Observations of newborn blue sharks Prionace glauca in shallow inshore waters of the north-east Atlantic Ocean.

The anomalous presence of numerous blue shark Prionace glauca neonates and juveniles in shallow inshore waters of Galicia, north-west Spain, during the summers of 2014 and 2015 is reported. Changes in oceanographic conditions, high recruitment events or changes in the pupping area are discussed as possible causes of this unusual behaviour.

Dark-bright mixing of interband transitions in symmetric semiconductor quantum dots.

In photoluminescence spectra of symmetric [111] grown GaAs/AlGaAs quantum dots in longitudinal magnetic fields applied along the growth axis, we observe in addition to the expected bright states also nominally dark transitions for both charged and neutral excitons. We uncover a strongly nonmonotonic, sign-changing field dependence of the bright neutral exciton splitting resulting from the interplay between exchange and Zeeman effects. Our theory shows quantitatively that these surprising experimental results are due to magnetic-field-induced ±3/2 heavy-hole mixing, an inherent property of systems with C(3v) point-group symmetry.

Lasing in ultra-narrow emission from GaAs quantum dots coupled with a two-dimensional layer.

We report electrically injected lasing in GaAs quantum dots (QDs) grown on GaAs(001) by droplet epitaxy. High-quality GaAs QDs with superior uniformity are formed using improved growth techniques involving the insertion of a two-dimensional layer, control of the As flux for GaAs crystallization, and thin AlGaAs layer capping with high-temperature annealing. The QDs show ultra-narrow luminescence with a linewidth of 20 meV. Ground-state lasing from a laser diode containing fivefold-stacked QD layers is observed at low temperature under pulsed operation.

Peripheral Blood BRCA1 Methylation Positively Correlates with Major Alzheimer's Disease Risk Factors.

BACKGROUND: Recent biomarker studies demonstrated that the central nervous system (CNS) environment can be observed from peripherally-derived samples. In a previous study, we demonstrated significant hypomethylation of the BRCA1 promoter region in neuronal cells from post-mortem brains of Alzheimer's disease patients through neuron-specific methylome analysis. Thus, we investigate the methylation changes in the BRCA1 promoter region in the blood samples. OBJECTIVES: To analyze the methylation level of the BRCA1 promoter in peripheral blood from AD patients and normal controls. DESIGN, SETTING, PARTICIPANTS: Genomic DNA samples from peripheral blood were obtained from the J-ADNI repository, and their biomarker data were obtained J-ADNI from the National Bioscience Database Center. Genomic DNA samples from an independent cohort for validation was obtained from Niigata University Hospital (Niigata, Japan). Amyloid positivity was defied by visual inspection of amyloid PET or a CSF Aß42 value ≤ 333 pg/mL at the baseline. MEASUREMENTS: Methylation level of the BRCA1 promoter was analyzed by pyrosequencing. RESULTS: Compared to normal controls, methylation of the BRCA1 promoter in AD patients was not significantly changed; however, in AD patients, it showed a positive correlation with AD risk factors. CONCLUSIONS: Our data confirmed the importance of cell-type specific methylome analysis and also suggested that environmental changes in the CNS can be detected by observing the peripheral blood, implying that the peripheral BRCA1 methylation level can be a surrogate for AD.

Cardiac magnetic resonance in the assessment of pericardial abnormalities: a case series.

BACKGROUND: Cardiac magnetic resonance (CMR) has a unique role in evaluating pericardial disease, permitting non-invasive tissue analysis, and haemodynamic assessment. CASE SUMMARY: In Case 1 of recurrent pericarditis, CMR confirmed reactivation of inflammation with late gadolinium enhancement and native T1/T2 mapping techniques, prompting therapeutic changes. In constrictive pericarditis, CMR is the only modality capable of differentiating a subacute potentially reversible form (Case 2), from a chronic, burnt out irreversible phase characterized by constrictive physiology (Case 3). DISCUSSION: Cardiac magnetic resonance is an effective tool to tailor individual therapy, particularly in cases of recurrent and constrictive pericarditis. Late gadolinium enhancement provides diagnostic and prognostic information, and multiparametric mapping has emerged as a promising tool with incremental diagnostic value.

Cohort-Specific Optimization of Models Predicting Preclinical Alzheimer's Disease, to Enhance Screening Performance in the Middle of Preclinical Alzheimer's Disease Clinical Studies.

