Evidence of a Hardening in the Cosmic Ray Proton Spectrum at around 166 TeV Observed by the GRAPES-3 Experiment.

We present the measurement of the cosmic ray proton spectrum from 50 TeV to 1.3 PeV using 7.81×10^{6} extensive air shower events recorded by the ground-based GRAPES-3 experiment between 1 January 2014 and 26 October 2015 with a live time of 460 day. Our measurements provide an overlap with direct observations by satellite and balloon-based experiments. The electromagnetic and muon components in the shower were measured by a dense array of plastic scintillator detectors and a tracking muon telescope, respectively. The relative composition of the proton primary from the air shower data containing all primary particles was extracted using the multiplicity distribution of muons which is a sensitive observable for mass composition. The observed proton spectrum suggests a spectral hardening at ∼166 TeV and disfavors a single power law description of the spectrum up to the Knee energy (∼3 PeV).

Evidence of the American Myxobolus dechtiari was introduced along with its host Lepomis gibbosus in Europe: Molecular and histological data.

The American pumpkinseed Lepomis gibbosus, was introduced to Europe more than one hundred years ago. Currently it is a common fish in European freshwaters but relatively few specific parasites infect this fish in this new habitat. In Europe only a single species, Myxobolus dechtiari seems to represent the American myxosporean fauna of centrarchid fishes. M. dechtiari was found in both Portugal and Hungary. This species forms plasmodia with elongated shape inside the cartilaginous rays of gill filaments. In the advanced stage of infection, after disruption of plasmodia, small groups of myxospores remain enclosed in the cartilaginous gill rays causing distortions in the filaments. Myxospores were ellipsoidal in frontal view and lemon-shape in sutural, length 12.5 ± 0.46 (12-13.4) µm, width 10 ± 0.37 (9.6-10.4) µm, and thickness 7.4 ± 0.37 (7-8) µm; the polar capsules were pyriform, equal in size, length 5.6 ± 0.21 (5.3-6) µm, width 3.2 ± 0.16 (3-3.6) µm; Seven to eight polar tube coils were arranged perpendicularly to the capsule length. There was a small, round, 0.4 ± 0.1 (0.3-05) (N = 50) intercapsular appendix in the spores. The small subunit ribosomal DNA (ssrDNA) of M. dechtiari differed from other myxozoans sequenced to date. Phylogenetic analysis of the ssrDNA gene sequence placed this species in a clade including actinospores and Myxobolus species: Raabeia type1, Triactinomyxon sp., and Myxobolus osburni infecting the same host fish. The focus of our study was to prove that the pumpkinseed, a fish originated from North-America introduced one of its myxosporean parasite to Europe. Emphasis was put on to demonstrate the unique feature of this parasite causing infection in the cartilaginous gill rays.

Molecular Genetic Studies on Myxobolus cylindricus and Henneguya mystasi (Myxosporea: Myxobolidae) Infecting Two Indian Fish Species, Channa gachua and Mystus vittatus, Respectively.

INTRODUCTION: Myxozoan infections of Indian freshwater fishes are relatively well studied, but their validity is supported with molecular and phylogenetic data only for a few species. OBJECTIVES: The primary objective was to present molecular data for two Myxozoan species, Myxobolus cylindricus and Henneguya gachua collected from Indian freshwater fishes, the dwarf snakehead Channa gachua and the striped dwarf catfish Mystus vittatus, respectively. METHODS: Various organs of 56 C. gachua and 48 M. vittatus were dissected. Myxozoan plasmodia with mature spores were collected from the gills under a dissecting microscope. Spores obtained from plasmodia from infected hosts were fixed in 80% ethanol in vials and sent for further morphological and molecular examinations to Hungary. The 18S rDNA gene of Myxobolus and Henneguya spp. was amplified using nested polymerase chain reaction (PCR). Phylogenetic analysis was performed using maximum likelihood (ML) and Bayesian inference (BI) methods. RESULTS: Morphological characteristics of M. cylindricus and H. mystasi spores corresponded to the original descriptions made by Sarkar, Mazumdar and Pramanik, 1985 and Haldar, Samal, and Mukhopadhyay, 1997, respectively. Phylogenetic analysis of the 18S rDNA gene revealed that the sequences of M. cylindricus differed from those of most Indian Myxobolus sp., known mostly from cyprinid fishes and formed a subgroup with Myxobolus neurophilus, a parasite of a perciform host, and with Henneguya chaudhuryi, a species belonging to a different genus but described from a closely related channid host. It was also closely related to another Henneguya species, H. lesteri, described from Sillago analis, a coastal fish. Henneguya mystasi had the closest similarity to Henneguya bicaudi, a species described from an Indian cyprinid fish and to Henneguya pellucida reported from a characid fish known from South America. CONCLUSION: Molecular data received by us gives a solid basis for further identification of these myxozoans, the pathogenicity of which probably plays an economic role at culturing the hosts.

