The histone deacetylase inhibiting drug Entinostat induces lipid accumulation in differentiated HepaRG cells

Dietary overload of toxic, free metabolic intermediates leads to disrupted insulin signalling and fatty liver disease. However, it was recently reported that this pathway might not be universal: depletion of histone deacetylase (HDAC) enhances insulin sensitivity alongside hepatic lipid accumulation in mice, but the mechanistic role of microscopic lipid structure in this effect remains unclear. Here we study the effect of Entinostat, a synthetic HDAC inhibitor undergoing clinical trials, on hepatic lipid metabolism in the paradigmatic HepaRG liver cell line. Specifically, we statistically quantify lipid droplet morphology at single cell level utilizing label-free microscopy, coherent anti-Stokes Raman scattering, supported by gene expression. We observe Entinostat efficiently rerouting carbohydrates and free-fatty acids into lipid droplets, upregulating lipid coat protein gene Plin4, and relocating droplets nearer to the nucleus. Our results demonstrate the power of Entinostat to promote lipid synthesis and storage, allowing reduced systemic sugar levels and sequestration of toxic metabolites within protected protein-coated droplets, suggesting a potential therapeutic strategy for diseases such as diabetes and metabolic syndrome

Fertilization in Broadcast-Spawning Corals of the Flower Garden Banks National Marine Sanctuary

Broadcast spawning is considered to be the dominant reproductive strategy for reef corals, but little is known about two critical postspawning processes, fertilization and early larval development. Instead, most efforts have focused on dispersal and recruitment. Since 1993, we have examined coral fertilization and development at the Flower Garden Banks, which contain two isolated reefs with predictable and dramatic annual mass spawning events in the northwestern Gulf of Mexico. Observations of in vitro fertilization indicate that the hermaphroditic scleractinian species Colpophyllia natans, Diploria strigosa, Monfastraea faveolata, and M. franksi all have high fertilization potentials when outcrossing. However, although D. strigosa can self-fertilize readily, self-fertilization levels within C. natans and the Montastraea species are low. In addition, interspecific crossing attempts among the hermaphroditic species of Montastraea (M. franksi, M. faveolata, and M. annularis) yielded low levels of fertilization. The differences observed in the timing of spawning and the low hybridization success between the Montastraea siblings lend additional support to their recent reclassification as separate species. Spawned egg samples collected immediately upon release from female colonies of the gonochoric species M. cavernosa and Stephanocoenia intersepta produced an unexpected observation—very high levels of fertilization. This suggests internal fertilization prior to egg release, a process that has not heretofore been observed in a broadcast-spawning scleractinian

Tight Temporal Consistency of Coral Mass Spawning at the Flower Garden Banks, Gulf of Mexico, from 1997-2003

Mass spawning by the hard corals of the Flower Garden Banks National Marine Sanctuary has been studied for over a decade. In this report we present observations by a single set of experienced observers on spawning events extending over seven years, on spawning activity, lack of activity and coordination within and between species. This compilation shows that the spawning times of each species are extremely consistent during major events, with onset and hiatus often predictable to within seven minutes, and in some species to within two minutes. In addition to the extraordinary degree of temporal regulation, the other striking feature of the spawning schedule is the uniqueness of most spawning windows. With the exception of Diploria strigosa, each of the major spawning species—Colpophyllia natans, Montrastraea cavernosa, M. annularis, M. faveolata, M. franksi and Stephanocoenia intersepta—has a unique window of time in which it and no other coral species releases gametes. Spawning times for the 2005-2008 seasons are predicted based on these findings

PERFORMANCE DETERMINING FACTORS IN ELITE SPRINTERS DURING SPRINT START AND TWO FOLLOWING SUCCESSIVE SUPPORTS

Sprint start out of the blocks and successive acceleration are technically challenging as the athlete goes from a bended to a forward leaning position. Therefore, the body center of mass (COM) has to be accelerated forward and upwards. Optimal sprinting performance relies on attaining maximal forward acceleration. However, adequate vertical acceleration must be generated to reach sufficient height to prepare for the following step (Weyand, 2000). Horizontal acceleration is mainly determined by the horizontal ground reaction force that will affect sprint velocity and therefore final sprint performance (Mero, 1988). Kinematics and kinetics of the start action and maximal sprinting were intensively studied; however little is known on the transition from the set position to the running position during the first two strides. This study aims to identify the factors in the start action as well as in the first and second contact after block clearance that determine sprinting performance in terms of speed and acceleration

The effect of paternalistic alternatives on attitudes toward default nudges

Nudges are increasingly being proposed and used as a policy tool around the world. The success of nudges depends on public acceptance. However, several questions about what makes a nudge acceptable remain unanswered. In this paper, we examine whether policy alternatives to nudges influence the public's acceptance of these nudges: Do attitudes change when the nudge is presented alongside either a more paternalistic policy alternative (legislation) or a less paternalistic alternative (no behavioral intervention)? In two separate samples drawn from the Swedish general public, we find a very small effect of alternatives on the acceptability of various default nudges overall. Surprisingly, we find that when the alternative to the nudge is legislation, acceptance decreases and perceived intrusiveness increases (relative to conditions where the alternative is no regulation). An implication of this finding is that acceptance of nudges may not always automatically increase when nudges are explicitly compared to more paternalistic alternatives

