bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of coronavirus infectious disease 2019-related neurologic diseases
Authors: Klein Robyn S. 
Published: March 2022

Purpose of review
As of January 8, 2022, a global pandemic caused by infection with severe acute respiratory syndrome coronavirus (SARS-CoV)-2, a new RNA virus, has resulted in 304,896,785 cases in over 222 countries and regions, with over 5,500,683 deaths (www.worldometers.info/coronavirus/). Reports of neurological and psychiatric symptoms in the context of coronavirus infectious disease 2019 (COVID-19) range from headache, anosmia, and dysgeusia, to depression, fatigue, psychosis, seizures, delirium, suicide, meningitis, encephalitis, inflammatory demyelination, infarction, and acute hemorrhagic necrotizing encephalopathy. Moreover, 30–50% of COVID-19 survivors develop long-lasting neurologic symptoms, including a dysexecutive syndrome, with inattention and disorientation, and/or poor movement coordination. Detection of SARS-CoV-2 RNA within the central nervous system (CNS) of patients is rare, and mechanisms of neurological damage and ongoing neurologic diseases in COVID-19 patients are unknown. However, studies demonstrating viral glycoprotein effects on coagulation and cerebral vasculature, and hypoxia- and cytokine-mediated coagulopathy and CNS immunopathology suggest both virus-specific and neuroimmune responses may be involved. This review explores potential mechanistic insights that could contribute to COVID-19-related neurologic disease.

Recent findings
While the development of neurologic diseases during acute COVID-19 is rarely associated with evidence of viral neuroinvasion, new evidence suggests SARS-CoV-2 Spike (S) protein exhibits direct inflammatory and pro-coagulation effects. This, in conjunction with immune dysregulation resulting in cytokine release syndrome (CRS) may result in acute cerebrovascular or neuroinflammatory diseases. Additionally, CRS-mediated loss of blood-brain barrier integrity in specific brain regions may contribute to the expression of proinflammatory mediators by neural cells that may impact brain function long after resolution of acute infection. Importantly, host co-morbid diseases that affect vascular, pulmonary, or CNS function may contribute to the type of neurologic disease triggered by SARS-COV-2 infection.

Summary
Distinct effects of SARS-CoV-2 S protein and CNS compartment- and region-specific responses to CRS may underlie acute and chronic neuroinflammatory diseases associated with COVID-19.
Einstein flow with matter sources: stability and convergence
Authors: Moncrief Vincent , Mondal Puskar 
Published: March 2022

Two recent articles (Moncrief V. 2015 InGeneral relativity and gravitation-A centennial perspective(eds A Asthekar, B Berger, J Isenberg, M MacCallum), pp. 480–498. Cambridge, UK: Cambridge University Press; Moncrief V, Mondal P. 2019Pure Appl. Math. Q.15, 921–965. (doi:10.4310/PAMQ.2019.v15.n3.a7)) suggested an interesting dynamical mechanism within the framework of the vacuum Einstein flow (orEinstein-Λflow if a positive cosmological constantΛis included) which suggests that many closed (compact without boundary) manifolds that do not support homogeneous and isotropic metricsat allwill nevertheless evolve to be asymptotically compatible with the observed approximate homogeneity and isotropy of the physical universe. These studies however did not include matter sources. Therefore, the aim of the present study is to include suitable matter sources and investigate whether one is able to draw a similar conclusion.This article is part of the theme issue ‘The future of mathematical cosmology, Volume 1’.
100 years of mathematical cosmology: Models, theories, and problems, Part A
Authors: Cotsakis Spiros , Yefremov A. P. 
Published: March 2022

An elementary survey of mathematical cosmology is presented. We cover certain key ideas and developments in a qualitative way, from the time of the Einstein static universe in 1917 until today. We divide our presentation into four main periods, the first one containing important cosmologies discovered until 1960. The second period (1960–80) contains discussions of geometric extensions of the standard cosmology, singularities, chaotic behaviour and the initial input of particle physics ideas into cosmology. Our survey for the third period (1980–2000) continues with brief descriptions of the main ideas of inflation, the multiverse, quantum, Kaluza-Klein and string cosmologies, wormholes and baby universes, cosmological stability and modified gravity. The last period that ends today includes various more advanced topics such as M-theoretic cosmology, braneworlds, the landscape, topological issues, the measure problem, genericity, dynamical singularities and dark energy. We emphasize certain threads that run throughout the whole period of development of theoretical cosmology and underline their importance in the overall structure of the field. This is Part A of our survey covering the first two periods of development of the subject. The second part will include the third and fourth periods. We end this outline with an inclusion of the abstracts of all papers contributed to the Philosophical Transactions of the Royal Society A theme issue, ‘The Future of Mathematical Cosmology’.This article is part of the theme issue ‘The future of mathematical cosmology, Volume 1’.
New futures for cosmological models
Authors: Fernández-Jambrina Leonardo , Lazkoz Ruth 
Published: March 2022