Studies on seasonal and topographical variations of periphyton in the rivers of Manipur.

Seasonal and topographical variations of abundance and quality composition of periphyton at up and down stream of Imphal, Thoubal and Khuga rivers were studied from 1999-2002. It was found that periphyton population was high (3,055-53,450 u cm(-2)) and fluctuated in a wide range. Upper stretches (3053-53,450 u cm(-2)) of the rivers have higher periphyton population and showed definite seasonal fluctuation than the middle and lower stretches (3,276-16,320 u cm2). Species richness was also higher in upper stretches in comparison to lower stretches of all the rivers. Bacillariophyceae dominated the periphyton population and contribution of Cyanophyceae was nominal. Shannon and Weaver species diversity index was within the favorable range and evenness value for all the rivers were near unity and reflected a stable and unpolluted aquatic environment of the rivers.

A novel small molecule antagonist of choline kinase-α that simultaneously suppresses MAPK and PI3K/AKT signaling.

Choline kinase-α expression and activity are increased in multiple human neoplasms as a result of growth factor stimulation and activation of cancer-related signaling pathways. The product of choline kinase-α, phosphocholine, serves as an essential metabolic reservoir for the production of phosphatidylcholine, the major phospholipid constituent of membranes and substrate for the production of lipid second messengers. Using in silico screening for small molecules that may interact with the choline kinase-α substrate binding domain, we identified a novel competitive inhibitor, N-(3,5-dimethylphenyl)-2-[[5-(4-ethylphenyl)-1H-1,2,4-triazol-3-yl]sulfanyl] acetamide (termed CK37) that inhibited purified recombinant human choline kinase-α activity, reduced the steady-state concentration of phosphocholine in transformed cells, and selectively suppressed the growth of neoplastic cells relative to normal epithelial cells. Choline kinase-α activity is required for the downstream production of phosphatidic acid, a promoter of several Ras signaling pathways. CK37 suppressed mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT signaling, disrupted actin cytoskeletal organization, and reduced plasma membrane ruffling. Finally, administration of CK37 significantly decreased tumor growth in a lung tumor xenograft mouse model, suppressed tumor phosphocholine, and diminished activating phosphorylations of extracellular signal-regulated kinase and AKT in vivo. Together, these results further validate choline kinase-α as a molecular target for the development of agents that interrupt Ras signaling pathways, and indicate that receptor-based computational screening should facilitate the identification of new classes of choline kinase-α inhibitors.

Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling.

Choline is an essential anabolic substrate for the synthesis of phospholipids. Choline kinase phosphorylates choline to phosphocholine that serves as a precursor for the production of phosphatidylcholine, the major phospholipid constituent of membranes and substrate for the synthesis of lipid signaling molecules. Nuclear magnetic resonance (NMR)-based metabolomic studies of human tumors have identified a marked increase in the intracellular concentration of phosphocholine relative to normal tissues. We postulated that the observed intracellular pooling of phosphocholine may be required to sustain the production of the pleiotropic lipid second messenger, phosphatidic acid. Phosphatidic acid is generated from the cleavage of phosphatidylcholine by phospholipase D2 and is a key activator of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT survival signaling pathways. In this study we show that the steady-state concentration of phosphocholine is increased by the ectopic expression of oncogenic H-Ras(V12) in immortalized human bronchial epithelial cells. We then find that small interfering RNA (siRNA) silencing of choline kinase expression in transformed HeLa cells completely abrogates the high concentration of phosphocholine, which in turn decreases phosphatidylcholine, phosphatidic acid and signaling through the MAPK and PI3K/AKT pathways. This simultaneous reduction in survival signaling markedly decreases the anchorage-independent survival of HeLa cells in soft agar and in athymic mice. Last, we confirm the relative importance of phosphatidic acid for this pro-survival effect as phosphatidic acid supplementation fully restores MAPK signaling and partially rescues HeLa cells from choline kinase inhibition. Taken together, these data indicate that the pooling of phosphocholine in cancer cells may be required to provide a ready supply of phosphatidic acid necessary for the feed-forward amplification of cancer survival signaling pathways.

