Recruitment of Brown Adipose Tissue as a Therapy for Obesity-Associated Diseases

Brown adipose tissue (BAT) has been recognized for more than 20 years to play a key role in cold-induced non-shivering thermogenesis (CIT, NST), and body weight homeostasis in animals. BAT is a flexible tissue that can be recruited by stimuli (including small molecules in animals), and atrophies in the absence of a stimulus. In fact, the contribution of BAT (and UCP1) to resting metabolic rate and healthy body weight homeostasis in animals (rodents) is now well established. Many investigations have shown that resistance to obesity and associated disorders in various rodent models is due to increased BAT mass and the number of brown adipocytes or UCP1 expression in various depots. The recent discovery of active BAT in adult humans has rekindled the notion that BAT is a therapeutic target for combating obesity-related metabolic disorders. In this review, we highlight investigations performed in rodents that support the contention that activation of BAT formation and/or function in obese individuals is therapeutically powerful. We also propose that enhancement of brown adipocyte functions in white adipose tissue (WAT) will also regulate energy balance as well as reduce insulin resistance in obesity-associated inflammation in WAT

Ultrasound enhancement of microfiltration performance for natural organic matter removal

Sonication of water at 1500 W power prior to microfiltration showed that short sonication times (60 s) gave a reduced flux decline. It is suggested that a less potent, smaller molecular form of the natural organic matter (NOM) was produced by sonication. Longer sonication times diminished this beneficial effect. This may be due to the formation of aggregates or compounds that are more readily adsorbed on the membrane. Where the sonication was preceded by an alum treatment, the flux loss showed a regular decrease with longer sonication times. It is suggested that the effects of sonication on the alum flocs and on the flocs; NOM interactions may play a critical role in regulating the flux. Where sand was present on sonication at 800 and 1400 W, the cavitational energy was focussed on adsorbed organic material, resulting in more efficient destruction and the formation of compounds that counteracted the flux enhancement

Brown Fat and Skeletal Muscle: Unlikely Cousins?

Although the functions of white fat and brown fat are increasingly well understood, their developmental origins remain unclear. A recent study published in Nature (Seale et al., 2008) identifies a population of progenitor cells that gives rise to brown fat and skeletal muscle but not white fat

Urinary ATP and visualization of intracellular bacteria: a superior diagnostic marker for recurrent UTI in renal transplant recipients?

Renal transplant recipients (RTR) are highly susceptible to urinary tract infections (UTIs) with over 50% of patients having at least one UTI within the first year. Yet it is generally acknowledged that there is considerable insensitivity and inaccuracy in routine urinalysis when screening for UTIs. Thus a large number of transplant patients with genuine urine infections may go undiagnosed and develop chronic recalcitrant infections, which can be associated with graft loss and morbidity. Given a recent study demonstrating ATP is released by urothelial cells in response to bacteria exposure, possibly acting at metabotropic P2Y receptors mediating a proinflammatory response, we have investigated alternative, and possibly more appropriate, urinalysis techniques in a cohort of RTRs.Mid-stream urine (MSU) samples were collected from 53 outpatient RTRs. Conventional leukocyte esterase and nitrite dipstick tests, and microscopic pyuria counts (in 1 ?l), ATP concentration measurements, and identification of intracellular bacteria in shed urothelial cells, were performed on fresh unspun samples and compared to ‘gold-standard’ bacterial culture results.Of the 53 RTRs, 22% were deemed to have a UTI by ‘gold-standard’ conventional bacteria culture, whereas 87%, 8% and 4% showed evidence of UTIs according to leukocyte esterase dipstick, nitrite dipstick, and a combination of both dipsticks, respectively. Intracellular bacteria were visualized in shed urothelial cells of 44% of RTRs, however only 1 of the 23 RTRs (44%) was deemed to have a UTI by conventional bacteria culture. A significant association of the ‘gold-standard’ test with urinary ATP concentration combined with visualization of intracellular bacteria in shed urothelial cells was determined using the Fisher’s exact test.It is apparent that standard bedside tests for UTIs give variable results and that seemingly quiescent bacteria in urothelial cells are very common in RTRs and may represent a focus of subclinical infection. Furthermore, our results suggest urinary ATP concentration combined with detection of intracellular bacteria in shed urinary epithelial cells may be a sensitive means by which to detect ‘occult’ infection in RTRs

