bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translating in vitro CFTR rescue into small molecule correctors for cystic fibrosis using the Library of Integrated Network‐based Cellular Signatures drug discovery platform
Authors: Strub Matthew D. , Ramachandran Shyam , Boudko Dmitri Y. , Meleshkevitch Ella A. , Pezzulo Alejandro A. , Subramanian Aravind , Liberzon Arthur , Bridges Robert J. , McCray Paul B. 
Published: December 2021

AbstractCystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The common ΔF508‐CFTR mutation results in protein misfolding and proteasomal degradation. If ΔF508‐CFTR trafficks to the cell surface, its anion channel function may be partially restored. Several in vitro strategies can partially correct ΔF508‐CFTR trafficking and function, including low‐temperature, small molecules, overexpression of miR‐138, or knockdown of SIN3A. The challenge remains to translate such interventions into therapies and to understand their mechanisms. One approach for connecting such interventions to small molecule therapies that has previously succeeded for CF and other diseases is via mRNA expression profiling and iterative searches of small molecules with similar expression signatures. Here, we query the Library of Integrated Network‐based Cellular Signatures using transcriptomic signatures from previously generated CF expression data, including RNAi‐ and low temperature‐based rescue signatures. This LINCS in silico screen prioritized 135 small molecules that mimicked our rescue interventions based on their genomewide transcriptional perturbations. Functional screens of these small molecules identified eight compounds that partially restored ΔF508‐CFTR function, as assessed by cAMP‐activated chloride conductance. Of these, XL147 rescued ΔF508‐CFTR function in primary CF airway epithelia, while also showing cooperativity when administered with C18. Improved CF corrector therapies are needed and this integrative drug prioritization approach offers a novel method to both identify small molecules that may rescue ΔF508‐CFTR function and identify gene networks underlying such rescue.
The sensitivity of probabilistic convective‐scale forecasts of an extratropical cyclone to atmosphere–ocean–wave coupling
Authors: Gentile Emanuele S. , Gray Suzanne L. , Lewis Huw W. 
Published: December 2021

AbstractThe benefits of dynamical atmosphere–ocean–wave coupling in probabilistic weather forecasts generated using convective‐scale ensemble prediction systems are to date unknown. We investigate the respective impacts of atmosphere–ocean–wave coupling, and initial condition (IC), lateral boundary condition (LBC), and stochastic physics perturbations within a convective‐scale ensemble coupled system for an extratropical cyclone case study. Towards this aim, we developed the first 18‐member, 2.2 km grid spacing ensemble regional coupled system (Ensemble‐RCS) with domain covering the British Isles and surrounding seas. Ensemble‐RCS coupled and uncoupled simulations of cyclone (February 2020) were performed. Adding stochastic perturbations to the model physics parametrizations enhances the ensemble spread of the uncoupled atmosphere‐only ensemble driven by IC and LBC perturbations, while slightly reducing (by up to 0.5 ms) the median of the ensemble 95th percentile 10‐m wind speeds from its value of about 24 ms at peak time. A substantial proportion of this impact is attributable to Charnock parameter perturbations alone. By coupling the atmosphere‐only ensemble, with stochastic physics, to the ocean, the ensemble median and spread is mainly unaffected. However, additional coupling to waves reduces the median wind speed by 1 ms, which leads to reductions of up to 70% in strong wind strike probability, and halving of the spatial coverage of high values (>50%) of this probability. Finally, we demonstrate the usefulness of two metrics originally developed for precipitation verification – the neighbourhood‐based Fraction Skill Score (FSS) and the object‐based Structure, Amplitude, Location (SAL) – for examining the spread in convective‐scale ensemble forecasts. It is concluded that coupling has a consistent impact across the ensemble members. Remarkably, the impact of coupling to waves is found to be comparable in size to that of adding IC, LBC and stochastic physics perturbations to the uncoupled atmosphere‐only ensemble simulation, implying that the dynamical coupling to ocean and sea‐state are important aspects of model uncertainty.
Assessing observation network design predictions for monitoring Antarctic surface temperature
Authors: Tardif Robert , Hakim Gregory J. , Bumbaco Karin A. , Lazzara Matthew A. , Manning Kevin W. , Mikolajczyk David E. , Powers Jordan G. 
Published: December 2021

