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As one of the top public health challenges outlined by the Centers for Disease Control (CDC), estimates report that hospital acquired infections (HAIs) claim the lives of 99,000 Americans and cost healthcare providers over $28 billion each year. In addition to underlying conditions related to age, elderly patients in long-term care facilities are at an elevated risk of acquiring HAIs. A large percentage of HAIs is attributable to contaminated surfaces and medical devices. To that end, this study utilized a metatranscriptomic sequencing workflow (CSI-Dx™) to profile active microbial communities from surfaces in the HJ Heinz Community Living Center, a long-term care facility in the Veterans Affairs Pittsburgh Health Care System. Swabs were collected from high-touch surfaces (Keyboard, Ledge, Workstation on Wheels, Worksurfaces) before (Baseline) and after cleanSURFACES

Integrating renewable energy and energy storage systems provides a way of operating the electrical grid system more energy efficiently and stably. Thermal storage and batteries are the most common devices for integration. However, it is not clear which integrated storage system performs better in terms of overall economics. Ice storage has low initial and maintenance costs, but there is an efficiency penalty for charging of storage and it can only shift electrical loads associated with building cooling requirements. A battery's round-trip efficiency, on the contrary, is quite consistent and batteries can be used to shift both HVAC and non-HVAC loads. However, batteries have greater initial costs and a shorter life. This research presents a tool, using model predictive control and optimal sizing, and provides a case study for comparing life-cycle economics of battery and ice storage systems for commercial buildings that have chillers for cooling and an on-site photovoltaic system.

Increased vascularization, also known as neoangiogenesis, plays a major role in many cancers, including glioblastoma multiforme (GBM), by contributing to their aggressive growth and metastasis. Although anti-angiogenic therapies provide some clinical improvement, they fail to significantly improve the overall survival of GBM patients. Since various pro-angiogenic mediators drive GBM, we hypothesized that identifying targetable genes that broadly inhibit multiple pro-angiogenic mediators will significantly promote favorable outcomes. Here, we identified TRAF3IP2 (TRAF3-interacting protein 2) as a critical regulator of angiogenesis in GBM. We demonstrated that knockdown of TRAF3IP2 in an intracranial model of GBM significantly reduces vascularization. Targeting TRAF3IP2 significantly downregulated VEGF, IL6, ANGPT2, IL8, FZGF2, PGF, IL1β, EGF, PDGFRB, and VEGFR2 expression in residual tumors. Our data also indicate that exogenous addition of VEGF partially restores angiogenesis by TRAF3IP2-silenced cells, suggesting that TRAF3IP2 promotes angiogenesis through VEGF- and non-VEGF-dependent mechanisms. These results indicate the anti-angiogenic and anti-tumorigenic potential of targeting TRAF3IP2 in GBM, a deadly cancer with limited treatment options.

Controlling the physical properties of solid forms for active pharmaceutical ingredients (APIs) through cocrystallization is an important part of drug product development. However, it is difficult to know

In this paper, we introduce a real-time modelling approach to predict the heating and cooling energy consumption of each housing unit in multi-family residential buildings. We first present measure...

To test unitary residential cooling equipment with integrated controls and typical load responses, a load-based testing methodology has been developed where a virtual building model is used to emulate building-equipment dynamic interactions. With this approach, the temperature of an environmental chamber that simulates indoor conditions continuously tracks virtual room temperature setpoints that are adjusted based on outputs from the virtual building model. The test equipment thermostat senses the floating air temperature and communicates with the test equipment as if it were installed in the field. In order to achieve realistic dynamic behavior, it is important to properly emulate inlet flow conditions and inlet temperature dynamics provided to the thermostat that are representative of field conditions and that can be reproduced across different test facilities. The goal of the work described in this paper was to develop a thermostat environment emulator for use in load-based testing. The proposed emulator can dynamically control the thermostat inlet air temperature to the virtual room temperature setpoints using thermoelectric devices. Sample test results obtained using the emulator are presented in this paper to demonstrate its ability to track emulated building responses during load-based testing. A description of the design and control of the emulator is provided with sufficient detail to allow future researchers to reproduce it. Additionally, a two-dimensional dynamic model of the thermoelectric conditioning devices is presented that guided the overall design process. This emulator is a basis for a standardized solution for applying load-based testing that is reproducible across different facilities.

In this paper, we present a new unit-level data-driven modelling approach to normalize heating and cooling (HC) energy usage in multi-family residential buildings based on easily accessible data fr...

