Orthostatic intolerance: potential pathophysiology and therapy

Orthostatic intolerance affects an estimated 1 in 500 persons and causes a wide range of disabilities. After essential hypertension, it is the most frequently encountered dysautonomia, accounting for the majority of patients referred to centers specializing in autonomic disorders. Patients are typically young females with symptoms such as dizziness, visual changes, head and neck discomfort, poor concentration, fatigue, palpitations, tremulousness, anxiety, and, in some cases, syncope. Syncope is the most hazardous symptom of orthostatic intolerance, presumably occurring because of impaired cerebral perfusion and in part to compensatory autonomic mechanisms. The etiology of this syndrome is still unclear but is heterogeneous. Orthostatic intolerance used to be characterized by an overall enhancement of noradrenergic tone at rest in some patients and by a patchy dysautonomia of postganglionic sympathetic fibers with a compensatory cardiac sympathetic activation in others. However, recent advances in molecular genetics are improving our understanding of orthostatic intolerance, such as several genetic diseases (such as Ehler-Danlos syndrome and norepinephrine transporter deficiency) presenting with symptoms typical of orthostatic intolerance. Future work will include investigation of genetic functional mutations underlying interindividual differences in autonomic cardiovascular control, body fluid regulation, and vascular regulation in orthostatic intolerance patients. The goal of this review article is to describe recent advances in understanding the pathophysiological mechanisms of orthostatic intolerance and their clinical significance.     

Overexpression of MTA3 Correlates with Tumor Progression in Non-Small Cell Lung Cancer

The objective of the current study was to investigate the expression pattern and clinicopathological significance of MTA3 in patients with non-small cell lung cancer (NSCLC). The expression profile of MTA3 in NSCLC tissues and adjacent noncancerous lung tissues was detected by immunohistochemistry. MTA3 was overexpressed in 62 of 108 (57.4%) human lung cancer samples and correlated with p-TNM stage (p<0.0001), nodal metastasis (p = 0.0009) and poor prognosis (p<0.05). In addition, the depletion of MTA3 expression with small interfering RNAs inhibited cell growth and colony formation in the A549 and H157 lung cancer cell lines. Moreover, MTA3 depletion induced cell cycle arrest at the G1/S boundary. Western blotting analysis revealed that the knockdown of MTA3 decreased the protein levels of cyclin A, cyclin D1 and p-Rb. These results indicate that MTA3 plays an important role in NSCLC progression.     

<Emphasis Type="Italic">Acheilognathus striatus</Emphasis> (Family: Cyprinidae), a new bitterling species from the lower Yangtze River,China

A new species of bitterling, Acheilognathus striatus sp. nov., is described on the basis of 57 specimens collected from the lower Yangtze River in Jiangxi Province, China. It can be distinguished from all congeners by the following combined characters: a pair of relatively long barbels, slightly longer than half of eye diameter; dorsal fin with three simple and 8–9 branched fin rays, anal fin with three simple and 7–8 branched fin rays; a black longitudinal stripe on body from the base of caudal peduncle, distinctly reaching anteriorly to the vertical line from the origin of dorsal fin, broader in males than in females; a scale distance between the longitudinal stripe and lateral line below the origin of dorsal fin; dorsal and anal fin margined with black band in males.     

Two storage hexamerins from the beet armyworm <Emphasis Type="Italic">Spodoptera exigua</Emphasis>: Cloning,characterization and the effect of gene silencing on survival

Background  

In insects, hemocyanin superfamily proteins accumulate apparently to serve as sources of amino acids during metamorphosis, reproduction and development. Storage hexamerins are important members of the hemocyanin superfamily. Although insects possess storage hexamerins, very little is known about the character and specific functions of hexamerin 1 and storage protein 1 in insect development.     

