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"Richardson, Rachel"
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The New English garden
The author \"discusses twenty-five significant English gardens made or remade over the past decade\"--Dust jacket flap.
Book
Memory deficiency, cerebral amyloid angiopathy, and amyloid-β plaques in APP+PS1 double transgenic rat model of Alzheimer’s disease
Transgenic rat models of Alzheimer's disease were used to examine differences in memory and brain histology. Double transgenic female rats (APP+PS1) over-expressing human amyloid precursor protein (APP) and presenilin 1 (PS1) and single transgenic rats (APP21) over-expressing human APP were compared with wild type Fischer rats (WT). The Barnes maze assessed learning and memory and showed that both APP21 and APP+PS1 rats made significantly more errors than the WT rats during the acquisition phase, signifying slower learning. Additionally, the APP+PS1 rats made significantly more errors following a retention interval, indicating impaired memory compared to both the APP21 and WT rats. Immunohistochemistry using an antibody against amyloid-β (Aβ) showed extensive and mostly diffuse Aβ plaques in the hippocampus and dense plaques that contained tau in the cortex of the brains of the APP+PS1 rats. Furthermore, the APP+PS1 rats also showed vascular changes, including cerebral amyloid angiopathy with extensive Aβ deposits in cortical and leptomeningeal blood vessel walls and venous collagenosis. In addition to the Aβ accumulation observed in arterial, venous, and capillary walls, APP+PS1 rats also displayed enlarged blood vessels and perivascular space. Overall, the brain histopathology and behavioral assessment showed that the APP+PS1 rats demonstrated behavioral characteristics and vascular changes similar to those commonly observed in patients with Alzheimer's disease.
Journal Article
A systematic review of school meal nudge interventions to improve youth food behaviors
Background
School meal programs have a large reach and thus are ideal environments in which to implement interventions targeting improved youth eating behaviors and reduced food waste. This systematic review summarizes the evidence on the effectiveness of school meal nudge interventions on influencing children’s eating and waste behaviors.
Methods
Inclusion criteria required studies have participants in primary or secondary school (grades K-12) with interventions that occurred during school lunch or breakfast in the cafeteria and included at least one of the following outcomes: selection, consumption, waste, or school meal participation. Analyses of intervention outcomes were restricted to studies of strong and moderate quality.
Results
Twenty-nine studies were included in the quality assessment. Included interventions fell into three categories: 1) placement/convenience, 2) marketing/promotion, or 3) variety/portions. The 20 strong and moderate quality studies included in outcome analyses generally used strong data collection methods and study designs, but were limited by an overall lack of intervention fidelity checks. Multi-component interventions often did not use methods that allowed for separate analyses of outcomes for different intervention components.
Conclusions
School meal nudge interventions were positively associated with food selection, and had an inconsistent relationship with food consumption. There were few studies evaluating the impact of nudge interventions on meal participation or food waste. The limited evidence available links nudges to improved meal participation, as well as undesirable increases in food waste. Future research in this area should use methods that incorporate implementation metrics, attend to systems factors, and allow the outcomes of individual intervention components to be isolated.
Journal Article
eNOS plays essential roles in the developing heart and aorta linked to disruption of Notch signalling
eNOS (NOS3) is the enzyme that generates nitric oxide, a signalling molecule and regulator of vascular tone. Loss of eNOS function is associated with increased susceptibility to atherosclerosis, hypertension, thrombosis and stroke. Aortopathy and cardiac hypertrophy have also been found in eNOS null mice, but their aetiology is unclear. We evaluated eNOS nulls before and around birth for cardiac defects, revealing severe abnormalities in the ventricular myocardium and pharyngeal arch arteries. Moreover, in the aortic arch, there were fewer baroreceptors, which sense changes in blood pressure. Adult eNOS null survivors showed evidence of cardiac hypertrophy, aortopathy and cartilaginous metaplasia in the periductal region of the aortic arch. Notch1 and neuregulin were dysregulated in the forming pharyngeal arch arteries and ventricles, suggesting that these pathways may be relevant to the defects observed. Dysregulation of eNOS leads to embryonic and perinatal death, suggesting mutations in eNOS are candidates for causing congenital heart defects in humans. Surviving eNOS mutants have a deficiency of baroreceptors that likely contributes to high blood pressure and may have relevance to human patients who suffer from hypertension associated with aortic arch abnormalities.