Blood lactate levels in 31 female dogs with pyometra

<p>Abstract</p> <p>Background</p> <p>Canine pyometra is a life-threatening disease common in countries where spaying of dogs is not routinely performed. The disease is associated with endotoxemia, sepsis, systemic inflammatory response syndrome (SIRS) and a 3–4% mortality rate. Blood lactate analysis is clinically valuable in predicting prognosis and survival, evaluating tissue perfusion and treatment response in human and veterinary critical care settings. The aims of the present study were to investigate 1) the blood lactate levels of female dogs with pyometra by a hand-held analyser and 2) if these levels are related with the clinical status or other biochemical or hematological disorders.</p> <p>Methods</p> <p>In total 31 female dogs with pyometra admitted for surgical ovariohysterectomy and 16 healthy female control dogs were included in the present study. A complete physical examination including SIRS-status determination was performed. Blood samples for lactate concentrations, hematological and biochemical parameters, acid-base and blood gas analysis and other laboratory parameters were collected and subsequently analysed. The diagnosis pyometra was verified with histopathological examination of the uterus and ovaries. Increased hospitalisation length and presence of SIRS were used as indicators of outcome.</p> <p>Results</p> <p>In the pyometra group the median blood lactate level was 1,6 mmol l^-1(range <0.8–2.7 mmol l^-1). In the control group the median lactate level was 1,2 mmol l^-1(range <0.8–2.1 mmol l^-1). Of the 31 bitches 19 (61%) fulfilled 2 or more criteria for SIRS at inclusion, 10 bitches (32%) fulfilled 3 of the SIRS criteria whereas none accomplished more than 3 criteria. Lactate levels did not differ significantly between the pyometra and control group, or between the SIRS positive and SIRS negative dogs with pyometra. Increased lactate concentration (>2.5 mmol l^-1) was demonstrated in one female dog with pyometra (3%), and was not associated with longer hospitalisation or presence of SIRS. Lactate measurement was not indicative of peritonitis. None of the bitches died during or within two months of the hospital stay. The measurements of temperature, heart rate, respiratory rate, percentage bandforms of neutrophilic granulocytes, α₂-globulins, creatinin, pvCO₂, TCO₂and base excess showed significant differences between the SIRS positive and the SIRS negative pyometra cases.</p> <p>Conclusion</p> <p>Increased blood lactate concentrations were demonstrated in 3% (1/31), and SIRS was present in 61% (19/31) of the female dogs with pyometra. Preoperative lactate levels were not related with presence of SIRS or prolonged hospitalisation. Lactate measurement was not indicative of peritonitis. The value of a single and repeated lactate analysis in more severely affected cases remains to be determined.</p

Particle Dark Matter Physics: An Update

This write--up gives a rather elementary introduction into particle physics aspects of the cosmological Dark Matter puzzle. A fairly comprehensive list of possible candidates is given; in each case the production mechanism and possible ways to detect them (if any) are described. I then describe detection of the in my view most promising candidates, weakly interacting massive particles or WIMPs, in slightly more detail. The main emphasis will be on recent developments.Comment: Invited talk at the 5th Workshop on Particle Physics Phenomenology, Pune, India, January 1998; 21 pages, LaTeX with equation.st

Mi-2β promotes immune evasion in melanoma by activating EZH2 methylation

Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitive will provide a significant improvement in patient outcome. Here we identify Mi-2β as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Studies in genetically engineered mouse melanoma models indicate that loss of Mi-2β rescues the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq analysis shows that Mi-2β controls the accessibility of IFN-γ-stimulated genes (ISGs). Mi-2β binds to EZH2 and promotes K510 methylation of EZH2, subsequently activating the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2β-targeted inhibitor, Z36-MP5, which reduces Mi-2β ATPase activity and reactivates ISG transcription. Consequently, Z36-MP5 induces a response to immune checkpoint inhibitors in otherwise resistant melanoma models. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones

A robotic wheelchair trainer: design overview and a feasibility study

<p>Abstract</p> <p>Background</p> <p>Experiencing independent mobility is important for children with a severe movement disability, but learning to drive a powered wheelchair can be labor intensive, requiring hand-over-hand assistance from a skilled therapist.</p> <p>Methods</p> <p>To improve accessibility to training, we developed a robotic wheelchair trainer that steers itself along a course marked by a line on the floor using computer vision, haptically guiding the driver's hand in appropriate steering motions using a force feedback joystick, as the driver tries to catch a mobile robot in a game of "robot tag". This paper provides a detailed design description of the computer vision and control system. In addition, we present data from a pilot study in which we used the chair to teach children without motor impairment aged 4-9 (n = 22) to drive the wheelchair in a single training session, in order to verify that the wheelchair could enable learning by the non-impaired motor system, and to establish normative values of learning rates.</p> <p>Results and Discussion</p> <p>Training with haptic guidance from the robotic wheelchair trainer improved the steering ability of children without motor impairment significantly more than training without guidance. We also report the results of a case study with one 8-year-old child with a severe motor impairment due to cerebral palsy, who replicated the single-session training protocol that the non-disabled children participated in. This child also improved steering ability after training with guidance from the joystick by an amount even greater than the children without motor impairment.</p> <p>Conclusions</p> <p>The system not only provided a safe, fun context for automating driver's training, but also enhanced motor learning by the non-impaired motor system, presumably by demonstrating through intuitive movement and force of the joystick itself exemplary control to follow the course. The case study indicates that a child with a motor system impaired by CP can also gain a short-term benefit from driver's training with haptic guidance.</p