Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes.

The increasing number of people afflicted with diabetes throughout the world is a major health issue. Inhibitors of the sodium-dependent glucose cotransporters (SGLT) have appeared as viable therapeutics to control blood glucose levels in diabetic patents. Herein we report the discovery of LX2761, a locally acting SGLT1 inhibitor that is highly potent in vitro and delays intestinal glucose absorption in vivo to improve glycemic control.

Differential effects of Mas receptor deficiency on cardiac function and blood pressure in obese male and female mice.

Angiotensin-(1-7) [ANG-(1-7)] acts at Mas receptors (MasR) to oppose effects of angiotensin II (ANG II). Previous studies demonstrated that protection of female mice from obesity-induced hypertension was associated with increased systemic ANG-(1-7), whereas male obese hypertensive mice exhibited increased systemic ANG II. We hypothesized that MasR deficiency ( ) augments obesity-induced hypertension in males and abolishes protection of females.

Accuracy of a dynamic surgical guidance probe for screw insertion in the cervical spine: a cadaveric study.

Study Design: A fresh frozen cadaver study was conducted.

Objective: To report the cortical breach rate using the dynamic surgical guidance (DSG) probe versus traditional freehand technique for cervical lateral mass, cervical pedicle and cervical laminar screws.

Methods: Nine male fresh frozen cadaveric torsos were utilized for this study.

Trophic dilution of cyclic volatile methylsiloxanes (cVMS) in the pelagic marine food web of Tokyo Bay, Japan.

Bioaccumulation and trophic transfer of cyclic volatile methylsiloxanes (cVMS), specifically octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), and dodecamethylcyclohexasiloxane (D6), were evaluated in the pelagic marine food web of Tokyo Bay, Japan. Polychlorinated biphenyl (PCB) congeners that are "legacy" chemicals known to bioaccumulate in aquatic organisms and biomagnify across aquatic food webs were used as a benchmark chemical (CB-180) to calibrate the sampled food web and as a reference chemical (CB-153) to validate the results. Trophic magnification factors (TMFs) were calculated from slopes of ordinary least-squares (OLS) regression models and slopes of bootstrap regression models, which were used as robust alternatives to the OLS models.

The chemical exposure toxicity space (CETS) model: Displaying exposure time, aqueous and organic concentration, activity, and onset of toxicity.

A 1-compartment toxicokinetic model is used to characterize the chemical exposure toxicity space (CETS), providing a novel graphic tool that can aid in the design of aquatic toxicity tests for fish and for interpreting their results. The graph depicts the solution to the differential equation describing the uptake kinetics of a chemical by a modeled fish under conventional bioassay conditions. The model relates the exposure concentration in the water to a dimensionless time and the onset of toxicity as determined by an estimated or assumed critical body residue or incipient lethal aqueous concentration.

Combined Deletion of Slc30a7 and Slc30a8 Unmasks a Critical Role for ZnT8 in Glucose-Stimulated Insulin Secretion.

Polymorphisms in the SLC30A8 gene, which encodes the ZnT8 zinc transporter, are associated with altered susceptibility to type 2 diabetes (T2D), and SLC30A8 haploinsufficiency is protective against the development of T2D in obese humans. SLC30A8 is predominantly expressed in pancreatic islet β-cells, but surprisingly, multiple knockout mouse studies have shown little effect of Slc30a8 deletion on glucose tolerance or glucose-stimulated insulin secretion (GSIS). Multiple other Slc30a isoforms are expressed at low levels in pancreatic islets.

Impact of endurance exercise training on adipocyte microRNA expression in overweight men.

Adipocytes are major regulators of metabolism, and endurance exercise training improves adipocyte function; however, the molecular mechanisms that regulate chronic adaptive responses remain unresolved. microRNAs (miRNAs) influence adipocyte differentiation and metabolism. Accordingly, we aimed to determine whether adipocyte miRNA expression is responsive to exercise training and to identify exercise-responsive miRNAs that influence adipocyte metabolism.

Strong terahertz absorption in all-dielectric Huygens' metasurfaces.

We propose an all dielectric metamaterial that acts as a perfect terahertz absorber without a ground plane. The unit cell consists of a dielectric cylinder embedded in a low index material. In order to achieve near-perfect terahertz absorption (99.

