Neurons migrate from their birthplaces to the destinations, and extending axons navigate to their synaptic targets by sensing various extracellular cues in spatiotemporally controlled manners. These evolutionally conserved guidance cues and their receptors regulate multiple aspects of neural development to establish the highly complex nervous system by mediating both short- and long-range cell-cell communications. Neuronal guidance genes (encoding cues, receptors, or downstream signal transducers) are critical not only for development of the nervous system but also for synaptic maintenance, remodeling, and function in the adult brain. One emerging theme is the combinatorial and complementary functions of relatively limited classes of neuronal guidance genes in multiple processes, including neuronal migration, axonal guidance, synaptogenesis, and circuit formation. Importantly, neuronal guidance genes also regulate cell migration and cell-cell communications outside the nervous system. We are just beginning to understand how cells integrate multiple guidance and adhesion signaling inputs to determine overall cellular/subcellular behavior and how aberrant guidance signaling in various cell types contributes to diverse human diseases, ranging from developmental, neuropsychiatric, and neurodegenerative disorders to cancer metastasis. We review classic studies and recent advances in understanding signaling mechanisms of the guidance genes as well as their roles in human diseases. Furthermore, we discuss the remaining challenges and therapeutic potentials of modulating neuronal guidance pathways in neural repair.
Humans ; Axon Guidance/genetics* ; Neurons ; Axons/metabolism* ; Signal Transduction/genetics* ; Cell Communication

BACKGROUND/OBJECTIVES: Aging is an imperative problem for many countries in this century, and presents several challenges for the maintenance of good nutritional status. This study aims to assess the impact of socio-demographic factors, lifestyle and health status on the nutritional status among the elderly in Taiwan. SUBJECTS/METHODS: A cross-sectional study was carried out in Taiwan. Data were obtained from the Mei Jau Health Management Institution, which is a private health evaluation provider with multiple health screening centers in Taiwan and Asia. This study included 7947 adults aged 65 years or above. The data were extracted between 2001 to 2010. Nutritional status was assessed using anthropometric data, biochemical data and dietary intake information. RESULTS: Among the 7947 participants with mean age of 70.1 (SD = 4.5) years, 20.2%, 6.6%, 10.5% and 52.5% experienced underweight, protein malnutrition, anemia and inadequate dietary intake in the past month, respectively. Age was negatively correlated with body weight (r = −0.19, P = 0.02), body mass index (r = −0.41, P < 0.001), albumin level (r = −0.93, P < 0.001) and hemoglobin level (r = −0.30, P = 0.008). Age above 70 years, gender, unmarried status, retirement, lack of education, low family income, smoking, alcohol drinking, sleep duration of 6-8 hours, vegetarian diet, multiple medications, comorbidity and dysphagia were positively associated with malnutrition in older adults. CONCLUSIONS: Underweight and inadequate dietary intake are prevalent among the elderly in Taiwan. Vegetarian diet, multiple medications, comorbidity, dysphagia and lifestyle factors such as smoking, alcohol drinking and sleep duration of 6–8 hours are risk factors for undernutrition in older adults.
Adult ; Aged ; Aging ; Alcohol Drinking ; Anemia ; Asia ; Body Mass Index ; Body Weight ; Comorbidity ; Cross-Sectional Studies ; Deglutition Disorders ; Diet ; Diet, Vegetarian ; Education ; Humans ; Life Style ; Malnutrition ; Mass Screening ; Nutritional Status ; Retirement ; Risk Factors ; Single Person ; Smoke ; Smoking ; Taiwan ; Thinness

Aberrant regulation of miRNA genes contributes to pathogenesis of a wide range of human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a RNA/DNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs regulated by TDP-43 using RNA-Seq coupled with an siRNA-mediated knockdown approach. TDP-43 knockdown affected the expression of a number of miRNAs. In addition, TDP-43 down-regulation led to alterations in the patterns of different isoforms of miRNAs (isomiRs) and miRNA arm selection, suggesting a previously unknown role of TDP-43 in miRNA processing. A number of TDP-43 associated miRNAs, and their candidate target genes, are associated with human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p. In contrast, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Reduced expression of miR-500a-3p is associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Cancer-associated genes LIF and PAPPA are possible targets of miR-500a-3p. Our work suggests that TDP-43-regulated miRNAs may play multifaceted roles in the pathogenesis of cancer.
Animals ; Cells, Cultured ; DNA-Binding Proteins ; metabolism ; Electrophoretic Mobility Shift Assay ; Humans ; Immunoprecipitation ; Mice ; MicroRNAs ; genetics ; metabolism ; Neoplasms ; genetics ; metabolism

