Analysis and prediction of effectiveness for residential HVAC ductwork

An analysis of residential HVAC ductwork has been performed. Ductwork in 55 homes in Northern Louisiana was tested to determine duct leakage by means of using various measurement techniques to determine the differences between the existing methods as well as the revised method developed in this project referred to as Generalized Subtraction Correction Algorithm (GSCA). A protocol to measure and estimate return leaks at operating pressure was developed. The weighted average return leakage for the homes sampled was determined to be 115 cfm at operating pressure whereas the weighted average duct leakage was determined to be 348 cfm at 25 Pa. A methodology for determining supply leaks at operating pressure based on the input from the return leaks was also derived. Annual energy savings by sealing duct leaks was determined using both REM/Rate™ and a new protocol developed by combining REM/Rate™ and ASHRAE™ 152. These protocols gave substantially different results and the reasons for using the newly developed protocol are presented. Using the combined protocol, the average annual heating and cooling cost per home due to duct leakage was determined to be $347. Homes were also tested for duct leaks in both pressurization and depressurization mode to determine whether the measurements differed. A statistical test on these differences indicates that there are reservations in using these two modes interchangeably. Additionally, the data was statistically analyzed to determine various correlations between various measured and derived parameters

Glycogen Synthase Kinase-3: a Role in Ageing and Metabolism

Programa de Doctorado en Biotecnología, Ingeniería y Tecnología QuímicaLínea de Investigación: Modelos Animales en Biotecnología y BiomedicinaClave Programa: DBICódigo Línea: 22Prohibitins (PHBs) are a class of conserved mitochondrial proteins that profoundly influence ageing. PHB depletion shortens the lifespan of wild type animals, while it causes a dramatic extension in metabolically compromised daf-2(e1370) mutants. This opposing lifespan phenotype is attributed to alterations in mitochondrial function and metabolism, but the exact function of PHBs is yet to be deciphered. This project was developed to better understand the function of the essential mitochondrial prohibitins in the regulation of ageing. To elucidate novel signalling mechanisms mediating the metabolic adjustments that lead to opposite ageing outcomes in response to PHB depletion, we performed a kinase RNAi screen using prohibitin deletion mutants. First, we characterized prohibitin deletion mutants. As these mutants are sterile, they are maintained balanced heterozygous. We accomplished a sorting protocol for selection of homozygous PHB mutants. We used vital Nile Red (NR) staining as a read-out as PHB depletion reduces NR staining. In order to quantify the intensity of NR staining, we developed an image analysis protocol. From the screen, we identified the conserved Glycogen Synthase Kinase-3 (GSK-3), as a strong suppressor of the reduced NR staining phenotype caused by prohibitin deletion mutants. Beyond its role as a regulator of insulin-dependent glycogen synthesis, GSK-3 also controls critical cellular functions. We investigated how GSK-3 influences longevity in conditions of compromised insulin signalling and mitochondrial impairment. We demonstrate that GSK-3 depletion decreases wild type lifespan but does not affect phb-2 mutants. However, the long lived daf-2 and phb-2;daf-2 mutants show strong suppression in lifespan upon loss of GSK-3. We show that GSK-3 is ubiquitously expressed via CRISPR-Cas9 endogenous gene tagging. We examined several parameters, including alterations in energy stores - glycogen/triglycerides, mitochondrial respiration and lipid composition to deduce how metabolic alterations upon GSK-3 depletion influence lifespan and found that these varied in a genetic background specific manner. Additionally, we also prove that the activity of GSK-3 is essential in the intestine for normal ageing and especially for the long lived daf-2 mutants. Our data thus, delineates a novel role for GSK-3 in metabolism and its interplay with IIS and mitochondrial metabolism in ageing regulation.Universidad Pablo de Olavide de Sevilla. Departamento de Biología Molecular e Ingeniería BioquímicaPostprin

Combined flow cytometry and high-throughput image analysis for the study of essential genes in Caenorhabditis elegans