The discovery of accelerated expansion of the Universe opened up the possibility of new scenarios for the doom of our space–time, besides eternal expansion and a final contraction. In this paper, we review the chances that may await our universe. In particular, there are new possible singular fates (sudden singularities, big rip, etc.), but there also other evolutions that cannot be considered as singular. In addition to this, some of the singular fates are not strong enough in the sense that the space–time can be extended beyond the singularity. For deriving our results, we make use of generalized power and asymptotic expansions of the scale factor of the Universe.
This article is part of the theme issue ‘The future of mathematical cosmology, Volume 1’.
ACE2 gene expression and inflammatory conditions in periodontal microenvironment of COVID-19 patients with and without diabetes evaluated by qPCR
Authors: Bachtiar Boy M. , Bachtiar Endang W. , Sunarto Hari , Soeroso Yuniarti , Sulijaya Benso , Theodorea Citra Fragrantia , Pratomo Irandi Putra , Yudhistira  , Kusumaningrum Ardiana , Efendi Defi , Apriyanti Efa , Utami Nastiti Rilo , Deviana Astri , Andriyani Anissa Dien 
Published: March 2022

AbstractObjectiveChronic periodontitis has been proposed to be linked to coronavirus disease (COVID-19) on the basis of its inflammation mechanism. We aimed to evaluate this association by investigating the expression of Angiotensin Converting Enzyme-2 (ACE2) in periodontal compartments, which contain dysbiosis-associated pathogenic bacteria, and how it can be directly or indirectly involved in exacerbating inflammation in periodontal tissue.Material and MethodsThis observational clinical study included 23 adult hospitalized patients admitted to Universitas Indonesia Hospital with PCR-confirmed COVID-19, while 6 non-COVID-19 participants come to periodontal clinic were included as control. Using real time-PCR (qPCR) and gingival crevicular fluids (GCF) samples from COVID-19 patients with and without diabetes and periodontitis, we assessed the mRNA expression of angiotensin-converting enzyme 2 (ACE2), IL-6, IL-8, complement C3, and LL-37 as well as the relative proportion of Porphyromonas gingivalis, Fusobacterium nucleatum, and Veillonella parvula to represent the dysbiosis condition in periodontal microenvironment. All analyses were performed to determine their relationship.ResultsACE2 mRNA expression was detected in the GCF of periodontitis-COVID-19 patients with and without diabetes. However, only periodontitis-COVID-19 patients with diabetes showed a positive relationship between ACE2 expression and inflammatory conditions in the periodontal microenvironment. In addition, the interplay between pro-inflammatory cytokine (IL-6) and complement C3 could be used as a predictor of the severity of periodontal inflammation in COVID-19 patients with diabetes.ConclusionThe study data show that the SARS-CoV-2 entry gene is expressed in the GCF of patients with COVID-19, and its expression correlates with inflammatory markers.
Presence of Mediastinal Lymphadenopathy in Hospitalized Covid-19 Patients in a Tertiary Care Hospital in Pakistan – A cross-sectional study
Authors: Bhatti Faryal S. , Malik Amyn A. , Malik Adeel A. 
Published: March 2022