AbstractNetworks of observations ideally provide adequate sampling of parameters to be monitored for climate and weather forecasting applications. This is a challenge for any network, but is particularly difficult in the harsh environment of the Antarctic continent. We evaluate a network design method providing objective information on station siting for optimal sampling of a variable, here taken to be surface air temperature. The method uses the concept of ensemble sensitivity to predict locations reducing the most total ensemble variance, that is, uncertainty, across the continent. The method is applied to a network of frequently‐reporting stations, and validation is performed using results from assimilating station observations. A cost‐efficient “offline” data assimilation framework is used to allow testing over a large sample of experiments, including a large number of randomly chosen networks that serve as a null hypothesis. Network design predictions agree well with observed error reductions from assimilation. The important role of stations on the East Antarctic Plateau in monitoring surface air temperature is evident in network design and data assimilation results, followed by stations in West Antarctica and the Ross Ice Shelf region. Antarctic coastal and Peninsula stations are found to provide the smallest information content integrated over the continent. Validation results are also robust to covariance localization, an essential factor for ensemble methods. Optimal networks outperform randomly chosen‐networks in all cases, by up to nearly 50%, depending on the size of the network and the covariance localization distance.
Effect of hypothyroidism and thyroid autoimmunity on the ovarian reserve: A systematic review and meta‐analysis
Authors: Hasegawa Yuko , Kitahara Yoshikazu , Osuka Satoko , Tsukui Yumiko , Kobayashi Mio , Iwase Akira 
Published: December 2021

AbstractBackgroundEvidence suggests that hypothyroidism and thyroid autoimmunity (TAI) are possibly associated with ovarian dysfunction. This meta‐analysis aimed to investigate whether hypothyroidism and/or TAI affect the ovarian reserve and evaluated using the anti‐Mullerian hormone (AMH).MethodsPubMed, EMBASE, Web of Science, and Cochrane Controlled Trials Register databases from inception to October 2020 were searched to identify relevant studies. Studies comparing the AMH levels between the control and the affected groups were included in the data synthesis. The primary endpoint in the meta‐analysis was AMH levels compared with the controls.Main findingsNine trials were included in the analysis. The AMH levels were significantly lower in the adults with euthyroid TAI (mean difference −0.12, [95% CI: −0.18 to −0.06]). The AMH levels tended to be lower in subclinical hypothyroidism and overt hypothyroidism than in the control group, although the differences were not significant. The AMH levels were significantly higher in the euthyroid TAI group in the adolescents (mean difference 2.51, [95% CI 1.82 to 3.21]).ConclusionTAI and hypothyroidism may affect the ovarian reserve. The opposite effects on AMH levels depending on age suggest that TAI may be implicated in the depletion of follicles in adults following extensive activation of primordial follicles in adolescence.
Gender and Immunosuppression Impact on Merkel Cell Carcinoma Diagnosis and Prognosis. A Population Based Cohort Study
Authors: Keeling E. , O'Leary E. , Deady S. , O Neill J. P. , Conlon P. J. , Moloney F. J. 
Published: December 2021

Abstract

Background
Merkel cell carcinoma (MCC), a rare cutaneous neuroendocrine endocrine tumour is increasing in incidence, and continues to carry a poor prognosis.

Objectives
The objectives of this study were to examine all Irish cases of MCC from 1 January 1994 over 2 decades, focusing on gender and organ transplantation recipients (OTRs). Cases were identified from the National Cancer Registry of Ireland. Covariates of interest included age, body site, period of diagnosis, deprivation-status and history of non-melanoma skin cancer (NMSC).

Results
In total 314 MCC cases were identified. A female predominance was noted (53.8%). Comparison between age-standardised rates between the earliest period (1994–1996) with the latest period (2012–2014) showed an increase of 105% in total. The trend in age-standardised incidence rates were noted to be increasing significantly (p = 0.0004). Average age at diagnosis was 77.6 years (male 75.1 years, female 79.7 years). Overall, the majority of MCC cases presented on the head and neck (n = 170, 54.1%). Differences in anatomical location of MCCs were noted between genders. Males were found to be more likely to have a history of previous NMSCs (males n = 73 [57.9%], females n = 53 [42.1%]). Thirty-one percentage of patients died from MCC, average survival was 3.5 years in those who died of this malignancy. Ten organ transplant recipients developed MCC. OTR who developed MCC were diagnosed at a younger average age of 65.1 years. Standardized incidence ratio for MCC in OTR was 59.96. A higher proportion of OTR died from MCC (70%), with a shorter median survival of 0.14 years. In competing risks regression, gender was not significantly associated with risk of dying, females having a non-significantly higher hazard of dying. Organ transplant recipients and patients from less deprived areas were at greater risk of dying from MCC.