The neurocognitive performance of drug-free and medicated euthymic bipolar patients do not differ.

OBJECTIVE: Although it is established that euthymic bipolar patients have neurocognitive deficits, the influence of medication on their cognitive performance is uncertain and requires investigation. METHOD: Neuropsychological tests of executive function, memory and attention were performed on 44 prospectively verified, euthymic bipolar I patients, 22 of whom were drug-free. Residual mood symptom effects were controlled statistically using ancova. RESULTS: Drug-free and medicated patients differed only in delayed verbal recall (Rey AVLT list A7, drug-free > medicated), and perseverations during the five-point test (drug-free > medicated). When residual mood symptoms were controlled statistically, differences between drug-free and medicated subjects became insignificant. Medication effect sizes were modest. Significant correlations were found between residual depression scores and measures of verbal learning. CONCLUSION: Medications did not have any significant influence on neurocognitive performance, suggesting that neurocognitive deficits are an integral part of bipolar disorder.

Toxic effect of environmental acid-stress on the sperm of a hill-stream fish Devario aequipinnatus: a scanning electron microscopic evaluation.

Environmental stress due to acidic pH of water was found to be one of the major factors leading to toxic effects on the sperm of a hill-stream fish Devario aequipinnatus of Meghalaya, India. The Scanning Electron Microscopy of the transverse section of testes of the fish collected from its natural habitat with acidic pH (5.6-6.0) showed that the sperms were clumped together and their tails were either absent or were of extremely small length. The acrosome and midpiece were also not well differentiated. When the fingerlings from the natural habitat were reared to maturity in aquarium with water from natural habitat after changing the pH to alkaline range (8.0-8.2), the clumping of the sperm was not observed. The sperm tail was found to be well-developed along with well-differentiated acrosome and midpiece. Since the only change in the water quality parameters of the experimental aquarium as compared to those of the natural habitat was the pH, it is evident that the abnormal features of the sperm observed in fish from natural habitat is mainly because of environmental acid stress.

A serine protease inhibitor from hemolymph of green mussel, Perna viridis.

Bioactivity guided fractions of cell-free hemolymph of bacterially challenged marine mussel, Perna viridis led to the isolation of a novel quaternary alkaloid 1, which was identified by its spectral data. The isolated molecule 1 has been found to be a potent serine protease inhibitor (SPI) showing IC(50) and K(i) values of 102.5 and 97.1-104.68 microM, respectively. The E(t)/K(i) value of SPI is 6.3, whereas E(t)/K(m) value is 1.04. The Van't Hoff analysis showed that the value of K(i) decreases with increase in temperature, and the binding of the inhibitor is entropically driven.

Neuro-cognitive functions in patients of major depression.

Earlier studies have shown conflicting results regarding impairment of executive functions in patients of major depression. In the present study, subjects were divided into following groups-Group 1 (19 Males & 11 females, age 18-45 years) consisting of patients of major depression diagnosed on the basis of DSM IV criteria and Group 2 (20 Males & 10 females, age 18-45 years) consisting of healthy subjects who had been screened for any sub-psychiatric illness by standardized hindi version of Goldberg's General Health Questionnaire (G.H.Q.). All the Group 1 & Group 2 subjects were rated on Hamilton Rating Scale for Depression (HAM-D) and then administered Neuro-cognitive test battery consisting of Letter Cancellation test, Trail Making test 'A' & 'B', Ruff Figural Fluency test, Forward & Reverse Digit Span test for assessing following cognitive domains: Attention span, visuo-motor scanning, short term memory and executive functions like working memory, information manipulation, set-shifting strategy analysis etc. Results showed significant impairment on all the studied neuro-cognitive parameters in Group 1 subjects as compared to Group 2 subjects, which demonstrate significant impairment of attention, visuomotor speed, immediate verbal memory, short-term retentive capacity and executive functions (strategic planning, attentional set shifting and working memory) in patients of major depression. It may probably be due to the disruption of dorso-lateral prefrontal cortex (dlpfc) and orbito-frontal networks in patients of major depression.

