Hex is a transcriptional repressor that contributes to anterior identity and suppresses Spemann organiser function

One of the earliest markers of anterior asymmetry in vertebrate embryos is the transcription factor Hex. We find that Hex is a transcriptional repressor that can be converted to an activator by fusing full length Hex to two copies of the minimal transcriptional activation domain of VP16 together with the flexible hinge region of the (lambda) repressor (Hex-(lambda)VP2). Retention of the entire Hex open reading frame allows one to examine Hex function without disrupting potential protein-protein interactions. Expression of Hex-(lambda)VP2 in Xenopus inhibits expression of the anterior marker Cerberus and results in anterior truncations. Such embryos have multiple notochords and disorganised muscle tissue. These effects can occur in a cell non-autonomous manner, suggesting that one role of wild-type Hex is to specify anterior structures by suppressing signals that promote dorsal mesoderm formation. In support of this idea, over-expression of wild-type Hex causes cell non-autonomous dorso-anteriorization, as well as cell autonomous suppression of dorsal mesoderm. Suppression of dorsal mesoderm by Hex is accompanied by the down-regulation of Goosecoid and Chordin, while induction of dorsal mesoderm by Hex-(lambda)VP2 results in activation of these genes. Transient transfection experiments in ES cells suggest that Goosecoid is a direct target of Hex. Together, our results support a model in which Hex suppresses organiser activity and defines anterior identity

Post-mortem brain analyses of the Lothian Birth Cohort 1936:Extending lifetime cognitive and brain phenotyping to the level of the synapse

INTRODUCTION: Non-pathological, age-related cognitive decline varies markedly between individuals andplaces significant financial and emotional strain on people, their families and society as a whole.Understanding the differential age-related decline in brain function is critical not only for the development oftherapeutics to prolong cognitive health into old age, but also to gain insight into pathological ageing suchas Alzheimer’s disease. The Lothian Birth Cohort of 1936 (LBC1936) comprises a rare group of people forwhom there are childhood cognitive test scores and longitudinal cognitive data during older age, detailedstructural brain MRI, genome-wide genotyping, and a multitude of other biological, psycho-social, andepidemiological data. Synaptic integrity is a strong indicator of cognitive health in the human brain;however, until recently, it was prohibitively difficult to perform detailed analyses of synaptic and axonalstructure in human tissue sections. We have adapted a novel method of tissue preparation at autopsy toallow the study of human synapses from the LBC1936 cohort in unprecedented morphological andmolecular detail, using the high-resolution imaging techniques of array tomography and electronmicroscopy. This allows us to analyze the brain at sub-micron resolution to assess density, proteincomposition and health of synapses. Here we present data from the first donated LBC1936 brain andcompare our findings to Alzheimer’s diseased tissue to highlight the differences between healthy andpathological brain ageing. RESULTS: Our data indicates that compared to an Alzheimer’s disease patient, the cognitively normalLBC1936 participant had a remarkable degree of preservation of synaptic structures. However,morphological and molecular markers of degeneration in areas of the brain associated with cognition(prefrontal cortex, anterior cingulate cortex, and superior temporal gyrus) were observed. CONCLUSIONS: Our novel post-mortem protocol facilitates high-resolution neuropathological analysis of the well-characterized LBC1936 cohort, extending phenotyping beyond cognition and in vivo imaging to nowinclude neuropathological changes, at the level of single synapses. This approach offers an unprecedentedopportunity to study synaptic and axonal integrity during ageing and how it contributes to differences in agerelatedcognitive change. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-015-0232-0) contains supplementary material, which is available to authorized users

The use of happiness research for public policy

Research on happiness tends to follow a "benevolent dictator" approach where politicians pursue people's happiness. This paper takes an antithetic approach based on the insights of public choice theory. First, we inquire how the results of happiness research may be used to improve the choice of institutions. Second, we show that the policy approach matters for the choice of research questions and the kind of knowledge happiness research aims to provide. Third, we emphasize that there is no shortcut to an optimal policy maximizing some happiness indicator or social welfare function since governments have an incentive to manipulate this indicator

Transcriptional regulation of Hhex in hematopoiesis and hematopoietic stem cell ontogeny

