bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synonymous variants that disrupt messenger RNA structure are significantly constrained in the human population
Authors: Gaither Jeffrey B S , Lammi Grant E , Li James L , Gordon David M , Kuck Harkness C , Kelly Benjamin J , Fitch James R , White Peter 
Published: April 2021

Abstract

Background
The role of synonymous single-nucleotide variants in human health and disease is poorly understood, yet evidence suggests that this class of “silent” genetic variation plays multiple regulatory roles in both transcription and translation. One mechanism by which synonymous codons direct and modulate the translational process is through alteration of the elaborate structure formed by single-stranded mRNA molecules. While tools to computationally predict the effect of non-synonymous variants on protein structure are plentiful, analogous tools to systematically assess how synonymous variants might disrupt mRNA structure are lacking.

Results
We developed novel software using a parallel processing framework for large-scale generation of secondary RNA structures and folding statistics for the transcriptome of any species. Focusing our analysis on the human transcriptome, we calculated 5 billion RNA-folding statistics for 469 million single-nucleotide variants in 45,800 transcripts. By considering the impact of all possible synonymous variants globally, we discover that synonymous variants predicted to disrupt mRNA structure have significantly lower rates of incidence in the human population.

Conclusions
These findings support the hypothesis that synonymous variants may play a role in genetic disorders due to their effects on mRNA structure. To evaluate the potential pathogenic impact of synonymous variants, we provide RNA stability, edge distance, and diversity metrics for every nucleotide in the human transcriptome and introduce a “Structural Predictivity Index” (SPI) to quantify structural constraint operating on any synonymous variant. Because no single RNA-folding metric can capture the diversity of mechanisms by which a variant could alter secondary mRNA structure, we generated a SUmmarized RNA Folding (SURF) metric to provide a single measurement to predict the impact of secondary structure altering variants in human genetic studies.
Insights into the roles of charged residues in substrate binding and mode of action of mannuronan C-5 epimerase AlgE4
Authors: Gaardløs Margrethe , Samsonov Sergey A , Sletmoen Marit , Hjørnevik Maya , Sætrom Gerd Inger , Tøndervik Anne , Aachmann Finn Lillelund 
Published: April 2021

Abstract
Mannuronan C-5 epimerases catalyze the epimerization of monomer residues in the polysaccharide alginate, changing the physical properties of the biopolymer. The enzymes are utilized to tailor alginate to numerous biological functions by alginate-producing organisms. The underlying molecular mechanism that control the processive movement of the epimerase along the substrate chain is still elusive. To study this, we have used an interdisciplinary approach combining molecular dynamics simulations with experimental methods from mutant studies of AlgE4, where initial epimerase activity and product formation were addressed with nuclear magnetic resonance spectroscopy, and characteristics of enzyme–substrate interactions were obtained with isothermal titration calorimetry and optical tweezers. Positive charges lining the substrate-binding groove of AlgE4 appear to control the initial binding of poly-mannuronate, and binding also seems to be mediated by both electrostatic and hydrophobic interactions. After the catalytic reaction, negatively charged enzyme residues might facilitate dissociation of alginate from the positive residues, working like electrostatic switches, allowing the substrate to translocate in the binding groove. Molecular simulations show translocation increments of two monosaccharide units before the next productive binding event resulting in mannuronate and guluronate (MG)-block formation, with the epimerase moving with its N-terminus towards the reducing end of the alginate chain. Our results indicate that the charge pair R343–D345 might be directly involved in conformational changes of a loop that can be important for binding and dissociation. The computational and experimental approaches used in this study complement each other, allowing for a better understanding of individual residues’ roles in binding and movement along the alginate chains.
Deep neural network approximation for high-dimensional elliptic PDEs with boundary conditions
Authors: Grohs Philipp , Herrmann Lukas 
Published: April 2021

Abstract
In recent work it has been established that deep neural networks (DNNs) are capable of approximating solutions to a large class of parabolic partial differential equations without incurring the curse of dimension. However, all this work has been restricted to problems formulated on the whole Euclidean domain. On the other hand, most problems in engineering and in the sciences are formulated on finite domains and subjected to boundary conditions. The present paper considers an important such model problem, namely the Poisson equation on a domain $D\subset \mathbb {R}^d$ subject to Dirichlet boundary conditions. It is shown that DNNs are capable of representing solutions of that problem without incurring the curse of dimension. The proofs are based on a probabilistic representation of the solution to the Poisson equation as well as a suitable sampling method.
GC-MS Analysis and Antioxidant Activity ofWrightia tinctoriaR.Br. Leaf Extract
Authors: Khan Nausheen , Ali Amena , Qadir Abdul , Ali Athar , Warsi Musarrat Husain , Tahir Abu , Ali Abuzer 
Published: April 2021

AbstractBackgroundWrightia tinctoria R.Br. (Apocyanaceae) is known as a biologically effective plant for the treatment of jaundice in the Indian traditional system of medicine. It is a wild medicinal tree possessing anti-inflammatory, antidiabetic, antinociceptive, hepatoprotective, antibacterial, antifungal, antiviral, antipsoriatic, anticancerous, anthelmintic, aphrodisiac, analgesic, and antipyretic activities. Its constituents are of utmost interest to pharmaceutical industries owing to their many actions and biological activities.MethodMethanolic extract of W. tinctoria (MEWT) was investigated by gas chromatography-mass spectroscopy and provided affirmative results assisting in the identification and characterization of therapeutic claims regarding this species in the traditional system. The antioxidant activity of MEWT was determined by the most suitable DPPH method.ResultsThe basic compounds found in MEWT were β-caryophyllene (0.22%), mome inositol (12.02%), neophytadiene (1.61%), eicosanoic acid methyl ester (0.32%), 8,11,14-eicosatrienoic acid methyl ester (0.60%), phytol (0.94%), phytol palmitate (1.37%), squalene (1.57%), flavone 4-OH, 5-OH, 7-di-O-glucoside (29.34%), γ-tocopherol (0.49%), stigmast-5-en-3-ol (3.14%), methyl commate B (1.76%), methyl commate A (5.20%), and 24-norursa-3,12-diene (20.36%). The obtained results in the analysis of antioxidant activity of MEWT exhibited considerable free radical scavenging capacity against DPPH-generated free radicals.ConclusionsThis study expands the knowledge of MEWT chemical composition and provides evidence to substantiate ethno-medicinal use of the plant by exploring antioxidant activity. The substantial antioxidant activity of MEWT could be due to presence of terpenes, flavonoids, vitamin E, and other reported compounds.HighlightsThis study includes identification of phytochemicals and antioxidant potential of methanolic extract of Wrightia tinctoria, assisting in therapeutic claims regarding this species in the traditional system.
Unpacking a(nother) voyage round the world
Authors: MacKinney Anne Greenwood , Glaubrecht Matthias 
Published: April 2021

Abstract
This article studies the history of the specimen collection formed by the Franco-Prussian naturalist Adelbert von Chamisso (1781–1838), particularly its assembly during the Russian-led Rurik expedition (1815–18) and its subsequent donation to the museums of Berlin University. It examines three inventories which emerged in the process of transferring objects from an individual collector to an institutional collection, and which demonstrate how transformations in the textual documentation of the collection shaped the objects’ perceived significance. Paying attention to the people who generated collection documents, as well as the intended audiences and the purposes for which they were written, the article argues, is a crucial prerequisite for analysing the history, movements and meaning of collections and collected objects.
Screening of chronic radiation proctitis and colorectal cancer using periodic total colonoscopy after external beam radiation therapy for prostate cancer
Authors: Nakamura Yuki , Soma Takahiko , Izumi Keita , Sakai Yasuyuki , Ushijima Hiroki , Kudo Shigehiro , Saito Yoshihiro , Kageyama Yukio 
Published: April 2021

Abstract

Objective
To investigate the incidence of colorectal cancer and chronic radiation proctitis after prostate radiotherapy using periodic total colonoscopy screening.