Dapagliflozin Binds Specifically to Sodium-Glucose Cotransporter 2 in the Proximal Renal Tubule.

Kidneys contribute to glucose homeostasis by reabsorbing filtered glucose in the proximal tubules sodium-glucose cotransporters (SGLTs). Reabsorption is primarily handled by SGLT2, and SGLT2-specific inhibitors, including dapagliflozin, canagliflozin, and empagliflozin, increase glucose excretion and lower blood glucose levels. To resolve unanswered questions about these inhibitors, we developed a novel approach to map the distribution of functional SGLT2 proteins in rodents using positron emission tomography with 4-[F]fluoro-dapagliflozin (F-Dapa).

An interactive videogame designed to improve respiratory navigator efficiency in children undergoing cardiovascular magnetic resonance.

Background: Advanced cardiovascular magnetic resonance (CMR) acquisitions often require long scan durations that necessitate respiratory navigator gating. The tradeoff of navigator gating is reduced scan efficiency, particularly when the patient's breathing patterns are inconsistent, as is commonly seen in children. We hypothesized that engaging pediatric participants with a navigator-controlled videogame to help control breathing patterns would improve navigator efficiency and maintain image quality.

A hybrid polyketide-nonribosomal peptide in nematodes that promotes larval survival.

Polyketides and nonribosomal peptides are two important types of natural products that are produced by many species of bacteria and fungi but are exceedingly rare in metazoans. Here, we elucidate the structure of a hybrid polyketide-nonribosomal peptide from Caenorhabditis elegans that is produced in the canal-associated neurons (CANs) and promotes survival during starvation-induced larval arrest. Our results uncover a novel mechanism by which animals respond to nutrient fluctuations to extend survival.

Haplotyping the human leukocyte antigen system from single chromosomes.

We describe a method for determining the parental HLA haplotypes of a single individual without recourse to conventional segregation genetics. Blood samples were cultured to identify and sort chromosome 6 by bivariate flow cytometry. Single chromosome 6 amplification products were confirmed with a single nucleotide polymorphism (SNP) array and verified by deep sequencing to enable assignment of both alleles at the HLA loci, defining the two haplotypes.

Optimal configuration of respiratory navigator gating for the quantification of left ventricular strain using spiral cine displacement encoding with stimulated echoes (DENSE) MRI.

Purpose: To determine the optimal respiratory navigator gating configuration for the quantification of left ventricular strain using spiral cine displacement encoding with stimulated echoes (DENSE) MRI.

Materials And Methods: Two-dimensional spiral cine DENSE was performed on a 3 Tesla MRI using two single-navigator configurations (retrospective, prospective) and a combined "dual-navigator" configuration in 10 healthy adults and 20 healthy children. The adults also underwent breathhold DENSE as a reference standard for comparisons.

Fatty acid desaturase 1 knockout mice are lean with improved glycemic control and decreased development of atheromatous plaque.

Delta-5 desaturase (D5D) and delta-6 desaturase (D6D), encoded by fatty acid desaturase 1 (FADS1) and FADS2 genes, respectively, are enzymes in the synthetic pathways for ω3, ω6, and ω9 polyunsaturated fatty acids (PUFAs). Although PUFAs appear to be involved in mammalian metabolic pathways, the physiologic effect of isolated D5D deficiency on these pathways is unclear. After generating >4,650 knockouts (KOs) of independent mouse genes and analyzing them in our high-throughput phenotypic screen, we found that Fads1 KO mice were among the leanest of 3,651 chow-fed KO lines analyzed for body composition and were among the most glucose tolerant of 2,489 high-fat-diet-fed KO lines analyzed by oral glucose tolerance test.

Elastic metamaterials for tuning circular polarization of electromagnetic waves.

Electromagnetic resonators are integrated with advanced elastic material to develop a new type of tunable metamaterial. An electromagnetic-elastic metamaterial able to switch on and off its electromagnetic chiral response is experimentally demonstrated. Such tunability is attained by harnessing the unique buckling properties of auxetic elastic materials (buckliballs) with embedded electromagnetic resonators.

Design and Implementation of High-Throughput Screening Assays.

