bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel methodology for predicting the high rate mechanical response of polymers from low rate data: application to (plasticised) poly(vinyl chloride)
Authors: Trivedi Akash R. , Siviour Clive R.
Published: May 2020

Plasticised and unplasticised poly(vinyl chloride) (PVC) are used as engineering materials in many applications where they may be subjected to impact loading leading to high strain rate deformation at a variety of temperatures. It is therefore necessary to study the mechanical responses of these and similar materials over a range of loading conditions, especially as they exhibit strong rate and temperature dependence, and could include a low temperature brittle transition. In this paper, a model of the mechanical response of a PVC with 20 wt% plasticiser and one with no plasticiser is applied over a wide range of strain rates and strains and shown to have excellent agreement with experiments conducted in a previous study. As it is challenging to obtain high rate data on rubbery materials using conventional apparatus, such as the split-Hopkinson pressure bar (SHPB), an alternative approach is presented based on a novel modelling framework, which uses the time–temperature superposition principle and is fully calibrated using quasi-static experiments at different temperatures.
Neurocognitive functioning and health-related quality of life in adult medulloblastoma patients: long-term outcomes of the NOA-07 study
Authors: Dirven Linda , Luerding Ralf , Beier Dagmar , Bumes Elisabeth , Reinert Christiane , Seidel Clemens , Bonsanto Matteo Mario , Bremer Michael , Rieken Stefan , Combs Stephanie E. , Herrlinger Ulrich , Seliger Corinna , Kuntze Holger , Mayer-Steinacker Regine , Dieing Annette , Bartels Claudius , Schnell Oliver , Weyerbrock Astrid , Seidel Sabine , Grauer Oliver , Nadji-Ohl Minou , Paulsen Frank , Weller Michael , Wick Wolfgang , Hau Peter
Published: May 2020

Background

Combined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult medulloblastoma patients. Here we investigated the long-term impact of this treatment, focusing on neurocognitive functioning and health-related quality of life (HRQoL).

Methods

Neurocognitive functioning and HRQoL scores over time were determined, and differences between the post-treatment and follow-up assessments were calculated up to 18 months for neurocognition and 60 months for HRQoL.

Results

28/30 patients were analyzed. The three preselected HRQoL scales (role, social and cognitive functioning) showed improved scores, to a clinically relevant extent (≥ 10 points), compared to post-treatment levels up to 30 months, but decreased afterwards. Z-scores for verbal working memory were worse during follow-up compared to post-treatment scores and remained impaired during 18 months follow-up (i.e. z-score below − 1 standard deviation). Attention was impaired post-treatment, and remained impaired to a clinically relevant extent during follow-up. Coordination/processing speed and lexical verbal fluency improved compared to post-treatment scores, and remained within the normal range thereafter. Other tests of verbal fluency were stable over time, with z-scores within the normal range.

Conclusions

This long-term follow-up study showed that the NOA-07 treatment regimen was not associated with a deterioration in HRQoL in the post-treatment period. Verbal working memory deteriorated, while other neurocognitive domains did not seem to be impacted negatively by the treatment.
Natural hazard information and migration across cities: evidence from the anticipated Nankai Trough earthquake
Authors: Naoi Michio , Sato Keiichi , Tanaka Yozo , Matsuura Hiroaki , Nagamatsu Shingo
Published: May 2020

This paper examines the effects of the 2012 revisions to the damage predictions of an anticipated Nankai Trough megathrust earthquake on subsequent inter-municipality migration in Japan’s coastal areas. We find that an increase in predicted tsunami height—rather than anticipated seismic movements—after the 2012 revision is associated with a subsequent reduction in net migration. While the reducing effect of tsunami predictions on in-migration persisted throughout the study period, the effect on out-migration was only temporary. Moreover, working-age people are more likely to respond to tsunami risk and avoid moving to municipalities with a high tsunami risk after the revisions.
European Human Rights Dimension of the Online Access to Cultural Heritage in Times of the COVID-19 Outbreak
Authors: Kużelewska Elżbieta , Tomaszuk Mariusz
Published: May 2020

The 1948 Universal Declaration of Human Rights recognized that “everyone has the right freely to participate in the cultural life of the community, to enjoy the arts and to share in scientific advancement and its benefits”. As a result, cultural rights have been understood as inseparable from human rights and require protection mechanisms within particular international (including regional) legal systems. The European continent is proud to have developed one of the most effective mechanisms of the human rights protection by establishing the Council of Europe and adopting the European Court of Human Rights. The recent outbreak of the COVID-19 reformulated many concepts of access to human rights and possibilities to enjoy freedoms. Even if access to culture (access to cultural heritage) has been available online for many years, it is the time of globally occurring lockdowns that forced people to stay home and found themselves in a situation when all of a sudden online access to culture became the only way of access to culture. The article aims to analyze the current situation in Europe by asking questions if and how online access to culture is recognized and protected under the Council of Europe’s mechanisms with special emphasis on the case-law of the European Court of Human Rights in this field.
Clinical outcomes and characteristics of P30L mutations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Authors: Kocova Mirjana , Anastasovska Violeta , Falhammar Henrik
Published: May 2020

