Simple and effective exercise design for assessing in vivo mitochondrial function in clinical applications using (31)P magnetic resonance spectroscopy.

The growing recognition of diseases associated with dysfunction of mitochondria poses an urgent need for simple measures of mitochondrial function. Assessment of the kinetics of replenishment of the phosphocreatine pool after exercise using (31)P magnetic resonance spectroscopy can provide an in vivo measure of mitochondrial function; however, the wider application of this technique appears limited by complex or expensive MR-compatible exercise equipment and protocols not easily tolerated by frail participants or those with reduced mental capacity. Here we describe a novel in-scanner exercise method which is patient-focused, inexpensive, remarkably simple and highly portable.

31P magnetization transfer measurements of Pi→ATP flux in exercising human muscle.

Fundamental criticisms have been made over the use of (31)P magnetic resonance spectroscopy (MRS) magnetization transfer estimates of inorganic phosphate (Pi)→ATP flux (VPi-ATP) in human resting skeletal muscle for assessing mitochondrial function. Although the discrepancy in the magnitude of VPi-ATP is now acknowledged, little is known about its metabolic determinants. Here we use a novel protocol to measure VPi-ATP in human exercising muscle for the first time.

Conserved Amphipathic Helices Mediate Lipid Droplet Targeting of Perilipins 1-3.

Perilipins (PLINs) play a key role in energy storage by orchestrating the activity of lipases on the surface of lipid droplets. Failure of this activity results in severe metabolic disease in humans. Unlike all other lipid droplet-associated proteins, PLINs localize almost exclusively to the phospholipid monolayer surrounding the droplet.

Programmed Ribosomal Frameshifting Mediates Expression of the α-Carboxysome.

Many bacteria employ a protein organelle, the carboxysome, to catalyze carbon dioxide fixation in the Calvin Cycle. Only 10 genes from Halothiobacillus neapolitanus are sufficient for heterologous expression of carboxysomes in Escherichia coli, opening the door to detailed mechanistic analysis of the assembly process of this complex (more than 200MDa). One of these genes, csoS2, has been implicated in assembly but ascribing a molecular function is confounded by the observation that the single csoS2 gene yields expression of two gene products and both display an apparent molecular weight incongruent with the predicted amino acid sequence.

Second-Harmonic Coherent Driving of a Spin Qubit in a Si/SiGe Quantum Dot.

We demonstrate coherent driving of a single electron spin using second-harmonic excitation in a Si/SiGe quantum dot. Our estimates suggest that the anharmonic dot confining potential combined with a gradient in the transverse magnetic field dominates the second-harmonic response. As expected, the Rabi frequency depends quadratically on the driving amplitude, and the periodicity with respect to the phase of the drive is twice that of the fundamental harmonic.

Truncation of POC1A associated with short stature and extreme insulin resistance.

We describe a female proband with primordial dwarfism, skeletal dysplasia, facial dysmorphism, extreme dyslipidaemic insulin resistance and fatty liver associated with a novel homozygous frameshift mutation in POC1A, predicted to affect two of the three protein products of the gene. POC1A encodes a protein associated with centrioles throughout the cell cycle and implicated in both mitotic spindle and primary ciliary function. Three homozygous mutations affecting all isoforms of POC1A have recently been implicated in a similar syndrome of primordial dwarfism, although no detailed metabolic phenotypes were described.

A New Imaging Platform for Visualizing Biological Effects of Non-Invasive Radiofrequency Electric-Field Cancer Hyperthermia.

Herein, we present a novel imaging platform to study the biological effects of non-invasive radiofrequency (RF) electric field cancer hyperthermia. This system allows for real-time in vivo intravital microscopy (IVM) imaging of radiofrequency-induced biological alterations such as changes in vessel structure and drug perfusion. Our results indicate that the IVM system is able to handle exposure to high-power electric-fields without inducing significant hardware damage or imaging artifacts.