Background: Advances in automated image-based microscopy platforms coupled with high-throughput liquid workflows have facilitated the design of large-scale screens utilising multicellular model organisms such as Caenorhabditis elegans to identify genetic interactions, therapeutic drugs or disease modifiers. However, the analysis of essential genes has lagged behind because lethal or sterile mutations pose a bottleneck for high-throughput approaches, and a systematic way to analyse genetic interactions of essential genes in multicellular organisms has been lacking. Results: In C. elegans, non-conditional lethal mutations can be maintained in heterozygosity using chromosome balancers, commonly expressing green fluorescent protein (GFP) in the pharynx. However, gene expression or function is typically monitored by the use of fluorescent reporters marked with the same fluorophore, presenting a challenge to sort worm populations of interest, particularly at early larval stages. Here, we develop a sorting strategy capable of selecting homozygous mutants carrying a GFP stress reporter from GFP-balanced animals at the second larval stage. Because sorting is not completely error-free, we develop an automated high-throughput image analysis protocol that identifies and discards animals carrying the chromosome balancer. We demonstrate the experimental usefulness of combining sorting of homozygous lethal mutants and automated image analysis in a functional genomic RNA interference (RNAi) screen for genes that genetically interact with mitochondrial prohibitin (PHB). Lack of PHB results in embryonic lethality, while homozygous PHB deletion mutants develop into sterile adults due to maternal contribution and strongly induce the mitochondrial unfolded protein response (UPR mt ). In a chromosome-wide RNAi screen for C. elegans genes having human orthologues, we uncover both known and new PHB genetic interactors affecting the UPR mt and growth. Conclusions: The method presented here allows the study of balanced lethal mutations in a high-throughput manner. It can be easily adapted depending on the user's requirements and should serve as a useful resource for the C. elegans community for probing new biological aspects of essential nematode genes as well as the generation of more comprehensive genetic networks.European Research Council ERC-2011-StG-281691Ministerio de Economía y Competitividad BFU2012–3550

Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors

The age-related loss of protein homeostasis (proteostasis) is at the heart of numerous neurodegenerative diseases. Therefore, finding ways to preserve proteome integrity in aged cells may be a powerful way to promote long-term health. Here, we show that reducing the activity of a highly conserved mitochondrial outer membrane protein, MTCH-1/MTCH2, suppresses age-related proteostasis collapse in Caenorhabditis elegans without disrupting development, growth, or reproduction. Loss of MTCH-1 does not influence proteostasis capacity in aged tissues through previously described pathways but instead operates by reducing CED-4 levels. This results in the sequestration of HSP-90 by inactive CED-3, which in turn leads to an increase in HSF-1 activity, transcriptional remodeling of the proteostasis network, and maintenance of proteostasis capacity with age. Together, our findings reveal a role for programmed cell death factors in determining proteome health and suggest that inhibiting MTCH-1 activity in adulthood may safeguard the aging proteome and suppress age-related diseases

Population distributions in the vibrational deactivation of benzene and benzene-d6. First and second moments derived from two-color infrared fluorescence measurements

Time-resolved two-color infrared fluorescence (IRF) from highly vibrationally excited benzene and benzene-d6 has been used to determine means and variances of the excited molecule population distributions over the majority of the energy range during deactivation via collisional energy transfer to unexcited molecules. These measurements extend the IRF technique to produce information about the first two moments of energy transfer induced population distributions present during the collisional deactivation process. A simple means of analysis of IRF from multiple emission bands is presented, which in principle yields information about higher moments, as well as increasingly precise determination of lower moments. Results from this analysis are independent of any assumed models for collisional energy transfer. In the experiments, simultaneous monitoring of IRF from the C---H (C---D) stretching mode fundamental region at [approximate]3060 cm-1 ([approximate]2290 cm-1) and first overtone region at [approximate]6000 cm-1 ([approximate]4500 cm-1), allows independent observation of two subsets of the total population of excited molecules, each containing the vibrational energy required to emit photons in the observed bands. Similar results are obtained from analysis of the time- and wavelength-resolved [Delta][nu]= -1 C---H stretch emission spectrum of highly excited benzene-h6 as it is deactivated by collisions. The two-color results are shown to provide meaningful information about the first two moments of the energy population distribution over much of the energy range. Knowledge of the population distribution is important since it results directly from the form of Pc(E', E), the step size probability distribution function for collisional energy transfer. Master equation simulations are used together with these results in order to derive some limitations on the possible forms of Pc(E', E).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30588/1/0000225.pd

Impaired wound healing secondary to bevacizumab

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150555/1/iwj13139_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150555/2/iwj13139.pd