BACKGROUND: Models that can predict brain amyloid beta (Aß) status more accurately have been desired to identify participants for clinical trials of preclinical Alzheimer's disease (AD). However, potential heterogeneity between different cohorts and the limited cohort size have been the reasons preventing the development of reliable models applicable to the Asian population, including Japan. OBJECTIVES: We aim to propose a novel approach to predict preclinical AD while overcoming these constraints, by building models specifically optimized for ADNI or for J-ADNI, based on the larger samples from A4 study data. DESIGN AND PARTICIPANTS: This is a retrospective study including cognitive normal participants (CDR-global = 0) from A4 study, Alzheimer Disease Neuroimaging Initiative (ADNI), and Japanese-ADNI (J-ADNI) cohorts. MEASUREMENTS: The model is made up of age, sex, education years, history of AD, Clinical Dementia Rating-Sum of Boxes, Preclinical Alzheimer Cognitive Composite score, and APOE genotype, to predict the degree of amyloid accumulation in amyloid PET as Standardized Uptake Value ratio (SUVr). The model was at first built based on A4 data, and we can choose at which SUVr threshold configuration the A4-based model may achieve the best performance area under the curve (AUC) when applied to the random-split half ADNI or J-ADNI subset. We then evaluated whether the selected model may also achieve better performance in the remaining ADNI or J-ADNI subsets. RESULT: When compared to the results without optimization, this procedure showed efficacy of AUC improvement of up to approximately 0.10 when applied to the models "without APOE;" the degree of AUC improvement was larger in the ADNI cohort than in the J-ADNI cohort. CONCLUSIONS: The obtained AUC had improved mildly when compared to the AUC in case of literature-based predetermined SUVr threshold configuration. This means our procedure allowed us to predict preclinical AD among ADNI or J-ADNI second-half samples with slightly better predictive performance. Our optimizing method may be practically useful in the middle of the ongoing clinical study of preclinical AD, as a screening to further increase the prior probability of preclinical AD before amyloid testing.

FLICE-inhibitory protein expression during macrophage differentiation confers resistance to fas-mediated apoptosis.

Macrophages differentiated from circulating peripheral blood monocytes are essential for host immune responses and have been implicated in the pathogenesis of rheumatoid arthritis and atherosclerosis. In contrast to monocytes, macrophages are resistant to Fas-induced cell death by an unknown mechanism. FLICE (Fas-associated death domain-like interleukin 1beta-converting enzyme)-inhibitory protein (Flip), a naturally occurring caspase-inhibitory protein that lacks the critical cysteine domain necessary for catalytic activity, is a negative regulator of Fas-induced apoptosis. Here, we show that monocyte differentiation into macrophages was associated with upregulation of Flip and a decrease in Fas-mediated apoptosis. Overexpression of Flip protected monocytes from Fas-mediated apoptosis, whereas acute Flip inhibition in macrophages induced apoptosis. Addition of an antagonistic Fas ligand antibody to Flip antisense-treated macrophages rescued cultures from apoptosis, demonstrating that endogenous Flip blocked Fas-induced cell death. Thus, the expression of Flip in macrophages conferred resistance to Fas-mediated apoptosis, which may contribute to the development of inflammatory disease.

Allelic diversity of the MHC class II DRB genes in brown bears (Ursus arctos) and a comparison of DRB sequences within the family Ursidae.

The allelic diversity of the DRB locus in major histocompatibility complex (MHC) genes was analyzed in the brown bear (Ursus arctos) from the Hokkaido Island of Japan, Siberia, and Kodiak of Alaska. Nineteen alleles of the DRB exon 2 were identified from a total of 38 individuals of U. arctos and were highly polymorphic. Comparisons of non-synonymous and synonymous substitutions in the antigen-binding sites of deduced amino acid sequences indicated evidence for balancing selection on the bear DRB locus. The phylogenetic analysis of the DRB alleles among three genera (Ursus, Tremarctos, and Ailuropoda) in the family Ursidae revealed that DRB allelic lineages were not separated according to species. This strongly shows trans-species persistence of DRB alleles within the Ursidae.

Inhibition of synthesis of alpha-fetoprotein by glucocorticoids in cultured hepatoma cells.

alpha-Fetoprotein (AFP) synthesis was studied in the presence and absence of glucocorticoids in rat hepatoma Mc-A-RH-7777 cells. Radioimmunoassay of media from cell cultures grown in the presence of glucocorticoid (dexamethasone or cortisol) showed a reduction in AFP, an increase in albumin, and no significant change in transferrin accumulation, as compared to controls. Labeling experiments with L-[35S]methionine indicated that in both cells and media of dexamethasone-treated cultures there was a 50--80% reduction in polypeptide precipitated by anti-AFP serum, as compared with controls; no change was seen in polypeptide precipitated by anti-transferrin serum. Pulse and pulse-chase experiments demonstrated that dexamethasone inhibited the synthesis of AFP but not its secretion. The half-time for secretion of AFP in the presence and absence of dexamethasone was 43 min.