In the U.S., with about 64% of primary occupied homes having unitary air conditioners, a small improvement in the energy efficiency of residential cooling equipment can lead to significant energy savings. Currently, standardized equipment energy efficiency rating is based on standard AHRI 210/240, that provides a metric for comparing the performance of different equipment. However, it is generally recognized that this approach fails to appropriately rate and credit equipment with advanced controls and variable-speed components. Contrarily, a load-based testing and rating approach is presented in this paper that can capture equipment performance with its integrated controls that is more representative of the field. In this approach, representative building sensible and latent loads are emulated in a psychrometric test facility at different indoor and outdoor test conditions utilizing a virtual building model. The indoor test room conditions are continuously adjusted to emulate the dynamic response of the virtual building to the test equipment sensible and latent cooling rates and the equipment dynamic response is measured. Moreover, an automated testing procedure is presented along with convergence criteria for measuring equipment steady-periodic performance. Climate-specific cooling seasonal performance ratings can be determined by propagating the coefficient of performance (COP) from load-based testing results through a temperature-bin method to estimate a seasonal COP (SCOP). In this work, the proposed approach was implemented to test and rate a variable-speed residential heat pump. Furthermore, the sensitivity of load-based testing results to virtual building parameters was investigated. Finally, repeatability results from the load-based testing approach are presented.

Using a vapor compression cycle for cooling in microgravity environments was already suggested in the 1970s to leverage the high coefficient of performance. Since then, only a few systems have operated in microgravity with scarce documentation of these flights. The lack of measured data and detailed documentation makes identifying the necessary next steps difficult for researchers entering the field of refrigeration in space. This paper provides a review of available literature for vapor compression systems flown in microgravity by outlining the history of vapor compression devices in space and presenting performance data. Moreover, gaps in the literature are highlighted and open questions are posed based on the reviewed material. Next steps of research are suggested to support and ultimately achieve reliable vapor compression refrigeration in space. Calculating equivalent masses for a fair comparison of different microgravity cooling technologies is proposed by capturing both energy consumption and used volume.

Three gene therapy strategies have received US Food and Drug Administration (FDA) approval; one includes HIV-1-based lentiviral vectors. These vectors incorporate features to provide long-term gene transfer and expression while minimizing generation of a replication-competent virus or pathogenicity. Importantly, the coding regions of viral proteins were deleted, and the cis-acting regulatory elements were retained. With the use of representative vectors developed for clinical/commercial applications, we compared the vector backbone sequences to the initial sources of the HIV-1. All vectors included required elements: 5′ long terminal repeat (LTR) through the Ψ packaging signal, central polypurine tract/chain termination sequence (cPPT/CTS), Rev responsive element (RRE), and 3′ LTR, including a poly(A) signal. The Ψ signaling sequence demonstrated the greatest similarity between all vectors with only minor changes. The 3′ LTR was the most divergent sequence with a range of deletions. The RRE length varied between vectors. Phylogenetic analysis of the cPPT/CTS indicated multiple sources, perhaps because of its later inclusion into lentiviral vector systems, whereas other regions revealed node clusters around the HIV-1 reference genomes HXB2 and NL4-3. We examine the function of each region in a lentiviral vector, the molecular differences between vectors, and where optimization may guide development of the lentiviral delivery systems., Graphical abstract, Schematic diagram of the HIV genome and the elements included in lentiviral (LV) vectors. The functional roles of each element in the HIV life cycle and in the LV vectors are discussed. The phylogenetic origin of the various clinical and commercial LV vectors is compared with HIV-1 genomes.

Four solidification methods for self-emulsifying drug delivery systems (SEDDS) were compared to evaluate the impact of solidification on storage stability of an incorporated protein. Papain was loaded in SEDDS via hydrophobic ion pairing (HIP). Liquid SEDDS (l-SEDDS) were either solidified by adsorption to solid excipients such as magnesium-aluminometasilicate via wet granulation (ssilica-SEDDS) and carbohydrates via lyophilisation (scarbo-SEDDS) or by incorporation of high-melting PEG-surfactants (sPEG-SEDDS) and triglycerides (soil-SEDDS) in SEDDS preconcentrates. L- and s-SEDDS were compared regarding intrinsic emulsion properties, solid-state form of papain, enzyme stability and activity during storage. HIP with deoxycholate showed a precipitation efficiency of 82% and papain maintained 90% of its initial activity. Incorporated papain was present in an amorphous state, confirming a molecular dispersion in all preconcentrates. In comparison to l-SEDDS each solidification method investigated improved the storage stability of incorporated papain. Neither precipitation nor phase separation was observed for s-SEDDS. sPEG-SEDDS demonstrated with 87.8% the highest enzymatic activity and displayed according to the following rank order: sPEG-SEDDS > soil-SEDDS > ssilica-SEDDS > scarbo-SEDDS > l-SEDDS the highest remaining papain activity after 30 days of storage. This work clearly demonstrates that solidified SEDDS can provide a significantly improved storage stability for therapeutic proteins compared to corresponding liquid formulations.

CCR5 is a coreceptor of human immunodeficiency virus type 1 (HIV-1). Transplantation of hematopoietic stem cells homozygous for a 32-bp deletion in CCR5 resulted in a loss of detectable HIV-1 in two patients, suggesting that genetic strategies to knockout CCR5 expression would be a promising gene therapy approach for HIV-1-infected patients. In this study, we targeted CCR5 by CRISPR-Cas9 with a single-guide (sgRNA) and observed 35% indel frequency. When we expressed hCas9 and two gRNAs, the Surveyor assay showed that Cas9-mediated cleavage was increased by 10% with two sgRNAs. Genotype analysis on individual clones showed 11 of 13 carried biallelic mutations, where 4 clones had frameshift (FS) mutations. Taken together, these results indicate that the efficiency of biallelic FS mutations and the knockout of the CCR5 necessary to prevent viral replication were significantly increased with two sgRNAs. These studies demonstrate the knockout of CCR5 and the potential for translational development.

To develop an experimental method for routine isolation and short-term culture of primary lymphatic endothelial cells from specific collecting vessels.Lymphatic endothelial cell tubes (LECTs) were isolated from micro-dissected collecting vessels. LECTs were allowed to attach and grow for ~3 weeks before being passaged. Non-purified cultures were partially characterized by immunofluorescence and RT-PCR at passages 1-2.The method was validated in cultures of primary lymphatic endothelial cells (LECs) from male and female mice. After 1 or 2 passages,60% of the LECs maintained expression of Prox1. Expression of 22 different genes was assessed using RT-PCR. Prox1, Vegfr3, eNos, Cdh5, Pecam1, Cx43, Cx37, and Cx47, among others, were expressed in these short-term cultured LECs, while Myh11, Cnn1, Desmin, and Cd11b were not detected. Prox1 expression, as determined by western blotting, was similar in cultured LECs from age-matched male and female mice. Confocal imaging of intracellular calcium in cultures of primary LECs from Cdh5-GCaMP8 mice demonstrated that a functional phenotype was maintained, similar to lymphatic endothelial cells in freshly isolated vessels.This method provides an innovative tool for routine isolation and study of primary LECs from specific collecting lymphatic vessels from any mouse, and in fact, from other species.

Small and medium-sized commercial buildings (SMCB) are significant demand response resources, and it is important to develop grid-responsive control algorithms that exploit those resources and create financial benefits for building owners and HVAC service providers. Furthermore, unlike large-sized commercial buildings, there is an opportunity to have universally applicable control solutions for many SMCBs since those buildings have a consistent HVAC system configuration: SMCBs are commonly served by multiple-staged air conditioning units controlled by their own thermostats. Despite the demand response potential and scalability, however, very few control solutions are available for SMCBs. Typical model predictive control (MPC) and heuristic control approaches for cooling load shifting that lower thermostat setpoints before an electric price jump are suitable mainly for large-sized commercial buildings where a continuous capacity modulation is possible, e.g., via dampers in variable air volume terminal units. However, those approaches can cause undesired, high peaks for SMCBs due to the nature of ON/OFF unit staging and narrow thermostat deadbands. This could discourage the use of advanced grid-responsive controls for SMCBs due to the concern of high demand charges, and has to be resolved. This paper presents a MPC solution that overcomes this challenge. It has a hierarchical MPC structure where an upper level MPC is responsible for electrical load shifting in response to an electric price signal while a lower level MPC is responsible for coordinating compressor stages to eliminate unnecessary peaks and follows the setpoints determined by the upper level MPC. Two one-month, comprehensive laboratory tests have been carried out to demonstrate load shifting and cost savings for the algorithm. Interesting trade-offs between energy efficiency and load flexibility were observed and are discussed, and lessons learned for applying MPCs for SMCBs are also presented.

