julilili42/papers huggingface dataset:
Strong error estimates for a space-time discretization of the linear-quadratic control problem with the stochastic heat equation with linear noise
2021-08-09

Abstract We propose a time-implicit, finite-element-based space-time discretization of the necessary and sufficient optimality conditions for the stochastic linear-quadratic optimal control problem with the stochastic heat equation driven by linear noise of type and prove optimal convergence w.r.t. both space and time discretization parameters. In particular, we employ the stochastic Riccati equation as a proper analytical tool to handle the linear noise, and thus extend the applicability of the earlier work by Prohl &amp; Wang (2021, Strong rates of convergence for a space-time discretization of the backward stochastic heat equation, and of a linear-quadratic control problem for the stochastic heat equation. ESAIM Control Optim. Calc. Var., 27, 54), where the error analysis was restricted to additive noise.
Reduction, reorganization and stasis in the evolution of turtle shell elements
2021-08-09

Abstract Novel phenotypic configurations can profoundly alter the evolutionary trajectories of species. Although innovation can precede lengthy periods of evolutionary stasis, the potential for species to diversify further can be realized via modular changes across distinct levels of hierarchical organization. To test this expectation, we undertook anatomical network analyses to model the organization and composition of the turtle’s shell. Our results suggest that stem turtles featured the greatest diversity in the number of skeletal (bones) and epidermal (scutes) shell elements. The shell subsequently underwent numerical simplification. Thus, the sum of potential connections (links) in shell networks has diminished in modern turtles. Some network system descriptors of complexity, integration and modularity covaried with the number of network components (nodes), which has remained evolutionarily stable since the Jurassic. We also demonstrated that shell reorganization might be feasible within modular subdivisions, particularly in modern turtles with simplified and less integrated network structures. We discuss how these findings align with previous studies on numerical simplification with enhanced skeletal specialization in the tetrapod skull. Altogether, our analyses expose the evolvability of the turtle’s shell and bolster the foundation for further macroevolutionary comparisons of ancient and modern species.
Reflective Willingness to Pay: Preferences for Sustainable Consumption in a Consumer Welfare Analysis
2021-08-09

Abstract Our starting point is the following simple but potentially underappreciated observation: When assessing willingness to pay (WTP) for hedonic features of a product, the results of such measurement are influenced by the context in which the consumer makes her real or hypothetical choice or in which the questions to which she replies are set (such as in a contingent valuation analysis). This observation is of particular relevance when WTP regards sustainability, the ‘non-use value’ of which does not derive from a direct (physical) sensation and where perceived benefits depend heavily on available information and deliberations. The recognition of such context sensitivity paves the way for a broader conception of consumer welfare (CW), and our proposed standard of ‘reflective WTP’ may materially change the scope for private market initiatives with regards to sustainability, while keeping the analytical framework within the realm of the CW paradigm. In terms of practical implications, we argue, for instance, that actual purchasing decisions may prove insufficient to measure consumer appreciation of sustainability, as they may rather echo learnt but unreflected heuristics and may be subject to the specific shopping context, such as heavy price promotions. Also, while preferences may reflect the current social norm, the latter may change considerably over time as more consumers adapt their behaviour.
A broadly neutralizing biparatopic Nanobody protects mice from lethal challenge with SARS-CoV-2 variants of concern
2021-08-09

Abstract The ongoing COVID-19 pandemic and the frequent emergence of new SARS-CoV-2 variants of concern (VOCs), requires continued development of fast and effective therapeutics. Recently, we identified high-affinity neutralizing nanobodies (Nb) specific for the receptor-binding domain (RBD) of SARS-CoV-2, which are now being used as biparatopic Nbs (bipNbs) to investigate their potential as future drug candidates. Following detailed in vitro characterization, we chose NM1267 as the most promising candidate showing high affinity binding to several recently described SARS-CoV-2 VOCs and strong neutralizing capacity against a patient isolate of B.1.351 (Beta). To assess if bipNb NM1267 confers protection against SARS-CoV-2 infection in vivo , human ACE2 transgenic mice were treated by intranasal route before infection with a lethal dose of SARS-CoV-2. NM1267-treated mice showed significantly reduced disease progression, increased survival rates and secreted less infectious virus via their nostrils. Histopathological analyses and in situ hybridization further revealed a drastically reduced viral load and inflammatory response in lungs of NM1267-treated mice. These data suggest, that bipNb NM1267 is a broadly active and easily applicable drug candidate against a variety of emerging SARS-CoV-2 VOCs.
Cryoturbation leads to iron-organic carbon associations along a permafrost soil chronosequence in northern Alaska
2021-08-09