Hematopoietic stem cells (HSCs) emerge during development via an endothelial-to-hematopoietic transition from hemogenic endothelium of the dorsal aorta (DA). Using in situ hybridization and analysis of a knock-in RedStar reporter, we show that the transcriptional regulator Hhex is expressed in endothelium of the dorsal aorta (DA) and in clusters of putative HSCs as they are specified during murine development. We exploited this observation, using the Hhex locus to define cis regulatory elements, enhancers and interacting transcription factors that are both necessary and sufficient to support gene expression in the emerging HSC. We identify an evolutionarily conserved non-coding region (ECR) in the Hhex locus with the capacity to bind the hematopoietic-affiliated transcriptional regulators Gata2, SCL, Fli1, Pu.1 and Ets1/2. This region is sufficient to drive the expression of a transgenic GFP reporter in the DA endothelium and intra-aortic hematopoietic clusters. GFP-positive AGM cells co-expressed HSC-associated markers c-Kit, CD34, VE-Cadherin, and CD45, and were capable of multipotential differentiation and long term engraftment when transplanted into myelo-ablated recipients. The Hhex ECR was also sufficient to drive expression at additional blood sites including the yolk sac blood islands, fetal liver, vitelline and umbilical arteries and the adult bone marrow, suggesting a common mechanism for Hhex regulation throughout ontogenesis of the blood system. To explore the physiological requirement for the Hhex ECR region during hematoendothelial development, we deleted the ECR element from the endogenous locus in the context of a targeted Hhex-RedStar reporter allele. Results indicate a specific requirement for the ECR in blood-associated Hhex expression during development and further demonstrate a requirement for this region in the adult HSC compartment. Taken together, our results identified the ECR region as an enhancer both necessary and sufficient for gene expression in HSC development and homeostasis. The Hhex ECR thus appears to be a core node for the convergence of the transcription factor network that governs the emergence of HSCs

Motional Averaging in a Superconducting Qubit

Superconducting circuits with Josephson junctions are promising candidates for developing future quantum technologies. Of particular interest is to use these circuits to study effects that typically occur in complex condensed-matter systems. Here, we employ a superconducting quantum bit (qubit),a transmon, to carry out an analog simulation of motional averaging, a phenomenon initially observed in nuclear magnetic resonance (NMR) spectroscopy. To realize this effect, the flux bias of the transmon is modulated by a controllable pseudo-random telegraph noise, resulting in stochastic jumping of the energy separation between two discrete values. When the jumping is faster than a dynamical threshold set by the frequency displacement of the levels, the two separated spectral lines merge into a single narrow-width, motional-averaged line. With sinusoidal modulation a complex pattern of additional sidebands is observed. We demonstrate experimentally that the modulated system remains quantum coherent, with modified transition frequencies, Rabi couplings, and dephasing rates. These results represent the first steps towards more advanced quantum simulations using artificial atoms.Comment: Main text (5 pages and 4 figures) and Supplementary Information (11 pages and 5 figures

Semidiurnal temperature changes caused by tidal front movements in the warm season in seabed habitats on the Georges Bank northern margin and their ecological implications

This article is distributed under the terms of the Creative Commons Public Domain. The definitive version was published in PLoS ONE 8 (2013): e55273, doi:10.1371/journal.pone.0055273.Georges Bank is a large, shallow feature separating the Gulf of Maine from the Atlantic Ocean. Previous studies demonstrated a strong tidal-mixing front during the warm season on the northern bank margin between thermally stratified water in the Gulf of Maine and mixed water on the bank. Tides transport warm water off the bank during flood tide and cool gulf water onto the bank during ebb tide. During 10 days in August 2009, we mapped frontal temperatures in five study areas along ~100 km of the bank margin. The seabed “frontal zone”, where temperature changed with frontal movment, experienced semidiurnal temperature maxima and minima. The tidal excursion of the frontal boundary between stratified and mixed water ranged 6 to 10 km. This “frontal boundary zone” was narrower than the frontal zone. Along transects perpendicular to the bank margin, seabed temperature change at individual sites ranged from 7.0°C in the frontal zone to 0.0°C in mixed bank water. At time series in frontal zone stations, changes during tidal cycles ranged from 1.2 to 6.1°C. The greatest rate of change (−2.48°C hr−1) occurred at mid-ebb. Geographic plots of seabed temperature change allowed the mapping of up to 8 subareas in each study area. The magnitude of temperature change in a subarea depended on its location in the frontal zone. Frontal movement had the greatest effect on seabed temperature in the 40 to 80 m depth interval. Subareas experiencing maximum temperature change in the frontal zone were not in the frontal boundary zone, but rather several km gulfward (off-bank) of the frontal boundary zone. These results provide a new ecological framework for examining the effect of tidally-driven temperature variability on the distribution, food resources, and reproductive success of benthic invertebrate and demersal fish species living in tidal front habitats.This study was supported by salary funds from the regular annual salary budget from Northeast Fisheries Science Center (NEFSC) and United States Geological Survey Woods Hole Coastal and Marine Science Center (USGS WH C&MSC), respectively; ship time funds from the NEFSC annual budget for days-at-sea ship operations; equipment from the NEFSC and USGS WH C&MSC annual equipment budgets

Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease

Objective: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds (CMBs) and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we evaluated longitudinally families affected by dominantly inherited Alzheimer disease (DIAD). Methods: Mutation carriers (n=310) and non-carriers (n=201) underwent neuroimaging, including gradient echo MR sequences to detect CMHs, neuropsychological, and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical marker of disease. Results: Three percent of non-carriers and eight percent of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMH. APOE-ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in clinical dementia rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of two or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95±10.04 per year). Conclusion: Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug related CMHs

Baseline Morbidity in 2,990 Adult African Volunteers Recruited to Characterize Laboratory Reference Intervals for Future HIV Vaccine Clinical Trials

BACKGROUND: An understanding of the health of potential volunteers in Africa is essential for the safe and efficient conduct of clinical trials, particularly for trials of preventive technologies such as vaccines that enroll healthy individuals. Clinical safety laboratory values used for screening, enrolment and follow-up of African clinical trial volunteers have largely been based on values derived from industrialized countries in Europe and North America. This report describes baseline morbidity during recruitment for a multi-center, African laboratory reference intervals study. METHODS: Asymptomatic persons, aged 18-60 years, were invited to participate in a cross-sectional study at seven sites (Kigali, Rwanda; Masaka and Entebbe, Uganda; Kangemi, Kenyatta National Hospital and Kilifi, Kenya; and Lusaka, Zambia). Gender equivalency was by design. Individuals who were acutely ill, pregnant, menstruating, or had significant clinical findings were not enrolled. Each volunteer provided blood for hematology, immunology, and biochemistry parameters and urine for urinalysis. Enrolled volunteers were excluded if found to be positive for HIV, syphilis or Hepatitis B and C. Laboratory assays were conducted under Good Clinical Laboratory Practices (GCLP). RESULTS AND CONCLUSIONS: Of the 2990 volunteers who were screened, 2387 (80%) were enrolled, and 2107 (71%) were included in the analysis (52% men, 48% women). Major reasons for screening out volunteers included abnormal findings on physical examination (228/603, 38%), significant medical history (76, 13%) and inability to complete the informed consent process (73, 13%). Once enrolled, principle reasons for exclusion from analysis included detection of Hepatitis B surface antigen (106/280, 38%) and antibodies against Hepatitis C (95, 34%). This is the first large scale, multi-site study conducted to the standards of GCLP to describe African laboratory reference intervals applicable to potential volunteers in clinical trials. Approximately one-third of all potential volunteers screened were not eligible for analysis; the majority were excluded for medical reasons

The impact of ageing reveals distinct roles for human dentate gyrus and CA3 in pattern separation and object recognition memory

© 2017 The Author(s). Both recognition of familiar objects and pattern separation, a process that orthogonalises overlapping events, are critical for effective memory. Evidence is emerging that human pattern separation requires dentate gyrus. Dentate gyrus is intimately connected to CA3 where, in animals, an autoassociative network enables recall of complete memories to underpin object/event recognition. Despite huge motivation to treat age-related human memory disorders, interaction between human CA3 and dentate subfields is difficult to investigate due to small size and proximity. We tested the hypothesis that human dentate gyrus is critical for pattern separation, whereas, CA3 underpins identical object recognition. Using 3 T MR hippocampal subfield volumetry combined with a behavioural pattern separation task, we demonstrate that dentate gyrus volume predicts accuracy and response time during behavioural pattern separation whereas CA3 predicts performance in object recognition memory. Critically, human dentate gyrus volume decreases with age whereas CA3 volume is age-independent. Further, decreased dentate gyrus volume, and no other subfield volume, mediates adverse effects of aging on memory. Thus, we demonstrate distinct roles for CA3 and dentate gyrus in human memory and uncover the variegated effects of human ageing across hippocampal regions. Accurate pinpointing of focal memory-related deficits will allow future targeted treatment for memory loss