Methods
From February 2013 to January 2018, 270 patients who underwent external beam radiation therapy for prostate cancer were advised to receive periodic total colonoscopy screening annually. We evaluated the incidence and characteristics of colorectal cancer and chronic radiation proctitis.

Results
First, second, third, fourth and fifth total colonoscopy were performed in 256 (95%), 151 (56%), 60 (22%), 23 (8.5%) and 7 (2.6%) patients at a median of 14, 31, 42, 54 and 72 months after radiotherapy, respectively. The prevalence proportion of colorectal cancer in the first colonoscopy since radiotherapy was 3.9%. Twelve (4.4%) patients were diagnosed with colorectal cancer, including four invasive cancers, during a follow-up period. Eight of these 12 patients had not experienced rectal bleeding. The median time to diagnosis of colorectal cancer was 21 months. Chronic radiation proctitis was observed in 136 (50%) patients, including 67 (25%) patients with symptomatic bleeding.

Conclusions
The high detection rate of asymptomatic radiation proctitis suggests the utility of total colonoscopy to screen for early-stage colorectal cancer prior to or following radiotherapy for prostate cancer. Considering the longevity after localized prostate cancer treatment, the awareness of chronic radiation-induced proctitis and the risk of colorectal cancer masked by bleeding is needed in treatment decision -making.
Disability and the Complexity of Choice in the Ethics of Abortion and Voluntary Euthanasia
Authors: Clifton Shane 
Published: April 2021

Abstract
In the polarized debates about abortion and voluntary euthanasia, disability advocates, who normally align with left-wing social forces, have tended to side with conservative and religious voices in expressing concerns about the impact of technological and sociopolitical developments on disabled futures. This paper draws on the social model of disability and the virtue ethics tradition to explain the alignment between the religious and disability perspectives, and the theory of transformative choice to highlight the limits and biases of the pro-choice logic. Yet, it also recognizes the inherent contradiction of disabled advocates taking a paternalistic position against the personal agency of women and people facing terminal illnesses. A disability perspective serves the discussion of abortion and euthanasia as an encouragement to work together for the building of a society that enables people with diverse disabilities to exist and flourish, and helps pregnant women, people facing disabling and terminal illnesses, and politicians and social influencers to make informed choices.
Miscarriage Is Not a Cause of Death: A Response to Berg’s “Abortion and Miscarriage”
Authors: Colgrove Nicholas 
Published: April 2021

Abstract
Some opponents of abortion claim fetuses are persons from the moment of conception. Call these “Personhood-At-Conception” (or PAC), opponents of abortion. Amy Berg (2017, Philosophical Studies 174:1217–26) argues that if fetuses are persons from the moment of conception, then miscarriage kills far more people than abortion. Thus, PAC opponents of abortion must “immediately” and “substantially” shift their attention, resources, etc., toward preventing miscarriage or admit they do not believe that personhood begins at conception (or, at least, they should recognize they are not acting in ways consistent with this belief). Unfortunately, Berg’s argument fails at every step. After outlining her argument, I show that her claim—that “miscarriage . . . is much deadlier than abortion”—is false (when taken literally) and misleading otherwise. Further, Berg’s argument is identical in structure to a criticism sometimes levied against the “Black Lives Matter” movement. In the latter context, the argument has been vehemently rejected. Berg’s argument should be rejected for the same reasons. Finally, Berg cites no evidence when claiming that PAC opponents of abortion are “not doing enough” to prevent miscarriage. And, even if PAC opponents of abortion are not diverting substantial funds toward miscarriage prevention, Berg fails to notice that this may be for good reason.
Biomarkers of Stress in Music Interventions: A Systematic Review
Authors: Wong Melanie Mitsui , Tahir Talha , Wong Michael Mitsui , Baron Annilee , Finnerty Rachael 
Published: April 2021

