Stochastic and deterministic dynamics of intrinsically irregular firing in cortical inhibitory interneurons

Most cortical neurons fire regularly when excited by a constant stimulus. In contrast, irregular-spiking (IS) interneurons are remarkable for the intrinsic variability of their spike timing, which can synchronize amongst IS cells via specific gap junctions. Here, we have studied the biophysical mechanisms of this irregular spiking in mice, and how IS cells fire in the context of synchronous network oscillations. Using patch-clamp recordings, artificial dynamic conductance injection, pharmacological analysis and computational modeling, we show that spike time irregularity is generated by a nonlinear dynamical interaction of voltage-dependent sodium and fast-inactivating potassium channels just below spike threshold, amplifying channel noise. This $\textit{active irregularity}$ may help IS cells synchronize with each other at gamma range frequencies, while resisting synchronization to lower input frequencies.Biotechnology and Biological Sciences Research Council, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Cambridge Overseas Trus

Assessment of Objectively Measured Physical Activity Levels in Individuals with Intellectual Disabilities with and without Down's Syndrome

Objective: To investigate, using accelerometers, the levels of physical activity being undertaken by individuals with intellectual disabilities with and without Down’s syndrome. Methods: One hundred and fifty two individuals with intellectual disabilities aged 12–70 years from East and South-East England. Physical activity levels in counts per minute (counts/min), steps per day (steps/day), and minutes of sedentary, light, moderate, vigorous, and moderate to vigorous physical activity (MVPA) measured with a uni-axial accelerometer (Actigraph GT1M) for seven days. Results: No individuals with intellectual disabilities met current physical activity recommendations. Males were more active than females. There was a trend for physical activity to decline and sedentary behaviour to increase with age, and for those with more severe levels of intellectual disability to be more sedentary and less physically active, however any relationship was not significant when adjusted for confounding variables. Participants with Down’s syndrome engaged in significantly less physical activity than those with intellectual disabilities without Down’s syndrome and levels of activity declined significantly with age. Conclusions: Individuals with intellectual disabilities, especially those with Down’s syndrome may be at risk of developing diseases associated with physical inactivity. There is a need for well-designed, accessible, preventive health promotio

Endogenous antigen processing drives the primary CD4+ T cell response to influenza.

By convention, CD4+ T lymphocytes recognize foreign and self peptides derived from internalized antigens in combination with major histocompatibility complex class II molecules. Alternative pathways of epitope production have been identified, but their contributions to host defense have not been established. We show here in a mouse infection model that the CD4+ T cell response to influenza, critical for durable protection from the virus, is driven principally by unconventional processing of antigen synthesized within the infected antigen-presenting cell, not by classical processing of endocytosed virions or material from infected cells. Investigation of the cellular components involved, including the H2-M molecular chaperone, the proteasome and γ-interferon-inducible lysosomal thiol reductase revealed considerable heterogeneity in the generation of individual epitopes, an arrangement that ensures peptide diversity and broad CD4+ T cell engagement. These results could fundamentally revise strategies for rational vaccine design and may lead to key insights into the induction of autoimmune and anti-tumor responses

African trypanosomes evade immune clearance by O-glycosylation of the VSG surface coat

The African trypanosome, Trypanosoma brucei spp., is a paradigm for antigenic variation, the orchestrated alteration of cell surface molecules to evade host immunity. The parasite elicits robust antibody-mediated immune responses to its Variant Surface Glycoprotein (VSG) coat, but evades immune clearance by repeatedly accessing a large genetic VSG repertoire and “switching” to antigenically distinct VSGs. This persistent immune evasion has been ascribed exclusively to amino acid variance on the VSG surface presented by a conserved underlying protein architecture. We establish here that this model does not account for the scope of VSG structural and biochemical diversity. The 1.4Å resolution crystal structure of variant VSG3 manifests heretofore unappreciated divergence in the tertiary fold and oligomeric state. The structure also reveals an O linked carbohydrate on the top surface of VSG3, a modification previously unknown in African trypanosomes. Mass spectrometric analysis indicates that this O -glycosylation site is heterogeneously occupied in VSG3 by 0 to 3 hexose residues and is also present in other VSGs. We demonstrate that this O -glycosylation increases parasite virulence by impairing the generation of protective immunity. These data alter the paradigm of antigenic variation by the African trypanosome, expanding VSG variability beyond amino acid sequence to include surface posttranslational modifications with immunomodulatory impact

Structural basis for inhibition of homologous recombination by the RecX protein

The RecA/RAD51 nucleoprotein filament is central to the reaction of homologous recombination (HR). Filament activity must be tightly regulated in vivo as unrestrained HR can cause genomic instability. Our mechanistic understanding of HR is restricted by lack of structural information about the regulatory proteins that control filament activity. Here, we describe a structural and functional analysis of the HR inhibitor protein RecX and its mode of interaction with the RecA filament. RecX is a modular protein assembled of repeated three-helix motifs. The relative arrangement of the repeats generates an elongated and curved shape that is well suited for binding within the helical groove of the RecA filament. Structure-based mutagenesis confirms that conserved basic residues on the concave side of RecX are important for repression of RecA activity. Analysis of RecA filament dynamics in the presence of RecX shows that RecX actively promotes filament disassembly. Collectively, our data support a model in which RecX binding to the helical groove of the filament causes local dissociation of RecA protomers, leading to filament destabilisation and HR inhibition