Despite numerous studies in the field of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, some clinical variability of the presentation and discrepancies in the genotype/phenotype correlation are still unexplained. Some, but not all, discordant phenotypes caused by mutations with known enzyme activity have been explained by in silico structural changes in the 21-hydroxylase protein. The incidence of P30L mutation varies in different populations and is most frequently found in several Central and Southeast European countries as well as Mexico. Patients carrying P30L mutation present predominantly as non-classical CAH; however, simple virilizing forms are found in up to 50% of patients. Taking into consideration the residual 21-hydroxulase activity present with P30L mutation this is unexpected. Different mechanisms for increased androgenization in patients carrying P30L mutation have been proposed including influence of different residues, accompanying promotor allele variability or mutations, and individual androgene sensitivity. Early diagnosis of patients who would present with SV is important in order to improve outcome. Outcome studies of CAH have confirmed the uniqueness of this mutation such as difficulties in phenotype classification, different fertility, growth, and psychologic issues in comparison with other genotypes. Additional studies of P30L mutation are warranted.
Toward a Lockean Unification of Formal and Traditional Epistemology
Authors: Lee Matthew Brandon , Silva Paul
Published: May 2020

A Lockean metaphysics of belief that understands outright belief as a determinable with degrees of confidence as determinates is supposed to effect a unification of traditional coarse-grained epistemology of belief with fine-grained epistemology of confidence. But determination of belief by confidence would not by itself yield the result that norms for confidence carry over to norms for outright belief unless belief and high confidence are token identical. We argue that this token-identity thesis is incompatible with the neglected phenomenon of “mistuned knowledge” – knowledge in the absence of rational confidence. We show how partial epistemological unification can be secured, even without token identity, given determination of outright belief by degrees of confidence. Finally, we suggest a direction for the pursuit of thoroughgoing epistemological unification.
The role of triage in the prevention and control of COVID-19
Authors: Wang Qiaoxia , Wang Xiaoping , Lin Huanping
Published: May 2020

Objective:

To prevent and control public health emergencies, we set up a prescreening and triage workflow and analyzed the effects on coronavirus disease 2019 (COVID-19).

Methods:

In accordance with the requirements of the level 1 emergency response of public health emergencies in Shaanxi Province, China, a triage process for COVID-19 was established to guide patients through a 4-level triage process during their hospital visits. The diagnosis of COVID-19 was based on positive COVID-19 nucleic acid testing according to the unified triage standards of the Guidelines for the Diagnosis and Treatment of Novel Coronavirus Pneumonia (Trial version 4),4 issued by the National Health Commission of the People’s Republic of China.

Results:

The screened rate of suspected COVID-19 was 1.63% (4 of 246) in the general fever outpatient clinic and 8.28% (13 of 157) in the COVID-19 outpatient clinic, and they showed a significant difference (P = .00).

Conclusions:

The triage procedure effectively screened the patients and identified the high-risk population.
Improvements on the distribution of maximal segmental scores in a Markovian sequence
Authors: Grusea S. , Mercier S.
Published: May 2020

Let
$(A_i)_{i \geq 0}$
be a finite-state irreducible aperiodic Markov chain and f a lattice score function such that the average score is negative and positive scores are possible. Define
$S_0\coloneqq 0$
and
$S_k\coloneqq \sum_{i=1}^k f(A_i)$
the successive partial sums,
$S^+$
the maximal non-negative partial sum,
$Q_1$
the maximal segmental score of the first excursion above 0, and
$M_n\coloneqq \max_{0\leq k\leq\ell\leq n} (S_{\ell}-S_k)$
the local score, first defined by Karlin and Altschul (1990). We establish recursive formulae for the exact distribution of
$S^+$
and derive a new approximation for the tail behaviour of
$Q_1$
, together with an asymptotic equivalence for the distribution of
$M_n$
. Computational methods are explicitly presented in a simple application case. The new approximations are compared with those proposed by Karlin and Dembo (1992) in order to evaluate improvements, both in the simple application case and on the real data examples considered by Karlin and Altschul (1990).
Directed preferential attachment models: Limiting degree distributions and their tails
Authors: Britton Tom
Published: May 2020

The directed preferential attachment model is revisited. A new exact characterization of the limiting in- and out-degree distribution is given by two independent pure birth processes that are observed at a common exponentially distributed time T (thus creating dependence between in- and out-degree). The characterization gives an explicit form for the joint degree distribution, and this confirms previously derived tail probabilities for the two marginal degree distributions. The new characterization is also used to obtain an explicit expression for tail probabilities in which both degrees are large. A new generalized directed preferential attachment model is then defined and analyzed using similar methods. The two extensions, motivated by empirical evidence, are to allow double-directed (i.e. undirected) edges in the network, and to allow the probability of connecting an ingoing (outgoing) edge to a specified node to also depend on the out-degree (in-degree) of that node.
Weak convergence of random processes with immigration at random times
Authors: Dong Congzao , Iksanov Alexander
Published: May 2020

By a random process with immigration at random times we mean a shot noise process with a random response function (response process) in which shots occur at arbitrary random times. Such random processes generalize random processes with immigration at the epochs of a renewal process which were introduced in Iksanov et al. (2017) and bear a strong resemblance to a random characteristic in general branching processes and the counting process in a fixed generation of a branching random walk generated by a general point process. We provide sufficient conditions which ensure weak convergence of finite-dimensional distributions of these processes to certain Gaussian processes. Our main result is specialised to several particular instances of random times and response processes.
An invariance principle and a large deviation principle for the biased random walk on
Authors: Liu Yuelin , Sidoravicius Vladas , Wang Longmin , Xiang Kainan
Published: May 2020