Binding of Solvated Peptide (EPLQLKM) With a Graphene Sheet Via Simulated Coarse-Grained Approach

Binding of a solvated peptide A1 (1E 2P 3L 4Q 5L 6K 7M) with a graphene sheet is studied by a coarse-grained computer simulation involving input from three independent simulated interaction potentials in hierarchy. A number of local and global physical quantities such as energy, mobility, and binding profiles and radius of gyration of peptides are examined as a function of temperature (T). Quantitative differences (e.g., the extent of binding within a temperature range) and qualitative similarities are observed in results from three simulated potentials. Differences in variations of both local and global physical quantities suggest a need for such analysis with multiple inputs in assessing the reliability of both quantitative and qualitative observations. While all three potentials indicate binding at low T and unbinding at high T, the extent of binding of peptide with the temperature differs. Unlike un-solvated peptides (with little variation in binding among residues), solvation accentuates the differences in residue binding. As a result the binding of solvated peptide at low temperatures is found to be anchored by three residues, 1E, 4Q, and 6K (different from that with the un-solvated peptide). Binding to unbinding transition can be described by the variation of the transverse (with respect to graphene sheet) component of the radius of gyration of the peptide (a potential order parameter) as a function of temperature

An Unsupervised Autoencoder Developed from Dynamic Contrast-Enhanced (DCE)-MRI Datasets for Classification of Acute Tumor Response in an Animal Model

Purpose/Objective(s): Recent studies have shown that vascular parameters of brain tumors derived from DCE-MRI may act as potential biomarkers for radiation-induced acute effects. However, accurate characterization of the spatial regions affected by radiation therapy (RT) remains challenging. Here, we introduce an unsupervised adaptive model for classification and ranking of the RT-affected regions in an animal model of cerebral U-251n tumors. Materials/Methods: Twenty-three immune-compromised-RNU rats were implanted with human U251n cancer cells to form an orthotopic glioma (IACUC #1509). For each rat, 28 days after implantation, two DCE-MRI studies (Dual Gradient Echo, DGE, FOV: 32 × 32 mm2, TR/(TE1-TE2) = 24 ms/(2 ms-4 ms), flip angle = 18°, 400 acquisitions, 1.55 sec interval with Magnevist contrast agent, CA injection at ∼ 24 sec) were performed 24h apart using a 7T MRI scanner. A single 20 Gy stereotactic radiation exposure was performed before the second MRI, which was acquired 1-6.5 hrs after RT. DCE-MRI analysis was done using a model selection technique to distinguish three different brain regions as follows: Normal vasculature (Model 1: No leakage, only plasma volume, vp, is estimated), leaky tumor tissues with no back-flux to the vasculature (Model 2: vp and forward volumetric transfer constant, Ktrans, are estimated), and leaky tumor tissues with back-flux (Model 3: vp, Ktrans, and interstitial volume fraction, ve, are estimated). Normalized time traces of DCE-MRI information (24 pre, and 24 post-RT for each rat, total of 64108 training datasets) of tumors and their soft surrounding normal tissues were extracted from the 3 different model regions. To eliminate high-dimensional data similarity, an unsupervised autoencoder (AE) was trained to map out the model-derived data into a feature space (latent variables, N=10). For each model, the pre and post RT latent variables were compared (by appropriate tests of significance: ANOVA/Welch, CI=95%) to reveal RT-discriminant features. Pearson correlation coefficients were used to compare the decoded data to rank the effect of RT on different models. Results: The time trace of DCE-MRI information of rat brain in normal (Model 1, non-leaky) and highly permeable (Model 3) regions are less impacted by RT (Higher correlation between pre and post RT: r= 0.8518, p\u3c0.0001 and r= 0.9040, p\u3c0.0001 for Model 1 and Model 3, respectively) compared to the peritumoral regions pertaining to Model 2 (r= 0.8077, p\u3c0.0001). Conclusion: This pilot study suggests that among different brain regions, peritumoral zones (infiltrative tumor borders with enhanced rim) are highly affected by RT. Spatial assessment of RT-affected brain regions can play a key role in optimization of treatment planning in cancer patients, but presents a challenging task in conventional DCE-MRI. This study represents an important step toward classification and ranking the RT-affected brain spatial regions according to their vascular response following hypofractionated RT

