Peripheral arterial volume distensibility changes with applied external pressure: significant difference between arteries with different compliance

This study aimed to quantify the different effect of external cuff pressure on arterial volume distensibility between peripheral arteries with different compliance. 30 healthy subjects were studied with the arm at two positions (0° and 45° from the horizontal level) to introduce different compliance of arteries. The electrocardiogram and finger and ear photoplethysmograms were recorded simultaneously under five external cuff pressures (0, 10, 20, 30 and 40 mmHg) on the whole arm to obtain arterial volume distensibility. With the applied external cuff pressures of 10, 20, 30 and 40 mmHg, the overall changes in arterial volume distensibility referred to those without external pressure were 0.010, 0.029, 0.054 and 0.108% per mmHg for the arm at the horizontal level, and 0.026, 0.071, 0.170 and 0.389% per mmHg for the arm at 45° from the horizontal level, confirming the non-linearity between arterial volume distensibility and external pressure. More interestingly, the significant differences in arterial volume distensibility changes were observed between the two arm positions, which were 0.016, 0.043, 0.116 and 0.281% per mmHg (all P < 0.01). Our findings demonstrated that arterial volume distensibility of peripheral arm arteries increased with external pressure, with a greater effect for more compliant arteries

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Barking up the same tree: a comparison of ethnomedicine and canine ethnoveterinary medicine among the Aguaruna

<p>Abstract</p> <p>Background</p> <p>This work focuses on plant-based preparations that the Aguaruna Jivaro of Peru give to hunting dogs. Many plants are considered to improve dogs' sense of smell or stimulate them to hunt better, while others treat common illnesses that prevent dogs from hunting. This work places canine ethnoveterinary medicine within the larger context of Aguaruna ethnomedicine, by testing the following hypotheses: H1 -- Plants that the Aguaruna use to treat dogs will be the same plants that they use to treat people and H2 -- Plants that are used to treat both people and dogs will be used for the same illnesses in both cases.</p> <p>Methods</p> <p>Structured interviews with nine key informants were carried out in 2007, in Aguaruna communities in the Peruvian department of Amazonas. Informants provided freelists of plants given to dogs and explained the purpose, preparation and route of administration used. For each plant, informants also described any uses for treating people. Botanical voucher specimens were collected and additional informal observations were made, accompanying people on hunting trips.</p> <p>Results</p> <p>Out of 35 plant species given to dogs, 29 (83%) are also given to humans for some medicinal purpose, while five are used only for dogs. However, the same plant is used to treat the same illness in both humans and dogs in only 53% of the cases. Forty-three percent of plants used to treat a particular illness for both dogs and people are administered in the same manner for both.</p> <p>Conclusion</p> <p>Results suggest that Aguaruna canine ethnoveterinary medicine is, at least partly, an independent cognitive domain. Some of the difference in plant use between dogs and people can be explained by the fact that certain diseases mentioned only apply to dogs. Although reports of canine ethnoveterinary medicine are very sparse in the literature, Aguaruna practices show some similarities with a few trends reported for other Amazonian societies, particularly, in the prevalence of the nasal route of administration, the use of plant-based psychoactives and in the importance of ants and wasps, in some form, for training dogs.</p

A first order phase transition mechanism underlies protein aggregation in mammalian cells

The formation of misfolded protein aggregates is a hallmark of neurodegenerative diseases. The aggregate formation process exhibits an initial lag phase when precursor clusters spontaneously assemble. However, most experimental assays are blind to this lag phase. We develop a quantitative assay based on super-resolution imaging in fixed cells and light sheet imaging of living cells to study the early steps of aggregation in mammalian cells. We find that even under normal growth conditions mammalian cells have precursor clusters. The cluster size distribution is precisely that expected for a so-called super-saturated system in first order phase transition. This means there exists a nucleation barrier, and a critical size above which clusters grow and mature. Homeostasis is maintained through a Szilard model entailing the preferential clearance of super-critical clusters. We uncover a role for a putative chaperone (RuvBL) in this disassembly of large clusters. The results indicate early aggregates behave like condensates. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).National Institutes of Health (U.S.) (Grant DP2CA195769

A phase II study of the bispecific antibody MDX-H210 (anti-HER2 × CD64) with GM-CSF in HER2+ advanced prostate cancer