We establish an invariance principle and a large deviation principle for a biased random walk
${\text{RW}}_\lambda$
with
$\lambda\in [0,1)$
on
$\mathbb{Z}^d$
. The scaling limit in the invariance principle is not a d-dimensional Brownian motion. For the large deviation principle, its rate function is different from that of a drifted random walk, as may be expected, though the reflected biased random walk evolves like the drifted random walk in the interior of the first quadrant and almost surely visits coordinate planes finitely many times.
Reproductive biology and diet of the longtail butterfly rayGymnura poecilura(Shaw, 1804) along western Bay of Bengal
Authors: Menon Muktha , Maheswarudu G. , Sree Ramulu K. , Kizhakudan Shoba Joe
Published: May 2020

The reproductive biology and diet of the longtail butterfly rayGymnura poecilurais described based on 630 specimens (N = 377 females and 253 males). The mean disc width (WD) of females and males was 576.7 mm (range = 190–920 mm) and 416.3 mm (230–550 mm), respectively. Sexual dimorphism in size was seen, with the maximum size of males being only 60% of the maximum female size. The disc widths at 50% maturity (WD50) were estimated to be 506.5 mm (females) and 435.9 mm (males). The mean uterine fecundity was 3.3 (range = 1–8). The size at birth was between 190 and 220 mmWD. Year-round reproduction was indicated, due to the presence of mature males and gravid females throughout the year, neonates in multiple months and large variations in embryo size within months. Feeding intensity increased with body size. Fish accounted for 80.9% of the diet (Index of Relative Importance, IRI), followed by crustaceans (18.9%) and molluscs. The species was found to be a specialized feeder.
Hybrid closure of a large atrial septal defect using Occlutech Flex II septal occluder in a patient with interrupted inferior caval vein
Authors: Bani Hani Amjad , Abdullattif Mai , AL-Ammouri Iyad
Published: May 2020

We present a case of a 31-year-old male with a large atrial septal defect, who was found to have interrupted inferior caval vein with azygous continuation to the superior caval vein, which precluded transcutaneous closure by device. The defect was successfully closed with a 33 mm Occlutech Figula septal occluder using a sub-mammary small thoracotomy incision and per-atrial approach without using cardiopulmonary bypass. The patient was discharged home after 48 hours of procedure.
Civil War, Genocide and Beyond: How to Re-found the Narrative Framework on the Destruction of the Spanish Democratic Republic after 1936
Authors: Sánchez León Pablo
Published: May 2020

This article contends that the category of civil war is not suitable for studying the massacres of civilians during the Spanish 1936–1039 war and its aftermath. In trying to build an alternative narrative for the understanding of the destruction of the democratic republic of 1931 founded on the human rights paradigm, an analytical framework is devised based on the deficit in deliberation processes allowing for the re-classification of social constituencies as ontological enemies. By showing that the repression by Franco's followers supplemented institutional logics and rationalities from colonial warfare and religious wars, the article also provides insights for a qualitative differentiation in repression between the two contending sides.
Spoken Arabic dialect recognition using X-vectors
Authors: Hanani Abualsoud , Naser Rabee
Published: May 2020

This paper describes our automatic dialect identification system for recognizing four major Arabic dialects, as well as Modern Standard Arabic. We adapted the X-vector framework, which was originally developed for speaker recognition, to the task of Arabic dialect identification (ADI). The training and development ADI VarDial 2018 and VarDial 2017 were used to train and test all of our ADI systems. In addition to the introduced X-vectors, other systems use the traditional i-vectors, bottleneck features, phonetic features, words transcriptions, and GMM-tokens. X-vectors achieved good performance (0.687) on the ADI 2018 Discriminating between Similar Languages shared task testing dataset, outperforming other systems. The performance of the X-vector system is slightly improved (0.697) when fused with i-vectors, bottleneck features, and word uni-gram features.
Incidence of multiple herbicide resistance in annual bluegrass (Poa annua) across southeastern Australia
Authors: Barua Rajesh , Boutsalis Peter , Malone Jenna , Gill Gurjeet , Preston Christopher
Published: May 2020

Annual bluegrass (Poa annua L.) is a problematic annual weed in established turf where the intensive use of herbicides has resulted in the evolution of herbicide resistance. In 2017, 31 populations of P. annua suspected to be resistant to herbicides commonly used to control this weed in turf were collected from golf courses across southeastern Australia to check the resistance status to different herbicide groups. All populations were found to be resistant to multiple turf herbicides. Dose–response experiments confirmed resistance to propyzamide, simazine, rimsulfuron, foramsulfuron, endothall, and pinoxaden. Levels of resistance to rimsulfuron (>56-fold), foramsulfuron (>19-fold), endothall (>7-fold), and pinoxaden (>4.3-fold) compared with the susceptible population were high, but levels of resistance to propyzamide (>2-fold) and simazine (>2-fold) were lower. Considerable variation in resistance to endothall and pinoxaden was observed among the populations of P. annua. Target-site resistance was confirmed for acetolactate synthase and acetyl-CoA carboxylase inhibitors, but not for photosystem II and microtubule assembly inhibitors. This study documented the extensive resistance to herbicides in P. annua from turf in Australia. Three of the populations investigated exhibited multiple resistance to herbicides from five mechanisms of action. The identification of multiple-resistant P. annua on several golf courses is a serious concern for turf managers.
„Man muss stets aufmerksam sein“
Authors: Huber Evelyn , Kleinknecht-Dolf Michael , Kugler Christiane , Spirig Rebecca
Published: May 2020