Conclusions
This population based study provides epidemiological, clinical and outcome data for MCC over a 20-year period.
Extraction of Lysozyme from Chicken Albumen Using Polyelectrolyte Complexes
Authors: van Lente Jéré J. , Lindhoud Saskia 
Published: December 2021

AbstractCells use droplet‐like membrane‐less organelles (MLOs) to compartmentalize and selectively take‐up molecules, such as proteins, from their internal environment. These membraneless organelles can be mimicked by polyelectrolyte complexes (PECs) consisting of oppositely charged polyelectrolytes. Previous research has demonstrated that protein uptake strongly depends on the PEC composition. This suggests that PECs can be used to selectively extract proteins from a multi‐protein mixture. With this in mind, the partitioning of the protein lysozyme in four PEC systems consisting of different weak and strong polyelectrolyte combinations is investigated. All systems show similar trends in lysozyme partitioning as a function of the complex composition. The release of lysozyme from complexes at their optimal lysozyme uptake composition is investigated by increasing the salt concentration to 500 mm NaCl or lowering the pH from 7 to 4. Complexes of poly(allylamine hydrochloride) and poly(acrylic acid) have the best uptake and release properties. These are used for selective extraction of lysozyme from a hen‐egg white protein matrix. The (back)‐extracted lysozyme retains its enzymatic activity, showing the capability of PECs to function as extraction media for proteins.
Mehrkernige Hohlprofil‐Verbundstützen
Authors: Chanou Mohamed , Naujoks Bernd 
Published: December 2021

AbstractStützen in Verbundbauweise zeichnen sich gegenüber herkömmlichen Stahlbetonstützen durch höhere Tragfähigkeiten aus. Ihre Bemessung für den Kaltzustand ist in DIN EN 1994‐1‐1 geregelt. Einen gebräuchlichen Verbundstützentyp stellt die Hohlprofil‐Verbundstütze dar. Durch den Einsatz mehrerer kreisrunder Stahlkerne als Einstellprofile, die sich im Hinblick auf Anzahl und Anordnung im Querschnitt variabel gestalten lassen, wird das Stützentragverhalten wesentlich verbessert. Der mehrkernige Verbundstützentyp wird jedoch nicht vom Anwendungsbereich des in DIN EN 1994‐1‐1 beschriebenen vereinfachten Nachweisverfahrens für den Nachweis der Gesamtstabilität abgedeckt. Das Regelwerk erlaubt zwar die Bemessung mithilfe des komplexen allgemeinen Bemessungsverfahrens, jedoch ist dieses mit einem hohen numerischen Berechnungsaufwand verbunden. Vor diesem Hintergrund wird in Anlehnung an das vereinfachte Verfahren nach DIN EN 1994‐1‐1 ein Konzept für ein Rechenverfahren erarbeitet. Im Rahmen des definierten Anwendungsbereichs ermöglicht dieses eine baupraktische Bemessung des mehrkernigen Stützentyps bei planmäßig zentrischem Druck sowie bei kombinierter Beanspruchung aus Druck und Biegung. Grundlage für die Herleitung sind umfangreiche theoretische Untersuchungen zur Beurteilung des Tragverhaltens des Verbundstützentyps.
Chemical Modifications in Nucleic Acids for Therapeutic and Diagnostic Applications
Authors: Fàbrega Carme , Aviñó Anna , Eritja Ramon 
Published: December 2021

AbstractThe last decade has witnessed the blooming of nucleic acids for therapeutic and diagnostic applications. In the present article, we describe the most important results from our group in this area covering the international context that surrounded this research. These include the study of modifications at the terminal and internal positions of siRNA duplexes to enhance nuclease resistance, increase loading of the antisense strand to RISC and avoid side effects such as activation of immune response and sense strand misloading. Then, we describe the design of novel lipid, carbohydrate and peptide conjugates to enhance cellular uptake. Finally, we describe the use of nanostructures for drug delivery and for the controlled deposition of matter on surfaces. We invite the readers to submerge into a highly interdisciplinary discipline that combines organic chemistry, biochemical assays, pharmacology issues as well as materials chemistry and structural studies in order to increase the applications of nucleic acids.
DNA damage and cell apoptosis induced by fungicide difenoconazole in mouse mononuclear macrophage RAW264.7
Authors: Li Ruirui , Liu Bin , Xu Wenping , Yu Lvnan , Zhang Cheng , Cheng Jiagao , Tao Liming , Li Zhong , Zhang Yang 
Published: December 2021

