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

Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Recent genomic analyses of pathologically-defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies

Configuration of fibrous and adipose tissues in the cavernous sinus.

OBJECTIVE: Three-dimensional anatomical appreciation of the matrix of the cavernous sinus is one of the crucial necessities for a better understanding of tissue patterning and various disorders in the sinus. The purpose of this study was to reveal configuration of fibrous and adipose components in the cavernous sinus and their relationship with the cranial nerves and vessels in the sinus and meningeal sinus wall. MATERIALS AND METHODS: Nineteen cadavers (8 females and 11 males; age range, 54-89 years; mean age, 75 years) were prepared as transverse (6 sets), coronal (3 sets) and sagittal (10 sets) plastinated sections that were examined at both macroscopic and microscopic levels. RESULTS: Two types of the web-like fibrous networks were identified and localized in the cavernous sinus. A dural trabecular network constituted a skeleton-frame in the sinus and contributed to the sleeves of intracavernous cranial nerves III, IV, V1, V2 and VI. A fine trabecular network, or adipose tissue, was the matrix of the sinus and was mainly distributed along the medial side of the intracavernous cranial nerves, forming a dumbbell-shaped adipose zone in the sinus. CONCLUSIONS: This study revealed the nature, fine architecture and localization of the fine and dural trabecular networks in the cavernous sinus and their relationship with intracavernous cranial nerves and vessels. The results may be valuable for better understanding of tissue patterning in the cranial base and better evaluation of intracavernous disorders, e.g. the growth direction and extent of intracavernous tumors

Sheet plastination sections of the cavernous sinus.

<p><b>A, B</b> and <b>C</b> are the sagittal, transverse and coronal sections, respectively. <b>D, E</b> and <b>F</b> are the mirror confocal images of the selected areas (dashed-line boxes) of <b>A</b> and <b>C</b>. <b>A:</b> A sagittal section through the cavernous sinus at the level of the lateral edge of the dorsum sellae (DS). Arrows point to the dural roof of the cavernous sinus. Asterisks indicate the areas that are mainly occupied by adipose tissue and small cavernous veins (cv). <b>B:</b> A transverse section at the level of nerves V₁ and VI. Arrows point the lateral meningeal wall of the sinus. Asterisks indicate the dumbbell-shaped adipose zone medial to intracavernous cranial nerves III, IV, V₁ and VI. <b>C:</b> A coronal section at the middle level of the cavernous sinus. A cerebral bridging vein (BV) (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089182#pone-0089182-g002" target="_blank">Figure 2D</a> for its anterior segment) entered the sinus between the lateral meningeal wall (arrows) and nerve V₂. <b>D:</b> The mirror confocal image of the dashed-line box in C, showing that the dural trabeculae (single arrowheads) originate from the medial laminae of the lateral dural wall (arrows) and encircle the branches of nerves V₁ and VI, forming a dural trabecular network. Some dural trabeculae (double arrowheads) spirally encircle a nerve and contribute to the sleeve of the nerve. Asterisk indicates a fine trabecular network. <b>E:</b> The mirror confocal image of an area in the dashed-line circle in A, showing that some dural trabeculae (single arrowheads) from Meckel's cave (MC) longitudinally and loosely accompany a branch of nerve V₁. <b>F:</b> The mirror confocal image of another area in the dashed-line circle in A, showing that the longitudinal dural fibers (single arrowheads) scatter and merge with the fine trabeculae in adipose tissue (asterisks). The dashed-line circles outline the basal membrane of some adipocytes. Double asterisks indicate a small vessel. ACP: anterior clinoid process; BV: cerebral bridging vein; CA: internal carotid artery; cv: cavernous veins; DS: dorsum sellae; MC: Meckel's cave; PG: pituitary gland; Sph: sphenoid bone; TL: temporal lobe; Cranial nerves II, III, IV, V₁, V₂ and VI; bars = 1 mm.</p

Localization of the adipose zone (A–C) and fibrous configuration of the sleeves of cranial nerves III and IV (D–G).