In permafrost soils, substantial amounts of organic carbon (OC) are potentially protected from microbial degradation and transformation into greenhouse gases by association with reactive iron (Fe) minerals. As permafrost environments respond to climate change, increased drainage of thaw lakes in permafrost regions is predicted. Soils will subsequently develop on these drained thaw lakes, but the role of Fe-OC associations in future OC stabilization during this predicted soil development is unknown. To fill this knowledge gap, we have examined Fe-OC associations in organic, cryoturbated and mineral horizons along a 5500-year chronosequence of drained thaw lake basins in Utqiaġvik, Alaska. By applying chemical extractions, we found that ~17 % of the total OC content in cryoturbated horizons is associated with reactive Fe minerals, compared to ~10 % in organic or mineral horizons. As soil development advances, the total stocks of Fe-associated OC more than double within the first 50 years after thaw lake drainage, because of increased storage of Fe-associated OC in cryoturbated horizons (from 8 to 75 % of the total Fe-associated OC stock). Spatially-resolved nanoscale secondary ion mass spectrometry showed that OC is primarily associated with Fe(III) (oxyhydr)oxides which were identified by <sup>57</sup>Fe Mössbauer spectroscopy as ferrihydrite. High OC:Fe mass ratios (&gt;0.22) indicate that Fe-OC associations are formed via co-precipitation, chelation and aggregation. These results demonstrate that, given the proposed enhanced drainage of thaw lakes under climate change, OC is increasingly incorporated and stabilized by the association with reactive Fe minerals as a result of soil formation and increased cryoturbation.
Efficacy, tolerability, and retention of fenfluramine for the treatment of seizures in patients with Dravet syndrome: Compassionate use program in Germany
2021-08-10

Abstract Objective Dravet syndrome (DS) is a rare but severe drug‐resistant epilepsy. Before the approval of fenfluramine (FFA) for the treatment of seizures in DS, patients in Germany could receive treatment under a compassionate use program (CUP). Methods We conducted a multicenter, retrospective, observational study to describe the efficacy, tolerability, and retention of FFA within the CUP. Patients received add‐on therapy with oral FFA gradually titrated to a target dose between .13 and .7 mg/kg/day. Results Overall, 78 patients with DS (median age = 8.0 years, range = 2.1–46.0; 53% female, median concomitant antiseizure medications [ASMs] = 3) were treated with FFA for a median duration of 255.5 days (range = 31–572). Responder rates (a ≥50% reduction; n = 78) and seizure‐freedom rates at 3 months were 68% and 14% for total seizures, respectively, and 67% and 23% for generalized tonic–clonic seizures. Responder rates were consistent at 6 and 12 months ( n = 66 and n = 43, respectively). Median seizure days per month significantly decreased from 10.0 (range = .5–30) to 3.0 (range = 0–30) in the 3‐month period before and after FFA treatment ( p &lt; .001). Significantly fewer patients reported at least one episode of status epilepticus (28% vs. 14% patients before and after FFA initiation, p = .005). During FFA treatment, 35 (45%) patients were able to discontinue a concomitant ASM. At the last follow‐up date, 66 (85%) patients remained on treatment with FFA. The most common adverse events were somnolence (36%), decreased appetite (22%), and ataxia (8%). Forty‐eight (62%) patients were reported as having a meaningful global clinical improvement. Significance In a large cohort of patients, FFA demonstrated efficacy across a range of outcomes including clinically significant reductions in convulsive seizures, and was well tolerated, providing valuable information for real‐world practice.
Safety and Efficacy of Mepolizumab in Hypereosinophilic Syndrome: An Open-Label Extension Study
2021-08-10

