bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic architecture of orbital telorism
Authors: Knol Maria J , Pawlak Mikolaj A , Lamballais Sander , Terzikhan Natalie , Hofer Edith , Xiong Ziyi , Klaver Caroline C W , Pirpamer Lukas , Vernooij Meike W , Ikram M Arfan , Schmidt Reinhold , Kayser Manfred , Evans Tavia E , Adams Hieab H H 
Published: November 2021

AbstractThe interocular distance, or orbital telorism, is a distinctive craniofacial trait that also serves as a clinically informative measure. While its extremes, hypo- and hypertelorism, have been linked to monogenic disorders and are often syndromic, little is known about the genetic determinants of interocular distance within the general population. We derived orbital telorism measures from cranial magnetic resonance imaging by calculating the distance between the eyeballs’ centre of gravity, which showed a good reproducibility with an intraclass correlation coefficient of 0.991 (95% confidence interval 0.985–0.994). Heritability estimates were 76% (standard error = 12%) with a family-based method (N = 364) and 39% (standard error = 2.4%) with a single nucleotide polymorphism-based method (N = 34 130) and were unaffected by adjustment for height (model II) and intracranial volume (model III) or head width (model IV). Genome-wide association studies in 34 130 European individuals identified 56 significantly associated genomic loci (P &lt; 5 × 10−8) across four different models of which 46 were novel for facial morphology, and overall these findings replicated in an independent sample (N = 10 115) with telorism-related horizontal facial distance measures. Genes located nearby these 56 identified genetic loci were 4.9-fold enriched for Mendelian hypotelorism and hypertelorism genes, underlining their biological relevance. This study provides novel insights into the genetic architecture underlying interocular distance in particular, and the face in general, and explores its potential for applications in a clinical setting.
A Randomized, Double-Blind, Multicenter, Noninferiority Study Comparing Paliperidone Palmitate 6-Month Versus the 3-Month Long-Acting Injectable in Patients With Schizophrenia
Authors: Najarian Dean , Sanga Panna , Wang Steven , Lim Pilar , Singh Arun , Robertson Mary Jane , Cohen Kristin , Schotte Alain , Milz Ruth , Venkatasubramanian Raja , T’Jollyn Huybrecht , Walling David P , Galderisi Silvana , Gopal Srihari 
Published: November 2021

Abstract

Background
This double-blind (DB), randomized, parallel-group study was designed to evaluate efficacy and safety of paliperidone palmitate 6-month (PP6M) formulation relative to paliperidone palmitate 3-month (PP3M) formulation in patients with schizophrenia.

Methods
Following screening, patients entered an open-label (OL) maintenance phase and received 1 injection cycle of paliperidone palmitate 1-month (PP1M; 100 or 150 mg eq.) or PP3M (350 or 525 mg eq.). Clinically stable patients were randomized (2:1) to receive PP6M (700 or 1000 mg eq., gluteal injections) or PP3M (350 or 525 mg eq.) in a 12-month DB phase; 2 doses of PP6M (corresponding to doses of PP1M and PP3M) were chosen.

Results
Overall, 1036 patients were screened, 838 entered the OL phase, and 702 (mean age: 40.8 years) were randomized (PP6M: 478; PP3M: 224); 618 (88.0%) patients completed the DB phase (PP6M: 416 [87.0%]; PP3M: 202 [90.2%]). Relapse rates were PP6M, 7.5% (n = 36) and PP3M, 4.9% (n = 11). The Kaplan-Meier estimate of the difference (95% CI) between treatment groups (PP6M − PP3M) in the percentages of patients who remained relapse free was −2.9% (−6.8%, 1.1%), thus meeting noninferiority criteria (95% CI lower bound is larger than the pre-specified noninferiority margin of −10%). Secondary efficacy endpoints corroborated the primary analysis. Incidences of treatment-emergent adverse events were similar between PP6M (62.1%) and PP3M (58.5%). No new safety concerns emerged.

Conclusions
The efficacy of a twice-yearly dosing regimen of PP6M was noninferior to that of PP3M in preventing relapse in patients with schizophrenia adequately treated with PP1M or PP3M.