Zusammenfassung. Hintergrund: Die Zunahme von chronischen Krankheiten und Multimorbidität sowie anspruchsvollere Behandlungsmethoden führten in Akutspitälern zu erhöhter Akuität und Komplexität von Pflegesituationen. Ziel: Diese Untersuchung verfolgte das Ziel, Kategorien unterschiedlich ausgeprägter, patientenbezogener Komplexität der Pflege zu explorieren und zu beschreiben. Damit soll das Verständnis der Anforderungen an die Pflege aufgrund von Patientensituationen erweitert werden. Methode: Mit einem kollektiven Case Study Design ließen wir diplomierte Pflegefachpersonen und Pflegeexpertinnen die Komplexität von zwölf Pflegesituationen mit einem Fragebogen einschätzen und interviewten sie zu ihren Überlegungen dazu. In dieser Substudie führten wir eine qualitative Sekundäranalyse dieser Daten durch und suchten nach Kategorien vergleichbarer Komplexitätsausprägung. Ergebnisse: Wir fanden fünf Komplexitätskategorien zwischen „wenig komplex“ und „höchst komplex“. Wenig komplexe Situationen benötigten die Aufmerksamkeit der Pflegefachperson auf Routineinterventionen, während höchst komplexe Situationen ihre dauernde Aufmerksamkeit auf schlecht einschätzbare und kontrollierbare Zustände mit offenem Ausgang erforderten. Schlussfolgerungen: Die fünf Komplexitätskategorien können Hinweise auf unterschiedlich ausgeprägte Komplexität von Pflegesituationen geben. Sie können Führungspersonen bei der bedarfsgerechten Zuteilung von Pflegefachpersonen zu Patientinnen und Patienten unterstützen und einen Rahmen für Reflexionen bei komplexen Pflegesituationen in der Aus- und Weiterbildung bilden.
Millstone Hill ISR Measurements of Small Aspect Angle Spectra
Authors: Longley William J. , Erickson Philip J. , Vierinen Juha , Oppenheim Meers M. , Lind Frank D. , Dimant Yakov S.
Published: May 2020

The Millstone Hill incoherent scatter (IS) radar is used to measure spectra close to perpendicular to the Earth's magnetic field, and the data are fit to three different forward models to estimate ionospheric temperatures. IS spectra measured close to perpendicular to the magnetic field are heavily influenced by Coulomb collisions, and the temperature estimates are sensitive to the collision operator used in the forward model. The standard theoretical model for IS radar spectra treats Coulomb collisions as a velocity independent Brownian motion process. This gives estimates of Te/Ti < 1 when fitting the measured spectra for aspect angles up to 3.6°, which is a physically unrealistic result. The numerical forward model from Milla and Kudeki (2011, https://doi.org/10.1109/TGRS.2010.2057253) incorporates single‐particle simulations of velocity‐dependent Coulomb collisions into a linear framework, and when applied to the Millstone data, it predicts the same Te/Ti ratios as the Brownian theory. The new approach is a nonlinear particle‐in‐cell (PIC) code that includes velocity‐dependent Coulomb collisions which produce significantly more collisional and nonlinear Landau damping of the measured ion‐acoustic wave than the other forward models. When applied to the radar data, the increased damping in the PIC simulations will result in more physically realistic estimates of Te/Ti. This new approach has the greatest impact for the largest measured ionospheric densities and the lowest radar frequencies. The new approach should enable IS radars to obtain accurate measurements of plasma temperatures at times and locations where they currently cannot.
Mobile Laboratory Measurements of High Surface Ozone Levels and Spatial Heterogeneity During LISTOS 2018: Evidence for Sea Breeze Influence
Authors: Zhang Jie , Ninneman Matthew , Joseph Everette , Schwab Margaret J. , Shrestha Bhupal , Schwab James J.
Published: May 2020

The Long Island Sound Tropospheric Ozone Study (LISTOS) was organized to investigate ozone formation and transport in the New York City metropolitan area and locations downwind. During LISTOS, the University at Albany Atmospheric Sciences Research Center (ASRC) mobile laboratory was used for measuring surface O3, NO2, and aerosol number and mass concentration. Sharp O3 concentration gradients, with ΔO3 Δy−1 over 15 ppb km−1, were measured both at and near the land‐water interface and on the highway on days characterized by high regional O3 concentrations. These large O3 gradients at or near the land‐water interface, and in air masses relatively low in NO2, are shown to be influenced in part by the transport of highly oxidized air masses via sea breeze circulation and convergence with gradient flow. On the highway under regionally high O3 concentrations, strong anticorrelation (R2 = 0.78, p < 0.05) between O3 and NO2 and an absolute slope less than 1 suggested that Ox concentrations (O3 + NO2) increased with increasing NO2. Overall, the on‐road measurements made during LISTOS help to better characterize the interaction between the emitted pollution and the meteorological conditions on Long Island, thereby having potential policy implications.
Reduction of depression-like behavior in rat model induced by ShRNA targeting norepinephrine transporter in locus coeruleus
Authors: Du Xiangdong , Yin Ming , Yuan Lian , Zhang Guangya , Fan Yan , Li Zhe , Yuan Nian , Lv Xiaoli , Zhao Xueli , Zou Siyun , Deng Wei , Kosten Thomas R. , Zhang Xiang Yang
Published: May 2020