Journal Article
Hypoxia and radiotherapy: opportunities for improved outcomes in cancer treatment
A large body of clinical evidence exists to suggest that tumor hypoxia negatively impacts radiotherapy. As a result, there has been longstanding active research into novel methods of improving tumor oxygenation, targeting hypoxic tumor cells, and otherwise modulating the effect hypoxia has on how tumors respond to radiation. Over time, as more has been learned about the many ways hypoxia affects tumors, our understanding of the mechanisms connecting hypoxia to radiosensitivity has become increasingly broad and complicated. This has opened up new potential avenues for interrupting hypoxia's negative effects on tumor radiosensitivity. Here, we will review what is currently known about the spectrum of influence hypoxia has over the way tumors respond to radiation. Particular focus will be placed on recent discoveries suggesting that hypoxia-inducible factor-1 (HIF-1), a transcription factor that upregulates its target genes under hypoxic conditions, plays a major role in determining tumor radiosensitivity. HIF-1 and/or its target genes may represent therapeutic targets which could be manipulated to influence hypoxia's impact on tumor radiosensitivity.
Journal Article
When Winners Become Losers: Predicted Nonlinear Responses of Arctic Birds to Increasing Woody Vegetation
Climate change is facilitating rapid changes in the composition and distribution of vegetation at northern latitudes, raising questions about the responses of wildlife that rely on arctic ecosystems. One widely observed change occurring in arctic tundra ecosystems is an increasing dominance of deciduous shrub vegetation. Our goals were to examine the tolerance of arctic-nesting bird species to existing gradients of vegetation along the boreal forest-tundra ecotone, to predict the abundance of species across different heights and densities of shrubs, and to identify species that will be most or least responsive to ongoing expansion of shrubs in tundra ecosystems. We conducted 1,208 point counts on 12 study blocks from 2012-2014 in northwestern Alaska, using repeated surveys to account for imperfect detection of birds. We considered the importance of shrub height, density of low and tall shrubs (i.e. shrubs >0.5 m tall), percent of ground cover attributed to shrubs (including dwarf shrubs <0.5 m tall), and percent of herbaceous plant cover in predicting bird abundance. Among 17 species considered, only gray-cheeked thrush (Catharus minimus) abundance was associated with the highest values of all shrub metrics in its top predictive model. All other species either declined in abundance in response to one or more shrub metrics or reached a threshold where further increases in shrubs did not contribute to greater abundance. In many instances the relationship between avian abundance and shrubs was nonlinear, with predicted abundance peaking at moderate values of the covariate, then declining at high values. In particular, a large number of species were responsive to increasing values of average shrub height with six species having highest abundance at near-zero values of shrub height and abundance of four other species decreasing once heights reached moderate values (≤ 33 cm). Our findings suggest that increases in shrub cover and density will negatively affect abundance of only a few bird species and may potentially be beneficial for many others. As shrub height increases further, however, a considerable number of tundra bird species will likely find habitat increasingly unsuitable.
Journal Article
Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders
BACKGROUNDKisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders.METHODSWe conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1R-mediated inositol monophosphate (IP1) and Ca2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices.RESULTSIn healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU∙h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012).CONCLUSIONTaken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders.TRIAL REGISTRATIONInternational Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.FUNDINGNational Institute for Health Research and NIH.