The proto-oncogene HER2 presents a novel therapeutic target. We report results in 25 patients with HER2+ advanced prostate cancer treated with the bispecific antibody MDX-H210 15 μg m−2by intravenous infusion plus GM-CSF 5 μg kg−1day−1by subcutaneous injection for 4 days repeated weekly for 6 weeks. Patients with stable disease or better received further cycles of treatment until disease progression or study withdrawal. 1 patient received no treatment and 4 received less than 1 cycle and are included in the toxicity analysis only. Median duration of follow up was 105+ (range 21–188) days. Toxicity was generally NCI-CTG 0–2. There were 2 grade 4 adverse events (heart failure and dyspnoea) and 1 grade 3 event (allergic reaction) resulting in discontinuation of the study medication. There were 9 further grade 3 events not resulting in trial withdrawal. There were no treatment-related deaths. 7/20 (35%) evaluable patients had a >50% PSA response of median duration 128 (range 71–184+) days. 7/12 (58%) patients with evaluable pain had improvements in pain scores. The PSA relative velocity on therapy decreased in 15/18 (83%) assessable patients compared to pre-study. GM-CSF and MDX-H210 is active in hormone refractory prostate carcinoma with acceptable toxicity; further studies are warranted. © 2001 Cancer Research Campaign http://www.bjcancer.co

Multi-dimensionality and variability in folk classification of stingless bees (Apidae: Meliponini)

Background: Not long ago Eugene Hunn suggested using a combination of cognitive, linguistic, ecological and evolutionary theories in order to account for the dynamic character of ethnoecology in the study of folk classification systems. In this way he intended to question certain homogeneity in folk classifications models and deepen in the analysis and interpretation of variability in folk classifications. This paper studies how a rural culturally mixed population of the Atlantic Forest of Misiones (Argentina) classified honey-producing stingless bees according to the linguistic, cognitive and ecological dimensions of folk classification. We also analyze the socio-ecological meaning of binomialization in naming and the meaning of general local variability in the appointment of stingless bees. Methods: We used three different approaches: the classical approach developed by Brent Berlin which relies heavily on linguistic criteria, the approach developed by Eleonor Rosch which relies on psychological (cognitive) principles of categorization and finally we have captured the ecological dimension of folk classification in local narratives. For the second approximation, we developed ways of measuring the degree of prototypicality based on a total of 107 comparisons of the type "X is similar to Y" identified in personal narratives. Results: Various logical and grouping strategies coexist and were identified as: graded of lateral linkage, hierarchical and functional. Similarity judgments among folk taxa resulted in an implicit logic of classification graded according to taxa's prototypicality. While there is a high agreement on naming stingless bees with monomial names, a considerable number of underrepresented binomial names and lack of names were observed. Two possible explanations about reported local naming variability are presented. Conclusions: We support the multidimensionality of folk classification systems. This confirms the specificity of local classification systems but also reflects the use of grouping strategies and mechanisms commonly observed in other cultural groups, such as the use of similarity judgments between more or less prototypical organisms. Also we support the idea that alternative naming results from a process of fragmentation of knowledge or incomplete transmission of knowledge. These processes lean on the facts that culturally based knowledge, on the one hand, and biologic knowledge of nature on the other, can be acquired through different learning pathways.Fil: Zamudio, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); ArgentinaFil: Hilgert, Norma Ines. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Centro Cientifico Tecnologico Nordeste. Instituto de Biologia Subtropical. Instituto de Biologia Subtropical - Nodo Puerto Iguazu; Argentin

Thymosin β10 Expression Driven by the Human TERT Promoter Induces Ovarian Cancer-Specific Apoptosis through ROS Production

Thymosin β10 (Tβ10) regulates actin dynamics as a cytoplasm G-actin sequestering protein. Previously, we have shown that Tβ10 diminishes tumor growth, angiogenesis, and proliferation by disrupting actin and by inhibiting Ras. However, little is known about its mechanism of action and biological function. In the present study, we establish a new gene therapy model using a genetically modified adenovirus, referred to as Ad.TERT.Tβ10, that can overexpress the Tβ10 gene in cancer cells. This was accomplished by replacing the native Tβ10 gene promoter with the human TERT promoter in Ad.TERT.Tβ10. We investigated the cancer suppression activity of Tβ10 and found that Ad.TERT.Tβ10 strikingly induced cancer-specific expression of Tβ10 as well as apoptosis in a co-culture model of human primary ovarian cancer cells and normal fibroblasts. Additionally, Ad.TERT.Tβ10 decreased mitochondrial membrane potential and increased reactive oxygen species (ROS) production. These effects were amplified by co-treatment with anticancer drugs, such as paclitaxel and cisplatin. These findings indicate that the rise in ROS production due to actin disruption by Tβ10 overexpression increases apoptosis of human ovarian cancer cells. Indeed, the cancer-specific overexpression of Tβ10 by Ad.TERT.Tβ10 could be a valuable anti-cancer therapeutic for the treatment of ovarian cancer without toxicity to normal cells

