The dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins and role in neurite outgrowth.

Previous studies have implicated DTNBP1 as a schizophrenia susceptibility gene and its encoded protein, dysbindin, as a potential regulator of synaptic vesicle physiology. In this study, we found that endogenous levels of the dysbindin protein in the mouse brain are developmentally regulated, with higher levels observed during embryonic and early postnatal ages than in young adulthood. We obtained biochemical evidence indicating that the bulk of dysbindin from brain exists as a stable component of biogenesis of lysosome-related organelles complex-1 (BLOC-1), a multi-subunit protein complex involved in intracellular membrane trafficking and organelle biogenesis. Selective biochemical interaction between brain BLOC-1 and a few members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) superfamily of proteins that control membrane fusion, including SNAP-25 and syntaxin 13, was demonstrated. Furthermore, primary hippocampal neurons deficient in BLOC-1 displayed neurite outgrowth defects. Taken together, these observations suggest a novel role for the dysbindin-containing complex, BLOC-1, in neurodevelopment, and provide a framework for considering potential effects of allelic variants in DTNBP1--or in other genes encoding BLOC-1 subunits--in the context of the developmental model of schizophrenia pathogenesis

Discriminating active from latent tuberculosis in patients presenting to community clinics.

BACKGROUND: Because of the high global prevalence of latent TB infection (LTBI), a key challenge in endemic settings is distinguishing patients with active TB from patients with overlapping clinical symptoms without active TB but with co-existing LTBI. Current methods are insufficiently accurate. Plasma proteomic fingerprinting can resolve this difficulty by providing a molecular snapshot defining disease state that can be used to develop point-of-care diagnostics. METHODS: Plasma and clinical data were obtained prospectively from patients attending community TB clinics in Peru and from household contacts. Plasma was subjected to high-throughput proteomic profiling by mass spectrometry. Statistical pattern recognition methods were used to define mass spectral patterns that distinguished patients with active TB from symptomatic controls with or without LTBI. RESULTS: 156 patients with active TB and 110 symptomatic controls (patients with respiratory symptoms without active TB) were investigated. Active TB patients were distinguishable from undifferentiated symptomatic controls with accuracy of 87% (sensitivity 84%, specificity 90%), from symptomatic controls with LTBI (accuracy of 87%, sensitivity 89%, specificity 82%) and from symptomatic controls without LTBI (accuracy 90%, sensitivity 90%, specificity 92%). CONCLUSIONS: We show that active TB can be distinguished accurately from LTBI in symptomatic clinic attenders using a plasma proteomic fingerprint. Translation of biomarkers derived from this study into a robust and affordable point-of-care format will have significant implications for recognition and control of active TB in high prevalence settings

Alginate foam-based three-dimensional culture to investigate drug sensitivity in primary leukaemia cells

The development of assays for evaluating the sensitivity of leukaemia cells to anti-cancer agents is becoming an important aspect of personalized medicine. Conventional cell cultures lack the three-dimensional (3D) structure of the bone marrow (BM), the extracellular matrix and stromal components which are crucial for the growth and survival of leukaemia stem cells. To accurately predict the sensitivity of the leukaemia cells in an in vitro assay a culturing system containing the essential components of BM is required. In this study, we developed a porous calcium alginate foam-based scaffold to be used for 3D culture. The new 3D culture was shown to be cell compatible as it supported the proliferation of both normal haematopoietic and leukaemia cells. Our cell differential assay for myeloid markers showed that the porous foam-based 3D culture enhanced myeloid differentiation in both leukaemia and normal haematopoietic cells compared to two-dimensional culture. The foam-based scaffold reduced the sensitivity of the leukaemia cells to the tested antileukaemia agents in K562 and HL60 leukaemia cell line model and also primary myeloid leukaemia cells. This observation supports the application of calcium alginate foams as scaffold components of the 3D cultures for investigation of sensitivity to antileukaemia agents in primary myeloid cells

