Vascular adaptation to exercise in humans: Role of hemodynamic stimuli

On the 400th anniversary of Harvey’s Lumleian lectures, this review focuses on “hemodynamic” forces associated with the movement of blood through arteries in humans and the functional and structural adaptations that result from repeated episodic exposure to such stimuli. The late 20th century discovery that endothelial cells modify arterial tone via paracrine transduction provoked studies exploring the direct mechanical effects of blood flow and pressure on vascular function and adaptation in vivo. In this review, we address the impact of distinct hemodynamic signals that occur in response to exercise, the interrelationships between these signals, the nature of the adaptive responses that manifest under different physiological conditions, and the implications for human health. Exercise modifies blood flow, luminal shear stress, arterial pressure, and tangential wall stress, all of which can transduce changes in arterial function, diameter, and wall thickness. There are important clinical implications of the adaptation that occurs as a consequence of repeated hemodynamic stimulation associated with exercise training in humans, including impacts on atherosclerotic risk in conduit arteries, the control of blood pressure in resistance vessels, oxygen delivery and diffusion, and microvascular health. Exercise training studies have demonstrated that direct hemodynamic impacts on the health of the artery wall contribute to the well-established decrease in cardiovascular risk attributed to physical activity. © 2017 the American Physiological Society

Phenotype and Genetics of Progressive Sensorineural Hearing Loss (Snhl1) in the LXS Set of Recombinant Inbred Strains of Mice

Progressive sensorineural hearing loss is the most common form of acquired hearing impairment in the human population. It is also highly prevalent in inbred strains of mice, providing an experimental avenue to systematically map genetic risk factors and to dissect the molecular pathways that orchestrate hearing in peripheral sensory hair cells. Therefore, we ascertained hearing function in the inbred long sleep (ILS) and inbred short sleep (ISS) strains. Using auditory-evoked brain stem response (ABR) and distortion product otoacoustic emission (DPOAE) measurements, we found that ISS mice developed a high-frequency hearing loss at twelve weeks of age that progressed to lower frequencies by 26 weeks of age in the presence of normal endocochlear potentials and unremarkable inner ear histology. ILS mice exhibited milder hearing loss, showing elevated thresholds and reduced DPOAEs at the higher frequencies by 26 weeks of age. To map the genetic variants that underlie this hearing loss we computed ABR thresholds of 63 recombinant inbred stains derived from the ISS and ILS founder strains. A single locus was linked to markers associated with ISS alleles on chromosome 10 with a highly significant logarithm of odds (LOD) score of 15.8. The 2-LOD confidence interval spans ∼4 Megabases located at position 54–60 Mb. This locus, termed sensorineural hearing loss 1 (Snhl1), accounts for approximately 82% of the phenotypic variation. In summary, this study identifies a novel hearing loss locus on chromosome 10 and attests to the prevalence and genetic heterogeneity of progressive hearing loss in common mouse strains

Two-dimensional transport and transfer of a single atomic qubit in optical tweezers

Quantum computers have the capability of out-performing their classical counterparts for certain computational problems1. Several scalable quantum-computing architectures have been proposed. An attractive architecture is a large set of physically independent qubits arranged in three spatial regions where (1) the initialized qubits are stored in a register, (2) two qubits are brought together to realize a gate and (3) the readout of the qubits is carried out2, 3. For a neutral-atom-based architecture, a natural way to connect these regions is to use optical tweezers to move qubits within the system. In this letter we demonstrate the coherent transport of a qubit, encoded on an atom trapped in a submicrometre tweezer, over a distance typical of the separation between atoms in an array of optical traps4, 5, 6. Furthermore, we transfer a qubit between two tweezers, and show that this manipulation also preserves the coherence of the qubit

Characterization and Control of the Microbial Community Affiliated with Copper or Aluminum Heat Exchangers of HVAC Systems

Microbial growth in heating ventilation and air-conditioning (HVAC) systems with the subsequent contamination of indoor air is of increasing concern. Microbes and the subsequent biofilms grow easily within heat exchangers. A comparative study where heat exchangers fabricated from antimicrobial copper were evaluated for their ability to limit microbial growth was conducted using a full-scale HVAC system under conditions of normal flow rates using single-pass outside air. Resident bacterial and fungal populations were quantitatively assessed by removing triplicate sets of coupons from each exchanger commencing the fourth week after their installation for the next 30 weeks. The intrinsic biofilm associated with each coupon was extracted and characterized using selective and differential media. The predominant organisms isolated from aluminum exchangers were species of Methylobacterium of which at least three colony morphologies and 11 distinct PFGE patterns we found; of the few bacteria isolated from the copper exchangers, the majority were species of Bacillus. The concentrations and type of bacteria recovered from the control, aluminum, exchangers were found to be dependent on the type of plating media used and were 11,411–47,257 CFU cm−2 per coupon surface. The concentration of fungi was found to average 378 CFU cm−2. Significantly lower concentrations of bacteria, 3 CFU cm−2, and fungi, 1 CFU cm−2, were recovered from copper exchangers regardless of the plating media used. Commonly used aluminum heat exchangers developed stable, mixed, bacterial/fungal biofilms in excess of 47,000 organisms per cm2 within 4 weeks of operation, whereas the antimicrobial properties of metallic copper were able to limit the microbial load affiliated with the copper heat exchangers to levels 99.97 % lower during the same time period

