generation and susceptibility to cardiac stress

RELICS: Reionization Lensing Cluster Survey

Large surveys of galaxy clusters with the Hubble and Spitzer Space Telescopes, including CLASH and the Frontier Fields, have demonstrated the power of strong gravitational lensing to efficiently deliver large samples of high-redshift galaxies. We extend this strategy through a wider, shallower survey named RELICS, the Reionization Lensing Cluster Survey. This survey, described here, was designed primarily to deliver the best and brightest high-redshift candidates from the first billion years after the Big Bang. RELICS observed 41 massive galaxy clusters with Hubble and Spitzer at 0.4-1.7um and 3.0-5.0um, respectively. We selected 21 clusters based on Planck PSZ2 mass estimates and the other 20 based on observed or inferred lensing strength. Our 188-orbit Hubble Treasury Program obtained the first high-resolution near-infrared images of these clusters to efficiently search for lensed high-redshift galaxies. We observed 46 WFC3/IR pointings (~200 arcmin^2) with two orbits divided among four filters (F105W, F125W, F140W, and F160W) and ACS imaging as needed to achieve single-orbit depth in each of three filters (F435W, F606W, and F814W). As previously reported by Salmon et al., we discovered 322 z ~ 6 - 10 candidates, including the brightest known at z ~ 6, and the most distant spatially-resolved lensed arc known at z ~ 10. Spitzer IRAC imaging (945 hours awarded, plus 100 archival) has crucially enabled us to distinguish z ~ 10 candidates from z ~ 2 interlopers. For each cluster, two HST observing epochs were staggered by about a month, enabling us to discover 11 supernovae, including 3 lensed supernovae, which we followed up with 20 orbits from our program. We delivered reduced HST images and catalogs of all clusters to the public via MAST and reduced Spitzer images via IRSA. We have also begun delivering lens models of all clusters, to be completed before the JWST GO call for proposals.Comment: 29 pages, 6 figures, submitted to ApJ. For reduced images, catalogs, lens models, and more, see relics.stsci.ed

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

MMPI CHARACTERISTICS OF THE DSM-III BORDERLINE PERSONALITY DISORDER IN A FORENSIC POPULATION

This investigation attempted to determine whether a distinct borderline MMPI profile would emerge in a forensic population, whether the borderline group could be significantly differentiated from three comparison groups selected from the same population, and whether group membership (diagnosis) could be predicted using discriminant analysis solutions based on MMPI variables. The groups were constructed from 154 adult male psychiatric inpatients committed to the Forensic Services Division (FSD) of Middle Tennessee Mental Health Institute. The mean borderline MMPI profile consisted of elevations on the Sc(8), Pa(6), D(2), Pd(4) and Pt(7) scales. While only 9 of the 39 individuals (23%) in the borderline group actually possessed such a profile, the cumulative total was raised to 89% where two-point combinations of 8-6, 8-4, 8-2, or 8-7 were included. Secondly, multivariate and univariate analyses of variance were performed to determine whether the borderline group differed significantly from the three comparison groups. A highly significant MANOVA indicated an overall significant difference in MMPI T score profile elevations in relation to the four diagnostic groupings. Scheffe\u27s tests revealed the significance was between the borderline and antisocial/malingering groups. A second MANOVA was conducted using two groups. The original 39 borderline patients were compared to the remaining 115 patients collapsed into one group. An overall significance was again obtained through a Wilk\u27s lambda. As a follow-up to the significant MANOVA\u27s several discriminant function analyses were performed. Function I was highly loaded from the antisocial/malingerer group; Function II was loaded by the borderline group. The resulting classification analysis was successful in predicting group membership (diagnosis) for 17 of 39 (43.6%) of the borderline patients and for 26 of 36 (72.2%) of the antisocial/malingering patients. The overall four groups hit rate was 50.65%. Finally, a two-group discriminant Function was identified by using the original borderline group and combining the remaining 115 patients. The resulting function was found to have the most loading from the L scale. The major findings suggested that while a characteristic borderline MMPI profile was identified, this profile did not distinguish the borderline group from the comparison groups as found in the literature. The validity scale L was the only variable that appeared to discriminate the borderline groups from the present comparison groups. (Abstract shortened with permission of author.