Effect of Sahaj Yoga on neuro-cognitive functions in patients suffering from major depression.

Cognitive functions are impaired in Major Depression. Studies on the effects of Yoga on cognitive functions have shown improvement in memory, vigilance and anxiety levels. 30 patients suffering from Major depression (age 18 to 45 years) were randomly divided into two groups: Group 1: (10 males and 5 Females) Patients who practised Sahaj Yoga meditation and also received conventional anti-depressant medication. Group 2: (9 males and 6 Females) Patients who only received conventional antidepressant medication. Group 1 patients were administered Sahaj Yoga practice for 8 weeks. Neuro-cognitive test battery consisting of Letter cancellation test (LCT), Trail making test 'A' (TTA), Trail making test 'B' (TTB), Ruff figural fluency test (RFFT), Forward digit span (FDS) & Reverse digit span test (RDS) was used to assess following cognitive domains: Attention span, visuo-motor speed, short-term memory, working memory and executive functions. After 8 weeks, both Group 1 and Group 2 subjects showed significant improvement in LCT, TTA & TTB but improvement in LCT was more marked in Group 1 subjects. Also, there was significant improvement in RDS scores in only Group 1 subjects (P < 0.05). The results thereby, demonstrate that Sahaj Yoga practice in addition to the improvement in various other cognitive domains seen with conventional anti-depressants, can lead to additional improvement in executive functions like manipulation of information in the verbal working memory and added improvement in attention span and visuo-motor speed of the depressives.

Pharmacokinetics of valproic acid in patients with bipolar disorder.

The pharmacokinetics of valproic acid (VPA) were studied in nine patients with bipolar disorder who were receiving VPA as prophylactic therapy, following the full daily dose (400-1500 mg), on which the patients had been maintained for at least the past 3 months. The data from our study showed that the pharmacokinetics of valproate followed a two compartment open model. A time lag of 1-2 h was observed in each patient, followed by rapid absorption, with the peak concentrations being recorded approximately 4 h after drug administration. The average 12 h trough concentration was found to be 54.73+/-11.96 microg/ml. The plasma level decline was biphasic with a terminal half-life of 14.2+/-6.39 h. Total plasma clearance was 0.095+/-0.035 ml/min/kg. The steady-state apparent volume of distribution was found to be 0.11+/-0.05 l/kg. A positive correlation (r = 0.69) was found between the dose (mg/kg) and steady-state serum concentration (Css) of VPA and all patients, except one, had their Css above 50 microg/ml. Most of the pharmacokinetic parameters in this study involving euthymic bipolar patients on long-term VPA monotherapy were found to be in agreement with those reported in literature on seizure disorder patients on similar regime; however, the plasma elimination half-life appears to be prolonged in bipolar patients.

Cognitive development: no stages please--we're British.

British cognitive developmental psychology is characterized by its interest in philosophical questions, its preference for linking basic research to applied issues in education and cognitive disorders, and its willingness to learn both methodologically and theoretically from work in animal psychology and in physiology more generally. It has also been influenced profoundly by Jean Piaget's cognitive stage theory although in general British work has focused on demonstrating early strengths, rather than early deficits, in infant and child cognition. Following an overview of British work that encompasses past and present interests, issues and challenges for the future are highlighted. While the perspectives of the founding members of the British Psychological Society (BPS), as outlined by Edgell (1947), are still apparent in British research in cognitive developmental psychology today, it is argued that future cognitive work must become even more interdisciplinary and that the symbiotic relationship between research in adult cognition and in cognitive development needs greater recognition.