Trial Registration
Clinical Trials.gov identifier: NCT03345342
7-Aryl-7-deazapurine 3′-deoxyribonucleoside derivative as a novel lead for Chagas’ disease therapy: in vitro and in vivo pharmacology
Authors: Cardoso-Santos Camila , Ferreira de Almeida Fiuza Ludmila , França da Silva Cristiane , Mazzeti Ana Lia , Donola Girão Roberson , Melo de Oliveira Gabriel , da Gama Jaen Batista Denise , Cruz Moreira Otacilio , Lins da Silva Gomes Natália , Maes Louis , Caljon Guy , Hulpia Fabian , Calenbergh Serge V , Correia Soeiro Maria de Nazaré 
Published: November 2021

Abstract

Background
The protozoan Trypanosoma cruzi is auxotrophic for purines and causes Chagas’ disease (CD), a neglected illness affecting &gt;6 million people. Combining the 3-deoxyribofuranose part of cordycepin with the modified purine ring of a nucleoside ‘hit’ led to the discovery of 4-amino-5-(4-chlorophenyl)-N7-(3′-deoxy-β-d-ribofuranosyl)-pyrrolo[2,3-d]pyrimidine (Cpd1), revealing promising anti-T. cruzi activity.

Objectives
To further evaluate Cpd1 in vitro and in vivo to fully assess its therapeutic potential against CD, covering cell culture sterilization through washout assays, drug combination with benznidazole and long-term administration in T. cruzi-infected mice.

Results
Although less susceptible to Cpd1 than amastigotes, trypomastigotes present an impaired capacity to successfully establish intracellular infection of cardiac cultures. Combination of benznidazole with Cpd1 indicated no interaction (additive effect) (FIC index = 0.72) while administration to mice at one-tenth of the optimal dose (2.5 mg/kg and 10 mg/kg for Cpd1 and benznidazole, respectively) suppressed parasitaemia but failed to avoid mortality. Long-term treatment (60 days) gave a rapid drop of the parasitaemia (&gt;98% decline) and 100% mice survival but only 16% cure. In vitro washout experiments demonstrated that although parasite release into the supernatant of infected cardiac cultures was reduced by &gt;94%, parasite recrudescence did occur after treatment.

Conclusions
Parasite recrudescence did occur after treatment corroborating the hypothesis of therapeutic failure due to subpopulations of dormant forms and/or genetic factors in persister parasites involved in natural drug resistance.
Selecting Processing Robust Markers Using High-Resolution Mass Spectrometry for the Detection of Milk in Food Products
Authors: Van Vlierberghe Kaatje , Gavage Maxime , Dieu Marc , Renard Patsy , Arnould Thierry , Gillard Nathalie , Coudijzer Katleen , de Loose Marc , Gevaert Kris , Van Poucke Christof 
Published: November 2021

Abstract

Background
Cow’s milk allergy is one of the most reported food allergies in Europe. To help patients suffering from food allergies it is important to be able to detect milk in different foods. An analytical method that is gaining interest in the field of allergen detection is ultrahigh performance liquid chromatography-tandem mass spectrometry, where the analyte is a target peptide. When these peptide biomarkers are selected, the effect of food processing should be taken into account to allow a robust detection method.

Objective
This work aims at identifying such processing stable peptide markers for milk for the ultrahigh performance liquid chromatography-tandem mass spectrometry based detection of food allergens in different food products.

Method
Milk-incurred food materials that underwent several processing techniques were produced. This was followed by establishing tryptic peptide profiles from each matrix using ultrahigh performance liquid chromatography-high resolution mass spectrometry.

Results
A careful comparison of peptide profiles/intensities and the use of specific exclusion criteria resulted in the selection of eight peptide biomarkers suitable for application in ultrahigh performance liquid chromatography-tandem mass spectrometry based milk detection methods. One of these markers is an α-lactalbumin specific peptide, which has been determined to be stable in different incurred materials for the first time.

Conclusions
To our knowledge, this is the first systematic and experimentally based approach for the selection of suitable milk peptide biomarkers robust toward multiple, often applied food processing techniques for milk. Ensuring the exact knowledge of the food processing circumstances by starting from well-defined raw material and using fully controlled settings to produce incurred test material allowed the construction of a peptide database with robust markers. These robust markers can be used for the development of a robust detection method for milk in different food matrixes.