Axonal transport of mitochondria is critical for neuronal survival and function. Automatically quantifying and analyzing mitochondrial movement in a large quantity remain challenging. Here, we report an efficient method for imaging and quantifying axonal mitochondrial transport using microfluidic-chamber-cultured neurons together with a newly developed analysis package named "MitoQuant". This tool-kit consists of an automated program for tracking mitochondrial movement inside live neuronal axons and a transient-velocity analysis program for analyzing dynamic movement patterns of mitochondria. Using this method, we examined axonal mitochondrial movement both in cultured mammalian neurons and in motor neuron axons of Drosophila in vivo. In 3 different paradigms (temperature changes, drug treatment and genetic manipulation) that affect mitochondria, we have shown that this new method is highly efficient and sensitive for detecting changes in mitochondrial movement. The method significantly enhanced our ability to quantitatively analyze axonal mitochondrial movement and allowed us to detect dynamic changes in axonal mitochondrial transport that were not detected by traditional kymographic analyses.
Animals ; Axonal Transport ; physiology ; Cerebral Cortex ; cytology ; metabolism ; Drosophila melanogaster ; cytology ; metabolism ; Embryo, Mammalian ; Gene Expression ; Lab-On-A-Chip Devices ; Microscopy, Confocal ; Mitochondria ; metabolism ; ultrastructure ; Motor Neurons ; metabolism ; ultrastructure ; Movement ; Mutation ; Primary Cell Culture ; RNA-Binding Protein FUS ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Software

MicroRNAs (miRNAs) are critical for both development and function of the central nervous system. Significant evidence suggests that abnormal expression of miRNAs is associated with neurodevelopmental disorders. MeCP2 protein is an epigenetic regulator repressing or activating gene transcription by binding to methylated DNA. Both loss-of-function and gain-of-function mutations in the MECP2 gene lead to neurodevelopmental disorders such as Rett syndrome, autism and MECP2 duplication syndrome. In this study, we demonstrate that miR-130a inhibits neurite outgrowth and reduces dendritic spine density as well as dendritic complexity. Bioinformatics analyses, cell cultures and biochemical experiments indicate that miR-130a targets MECP2 and down-regulates MeCP2 protein expression. Furthermore, expression of the wild-type MeCP2, but not a loss-of-function mutant, rescues the miR-130a-induced phenotype. Our study uncovers the MECP2 gene as a previous unknown target for miR-130a, supporting that miR-130a may play a role in neurodevelopment by regulating MeCP2. Together with data from other groups, our work suggests that a feedback regulatory mechanism involving both miR-130a and MeCP2 may serve to ensure their appropriate expression and function in neural development.
Animals ; Dendrites ; genetics ; metabolism ; Dendritic Spines ; genetics ; metabolism ; Down-Regulation ; physiology ; Methyl-CpG-Binding Protein 2 ; biosynthesis ; genetics ; MicroRNAs ; genetics ; metabolism ; Rats

Gadoxetate disodium is a widely used magnetic resonance (MR) contrast agent for liver MR imaging, and it provides both dynamic and hepatobiliary phase images. However, acquiring optimal arterial phase images at liver MR using gadoxetate disodium is more challenging than using conventional extracellular MR contrast agent because of the small volume administered, the gadolinium content of the agent, and the common occurrence of transient severe motion. In this article, we identify the challenges in obtaining high-quality arterial-phase images of gadoxetate disodium-enhanced liver MR imaging and present strategies for optimizing arterial-phase imaging based on the thorough review of recent research in this field.
Angiography ; Arteries/anatomy & histology ; Contrast Media/*chemistry ; Gadolinium DTPA/*chemistry ; Humans ; Liver/*radiography ; *Magnetic Resonance Imaging

OBJECTIVEThe objective of this study was to review the research on clinical genetics of Wilson's disease (WD).