AbstractBackgroundThe aim of this study was to investigate the presence of mediastinal lymphadenopathy in hospitalized Covid-19 patients in a tertiary care hospital in the metropolitan city of Lahore, Pakistan from September 2020 till July 2021.MethodsWe retrospectively collected data of Covid-19 patients hospitalized from September 2020 till July 2021. Only those patients who tested PCR positive through a nasopharyngeal swab, were enrolled in the study. Patients’ whose data were missing were excluded from this study. Our exclusion criteria included patients who tested negative on Covid-19 PCR, patients with comorbidities that may cause enlarged mediastinal lymphadenopathies such as haemophagocytic lymphohistiocytosis, neoplasia, tuberculosis, sarcoidosis or a systemic disease. The extent of lung involvement in Covid-19 patients was quantified by using a 25-point visual quantitative assessment called the Chest Computed Tomography Score. This score was then correlated with the presence of mediastinal lymphadenopathy.FindingsOf the 210 hospitalized patients included in the study, 131 (62.4%) had mediastinal lymphadenopathy. The mean and median Severity Score of Covid-19 patients with mediastinal lymphadenopathy (mean: 17.1, SD:5.7; median: 17, IQR: 13-23) were higher as compared to those without mediastinal lymphadenopathy (mean: 12.3, SD:5.4; median: 12, IQR:9-16)InterpretationOur study documents a high prevalence of mediastinal lymphadenopathy in hospitalized patients with Covid-19 with the severity score being higher in its presence representing a more severe course of disease.
Photoacoustic imaging reveals mechanisms of rapid-acting insulin formulations dynamics at the injection site
Authors: Khadria Anjul , Paavola Chad D. , Maslov Konstantin , Valenzuela Francisco A. , Sperry Andrea E. , Cox Amy L. , Cao Rui , Shi Junhui , Brown-Augsburger Patricia L. , Lozano Emmanuel , Blankenship Ross L. , Majumdar Ranajoy , Bradley Scott A. , Beals John M. , Oladipupo Sunday S. , Wang Lihong V. 
Published: March 2022

AbstractObjectiveUltra-rapid insulin formulations control postprandial hyperglycemia; however, inadequate understanding of injection site absorption mechanisms is limiting further advancement. We used photoacoustic imaging to investigate the injection site dynamics of dye-labeled insulin lispro in the Humalog® and Lyumjev® formulations using the murine ear cutaneous model and correlated it with results from unlabeled insulin lispro in pig subcutaneous injection model.MethodsWe employed dual-wavelength optical-resolution photoacoustic microscopy to study the absorption and diffusion of the near-infrared dye-labeled insulin lispro in the Humalog and Lyumjev formulations in mouse ears. We mathematically modeled the experimental data to calculate the absorption rate constants and diffusion coefficients. We studied the pharmacokinetics of the unlabeled insulin lispro in both the Humalog and Lyumjev formulations as well as a formulation lacking both the zinc and phenolic preservative in pigs. The association state of insulin lispro in each of the formulations was characterized using SV-AUC and NMR spectroscopy.ResultsThrough experiments using murine and swine models, we show that the hexamer dissociation rate of insulin lispro is not the absorption rate-limiting step. We demonstrated that the excipients in the Lyumjev formulation produce local tissue expansion and speed both insulin diffusion and microvascular absorption. We also show that the diffusion of insulin lispro at the injection site drives its initial absorption; however, the rate at which the insulin lispro crosses the blood vessels is its overall absorption rate-limiting step.ConclusionsThis study provides insights into injection site dynamics of insulin lispro and the impact of formulation excipients. It also demonstrates photoacoustic microscopy as a promising tool for studying protein therapeutics. The results from this study address critical questions around the subcutaneous behavior of insulin lispro and the formulation excipients, which could be useful to make faster and better controlled insulin formulations in the future.HighlightsHexamer dissociation is not the absorption rate-limiting step for insulin lisproLyumjev excipients enhance insulin microvascular absorption and diffusionVascular endothelial transit determines the overall absorption for insulin lisprInsulin diffusion studied for the first time at the injection site of live animalsIn vivo imaging is a powerful tool to study injection site dynamics
Reliability of M1-P15 as a cortical marker for transcallosal inhibition: a preregistered TMS-EEG study
Authors: Zazio Agnese , Barchiesi Guido , Ferrari Clarissa , Marcantoni Eleonora , Bortoletto Marta 
Published: March 2022