Highlights
To facilitate food allergen detection in processed food, processing stable peptide markers for the detection of milk in food products were determined using Ultra-High Performance Liquid Chromatography-High Resolution Mass Spectrometry on well-defined raw materials which were processed in accordance with often used processing techniques.
Impact of Honey Bee Migratory Management on Pathogen Loads and Immune Gene Expression is Affected by Complex Interactions With Environment, Worker Life History, and Season
Authors: Simone-Finstrom Michael , Strand Micheline K , Tarpy David R , Rueppell Olav 
Published: November 2021

AbstractThe effects of honey bee management, such as intensive migratory beekeeping, are part of the ongoing debate concerning causes of colony health problems. Even though comparisons of disease and pathogen loads among differently managed colonies indicate some effects, the direct impact of migratory practices on honey bee pathogens is poorly understood. To test long- and short-term impacts of managed migration on pathogen loads and immunity, experimental honey bee colonies were maintained with or without migratory movement. Individuals that experienced migration as juveniles (e.g., larval and pupal development), as adults, or both were compared to control colonies that remained stationary and therefore did not experience migratory relocation. Samples at different ages and life-history stages (hive bees or foragers), taken at the beginning and end of the active season, were analyzed for pathogen loads and physiological markers of health. Bees exposed to migratory management during adulthood had increased levels of the AKI virus complex (Acute bee paralysis, Kashmir bee, and Israeli acute bee paralysis viruses) and decreased levels of antiviral gene expression (dicer-like). However, those in stationary management as adults had elevated gut parasites (i.e. trypanosomes). Effects of environment during juvenile development were more complex and interacted with life-history stage and season. Age at collection, life-history stage, and season all influenced numerous factors from viral load to immune gene expression. Although the factors that we examined are not independent, the results illuminate potential factors in both migratory and nonmigratory beekeeping that are likely to contribute to colony stress, and also indicate potential mitigation measures.
A stringent upper limit on dark matter self-interaction cross-section from cluster strong lensing
Authors: Andrade Kevin E , Fuson Jackson , Gad-Nasr Sophia , Kong Demao , Minor Quinn , Roberts M Grant , Kaplinghat Manoj 
Published: November 2021

ABSTRACT
We analyse strongly lensed images in eight galaxy clusters to measure their dark matter density profiles in the radial region between 10 kpc and 150 kpc, and use this to constrain the self-interaction cross-section of dark matter (DM) particles. We infer the mass profiles of the central DM haloes, bright central galaxies, key member galaxies, and DM subhaloes for the member galaxies for all eight clusters using the qlens code. The inferred DM halo surface densities are fit to a self-interacting dark matter model, which allows us to constrain the self-interaction cross-section over mass σ/m. When our full method is applied to mock data generated from two clusters in the Illustris-TNG simulation, we find results consistent with no dark matter self-interactions as expected. For the eight observed clusters with average relative velocities of $1458_{-81}^{+80}$ km s−1, we infer $\sigma /m = 0.082_{-0.021}^{+0.027} \rm cm^2\, g^{ -1}$ and $\sigma /m \lt 0.13~ \rm cm^2\, g^{ -1}$ at the 95 per cent confidence level.
The impact of stellar companion UV photons on the chemistry of the circumstellar environments of AGB stars
Authors: Van de Sande M , Millar T J 
Published: November 2021

ABSTRACT
Spherical asymmetries are prevalent within the outflows of AGB stars. Since binary interaction with a stellar or planetary companion is thought to be the underlying mechanism behind large-scale structures, we included the effects of UV radiation originating from a stellar companion in our chemical kinetics model. The one-dimensional model provides a first approximation of its effects on the chemistry throughout the outflow. The presence of a close-by stellar companion can strongly influence the chemistry within the entire outflow. Its impact depends on the intensity of the radiation (set by the stellar radius and blackbody temperature) and on the extinction, the UV radiation experiences (set by the outflow density, density structure, and assumed radius of dust formation). Parent species can be photodissociated by the companion, initiating a rich photon-driven chemistry in the inner parts of the outflow. The outcome depends on the balance between two-body reactions and photoreactions. If two-body reactions dominate, chemical complexity within the outflow increases. This can make the abundance profiles of daughters appear like those of parents, with a larger inner abundance and a Gaussian decline. If photoreactions dominate, the outflow can appear molecule-poor. We model three stellar companions. The impact of a red dwarf companion is limited. Solar-like companions show the largest effect, followed by a white dwarf. A stellar companion can also lead to the formation of unexpected species. The outflow’s molecular content, especially combined with abundance profiles, can indicate a stellar companion’s presence. Our results pave the way for further outflow-specific (three-dimensional) model development.
Electron mirror and cyclotron instabilities for solar wind plasma
Authors: Sarfraz M , López R A , Ahmed Shahzad , Yoon P H 
Published: November 2021