Mechanistic insights revealed by lipid profiling in monogenic insulin resistance syndromes.

Background: Evidence from several recent metabolomic studies suggests that increased concentrations of triacylglycerols with shorter (14-16 carbon atoms), saturated fatty acids are associated with insulin resistance and the risk of type 2 diabetes. Although causality cannot be inferred from association studies, patients in whom the primary cause of insulin resistance can be genetically defined offer unique opportunities to address this challenge.

Methods: We compared metabolite profiles in patients with congenital lipodystrophy or loss-of-function insulin resistance (INSR gene) mutations with healthy controls.

Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy.

Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10-41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors.

Ethylglucuronide in maternal hair as a biomarker of prenatal alcohol exposure.

While direct ethanol metabolites, including ethylglucuronide (EtG), play an important role for the confirmation of prenatal alcohol exposure (PAE), their utility is often limited by their short half-lives in blood and urine. Maternal hair allows for a retrospective measure of PAE for up to several months. This study examined the validity of hair EtG (hEtG) relative to self-reporting and five other biomarkers in 85 pregnant women.

Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis.

Background: Insulinemia and type 2 diabetes (T2D) have been associated with endometrial cancer risk in numerous observational studies. However, the causality of these associations is uncertain. Here we use a Mendelian randomization (MR) approach to assess whether insulinemia and T2D are causally associated with endometrial cancer.

Lipid droplet-organelle interactions: emerging roles in lipid metabolism.

Cellular homeostasis depends on the precisely coordinated use of lipids as fuels for energy production, building blocks for membrane biogenesis or chemical signals for intra-cellular and inter-cellular communication. Lipid droplets (LDs) are universally conserved dynamic organelles that can store and mobilize fatty acids and other lipid species for their multiple cellular roles. Increasing evidence suggests that contact zones between LDs and other organelles play important roles in the trafficking of lipids and in the regulation of lipid metabolism.

The genetics of lipid storage and human lipodystrophies.

Life depends on securing sufficient energy intake to enable growth, movement, and reproduction. Throughout evolution, lifeforms have struggled to ensure adequate energy intake, and this remains a major challenge for many species. Modern humans are particularly well adapted to store surplus energy efficiently, but they are considerably less well adapted for coping with sustained access to energy-dense food.

Electronic Transport Properties of Epitaxial Si/SiGe Heterostructures Grown on Single-Crystal SiGe Nanomembranes.

To assess possible improvements in the electronic performance of two-dimensional electron gases (2DEGs) in silicon, SiGe/Si/SiGe heterostructures are grown on fully elastically relaxed single-crystal SiGe nanomembranes produced through a strain engineering approach. This procedure eliminates the formation of dislocations in the heterostructure. Top-gated Hall bar devices are fabricated to enable magnetoresistivity and Hall effect measurements.

Identifying single electron charge sensor events using wavelet edge detection.

The operation of solid-state qubits often relies on single-shot readout using a nanoelectronic charge sensor, and the detection of events in a noisy sensor signal is crucial for high fidelity readout of such qubits. The most common detection scheme, comparing the signal to a threshold value, is accurate at low noise levels but is not robust to low-frequency noise and signal drift. We describe an alternative method for identifying charge sensor events using wavelet edge detection.

Developing emergency department physician shift schedules optimized to meet patient demand.

Objectives: 1) To assess temporal patterns in historical patient arrival rates in an emergency department (ED) to determine the appropriate number of shift schedules in an acute care area and a fast-track clinic and 2) to determine whether physician scheduling can be improved by aligning physician productivity with patient arrivals using an optimization planning model.

Methods: Historical data were statistically analyzed to determine whether the number of patients arriving at the ED varied by weekday, weekend, or holiday weekend. Poisson-based generalized additive models were used to develop models of patient arrival rate throughout the day.

Moderate prenatal alcohol exposure enhances GluN2B containing NMDA receptor binding and ifenprodil sensitivity in rat agranular insular cortex.