Obesity related methylation changes in DNA of peripheral blood leukocytes

<p>Abstract</p> <p>Background</p> <p>Despite evidence linking obesity to impaired immune function, little is known about the specific mechanisms. Because of emerging evidence that immune responses are epigenetically regulated, we hypothesized that DNA methylation changes are involved in obesity induced immune dysfunction and aimed to identify these changes.</p> <p>Method</p> <p>We conducted a genome wide methylation analysis on seven obese cases and seven lean controls aged 14 to 18 years from extreme ends of the obesity distribution and performed further validation of six CpG sites from six genes in 46 obese cases and 46 lean controls aged 14 to 30 years.</p> <p>Results</p> <p>In comparison with the lean controls, we observed one CpG site in the UBASH3A gene showing higher methylation levels and one CpG site in the TRIM3 gene showing lower methylation levels in the obese cases in both the genome wide step (<it>P </it>= 5 × 10^-6and <it>P </it>= 2 × 10^-5for the UBASH3A and the TRIM3 gene respectively) and the validation step (<it>P </it>= 0.008 and <it>P </it>= 0.001 for the UBASH3A and the TRIM3 gene respectively).</p> <p>Conclusions</p> <p>Our results provide evidence that obesity is associated with methylation changes in blood leukocyte DNA. Further studies are warranted to determine the causal direction of this relationship as well as whether such methylation changes can lead to immune dysfunction.</p> <p>See commentary: <url>http://www.biomedcentral.com/1741-7015/8/88/abstract</url></p

Activation of PyMT in β Cells Induces Irreversible Hyperplasia, but Oncogene-Dependent Acinar Cell Carcinomas When Activated in Pancreatic Progenitors

It is unclear whether the cellular origin of various forms of pancreatic cancer involves transformation or transdifferentiation of different target cells or whether tumors arise from common precursors, with tumor types determined by the specific genetic alterations. Previous studies suggested that pancreatic ductal carcinomas might be induced by polyoma middle T antigen (PyMT) expressed in non-ductal cells. To ask whether PyMT transforms and transdifferentiates endocrine cells toward exocrine tumor phenotypes, we generated transgenic mice that carry tetracycline-inducible PyMT and a linked luciferase reporter. Induction of PyMT in β cells causes β-cell hyperplastic lesions that do not progress to malignant neoplasms. When PyMT is de-induced, β cell proliferation and growth cease; however, regression does not occur, suggesting that continued production of PyMT is not required to maintain the viable expanded β cell population. In contrast, induction of PyMT in early pancreatic progenitor cells under the control of Pdx1 produces acinar cell carcinomas and β-cell hyperplasia. The survival of acinar tumor cells is dependent on continued expression of PyMT. Our findings indicate that PyMT can induce exocrine tumors from pancreatic progenitor cells, but cells in the β cell lineage are not transdifferentiated toward exocrine cell types by PyMT; instead, they undergo oncogene-dependent hyperplastic growth, but do not require PyMT for survival

Information resource preferences by general pediatricians in office settings: a qualitative study