RNA is the most versatile macromolecule in nature. The linear sequence of an RNA can encode large amounts of complex information that is subsequently transformed into functional proteins. However, many RNA sequences also contain sufficient information to fold themselves into specific shapes with distinct chemical properties. Thus, RNA is unique amongst biopolymers in that it encodes genetic information, provides structural scaffolding, recognizes and transports other molecules and carries out many forms of chemical catalysis in the cell. For example, messenger RNA (mRNA) encodes protein sequences, transfer RNA (tRNA) acts at the ribosome to decode mRNA information to specify particular amino acids, ribosomal RNAs (rRNA) assemble into the ribosome where protein is manufactured, small nuclear RNAs (snRNAs) tailor other RNAs to the proper size and microRNAs (miRNAs) are tiny sequences that bind and regulate the function of other RNAs. In this chapter, we focus on the lives of the many cellular RNA species – how they are generated, modified and regulated and play central roles in the flow of genetic information.

Following the computational prediction that 3-hydroxybenzoic acid (3HBA) could exist in more than the two literature polymorphs, an experimental investigation targeting computationally generated structures was performed. The third polymorph III, solved from powder X-ray diffraction data, and the literature form II share a common hydrogen-bonded ladder motif in contrast to the carboxylic acid dimer based form I. The two metastable polymorphs (II and III) are storage stable if phase pure and monotropically related to form I. Calorimetric measurements and (lattice) energy minimisations revealed that the three polymorphs are close in energy.

Previous mode switching algorithms for heat exchanger moving boundary models in the literature are composed of a set of IF-THEN rules. These representations could lead to numerical challenges due to the inherited discontinuities associated with IF-THEN rules. This paper presents an alternative mode switching methodology which results in a continuous moving boundary heat exchanger model over all possible mode changes. Numerical performance of the proposed method for a heat exchanger has been tested using simulations and sample results are compared with a moving boundary model with switching based on IF-THEN rules and also a finite-volume method. The proposed switching algorithm was implemented within a complete vapor compression cycle model and results were compared with experimental data for a start-up transient.

The internal flow structures of detonation wave were experimentally analyzed in an optically accessible hollow rotating detonation combustor with multiple chamber lengths. The cylindrical RDC has a glass chamber wall, 20 mm in diameter, which allowed us to capture the combustion self-luminescence. A chamber 70 mm in length was first tested using C2H4single bondO2 and H2–O2 as propellants. Images with a strong self-luminescence region near the bottom were obtained, confirming the small extent of the region where most of the heat release occurs as found in our previous research. Based on the visualization experiments, we tested RDCs with shorter chamber walls of 40 and 20 mm. The detonation wave was also observed in the shorter chambers, and its velocity was not affected by the difference in chamber length. Thrust performance was also maintained compared to the longer chamber, and the short cylindrical RDC had the same specific impulse tendency as the cylindrical (hollow) or annular 70-mm chamber RDC. Finally, we calculated the pressure distributions of various chamber lengths, and found they were also consistent with the measured pressure at the bottom and exit. We concluded that the short-chamber cylindrical RDC with equal length and diameter maintained thrust performance similar to the longer annular RDC, further expanding the potential of compact RDCs., Available online 17 August 2020

Many studies have documented that exposure to post event misinformation can lead eyewitnesses to misremember witnessing events they did not see and do so with high confidence. The goal of the present study was to investigate whether reporting of suggested misinformation can be reversed following a correction, and if so, whether misinformation would be more resistant to correction when it serves an explanatory function than when it does not. In two experiments participants witnessed an event, were exposed to a blatantly false suggestion(s) and one week later received a correction followed by a test of their memory for the witnessed event. We found evidence for both the persistence of misinformation following a correction (E1) and the complete reversibility of misinformation effects following a highly salient correction (E2). Although false reporting of the misinformation doubled when it served an explanatory function relative to when it did not (E1 and E2), in both experiments we found no evidence that resistance to correction varied as a function of the misinformation's explanatory role. Our findings suggest that, with a salient correction provided by a credible source, people are capable of updating their knowledge with new information that reverses what they previously thought.