AbstractDifenoconazole (DFC) is a typical triazole fungicide. Because of its effective bactericidal activity, it has been widely used in agricultural products such as fruits and vegetables. This study revealed the cytotoxic effect of fungicide DFC on mouse monocyte macrophage RAW264.7. The results showed that the IC50 value of DFC on RAW264.7 cells was 37.08 μM (24 h). DFC can significantly inhibit the viability of RAW264.7 cells, induce DNA damage and enhance apoptosis. The established cytotoxicity test showed that DFC‐induced DNA double strand breaks in RAW264.7 cells. DFC‐treated cells showed typical morphological changes of apoptosis, including chromatin condensation and nuclear lysis. In addition, DFC can induce the release of Cyt c, promote the collapse of mitochondrial membrane potential and increase the Bax/Bcl‐2 ratio in RAW264.7 cells. Through this research, people further understand the toxicity of DFC and provide a more scientific basis for its safety application and risk management.
Use of a new device for gasless endosurgery in a laparoscopic diaphragmatic hernia repair ex vivo canine model: A pre‐clinical study
Authors: Brun Maurício V. , Sánchez‐Margallo Juan A. , Machado‐Silva Marco A. , Sánchez‐Margallo Francisco M. 
Published: December 2021

AbstractObjectivesTo test the feasibility of a new device for gasless laparoscopy in providing working space for diaphragmatic hernia repair in an ex vivo canine model as a pre‐clinical study.Study designTechnical feasibility study.AnimalEight beagles and two greyhound cadavers (not client‐owned).MethodsThe new device was used for abdominal traction in gasless laparoscopic reconstruction of diaphragmatic hernias produced in dog cadavers. It consists of three main parts (vertical and horizontal rods, a three‐piece structure, and a 3D‐printed unit that incorporates slots for haemostatic forceps). Composite hernias (two incisions of about 4 cm) were closed by an intra‐corporeal suture [suture group (GS), n = 5] or by a central suture and a polypropylene mesh [mesh group (GM), n = 5]. Surgical steps were T1 (primary port access up to third port placement), T2 (defect development), and T3 (diaphragmatic reconstruction). Total surgical time (TT) was also recorded.ResultsThe defect was successfully developed and reconstructed in all cadavers. To close the defect, 7.0 ± 0.7 crossed mattress sutures were required in the GS, and 15.2 ± 1.9 hernia staples and one intra‐corporal suture were used in the GM. T3 was longer (p = 0.0076) in GS (50.00 ± 16.46 min) than in GM (23.24 ± 5.25 min). TT was 87.22 ± 19.23 min in GS and 66.45 ± 6.38 min in GM (p = 0.0547).ConclusionsGasless laparoscopic diaphragmatic hernia repair using the developed device is feasible in the canine cadaver model. Both suture and mesh graft techniques for experimental diaphragmatic herniorrhaphy can be performed using this new device in this pre‐clinical model.Clinical significanceThis new device for gasless laparoscopy allows diaphragmatic herniorrhaphy by intra‐corporeal suture or mesh implantation in ex vivo canine model. The device demonstrates potential for future use in clinical cases.
Politics of attributing extreme events and disasters to climate change
Authors: Lahsen Myanna , Ribot Jesse 
Published: December 2021

AbstractClimate change certainly shapes weather events. However, describing climate and weather as the cause of disasters can be misleading, since disasters are caused by pre‐existing fragilities and inequalities on the ground. Analytic frames that attribute disaster to climate can divert attention from these place‐based vulnerabilities and their socio‐political causes. Thus, while politicians may want to blame crises on climate change, members of the public may prefer to hold government accountable for inadequate investments in flood or drought prevention and precarious living conditions. To be both strategic and moral, framing choices must therefore be sensitive to context‐dependent political meanings and particularities, and to how the values implicit within analytic frames about the causes of disasters shape policy responses. Such sensitivity requires multicausal analysis of weather‐linked disasters to illuminate a broader range of means to reduce the damages associated with climate change and weather extremes. Through examples from around the world, and especially Brazil, we discuss how and why climate‐centric disaster framing can erase from view—and, thus, from policy agendas—the very socio‐economic and political factors that most centrally cause vulnerability and suffering in weather extremes and disasters. We also offer a theoretical discussion of why attribution is not neutral. Analytic frameworks always embed choices about factors that matter, and thus are inherently normative and consequential for understandings of responsibility and action.This article is categorized under:
Social Status of Climate Change Knowledge > Climate Science and Decision Making
Highlight
Attributing crises only to climate is inadequate from a mechanical, moral, and strategic policy points of view.
Plant Community Response and Implications for Wildlife Following Control of a Nonnative Perennial Grass
Authors: Harper Craig A. , Gefellers J. Wade , Buehler David A. , Moorman Christopher E. , Zobel John M. 
Published: December 2021