ABSTRACT
The solar wind plasma is characterized by unequal effective kinetic temperatures defined in perpendicular and parallel directions with respect to the ambient magnetic field. For electrons, the excessive perpendicular temperature anisotropy leads to quasi-parallel electromagnetic electron cyclotron (or whistler) instability and aperiodic electron-mirror instability with oblique wave vectors. The present paper carries out a direct side-by-side comparison of quasi-linear (QL) theory and particle-in-cell (PIC) simulation of combined mirror and cyclotron instabilities acting upon the initially anisotropic electron temperatures, and find that the QL theory satisfactorily encapsulates the non-linear aspect of the combined instability effects. However, a discrepancy between the present study and a previous PIC simulation result is also found, which points to the need for further investigation to resolve such an issue.
Mapping the cosmic mass distribution with stacked weak gravitational lensing and Doppler lensing
Authors: Hossen Md Rasel , Ema Sonia Akter , Bolejko Krzysztof , Lewis Geraint F 
Published: November 2021

ABSTRACT
Dark matter haloes represent the highest density peaks in the matter distribution. Conversely, cosmic voids are underdense patches of the universe. Probing the mass distribution of the universe requires various approaches, including weak gravitational lensing that subtly modifies the shape of distant sources, and Doppler lensing that changes the apparent size and magnitude of objects due to peculiar velocities. In this work, we adopt both gravitational and Doppler lensing effects to study the underlying matter distribution in and around cosmic voids or haloes. We use the relativistic N-body code gevolution, to generate the mass perturbations and develop a new ray-tracing code that relies on the design of the ray bundle method. We consider three categories of halo masses and void radii, and extract the cosmological information by stacking weak-lensing and Doppler lensing signals around voids or haloes. The results of this paper show that the most optimal strategy that combines both gravitational and Doppler lensing effects to map the mass distribution should focus on the redshift range z ≈ 0.3−0.4. The recommendation of this paper is that future spectroscopic surveys should focus on these redshifts and utilize the gravitational and Doppler lensing techniques to extract information about underlying matter distribution across the cosmic web, especially inside cosmic voids. This could provide a complimentary cosmological analysis for ongoing or future low-redshift spectroscopic surveys.
Systematic review and meta-analysis of PD-L1 expression discordance between primary tumor and lung cancer brain metastasis
Authors: Tonse Raees , Rubens Muni , Appel Haley , Tom Martin C , Hall Matthew D , Odia Yazmin , McDermott Michael W , Ahluwalia Manmeet S , Mehta Minesh P , Kotecha Rupesh 
Published: November 2021

Abstract

Background
Novel immunotherapeutic strategies targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis are often administered when metastatic tumors show PD-L1 positivity, even in the setting of lung cancer brain metastasis (LCBM). However, biological differences exist between primary tumors and metastatic sites. The objective of this study was to analyze rates of PD-L1 receptor discordance between primary tumors and LCBM.

Methods
A systematic review of studies of biopsied or resected LCBM evaluating PD-L1 discordance published in the Medline database was performed using PRISMA guidelines. Weighted random effects models were used to calculate pooled estimates.

Results
Six full-text articles (n = 230 patients) with a median of 32 patients in each study (range: 24–73) reported PD-L1 receptor expression analyses of both primary lung tumors and brain metastases and met inclusion criteria. The pooled estimate for tumor cell (TC) PD-L1 receptor discordance between primary tumors and LCBM was 19% (95% confidence interval [CI]: 10–27%). For PD-L1 receptor expression in tumor-infiltrating lymphocytes (TIL), the weighted pooled estimate for discordance was 21% (95% CI: 8–44%). For primary versus LCBM, the positive rates by expression levels of &lt;1%, 1–50%, and &gt;50% were 52% (95% CI: 30–73%) versus 56% (95% CI: 34–76%), 30% (95% CI: 22–40%) versus 20% (95% CI: 10–35%), and 15% (95% CI: 6–36%) versus 22% (95% CI: 15–31%) (P = .425), respectively.