HTS remains at the core of the drug discovery process, and so it is critical to design and implement HTS assays in a comprehensive fashion involving scientists from the disciplines of biology, chemistry, engineering, and informatics. This requires careful consideration of many options and variables, starting with the choice of screening strategy and ending with the discovery of lead compounds. At every step in this process, there are decisions to be made that can greatly impact the outcome of the HTS effort, to the point of making it a success or a failure.

Investigating the reinforcing value of binge anticipation.

Binge eating is a hallmark feature of several types of eating disorders, including bulimia nervosa, anorexia nervosa (binge/purge type), and binge-eating disorder, and is associated with numerous harmful consequences. For decades, researchers have sought to understand what maintains and reinforces this behavior in the face of such profound negative consequences. In this context, researchers have focused on the binge-eating behavior itself, and given little consideration to what may be a crucial part of the process: anticipating or planning binge-eating episodes.

Behavioral changes in female Asian elephants when given access to an outdoor yard overnight.

A study was conducted at the Bronx Zoo to determine whether providing elephants with access to an outdoor corral at night had any significant effects on behavior, use of space, and use of a sand corral. Activity budgets for three female Asian elephants were compared when the subjects were housed indoors overnight and when they were given access to an outdoor yard overnight. Observations were recorded via infrared video cameras between the hours of 1900 and 0700 during the months of July-September.

Identification of Salmonella for public health surveillance using whole genome sequencing.

In April 2015, Public Health England implemented whole genome sequencing (WGS) as a routine typing tool for public health surveillance of Salmonella, adopting a multilocus sequence typing (MLST) approach as a replacement for traditional serotyping. The WGS derived sequence type (ST) was compared to the phenotypic serotype for 6,887 isolates of S. enterica subspecies I, and of these, 6,616 (96%) were concordant.

Processes influencing chemical biomagnification and trophic magnification factors in aquatic ecosystems: Implications for chemical hazard and risk assessment.

Bioconcentration factors (BCFs) and bioaccumulation factors (BAFs) are widely used in scientific and regulatory programs to assess chemical hazards. There is increasing interest in also using biomagnification factors (BMFs) and trophic magnification factors (TMFs) for this purpose, especially for highly hydrophobic substances that may reach high concentrations in predatory species that occupy high trophic level positions in ecosystems. Measurements of TMFs in specific ecosystems can provide invaluable confirmation that biomagnification or biodilution has occurred across food webs, but their use in a regulatory context can be controversial because of uncertainties related to the reliability of measurements and their regulatory interpretation.

Revisiting the physiological roles of SGLTs and GLUTs using positron emission tomography in mice.

Key Points: Glucose transporters are central players in glucose homeostasis. There are two major classes of glucose transporters in the body, the passive facilitative glucose transporters (GLUTs) and the secondary active sodium-coupled glucose transporters (SGLTs). In the present study, we report the use of a non-invasive imaging technique, positron emission tomography, in mice aiming to evaluate the role of GLUTs and SGLTs in controlling glucose distribution and utilization.

Electrically tunable terahertz metamaterials with embedded large-area transparent thin-film transistor arrays.

Engineering metamaterials with tunable resonances are of great importance for improving the functionality and flexibility of terahertz (THz) systems. An ongoing challenge in THz science and technology is to create large-area active metamaterials as building blocks to enable efficient and precise control of THz signals. Here, an active metamaterial device based on enhancement-mode transparent amorphous oxide thin-film transistor arrays for THz modulation is demonstrated.

IKKβ Is Essential for Adipocyte Survival and Adaptive Adipose Remodeling in Obesity.

IκB kinase β (IKKβ), a central coordinator of inflammatory responses through activation of nuclear factor-κB (NF-κB), has been implicated as a critical molecular link between inflammation and metabolic disorders; however, the role of adipocyte IKKβ in obesity and related metabolic disorders remains elusive. Here we report an essential role of IKKβ in the regulation of adipose remodeling and adipocyte survival in diet-induced obesity. Targeted deletion of IKKβ in adipocytes does not affect body weight, food intake, and energy expenditure but results in an exaggerated diabetic phenotype when challenged with a high-fat diet (HFD).