AbstractBackgroundIn a recently published study combining transcranial magnetic stimulation and electroencephalography (TMS-EEG), we provided first evidence of M1-P15, an early component of TMS-evoked potentials, as a measure of transcallosal inhibition between motor cortices. However, considering the technical challenges of TMS-EEG recordings, further evidence is needed before M1-P15 can be considered a reliable index.ObjectiveHere, we aimed at validating M1-P15 as a cortical index of transcallosal inhibition, by replicating previous findings on its relationship with the ipsilateral silent period (iSP) and with performance in bimanual coordination. Moreover, we aimed at inducing a task-dependent modulation of transcallosal inhibition.MethodsA new sample of 32 healthy right-handed participants underwent behavioral motor tasks and TMS-EEG recording, in which left and right M1 were stimulated during bimanual tasks and during an iSP paradigm. Hypotheses and methods were preregistered before data collection.ResultsWe successfully replicated our previous findings on the positive relationship between M1-P15 amplitude and the iSP normalized area. However, we did not confirm the relationship between M1-P15 latency and bimanual coordination. Finally, we show a task-dependent modulation of M1-P15 amplitude, which was affected by the characteristics of the bimanual task the participants were performing, but not by the contralateral hand activity during the iSP paradigm.ConclusionsThe present results corroborate our previous findings in validating the M1-P15 as a reliable cortical marker of transcallosal inhibition, and provide novel evidence of its task-dependent modulation. Importantly, we demonstrate the feasibility of a preregistration approach in the TMS-EEG field to increase methodological rigor and transparency.
Chondroitin Sulfate Proteoglycan 4,6 sulfation regulates sympathetic nerve regeneration after myocardial infarction
Authors: Blake MR , Parrish DC , Staffenson MA , Sueda S , Woodward W , Habecker BA 
Published: March 2022

AbstractSympathetic denervation of the heart following myocardial infarction (MI) is sustained by chondroitin sulfate proteoglycans (CSPGs) in the cardiac scar, and denervation predicts risk of sudden cardiac death. Blocking CSPG signaling restores sympathetic axon outgrowth into the cardiac scar, decreasing arrhythmia susceptibility. Axon growth inhibition by CSPGs is thought to depend on the sulfation status of the glycosaminoglycans (CS-GAGs) attached to the core protein. Tandem sulfation of CS-GAGs at the 4th (4S) and 6th (6S) positions of n-acetyl-galactosamine inhibits outgrowth in several types of neurons within the central nervous system, but it is not known if sulfation is similarly critical during peripheral nerve regeneration. We asked if CSPG sulfation prevented sympathetic axon outgrowth. Sympathetic neurite outgrowth across purified CSPGs is restored in vitro by reducing 4S with the 4-sulfatase enzyme Arylsulfatase-B (ARSB). Additionally, we co-cultured cardiac scar tissue with sympathetic ganglia ex vivo and found that reducing 4S with ARSB restored axon outgrowth to control levels. We examined levels of the enzymes responsible for adding and removing sulfation to CS-GAGs by western blot to determine if they were altered in the left ventricle after MI. We found that CHST15 (4S dependent 6-sulfotransferase) was upregulated, and ARSB was downregulated after MI. Increased CHST15 combined with decreased ARSB suggests a mechanism for production and maintenance of sulfated CSPGs in the cardiac scar. We altered tandem sulfated 4S,6S CS-GAGs in vivo by transient siRNA knockdown of Chst15 and found that reducing 4S,6S restored Tyrosine Hydroxylase (TH) positive sympathetic nerve fibers in the cardiac scar after MI and reduced arrhythmias. Overall, our results suggest that modulating CSPG-sulfation after MI may be a therapeutic target to promote sympathetic nerve regeneration in the cardiac scar and reduce post-MI cardiac arrhythmias.
sstar: A Python package for detecting archaic introgression from population genetic data with S*
Authors: Huang Xin , Kruisz Patricia , Kuhlwilm Martin 
Published: March 2022

AbstractS* is a widely used statistic for detecting archaic admixture from population genetic data. Previous studies used freezing-archer to apply S*, which is only directly applicable to the specific case of Neanderthal and Denisovan introgression in Papuans. Here, we implemented sstar for a more general purpose. Compared with several tools, including SPrime, SkovHMM, and ArchaicSeeker2.0, for detecting introgressed fragments with simulations, our results suggest that sstar is robust to differences in demographic models, including ghost introgression and two-source introgression. We believe sstar will be a useful tool for detecting introgressed fragments in various scenarios and in non-human species.
An immune-lncRNA risk model to predict prognosis for patients with head and neck squamous cell carcinoma
Authors: Jiang Xu , Qin Ying , Xia Wei , Li Jian , Shi Nan , Feng Qingyuan , Tang Anzhou , Yi Xiang 
Published: March 2022

