Search

Sleep is a critical process that is well-conserved across mammalian species, and perhaps most animals, yet its functions and underlying mechanisms remain poorly understood. Identification of genes and pathways that can influence sleep may shed new light on these functions. Genomic screens enable the detection of previously unsuspected molecular processes that influence sleep. In this study, we report results from a large-scale phenotyping study of sleep-wake parameters for a population of single-gene knockout mice. Sleep-wake parameters were measured using a high throughput, non-invasive piezoelectric system called PiezoSleep. Knockout mice generated on a C57BL6/N (B6N) background were monitored for sleep and wake parameters for five days. By analyzing data from over 6000 mice representing 343 single gene knockout lines, we identified 122 genes influencing traits like sleep duration and bout length that have not been previously implicated in sleep, including those that affect sleep only during a specific circadian phase. PiezoSleep also allows assessment of breath rates during sleep and this was integrated as a supplemental tool in identifying aberrant physiology in these knockout lines. Sex differences were evident in both normal and altered sleep behavior. Through a combination of genetic and phenotypic associations, and known QTLs for sleep, we propose a set of candidate genes playing specific roles in sleep. The high “hit rate” demonstrates that many genes can alter normal sleep behaviors through a variety of mechanisms. Further investigation of these genes may provide insight into the pathways regulating sleep, functional aspects of sleep, or indirect potentially pathological processes that alter normal sleep.

Background: FGFR inhibition is a promising and clinically proven therapeutic approach in a number of solid tumors where genetic alterations of FGFR drive oncogenesis. PRN1371 is a highly selective oral, irreversible inhibitor of FGFR1-4 that exhibits high potency in cancer cell lines harboring FGFR alterations, including mutations and fusions. Methods: Part A of this phase 1 open-label, multicenter clinical trial explored ascending doses of PRN1371 in adult patients with advanced solid tumors who had received at least one prior treatment for recurrent, metastatic, and/or locally advanced disease, and for whom no standard therapy options were anticipated to result in a durable remission. The primary objectives were to investigate the safety and tolerability and determine the maximum tolerated dose (MTD). Secondary objectives included determination of the pharmacokinetic (PK) profile. The trial employed a “3 + 3” design, where cohorts of three patients are studied at each dose level until additional patients need to be added to better assess safety. PRN1371 was dosed once or twice daily in continuous, 28-day cycles until disease progression. Elevated serum phosphorus, a known effect of systemic FGFR inhibition, was managed with oral phosphate-binding medications and a low phosphate diet, with dose interruptions and use of acetazolamide if certain thresholds were exceeded. Results: In part A, PRN1371 was administered to 36 patients in cohorts at doses of 15mg, 20mg, 25mg, and 35mg QD as well as BID doses of 15mg and 25mg. The drug has been generally well tolerated. The most common side effect observed was hyperphosphatemia, which was generally managed by administration of phosphate binders, and there were no treatment-related adverse events leading to study drug discontinuation. Five of 36 patients reported treatment-related serious adverse events (SAEs). PRN1371 was well absorbed, exhibited moderate PK variability with minimal accumulation, and was approximately dose proportional between 15 and 35mg doses. Exposure of parent drug in urine exceeded the cellular IC90 at all dose levels, which may be particularly relevant for localized bladder cancer. Part B of the study has been initiated, which will enroll patients with metastatic urothelial cell carcinoma (mUC) with FGFR1, 2, 3, or 4 genetic alterations. Citation Format: Sarina A. Piha-Paul, Cinta Hierro, Ignacio Matos, Valentina Boni, Noah Hahn, Rhonda Bitting, Todd Bauer, Aggarwal Rahul, Funda Meric-Bernstam, Steven Gourlay, Timothy D. Owens, Ken Brameld, Ann Neale, Richard Schwartz, Steve Murray, Sibel Ucpinar, Peter Foote, Eleni Venetsanakos, Josep Tabernero. A phase 1, multicenter, dose-escalation study of PRN1371, an irreversible covalent FGFR1-4 kinase inhibitor, in patients with advanced solid tumors including metastatic urothelial carcinoma (mUC) [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A19.

