Truncating mutations in LRP4 lead to a prenatal lethal form of Cenani-Lenz syndrome.

Cenani-Lenz syndrome (CLS) is an autosomal recessive skeletal dysplasia that results in malformations of the distal limb, renal anomalies, and characteristic facies. In 2010, this condition was found to be caused by mutations in LRP4, a member of the low-density lipoprotein family of receptors. LRP4 has been shown to antagonize LRP5/LRP6 activation of WNT and β-catenin signaling.

Alpha-thalassemia intellectual disability: variable phenotypic expression among males with a recurrent nonsense mutation - c.109C>T (p.R37X).

Alpha-thalassemia intellectual disability, one of the recognizable X-linked disability syndromes, is characterized by short stature, microcephaly, distinctive facies, hypotonic appearance, cardiac and genital anomalies, and marked skewing of X-inactivation in female carriers. With the advent of next generation sequencing, mutations have been identified that result in less severe phenotypes lacking one or more of these phenotypic manifestations. Here we report five unrelated kindreds in which a c.

Diagnosing and treating dizziness.

Dizziness is a common presenting concern in primary care practice. The most useful diagnostic approach in distinguishing different types of dizziness is a thorough history and physical examination; additional tests are rarely necessary. Effective treatments exist for many causes of dizziness, and these treatments are often accomplished in the clinic or at home without the need for medication.

Time-Dependent Regulation of Apoptosis by AEN and BAX in Response to 2-Aminoanthracene Dietary Consumption.

Background/objective: The modulation of the toxic effects of 2-aminoanthracene (2AA) on the liver by apoptosis was investigated. Fisher-344 (F344) rats were exposed to various concentrations of 2AA for 14 and 28 days. The arylamine 2AA is an aromatic hydrocarbon employed in manufacturing chemicals, dyes, inks, and it is also a curing agent in epoxy resins and polyurethanes.

Predictive genomics: a cancer hallmark network framework for predicting tumor clinical phenotypes using genome sequencing data.

Tumor genome sequencing leads to documenting thousands of DNA mutations and other genomic alterations. At present, these data cannot be analyzed adequately to aid in the understanding of tumorigenesis and its evolution. Moreover, we have little insight into how to use these data to predict clinical phenotypes and tumor progression to better design patient treatment.

Compensatory regulation of HDAC5 in muscle maintains metabolic adaptive responses and metabolism in response to energetic stress.

Some gene deletions or mutations have little effect on metabolism and metabolic adaptation because of redundancy and/or compensation in metabolic pathways. The mechanisms for redundancy and/or compensation in metabolic adaptation in mammalian cells are unidentified. Here, we show that in mouse muscle and myogenic cells, compensatory regulation of the histone deacetylase (HDAC5) transcriptional repressor maintains metabolic integrity.

Discordance between changes in the gut microbiota and pathogenicity in a mouse model of spontaneous colitis.

Under conventional conditions, mice deficient in core 1-derived O-glycans (TM-IEC C1galt1(-/-)), which have a defective mucus layer, experienced spontaneous inflammation of the colon. Analysis of fecal bacterial populations by pyrosequencing of 16S rRNA gene showed that disease in conventional TM-IEC C1galt1(-/-) was associated with shifts in the microbiota manifested by increases in Lactobacillus and Clostridium species, and decreases in unclassified Ruminococcaceae and Lachnospiraceae. Under germ-free (GF) conditions, TM-IEC C1galt1(-/-) presented decreased goblet cells, but did not develop inflammation.

microRNAs: a new class of breast cancer biomarkers.

MicroRNAs (miRNAs) are regulatory molecules known to be aberrantly expressed in cancer and contribute to numerous aspects of tumor biology including the initiation, growth and spread of the tumor. With such diverse roles, it is becoming apparent that some may also provide valuable information which may be of use in a clinical setting, demonstrating the potential to act as both screening tools for the stratification of high-risk patients, while informing the treatment decision-making process. There is mounting evidence to suggest that some miRNAs may even provide assistance in the diagnosis of patients with breast cancer.

Precedent autonomy should be respected in life-sustaining treatment decisions.

In the 2011 landmark case of W v M, the English Court of Protection ruled that it was unlawful to withdraw artificial nutrition and hydration from a woman who had been in a minimally conscious state for 8 years. From the perspective of the court, the absence of a written advance directive negated the woman's previous, autonomous interests and, consequently, emphasis was given to her current welfare and well-being. While life itself is a moral good, prolonging life for a person in regular pain with no hope of recovering to a more complete state of awareness simply because that person only verbalized her wishes about her treatment decisions seems to drastically undervalue the principle of autonomy.

Using patient lists to add value to integrated data repositories.

Patient lists are project-specific sets of patients that can be queried in integrated data repositories (IDR's). By allowing a set of patients to be an addition to the qualifying conditions of a query, returned results will refer to, and only to, that set of patients. We report a variety of use cases for such lists, including: restricting retrospective chart review to a defined set of patients; following a set of patients for practice management purposes; distributing "honest-brokered" (deidentified) data; adding phenotypes to biosamples; and enhancing the content of study or registry data.

Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis.

Unlabelled: Deregulated glucose metabolism fulfills the energetic and biosynthetic requirements for tumor growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in glucose uptake and a strong clinical benefit in BRAF-mutant melanoma, we examined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consistent decreases in glycolytic activity in BRAF-mutant melanoma cells.

Improved synthesis and structural reassignment of MC1568: a class IIa selective HDAC inhibitor.

An improved synthesis and structural reassignment of the class IIa selective histone deacetylase (HDAC) inhibitor MC1568 are described.

Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance.

Induction of heat shock protein (HSP)72 protects against obesity-induced insulin resistance, but the underlying mechanisms are unknown. Here, we show that HSP72 plays a pivotal role in increasing skeletal muscle mitochondrial number and oxidative metabolism. Mice overexpressing HSP72 in skeletal muscle (HSP72Tg) and control wild-type (WT) mice were fed either a chow or high-fat diet (HFD).

Hydrocodone in postoperative personalized pain management: pro-drug or drug?

Background: Genetic variations in enzymes that produce active metabolites from pro-drugs are well known. Such variability could account for some of the clinically observed differences in analgesia and side effects seen in postoperative patients. Using genotyping and quantitation of serum concentrations of hydrocodone and its metabolites, we sought to demonstrate the clinical effects of the metabolites of hydrocodone on pain relief.

The forkhead transcription factor, FOXP3: a critical role in male fertility in mice.

Fertility is dependent on the hypothalamic-pituitary-gonadal axis. Each component of this axis is essential for normal reproductive function. Mice with a mutation in the forkhead transcription factor gene, Foxp3, exhibit autoimmunity and infertility.

miRNA dysregulation in breast cancer.

miRNAs have emerged, in the last decade, as key players in the carcinogenic process, with many candidates identified as playing important roles in many aspects of tumor development, growth, metastasis, and drug resistance. More recently, polymorphisms in miRNAs themselves or in their binding sites in target genes have been identified to incur increased risk of breast cancer in certain populations. In addition, epigenetic regulation and differential expression of processing enzymes has been shown to contribute to the aberrant expression of miRNAs in breast cancer.

Anti-inflammatory effects of fish oil in ovaries of laying hens target prostaglandin pathways.

Background: An effective way to control cancer is by prevention. Ovarian cancer is the most lethal gynecological malignancy. Progress in the treatment and prevention of ovarian cancer has been hampered due to the lack of an appropriate animal model and absence of effective chemo-prevention strategies.

The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass.

Although the canonical transforming growth factor β signaling pathway represses skeletal muscle growth and promotes muscle wasting, a role in muscle for the parallel bone morphogenetic protein (BMP) signaling pathway has not been defined. We report, for the first time, that the BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling.

The role of mitochondria in the aetiology of insulin resistance and type 2 diabetes.

Background: The prevalence of type 2 diabetes is rapidly increasing world-wide and insulin resistance is central to the aetiology of this disease. The biology underpinning the development of insulin resistance is not completely understood and the role of impaired mitochondrial function in the development of insulin resistance is controversial.

Scope Of Review: This review will provide an overview of the major processes regulated by mitochondria, before examining the evidence that has investigated the relationship between mitochondrial function and insulin action.

Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2.

Circulating lymphocytes continuously enter lymph nodes for immune surveillance through specialized blood vessels named high endothelial venules, a process that increases markedly during immune responses. How high endothelial venules (HEVs) permit lymphocyte transmigration while maintaining vascular integrity is unknown. Here we report a role for the transmembrane O-glycoprotein podoplanin (PDPN, also known as gp38 and T1α) in maintaining HEV barrier function.

Effect of DHA and coenzymeQ10 against Aβ- and zinc-induced mitochondrial dysfunction in human neuronal cells.

Background: Beta-amyloid (Aβ) protein is a key factor in the pathogenesis of Alzheimer's disease (AD) and it has been reported that mitochondria is involved in the biochemical pathway by which Aβ can lead to neuronal dysfunction. Coenzyme Q10 (CoQ10) is an essential cofactor involved in the mitochondrial electron transport chain and has been suggested as a potential therapeutic agent in AD. Zinc toxicity also affects cellular energy production by decreasing oxygen consumption rate (OCR) and ATP turnover in human neuronal cells, which can be restored by the neuroprotective effect of docosahexaenoic acid (DHA).

Precocious puberty and Leydig cell hyperplasia in male mice with a gain of function mutation in the LH receptor gene.

The LH receptor (LHR) is critical for steroidogenesis and gametogenesis. Its essential role is underscored by the developmental and reproductive abnormalities that occur due to genetic mutations identified in the human LHR. In males, activating mutations are associated with precocious puberty and Leydig cell hyperplasia.

Caveolin-1 is necessary for hepatic oxidative lipid metabolism: evidence for crosstalk between caveolin-1 and bile acid signaling.

Caveolae and caveolin-1 (CAV1) have been linked to several cellular functions. However, a model explaining their roles in mammalian tissues in vivo is lacking. Unbiased expression profiling in several tissues and cell types identified lipid metabolism as the main target affected by CAV1 deficiency.