Ultra-narrow emission from single GaAs self-assembled quantum dots grown by droplet epitaxy.

We realized ultra-narrow excitonic emission from single GaAs/AlGaAs quantum dots (QDs) grown by a refined droplet epitaxy technique. We found that uncapped quantum dots can be annealed at 400 degrees C without major changes in their morphology, thus enabling an AlGaAs capping layer to be grown at that temperature. Consequently, we demonstrate a fourfold reduction of the linewidth of the emission together with an increased recombination lifetime, compared to the conventional droplet epitaxial QDs. The averaged linewidth of neutral excitons measured by micro-photoluminescence on single quantum dots was around 35 microeV.

Elevated sympathetic nerve activity in patients with accelerated essential hypertension.

To determine if an abnormality exists in the sympathetic nervous system of patients with accelerated hypertension, we recorded muscle sympathetic nerve activity (MSNA) from the tibial nerve by microneurography in eight benign essential hypertensives and seven accelerated essential hypertensives. Basal MSNA, plasma renin activity, and plasma angiotensin II levels were significantly higher in accelerated hypertensives than in benign hypertensives (P < 0.05). To clarify the relationship between the renin-angiotensin axis and sympathetic nervous system in the accelerated hypertensives, we measured the MSNA after 7 d of oral administration of captopril (75 mg/d) for antihypertensive treatment in the benign hypertensives and accelerated hypertensives. After administering captopril, the arterial pressure decreased significantly in the benign hypertensives and accelerated hypertensives with decreases in plasma angiotensin II levels, and the decreases in arterial pressure were greater in the accelerated hypertensive than in the benign hypertensives. After captopril administration, the MSNA decreased significantly in the accelerated hypertensives but did not change in the benign hypertensives. Thus, in accelerated hypertensives, sympathetic tone is elevated, and the elevated sympathetic tone is closely related to the activated renin-angiotensin axis tone.

Cell cycle withdrawal promotes myogenic induction of Akt, a positive modulator of myocyte survival.

During myogenesis, proliferating myoblasts withdraw from the cell cycle, acquire an apoptosis-resistant phenotype, and differentiate into myotubes. Previous studies indicate that myogenic induction of the cyclin-dependent kinase inhibitor p21 results in an inhibition of apoptotic cell death in addition to its role as a negative cell cycle regulator. Here we demonstrate that the protein encoded by the Akt proto-oncogene is induced in C2C12 cells during myogenic differentiation with a corresponding increase in kinase activity. In differentiating cultures, expression of dominant-negative forms of Akt increase the frequency of cell death whereas expression of wild-type Akt protects against death, indicating that Akt is a positive modulator of myocyte survival. Antisense oligonucleotides against p21 block cell cycle withdrawal, inhibit Akt induction, and enhance cell death in differentiating myocyte cultures. Adenovirus-mediated transfer of wild-type or constitutively active Akt constructs confer partial resistance to cell death under conditions where cell cycle exit is blocked by the antisense oligonucleotides. Collectively, these data indicate that cell cycle withdrawal facilitates the induction of Akt during myogenesis, promoting myocyte survival.

Neuronal intranuclear hyaline inclusion disease with rapidly progressive neurological symptoms.

This report describes a male patient who presented with symptoms suggestive of spinocerebellar degeneration and who died of respiratory failure at the age of 7 years but was diagnosed, at autopsy, as having neuronal intranuclear hyaline inclusion disease. Neuronal intranuclear hyaline inclusion disease is a progressive and degenerative disease; diagnosis is possible only by neuropathological analysis. This is a rare disorder; few cases with early childhood onset and rapidly progressive neurologic symptoms have been documented. According to previous reports, most neurons in the central nervous system exhibited intranuclear eosinophilic inclusion bodies; neuronal depletion appeared to be restricted to the cerebellar cortex and the medullary inferior olivary nuclei, consistent with the fact that clinical deficit appears to correspond to the site of neuronal depletion and not to where eosinophilic bodies are detected. Immunohistochemical analysis revealed that these inclusions were positive for ubiquitin. The case presented herein clearly indicates that neuronal intranuclear hyaline inclusion disease should be considered as a differential diagnosis of cases involving spinocerebellar degeneration with childhood onset.

Phosphatidylinositol 3-kinase/Akt signaling controls endothelial cell sensitivity to Fas-mediated apoptosis via regulation of FLICE-inhibitory protein (FLIP).

Fas is constitutively expressed on endothelial cells, but in contrast to smooth muscle and other cell types, endothelial cells are highly resistant to Fas-mediated apoptosis. In this study, we examined the role of the serine/threonine kinase Akt/PKB in controlling the sensitivity of endothelial cells to Fas-mediated apoptosis. Serum deprivation inhibited expression of the caspase-8 inhibitor FLICE-inhibitory protein (FLIP), which functions downstream from Fas. FLIP expression levels were restored when serum-depleted cells were treated with vascular endothelial growth factor. Treatment with the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitors wortmannin or LY294002 or infection of the adenoviral construct expressing dominant-negative Akt (Adeno-dnAkt) also inhibited the expression of FLIP in endothelial cells, whereas the MEK inhibitor PD98059 had no effect. Conversely, adenovirus-mediated transfection of a constitutively-active Akt gene abolished the wortmannin- and LY294002-mediated downregulation of FLIP. Suppression of PI 3-kinase signaling sensitized endothelial cells to Fas-mediated apoptosis. Under conditions of suppressed PI 3-kinase signaling, restoration of FLIP expression reversed the induced sensitivity of endothelial cells to Fas-mediated apoptosis. These data suggest that inhibition of Fas-mediated apoptosis, via promotion of FLIP expression, is a mechanism through which Akt signaling can promote endothelial cell survival.

Cyclin A downregulation and p21(cip1) upregulation correlate with GATA-6-induced growth arrest in glomerular mesangial cells.

The GATA-6 transcription factor is reported to be expressed in vascular myocytes. Because glomerular mesangial cells (GMCs) and vascular myocytes have similar properties, we examined whether GATA-6 was expressed in cultured GMCs and whether overexpression of GATA-6 induced cell cycle arrest in GMCs, using a recombinant adenovirus that expresses GATA-6 (Ad GATA-6). GATA-6 expression in GMCs was downregulated when quiescent GMCs were stimulated by serum to reenter the cell cycle. [(3)H]thymidine uptake was inhibited in GMCs infected with Ad GATA-6 in a dose- and time-dependent manner. The expression of cyclin A protein was decreased and that of the cyclin-dependent kinase inhibitor p21(cip1) was increased in GMCs infected with Ad GATA-6. Although the expression of p21(cip1) transcripts did not change remarkably, p21(cip1) protein was stabilized in GMCs infected with Ad GATA-6, suggesting a post-transcriptional regulation of p21(cip1) expression. Northern blot analysis showed that expression of the cyclin A transcript was decreased in Ad GATA-6-infected cells, whereas this decrease of cyclin A was not observed in GMCs derived from p21(cip1) null mice. Our results demonstrate that GATA-6 is endogenously expressed in GMCs and that overexpression of GATA-6 can induce cell cycle arrest. Our results also show that GATA-6-induced cell cycle arrest is associated with inhibition of cyclin A expression and p21(cip1) upregulation. Finally, our results indicate that the GATA-6-induced suppression of cyclin A expression depends on the presence of p21(cip1).

Residues interacting with serine-174 and alanine-295 in the beta-subunit of Escherichia coli H(+)-ATP synthase: possible ternary structure of the center region of the subunit.

The mutation of serine-174 to phenylalanine that causes a defect in the Escherichia coli F1-ATPase beta-subunit is suppressed by further mutations; Gly-149 to Ser, Ala-295 to Thr, Ala-295 to Pro, or Leu-400 to Gln (Miki, J., Fujiwara, K., Tsuda, M., Tsuchiya, T. and Kanazawa, H. (1990) J. Biol. Chem. 265, 21567-21572). We analyzed the effects of these second site mutations and of a newly identified Asn-158 to Tyr mutation on the activities of the ATPase without the original Ser-174 to Phe mutation. The beta-subunit with each amino acid replacement was expressed in the mutant strain JP17, which does not have a beta-subunit. Cells transformed with the plasmid carrying Ala-295 to Pro mutation alone did not grow on minimal medium agar supplemented with succinate as the sole carbon source, and showed 3% of the wild-type ATPase activity, suggesting that this mutation caused structural alterations affecting the catalytic function of the enzyme. Conversely transformants with other mutations grew well and had higher ATPase activities, suggesting that these mutations did not cause extensive structural alterations. From the transformants with the plasmid carrying the Ala-295 to Pro mutation, seven revertants capable of cell growth on succinate plates were isolated and reversion mutations were identified at residues 140, 159, 166, 171, 172 and 184 of the beta-subunits. The results suggested that Ser-174 and Ala-295 do not necessarily interact directly, but that the regions including these suppression mutation sites close to Ser-174, and Ala-295 interact with each other for the proper functioning of the ATPase. The ternary structure of the region surrounded by the residues which were identified as the reversion mutation sites for Ser-174 to Phe and Ala-295 to Pro mutations is important for the catalytic function of this enzyme.