Society of pediatric liver transplantation: Current registry status 2011‐2018

BackgroundSPLIT was founded in 1995 in order to collect comprehensive prospective data on pediatric liver transplantation, including waiting list data, transplant, and early and late outcomes. Since 2011, data collection of the current registry has been refined to focus on prospective data and outcomes only after transplant to serve as a foundation for the future development of targeted clinical studies.ObjectiveTo report the outcomes of the SPLIT registry from 2011 to 2018.MethodsThis is a multicenter, cross‐sectional analysis characterizing patients transplanted and enrolled in the SPLIT registry between 2011 and 2018. All patients, <18 years of age, received a first liver‐only, a combined liver‐kidney, or a combined liver‐pancreas transplant during this study period.ResultsA total of 1911 recipients from 39 participating centers in North America were registered. Indications included biliary atresia (38.5%), metabolic disease (19.1%), tumors (11.7%), and fulminant liver failure (11.5%). Greater than 50% of recipients were transplanted as either Status 1A/1B or with a MELD/PELD exception score. Incompatible transplants were performed in 4.1%. Kaplan‐Meier estimates of 1‐year patient and graft survival were 97.3% and 96.6%. First 30 days of surgical complications included reoperation (31.7%), hepatic artery thrombosis (6.3%), and portal vein thrombosis (3.2%). In the first 90 days, biliary tract complications were reported in 13.6%. Acute cellular rejection during first year was 34.7%. At 1 and 2 years of follow‐up, 39.2% and 50.6% had normal liver tests on monotherapy (tacrolimus or sirolimus). Further surgical, survival, allograft function, and complications are detailed.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153657/1/petr13605_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153657/2/petr13605.pd

Population Pharmacokinetics of Olanzapine in Children

Aims The aim of this study was to evaluate the population pharmacokinetics (PopPK) of olanzapine in children and devise a model-informed paediatric dosing scheme. Methods The PopPK of olanzapine was characterized using opportunistically collected plasma samples from children receiving olanzapine per standard of care for any indication. A nonlinear mixed effect modelling approach was employed for model development using the software NONMEM (v7.4). Simulations from the developed PopPK model were used to devise a paediatric dosing scheme that targeted comparable plasma exposures to adolescents and adults. Results Forty-five participants contributed 83 plasma samples towards the analysis. The median (range) postnatal age and body weight of participants were 3.8 years (0.2–19.2) and 14.1 kg (4.2–111.7), respectively. The analysis was restricted to pharmacokinetic (PK) samples collected following enteral administration (oral and feeding tube). A one-compartment model with linear elimination provided an appropriate fit to the data. The final model included the covariates body weight and postmenstrual age (PMA) on apparent olanzapine clearance (CL/F). Typical CL/F and apparent volume of distribution (scaled to 70 kg) were 16.8 L/h (21% RSE) and 663 L (13% RSE), respectively. Developed dosing schemes used weight-normalized doses for children ≤6 months postnatal age or \u3c15 kg and fixed doses for children ≥15 kg. Conclusion We developed a paediatric PopPK model for enterally-administered olanzapine. To our knowledge, this analysis is the first study to characterize the PK of olanzapine in participants ranging from infants to adolescents. Body weight and PMA were identified as influential covariates for characterizing developmental changes in olanzapine apparent clearance

Evaluation of Negation and Uncertainty Detection and its Impact on Precision and Recall in Search

Radiology reports contain information that can be mined using a search engine for teaching, research, and quality assurance purposes. Current search engines look for exact matches to the search term, but they do not differentiate between reports in which the search term appears in a positive context (i.e., being present) from those in which the search term appears in the context of negation and uncertainty. We describe RadReportMiner, a context-aware search engine, and compare its retrieval performance with a generic search engine, Google Desktop. We created a corpus of 464 radiology reports which described at least one of five findings (appendicitis, hydronephrosis, fracture, optic neuritis, and pneumonia). Each report was classified by a radiologist as positive (finding described to be present) or negative (finding described to be absent or uncertain). The same reports were then classified by RadReportMiner and Google Desktop. RadReportMiner achieved a higher precision (81%), compared with Google Desktop (27%; p < 0.0001). RadReportMiner had a lower recall (72%) compared with Google Desktop (87%; p = 0.006). We conclude that adding negation and uncertainty identification to a word-based radiology report search engine improves the precision of search results over a search engine that does not take this information into account. Our approach may be useful to adopt into current report retrieval systems to help radiologists to more accurately search for radiology reports