Prenatal exposure to alcohol affects the expression and function of glutamatergic neurotransmitter receptors in diverse brain regions. The present study was undertaken to fill a current gap in knowledge regarding the regional specificity of ethanol-related alterations in glutamatergic receptors in the frontal cortex. We quantified subregional expression and function of glutamatergic neurotransmitter receptors (AMPARs, NMDARs, GluN2B-containing NMDARs, mGluR1s, and mGluR5s) by radioligand binding in the agranular insular cortex (AID), lateral orbital area (LO), prelimbic cortex (PrL) and primary motor cortex (M1) of adult rats exposed to moderate levels of ethanol during prenatal development.

Microwave-driven coherent operation of a semiconductor quantum dot charge qubit.

An intuitive realization of a qubit is an electron charge at two well-defined positions of a double quantum dot. This qubit is simple and has the potential for high-speed operation because of its strong coupling to electric fields. However, charge noise also couples strongly to this qubit, resulting in rapid dephasing at all but one special operating point called the 'sweet spot'.

Income and Health in Tanzania. An Instrumental Variable Approach.

There is a substantial debate over the direction of the causal relation between income and health. This is important for our understanding of the health production process and for the policy debate over improving healthcare. We instrument income with rainfall measurements by matching satellite information on timing and positioning of 21 rainfall stations to longitudinal data (1991-94) of over 4,000 individuals in 51 villages in Tanzania.

Insulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice.

Fsp27 is a lipid droplet-associated protein almost exclusively expressed in adipocytes where it facilitates unilocular lipid droplet formation. In mice, Fsp27 deficiency is associated with increased basal lipolysis, 'browning' of white fat and a healthy metabolic profile, whereas a patient with congenital CIDEC deficiency manifested an adverse lipodystrophic phenotype. Here we reconcile these data by showing that exposing Fsp27-null mice to a substantial energetic stress by crossing them with ob/ob mice or BATless mice, or feeding them a high-fat diet, results in hepatic steatosis and insulin resistance.

Moderate prenatal alcohol exposure and quantification of social behavior in adult rats.

Alterations in social behavior are among the major negative consequences observed in children with Fetal Alcohol Spectrum Disorders (FASDs). Several independent laboratories have demonstrated robust alterations in the social behavior of rodents exposed to alcohol during brain development across a wide range of exposure durations, timing, doses, and ages at the time of behavioral quantification. Prior work from this laboratory has identified reliable alterations in specific forms of social interaction following moderate prenatal alcohol exposure (PAE) in the rat that persist well into adulthood, including increased wrestling and decreased investigation.

Developing authentic clinical simulations for effective listening and communication in pediatric rehabilitation service delivery.

Purpose: To describe the creation and validation of six simulations concerned with effective listening and interpersonal communication in pediatric rehabilitation.

Methods And Findings: The simulations involved clinicians from various disciplines, were based on clinical scenarios related to client issues, and reflected core aspects of listening/communication. Each simulation had a key learning objective, thus focusing clinicians on specific listening skills.

Concomitant angiosarcoma and lymphoproliferative disorder in solid organ transplant recipients.

An increased risk of posttransplant malignancy has been consistently reported following various solid organ transplants. The malignancies most commonly encountered are non-melanoma skin cancers, carcinomas of lung or breast and posttransplant lymphoproliferative disorders. Angiosarcoma, an uncommon vascular mesenchymal neoplasm, is rare in the posttransplant setting.

Protein engineering of Cas9 for enhanced function.

CRISPR/Cas systems act to protect the cell from invading nucleic acids in many bacteria and archaea. The bacterial immune protein Cas9 is a component of one of these CRISPR/Cas systems and has recently been adapted as a tool for genome editing. Cas9 is easily targeted to bind and cleave a DNA sequence via a complementary RNA; this straightforward programmability has gained Cas9 rapid acceptance in the field of genetic engineering.