Sex differences in human placenta exist from early pregnancy to term, however, it is unclear whether these differences are driven solely by sex chromosome complement or are subject to differential sex hormonal regulation. Here, we survey the human chorionic villus (CV) transcriptome for sex-linked signatures from 11 to 16 gestational weeks, corresponding to the first window of increasing testis-derived androgen production in male fetuses. Illumina HiSeq RNA sequencing was performed on Lexogen Quantseq 3′ libraries derived from CV biopsies (n = 11 females, n = 12 males). Differential expression (DE) was performed to identify sex-linked transcriptional signatures, followed by chromosome mapping, pathway analysis, predicted protein interaction, and post-hoc linear regressions to identify transcripts that trend over time. We observe 322 transcripts DE between male and female CV from 11 to 16 weeks, with 22 transcripts logFC > 1. Contrary to our predictions, the difference between male and female expression of DE autosomal genes was more pronounced at the earlier gestational ages. In females, we found selective upregulation of extracellular matrix components, along with a number of X-linked genes. In males, DE transcripts centered on chromosome 19, with mitochondrial, immune, and pregnancy maintenance-related transcripts upregulated. Among the highest differentially expressed autosomal genes were CCRL2, LGALS13, and LGALS14, which are known to regulate immune cell interactions. Our results provide insight into sex-linked gene expression in late first and early second trimester developing human placenta and lay the groundwork to understand the mechanistic origins of sex differences in prenatal development.

The benzene, toluene, and xylene (BTX) compounds currently utilized in many building materials and paints have been linked to deleterious health effects, and thus, monitoring the presence of these ...

In comparison with other types of conventional positive displacement compressors for domestic refrigerators, oil-free linear compressors have a number of advantages due to their compactness, low friction, limited number of moving parts, and excellent performance. Limited work was found in the open literature related to comprehensive compressor modeling and model validation of commercially available linear compressors. A comprehensive and generalized simulation model of linear compressors has been recently presented by the same authors. The current paper expands on this work by using experimental data for the simulated compressors to characterize their performance over the operating envelopes and to validate the linear compressor model. The validated model was then used to quantify the major sources of losses and analyze system vibration as well as piston eccentricity, which ultimately could be used to design the next generation of linear compressors.

Commercial samples of strychnine sulfate were used as the starting material in crystallization experiments accompanied by stability studies. Eight hydrate forms (HyA–HyG), including five novel hydrates, were verified. The crystal structures of HyA (“pentahydrate”) and HyF (“hexahydrate”) were determined from single-crystal X-ray diffraction data. HyF was identified as the most stable hydrate at high water activities at room temperature (RT), and HyA and HyC were also found to be stable at ambient conditions. Long-time storage experiments over nearly two decades confirm that these three hydrates are stable at ambient conditions (20–60% relative humidity). The other five hydrates, HyB (“dihydrate”), HyD, HyE, HyG, and HyH, are only observable at the low(est) relative humidity (RH) levels at RT. Some of these latter forms can only exist within a very narrow RH range and are therefore intermediate phases. By applying a range of complementary experimental techniques such as gravimetric moisture sorption analysis, thermal analysis, moisture controlled PXRD measurements, and variable temperature IR spectroscopy in combination with principal component analysis, it was possible to identify the distinct hydrate phases and elucidate their stability and dehydration pathways. The observed (de)hydration routes, HyA ↔ HyB, HyC ↔ HyD ↔ HyE, HyF ↔ HyG ↔ HyH and HyF → HyA ↔ HyB, depended on the initial hydrate form, particle size, and atmospheric conditions. In addition, a transformation from HyC/HyA to HyF occurs at high RH values at RT. The specific moisture and temperature conditions of none of the applied drying regimes yielded a crystalline water-free form, which highlights the essential role of water molecules for the formation and stability of the crystalline strychnine sulfate phases., The complex moisture- and temperature-dependent interconversion pathways and the stability of eight hydrate forms of strychnine sulfate were unraveled by a complementary approach comprising gravimetric moisture (de)sorption analysis, moisture controlled powder X-ray diffraction measurements, thermal analysis, and variable temperature infrared spectroscopy combined with multivariate data treatment. The study highlights the importance of high-resolution, moisture-dependent investigations for gaining insight into the structural reorganization and transient states of hydrates.

Nipple-sparing mastectomy (NSM) has become increasingly popular, given its oncologic safety and preserved nipple areolar complex (NAC) aesthetics. Reconstruction has recently shifted from traditional submuscular (SM) to prepectoral (PP) implant placement. It remains unclear how the plane of implant placement might affect NAC perfusion. Our goal was to assess postoperative outcomes following NSM with SM versus PP implant placement. A retrospective single-institution review was performed of all patients undergoing NSM and immediate breast reconstruction in either the PP or SM plane from January 2015 to June 2019. Clinicopathologic details and 90-day complication rates were collected. SM and PP group complications were compared using Chi square analysis. A total of 288 breasts (160 patients) were included, including SM in 79 cases (44 patients) and PP in 209 cases (116 patients). Clinicopathologic features between groups were similar. Overall, the rate of NAC necrosis was 15.1%, with no differences between the SM and PP cohorts (p = 0.79). In cases of NAC necrosis, there was no difference between the SM and PP groups in return to the operating room for debridement (p = 1.0) or explant (p = 0.33). In our cohort, immediate implant-based reconstruction in the SM and PP planes following NSM was equally safe with respect to postoperative complications and NAC ischemia.