Conclusions
PD-L1 discordance occurs in ~20% of LCBM, with the greatest discordance in the 1–50% expression category. Although controversial, confirming discordance might be important for selection of immune checkpoint inhibitor therapy and in the analysis of patterns of failure after treatment.
Reduction of the canonical function of a glycolytic enzyme enolase triggers immune responses that further affect metabolism and growth in Arabidopsis
Authors: Yang Leiyun , Wang Zhixue , Zhang Aiqin , Bhawal Ruchika , Li Chunlong , Zhang Sheng , Cheng Lailiang , Hua Jian 
Published: November 2021

Abstract
Primary metabolism provides energy for growth and development as well as secondary metabolites for diverse environmental responses. Here we describe an unexpected consequence of disruption of a glycolytic enzyme enolase named LOW EXPRESSION OF OSMOTICALLY RESPONSIVE GENE 2 (LOS2) in causing constitutive defense responses or autoimmunity in Arabidopsis thaliana. The autoimmunity in the los2 mutant is accompanied by a higher expression of about one-quarter of intracellular immune receptor nucleotide-binding leucine-rich repeat (NLR) genes in the genome and is partially dependent on one of these NLR genes. The LOS2 gene was hypothesized to produce an alternatively translated protein c-Myc Binding Protein (MBP-1) that functions as a transcriptional repressor. Complementation tests show that LOS2 executes its function in growth and immunity regulation through the canonical enolase activity but not the production of MBP-1. In addition, the autoimmunity in the los2 mutants leads to a higher accumulation of sugars and organic acids and a depletion of glycolytic metabolites. These findings indicate that LOS2 does not exert its function in immune responses through an alternatively translated protein MBP-1. Rather, they show that a perturbation of glycolysis from the reduction of the enolase activity results in activation of NLR-involved immune responses which further influences primary metabolism and plant growth, highlighting the complex interaction between primary metabolism and plant immunity.
Inequality of access to advanced therapies for patients with inflammatory arthritis: a postcode lottery?
Authors: Kaul Arvind , Mistry Jatin , Iagnocco Annamaria , Baraliakos Xenofon , Bosworth Ailsa , McNicol Iain 
Published: November 2021

Abstract

Objectives
Advanced therapies (AT), including biologics, biosimilars and Janus kinase inhibitors, have dramatically improved the quality of life of patients with RA, PsA and axial spondyloarthritis (axSpA). Evidence-based criteria for prescribing these drugs in England and Wales is formulated by the National Institute for Health and Care Excellence (NICE) through health technology appraisals and guidelines, with the aim of providing equitable access to AT for patients with severe or resistant disease. Similar bodies exist in some, but not all European countries, with disparities in AT access between countries for RA. We examined whether this disparity was mirrored in England for RA, PsA and axSpA despite the National Health Service in England and Wales being legally obliged to provide funding for AT recommended by NICE’s Health Technology Appraisal board, through the commissioning bodies, the clinical commissioning groups (CCGs).

Methods
We requested AT pathways from CCGs in England. Where these were not available, individual hospital Trusts were contacted using freedom of information requests.

Results
We found marked variability in the way that CCGs in England interpret NICE guidance. We found 41, 29 and 25 different pathways for RA, PsA and axSpA, respectively. Similar disparities existed with sequential prescribing where one AT did not work, with limits on the numbers of sequential AT in 54%, 59% and 59% of CCGs for RA, PsA and axSpA, respectively, and with these limits being different for the same condition between CCGs.

Conclusion
Although patients at identical stages of their disease course should have access to the same NICE-approved AT, we found this is not the case for large parts of England. Inequality of access was found between regions, mirroring the variability that occurs between countries throughout Europe. Harmonization of access needs to be addressed by policymakers to ensure fairness in the way that clinicians and patients can access AT.