American palm ethnomedicine: A meta-analysis

<p>Abstract</p> <p>Background</p> <p>Many recent papers have documented the phytochemical and pharmacological bases for the use of palms (<it>Arecaceae</it>) in ethnomedicine. Early publications were based almost entirely on interviews that solicited local knowledge. More recently, ethnobotanically guided searches for new medicinal plants have proven more successful than random sampling for identifying plants that contain biodynamic ingredients. However, limited laboratory time and the high cost of clinical trials make it difficult to test all potential medicinal plants in the search for new drug candidates. The purpose of this study was to summarize and analyze previous studies on the medicinal uses of American palms in order to narrow down the search for new palm-derived medicines.</p> <p>Methods</p> <p>Relevant literature was surveyed and data was extracted and organized into medicinal use categories. We focused on more recent literature than that considered in a review published 25 years ago. We included phytochemical and pharmacological research that explored the importance of American palms in ethnomedicine.</p> <p>Results</p> <p>Of 730 species of American palms, we found evidence that 106 species had known medicinal uses, ranging from treatments for diabetes and leishmaniasis to prostatic hyperplasia. Thus, the number of American palm species with known uses had increased from 48 to 106 over the last quarter of a century. Furthermore, the pharmacological bases for many of the effects are now understood.</p> <p>Conclusions</p> <p>Palms are important in American ethnomedicine. Some, like <it>Serenoa repens </it>and <it>Roystonea regia</it>, are the sources of drugs that have been approved for medicinal uses. In contrast, recent ethnopharmacological studies suggested that many of the reported uses of several other palms do not appear to have a strong physiological basis. This study has provided a useful assessment of the ethnobotanical and pharmacological data available on palms.</p

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Prevention of acute kidney injury and protection of renal function in the intensive care unit

Acute renal failure on the intensive care unit is associated with significant mortality and morbidity. To determine recommendations for the prevention of acute kidney injury (AKI), focusing on the role of potential preventative maneuvers including volume expansion, diuretics, use of inotropes, vasopressors/vasodilators, hormonal interventions, nutrition, and extracorporeal techniques. A systematic search of the literature was performed for studies using these potential protective agents in adult patients at risk for acute renal failure/kidney injury between 1966 and 2009. The following clinical conditions were considered: major surgery, critical illness, sepsis, shock, and use of potentially nephrotoxic drugs and radiocontrast media. Where possible the following endpoints were extracted: creatinine clearance, glomerular filtration rate, increase in serum creatinine, urine output, and markers of tubular injury. Clinical endpoints included the need for renal replacement therapy, length of stay, and mortality. Studies are graded according to the international Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) group system Several measures are recommended, though none carries grade 1A. We recommend prompt resuscitation of the circulation with special attention to providing adequate hydration whilst avoiding high-molecular-weight hydroxy-ethyl starch (HES) preparations, maintaining adequate blood pressure using vasopressors in vasodilatory shock. We suggest using vasopressors in vasodilatory hypotension, specific vasodilators under strict hemodynamic control, sodium bicarbonate for emergency procedures administering contrast media, and periprocedural hemofiltration in severe chronic renal insufficiency undergoing coronary intervention

Morphoanatomy of the flower of Syagrus inajai (SPRUCE) Becc. (Arecaceae- Arecoideae- Attaleinae), Amazon

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The occurrence of Syagrus inajai (Spruce) Becc., popularly known as pupunha palm, among other names, has been registered in the Guianas and in the North of Brazil in areas of terra firme (non-flooding) and gallery forests. In order to characterize the inflorescence and further knowledge of this family, a morphoanatomical study was carried out of the palm S. inajai in a green area of the Campus of the Federal University of Amazonas - UFAM, Manaus, Amazonas. The inflorescences are branched to one order, pedunculate, and interfoliar, measuring 62-82 cm in length, with woody bracts with longitudinal grooves on the external surface, and flowers in triads. The number of flowers to each inflorescence varies from 5,904 to 17,316 for staminate flowers, and from 180 to 3,528 for pistillate flowers. Staminate flowers with six anthers and one vascular bundle each; three-lobed pistillodium, vascularized pistillodium. Its pistillate flowers have six staminodia joined to form a circle, syncarpic, tricarpellary, trilocular gynoecium, one ovule to each locule, synascidiate in the ovary, and plicated above. Tripartite stigma, apical and sessile, with epidermis composed of elongated papillary cells, pattern of epidermis that is maintained throughout the stylar canal. Bitegmented, anatrope, pachychalazal ovule.733649661Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Embryonic development of Syagrus inajai ( Spruce) Becc. ( Arecaceae, Arecoideae), an Amazonian palm

Syagrus inajai (pupunharana') is a native palm of Brazil, with phytogeographic prevalence in the Amazon region. A morpho-anatomical analysis was undertaken in order to gain a better knowledge on the embryonic development and germinative process of the S. inajai. Plant material was collected from the Campus of the Universidade Federal do Amazonas - UFAM, Manaus, Amazonas, Brazil, and processed using standard morphological and anatomical techniques. The development process of the embryo takes similar to 220 days, and is divided into four stages: proembryo, globular embryo, lateral cordiform and torpedo. The embryo is small, linear, and derived from the terminal cell of the proembryo, arising from mitotic divisions in the apical cell. The embryonic axis is straight, located in the proximal region, aligned parallel to the length of the embryo. The single cotyledon is formed by the ground meristem, procambium and protoderm. The procambium supplies the embryonic axis and the haustorium.618611621National Council for Scientific and Technological Developmen