Cerebral white matter lesions in bipolar affective disorder: relationship to outcome.

BACKGROUND: Twenty per cent of patients with bipolar affective disorder suffer an illness that responds inadequately to treatment and has a poor outcome. Many patients, but not all, with bipolar disorder show white matter abnormalities on T(2)-weighted magnetic resonance imaging (MRI). AIMS: To explore the hypothesis that white matter abnormalities on MRI are seen more frequently in subjects whose illness has a poor outcome compared with those with a good outcome or controls. METHOD: Two groups of age- and gender-matched patients with bipolar disorder (14 with a good outcome and 15 with a poor outcome) and 15 controls, aged 20-65 years, were studied. Axial T(2)-weighted MRI scans were examined for the presence and severity of white matter abnormalities. RESULTS: Significantly more poor outcome group members had deep subcortical punctate, but not periventricular, white matter hyperintensities than the good outcome group (P:=0.035) or controls (P:=0.003) and these abnormalities were of greater severity (P:=0.030 and P:<0.014, respectively). CONCLUSIONS: Subcortical white matter lesions are associated with poor outcome bipolar disorder.

Role of ureogenesis in the mud-dwelled Singhi catfish (Heteropneustes fossilis) under condition of water shortage.

The air-breathing Singhi catfish Heteropneustes fossilis was kept inside moist peat for 1 month mimicking their normal habitat in summer and the role of ureogenesis for their survival in a water-restricted condition was studied. The ammonia excretion rate by the mud-dwelled fish increased transiently between 6 and 12 h of re-immersion in water to approximately between eight and 10-fold, followed by a sharp decrease almost to the normal level at the later part of re-immersion. The urea-N excretion by the mud-dwelled fish increased to approximately 11-fold within 0-3 h of re-immersion, followed by a gradual decrease from 9 h onwards. The rate of urea-N excretion by the mud-dwelled fish, however, remained significantly higher (approx. threefold more) than the control fish even after 36-48 h of re-immersion. Although there was a significant increase of both ammonia and urea levels in the plasma and other tissues (except ammonia in the brain), the level of accumulation of urea was higher than ammonia in the mud-dwelled fish as indicated by the decrease in the ratio of ammonia: urea level in different tissues including the plasma. The activities (units/g tissue and /mg protein) of glutamine synthetase and three enzymes of the urea cycle, carbamyl phosphate synthetase, argininosuccinate synthetase and argininosuccinate lyase increased significantly in most of the tissues (except the brain) of the mud-dwelled fish as compared to the control fish. Higher accumulation of ammonia in vivo in the mud-dwelled Singhi catfish is suggested to be one of the major factors contributing to stimulation of ureogenesis. Due to this physiological adaptive strategy of ureogenesis, possibly along with other physiological adaptation(s), this air-breathing amphibious Singhi catfish is able to survive inside the moist peat for months in a water-restricted condition.

Phonological awareness of syllables, rhymes, and phonemes in deaf children.

Phonological awareness is important for reading development in hearing children, in whom it develops at the three consecutive levels of the syllable, rhyme, and phoneme. Deaf children typically have literacy difficulties, and previous research has been equivocal about whether deaf children can develop phonological awareness. Three experiments are presented that investigate the phonological skills of deaf children (mean age 11 years) at the three linguistic levels of syllable, rhyme, and phoneme. The first experiment showed that deaf children's syllable awareness can be equivalent to that of chronological age-matched hearing controls. In the second experiment, deaf children's ability to make rhyme judgements was above chance, but poorer than that of younger reading-matched hearing controls. The third experiment showed that deaf children could phonologically recode nonsense words at a level above chance, suggesting that they could draw on phonemic skills in certain conditions. We conclude that deaf children can develop phonological awareness, but that their phonological skills lag those of hearing children and may develop in different ways. Differences between our tasks and those used in other studies are discussed.

Phonological representations, reading development and dyslexia: towards a cross-linguistic theoretical framework.

