An increase in dietary n-3 fatty acids decreases a marker of bone resorption in humans

Human, animal, and in vitro research indicates a beneficial effect of appropriate amounts of omega-3 (n-3) polyunsaturated fatty acids (PUFA) on bone health. This is the first controlled feeding study in humans to evaluate the effect of dietary plant-derived n-3 PUFA on bone turnover, assessed by serum concentrations of N-telopeptides (NTx) and bone-specific alkaline phosphatase (BSAP). Subjects (n = 23) consumed each diet for 6 weeks in a randomized, 3-period crossover design: 1) Average American Diet (AAD; [34% total fat, 13% saturated fatty acids (SFA), 13% monounsaturated fatty acids (MUFA), 9% PUFA (7.7% LA, 0.8% ALA)]), 2) Linoleic Acid Diet (LA; [37% total fat, 9% SFA, 12% MUFA, 16% PUFA (12.6% LA, 3.6% ALA)]), and 3) α-Linolenic Acid Diet (ALA; [38% total fat, 8% SFA, 12% MUFA, 17% PUFA (10.5% LA, 6.5% ALA)]). Walnuts and flaxseed oil were the predominant sources of ALA. NTx levels were significantly lower following the ALA diet (13.20 ± 1.21 nM BCE), relative to the AAD (15.59 ± 1.21 nM BCE) (p < 0.05). Mean NTx level following the LA diet was 13.80 ± 1.21 nM BCE. There was no change in levels of BSAP across the three diets. Concentrations of NTx were positively correlated with the pro-inflammatory cytokine TNFα for all three diets. The results indicate that plant sources of dietary n-3 PUFA may have a protective effect on bone metabolism via a decrease in bone resorption in the presence of consistent levels of bone formation

Parental breeding age effects on descendants' longevity interact over 2 generations in matrilines and patrilines

Individuals within populations vary enormously in mortality risk and longevity, but the causes of this variation remain poorly understood. A potentially important and phylogenetically widespread source of such variation is maternal age at breeding, which typically has negative effects on offspring longevity. Here, we show that paternal age can affect offspring longevity as strongly as maternal age does and that breeding age effects can interact over 2 generations in both matrilines and patrilines. We manipulated maternal and paternal ages at breeding over 2 generations in the neriid fly Telostylinus angusticollis. To determine whether breeding age effects can be modulated by the environment, we also manipulated larval diet and male competitive environment in the first generation. We found separate and interactive effects of parental and grand-parental ages at breeding on descendants' mortality rate and life span in both matrilines and patrilines. These breeding age effects were not modulated by grand-parental larval diet quality or competitive environment. Our findings suggest that variation in maternal and paternal ages at breeding could contribute substantially to intrapopulation variation in mortality and longevity

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

The Impact of a Virtual Orthopaedic Surgery Symposium on Medical Students: Increasing Awareness and Knowledge of the Field

Background:. Orthopaedic surgery has become an increasingly popular field of residency training for medical students. Many institutions offer elective time to explore areas of interest through clinical rotations and research; however, most of these opportunities are reserved for senior medical students. The purpose of this study was to evaluate the impact of a dedicated medical student orthopaedic surgery symposium to increase awareness about the field and to assess students' interest and knowledge of orthopaedic surgery before and after the symposium. Methods:. Medical students were invited to submit orthopaedic surgery–related research to a free, 1-day virtual symposium held in April 2022. Abstracts were reviewed and selected from 9 different orthopaedic surgery subspecialty categories. Survey assessments were sent to medical students to complete before and after the symposium. The surveys included questions related to participant demographics as well as interest and knowledge about the field of orthopaedic surgery. Statistical analyses were completed to compare the participants' responses before and after the symposium. Results:. In total, 962 medical students registered for the 4-hour symposium. Of these, 58.5% completed the presymposium survey and 48.0% completed the postsymposium survey. 13.3% of the respondents reported being “very knowledgeable” about the various orthopaedic surgery subspecialties before the symposium, which increased to 18.4% after the symposium. 46.9% of the participants stated that they were “knowledgeable” about the daily life of an orthopaedic surgery resident before the symposium, which increased to 67.3% after the symposium. Similarly, the percentage of respondents who reported that they were “very knowledgeable” about the residency match process increased from 12.2% presymposium to 22.4% postsymposium. Conclusions:. As interest in pursuing a career in orthopaedic surgery increases, medical students will continue to seek information, mentorship, and opportunities to present their research in preparation for residency applications. Our study demonstrated that a large-scale, national, virtual orthopaedic surgery symposium provided a platform to augment medical students' knowledge of the field, present their research, and interact with faculty members. Level of Evidence:. Level V

Observations and models of low-mode internal waves in the ocean

The generation of internal gravity waves in the ocean is largely driven by tides, winds, and interaction of currents with the seafloor. Models and observations indicate a global energy supply for the internal wave field of about 1 TW by the conversion of barotropic tides at mid-ocean ridges and abrupt topographic features. Winds acting on the oceanic mixed layer contribute 0.3--1.5 TW, and mesoscale flow over rough topography adds about 0.2 TW. Globally, 1--2 TW are needed to maintain the observed stratification of the deep ocean by diapycnal mixing that results from the breaking of internal waves. Ocean circulation models show significant impact of the spatial distribution of internal wave dissipation and mixing on the ocean state, e.g., thermal structure, stratification, and meridional overturning circulation. Observations indicate that the local ratio of generation and dissipation of internal waves is often below unity, and thus, the energy available for mixing must be redistributed by internal tides and near-inertial waves at low vertical wavenumber that can propagate thousands of kilometers from their source regions. Eddy-permitting global ocean circulation models are able to quantify the different sources of energy input and can also simulate the propagation of the lowest internal wave modes. However, the variation of the internal wave energy flux along its paths by wave--wave interaction, topographic scattering, and refraction by mesoscale features as well as its ultimate fate by dissipation remains to be parameterized

APCCdh1 mediates EphA4-dependent downregulation of AMPA receptors in homeostatic plasticity

Homeostatic plasticity is crucial for maintaining neuronal output by counteracting unrestrained changes in synaptic strength. Chronic elevation of synaptic activity by bicuculline reduces the amplitude of miniature excitatory postsynaptic currents (mEPSCs), but the underlying mechanisms of this effect remain unclear. We found that activation of EphA4 resulted in a decrease in synaptic and surface GluR1 and attenuated mEPSC amplitude through a degradation pathway that requires the ubiquitin proteasome system (UPS). Elevated synaptic activity resulted in increased tyrosine phosphorylation of EphA4, which associated with the ubiquitin ligase anaphase-promoting complex (APC) and its activator Cdh1 in neurons in a ligand-dependent manner. APCCdh1 interacted with and targeted GluR1 for proteasomal degradation in vitro, whereas depletion of Cdh1 in neurons abolished the EphA4-dependent downregulation of GluR1. Knockdown of EphA4 or Cdh1 prevented the reduction in mEPSC amplitude in neurons that was a result of chronic elevated activity. Our results define a mechanism by which EphA4 regulates homeostatic plasticity through an APC Cdh1-dependent degradation pathway. © 2011 Nature America, Inc. All rights reserved.link_to_subscribed_fulltex

A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response

Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers(1–4). Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy(1,3). The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors(5–9), has not been fully explored. Here we use genetically engineered mouse models to conduct a ‘co-clinical’ trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244)(10) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors(6,9,11,12), markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies