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1.  Circadian Rhythms of Oxidative Stress Markers and Melatonin Metabolite in Patients with Xeroderma Pigmentosum Group A 
Xeroderma pigmentosum group A (XPA) is a genetic disorder in DNA nucleotide excision repair (NER) with severe neurological disorders, in which oxidative stress and disturbed melatonin metabolism may be involved. Herein we confirmed the diurnal variation of melatonin metabolites, oxidative stress markers, and antioxidant power in urine of patients with XPA and age-matched controls, using enzyme-linked immunosorbent assay (ELISA). The peak of 6-sulfatoxymelatonin, a metabolite of melatonin, was seen at 6:00 in both the XPA patients and controls, though the peak value is lower, specifically in the younger age group of XPA patients. The older XPA patients demonstrated an increase in the urinary levels of 8-hydroxy-2′-deoxyguanosine and hexanoyl-lysine, a marker of oxidative DNA damage and lipid peroxidation, having a robust peak at 6:00 and 18:00, respectively. In addition, the urinary level of total antioxidant power was decreased in the older XPA patients. Recently, it is speculated that oxidative stress and antioxidant properties may have a diurnal variation, and the circadian rhythm is likely to influence the NER itself. We believe that the administration of melatonin has the possibility of ameliorating the augmented oxidative stress in neurodegeneration, especially in the older XPA patients, modulating the melatonin metabolism and the circadian rhythm.
PMCID: PMC4861809  PMID: 27213030
2.  The Role of ARX in Human Pancreatic Endocrine Specification 
PLoS ONE  2015;10(12):e0144100.
The in vitro differentiation of human embryonic stem cells (hESCs) offers a model system to explore human development. Humans with mutations in the transcription factor Aristaless Related Homeobox (ARX) often suffer from the syndrome X-linked lissencephaly with ambiguous genitalia (XLAG), affecting many cell types including those of the pancreas. Indeed, XLAG pancreatic islets lack glucagon and pancreatic polypeptide-positive cells but retain somatostatin, insulin, and ghrelin-positive cells. To further examine the role of ARX in human pancreatic endocrine development, we utilized genomic editing in hESCs to generate deletions in ARX. ARX knockout hESCs retained pancreatic differentiation capacity and ARX knockout endocrine cells were biased toward somatostatin-positive cells (94% of endocrine cells) with reduced pancreatic polypeptide (rarely detected), glucagon (90% reduced) and insulin-positive (65% reduced) lineages. ARX knockout somatostatin-positive cells shared expression patterns with human fetal and adult δ-cells. Differentiated ARX knockout cells upregulated PAX4, NKX2.2, ISL1, HHEX, PCSK1, PCSK2 expression while downregulating PAX6 and IRX2. Re-expression of ARX in ARX knockout pancreatic progenitors reduced HHEX and increased PAX6 and insulin expression following differentiation. Taken together these data suggest that ARX plays a key role in pancreatic endocrine fate specification of pancreatic polypeptide, somatostatin, glucagon and insulin positive cells from hESCs.
PMCID: PMC4669132  PMID: 26633894
3.  Changes in Cerebrospinal Fluid Biomarkers in Human Herpesvirus-6-Associated Acute Encephalopathy/Febrile Seizures 
Mediators of Inflammation  2014;2014:564091.
To determine the involvement of oxidative stress in the pathogenesis of acute encephalopathy associated with human herpesvirus-6 (HHV-6) infection, we measured the levels of oxidative stress markers 8-hydroxy-2′-deoxyguanosine (8-OHdG) and hexanoyl-lysine adduct (HEL), tau protein, and cytokines in cerebrospinal fluid (CSF) obtained from patients with HHV-6-associated acute encephalopathy (HHV-6 encephalopathy) (n = 16) and complex febrile seizures associated with HHV-6 (HHV-6 complex FS) (n = 10). We also examined changes in CSF-8OHdG and CSF-HEL levels in patients with HHV-6 encephalopathy before and after treatment with edaravone, a free radical scavenger. CSF-8-OHdG levels in HHV-6 encephalopathy and HHV-6 complex FS were significantly higher than in control subjects. In contrast, CSF-HEL levels showed no significant difference between groups. The levels of total tau protein in HHV-6 encephalopathy were significantly higher than in control subjects. In six patients with HHV-6 infection (5 encephalopathy and 1 febrile seizure), the CSF-8-OHdG levels of five patients decreased after edaravone treatment. Our results suggest that oxidative DNA damage is involved in acute encephalopathy associated with HHV-6 infection.