Recently, linear compressor technology has gained increased attention in vapor compression systems due to its compactness and lower frictional losses compared with the conventional reciprocating compressors. Since the absence of the crank-mechanism eliminates the rotation and reduces the side loads on the piston centered inside the cylinder, it is possible to operate the linear compressors without oil lubrication. A number of advantages can be obtained in terms of the refrigerant compatibility, operation conditions and the system cost. In order to enable oil-free operation, while minimizing frictional losses and leakage flow between the piston and the cylinder wall, a gas bearing approach is applied. Little work was found in the open literature related to the numerical analysis of gas bearings coupled with a comprehensive dynamic linear compressor model. This paper presents a 1-D gas bearing model based on a Finite Volume Method (FVM) applied to a linear compressor. The dynamic characteristics of the gas bearings on the gas film pressure field are analyzed using the model. When integrated together with a comprehensive dynamic linear compressor model, it is possible to predict leakage and frictional losses within the compressor as well as the overall performance.

This paper presents a near-optimal control algorithm for minimizing energy costs in hybrid cooling plants in response to cooling loads. The approach is based upon an approximate solution to the par...

BACKGROUND: The Mayo Clinic imaging classification of autosomal dominant polycystic kidney disease (ADPKD) uses height-adjusted total kidney volume (htTKV) and age to identify patients at highest risk for disease progression. However, this classification applies only to patients with typical diffuse cystic disease (class 1). Because htTKV poorly predicts eGFR decline for the 5%–10% of patients with atypical morphology (class 2), imaging-based risk modeling remains unresolved. METHODS: Of 558 adults with ADPKD in the HALT-A study, we identified 25 patients of class 2A with prominent exophytic cysts (class 2Ae) and 43 patients of class 1 with prominent exophytic cysts; we recalculated their htTKVs to exclude exophytic cysts. Using original and recalculated htTKVs in association with imaging classification in logistic and mixed linear models, we compared predictions for developing CKD stage 3 and for eGFR trajectory. RESULTS: Using recalculated htTKVs increased specificity for developing CKD stage 3 in all participants from 82.6% to 84.2% after adjustment for baseline age, eGFR, BMI, sex, and race. The predicted proportion of class 2Ae patients developing CKD stage 3 using a cutoff of 0.5 for predicting case status was better calibrated to the observed value of 13.0% with recalculated htTKVs (45.5%) versus original htTKVs (63.6%). Using recalculated htTKVs reduced the mean paired difference between predicted and observed eGFR from 17.6 (using original htTKVs) to 4.0 ml/min per 1.73 m(2) for class 2Ae, and from −1.7 (using original htTKVs) to 0.1 ml/min per 1.73 m(2) for class 1. CONCLUSIONS: Use of a recalculated htTKV measure that excludes prominent exophytic cysts facilitates inclusion of class 2 patients and reclassification of class 1 patients in the Mayo classification model.

Tissue engineering is limited by the time of culture expansion of cells needed for scaffold seeding. Thus, a simple means of accelerated stem cell proliferation could represent a significant advance. Here, Nebivolol was investigated for its effect on the replicative capacity of adipose-derived stem cells (ASCs). This study indicates that the number of ASCs with Nebivolol treatment showed a significant population increase of 51.5% compared to untreated cells (p

Developing a computationally efficient but accurate building energy simulation (BES) model is important for many purposes. Model order reduction (MOR) methods are attractive and much more reliable ...

This paper presents the application of a multi-agent control methodology to large chiller plants. The approach, originally conceived to automate controller design and reduce engineering costs in bu...

Building audits are conducted in many commercial buildings to identify opportunities to reduce energy costs and improve building operation. Because audits require significant effort by building eng...