Depression may be associated with reduced monoamine neurotransmission, particularly serotonin and norepinephrine (NE). Reuptake of NE by the norepinephrine transporter (NET) is the primary mechanism by which many of the antidepressants are high-affinity substrates for NET. This study aimed to examine the effect of lentivirus-mediated shRNA targeting NET in locus coeruleus (LC) on depression-like behaviors of rats. We randomly assigned 60 male Wistar rats to 6 experimental groups: (1) Control group: without chronic unpredictable mild stress (CUMS) and without NET-shRNA treatment; (2) shRNA group: without CUMS + NET-shRNA; (3) CUMS group: 3-week CUMS without NET-shRNA; (4) CUMS + nonsense shRNA group; (5) CUMS + amygdala (Amy)-shRNA group; (6) CUMS+ locus coeruleus (LC)-shRNA group. First, recombinant lentiviral vector expressing shRNA (ShRNA-629, ShRNA-330, ShRNA-1222, ShRNA-1146 or ShRNA- negative control) against NET were produced, and their efficiency in knocking down of NET in PC12 cells were assessed by Q-PCR and western blot analysis. Second, shRNA was injected into the rat LC bilaterally to investigate whether it could prevent the depressive-like behavior induced by 3-week CUMS. Third, we tested the depressive-like behavior of the rats in the forced swimming test, the open field test, the sucrose preference test, as well as the body weight gain at the end of the seventh week. Finally, the protein expressions of NET was measured by western blot and the NE levels were measured by high performance liquid chromatography. Q-PCR and western blot showed that the ShRNA-1146 had the best interference efficiency targeting on NET in PC12 cells (p < 0.01). Compared to the depression model group, the immobility time in the forced swimming test was significantly reduced (p < 0.01), but the sucrose preference and the total scores in the open field test were significantly increased (all p < 0.01) in the group treated with shRNA in LC. Furthermore, compared with the depression model group, NET levels were significantly decreased (p < 0.01), but NE levels were significantly increased in the group treated with shRNA in LC (p < 0.05). Our findings suggest that Lentivirus-mediated shRNA targeting NET in LC downregulated NET both in vitro and in vivo, resulting in a significant decrease in depressive-like behavior of rats.
Impact of numerical variation, allele burden, mutation length and co-occurring mutations on the efficacy of tyrosine kinase inhibitors in newly diagnosed FLT3- mutant acute myeloid leukemia
Authors: Abou Dalle Iman , Ghorab Ahmad , Patel Keyur , Wang Xuemei , Hwang Hyunsoo , Cortes Jorge , Issa Ghayas C. , Yalniz Fevzi , Sasaki Koji , Chihara Dai , Price Allyson , Kadia Tapan , Pemmaraju Naveen , Daver Naval , DiNardo Courtney , Ravandi Farhad , Kantarjian Hagop M. , Borthakur Gautam
Published: May 2020

FLT3-ITD mutations in newly diagnosed acute myeloid leukemia (AML) are associated with worse overall survival (OS). FLT3-ITD diversity can further influence clinical outcomes. Addition of FLT3 inhibitors to standard chemotherapy has improved OS. The aim of this study is to evaluate the prognostic impact of FLT3 diversity and identify predictors of efficacy of FLT3 inhibitors. We reviewed prospectively collected data from 395 patients with newly diagnosed FLT3-ITD mutant AML. 156 (39%) patients received FLT3 inhibitors combined with either high or low intensity chemotherapy. There was no statistically significant difference in clinical outcomes among patients treated with FLT3 inhibitors based on FLT3 numerical variation (p = 0.85), mutation length (p = 0.67). Overall, the addition of FLT3 inhibitor to intensive chemotherapy was associated with an improved OS (HR = 0.35, 95% CI: 0.24–0.5, p = 0.0005), but not in combination with lower intensity chemotherapy (HR = 0.98, 95%CI: 0.7–1.36, p = 0.85). A differential effect of FLT3 inhibitor on OS was more pronounced in younger patients with FLT3 allelic ratio ≥0.5 (HR = 0.41, 95% CI: 0.25–0.66, p < 0.001), single ITD mutation (HR = 0.55, 95% CI: 0.34–0.88, p = 0.01), diploid cytogenetics (HR = 0.52, 95% CI: 0.35–0.76, p = 0.001), NPM1 co-mutation (HR = 0.35, 95% CI: 0.19–0.67, p = 0.001). Our analysis identifies predictors of survival among diverse FLT3 related variables in patients treated with FLT3 inhibitor.
Relationship between markers of malnutrition and clinical outcomes in older adults with cancer: systematic review, narrative synthesis and meta-analysis
Authors: Bullock Alex F. , Greenley Sarah L. , McKenzie Gordon A. G. , Paton Lewis W. , Johnson Miriam J.
Published: May 2020