In Vitro Comparative Acaricidal Efficacy of Azadirachtin A and Amitrax on Rhipicephalus (Boophilus) decoloratus Larvae

No Abstrac

Multiplicative random walk Metropolis-Hastings on the real line

In this article we propose multiplication based random walk Metropolis Hastings (MH) algorithm on the real line. We call it the random dive MH (RDMH) algorithm. This algorithm, even if simple to apply, was not studied earlier in Markov chain Monte Carlo literature. The associated kernel is shown to have standard properties like irreducibility, aperiodicity and Harris recurrence under some mild assumptions. These ensure basic convergence (ergodicity) of the kernel. Further the kernel is shown to be geometric ergodic for a large class of target densities on $\mathbb{R}$. This class even contains realistic target densities for which random walk or Langevin MH are not geometrically ergodic. Three simulation studies are given to demonstrate the mixing property and superiority of RDMH to standard MH algorithms on real line. A share-price return data is also analyzed and the results are compared with those available in the literature

Tennis play intensity distribution and relation with aerobic fitness in competitive players

15 p.Los objetivos de este estudio fueron (1) describir la intensidad relativa del juego de tenis simulado en función del tiempo acumulado en tres zonas de intensidad metabólica y (2) determinar las relaciones entre esta distribución de intensidad de juego y la aptitud aeróbica de un grupo de jugadores competitivos. 20 jugadores masculinos de nivel avanzado a élite (ITN) realizaron una prueba de tenis de resistencia específica en el campo incremental hasta el agotamiento para determinar el consumo máximo de oxígeno (VO2max) y los umbrales de ventilación primero y segundo (VT1, VT2). Los parámetros de ventilación y de intercambio de gases se monitorizaron utilizando un analizador de gas portátil telemétrico (K4 b2, Cosmed, Roma, Italia). Dos semanas después, los participantes jugaron un juego de tenis simulado contra un oponente de nivel similar. Las zonas de intensidad (1: baja, 2: moderada y 3: alta) fueron delimitadas por los valores individuales de VO2 correspondientes a VT1 y VT2, y se expresaron como porcentaje del VO2 máximo y la frecuencia cardíaca. Cuando se expresó en relación con el VO 2 máx. El porcentaje de tiempo de juego en la zona 1 (77 ± 25%) fue significativamente mayor (p <0,001) que en la zona 2 (20 ± 21%) y la zona 3 (3 ± 5%). Se encontraron correlaciones positivas de moderadas a altas entre VT1, VT2 y VO2max, y el porcentaje del tiempo de juego transcurrido en la zona 1 (r = 0,68-0,75), así como las correlaciones inversas de bajas a altas entre las variables metabólicas y el porcentaje de tiempo empleado en las zonas 2 y 3 (r = -0.49–0.75). Los jugadores con mejor aptitud aeróbica juegan a intensidades relativamente más bajas. Concluimos que los jugadores pasaron más del 75% del tiempo en su zona de baja intensidad, con menos del 25% del tiempo dedicado a intensidades moderadas a altas. La aptitud aeróbica parece determinar la intensidad metabólica que los jugadores pueden mantener durante todo el juegoS

Characterization of the Taenia spp HDP2 sequence and development of a novel PCR-based assay for discrimination of Taenia saginata from Taenia asiatica

A previously described Taenia saginata HDP2 DNA sequence, a 4-kb polymorphic fragment, was previously used as the basis for developing PCR diagnostic protocols for the species-specific discrimination of T. saginata from T. solium and for the differentiation of T. saginata from T. asiatica. The latter was shown subsequently to lack the required specificity, so we undertook genetic studies of the HDP2 sequence from T. saginata and T. asiatica to determine why, and to develop a novel HDP2-PCR protocol for the simultaneous unambiguous identification of human taeniids. Sequencing and further analysis of the HDP2 DNA fragments of 19 Asiatic isolates of T. saginata and T. asiatica indicated that the HDP2 sequences of both species exhibited clear genomic variability, due to polymorphic variable fragments, that could correspond to the non-transcribed region of ribosomal DNA. This newly observed polymorphism allowed us to develop a novel, reproducible and reliable HDP2-PCR protocol which permitted the simultaneous discrimination of all T. saginata and T. asiatica isolates examined. This species-specific identification was based on, and facilitated by, the clear size difference in amplicon profiles generated: fragments of 1300 bp, 600 bp and 300 bp were produced for T. asiatica, amplicons of 1300 bp and 300 bp being obtained for T. saginata. Control T. solium samples produced one amplicon of 600 bp with the HDP2-PCR protocol. The assay has the potential to prove useful as a diagnostic tool in areas such as South East Asia where T. saginata, T. asiatica and T. solium coexist