DEP and AFO Regulate Reproductive Habit in Rice

Sexual reproduction is essential for the life cycle of most angiosperms. However, pseudovivipary is an important reproductive strategy in some grasses. In this mode of reproduction, asexual propagules are produced in place of sexual reproductive structures. However, the molecular mechanism of pseudovivipary still remains a mystery. In this work, we found three naturally occurring mutants in rice, namely, phoenix (pho), degenerative palea (dep), and abnormal floral organs (afo). Genetic analysis of them indicated that the stable pseudovivipary mutant pho was a double mutant containing both a Mendelian mutation in DEP and a non-Mendelian mutation in AFO. Further map-based cloning and microarray analysis revealed that dep mutant was caused by a genetic alteration in OsMADS15 while afo was caused by an epigenetic mutation in OsMADS1. Thus, OsMADS1 and OsMADS15 are both required to ensure sexual reproduction in rice and mutations of them lead to the switch of reproductive habit from sexual to asexual in rice. For the first time, our results reveal two regulators for sexual and asexual reproduction modes in flowering plants. In addition, our findings also make it possible to manipulate the reproductive strategy of plants, at least in rice.     

Effects of GCK,GCKR, G6PC2 and MTNR1B Variants on Glucose Metabolism and Insulin Secretion

Background

Single nucleotide polymorphisms (SNPs) from GCK, GCKR, G6PC2 and MTNR1B were found to modulate the fasting glucose levels. The current study aimed to replicate this association in the Chinese population and further analyze their effects on biphasic insulin secretion.

Methods/Principal Findings

SNPs from GCK, GCKR, G6PC2 and MTNR1B were genotyped in the Shanghai Chinese, including 3,410 type 2 diabetes patients and 3,412 controls. The controls were extensively phenotyped for the traits related to glucose metabolism and insulin secretion. We replicated the association between GCK rs1799884, G6PC2 rs16856187 and MTNR1B rs10830963 and fasting glucose in our samples (p = 0.0003∼2.0×10⁻⁸). GCK rs1799884 and G6PC2 rs16856187 showed association to HOMA-β, insulinogenic index and both first- and second-phases insulin secretion (p = 0.0030∼0.0396). MTNR1B rs10830963 was associated to HOMA-β, insulinogenic index and first-phase insulin secretion (p = 0.0102∼0.0426), but not second-phase insulin secretion (p = 0.9933). Combined effect analyses showed individuals carrying more risk allele for high fasting glucose tended to have a higher glucose levels at both fasting and 2 h during OGTTs (p = 1.7×10⁻¹³ and 0.0009, respectively), as well as lower HOMA-β, insulinogenic index and both first- and second-phases insulin secretion (p = 0.0321∼1.1×10⁻⁷).

Conclusions/Significance

We showed that SNPs from GCK, G6PC2 and MTNR1B modulated the fasting glucose levels in the normoglycaemic population while SNPs from G6PC2 and GCKR was associated with type 2 diabetes. Moreover, we found GCK and G6PC2 genetic variants were associated to both first- and second-phases insulin secretion while MTNR1B genetic variant was associated with first-phase insulin secretion, but not second-phase insulin secretion.     

FragGeneScan: predicting genes in short and error-prone reads

The advances of next-generation sequencing technology have facilitated metagenomics research that attempts to determine directly the whole collection of genetic material within an environmental sample (i.e. the metagenome). Identification of genes directly from short reads has become an important yet challenging problem in annotating metagenomes, since the assembly of metagenomes is often not available. Gene predictors developed for whole genomes (e.g. Glimmer) and recently developed for metagenomic sequences (e.g. MetaGene) show a significant decrease in performance as the sequencing error rates increase, or as reads get shorter. We have developed a novel gene prediction method FragGeneScan, which combines sequencing error models and codon usages in a hidden Markov model to improve the prediction of protein-coding region in short reads. The performance of FragGeneScan was comparable to Glimmer and MetaGene for complete genomes. But for short reads, FragGeneScan consistently outperformed MetaGene (accuracy improved ∼62% for reads of 400 bases with 1% sequencing errors, and ∼18% for short reads of 100 bases that are error free). When applied to metagenomes, FragGeneScan recovered substantially more genes than MetaGene predicted (>90% of the genes identified by homology search), and many novel genes with no homologs in current protein sequence database.     

Design and synthesis of a new class of malonyl-CoA decarboxylase inhibitors with anti-obesity and anti-diabetic activities

A new series of thiazole-substituted 1,1,1,3,3,3-hexafluoro-2-propanols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Key analogs caused dose-dependent decreases in food intake and body weight in obese mice. Acute treatment with these compounds also led to a drop in elevated blood glucose in a murine model of type II diabetes.