Abstract
Psychological stress is a significant public health concern as it is associated with various comorbidities and long-term health implications. Music interventions are emerging therapies for alleviating psychological stress and improving one’s physical and mental well-being. We conducted a systematic literature review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement guidelines for reporting to identify all neuroendocrine biomarkers used to evaluate psychological stress in randomized control trials involving music interventions. We identified 18 unique biomarkers of stress from 14 full-text randomized controlled trials studies. Only one of the 14 music studies included a music therapy intervention. The most frequently used biomarkers across the studies were plasma cortisol, salivary cortisol, and salivary α-amylase. Of the 14 studies, 12 included in this review assessed at least one of these three biomarkers. Of these 12 studies, five papers reported p-values for changes in both stress biomarkers and psychological stress outcome measures. Four of the five studies found significant p-values for the reduction of both stress biomarkers and psychological stress in music intervention groups. The variety of stress biomarkers used and the variance in study protocols makes it difficult to assess the magnitude of effect of music interventions on psychological stress. However, our findings suggest that music interventions have the potential for reducing both stress biomarker levels and psychological stress in acute stress situations.
Dynamics of Large Corporate Forestland Ownerships in the United States
Authors: Sass Emma M , Markowski-Lindsay Marla , Butler Brett J , Caputo Jesse , Hartsell Andrew , Huff Emily , Robillard Amanda 
Published: April 2021

AbstractOwnership of forestland in the United States has changed in recent decades, including the proliferation of timber investment management organizations (TIMOs) and real estate investment trusts (REITs), with the potential to alter forest management and timber supply. This article quantifies forest ownership transitions among ownership categories between 2007 and 2017 and investigates how and why large corporate ownerships own and manage their forestlands. Ownership transitions were determined from refined USDA Forest Service, Forest Inventory and Analysis data; we also conducted a survey of large corporate forestland ownerships. Corporate forestland acreage increased between 2007 and 2017, while family and public forestland decreased. Large corporate landowners report multidimensional, financially focused land management, although industry, timber investment management organizations, real estate investment trusts, and other owners report some different motivations and income streams. This work provides a baseline to track future ownership transitions and the behaviors of large corporate forestland owners.
Prognosis of duodenal gangliocytic paraganglioma with lymph node metastasis: is follow-up &gt;5 years required?
Authors: Yepuri Natesh , Vanga Gautam R , Naous Rana , Pasham Sudhir , Ponnekanti Sravan , Kinthala Sudhakar 
Published: April 2021

Abstract
Gangliocytic paragangliomas (GP) are rare tumors encountered exclusively in the second portion of the duodenum. Duodenal gangliocytic paraganglioma (DGP) belongs to a subclass of neuroendocrine neoplasms, characterized with unique histologic features of carcinoid tumor, paraganglioma and ganglioneuromas. According to the recent World Health Organization classification of gastrointestinal neuroendocrine tumors (NETs), there is a debate to classify them either as low-grade NETs or as an independent entity. There are a few reports of regional lymph node (LN) metastasis that could argue DGP as a true neoplasm. However, majority of them had a benign course, raising the question of whether long-term follow-up is required. We report a case of a retroperitoneal LN involvement by metastatic GP and additionally performed a systematic review of the literature to determine the optimal follow-up, since no guidelines exist for this rare entity.
The end of the Great Speed-Up—and after
Authors: Salt Barry 
Published: April 2021

Abstract
The major shift in the feature film cutting rate over the sound film period is statistically investigated, with a demonstration of how this reduction in Average Shot Length has stopped since around the year 2000. The way in which other stylistic features, such as movement within the frame, colour saturation, and number of words spoken per minute, have increasingly been used by film-makers over the last 20 years for stylistic differentiation in their work is also shown.
Stellar mid-life crisis: subcritical magnetic dynamos of solar-like stars and the breakdown of gyrochronology
Authors: Tripathi Bindesh , Nandy Dibyendu , Banerjee Soumitro 
Published: April 2021

