Botulinum neurotoxin type-A enters a non-recycling pool of synaptic vesicles

Neuronal communication relies on synaptic vesicles undergoing regulated exocytosis and recycling for multiple rounds of fusion. Whether all synaptic vesicles have identical protein content has been challenged, suggesting that their recycling ability may differ greatly. Botulinum neurotoxin type-A (BoNT/A) is a highly potent neurotoxin that is internalized in synaptic vesicles at motor nerve terminals and induces flaccid paralysis. Recently, BoNT/A was also shown to undergo retrograde transport, suggesting it might enter a specific pool of synaptic vesicles with a retrograde trafficking fate. Using high-resolution microscopy techniques including electron microscopy and single molecule imaging, we found that the BoNT/A binding domain is internalized within a subset of vesicles that only partially co-localize with cholera toxin B-subunit and have markedly reduced VAMP2 immunoreactivity. Synaptic vesicles loaded with pHrodo-BoNT/A-Hc exhibited a significantly reduced ability to fuse with the plasma membrane in mouse hippocampal nerve terminals when compared with pHrodo-dextran-containing synaptic vesicles and pHrodo-labeled anti-GFP nanobodies bound to VAMP2-pHluorin or vGlut-pHluorin. Similar results were also obtained at the amphibian neuromuscular junction. These results reveal that BoNT/A is internalized in a subpopulation of synaptic vesicles that are not destined to recycle, highlighting the existence of significant molecular and functional heterogeneity between synaptic vesicles.

A glucose-centric perspective of hyperglycemia

Digestion of food in the intestines converts the compacted storage carbohydrates, starch and glycogen, to glucose. After each meal, a flux of glucose (>200 g) passes through the blood pool (4-6 g) in a short period of 2 h, keeping its concentration ideally in the range of 80-120 mg/100 mL. Tissue-specific glucose transporters (GLUTs) aid in the distribution of glucose to all tissues. The balance glucose after meeting the immediate energy needs is converted into glycogen and stored in liver (up to 100 g) and skeletal muscle (up to 300 g) for later use. High blood glucose gives the signal for increased release of insulin from pancreas. Insulin binds to insulin receptor on the plasma membrane and activates its autophosphorylation. This initiates the post-insulin-receptor signal cascade that accelerates synthesis of glycogen and triglyceride. Parallel control by phos-dephos and redox regulation of proteins exists for some of these steps. A major action of insulin is to inhibit gluconeogensis in the liver decreasing glucose output into blood. Cases with failed control of blood glucose have alarmingly increased since 1960 coinciding with changed life-styles and large scale food processing. Many of these turned out to be resistant to insulin, usually accompanied by dysfunctional glycogen storage. Glucose has an extended stay in blood at 8 mM and above and then indiscriminately adds on to surface protein-amino groups. Fructose in common sugar is 10-fold more active. This random glycation process interferes with the functions of many proteins (e.g., hemoglobin, eye lens proteins) and causes progressive damage to heart, kidneys, eyes and nerves. Some compounds are known to act as insulin mimics. Vanadium-peroxide complexes act at post-receptor level but are toxic. The fungus-derived 2,5-dihydroxybenzoquinone derivative is the first one known to act on the insulin receptor. The safe herbal products in use for centuries for glucose control have multiple active principles and targets. Some are effective in slowing formation of glucose in intestines by inhibiting alpha-glucosidases (e.g., salacia/saptarangi). Knowledge gained from French lilac on active guanidine group helped developing Metformin (1,1-dimethylbiguanide) one of the popular drugs in use. One strategy of keeping sugar content in diets in check is to use artificial sweeteners with no calories, no glucose or fructose and no effect on blood glucose (e.g., steviol, erythrytol). However, the three commonly used non-caloric artificial sweetener's, saccharin, sucralose and aspartame later developed glucose intolerance, the very condition they are expected to evade. Ideal way of keeping blood glucose under 6 mM and HbAlc, the glycation marker of hemoglobin, under 7% in blood is to correct the defects in signals that allow glucose flow into glycogen, still a difficult task with drugs and diets.