BosR (BB0647) Controls the RpoN-RpoS Regulatory Pathway and Virulence Expression in Borrelia burgdorferi by a Novel DNA-Binding Mechanism

In Borrelia burgdorferi (Bb), the Lyme disease spirochete, the alternative σ factor σ54 (RpoN) directly activates transcription of another alternative σ factor, σS (RpoS) which, in turn, controls the expression of virulence-associated membrane lipoproteins. As is customary in σ54-dependent gene control, a putative NtrC-like enhancer-binding protein, Rrp2, is required to activate the RpoN-RpoS pathway. However, recently it was found that rpoS transcription in Bb also requires another regulator, BosR, which was previously designated as a Fur or PerR homolog. Given this unexpected requirement for a second activator to promote σ54-dependent gene transcription, and the fact that regulatory mechanisms among similar species of pathogenic bacteria can be strain-specific, we sought to confirm the regulatory role of BosR in a second virulent strain (strain 297) of Bb. Indeed, BosR displayed the same influence over lipoprotein expression and mammalian infectivity for strain Bb 297 that were previously noted for Bb strain B31. We subsequently found that recombinant BosR (rBosR) bound to the rpoS gene at three distinct sites, and that binding occurred despite the absence of consensus Fur or Per boxes. This led to the identification of a novel direct repeat sequence (TAAATTAAAT) critical for rBosR binding in vitro. Mutations in the repeat sequence markedly inhibited or abolished rBosR binding. Taken together, our studies provide new mechanistic insights into how BosR likely acts directly on rpoS as a positive transcriptional activator. Additional novelty is engendered by the facts that, although BosR is a Fur or PerR homolog and it contains zinc (like Fur and PerR), it has other unique features that clearly set it apart from these other regulators. Our findings also have broader implications regarding a previously unappreciated layer of control that can be involved in σ54–dependent gene regulation in bacteria

Improvement of a synthetic lure for Anopheles gambiae using compounds produced by human skin microbiota

Background - Anopheles gambiae sensu stricto is considered to be highly anthropophilic and volatiles of human origin provide essential cues during its host-seeking behaviour. A synthetic blend of three human-derived volatiles, ammonia, lactic acid and tetradecanoic acid, attracts A. gambiae. In addition, volatiles produced by human skin bacteria are attractive to this mosquito species. The purpose of the current study was to test the effect of ten compounds present in the headspace of human bacteria on the host-seeking process of A. gambiae. The effect of each of the ten compounds on the attractiveness of a basic blend of ammonia, lactic and tetradecanoic acid to A. gambiae was examined. Methods- The host-seeking response of A. gambiae was evaluated in a laboratory set-up using a dual-port olfactometer and in a semi-field facility in Kenya using MM-X traps. Odorants were released from LDPE sachets and placed inside the olfactometer as well as in the MM-X traps. Carbon dioxide was added in the semi-field experiments, provided from pressurized cylinders or fermenting yeast. Results - The olfactometer and semi-field set-up allowed for high-throughput testing of the compounds in blends and in multiple concentrations. Compounds with an attractive or inhibitory effect were identified in both bioassays. 3-Methyl-1-butanol was the best attractant in both set-ups and increased the attractiveness of the basic blend up to three times. 2-Phenylethanol reduced the attractiveness of the basic blend in both bioassays by more than 50%. Conclusions - Identification of volatiles released by human skin bacteria led to the discovery of compounds that have an impact on the host-seeking behaviour of A. gambiae. 3-Methyl-1-butanol may be used to increase mosquito trap catches, whereas 2-phenylethanol has potential as a spatial repellent. These two compounds could be applied in push-pull strategies to reduce mosquito numbers in malaria endemic areas

Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy

The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy (DEE) and severe neurodevelopmental disorders (NDDs). Exome sequencing and family-based rare variant analyses on a cohort with NDD identified two siblings with DEE and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar DEE phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and cerebrospinal fluid of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for DEE and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis