Fetal liver blood flow distribution: role in human developmental strategy to prioritize fat deposition versus brain development

Among primates, human neonates have the largest brains but also the highest proportion of body fat. If placental nutrient supply is limited, the fetus faces a dilemma: should resources be allocated to brain growth, or to fat deposition for use as a potential postnatal energy reserve? We hypothesised that resolving this dilemma operates at the level of umbilical blood distribution entering the fetal liver. In 381 uncomplicated pregnancies in third trimester, we measured blood flow perfusing the fetal liver, or bypassing it via the ductus venosus to supply the brain and heart using ultrasound techniques. Across the range of fetal growth and independent of the mother's adiposity and parity, greater liver blood flow was associated with greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth (r = 0.43, P<0.001) and at age 4 years (r = 0.16, P = 0.02). In contrast, smaller placentas less able to meet fetal demand for essential nutrients were associated with a brain-sparing flow pattern (r = 0.17, p = 0.02). This flow pattern was also associated with a higher degree of shunting through ductus venosus (P = 0.04). We propose that humans evolved a developmental strategy to prioritize nutrient allocation for prenatal fat deposition when the supply of conditionally essential nutrients requiring hepatic inter-conversion is limited, switching resource allocation to favour the brain if the supply of essential nutrients is limited. Facilitated placental transfer mechanisms for glucose and other nutrients evolved in environments less affluent than those now prevalent in developed populations, and we propose that in circumstances of maternal adiposity and nutrient excess these mechanisms now also lead to prenatal fat deposition. Prenatal developmental influences play important roles in the human propensity to deposit fa

Diversity, urban space and the right to the provincial city

Using three vignettes of the same physical space this article contributes to understanding of how the right to the city is contested in provincial England in the early twenty-first century. Oral history and ethnographic material gathered in Peterborough between 2010 and 2012 are drawn on to shed new light on the politics of diversity and urban space. This highlights the multiple place attachments and trans-spatial practices of all residents, including the white ethnic majority, as well as contrasting forms of active intervention in space with their different temporalities and affective intensities. The article carries its own diversity politics, seeking to reduce the harm done by racism through challenging the normalisation of the idea of a local, indigenous population, left out by multiculturalism. It simultaneously raises critical questions about capitalist regeneration strategies in terms of their impact both on class inequality and on the environment

On the Erasure and Regeneration of the Primordial Baryon Asymmetry by Sphalerons

We show that a cosmological baryon asymmetry generated at the GUT scale, which would be destroyed at lower temperatures by sphalerons and possible new B- or L-violating effects, can naturally be preserved by an asymmetry in the number of right-handed electrons. This results in a significant softening of previously derived baryogenesis-based constraints on the strength of exotic B- or L-violating interactions.Comment: 10 pp. LaTex (2 figures, included) UMN-TH-1201/9

Non-invasive brain stimulation in Stroke patients (NIBS):A prospective randomized open blinded end-point (PROBE) feasibility trial using transcranial direct current stimulation (tDCS) in post-stroke hemispatial neglect

Up to 80% of people who experience a right-hemisphere stroke suffer from hemispatial neglect. This syndrome is debilitating and impedes rehabilitation. We carried out a clinical feasibility trial of transcranial direct current stimulation (tDCS) and a behavioural rehabilitation programme, alone or in combination, in patients with neglect. Patients >4 weeks post right hemisphere stroke were randomized to 10 sessions of tDCS, 10 sessions of a behavioural intervention, combined intervention, or a control task. Primary outcomes were recruitment and retention rates, with secondary outcomes effect sizes on measures of neglect and quality of life, assessed directly after the interventions, and at 6 months follow up. Of 288 confirmed stroke cases referred (representing 7% of confirmed strokes), we randomized 8% (0.6% of stroke cases overall). The largest number of exclusions (91/288 (34%)) were due to medical comorbidities that prevented patients from undergoing 10 intervention sessions. We recruited 24 patients over 29 months, with 87% completing immediate post-intervention and 67% 6 month evaluations. We established poor feasibility of a clinical trial requiring repeated hospital-based tDCS within a UK hospital healthcare setting, either with or without behavioural training, over a sustained time period. Future trials should consider intensity, duration and location of tDCS neglect interventions

ADCC Develops Over Time during Persistent Infection with Live-Attenuated SIV and Is Associated with Complete Protection against SIV(mac)251 Challenge

Live-attenuated strains of simian immunodeficiency virus (SIV) routinely confer apparent sterilizing immunity against pathogenic SIV challenge in rhesus macaques. Understanding the mechanisms of protection by live-attenuated SIV may provide important insights into the immune responses needed for protection against HIV-1. Here we investigated the development of antibodies that are functional against neutralization-resistant SIV challenge strains, and tested the hypothesis that these antibodies are associated with protection. In the absence of detectable neutralizing antibodies, Env-specific antibody-dependent cell-mediated cytotoxicity (ADCC) emerged by three weeks after inoculation with SIVDeltanef, increased progressively over time, and was proportional to SIVDeltanef replication. Persistent infection with SIVDeltanef elicited significantly higher ADCC titers than immunization with a non-persistent SIV strain that is limited to a single cycle of infection. ADCC titers were higher against viruses matched to the vaccine strain in Env, but were measurable against viruses expressing heterologous Env proteins. In two separate experiments, which took advantage of either the strain-specificity or the time-dependent maturation of immunity to overcome complete protection against SIV(mac)251 challenge, measures of ADCC activity were higher among the SIVDeltanef-inoculated macaques that remained uninfected than among those that became infected. These observations show that features of the antibody response elicited by SIVDeltanef are consistent with hallmarks of protection by live-attenuated SIV, and reveal an association between Env-specific antibodies that direct ADCC and apparent sterilizing protection by SIVDeltanef

Protecting the Primordial Baryon Asymmetry From Erasure by Sphalerons

If the baryon asymmetry of the universe was created at the GUT scale, sphalerons together with exotic sources of $(B-L)$-violation could have erased it, unless the latter satisfy stringent bounds. We elaborate on how the small Yukawa coupling of the electron drastically weakens previous estimates of these bounds.Comment: 41 pp., 4 latex figures included and 3 uuencoded or postscript figures available by request, UMN-TH-1213-9

Observations of Energetic-particle Population Enhancements along Intermittent Structures near the Sun from the Parker Solar Probe

Observations at 1 au have confirmed that enhancements in measured energetic-particle (EP) fluxes are statistically associated with "rough" magnetic fields, i.e., fields with atypically large spatial derivatives or increments, as measured by the Partial Variance of Increments (PVI) method. One way to interpret this observation is as an association of the EPs with trapping or channeling within magnetic flux tubes, possibly near their boundaries. However, it remains unclear whether this association is a transport or local effect; i.e., the particles might have been energized at a distant location, perhaps by shocks or reconnection, or they might experience local energization or re-acceleration. The Parker Solar Probe (PSP), even in its first two orbits, offers a unique opportunity to study this statistical correlation closer to the corona. As a first step, we analyze the separate correlation properties of the EPs measured by the Integrated Science Investigation of the Sun (IS⊙IS) instruments during the first solar encounter. The distribution of time intervals between a specific type of event, i.e., the waiting time, can indicate the nature of the underlying process. We find that the IS⊙IS observations show a power-law distribution of waiting times, indicating a correlated (non-Poisson) distribution. Analysis of low-energy (~15 – 200 keV/nuc) IS⊙IS data suggests that the results are consistent with the 1 au studies, although we find hints of some unexpected behavior. A more complete understanding of these statistical distributions will provide valuable insights into the origin and propagation of solar EPs, a picture that should become clear with future PSP orbits

Lynx X-Ray Observatory: An Overview

Lynx, one of the four strategic mission concepts under study for the 2020 Astrophysics Decadal Survey, provides leaps in capability over previous and planned x-ray missions and provides synergistic observations in the 2030s to a multitude of space- and ground-based observatories across all wavelengths. Lynx provides orders of magnitude improvement in sensitivity, on-axis subarcsecond imaging with arcsecond angular resolution over a large field of view, and high-resolution spectroscopy for point-like and extended sources in the 0.2- to 10-keV range. The Lynx architecture enables a broad range of unique and compelling science to be carried out mainly through a General Observer Program. This program is envisioned to include detecting the very first seed black holes, revealing the high-energy drivers of galaxy formation and evolution, and characterizing the mechanisms that govern stellar evolution and stellar ecosystems. The Lynx optics and science instruments are carefully designed to optimize the science capability and, when combined, form an exciting architecture that utilizes relatively mature technologies for a cost that is compatible with the projected NASA Astrophysics budget

Patient-specific iPSC model of a genetic vascular dementia syndrome reveals failure of mural cells to stabilize capillary structures

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common form of genetic stroke and vascular dementia syndrome resulting from mutations in NOTCH3. To elucidate molecular mechanisms of the condition and identify drug targets, we established a patient-specific induced pluripotent stem cell (iPSC) model and demonstrated for the first time a failure of the patient iPSC-derived vascular mural cells (iPSC-MCs) in engaging and stabilizing endothelial capillary structures. The patient iPSC-MCs had reduced platelet-derived growth factor receptor β, decreased secretion of the angiogenic factor vascular endothelial growth factor (VEGF), were highly susceptible to apoptotic insults, and could induce apoptosis of adjacent endothelial cells. Supplementation of VEGF significantly rescued the capillary destabilization. Small interfering RNA knockdown of NOTCH3 in iPSC-MCs revealed a gain-of-function mechanism for the mutant NOTCH3. These disease mechanisms likely delay brain repair after stroke in CADASIL, contributing to the brain hypoperfusion and dementia in this condition, and will help to identify potential drug targets

Response to Antenatal Cholecalciferol Supplementation Is Associated With Common Vitamin D-Related Genetic Variants.

Context: Single-nucleotide polymorphisms (SNPs) in genes related to vitamin D metabolism have been associated with serum 25-hydroxyvitamin D [25(OH)D] concentration, but these relationships have not been examined following antenatal cholecalciferol supplementation. Objective: To determine whether SNPs in DHCR7, CYP2R1, CYP24A1, and GC are associated with the response to gestational cholecalciferol supplementation. Design: Within-randomization group analysis of the Maternal Vitamin D Osteoporosis Study trial of antenatal cholecalciferol supplementation. Setting: Hospital antenatal clinics. Participants: In total, 682 women of white ethnicity (351 placebo, 331 cholecalciferol) were included. SNPs at rs12785878 (DHCR7), rs10741657 (CYP2R1), rs6013897 (CYP24A1), and rs2282679 (GC) were genotyped. Interventions: 1000 IU/d cholecalciferol from 14 weeks of gestation until delivery. Main Outcome Measure: 25(OH)D at randomization and 34 weeks of gestation were measured in a single batch (Liaison; Diasorin, Dartford, UK). Associations between 25(OH)D and the SNPs were assessed by linear regression using an additive model [β represents the change in 25(OH)D per additional common allele]. Results: Only rs12785878 (DHCR7) was associated with baseline 25(OH)D [β = 3.1 nmol/L; 95% confidence interval (CI), 1.0 to 5.2 nmol/L; P < 0.004]. In contrast, rs10741657 (CYP2R1) (β = -5.2 nmol/L; 95% CI, -8.2 to -2.2 nmol/L; P = 0.001) and rs2282679 (GC) (β = 4.2 nmol/L; 95% CI, 0.9 to 7.5 nmol/L; P = 0.01) were associated with achieved 25(OH)D status following supplementation, whereas rs12785878 and rs6013897 (CYP24A1) were not. Conclusions: Genetic variation in DHCR7, which encodes 7-dehyrocholesterol reductase in the epidermal vitamin D biosynthesis pathway, appears to modify baseline 25(OH)D. In contrast, the response to antenatal cholecalciferol supplementation was associated with SNPs in CYP2R1, which may alter 25-hydroxylase activity, and GC, which may affect vitamin D binding protein synthesis or metabolite affinity