Explicit Logic Circuits Predict Local Properties of the Neocortex's Physiology and Anatomy

Background: Two previous articles proposed an explicit model of how the brain processes information by its organization of synaptic connections. The family of logic circuits was shown to generate neural correlates of complex psychophysical phenomena in different sensory systems. Methodology/Principal Findings: Here it is shown that the most cost-effective architectures for these networks produce correlates of electrophysiological brain phenomena and predict major aspects of the anatomical structure and physiological organization of the neocortex. The logic circuits are markedly efficient in several respects and provide the foundation for all of the brain’s combinational processing of information. Conclusions/Significance: At the local level, these networks account for much of the physical structure of the neocortex as well its organization of synaptic connections. Electronic implementations of the logic circuits may be more efficient than current electronic logic arrays in generating both Boolean and fuzzy logic

BARCRAWL and BARTAB: software tools for the design and implementation of barcoded primers for highly multiplexed DNA sequencing

<p>Abstract</p> <p>Background</p> <p>Advances in automated DNA sequencing technology have greatly increased the scale of genomic and metagenomic studies. An increasingly popular means of increasing project throughput is by multiplexing samples during the sequencing phase. This can be achieved by covalently linking short, unique "barcode" DNA segments to genomic DNA samples, for instance through incorporation of barcode sequences in PCR primers. Although several strategies have been described to insure that barcode sequences are unique and robust to sequencing errors, these have not been integrated into the overall primer design process, thus potentially introducing bias into PCR amplification and/or sequencing steps.</p> <p>Results</p> <p><it>Barcrawl </it>is a software program that facilitates the design of barcoded primers, for multiplexed high-throughput sequencing. The program <it>bartab </it>can be used to deconvolute DNA sequence datasets produced by the use of multiple barcoded primers. This paper describes the functions implemented by <it>barcrawl </it>and <it>bartab </it>and presents a proof-of-concept case study of both programs in which barcoded rRNA primers were designed and validated by high-throughput sequencing.</p> <p>Conclusion</p> <p><it>Barcrawl </it>and <it>bartab </it>can benefit researchers who are engaged in metagenomic projects that employ multiplexed specimen processing. The source code is released under the GNU general public license and can be accessed at <url>http://www.phyloware.com</url>.</p

A novel isolator-based system promotes viability of human embryos during laboratory processing

In vitro fertilisation (IVF) and related technologies are arguably the most challenging of all cell culture applications. The starting material is a single cell from which one aims to produce an embryo capable of establishing a pregnancy eventually leading to a live birth. Laboratory processing during IVF treatment requires open manipulations of gametes and embryos, which typically involves exposure to ambient conditions. To reduce the risk of cellular stress, we have developed a totally enclosed system of interlinked isolator-based workstations designed to maintain oocytes and embryos in a physiological environment throughout the IVF process. Comparison of clinical and laboratory data before and after the introduction of the new system revealed that significantly more embryos developed to the blastocyst stage in the enclosed isolator-based system compared with conventional open-fronted laminar flow hoods. Moreover, blastocysts produced in the isolator-based system contained significantly more cells and their development was accelerated. Consistent with this, the introduction of the enclosed system was accompanied by a significant increase in the clinical pregnancy rate and in the proportion of embryos implanting following transfer to the uterus. The data indicate that protection from ambient conditions promotes improved development of human embryos. Importantly, we found that it was entirely feasible to conduct all IVF-related procedures in the isolator-based workstations

Barriers and facilitators to healthy lifestyle and acceptability of a dietary and physical activity intervention among African Caribbean prostate cancer survivors in the UK: a qualitative study.

OBJECTIVES: Diet and lifestyle may have a role in delaying prostate cancer progression, but little is known about the health behaviours of Black British prostate cancer survivors despite this group having a higher prostate cancer mortality rate than their White counterparts. We explored the barriers and facilitators to dietary and lifestyle changes and the acceptability of a diet and physical activity intervention in African Caribbean prostate cancer survivors. DESIGN: We conducted semistructured in-depth interviews and used thematic analysis to code and group the data. PARTICIPANTS AND SETTING: We recruited 14 African Caribbean prostate cancer survivors via letter or at oncology follow-up appointments using purposive and convenience sampling. RESULTS: A prostate cancer diagnosis did not trigger dietary and lifestyle changes in most men. This lack of change was underpinned by five themes: precancer diet and lifestyle, evidence, coping with prostate cancer, ageing, and autonomy. Men perceived their diet and lifestyle to be healthy and were uncertain about the therapeutic benefits of these factors on prostate cancer recurrence. They considered a lifestyle intervention as unnecessary because their prostate-specific antigen (PSA) level was kept under control by the treatments they had received. They believed dietary and lifestyle changes should be self-initiated and motivated, but were willing to make additional changes if they were perceived to be beneficial to health. Nonetheless, some men cited advice from health professionals and social support in coping with prostate cancer as facilitators to positive dietary and lifestyle changes. A prostate cancer diagnosis and ageing also heightened men's awareness of their health, particularly in regards to their body weight. CONCLUSIONS: A dietary and physical activity intervention framed as helping men to regain fitness and aid post-treatment recovery aimed at men with elevated PSA may be appealing and acceptable to African Caribbean prostate cancer survivors

Post-diagnosis serum insulin-like growth factors in relation to dietary and lifestyle changes in the Prostate testing for cancer and Treatment (ProtecT) trial.