Journal Article
Kinematic and Injury Response of Reclined PMHS in Frontal Impacts
Frontal impacts with reclined occupants are rare but severe, and they are anticipated to become more common with the introduction of vehicles with automated driving capabilities. Computational and physical human surrogates are needed to design and evaluate injury countermeasures for reclined occupants, but the validity of such surrogates in a reclined posture is unknown. Experiments with post-mortem human subjects (PMHS) in a recline posture are needed both to define biofidelity targets for other surrogates and to describe the biomechanical response of reclined occupants in restrained frontal impacts. The goal of this study was to evaluate the kinematic and injury response of reclined PMHS in 30 g, 50 km/h frontal sled tests. Five midsize adult male PMHS were tested. A simplified semi-rigid seat with an anti-submarining pan and a non-production threepoint seatbelt (pre-tensioned, force-limited, seat-integrated) were used. Global motions and local accelerations of the head, pelvis, and multiple vertebrae were measured. Seat and seatbelt forces were also measured. Injuries were assessed via post-test dissection. The initial reclined posture aligned body regions (pelvis, lumbar spine, and ribcage) in a way that reduced the likelihood of effective restraint by the seat and seatbelt: the occupant's pelvis was initially rotated posteriorly, priming the occupant for submarining, and the lumbar spine was loaded in combined compression and bending due to the inertia of the upper torso during forward excursion. Coupled with the high restraining forces of the seat and seatbelt, the unfavorable kinematics resulted in injuries of the sacrum/coccyx (four of five PMHS injured), iliac wing (two of five PMHS injured), lumbar spine (three of five PMHS injured), and ribcage (all five PMHS suffered sternal fractures, and three of five PMHS suffered seven or more rib fractures). The kinematic and injury outcomes strongly motivate the development of injury criteria for the lumbar spine and pelvis, the inclusion of intrinsic variability (e.g., abdomen depth and pelvis shape) in computational simulations of frontal impacts with reclined occupants, and the adaptation of comprehensive restraint paradigms to predicted variability of occupant posture.
Journal Article
Catabolism of Exogenous Lactate Reveals It as a Legitimate Metabolic Substrate in Breast Cancer
Lactate accumulation in tumors has been associated with metastases and poor overall survival in cancer patients. Lactate promotes angiogenesis and metastasis, providing rationale for understanding how it is processed by cells. The concentration of lactate in tumors is a balance between the amount produced, amount carried away by vasculature and if/how it is catabolized by aerobic tumor or stromal cells. We examined lactate metabolism in human normal and breast tumor cell lines and rat breast cancer: 1. at relevant concentrations, 2. under aerobic vs. hypoxic conditions, 3. under conditions of normo vs. hypoglucosis. We also compared the avidity of tumors for lactate vs. glucose and identified key lactate catabolites to reveal how breast cancer cells process it. Lactate was non-toxic at clinically relevant concentrations. It was taken up and catabolized to alanine and glutamate by all cell lines. Kinetic uptake rates of lactate in vivo surpassed that of glucose in R3230Ac mammary carcinomas. The uptake appeared specific to aerobic tumor regions, consistent with the proposed \"metabolic symbiont\" model; here lactate produced by hypoxic cells is used by aerobic cells. We investigated whether treatment with alpha-cyano-4-hydroxycinnamate (CHC), a MCT1 inhibitor, would kill cells in the presence of high lactate. Both 0.1 mM and 5 mM CHC prevented lactate uptake in R3230Ac cells at lactate concentrations at ≤ 20 mM but not at 40 mM. 0.1 mM CHC was well-tolerated by R3230Ac and MCF7 cells, but 5 mM CHC killed both cell lines ± lactate, indicating off-target effects. This study showed that breast cancer cells tolerate and use lactate at clinically relevant concentrations in vitro (± glucose) and in vivo. We provided additional support for the metabolic symbiont model and discovered that breast cells prevailingly take up and catabolize lactate, providing rationale for future studies on manipulation of lactate catabolism pathways for therapy.
Journal Article
A novel source of arterial valve cells linked to bicuspid aortic valve without raphe in mice
Abnormalities of the arterial valve leaflets, predominantly bicuspid aortic valve, are the commonest congenital malformations. Although many studies have investigated the development of the arterial valves, it has been assumed that, as with the atrioventricular valves, endocardial to mesenchymal transition (EndMT) is the predominant mechanism. We show that arterial is distinctly different from atrioventricular valve formation. Whilst the four septal valve leaflets are dominated by NCC and EndMT-derived cells, the intercalated leaflets differentiate directly from Tnnt2-Cre+/Isl1+ progenitors in the outflow wall, via a Notch-Jag dependent mechanism. Further, when this novel group of progenitors are disrupted, development of the intercalated leaflets is disrupted, resulting in leaflet dysplasia and bicuspid valves without raphe, most commonly affecting the aortic valve. This study thus overturns the dogma that heart valves are formed principally by EndMT, identifies a new source of valve interstitial cells, and provides a novel mechanism for causation of bicuspid aortic valves without raphe.
Journal Article