Appraisal of groundwater resource in Holocene soil deposits by resistivity, hydrochemical and granulomerial studies in the Gulf of Mannar Coast from Southern India

This article is aimed to delineate groundwater sources in Holocene deposits area in the Gulf of Mannar Coast from Southern India. For this purpose 2-D electrical resistivity tomography (ERT), hydrochemical and granulomerical studies were carried out and integrated to identify hydrogeological structures and portable groundwater resource in shallow depths which in general appears in the coastal tracts. The 2-D ERT was used to determine the two-dimensional subsurface geological formations by multicore cable with Wenner array. Low resistivity of 1-5 Omega m for saline water appeared due to calcite at the depth of about 5 m below the ground level (bgl). Sea water intrusion was observed around the maximum resistivity as 5 Omega m at the 8 m depth, bgl in the calcite environs, but the calcareous sandstone layer shows around 15-64 Omega m at the 6 m depth, bgl. The hydrochemical variation of TDS, HCO3-, Cl-, Na+, K+, Ca2+, and Mg2+ concentrations was observed for the saline and sea water intrusion in the groundwater system. The granulometic analysis shows that the study area was under the sea between 5400 and 3000 year ago. The events of ice melting an unnatural ice-stone rain/hail among 5000-4000 years ago resulted in the inundation of sea over the area and deposits of late Holocene marine transgression formation up to Puthukottai quartzite region for a stretch of around 17 km.

Reduced common-mode voltage operation of a new seven-level hybrid multilevel inverter topology with a single DC voltage source

In this study, analysis of extending the linear modulation range of a zero common-mode voltage (CMV) operated n-level inverter by allowing reduced CMV switching is presented. A new hybrid seven-level inverter topology with a single DC supply is also presented in this study and inverter operation for zero and reduced CMV is analysed. Each phase of the inverter is realised by cascading two three-level flying capacitor inverters with a half-bridge module in between. Proposed inverter topology is operated with zero CMV for modulation index <86% and is operated with a CMV magnitude of V-dc/18 to extend the modulation range up to 96%. Experimental results are presented for zero CMV operation and for reduced common voltage operation to extend the linear modulation range. A capacitor voltage balancing algorithm is designed utilising the pole voltage redundancies of the inverter, which works for every sampling instant to correct the capacitor voltage irrespective of load power factor and modulation index. The capacitor voltage balancing algorithm is tested for different modulation indices and for various transient conditions, to validate the proposed topology.

Bajo Dios y bajo la ley : fundamentos de Derecho natural en el sistema del Common-law inglés

Resumen: El common-law inglés tiene una herencia cristiana increíblemente rica. Los juristas ingleses más prestigiosos –incluyendo a Blackstone, Coke y Fortescue– frecuentemente partían desde la fe cristiana a la hora de iluminar y desarrollar lo que ahora son ya principios bien establecidos de la doctrina del common-law. Por consiguiente, este sistema fue desarrollándose históricamente con una particular referencia a la tradición cristiana del derecho natural. Este artículo demuestra cómo el common-law inglés fue mayoritariamente inspirado y desarrollado por estos principios cristianos de la teoría del derecho natural y cómo estos principios todavía subsisten válidos para la interpretación del common-law aun en el presente.

Quantitative RNA-seq analysis of the campylobacter jejuni transcriptome

Campylobacter jejuni is the most common bacterial cause of foodborne disease in the developed world. Its general physiology and biochemistry, as well as the mechanisms enabling it to colonize and cause disease in various hosts, are not well understood, and new approaches are required to understand its basic biology. High-throughput sequencing technologies provide unprecedented opportunities for functional genomic research. Recent studies have shown that direct Illumina sequencing of cDNA (RNA-seq) is a useful technique for the quantitative and qualitative examination of transcriptomes. In this study we report RNA-seq analyses of the transcriptomes of C. jejuni (NCTC11168) and its rpoN mutant. This has allowed the identification of hitherto unknown transcriptional units, and further defines the regulon that is dependent on rpoN for expression. The analysis of the NCTC11168 transcriptome was supplemented by additional proteomic analysis using liquid chromatography-MS. The transcriptomic and proteomic datasets represent an important resource for the Campylobacter research community. © 2011 SGM.

Pool Boiling In Microgravity: Recent Results And Perspectives For The Project Depa-Sj10

Two research projects on pool boiling in microgravity have been conducted aboard the Chinese recoverable satellites. Ground-based experiments have also been performed both in normal gravity and in short-term microgravity in the Drop Tower Beijing. Steady boiling of R113 on thin platinum wires was studied with a temperature-controlled heating method, while quasi-steady boiling of FC-72 on a plane plate was investigated with an exponentially increasing heating voltage. In the first case, slight enhancement of heat transfer is observed in microgravity, while diminution is evident for high heat flux in the second one. Lateral motions of bubbles on the heaters are observed before their departure in microgravity. The surface oscillation of the merged bubbles due to lateral coalescence between adjacent bubbles drives it to detach from the heaters. The Marangoni effect on the bubble behavior is also discussed. The perspectives for a new project DEPA-SJ10, which has been planned to be flown aboard the Chinese recoverable satellite SJ-10 in the future, are also presented.

The art of human rights : enriching the life of the law school through drawings and other visual resource

In the life of the Law School, focus on the “visual” can operate at three different levels: learning, teaching, and examining (legal concepts). My main interest in this paper is to explore the latter level, “examining”, broadly considered so as to encompass evaluation in general. Furthermore, that interest is pinned down here to the area of constitutional rights and human rights in general, even though the conclusions reached can (and should) likely be extrapolated to other areas of the law... In effect, the first logical step regarding the relevance of the visual approach has to do with using it yourself when you study —assuming that you came to the conclusion that you are a “visual learner”. As you know, VARK theorists propose a quadripartite classification of learners. The acronym VARK stands for Visual, Aural, Read/write, and Kinesthetic sensory modalities that are used for learning information. This model was designed in the late 80s by Neil Fleming and it has received some acceptance and a lot of attention...

Bubble Dynamics In Nucleate Pool Boiling On Thin Wires In Microgravity

A temperature-controlled pool boiling (TCPB) device has been developed to study the bubble behavior and heat transfer in pool boiling phenomenon both in normal gravity and in microgravity. A thin platinum wire of 60 mu m in diameter and 30 mm in length is simultaneously used as heater and thermometer. The fluid is R113 at 0.1 MPa and subcooled by 26 degrees C nominally for all cases. Three modes of heat transfer, namely single-phase natural convection, nucleate boiling, and two-mode transition boiling, are observed in the experiment both in microgravity aboard the 22nd Chinese recoverable satellite and in normal gravity on the ground before and after the space flight. Dynamic behaviors of vapor bubbles observed in these experiments are reported and analyzed in the present paper. In the regime of fully developed nucleate boiling, the interface oscillation due to coalescence of adjacent tiny bubbles is the primary reason of the departure of bubbles in microgravity. On the contrary, in the discrete bubble regime, it's observed that there exist three critical bubble diameters in microgravity, dividing the whole range of the observed bubbles into four regimes. Firstly, tiny bubbles are continually forming and growing on the heating surface before departing slowly from the wire when their sizes exceed some value of the order of 10(-1) mm. The bigger bubbles with about several millimeters in diameter stay on the wire, oscillate along the wire, and coalesce with adjacent bubbles. The biggest bubble with diameter of the order of 10 mm, which was formed immediately after the onset of boiling, stays continuously

Effects of preceding crop and weed control method on weeds and common bean (Phaseoulus vulgaris L.) yield in a no-tillage cropping system

En 1994, se inició un trabajo de investigación el cual se continuo durante tres años, con el objetivo de evaluar el efecto de cultivos antecesores y métodos de control de malezas sobre el rendimiento frijol común ( P h a s e o l u s vulgaris L.) y la dinámica de las malezas. El frijol y los cultivos antecesores fueron sembrados en sistema de cero labranza. Las secuencias de cultivos estudiadas fueron: maíz (Zea mays L), seguido de frijol y frijol seguido de frijol. Se analizaron tres ciclos de los cultivos (1994, 1995 y 1996). La secuencia de cultivo que produjo el máximo rendimiento fue maíz seguido de frijol en 1994, así como también el promedio de rendimiento a través de los años. Por otro lado, los mayores valores de vainas por planta y semillas por vaina se obtuvieron cuando el frijol antecedió al frijol en 1994. Parcelas con controles de malezas mecánico y químico obtuvieron menores densidades y peso seco de malezas y mejores rendimientos que aquellas parcelas en las cuales se controlo la maleza a través de cobertura muerta.