Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA.

Macroautophagy (hereafter autophagy) is a key pathway in neurodegeneration. Despite protective actions, autophagy may contribute to neuron demise when dysregulated. Here we consider X-linked spinal and bulbar muscular atrophy (SBMA), a repeat disorder caused by polyglutamine-expanded androgen receptor (polyQ-AR). We found that polyQ-AR reduced long-term protein turnover and impaired autophagic flux in motor neuron-like cells. Ultrastructural analysis of SBMA mice revealed a block in autophagy pathway progression. We examined the transcriptional regulation of autophagy and observed a functionally significant physical interaction between transcription factor EB (TFEB) and AR. Normal AR promoted, but polyQ-AR interfered with, TFEB transactivation. To evaluate physiological relevance, we reprogrammed patient fibroblasts to induced pluripotent stem cells and then to neuronal precursor cells (NPCs). We compared multiple SBMA NPC lines and documented the metabolic and autophagic flux defects that could be rescued by TFEB. Our results indicate that polyQ-AR diminishes TFEB function to impair autophagy and promote SBMA pathogenesis

Varroakvalstrets effekt på virus i angripna honungsbisamhällen

Vilken effekt har varroakvalster på de virus som infekterar bisamhällen? Forskare vid INRA (Frankrikes nationella institution för jordbruksforskning) i Avignon, Frankrike, University of Otago i Nya Zeeland och Sveriges lantbruksuniversitet (SLU), nyttjade en unik situation i Nya Zeeland där landet, liksom Sverige, har varroaangripna respektive icke angripna regioner. Varroa är relativt nyetablerad i Nya Zeeland. Den påvisades först på Nordön år 2000, och har stadigt spridits söderut under de 14 åren som gått sedan introduktionen. Forskarna har undersökt virusprofilen hos bisamhällena sedan etablering av kvalstret i de olika regionerna. Studien, som publicerades 2014, visar en drastisk ändring av det virala landskapet i bisamhällena som sammanfaller med etablering av varroa, vilket ökar risken för synergier mellan olika virus som är skadliga för bina

Nanoscale integration of single cell biologics discovery processes using optofluidic manipulation and monitoring.

The new and rapid advancement in the complexity of biologics drug discovery has been driven by a deeper understanding of biological systems combined with innovative new therapeutic modalities, paving the way to breakthrough therapies for previously intractable diseases. These exciting times in biomedical innovation require the development of novel technologies to facilitate the sophisticated, multifaceted, high-paced workflows necessary to support modern large molecule drug discovery. A high-level aspiration is a true integration of "lab-on-a-chip" methods that vastly miniaturize cellulmical experiments could transform the speed, cost, and success of multiple workstreams in biologics development. Several microscale bioprocess technologies have been established that incrementally address these needs, yet each is inflexibly designed for a very specific process thus limiting an integrated holistic application. A more fully integrated nanoscale approach that incorporates manipulation, culture, analytics, and traceable digital record keeping of thousands of single cells in a relevant nanoenvironment would be a transformative technology capable of keeping pace with today's rapid and complex drug discovery demands. The recent advent of optical manipulation of cells using light-induced electrokinetics with micro- and nanoscale cell culture is poised to revolutionize both fundamental and applied biological research. In this review, we summarize the current state of the art for optical manipulation techniques and discuss emerging biological applications of this technology. In particular, we focus on promising prospects for drug discovery workflows, including antibody discovery, bioassay development, antibody engineering, and cell line development, which are enabled by the automation and industrialization of an integrated optoelectronic single-cell manipulation and culture platform. Continued development of such platforms will be well positioned to overcome many of the challenges currently associated with fragmented, low-throughput bioprocess workflows in biopharma and life science research

Generalized Totalizer Encoding for Pseudo-Boolean Constraints

Pseudo-Boolean constraints, also known as 0-1 Integer Linear Constraints, are used to model many real-world problems. A common approach to solve these constraints is to encode them into a SAT formula. The runtime of the SAT solver on such formula is sensitive to the manner in which the given pseudo-Boolean constraints are encoded. In this paper, we propose generalized Totalizer encoding (GTE), which is an arc-consistency preserving extension of the Totalizer encoding to pseudo-Boolean constraints. Unlike some other encodings, the number of auxiliary variables required for GTE does not depend on the magnitudes of the coefficients. Instead, it depends on the number of distinct combinations of these coefficients. We show the superiority of GTE with respect to other encodings when large pseudo-Boolean constraints have low number of distinct coefficients. Our experimental results also show that GTE remains competitive even when the pseudo-Boolean constraints do not have this characteristic.Comment: 10 pages, 2 figures, 2 tables. To be published in 21st International Conference on Principles and Practice of Constraint Programming 201