ABSTRACT
Recent observations have revealed the surprising breakdown of stellar gyrochronology relations at about the age of the Sun hinting the middle-aged, solar-like stars transition to a magnetically inactive future. We provide a theoretical basis for these intriguing observations inspired by simulations with a mathematical-dynamo model that can explore long-term solar cycle fluctuations. We reproduce the observed bimodal distribution of sunspot numbers, but only for subcritical dynamos. Based on a bifurcation analysis, we argue that the ageing of solar-like stars makes the magnetically weak dynamo regime readily accessible. Weak magnetic field production in this regime compromises wind-driven angular momentum losses, thus disrupting the hegemony of magnetic braking on stellar rotational spin-down. This hypothesis of subcritical magnetic dynamos of solar-like stars provides a self-consistent, unifying physical basis for a diversity of solar-stellar phenomena such as why stars beyond their mid-life do not spin-down as fast as in their youth, the break-down of stellar gyrochronology relations, the observed bimodal distribution of long-term sunspot observations, and recent findings suggesting that the Sun may be transitioning to a magnetically inactive future.
Prognostic significance of genome-wide DNA methylation profiles within the randomized, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma
Authors: Tesileanu C Mircea S , van den Bent Martin J , Sanson Marc , Wick Wolfgang , Brandes Alba A , Clement Paul M , Erridge Sara C , Vogelbaum Michael A , Nowak Anna K , Baurain Jean F , Mason Warren P , Wheeler Helen , Chinot Olivier L , Gill Sanjeev , Griffin Matthew , Rogers Leland , Taal Walter , Rudà Roberta , Weller Michael , McBain Catherine , van Linde Myra E , Sabedot Thais S , Hoogstrate Youri , von Deimling Andreas , de Heer Iris , van IJcken Wilfred F J , Brouwer Rutger W W , Aldape Kenneth , Jenkins Robert B , Dubbink Hendrikus J , Kros Johan M , Wesseling Pieter , Cheung Kin Jip , Golfinopoulos Vassilis , Baumert Brigitta G , Gorlia Thierry , Noushmehr Houtan , French Pim J 
Published: April 2021

Abstract

Background
Survival in patients with IDH1/2-mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients.

Methods
The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/− concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumor classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using 1 of the 2 glioma-tailored NGS panels. The primary endpoint was overall survival measured from the date of randomization.

Results
Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumors. Of these, 432 tumors were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazard model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations, and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication.

Conclusion
Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification.
Renin Angiotensin Aldosterone System Antagonism in 2019 Novel Coronavirus Acute Lung Injury
Authors: Ventura Davide , Carr Amy L , Davis R Duane , Silvestry Scott , Bogar Linda , Raval Nirav , Gries Cynthia , Hayes Jillian E , Oliveira Eduardo , Sniffen Jason , Allison Steven L , Herrera Victor , Jennings Douglas L , Page Robert L , McDyer John F , Ensor Christopher R 
Published: April 2021

Abstract
It has been established that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme 2 (ACE2), a membrane-bound regulatory peptide, for host cell entry. Renin-angiotensin-aldosterone system (RAAS) inhibitors have been reported to increase ACE2 in type 2 pneumocyte pulmonary tissue. Controversy exists for the continuation of ACE inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists in the current pandemic. ACE2 serves as a regulatory enzyme in maintaining homeostasis between proinflammatory angiotensin II and anti-inflammatory angiotensin 1,7 peptides. Derangements in these peptides are associated with cardiovascular disease and are implicated in the progression of acute respiratory distress syndrome. Augmentation of the ACE2/Ang 1,7 axis represents a critical target in the supportive management of coronavirus disease 2019–associated lung disease. Observational data describing the use of RAAS inhibitors in the setting of SARS-CoV-2 have not borne signals of harm to date. However, equipoise persists, requiring an analysis of novel agents including recombinant human-ACE2 and existing RAAS inhibitors while balancing ongoing controversies associated with increased coronavirus infectivity and virulence.