PURPOSE: The insulin-like growth factor (IGF) system is modifiable by diet and lifestyle, and has been linked to prostate cancer development and progression. METHODS: We conducted a prospective cohort study of 621 men diagnosed with localized prostate cancer to investigate the associations of dietary and lifestyle changes with post-diagnosis circulating levels of IGF-I and IGFBP-3. We used analysis of covariance to estimate the associations, controlling for baseline IGF-I or IGFBP-3, respectively. RESULTS: Mean IGF-I levels were 6.5% (95% CI -12.8, -0.3%, p = 0.04) lower in men who decreased their protein intake after diagnosis compared to men who did not change. Men who changed their fruit and vegetable intake had lower IGF-I levels compared to non-changers [Decreased intake: -10.1%, 95% CI -18.4, -1.8%, p = 0.02; Increased intake: -12.0%, 95% CI -18.4, -1.8%, p = 0.002]. IGFBP-3 was 14.6% (95% CI -24.5, -4.8%, p = 0.004) lower in men who achieved a healthy body mass index after diagnosis. Men who became inactive had 9.5% higher average IGF-I levels (95% CI 0.1, 18.9%, p = 0.05). CONCLUSIONS: Decreased protein intake and body mass index, and increased physical activity and fruit and vegetable intake, following a prostate cancer diagnosis were associated with reduced post-diagnosis serum IGF-I and IGFBP-3. Counterintuitively, reduced fruit and vegetable intake was also associated with reduced IGF-I, but with weak statistical support, possibly implicating chance. If confirmed in other studies, our findings may inform potential lifestyle interventions in prostate cancer. ProtecT was registered at International Standard Randomised Controlled Trial Registry, http://isrctn.org as ISRCTN20141297

Transkingdom Networks: A Systems Biology Approach to Identify Causal Members of Host-Microbiota Interactions

Improvements in sequencing technologies and reduced experimental costs have resulted in a vast number of studies generating high-throughput data. Although the number of methods to analyze these "omics" data has also increased, computational complexity and lack of documentation hinder researchers from analyzing their high-throughput data to its true potential. In this chapter we detail our data-driven, transkingdom network (TransNet) analysis protocol to integrate and interrogate multi-omics data. This systems biology approach has allowed us to successfully identify important causal relationships between different taxonomic kingdoms (e.g. mammals and microbes) using diverse types of data

Autophagic flux blockage by accumulation of weakly basic tenovins leads to elimination of B-Raf mutant tumour cells that survive vemurafenib

This work was supported by five grants to Sonia Laín: Vetenskapsrådet (VR) 521-2014-3341, Cancerfonden (Swedish Cancer Society) 150393, CAN 2014/702, Association for International Cancer Research (AICR) 130086, Barncancerfonden (Swedish Childhood Cancer Foundation) TJ-2014-0038, Barncancerfonden (Swedish Childhood Cancer Foundation) PR-2014-0038; two grants to Ravi Bhatia: Leukemia and Lymphoma Society (LLS) 6137-14 and NIH R01 CA95684; one grant to David P Lane: Vetenskapsrådet (VR) 538-2013-8807; one grant to Marcus J G W Ladds: Karolinska Institute KID Doctoral Student Funding; one grant to Gergana Popova: Karolinska Institutet KID Doctoral Student Funding; two grants to Nicholas J Westwood: Cancer Research UK C21383 and Cancer Research UK A6950; two grants to Gerald McInerney: Vetenskapsrådet (VR) 621-2014-4718 and Cancerfonden (Swedish Cancer Society) 150393, CAN 2015/751; and four grants to Emmet McCormack: Kreftforeningen 182735, Kreftforeningen 732200, Halse Vest 911884, Halse Vest 911789.Tenovin-6 is the most studied member of a family of small molecules with antitumour activity in vivo. Previously, it has been determined that part of the effects of tenovin-6 associate with its ability to inhibit SirT1 and activate p53. However, tenovin-6 has also been shown to modulate autophagic flux. Here we show that blockage of autophagic flux occurs in a variety of cell lines in response to certain tenovins, that autophagy blockage occurs regardless of the effect of tenovins on SirT1 or p53, and that this blockage is dependent on the aliphatic tertiary amine side chain of these molecules. Additionally, we evaluate the contribution of this tertiary amine to the elimination of proliferating melanoma cells in culture. We also demonstrate that the presence of the tertiary amine is sufficient to lead to death of tumour cells arrested in G1 phase following vemurafenib treatment. We conclude that blockage of autophagic flux by tenovins is necessary to eliminate melanoma cells that survive B-Raf inhibition and achieve total tumour cell kill and that autophagy blockage can be achieved at a lower concentration than by chloroquine. This observation is of great relevance as relapse and resistance are frequently observed in cancer patients treated with B-Raf inhibitors.Publisher PDFPeer reviewe