Management of trypanosomiasis and leishmaniasis

<p>Background: The current treatments for human African trypanosomiasis (HAT), Chagas disease and leishmaniasis (collectively referred to as the kinetoplastid diseases) are far from ideal but, for some, there has been significant recent progress. For HAT the only advances in treatment over the past two decades have been the introduction of an eflornithine/nifurtimox co-administration and a shorter regime of the old standard melarsoprol.</p> <p>Sources of data: PubMed.</p> <p>Areas of Agreement: There is a need for new safe, oral drugs for cost-effective treatment of patients and use in control programmes for all the trypanosomatid diseases.</p> <p>Areas of controversy: Cutaneous leishmaniasis is not on the agenda and treatments are lagging behind.</p> <p>Growing points: There are three compounds in development for the treatment of the CNS stage of HAT: fexinidazole, currently due to entry into phase II clinical studies, a benzoxaborole (SCYX-7158) in phase I trials and a diamidine derivative (CPD-0802), in advanced pre-clinical development. For Chagas disease, two anti-fungal triazoles are now in clinical trial. In addition, clinical studies with benznidazole, a drug previously recommended only for acute stage treatment, are close to completion to determine the effectiveness in the treatment of early chronic and indeterminate Chagas disease. For visceral leishmaniasis new formulations, therapeutic switching, in particular AmBisome, and the potential for combinations of established drugs have significantly improved the opportunities for the treatment in the Indian subcontinent, but not in East Africa.</p> <p>Areas timely for developing research: Improved diagnostic tools are needed to support treatment, for test of cure in clinical trials and for monitoring/surveillance of populations in control programmes.</p&gt

Bipolar outflow on the Asymptotic Giant Branch - the case of IRC+10011

Near-IR imaging of the AGB star IRC+10011 (= CIT3) reveals the presence of a bipolar structure within the central ~0.1 arcsec of a spherical dusty wind. We show that the image asymmetries originate from ~1E-4 Msun of swept-up wind material in an elongated cocoon whose expansion is driven by bipolar jets. We perform detailed 2D radiative transfer calculations with the cocoon modeled as two cones extending to ~1,100 AU within an opening angle of ~30deg, imbedded in a wind with the standard r^{-2} density profile. The cocoon expansion started <~200 years ago, while the total lifetime of the circumstellar shell is ~5,500 years. Similar bipolar expansion, at various stages of evolution, has been recently observed in a number of other AGB stars, culminating in jet breakout from the confining spherical wind. The bipolar outflow is triggered at a late stage in the evolution of AGB winds, and IRC+10011 provides its earliest example thus far. These new developments enable us to identify the first instance of symmetry breaking in the evolution from AGB to planetary nebula.Comment: accepted for publication in MNRAS, high-resolution pdf version can be found at http://www.leluya.org/downloads/Vinkovic_et_al_IRC+10011.pd

Vascular contributions to the neurobiological effects of prenatal alcohol exposure

Background: Fetal alcohol spectrum disorders (FASD) are often characterized as a cluster of brain-based disabilities. Though cardiovascular effects of prenatal alcohol exposure (PAE) have been documented, the vascular deficits due to PAE are less understood, but may contribute substantially to the severity of neurobehavioral presentation and health outcomes in persons with FASD.Methods: We conducted a systematic review of research articles curated in PubMed to assess the strength of the research on vascular effects of PAE. 40 pertinent papers were selected, covering studies in both human populations and animal models.Results: Studies in human populations identified cardiac defects, and defects in vasculature, including increased tortuosity, defects in basement membranes, capillary basal hyperplasia, endarteritis, and disorganized and diminished cerebral vasculature due to PAE. Preclinical studies showed that PAE rapidly and persistently results in vasodilation of large afferent cerebral arteries, but to vasoconstriction of smaller cerebral arteries and microvasculature. Moreover, PAE continues to affect cerebral blood flow into middle-age. Human and animal studies also indicate that ocular vascular parameters may have diagnostic and predictive value. A number of intervening mechanisms were identified, including increased autophagy, inflammation and deficits in mitochondria. Studies in animals identified persistent changes in blood flow and vascular density associated with endocannabinoid, prostacyclin and nitric oxide signaling, as well as calcium mobilization.Conclusion: Although the brain has been a particular focus of studies on PAE, the cardiovascular system is equally affected. Studies in human populations, though constrained by small sample sizes, did link pathology in major blood vessels and tissue vasculature, including brain vasculature, to PAE. Animal studies highlighted molecular mechanisms that may be useful therapeutic targets. Collectively, these studies suggest that vascular pathology is a possible contributing factor to neurobehavioral and health problems across a lifespan in persons with a diagnosis of FASD. Furthermore, ocular vasculature may serve as a biomarker for neurovascular health in FASD