Ablation of TRIP-Br2, a novel regulator of fat lipolysis, thermogenesis and oxidative metabolism, prevents diet-induced obesity and insulin resistance

SUMMARY Obesity develops due to altered energy homeostasis favoring fat storage. Here we describe a novel transcription co-regulator for adiposity and energy metabolism, TRIP-Br2 (also called SERTAD2). TRIP-Br2 null mice are resistant to obesity and obesity-related insulin resistance. Adipocytes of the knockout (KO) mice exhibited greater stimulated lipolysis secondary to enhanced expression of hormone sensitive lipase (HSL) and β3-adrenergic (Adrb3) receptors. The KOs also exhibit higher energy expenditure due to increased adipocyte thermogenesis and oxidative metabolism by up-regulating key enzymes in respective processes. Our data show for the first time that a cell cycle transcriptional co-regulator, TRIP-Br2, modulates fat storage through simultaneous regulation of lipolysis, thermogenesis and oxidative metabolism. These data together with the observation that TRIP-BR2 expression is selectively elevated in visceral fat in obese humans suggests that this transcriptional co-regulator is a novel therapeutic target for counteracting the development of obesity, insulin resistance and hyperlipidemia

The water cycle and regolith-atmosphere interaction at Gale crater, Mars

We perform mesoscale simulations of the water cycle in a region around Gale crater, including the diffusion of water vapour in and out of the regolith, and compare our results with measurements from the REMS instrument on board the Curiosity rover. Simulations are performed at three times of year, and show that diffusion in and out of the regolith and adsorption/desorption needs to be taken into account in order to match the diurnal variation of relative humidity measured by REMS. During the evening and night, local downslope flows transport water vapour down the walls of Gale crater. When including regolith-atmosphere interaction, the amount of vapour reaching the crater floor is reduced (by factors of 2–3 depending on season) due to vapour diffusing into the regolith along the crater walls. The transport of vapour into Gale crater is also affected by the regional katabatic flow over the dichotomy boundary, with the largest flux of vapour into the regolith initially occurring on the northern crater wall, and moving to the southern wall by early morning. Upslope winds during the day transport vapour desorbing and mixing out of the regolith up crater walls, where it can then be transported a few hundred metres into the atmosphere at convergence boundaries. Regolith-atmosphere interaction limits the formation of surface ice by reducing water vapour abundances in the lower atmosphere, though in some seasons ice can still form in the early morning on eastern crater walls. Subsurface ice amounts are small in all seasons, with ice only existing in the upper few millimetres of regolith during the night. The results at Gale crater are representative of the behaviour at other craters in the mesoscale domain

Early and efficient detection of Mycobacterium tuberculosis in sputum by microscopic observation of broth cultures.

Early, efficient and inexpensive methods for the detection of pulmonary tuberculosis are urgently needed for effective patient management as well as to interrupt transmission. These methods to detect M. tuberculosis in a timely and affordable way are not yet widely available in resource-limited settings. In a developing-country setting, we prospectively evaluated two methods for culturing and detecting M. tuberculosis in sputum. Sputum samples were cultured in liquid assay (micro broth culture) in microplate wells and growth was detected by microscopic observation, or in Löwenstein-Jensen (LJ) solid media where growth was detected by visual inspection for colonies. Sputum samples were collected from 321 tuberculosis (TB) suspects attending Bugando Medical Centre, in Mwanza, Tanzania, and were cultured in parallel. Pulmonary tuberculosis cases were diagnosed using the American Thoracic Society diagnostic standards. There were a total of 200 (62.3%) pulmonary tuberculosis cases. Liquid assay with microscopic detection detected a significantly higher proportion of cases than LJ solid culture: 89.0% (95% confidence interval [CI], 84.7% to 93.3%) versus 77.0% (95% CI, 71.2% to 82.8%) (p = 0.0007). The median turn around time to diagnose tuberculosis was significantly shorter for micro broth culture than for the LJ solid culture, 9 days (interquartile range [IQR] 7-13), versus 21 days (IQR 14-28) (p<0.0001). The cost for micro broth culture (labor inclusive) in our study was US $4.56 per sample, versus US$11.35 per sample for the LJ solid culture. The liquid assay (micro broth culture) is an early, feasible, and inexpensive method for detection of pulmonary tuberculosis in resource limited settings