Why do women invest in pre-pregnancy health and care? A qualitative investigation with women attending maternity services

Background Despite the importance attributed to good pre-pregnancy care and its potential to improve pregnancy and child health outcomes, relatively little is known about why women invest in pre-pregnancy health and care. We sought to gain insight into why women invested in pre-pregnancy health and care. Methods We carried out 20 qualitative in-depth interviews with pregnant or recently pregnant women who were drawn from a survey of antenatal clinic attendees in London, UK. Interviewees were purposively sampled to include high and low investors in pre-pregnancy health and care, with variation in age, partnership status, ethnicity and pre-existing medical conditions. Data analysis was conducted using the Framework method. Results We identified three groups in relation to pre-pregnancy health and care: 1) The “prepared” group, who had high levels of pregnancy planning and mostly positive attitudes to micronutrient supplementation outside of pregnancy, carried out pre-pregnancy activities such as taking folic acid and making changes to diet and lifestyle. 2) The “poor knowledge” group, who also had high levels of pregnancy planning, did not carry out pre-pregnancy activities and described themselves as having poor knowledge. Elsewhere in their interviews they expressed a strong dislike of micronutrient supplementation. 3) The “absent pre-pregnancy period” group, had the lowest levels of pregnancy planning and also expressed anti-supplement views. Even discussing the pre-pregnancy period with this group was difficult as responses to questions quickly shifted to focus on pregnancy itself. Knowledge of folic acid was poor in all groups. Conclusion Different pre-pregnancy care approaches are likely to be needed for each of the groups. Among the “prepared” group, who were proactive and receptive to health messages, greater availability of information and better response from health professionals could improve the range of pre-pregnancy activities carried out. Among the “poor knowledge” group, better response from health professionals might yield greater uptake of pre-pregnancy information. A different, general health strategy might be more appropriate for the “absent pre-pregnancy period” group. The fact that general attitudes to micronutrient supplementation were closely related to whether or not women invested in pre-pregnancy health and care was an unanticipated finding and warrants further investigation.This report is independent research commissioned and funded by the Department of Health Policy Research Programme Pre-Pregnancy Health and Care in England: Exploring Implementation and Public Health Impact, 006/0068

Top quark forward-backward asymmetry in R-parity violating supersymmetry

The interaction of bottom squark-mediated top quark pair production, occurring in the R-parity violating minimal supersymmetric standard model (MSSM), is proposed as an explanation of the anomalously large $t\bar{t}$ forward-backward asymmetry (FBA) observed at the Tevatron. We find that this model can give a good fit to top quark data, both the inclusive and invariant mass-dependent asymmetries, while remaining consistent (at the 2-$\sigma$ level) with the total and differential production cross-sections. The scenario is challenged by strong constraints from atomic parity violation (APV), but we point out an extra diagram for the effective down quark-Z vertex, involving the same coupling constant as required for the FBA, which tends to weaken the APV constraint, and which can nullify it for reasonable values of the top squark masses and mixing angle. Large contributions to flavor-changing neutral currents can be avoided if only the third generation of sparticles is light.Comment: 24 pages, 7 figures. v3: included LHC top production cross section data; model still consistent at 2 sigma leve

A Sensitive and Quantitative Polymerase Chain Reaction-Based Cell Free In Vitro Non-Homologous End Joining Assay for Hematopoietic Stem Cells

Hematopoietic stem cells (HSCs) are responsible for sustaining hematopoietic homeostasis and regeneration after injury for the entire lifespan of an organism. Maintenance of genomic stability is crucial for the preservation of HSCs, which depends on their efficient repair of DNA damage, particularly DNA double strand breaks (DSBs). Because of the paucity of HSCs and lack of sensitive assays, directly measuring the ability of HSCs to repair DSBs has been difficult. Therefore, we developed a sensitive and quantitative cell free in vitro non-homologous end joining (NHEJ) assay using linearized plasmids as the substrates and quantitative polymerase chain reaction (qPCR) technique. This assay can sensitively detect DSB repair via NHEJ in less than 1 µg 293T cell nuclear proteins or nuclear extracts from about 5,000 to 10,000 human BM CD34+ hematopoietic cells. Using this assay, we confirmed that human bone marrow HSCs (CD34+CD38− cells) are less proficient in the repair of DSBs by NHEJ than HPCs (CD34+CD38+ cells). In contrast, mouse quiescent HSCs (Pyronin-Ylow LKS+ cells) and cycling HSCs (Pyronin-Yhi LKS+ cells) repaired the damage more efficiently than HPCs (LKS− cells). The difference in the abilities of human and mouse HSCs and HPCs to repair DSBs through NHEJ is likely attributed to their differential expression of key NHEJ DNA damage repair genes such as LIG4. These findings suggest that the qPCR-based cell free in vitro NHEJ assay can be used to sensitively measure the ability of human and mouse HSCs to repair DSBs