This paper attempts to integrate recent research findings in phonological development, reading development and dyslexia into a coherent theoretical framework that can provide a developmental account of reading and reading difficulties across languages. It is proposed that the factors governing phonological development across languages are similar, but that important differences in the speed and level of phonological development are found following the acquisition of alphabetic literacy. The causal framework offered is at the level of a cognitive model, which may prove useful in organizing future cross-linguistic developmental work.

Carbamazepine and valproate monotherapy: feasibility, relative safety and efficacy, and therapeutic drug monitoring in manic disorder.

RATIONALE: Search for alternatives to lithium therapy for mood disorders commenced with anticonvulsants, carbamazepine (CBZ) and valproic acid (VPA), in the late 1970s. The comparative safety and efficacy data of CBZ and VPA monotherapy in patients with bipolar disorder remain to be established. OBJECTIVES: The main objectives of the study were to assess the relative antimanic efficacy and safety of CBZ and VPA; to study the feasibility of using either, as a first line anti-manic agent; to investigate and generate clinically relevant parameters involving therapeutic drug monitoring of the two drugs. METHODS: After a 2-day screening period, suitable patients (n = 30) were randomly assigned to treatment with CBZ or VPA. Both the drugs were started with an average dose of approximately 20 mg/kg body weight per day. Further increment in dose was carried out at weekly intervals, guided by clinical improvement, serum levels and treatment emergent adverse events. The primary efficacy measure in the protocol was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale. A favourable clinical response was defined a priori as a decrease of more than 50% from baseline in Young Mania Rating Scale total score. RESULTS: Both CBZ and VPA were found to be efficacious as single first-line anti-manic agents, however VPA proved to be better. Using the intent-to-treat analysis, the VPA group showed a significant fall in YMRS total scores after week 1 while the CBZ group showed a significant fall after week 2. In the primary efficacy analysis, valproate group experienced significantly greater mean improvement in Young Mania Rating Scale total score than the CBZ group. Of the VPA treated patients, 73% showed a favourable clinical response while 53% of the patients on CBZ responded favourably. In the CBZ group, significantly more patients received rescue medication during the week 2 and the requirement was quantitatively more as compared to the VPA group. The steady state serum concentration (Css) of CBZ ranged from 3 to 9 micrograms/ml; however, it did not appear to correlate with the dose or clinical response. The Css of VPA ranged from 50 to 100 micrograms/ml; a linear correlation was found between the dose and serum levels of VPA as well as between weekly rise in serum levels and clinical response. Weekly dose escalations of VPA also correlated positively with corresponding rise in serum levels. Significantly more patients in the CBZ group reported adverse events, including nausea, vomiting and dizziness, than VPA. CONCLUSIONS: The findings from this study suggest that both CBZ and VPA monotherapy is feasible for treatment of acute mania; however, VPA is more efficacious in terms of its early onset of action, lesser requirement for rescue medication and better tolerability. Further work needs to be undertaken to characterise the manic patients in terms of their differential psychopharmacologic response profile.

Spherical scatters in the lens of Acrossocheilus hexagonolepis as revealed by scanning electron microscopy and UV-visible spectroscopy.

Scanning electron microscopy revealed the presence of spherical granules 0.25-0.75 micron in diameter in the lens fibres of the hill stream fish Acrossocheilus hexagonolepis. The density of the granules was approximately 8,500 per mm2. The size of the particles and their distribution pattern suggested they functioned in spherical scattering of the light. The absorbance and transmittance of light at different wavelengths obtained from the spectroscopic analysis of the lens indicated that a small percentage of light was neither absorbed nor transmitted. Since reflection usually does not take place from the ocular refractive structure, it may be that this proportion of the light was scattered from the lens.

The status of retinoids in women suffering from hyper- and hypothyroidism: interrelationship between vitamin A, beta-carotene and thyroid hormones.

Retinoid status with reference to beta-carotene and retinol has been studied in women suffering from hyper- and hypothyroid conditions. The interrelationship between the retinoids and triiodothyronine and thyroxine hormones has been established from the cases mentioned after estimation of the respective compounds from the blood serum. It has been found that there is an increase in beta-carotene and retinol in the hypothyroid and a decrease of the same in the hyperthyroid conditions respectively.