Effects of thyroid hormone on the sorbitol pathway in streptozotocin-induced diabetic rats.

Sorbitol accumulation plays an important role in diabetic complications involving the kidney, nerves, retina, lens and cardiac muscle. To investigate the influence of thyroid hormone on the sorbitol pathway, we studied the effects of thyroid hormone on polyol metabolism in normal and diabetic rats. Rats were divided into three groups: controls, streptozotocin (STZ)-induced diabetic euthyroid rats (DM) and STZ-induced diabetic hyperthyroid (thyroxine-injected) rats (DM+HT). The sorbitol (Sor) concentrations in the kidney, liver and sciatic nerve (2.53+/-0.74, 0.97+/-0.16 and 24.0+/-5.1 nmol/mg protein, respectively) of the DM rats were significantly higher than those (1.48+/-0.31, 0.58+/-0.13 and 3. 1+/-0.6 nmol/mg protein) of the control rats. The Sor concentrations in the kidney and sciatic nerve of the DM+HT rats (1.26+/-0.29 and 9. 40+/-1.2 nmol/mg protein) were significantly lower than those in the DM rats. These values were reduced in the liver, unchanged in the kidney, and increased in the sciatic nerve from the hyperthyroid rats without diabetes. Thyroid hormone reduced the aldose reductase (AR) activities in the kidney, liver and sciatic nerve of the DM rats, and similarly reduced AR in the kidney and liver, but not in the sciatic nerve, of the non-diabetic rats. The sorbitol dehydrogenase (SDH) activities were decreased by thyroid hormone in the kidney and liver but not the sciatic nerve of DM rats. In the non-diabetic rats, this enzyme activity was decreased in liver, but not in kidney or sciatic nerve. A positive correlation between the Sor concentration and AR activity was observed in the kidney and liver but not in the sciatic nerve from control, DM and DM+HT rats. A negative correlation was observed between the Sor concentration and SDH activities in the same organs. These data suggest that thyroid hormone affects the sorbitol pathway, but the detailed mechanism whereby this hormone reduces the sorbitol content (especially in diabetic rats) remains to be clarified.

Long-term administration of amlodipine prevents decompensation to diastolic heart failure in hypertensive rats.

UNLABELLED: OBJECTIVES; We assessed the effects of long-term amlodipine administration in a diastolic heart failure (DHF) rat model with preserved systolic function as well as the relationship between changes in left ventricular (LV) myocardial stiffening and alterations in extracellular matrix. BACKGROUND: Although the effect of long-term administration of amlodipine has been shown to be disappointing in patients with systolic failure, the effect is unknown in those with DHF. METHODS: Dahl salt-sensitive rats fed a high-salt diet for seven weeks were divided into three groups: eight untreated rats (DHF group), eight rats given high-dose amlodipine (10 mg/kg/day; HDA group) and seven rats given low-dose amlodipine (1 mg/kg/day; LDA group). RESULTS: High-dose administration of amlodipine decreased systolic blood pressure and controlled excessive hypertrophy, without a decrease in the collagen content, and prevented the elevation of LV end-diastolic pressure at 19 weeks. Low-dose administration of amlodipine with subdeppressive effects did not control either hypertrophy or fibrosis; however, it prevented myocardial stiffening and, hence, the elevation of LV end-diastolic pressure. The ratio of type I to type III collagen messenger ribonucleic acid levels was significantly lower in both the HDA and LDA groups than in the DHF group. CONCLUSIONS: Long-term administration of amlodipine prevented the transition to DHF both at the depressor and subdepressor doses. Amlodipine did not decrease the collagen content, but attenuated myocardial stiffness, with inhibition of the phenotype shift from type III to type I collagen. Thus, amlodipine may exert beneficial effects through amelioration of collagen remodeling in the treatment of DHF.