Malnutrition predicts poorer clinical outcomes for people with cancer. Older adults with cancer are a complex, growing population at high risk of weight-losing conditions. A number of malnutrition screening tools exist, however the best screening tool for this group is unknown. The aim was to systematically review the published evidence regarding markers and measures of nutritional status in older adults with cancer (age ≥ 70). A systematic search was performed in Ovid Medline, EMBASE, Web of Science, CINAHL, British Nursing Database and Cochrane CENTRAL; search terms related to malnutrition, cancer, older adults. Titles, abstracts and papers were screened and quality-appraised. Data evaluating ability of markers of nutritional status to predict patient outcomes were subjected to meta-analysis or narrative synthesis. Forty-two studies, describing 15 markers were included. Meta-analysis found decreased food intake was associated with mortality (OR 2.15 [2.03–4.20] p = < 0.00001) in univariate analysis. Prognostic Nutritional Index (PNI) was associated with overall survival (HR 1.89 [1.03–3.48] p = 0.04). PNI markers (albumin, total lymphocyte count) could be seen as markers of inflammation rather than nutrition. There a suggested relationship between very low body mass index (BMI) (<18 kg/m2) and clinical outcomes. No tool was identified as appropriate to screen for malnutrition, as distinct from inflammatory causes of weight-loss. Risk of cancer-cachexia and sarcopenia in older adults with cancer limits the tools analysed. Measures of food intake predicted mortality and should be included in clinical enquiry. A screening tool that distinguishes between malnutrition, cachexia and sarcopenia in older adults with cancer is needed.
Efficient correction of a deleterious point mutation in primary horse fibroblasts with CRISPR-Cas9
Authors: Pinzon-Arteaga Carlos , Snyder Matthew D. , Lazzarotto Cicera R. , Moreno Nicolas F. , Juras Rytis , Raudsepp Terje , Golding Michael C. , Varner Dickson D. , Long Charles R.
Published: May 2020

Phenotypic selection during animal domestication has resulted in unwanted incorporation of deleterious mutations. In horses, the autosomal recessive condition known as Glycogen Branching Enzyme Deficiency (GBED) is the result of one of these deleterious mutations (102C > A), in the first exon of the GBE1 gene (GBE1102C>A). With recent advances in genome editing, this type of genetic mutation can be precisely repaired. In this study, we used the RNA-guided nuclease CRISPR-Cas9 (clustered regularly-interspaced short palindromic repeats/CRISPR-associated protein 9) to correct the GBE1102C>A mutation in a primary fibroblast cell line derived from a high genetic merit heterozygous stallion. To correct this mutation by homologous recombination (HR), we designed a series of single guide RNAs (sgRNAs) flanking the mutation and provided different single-stranded donor DNA templates. The distance between the Cas9-mediated double-stranded break (DSB) to the mutation site, rather than DSB efficiency, was the primary determinant for successful HR. This framework can be used for targeting other harmful diseases in animal populations.
ATR Inhibition Broadly Sensitizes Soft-Tissue Sarcoma Cells to Chemotherapy Independent of Alternative Lengthening Telomere (ALT) Status
Authors: Laroche-Clary Audrey , Chaire Vanessa , Verbeke Stéphanie , Algéo Marie-Paule , Malykh Andrei , Le Loarer François , Italiano Antoine
Published: May 2020

Only few drugs have shown activity in patients with advanced soft-tissue and the median overall survival is only 18 months. Alterations of genes involved in the DNA damage repair pathway have been associated with sarcoma risk and prognosis. ATR plays a crucial role in maintaining genomic integrity by responding to a large spectrum of DNA damage, including double strand breaks (DSBs) that interfere with replication. The objective of this study is to evaluate the pre-clinical activity of ATR inhibition in soft tissue sarcomas (STS). We explored the ability of the ATR inhibitor, VE-822, to prevent chemotherapy-induced intra-S-phase checkpoint activation and evaluated the antitumor potential of this combination in vitro and in vivo in STS cell lines and in a patient-derived xenograft model. The combination of VE-822 and gemcitabine in vitro was synergistic, inhibited cell proliferation, induced apoptosis, and accumulated in the S phase of the cell cycle with higher efficacy than either single agent alone. The combination also resulted in enhanced γH2AX intranuclear accumulation as a result of DNA damage induction. These effects were unrelated to the alternative lengthening of telomeres pathway. In vivo, the combination of VE-822 and gemcitabine significantly enhanced tumor growth inhibition and progression-free survival in an aggressive model of undifferentiated pleomorphic sarcoma. The combination of ATR inhibitor and chemotherapy is beneficial in pre-clinical models of soft-tissue sarcoma and deserves further exploration in the clinical setting.
Comparative Analyses of the Conformational Dynamics Between the Soluble and Membrane-Bound Cytokine Receptors
Authors: Yang Chao-Yie
Published: May 2020

Cytokine receptors receive extracellular cues by binding with cytokines to transduce a signaling cascade leading to gene transcription in cells. Their soluble isoforms, functioning as decoy receptors, contain only the ectodomain. Whether the ectodomains of cytokine receptors at the membrane exhibit different conformational dynamics from their soluble forms is unknown. Using Stimulation-2 (ST2) as an example, we performed microsecond molecular dynamics (MD) simulations to study the conformational dynamics of the soluble and the membrane-bound ST2 (sST2 and ST2). Combined use of accelerated and conventional MD simulations enabled extensive sampling of the conformational space of sST2 for comparison with ST2. Using the interdomain loop conformation as the reaction coordinate, we built a Markov State Model to determine the slowest implied timescale of the conformational transition in sST2 and ST2. We found that the ectodomain of ST2 undergoes slower conformational relaxation but exhibits a faster rate of conformational transition in a more restricted conformational space than sST2. Analyses of the relaxed conformations of ST2 further suggest important contributions of interdomain salt-bridge interactions to the stabilization of different ST2 conformations. Our study elucidates differential conformational properties between sST2 and ST2 that may be exploited for devising strategies to selectively target each isoform.
The role of early social rearing, neurological, and genetic factors on individual differences in mutual eye gaze among captive chimpanzees
Authors: Hopkins William D. , Mulholland Michele M. , Reamer Lisa A. , Mareno Mary Catherine , Schapiro Steven J.
Published: May 2020