Extended mepolizumab treatment was associated with a positive benefit-risk profile. Continued control of disease flares and blood eosinophil counts, plus reductions in OCS use, were observed with mepolizumab in patients with FIP1-like-1-platelet-derived growth factor receptor α-negative HES.
MONARCH 2: Subgroup Analysis of Patients Receiving Abemaciclib Plus Fulvestrant as First-Line and Second-Line Therapy for HR+, HER2−-Advanced Breast Cancer
2021-08-10

Abstract Purpose: In MONARCH 2, abemaciclib plus fulvestrant significantly prolonged progression-free survival (PFS) and overall survival (OS) versus placebo plus fulvestrant in patients with hormone receptor positive (HR+), HER2− advanced breast cancer. This exploratory analysis assessed the efficacy of abemaciclib plus fulvestrant across subgroups of patients receiving study therapy as first- or second-line treatment for metastatic disease. Patients and Methods: Improvements were estimated using Cox models, and a test of interactions of subgroups with treatment was performed. Results: The benefit in PFS [first-line, HR, 0.57; 95% confidence interval (CI), 0.45–0.73; second-line, HR, 0.48; 95% CI, 0.36–0.64] and OS (first-line, HR, 0.85; 95% CI, 0.64–1.14; second-line, HR, 0.66; 95% CI, 0.46–0.94) was observed across both subgroups, consistent with the intent-to-treat (ITT) population. In first-line patients (abemaciclib arm, n = 265; placebo arm, n = 133), the numerically largest effect on PFS and OS was observed in patients with primary resistance to endocrine therapy (ET; PFS, HR, 0.40; 95% CI, 0.26–0.63; OS, HR, 0.58; 95% CI, 0.35–0.97) and visceral disease (PFS, HR, 0.54; 95% CI, 0.39–0.73; OS, HR, 0.82; 95% CI, 0.58–1.20). In second-line patients (abemaciclib arm, n = 170; placebo arm, n = 86), a numerical benefit in PFS and OS was observed across primary and secondary ET resistance, with numerically more pronounced effects observed in patients with visceral disease (PFS, HR, 0.39; 95% CI, 0.27–0.57; OS, HR, 0.51; 95% CI, 0.33–0.81). Prolongation of time to second disease progression, time to chemotherapy, and chemotherapy-free survival was observed in both subgroups. Conclusions: Consistent with the ITT population, a benefit in PFS and OS was observed across the first- and second-line subgroups in MONARCH 2.
M01 as a novel drug enhancer for specifically targeting the blood-brain barrier.
2021-08-10

Drug delivery to the brain is limited for most pharmaceuticals by the blood-brain barrier (BBB) where claudin-5 dominates the paraendothelial tightening. For circumventing the BBB, we identified the compound M01 as a claudin-5 interaction inhibitor. M01 causes transient permeabilisation of the BBB depending on the concentration of small molecules in different cell culture models within 3 to 48 h. In mice, brain uptake of fluorescein peaked within the first 3 h after M01 injection and normalised within 48 h. Compared to the cytostatic paclitaxel alone, M01 improved delivery of paclitaxel to mouse brain and reduced orthotopic glioblastoma growth. Results on interactions of M01 with claudin-5 were incorporated into a binding model which suggests association of its aromatic parts with highly conserved residues of the extracellular domain of claudin-5 and adjacent transmembrane segments. Our results indicate the following mode of action: M01 preferentially binds to the extracellular claudin-5 domain, which weakens trans-interactions between adhering cells. Further decrease in membranous claudin-5 levels due to internalization and transcriptional downregulation enables the paracellular passage of small molecules. In summary, the first small molecule is introduced here as a drug enhancer, which specifically permeabilises the BBB for a sufficient interval for allowing neuropharmaceuticals to enter the brain.
Emergence of Dengue 4 as Dominant Serotype During 2017 Outbreak in South India and Associated Cytokine Expression Profile
2021-08-10