AbstractBackgroundlong noncoding RNA (lncRNA) are closely correlated with the occurrence and development of tumors. The purpose of this research is to construct a risk model of immune-related lncRNAs that can be used for predicting the survival and prognosis of head and neck squamous cell carcinoma (HNSCC) patients and further exploring the immune function of immune-lncRNAs.Methodsobtained detailed transcriptional data and clinical information for 545 cases of HNSCC from The Cancer Genome Atlas (TCGA). Combined lncRNAs and the immune gene sets from the Molecular Signatures Database (MSigDB) were employed to construct co□expression networks, the significant correlation of immune-lncRNAs obtained from the results of Cox regression analysis were used to build the model. Survival analysis and QRT-PCR were used to confirm the expression of immune-lncRNAs and optimize the risk model. Then single-cell RNA Sequencing (scRNA-seq) dataset analysis of laryngeal squamous cell carcinoma (LSCC), co-expression analysis, correlation analysis and immunohistochemistry were used to explore the immune function of immune-lncRNAs.ResultsA total of 13 immune-lncRNAs including AC104083.1、AC004148.2、AL357033.4、AC116914.2、AC024075.1、AC008115.3、PCED1B-AS1、RAB11B-AS1、AC004687.1、 AL450992.2、EP300-AS1、AC024075.2、AC136475.2 were identified to construct the risk model. In this model, low-risk patients had higher overall survival (OS, P=1.923e-12, hazard ratio=2.104, 95% CI: 1.622-2.730). AC004687.1 and PCED1B-AS1 were overexpressed in T cells and were closely related to the genes encoding major histocompatibility complex II (MHC II) molecules. And the results of QRT-PCR and immunohistochemistry showed the expression significant positively correlated with HLA-DR which is one of the MHC II classical molecules.Conclusionthe immune-associated risk model constructed by 13 lncRNAs has good prognostic value for HNSCC. AC004687.1 and PCED1B-AS1 are significant correlating to clinical characteristics and MHC II, we provide a new insight into the immune function of lncRNAs.
Systems level analysis of time and stimuli specific signaling through PKA
Authors: Plank Michael , Carmiol Nicole , Mitri Bassam , Capaldi Andrew P. 
Published: March 2022

ABSTRACTEukaryotic cells create gradients of cAMP across space and time to regulate the cAMP dependent protein kinase (PKA) and, in turn, growth and metabolism. However, how PKA responds to different concentrations of cAMP is unclear. Here, to address this question, we examine PKA signaling in S. cerevisiae in different conditions, timepoints, and concentrations of the chemical inhibitor 1-NM-PP1 using phosphoproteomics. These experiments show that there are numerous proteins that are only phosphorylated when cAMP and PKA activity are at/near their maximum level, while other proteins are phosphorylated even when cAMP levels and PKA activity are low. The data also show that PKA drives cells into distinct growth states by acting on proteins with different thresholds for phosphorylation in different conditions. Analysis of the sequences surrounding the 118 PKA-dependent phosphosites suggests that the phosphorylation thresholds are set, at least in part, by the affinity of PKA for each site.
Empirical study on software and process quality in bioinformatics tools
Authors: Ferenc Katalin , Otto Konrad , de Oliveira Neto Francisco Gomes , López Marcela Dávila , Horkoff Jennifer , Schliep Alexander 
Published: March 2022

AbstractSoftware quality in computational tools impacts research output in a variety of scientific disciplines. Biology is one of these fields, especially for High Throughput Sequencing (HTS) data, such tools play an important role. This study therefore characterises the overall quality of a selection of tools which are frequently part of HTS pipelines, as well as analyses the maintainability and process quality of a selection of HTS alignment tools. Our findings highlight the most pressing issues, and point to software engineering best practices developed for the improvement of maintenance and process quality. To help future research, we share the tooling for the static code analysis with SonarCloud which we used to collect data on the maintainability of different alignment tools. The results of the analysis show that the maintainability level is generally high but trends towards increasing technical debt over time. We also observed that the development activities on alignment tools are generally driven by very few developers and are not utilising modern tooling to their advantage. Based on these observations, we recommend actions to improve both maintainability and process quality in open source alignment tools. Those actions include improvements in tooling like the use of linters as well as better documentation of architecture and features. We encourage developers to use these tools in order to ease future maintenance efforts, increase user experience, support reproducibility, and ultimately increase the quality of research through increasing the quality of research software tools.