Mutual eye gaze plays an important role in primate social development and communication. In the current study, we examined the underlying experiential, genetic, and neuroanatomical basis of mutual eye gaze variation in adult captive chimpanzees. A multivariate analysis of variance revealed a significant rearing effect on bout length, with human-reared chimpanzees engaging in longer bouts of mutual gaze compared to mother-reared and wild-born individuals. Next, we utilized source-based morphometry (SBM) to examine gray matter covariation in magnetic resonance imaging scans and determine the relationship between the resulting gray matter covariation components and mutual eye gaze. One SBM component was negatively correlated with gaze duration (nucleus accumbens and anterior insular cortex), while two components were positively correlated with bout length (posterior cingulate cortex, inferior occipital cortex, middle temporal cortex, hippocampus, and the precentral sulcus). Finally, heritability analyses revealed mutual eye gaze to be modestly heritable and significant genetic correlations between bout length and two gray matter covariation components. This study reveals that non-genetic factors, and to a lesser extent, genetic factors appear to influence mutual eye gaze in adult chimpanzees, and is the first to report neuroanatomical correlates of mutual eye gaze variation in chimpanzees.
Effects of Schizochytrium and micro-minerals on immune, antioxidant, inflammatory and lipid-metabolism status of Micropterus salmoides fed high- and low-fishmeal diets
Authors: Habte-Tsion Habte-Michael , Kolimadu Gagan D. , Rossi Waldemar , Filer Keith , Kumar Vikas
Published: May 2020

A 12-week factorial experiment was conducted to investigate the interactive effects of dietary algal meal (Schizochytrium sp., AM) and micro-minerals (MM, either organic [OM] or inorganic [IM]) on the immune and antioxidant status, and the expression of hepatic genes involved in the regulation of antioxidants, inflammatory cytokines, lipid metabolism, and organ growth of largemouth bass (LMB; Micropterus salmoides) fed high-and low-fishmeal (FM) diets. For this purpose, two sets of six iso-nitrogenous (42% crude protein) and iso-lipidic (12% lipid) diets, such as high (35%) and low (10%) FM diets were formulated. Within each FM level, AM was used to replace 50% or 100% of fish oil (FO), or without AM (FO control) and supplemented with either OM or IM (Fe, Zn, Mn, Cu, and Se). Diets were fed to juvenile LMB (initial weight, 25.87 ± 0.08 g) to near satiation twice daily. The results indicated that FO replacement by dietary AM did not change the levels of most biochemical (ALB, AMY, TP and GLOB), antioxidants (SOD, GPx and GSH), and immune (IgM and lysozyme) parameters in LMB, except ALP and CAT. MM affected only hepatic GSH, with lower values in fish fed the OM diets. FM influenced the levels of ALP, AMY, GLOB, IgM, and MDA (P < 0.05). A three-way interactive effect (P = 0.016) was found on IgM only, with lower levels in fish fed diet 12 (low-FM, AM100, OM). Subsequently, the relative expressions of hepatic antioxidants (Cu/Zn-SOD and GPx-4), inflammatory cytokines (TNF-α and TGF-β1), lipid metabolism (FASN and CYP7A1), and organ growth (IGF-I) related genes were affected by the dietary treatments, with interactions being present in Cu/Zn-SOD, TNF-α, TGF-β1, FASN and IGF-I. Overall, dietary AM could be used as an alternative to FO in low-FM diets without compromising the health of LMB, especially when it is supplemented with MM.
Incidence of acute type A aortic dissection in emergency departments
Authors: Wundram Maximilian , Falk Volkmar , Eulert-Grehn Jaime-Jürgen , Herbst Hermann , Thurau Jana , Leidel Bernd A. , Göncz Eva , Bauer Wolfgang , Habazettl Helmut , Kurz Stephan D.
Published: May 2020

Due to the symptoms, patients with acute type A aortic dissection are first seen by the ambulance service and diagnosed at the emergency department. How often an aortic dissection occurs in an emergency department per year has been studied. The incidence in the emergency department may be used as a quality marker of differential diagnostics of acute chest pain. A multi-institutional retrospective study with the municipal Berlin hospital chain Vivantes and its Department of Pathology and the Charité - University Medicine Berlin was performed. From the Berlin Hospital Society, the annual numbers of publicly insured emergency patients were obtained. Between 2006 and 2016, 631 aortic dissections were identified. The total number of patients treated in the emergency departments (n = 12,790,577) was used to calculate the “emergency department incidence.” The autopsy data from six clinics allowed an estimate on how many acute type A aortic dissections remained undetected. Across all Berlin hospitals, the emergency department incidence of acute type A aortic dissection was 5.24 cases in 100,000 patients per year. In tertiary referral hospitals and, particularly, in university hospitals the respective incidences were markedly higher (6.7 and 12.4, respectively). Based on the autopsy results, about 50% of the acute type A aortic dissection may remain undetected, which would double the reported incidences. Among different hospital types the emergency department incidences of acute type A aortic dissection vary between 5.93/100,000 and 24.92/100,000. Aortic dissection; Incidence; Emergency Department; Epidemiology
Transcriptome-wide analysis reveals different categories of response to a standardised immune challenge in a wild rodent
Authors: Wanelik Klara M. , Begon Mike , Arriero Elena , Bradley Janette E. , Friberg Ida M. , Jackson Joseph A. , Taylor Christopher H. , Paterson Steve
Published: May 2020