<p><b>A:</b> A transverse section through the cavernous segment of the internal carotid artery (CA). <b>B:</b> The mirror confocal image of the dashed-line box in A, showing a large anterior end of the dumbbell-shaped adipose zone (asterisks) on the surface of the sphenoid bone (Sph), anterior to the internal carotid artery (CA) and its surrounding cavernous veins (cv), and posteromedial to the anterior clinoid process (ACP). Arrows point to the lateral meningeal dural wall of the sinus. <b>C:</b> The mirror confocal image of the solid line box in A, showing a small and irregular posterior end of the dumbbell-shaped adipose zone (asterisks) medial to the sleeves of the intracavernous cranial nerves VI and V₁ and Meckel's cave (MC). Single arrowheads point to the dural trabeculae and arrows indicate multiple laminae of the lateral meningeal wall of the sinus. <b>D:</b> A coronal section at the level of the anterior clinoid process (ACP), about 6 mm anterior to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089182#pone-0089182-g001" target="_blank">Figure 1C</a>. A cerebral bridging vein (BV) is located lateral to intracavernous cranial nerves III, IV, V₁, V₂ and VI. <b>E:</b> The mirror confocal image of the dashed-line box in D, showing that the dural trabeculae (single arrowheads) originate from the meningeal dura of the anterior clinoid process (ACP), encircle nerves III and IV and connect with the fine trabecular network (asterisk) and sleeves of nerves V₁ and VI. Double arrowheads indicate the wall of the bridging vein. Single arrows point to the lateral wall of the cavernous sinus. <b>F</b> and <b>G:</b> The confocal images of two adjacent coronal sections about 6 mm (F) and 12 mm (G) posterior to E, showing that nerve III and its associated arachnoid cuff (asterisk) invaginate in the later wall (G) and then pieces the wall (F). The insert of F is from a different coronal section, showing that nerve IV pieces the lateral wall. Arrows point to the multiple laminae of the lateral dural wall of the cavernous sinus. Arrowheads point to the dural trabeculae originating from the medial lamina of the wall. ACP: anterior clinoid process; BV: cerebral bridging vein; CA: internal carotid artery; cv: cavernous veins; DS: dorsum sellae; MC: Meckel's cave; PG: pituitary gland; SAS: subarachnoid space; Sph: sphenoid bone; TL: temporal lobe; Cranial nerves III, IV, V₁, V₂ and VI; bars = 1 mm.</p

Conversion of adult human peripheral blood mononuclear cells into induced neural stem cell by using episomal vectors

Human neural stem cells (NSCs) hold great promise for research and therapy in neural diseases. Many studies have shown direct induction of NSCs from human fibroblasts, which require an invasive skin biopsy and a prolonged period of expansion in cell culture prior to use. Peripheral blood (PB) is routinely used in medical diagnoses, and represents a noninvasive and easily accessible source of cells. Here we show direct derivation of NSCs from adult human PB mononuclear cells (PB-MNCs) by employing episomal vectors for transgene delivery. These induced NSCs (iNSCs) can expand more than 60 passages, can exhibit NSC morphology, gene expression, differentiation potential, and self-renewing capability and can give rise to multiple functional neural subtypes and glial cells in vitro. Furthermore, the iNSCs carry a specific regional identity and have electrophysiological activity upon differentiation. Our findings provide an easily accessible approach for generating human iNSCs which will facilitate disease modeling, drug screening, and possibly regenerative medicine

Unique subcellular distribution of phosphorylated Plk1 (Ser137 and Thr210) in mouse oocytes during meiotic division and pPlk1^Ser137 involvement in spindle formation and REC8 cleavage

<div><p>Polo-like kinase 1 (Plk1) is pivotal for proper mitotic progression, its targeting activity is regulated by precise subcellular positioning and phosphorylation. Here we assessed the protein expression, subcellular localization and possible functions of phosphorylated Plk1 (pPlk1^Ser137 and pPlk1^Thr210) in mouse oocytes during meiotic division. Western blot analysis revealed a peptide of pPlk1^Ser137 with high and stable expression from germinal vesicle (GV) until metaphase II (MII), while pPlk1^Thr210 was detected as one large single band at GV stage and 2 small bands after germinal vesicle breakdown (GVBD), which maintained stable up to MII. Immunofluorescence analysis showed pPlk1^Ser137 was colocalized with microtubule organizing center (MTOC) proteins, γ-tubulin and pericentrin, on spindle poles, concomitantly with persistent concentration at centromeres and dynamic aggregation between chromosome arms. Differently, pPlk1^Thr210 was persistently distributed across the whole body of chromosomes after meiotic resumption. The specific Plk1 inhibitor, BI2536, repressed pPlk1^Ser137 accumulation at MTOCs and between chromosome arms, consequently disturbed γ-tubulin and pericentrin recruiting to MTOCs, destroyed meiotic spindle formation, and delayed REC8 cleavage, therefore arresting oocytes at metaphase I (MI) with chromosome misalignment. BI2536 completely reversed the premature degradation of REC8 and precocious segregation of chromosomes induced with okadaic acid (OA), an inhibitor to protein phosphatase 2A. Additionally, the protein levels of pPlk1^Ser137 and pPlk1^Thr210, as well as the subcellular distribution of pPlk1^Thr210, were not affected by BI2536. Taken together, our results demonstrate that Plk1 activity is required for meiotic spindle assembly and REC8 cleavage, with pPlk1^Ser137 is the action executor, in mouse oocytes during meiotic division.</p></div