Numerous studies provide estimates of nesting propensity rates (proportion of females attempting to nest at least once in a given year) for greater sage-grouse Centrocercus urophasianus. However, females may initiate nests without being detected during the course of normal research, leading to negatively biased estimates. We evaluated nesting propensity rates (rate of females laying ≥1 egg/y) by examining ovaries from 941 female sage-grouse collected at hunter-check stations in North Park, Colorado, during 1975–1984. Mean rate estimates of nesting propensity were lower for yearlings (0.926, 95% CI = 0.895–0.948) than adults (0.964, 95% CI = 0.945–0.978). We did not attempt to estimate laying rates (number of eggs laid per year) because they were likely unreliable. Nesting success—estimated as the probability of females producing a successful clutch in a given year based on primary feather replacement from hunter-harvested wings—was lower for yearlings (0.398, 95% CI = 0.370–0.427) than adults (0.571, 95% CI = 0.546–0.596). There were more chicks per female produced when nesting propensity rates were high, indicating nesting propensity rates correlate with the number of juveniles in the autumn population. Both nesting propensity rates and nesting success were positively related to precipitation during the lekking and brood-rearing seasons, respectively. Nesting propensity rates were positively related to spring abundance (as measured from annual lek counts), but nesting success was unrelated to spring abundance. A range-wide estimate of an unadjusted, apparent nesting propensity rate available from a previous study was approximately 7% lower than the North Park population. Postovulatory follicles provide a direct source of information on nesting propensity rates estimated from hunter-harvested sage-grouse. These estimated rates may prove useful to gain insights into annual variation of hunted populations' reproductive efforts.

In this paper, the first open-source generalized simulation framework for positive displacement machines (PDSim) reported in literature is employed to model different compressor and expander types. In particular, it is shown how PDSim handles specific numerical and modeling aspects common to positive displacement machines such as stiffness of differential equations, discontinuous volume curves, leakage flow models, in-chamber and shell heat transfer models, mechanical and frictional losses. A control volume approach based on a set of differential equations is used to predict the performance of different positive displacement machines under steady-periodic operations. Reciprocating, scroll, and two rotary compressors as well as a single-screw expander have been considered as examples. The source code of PDSim with examples are provided as an electronic annex.

A novel generalized framework is presented that can be used to simulate the quasi-steady-state performance of a wide range of positive displacement compressors and expanders (scroll, piston, screw, rotary, spool, etc.). The complete simulation algorithm is described, and an emphasis is placed on the numerical methods required to obtain robust behavior of the simulation. This formulation has been implemented into an open-source software package entitled PDSim written in the Python language. PDSim is the first open-source generalized compressor and expander simulation package and the complete source code is included in the Supplemental material. A piston expander is used as an example of the utilization of this framework. The framework has been applied to several positive displacement machines in the companion paper in order to demonstrate the flexibility of the approach (Ziviani et al., 2019).

Management of cleft lip and palate has been well characterized in pediatric patients, but limited data exist regarding the long-term functional outcomes of cleft patients once they reach adulthood.An institutional, cross-sectional survey of adult patients with a history of cleft lip and/or palate was performed. The survey recorded patient characteristics, concerns, and barriers to care. Patient-reported outcome measures were assessed using the Nasal Obstruction Symptom Evaluation Scale, Epworth Sleepiness Scale, Mandibular Function Impairment Questionnaire, and the CLEFT-Q Speech Modules.A total of 63 patients (18.2%) participated in the survey. The mean patient age was 43.7 years (median: 41 y, range: 19-93 y), and the most common diagnosis was cleft lip and palate (51%) followed by isolated cleft palate (35%) and isolated cleft lip (14%). A subset of patients scored with moderate to severe dysfunction on each outcome measure including the Nasal Obstruction Symptom Evaluation Instrument (59%), Epworth Sleepiness Scale (7%), and Mandibular Function Impairment Questionnaire (13%). Respondent scores on the CLEFT-Q Speech modules demonstrated a bimodal distribution with lower scores in a significant subset of patients with cleft palate and cleft lip and palate. Many respondents (41%) were interested in clinical evaluation but cited barriers to seeking treatment including financial barriers (35%) or lack awareness of clinical options (27%).Many cleft patients have persistent needs or concerns in adulthood, especially regarding speech and nasal breathing. Systemic barriers pose challenges to these patients undergoing clinical evaluation.