Individuals vary in their immune response and, as a result, some are more susceptible to infectious disease than others. Little is known about the nature of this individual variation in natural populations, or which components of immune pathways are most responsible, but defining this underlying landscape of variation is an essential first step to understanding the drivers of this variation and, ultimately, predicting the outcome of infection. We describe transcriptome-wide variation in response to a standardised immune challenge in wild field voles. We find that genes (hereafter 'markers') can be categorised into a limited number of types. For the majority of markers, the response of an individual is dependent on its baseline expression level, with significant enrichment in this category for conventional immune pathways. Another, moderately sized, category contains markers for which the responses of different individuals are also variable but independent of their baseline expression levels. This category lacks any enrichment for conventional immune pathways. We further identify markers which display particularly high individual variability in response, and could be used as markers of immune response in larger studies. Our work shows how a standardised challenge performed on a natural population can reveal the patterns of natural variation in immune response.
miR-744-5p contributes to ocular inflammation in patients with primary Sjogrens Syndrome
Authors: Pilson Qistina , Smith Siobhan , Jefferies Caroline A. , Ní Gabhann-Dromgoole Joan , Murphy Conor C.
Published: May 2020

In primary Sjögren’s syndrome (pSS) the exocrine glands become infiltrated with lymphocytes instigating severe damage to the salivary and lacrimal glands causing dry eyes and dry mouth. Previous investigations have suggested that dysregulated localized and systemic inflammation contributes to the development and pathogenesis of pSS. A miR microarray performed in primary human conjunctival epithelial cells (PECs) demonstrated significant differences in miR expression at the ocular surface between pSS patients and healthy controls. MicroRNA-744-5p (miR-744-5p) was identified as being of particular interest, as its top predicted target is Pellino3 (PELI3), a known negative regulator of inflammation. Validation studies confirmed that miR-744-5p expression is significantly increased in PECs from pSS patients, whilst PELI3 was significantly reduced. We validated the miR-744 binding site in the 3’ untranslated region (UTR) of PELI3 and demonstrated that increasing PELI3 levels with a miR-744-5p antagomir in an inflammatory environment resulted in reduced levels of IFN dependent chemokines Rantes (CCL5) and CXCL10. These results reveal a novel role for miR-744-5p in mediating ocular inflammation via Pellino3 expression in pSS patients and suggest that miR-744-5p may be a potential therapeutic target for the management of severe dry eye disease and ocular inflammation in pSS patients.
A Complex Life Habitable Zone Based On Lipid Solubility Theory
Authors: Ramirez Ramses M.
Published: May 2020

To find potentially habitable exoplanets, space missions employ the habitable zone (HZ), which is the region around a star (or multiple stars) where standing bodies of water could exist on the surface of a rocky planet. Follow-up atmospheric characterization could yield biosignatures signifying life. Although most iterations of the HZ are agnostic regarding the nature of such life, a recent study argues that a complex life HZ would be considerably smaller than that used in classical definitions. Here, I use an advanced energy balance model to show that such an HZ would be considerably wider than originally predicted given revised CO2 limits and (for the first time) N2 respiration limits for complex life. The width of this complex life HZ (CLHZ) increases by ~35% from ~0.95–1.2 AU to 0.95–1.31 AU in our solar system. Similar extensions are shown for stars with stellar effective temperatures between 2,600–9,000 K. I define this CLHZ using lipid solubility theory, diving data, and results from animal laboratory experiments. I also discuss implications for biosignatures and technosignatures. Finally, I discuss the applicability of  the CLHZ and other HZ variants to the search for both simple and complex life.
SWATH-MS analysis of cerebrospinal fluid to generate a robust battery of biomarkers for Alzheimer’s disease
Authors: Park Sun Ah , Jung Jin Myung , Park Jun Sung , Lee Jeong Ho , Park Bumhee , Kim Hyung Jun , Park Jeong-Ho , Chae Won Seok , Jeong Jee Hyang , Choi Seong Hye , Baek Je-Hyun
Published: May 2020

Cerebrospinal fluid (CSF) Aβ42 and tau protein levels are established diagnostic biomarkers of Alzheimer’s disease (AD). However, their inadequacy to represent clinical efficacy in drug trials indicates the need for new biomarkers. Sequential window acquisition of all theoretical fragment ion spectra (SWATH)-based mass spectrometry (MS) is an advanced proteomic tool for large-scale, high-quality quantification. In this study, SWATH-MS showed that VGF, chromogranin-A, secretogranin-1, and opioid-binding protein/cell adhesion molecule were significantly decreased in 42 AD patients compared to 39 controls, whereas 14-3-3ζ was increased (FDR < 0.05). In addition, 16 other proteins showed substantial changes (FDR < 0.2). The expressions of the top 21 analytes were closely interconnected, but were poorly correlated with CSF Aβ42, tTau, and pTau181 levels. Logistic regression analysis and data mining were used to establish the best algorithm for AD, which created novel biomarker panels with high diagnostic value (AUC = 0.889 and 0.924) and a strong correlation with clinical severity (all p < 0.001). Targeted proteomics was used to validate their usefulness in a different cohort (n = 36) that included patients with other brain disorders (all p < 0.05). This study provides a list of proteins (and combinations thereof) that could serve as new AD biomarkers.