ABSTRACTRestoration of early successional plant communities dominated by nonnative plant species is a central focus of many state and federal agencies to improve habitat for wildlife associated with these communities. Restoration efforts largely have concentrated on controlling nonnative species followed by planting native grasses and forbs. However, there are numerous establishment problems associated with planting that warrant evaluation of alternative approaches for restoration. We conducted a field experiment to compare vegetation composition and structure as related to habitat for focal wildlife among plant communities established by planting (Planted) native grasses and forbs and revegetation from the seedbank (Seedbank) without planting following control of tall fescue (Schedonorus arundinaceus) at 15 replicated sites in Tennessee and Alabama, USA. Planted and Seedbank treatments produced similar plant communities. Vegetation structure providing cover for nesting and brooding northern bobwhite (Colinus virginianus) and wild turkey (Meleagris gallopavo) was similar between Seedbank and Planted treatments except native grass cover was greatest in Planted, and we recorded greater openness at ground level in Seedbank than Planted or tall fescue control (Control). Abundance of northern bobwhite food plants and selected white‐tailed deer (Odocoileus virginianus) forage were similar between Planted and Seedbank treatments, but nutritional carrying capacity for deer was greatest in Seedbank. Despite similarities in food abundance, and even though all forbs included in the planting mixtures were food plants, the majority of food plants in Planted were from the seedbank. The compositional and structural characteristics deemed most influential in previous studies to selection of breeding sites by dickcissel (Spiza americana), field sparrow (Spizella pusilla), grasshopper sparrow (Ammodramus savannarum), Henslow's sparrow (Ammodramus henslowii), and northern bobwhite were similar in Planted and Seedbank. Tall fescue Control was most similar to characteristics of eastern meadowlark (Sturnella magna) breeding sites. Revegetation following Seedbank produced a plant community that provided habitat for many wildlife species equal to or better than Planted and was 3.7 times less expensive than Planted. © 2021 The Wildlife Society.
Duck Nest Density and Survival in Post‐Conservation Reserve Program Lands
Authors: Rischette Alexander C. , Geaumont Benjamin A. , Elmore R. Dwayne , Schauer Christopher S. , Sedivec Kevin K. , Hovick Torre J. 
Published: December 2021

AbstractFluctuations in both commodity prices and conservation policy have reduced producer enrollment into the U.S. Department of Agriculture Conservation Reserve Program (CRP) in the northern Great Plains. Reductions of CRP hectares result in reduced nesting cover for upland nesting ducks as perennial cover is often converted to row crops. Working landscapes that include livestock grazing and haying as management options can maintain perennial grass cover and continue to provide habitat for many wildlife species while simultaneously creating a commodity. To assess the potential of working landscapes for waterfowl conservation, we estimated density and survival of duck nests in post‐CRP fields used for cattle grazing, haying, and crop production over a 9‐year study period in southwestern North Dakota, USA. We used the chain‐drag method to locate 477 nests of 6 duck species. The density analysis was separated into 2 periods to correspond to changes in treatments (i.e., 2006–2011 and 2013–2015). Mean ± SE nest density was lowest in crop fields (0.01 ± 0.01 nests/ha−1), which differed from idle (0.33 ± 0.06 nests/ha−1), season‐long grazed ( 0.18 ± 0.02 nests/ha−1), and haying (0.15 ± 0.04 nests/ha−1). We found no evidence that density was affected by grassland treatment from 2013–2015. Daily nest survival increased with nest age and vegetation height but was lower for nests located in crop fields. Based on our findings, it appears that livestock grazing could be a viable option for waterfowl conservation in post‐CRP fields if nesting vegetation height is considered in grazing plans. Loss of CRP may be mitigated by working landscapes that offer a management alternative to crop production. © 2021 The Wildlife Society.