Transplanting HIV-1 positive patients with hematopoietic stem cells homozygous for a 32 bp deletion in the chemokine receptor type 5 (CCR5) gene resulted in a loss of detectable HIV-1, suggesting genetically disrupting CCR5 is a promising approach for HIV-1 cure. Targeting the CCR5-locus with CRISPR-Cas9 was shown to decrease the amount of CCR5 expression and HIV-1 susceptibility in vitro as well as in vivo. Still, only the individuals homozygous for the CCR5-Δ32 frameshift mutation confer complete resistance to HIV-1 infection. In this study we introduce a mechanism to target CCR5 and efficiently select for cells with biallelic frameshift insertion, using CRISPR-Cas9 mediated homology directed repair (HDR). We hypothesized that cells harboring two different selectable markers (double positive), each in one allele of the CCR5 locus, would carry a frameshift mutation in both alleles, lack CCR5 expression and resist HIV-1 infection. Inducing double-stranded breaks (DSB) via CRISPR-Cas9 leads to HDR and integration of a donor plasmid. Double-positive cells were selected via fluorescence-activated cell sorting (FACS), and CCR5 was analyzed genetically, phenotypically, and functionally. Targeted and selected populations showed a very high frequency of mutations and a drastic reduction in CCR5 surface expression. Most importantly, double-positive cells displayed potent inhibition to HIV-1 infection. Taken together, we show that targeting cells via CRISPR-Cas9 mediated HDR enables efficient selection of mutant cells that are deficient for CCR5 and highly resistant to HIV-1 infection.

RATIONALE: Recent guidelines consider chronic cough to be a unique clinical entity with different phenotypes. We aimed to investigate them in a general population and to describe prevalence, distribution, and characteristics of these phenotypes within the Austrian general population.METHODS: From the LEAD study, a longitudinal observational population-based cohort, data from questionnaires and spirometry of 10,057 adult participants was analysed. Chronic cough was defined as coughing nearly every day during the last 12 months for at least 3 months (>12 weeks).RESULTS: The prevalence of chronic cough was 9% and increased with age. We found no sex predominance but a female preponderance (68%) in never smokers. A presumable cause was identified in 85% of which more than half (53.9%) had two phenotypes, 36.9% belonged to one only and 9.2% to three or more. Regarding the distribution of phenotypes, 40.8% were current smokers, 32.6% had an ACE inhibitor intake, 18.2% GERD, 17.6% asthmatic cough, 9.7% UACS and 28.3% other diseases associated with chronic cough. 15% had unexplained chronic cough with no identifiable phenotype. Current smoking, low socioeconomic status, obesity, COPD and obstructive sleep apnea were associated factors with chronic cough.CONCLUSION: Chronic cough is common among adults in Austria and highly prevalent in the older population. Most participants can be phenotyped with simple questionnaire-based assessment and can therefore potentially receive specific treatment without intensive clinical workup.

Control over polymorphism and solvatomorphism in API assisted by structural information, e.g., molecular conformation or associations via hydrogen bonds, is crucial for the industrial development of new drugs, as the crystallization products differ in solubility, dissolution profile, compressibility, or melting temperature. The stability of the final formulation and technological factors of the pharmaceutical powders further emphasize the importance of precise crystallization protocols. This is particularly important when working with highly flexible molecules with considerable conformational freedom and a large number of hydrogen bond donors or acceptors (e.g., fluconazole, FLU). Here, cooling and suspension crystallization were applied to access polymorphs and solvates of FLU, a widely used azole antifungal agent with high molecular flexibility and several reported polymorphs. Each of four polymorphic forms, FLU I, II, III, or IV, can be obtained from the same set of alcohols (MeOH, EtOH, isPrOH) and DMF via careful control of the crystallization conditions. For the first time, two types of isostructural channel solvates of FLU were obtained (nine new structures). Type I solvates were prepared by cooling crystallization in Tol, ACN, DMSO, BuOH, and BuON. Type II solvates formed in DCM, ACN, nPrOH, and BuOH during suspension experiments. We propose desolvation pathways for both types of solvates based on the structural analysis of the newly obtained solvates and their desolvation products. Type I solvates desolvate to FLU form I by hydrogen-bonded chain rearrangements. Type II solvates desolvation leads first to an isomorphic desolvate, followed by a phase transition to FLU form II through hydrogen-bonded dimer rearrangement. Combining solvent-mediated phase transformations with structural analysis and solid-state NMR, supported by periodic electronic structure calculations, allowed us to elucidate the interrelations and transformation pathways of FLU.

BackgroundThe diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property.MethodsHere we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid, or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes. We explored a gene similarity approach for novel gene discovery and investigated unsolved cases from the 100,000 Genomes Project.ResultsWe found that genes in the early gestation lethal category have distinct characteristics and are enriched for genes linked with recessive forms of inherited metabolic disease. We identified several genes sharing multiple features with known biallelic forms of inborn errors of the metabolism and found signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes in patients recruited under this disease category. We highlight two novel gene candidates with phenotypic overlap between the patients and the mouse knockouts.ConclusionsInformation on the developmental period at which embryonic lethality occurs in the knockout mouse may be used for novel disease gene discovery that helps to prioritise variants in unsolved rare disease cases.