Dengue virus (DENV) infection is prevalent in tropical and subtropical regions of the world, which is fatal if untreated symptomatically. Emergence of new genotype within serotypes led to enhanced severity. The objective of the study is to identify the molecular characteristics of the DENV circulated during 2017 outbreak in Tamil Nadu, India, and to investigate the role of inflammatory cytokines in different “serotypes” and in “dengue severity”. A total of 135 suspected samples were tested for DENV infection using IgM, IgG, and qPCR assay; where 76 samples were positive for DENV and analyzed for 12 inflammatory cytokines using ELISA. Serotyping shows 14 DENV-1, 22 DENV-2, 7 DENV-3, and 33 DENV-4, where DENV-4 was predominant. Among 76, 42 isolates were successfully sequenced for C-prM region and grouped. A lineage shift was observed in DENV-4 genotype. Irrespective of serotypes, IFNγ was significantly elevated in all serotypes than control as well as in primary infection than secondary, indicating its role in immune response. GM-CSF and IP-10 were significantly elevated in secondary infection and could be used as prognostic biomarkers for secondary infection. Our observation shows differential cytokine expression profile varied with each serotype, indicating serotype/genotype-specific viral proteins might play a major role in dengue severity. DENV-4 as dominant serotype was reported in Tamil Nadu for the first time during an outbreak with a mixed Th1/Th17 cytokine expression profile that correlated with disease severity. We conclude it is essential to identify circulating viral genotype and their fitness by mutational analysis to correlate with disease severity and immune status, as this correlation will be helpful in diagnostics and therapeutics applications.
Relaxation‐corrected macromolecular model enables determination of 1H longitudinal T1‐relaxation times and concentrations of human brain metabolites at 9.4T
2021-08-10

Purpose Ultrahigh field MRS has improved characterization of the neurochemical profile. To compare results obtained at 9.4T to those from lower field strengths, it is of interest to quantify the concentrations of metabolites measured. Thus, measuring T 1 ‐relaxation times is necessary to correct for T 1 ‐weighting that occurs in acquisitions for single‐voxel spectroscopy and spectroscopic imaging. A macromolecule (MM) simulation model was developed to fit MM contributions to the short TE inversion series used to measure T 1 ‐relaxation times. Methods An inversion series with seven time points was acquired with metabolite‐cycled STEAM to estimate T 1 ‐relaxation times of metabolites. A short TE was employed in this study to retain signals from metabolites with short T 2 ‐relaxation times and J‐couplings. The underlying macromolecule spectrum was corrected by developing a sequence‐specific, relaxation‐corrected simulated MM model. Quantification of metabolite peaks was performed using internal water referencing and relaxation corrections. Results T 1 ‐relaxation times for metabolites range from approximately 750 to approximately 2000 ms and approximately 1000 to approximately 2400 ms in gray matter (GM)‐ and white matter (WM)‐ rich voxels, respectively. Quantification of metabolites was compared between GM and WM voxels, as well as between results that used a simulated MM spectrum against those that used an experimentally acquired MM spectrum. Metabolite concentrations are reported in mmol/kg quantities. Conclusion T 1 ‐relaxation times are reported for nonsinglet resonances for the first time at 9.4T by use of a MM simulation model to account for contributions from the MM spectrum. In addition to T 1 ‐relaxation times, quantification results of metabolites from GM‐ and WM‐rich voxels are reported.
The emergency medical service has a crucial role to unravel the genetics of sudden cardiac arrest in young, out of hospital resuscitated patients
2021-08-10

The EMS contributes especially in fatal OHCA-cases to increase the yield of identified genetic conditions by collecting a blood sample on scene. Thus, the EMS can contribute significantly to primary and secondary prophylaxis in affected families.
The Development of Vocational Interests in Early Adolescence: Stability, Change, and State-Trait Components
2021-08-10