DATA SOURCESWe searched documents from PubMed and Wanfang databases both in English and Chinese up to 2014 using the keywords WD in combination with genetic, ATP7B gene, gene mutation, genotype, phenotype.

STUDY SELECTIONPublications about the ATP7B gene and protein function associated with clinical features were selected.

RESULTSWilson's disease, also named hepatolenticular degeneration, is an autosomal recessive genetic disorder characterized by abnormal copper metabolism caused by mutations to the copper-transporting gene ATP7B. Decreased biliary copper excretion and reduced incorporation of copper into apoceruloplasmin caused by defunctionalization of ATP7B protein lead to accumulation of copper in many tissues and organs, including liver, brain, and cornea, finally resulting in liver disease and extrapyramidal symptoms. It is the most common genetic neurological disorder in the onset of adolescents, second to muscular dystrophy in China. Early diagnosis and medical therapy are of great significance for improving the prognosis of WD patients. However, diagnosis of this disease is usually difficult because of its complicated phenotypes. In the last 10 years, an increasing number of clinical studies have used molecular genetics techniques. Improved diagnosis and prediction of the progression of this disease at the molecular level will aid in the development of more individualized and effective interventions, which is a key to transition from molecular genetic research to the clinical study.

CONCLUSIONSClinical genetics studies are necessary to understand the mechanism underlying WD at the molecular level from the genotype to the phenotype. Clinical genetics research benefits newly emerging medical treatments including stem cell transplantation and gene therapy for WD patients.

Ubiquitin specific protease 33 (USP33) is a multifunctional protein regulating diverse cellular processes. The expression and role of USP33 in lung cancer remain unexplored. In this study, we show that USP33 is down-regulated in multiple cohorts of lung cancer patients and that low expression of USP33 is associated with poor prognosis. USP33 mediates Slit-Robo signaling in lung cancer cell migration. Downregulation of USP33 reduces the protein stability of Robo1 in lung cancer cells, providing a previously unknown mechanism for USP33 function in mediating Slit activity in lung cancer cells. Taken together, USP33 is a new player in lung cancer that regulates Slit-Robo signaling. Our data suggest that USP33 may be a candidate tumor suppressor for lung cancer with potential as a prognostic marker.
Blotting, Western ; Cell Line, Tumor ; Cell Movement ; genetics ; physiology ; Cohort Studies ; Down-Regulation ; Female ; Gene Expression Regulation, Neoplastic ; HEK293 Cells ; Humans ; Immunohistochemistry ; Intercellular Signaling Peptides and Proteins ; metabolism ; Kaplan-Meier Estimate ; Lung Neoplasms ; genetics ; metabolism ; pathology ; Male ; Middle Aged ; Nerve Tissue Proteins ; metabolism ; Prognosis ; RNA Interference ; Receptors, Immunologic ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; genetics ; physiology ; Ubiquitin Thiolesterase ; genetics ; metabolism

Chronic constipation (CC) may impact on quality of life. There is substantial patient dissatisfaction; possible reasons are failure to recognize underlying constipation, inappropriate dietary advice and inadequate treatment. The aim of these practical guidelines intended for primary care physicians, and which are based on Asian perspectives, is to provide an approach to CC that is relevant to the existing health-care infrastructure. Physicians should not rely on infrequent bowel movements to diagnose CC as many patients have one or more bowel movement a day. More commonly, patients present with hard stool, straining, incomplete feeling, bloating and other dyspeptic symptoms. Physicians should consider CC in these situations and when patients are found to use laxative containing supplements. In the absence of alarm features physicians may start with a 2-4 week therapeutic trial of available pharmacological agents including osmotic, stimulant and enterokinetic agents. Where safe to do so, physicians should consider regular (as opposed to on demand dosing), combination treatment and continuous treatment for at least 4 weeks. If patients do not achieve satisfactory response, they should be referred to tertiary centers for physiological evaluation of colonic transit and pelvic floor function. Surgical referral is a last resort, which should be considered only after a thorough physiological and psychological evaluation.
Asia ; Asian Continental Ancestry Group ; Colon ; Constipation ; Health Resorts ; Humans ; Pelvic Floor ; Physicians, Primary Care ; Primary Health Care ; Quality of Life ; Referral and Consultation ; Sprains and Strains