Reality monitoring impairment in schizophrenia reflects specific prefrontal cortex dysfunction

Reality monitoring impairment is often reported in schizophrenia but the neural basis of this deficit is poorly understood. Difficulties with reality monitoring could be attributable to the same pattern of neural dysfunction as other cognitive deficits that characterize schizophrenia, or might instead represent a separable and dissociable impairment. This question was addressed through direct comparison of behavioral performance and neural activity associated with reality monitoring and working memory in patients with schizophrenia and matched healthy controls. Participants performed a word-pair reality monitoring task and a Sternberg working memory task while undergoing fMRI scanning. Distinct behavioral deficits were observed in the patients during performance of each task, which were associated with separable task- and region-specific dysfunction in the medial anterior prefrontal cortex for reality monitoring and dorsolateral prefrontal cortex for working memory. The results suggest that reality monitoring impairment is a distinct neurocognitive deficit in schizophrenia. The findings are consistent with the presence of a range of dissociable cognitive deficits in schizophrenia which may be associated with variable functional and structural dysconnectivity in underlying processing networks.JRG was supported by a University of Cambridge Behavioural and Clinical Neuroscience Institute studentship, funded by a joint award from the UK Medical Research Council and the Wellcome Trust. JSS was supported by a James S. McDonnell Foundation Scholar award

Rationale and design of the Prevent Anal Cancer Self-Swab Study: a protocol for a randomised clinical trial of home-based self-collection of cells for anal cancer screening.

INTRODUCTION: Squamous cell carcinoma of the anus is a common cancer among sexual minority men, especially HIV-positive sexual minority men; however, there is no evidenced-based national screening protocol for detection of anal precancers. Our objective is to determine compliance with annual anal canal self-sampling or clinician-sampling for human papillomavirus (HPV) DNA. METHODS AND ANALYSIS: This is a prospective, randomised, two-arm clinical study to evaluate compliance with annual home-based versus clinic-based HPV DNA screening of anal canal exfoliated cells. The setting is primary care community-based clinics. Recruitment is ongoing for 400 HIV-positive and HIV-negative sexual minority men and transgender persons, aged >25 years, English or Spanish speaking, no current use of anticoagulants other than nonsteroidal anti-inflammatory drugs and no prior diagnosis of anal cancer. Participants are randomised to either receive a swab in the mail for home-based collection of an anal canal specimen at 0 and 12 months (arm 1) or attend a clinic for clinician collection of an anal canal specimen at 0 and 12 months (arm 2). Persons will receive clinic-based Digital Anal Rectal Examinations and high-resolution anoscopy-directed biopsy to assess precancerous lesions, stratified by study arm. Anal exfoliated cells collected in the study are assessed for high-risk HPV persistence and host/viral methylation. The primary analysis will use the intention-to-treat principle to compare the proportion of those who comply with 0-month and 12-month sampling in the home-based and clinic-based arms. The a priori hypothesis is that a majority of persons will comply with annual screening with increased compliance among persons in the home-based arm versus clinic-based arm. ETHICS AND DISSEMINATION: The study has been approved by the Medical College of Wisconsin Human Protections Committee. Results will be disseminated to communities where recruitment occurred and through peer-reviewed literature and conferences. TRIAL REGISTRATION NUMBER: NCT03489707