Both the training data and trained models used in the paper are found here. Dataset description Information for each dataset falls into 3 folders. Filenames portray the dataset split used in the paper that they belong to (eg Training_1.png or Validation_1.png). Ref/*.png: Input image (image before annotation) Seg/*.png: Segmentation image. Values = 0 are background. Values > 0 are mouse. Ell/*.txt: Ellipse-fit data. Data is tab-delimited as follows: X Center of Ellipse (px) Y Center of Ellipse (px) Minor Axis Length of Ellipse (px) Major Axis Length of Ellipse (px) Angle Direction (Degrees). 0 is down with + values going counter-clockwise. Trained Model Description We also release models trained on all the subsets of training data we share. Each trained model was trained using our code over on Github: https://github.com/KumarLabJax/MouseTracking Brief descriptions of the training subsets Please read the associated paper for additional detail. A brief summary of the environment is added here: Standard Open Field Strain Survey We annotated 16234 training and 568 validation images of a single mouse in the same open field. The mouse can be one of multiple coat colors, but visually appears as a black, light-grey, or white color. In the case the mouse���s posture created a poor ellipse-fit, portions of the mouse were removed (such as tail) to enable a good ellipse-fit. 24Hr Open Field Dataset We annotated 2099 training and 93 validation images of a single mouse in the same open field listed above augmented with bedding and a food container. All mice in this experiment appear black on video. There are 2 states, with visible light and with only infrared. The infrared-only imaging contains much higher visual noise. KOMP Open Field Dataset We annotated 1000 training and 83 validation images of a single mouse in JAX���s KOMP2 open field arena. All mice have a black coat color. Test Ground Truth Dataset To test the robustness of our system against conventional trackers that build a background model from multiple frames in a video, we re-sampled video a 20 minute video at 1 frame per second and annotated all the resulting frames (1179-1200 frames). We did this for the 6 environments in the paper of varying difficulty (Black, Gray, Piebald, Albino, 24Hr, KOMP2). The format of this data follows a DataSubset_FrameNumber format instead of Training/Validation_FrameNumber format., {"references":["Geuther, Brian Q., et al. \"Robust mouse tracking in complex environments using neural networks.\" Communications biology 2.1 (2019): 1-11."]}

Since ultraluminous X‐ray sources are typically found in late‐type systems, particularly in interacting or starburst galaxies, they are thought to be associated with young stellar populations. We find a significant population of ULXs in our sample of 94 nearby elliptical and lenticular galaxies, using the superior resolution of the Chandra X‐ray observatory, far exceeding the number expected from background AGN. We show that though some of these ULXs are associated with young stellar populations in the cores of early‐type galaxies, not all of the host galaxies show evidence of recent or ongoing star formation. We suggest that these ULXs come from a variety of sources, some being bright LMXBs, while some of them correspond to nuclei of recently accreted dwarf galaxies.

Our neighbouring galaxy M31 (Andromeda), located 780 kpc away, offers a unique opportunity to study the X‐ray population of a galaxy similar to the Milky Way. We have concentrated our monitoring campaign on following the X‐ray activity of the stellar‐mass black hole candidates, XRNe (X‐Ray Novae), in the central region of M31. Observations are made approximately once a month with Chandra, following up any bright outbursts with HST in order to identify the optical counterparts. Having measurements of the X‐ray and optical luminosities, both in outburst and quiescence, allows for the estimation of a system's orbital period. In this way we have now calculated or constrained this important parameter for 6 systems, and will have a further 6 by the end of the current Chandra cycle. With 12 orbital periods known, it will be possible to compare these values to those of the X‐ray binary population in our own galaxy.

Weibull analysis is a powerful predictive tool for studying failure trends of engineering systems. [1] One noted shortcoming is that traditional techniques require the size of the susceptible population to be known. The method described in this paper allows for estimation of the size of the susceptible population using only failure data and no assumptions about total population size or susceptible portion. In the analysis of failures of mass-produced products, a large amount of failure data may be available, but all the conditions that define the susceptible population may never be known. For example, units with a particular usage condition may be expected to fail over time following a Weibull model, but the number of units subjected to that usage condition may never be known. To assume that the entire population is susceptible to the failure mode would greatly over-predict future failures, and the model could not be used to guide decision-making. By doing a least squares fit to the trend of failures versus time, a Weibull model can be fit to the data and then used to estimate the total number of susceptible units expected in the population. The ability to accurately estimate the size of the susceptible sub-population from failure data will be explored as a function of the size of the data set used, for known sets of failure data. For example, for a failure distribution that has increased, peaked, and then decreased to zero, almost the entire population has failed, so an estimate of the size of the susceptible population from this data is likely to be accurate. On the contrary, for only a few data points that show an increasing failure rate over time, little can be determined. Monte Carlo simulations will be used in order to estimate the error associated with this technique. Our analysis will show that predictions of total susceptible populations become similar to the actual susceptible populations when the predicted mean time to failure (MTTF) from the observed data is shorter than the observation time. In effect, predictions become accurate when it is clear to the observer that the number of failures per unit time has peaked.Copyright © 2007 by ASME

Sjo and Biere have skillfully discussed a topic which is timely since there are intense public demands for more efficiency in the production and delivery of services by local governments, for a reduction in the size of public sector, and for an accompanying reduction in taxes. Community development researchers and extension personnel at land grant universities are concerned that local government officials in smaller cities trying to operate more efficiently may purchase expensive computer hardware and software which have limited applications in local government and may not provide government administrators and voters with useful information for making decisions. A management information system must furnish relevant data in useful form to the right person at the right time for use in management decisions. Computers assist in the process but, as Sjo and Biere explain, the computer itself is not the management information system. To be effective the system must supply administrators with information they need to deliver services efficiently (an "internal" use) and it must transmit information about the cost of the services to the voters (an "external" use). Through the political process the mix and level of services can be adjusted so. that the total utility of the community is maximized. There are levels of sophistication of computerized management information systems. At the first level the computer does what was formerly done by hand or with noncomputerized equipment. Even though the size of the application might be quite large, this is still the lowest level of computer utilization. In this mode the computer functions as a high-speed adding machine and typewriter. At the second level the computer is used to automate a portion of an agency's work. This includes the use of the computer as a low level decision maker in those instances where all the factors needed to make a decision can be