PMCID: PMC4177780  PMID: 25294958
4.  Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy 
Nature genetics  2012;45(1):83-87.
Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 patients. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homologue of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies demonstrated a severe block of autophagosomal clearance in muscle and fibroblasts from EPG5 mutant patients, resulting in autophagic cargo accumulation in autophagosomes. These findings indicate Vici syndrome as a paradigm of a human multisystem disorder associated with defective autophagy, and suggest a fundamental role of the autophagy pathway in the anatomical and functional formation of organs such as the brain, the heart and the immune system.
PMCID: PMC4012842  PMID: 23222957
5.  Common allometric response of open-grown leader shoots to tree height in co-occurring deciduous broadleaved trees 
Annals of Botany  2011;108(7):1279-1286.
Background and Aims
Morphology of crown shoots changes with tree height. The height of forest trees is usually correlated with the light environment and this makes it difficult to separate the effects of tree size and of light conditions on the morphological plasticity of crown shoots. This paper addresses the tree-height dependence of shoot traits under full-light conditions where a tree crown is not shaded by other crowns.
Focus is given to relationships between tree height and top-shoot traits, which include the shoot's leaf-blades and non-leafy mass, its total leaf-blade area and the length and basal diameter of the shoot's stem. We examine the allometric characteristics of open-grown current-year leader shoots at the tops of forest tree crowns up to 24 m high and quantify their responses to tree height in 13 co-occurring deciduous hardwood species in a cool-temperate forest in northern Japan.
Key Results
Dry mass allocated to leaf blades in a leader shoot increased with tree height in all 13 species. Specific leaf area decreased with tree height. Stem basal area was almost proportional to total leaf area in a leader shoot, where the proportionality constant did not depend on tree height, irrespective of species. Stem length for a given stem diameter decreased with tree height.
In the 13 species observed, height-dependent changes in allometry of leader shoots were convergent. This finding suggests that there is a common functional constraint in tree-height development. Under full-light conditions, leader shoots of tall trees naturally experience more severe water stress than those of short trees. We hypothesize that the height dependence of shoot allometry detected reflects an integrated response to height-associated water stress, which contributes to successful crown expansion and height gain.
PMCID: PMC3197456  PMID: 21914698
Allometry; current-year leader shoot; hierarchical Bayesian model; pipe model; tree height; water stress
6.  Lesions of Acetylcholine Neurons in Refractory Epilepsy 
ISRN Neurology  2012;2012:404263.
We have examined brainstem lesions in patients with refractory epilepsy disorders, including West syndrome (WS), Lennox-Gastaut syndrome (LGS), and dentatorubral-pallidoluysian atrophy (DRPLA). Acetylcholinergic neurons (AchNs) in the pedunculopontine tegmental nucleus (PPN) are involved in mental development, and disruption of neuronal nicotinic acetylcholine receptors can lead to epilepsy. In order to investigate the involvement of lesions of AchNs in refractory epilepsy, we performed immunohistochemical analyses of AchNs in the PPN in autopsy cases who had a past history of WS and/or LGS and in DRPLA cases who showed progressive myoclonic epilepsy. In addition, we performed a preliminary quantification of the levels of acetylcholine, neuropeptides, and monoamine metabolites in the cerebrospinal fluid (CSF) of patients with WS and benign convulsions associated with mild gastroenteritis (CwG). In the PPN analysis, the total number of neurons and the number of AchNs were reduced in WS/LGS and WS cases, while DRPLA cases showed a decrease in the number and percentage of AchNs. In the CSF analysis, WS patients demonstrated a reduction in the levels of inhibitory neuropeptides, while CwG patients showed increased levels of acetylcholine and decreased levels of serotonin metabolites. These data suggest the possible involvement of lesions of AchNs in WS and DRPLA.
PMCID: PMC3425792  PMID: 22934193

Results 1-6 (6)