Vocational interests predict major life outcomes such as job performance, college major choice, and life goals. It is therefore important to gain a better understanding of their development during the crucial years of late childhood and early adolescence, when trait-like interests are starting to develop. The present study investigated the development of vocational interests in a longitudinal sample, comprising N = 3,876 participants—assessed at four time points from ages 11 to 14. Stability, state-trait variance components, mean-level development, and gender differences in mean-levels of Realistic, Investigative, Artistic, Social, Enterprising, and Conventional (RIASEC) dimensions were examined. Stabilities were moderate for all dimensions, but Realistic, Investigative, Social, and Conventional interests became more stable over time. For Realistic, Artistic, Social, and Conventional interests, the trait variance increased over time. At age 14, all dimensions had substantial trait variance components. The mean-levels of Realistic, Investigative, Artistic, and Conventional interests decreased over the 3 years (–0.44 &lt; d &lt; –0.24). Initial gender differences—with girls having higher Artistic and Social interests and boys having higher Realistic and Investigative interests—increased over time. By investigating the development of vocational interests in late childhood and early adolescence, we complement previous findings and provide first insights about state-trait proportions in early adolescence.
Health-related fitness knowledge in adolescence: evaluation of a new test considering different psychometric approaches (CTT and IRT)
2021-08-10

Abstract Fostering health-related fitness knowledge is a common goal across physical education curricula. However, carefully developed knowledge tests that satisfy the psychometric criteria of educational assessment are lacking. Therefore, two studies were conducted to evaluate a newly developed health-related fitness knowledge test within the framework of classical test and item response theory regarding item quality, test reliability, construct validity, and dimensionality. Overall, 794 ninth graders ( M age = 14.3 years, 50.6% girls) took part in Study 1. They differed in the type of physical education classes (minor or major subject) and school (lower or higher educational level) they attended. Study 2 incorporated 834 ninth graders at the same educational level ( M age = 14.2 years, 52.5% girls). Item–test correlation, test reliability, and validity were examined. In addition, item and test quality were investigated using unidimensional two-parameter logistic item response models. In Study 1, pupils at the same educational level with physical education as a major achieved higher knowledge scores than pupils with physical education as a minor ( t = −5.99, p &lt; 0.001; d = 0.58), which confirmed the test’s construct validity. In Study 2, the weighted likelihood estimate reliability of the final 27 items was 0.65, and the test–retest reliability reached r tt = 0.70. The items satisfied the assumption of local independence. The final test fulfilled the psychometric criteria of reliability and construct validity to assess health-related fitness knowledge in cross-sectional and interventional studies. This test extends the possibilities of research on health-related fitness knowledge in physical education.
Does attentional focus modulate affective information processing in male violent offenders with psychopathic traits?
2021-08-10

Abstract Antisocial and psychopathic individuals are characterized by a reduced responsivity to affective information. Yet, the role of attentional processes as possible modulator of these deficits is poorly understood. The current study investigated early and late processing of emotional stimuli in a sample of incarcerated offenders while manipulating the attentional focus. Twenty‐seven male violent offenders with psychopathic traits and 27 healthy controls completed two experimental tasks while electroencephalography (EEG) data were collected. Task 1 assessed indirect processing of emotional or neutral distractors during a perceptual judgment task, while Task 2 measured direct processing of the emotional or neutral stimuli and required participants to rate the stimuli regarding valence and arousal. EEG data indicated no differences in early stage processing (early posterior negativity) between the experimental groups. However, we found significant group differences with regard to the late processing stage (late positive potential, LPP). Controls showed increased LPP amplitudes in Task 2 as compared to Task 1, indicating that task demands (i.e., attentional focus) had an effect on the processing of the emotional stimuli. In contrast, LPP amplitudes in the violent offender group were largely unaffected by task demands, suggesting specific late alterations in the neural processing of emotional stimuli. In sum, this study provides new evidence for a modulatory impact of attention on affective information processing in male violent offenders with psychopathic traits.