BACKGROUND: Information needs and resource preferences of office-based general pediatricians have not been well characterized. METHODS: Data collected from a sample of twenty office-based urban/suburban general pediatricians consisted of: (a) a demographic survey about participants' practice and computer use, (b) semi-structured interviews on their use of different types of information resources and (c) semi-structured interviews on perceptions of information needs and resource preferences in response to clinical vignettes representing cases in Genetics and Infectious Diseases. Content analysis of interviews provided participants' perceived use of resources and their perceived questions and preferred resources in response to vignettes. RESULTS: Participants' average time in practice was 15.4 years (2–28 years). All had in-office online access. Participants identified specialist/generalist colleagues, general/specialty pediatric texts, drug formularies, federal government/professional organization Websites and medical portals (when available) as preferred information sources. They did not identify decision-making texts, evidence-based reviews, journal abstracts, medical librarians or consumer health information for routine office use. In response to clinical vignettes in Genetics and Infectious Diseases, participants identified Question Types about patient-specific (diagnosis, history and findings) and general medical (diagnostic, therapeutic and referral guidelines) information. They identified specialists and specialty textbooks, history and physical examination, colleagues and general pediatric textbooks, and federal and professional organizational Websites as information sources. Participants with access to portals identified them as information resources in lieu of texts. For Genetics vignettes, participants identified questions about prenatal history, disease etiology and treatment guidelines. For Genetics vignettes, they identified patient history, specialists, general pediatric texts, Web search engines and colleagues as information sources. For Infectious Diseases (ID) vignettes, participants identified questions about patients' clinical status at presentation and questions about disease classification, diagnosis/therapy/referral guidelines and sources of patient education. For ID vignettes, they identified history, laboratory results, colleagues, specialists and personal experience as information sources. CONCLUSION: Content analysis of office-based general pediatricians' responses to clinical vignettes provided a qualitative description of their perceptions of information needs and preferences for information resource for cases in Genetics and Infectious Diseases. This approach may provide complementary information for discovering practitioner's information needs and resource preferences in different contexts

Association between maternal depression symptoms across the first eleven years of their child’s life and subsequent offspring suicidal ideation

Depression is common, especially in women of child-bearing age; prevalence estimates for this group range from 8% to 12%, and there is robust evidence that maternal depression is associated with mental health problems in offspring. Suicidal behaviour is a growing concern amongst young people and those exposed to maternal depression are likely to be especially at high risk. The aim of this study was to utilise a large, prospective population cohort to examine the relationship between depression symptom trajectories in mothers over the first eleven years of their child’s life and subsequent adolescent suicidal ideation. An additional aim was to test if associations were explained by maternal suicide attempt and offspring depressive disorder. Data were utilised from a population-based birth cohort: the Avon Longitudinal Study of Parents and Children. Maternal depression symptoms were assessed repeatedly from pregnancy to child age 11 years. Offspring suicidal ideation was assessed at age 16 years. Using multiple imputation, data for 10,559 families were analysed. Using latent class growth analysis, five distinct classes of maternal depression symptoms were identified (minimal, mild, increasing, sub-threshold, chronic-severe). The prevalence of past-year suicidal ideation at age 16 years was 15% (95% CI: 14-17%). Compared to offspring of mothers with minimal symptoms, the greatest risk of suicidal ideation was found for offspring of mothers with chronic-severe symptoms [OR 3.04 (95% CI 2.19,4.21)], with evidence for smaller increases in risk of suicidal ideation in offspring of mothers with sub-threshold, increasing and mild symptoms. These associations were not fully accounted for by maternal suicide attempt or offspring depression diagnosis. Twenty-six percent of non-depressed offspring of mothers with chronic-severe depression symptoms reported suicidal ideation. Risk for suicidal ideation should be considered in young people whose mothers have a history of sustained high levels of depression symptoms, even when the offspring themselves do not have a depression diagnosis

miR-125b Promotes Early Germ Layer Specification through Lin28/let-7d and Preferential Differentiation of Mesoderm in Human Embryonic Stem Cells

Unlike other essential organs, the heart does not undergo tissue repair following injury. Human embryonic stem cells (hESCs) grow indefinitely in culture while maintaining the ability to differentiate into many tissues of the body. As such, they provide a unique opportunity to explore the mechanisms that control human tissue development, as well as treat diseases characterized by tissue loss, including heart failure. MicroRNAs are small, non-coding RNAs that are known to play critical roles in the regulation of gene expression. We profiled the expression of microRNAs during hESC differentiation into myocardial precursors and cardiomyocytes (CMs), and determined clusters of human microRNAs that are specifically regulated during this process. We determined that miR-125b overexpression results in upregulation of the early cardiac transcription factors, GATA4 and Nkx2-5, and accelerated progression of hESC-derived myocardial precursors to an embryonic CM phenotype. We used an in silico approach to identify Lin28 as a target of miR-125b, and validated this interaction using miR-125b knockdown. Anti-miR-125b inhibitor experiments also showed that miR-125b controls the expression of miRNA let-7d, likely through the negative regulatory effects of Lin28 on let-7. We then determined that miR-125b overexpression inhibits the expression of Nanog and Oct4 and promotes the onset of Brachyury expression, suggesting that miR-125b controls the early events of human CM differentiation by inhibiting hESC pluripotency and promoting mesodermal differentiation. These studies identified miR-125b as an important regulator of hESC differentiation in general, and the development of hESC-derived mesoderm and cardiac muscle in particular. Manipulation of miR-125b-mediated pathways may provide a novel approach to directing the differentiation of hESC-derived CMs for cell therapy applications