bluuebunny/crossref_metadata_2025 huggingface dataset:
Changing Emissions Results in Changed PM2.5 Composition and Health Impacts
Authors: Hopke Philip K. , Hidy George
Published: January 2022

In the period of 2005 to 2016, multiple air pollution control regulations have entered into effect in the United States at both the Federal and state level. In addition, economic changes have also occurred primarily in the electricity generation sector that substantially changed the emissions from this sector. This combination of policy implementations and economics has led to substantial reductions in PM2.5, its major constituents, and source specific PM2.5 concentrations across the New York State, particularly those of sulfate, nitrate, and primary organic carbon. However, secondary organic carbon and spark-ignition vehicular emission contributions have increased. Related studies of changes in health outcomes, the excess rates of emergency department visits and hospitalizations for a variety of cardiovascular and respiratory diseases and respiratory infections have increased per unit mass of PM2.5. It appears that the increased toxicity per unit mass was due to the reduction in low toxicity constituents such that the remaining mass had greater impacts on public health.
Morphology of Traveling Wave Disturbances Recorded in Eastern Siberia in 630 nm Atomic Oxygen Emission
Authors: Syrenova Tatyana E. , Beletsky Alexander B. , Ratovsky Konstantin G. , Tolstikov Maxim V. , Vasilyev Roman V.
Published: January 2022

Our paper presents the results of investigating wave structures detected in 630 nm atomic oxygen emission intensity (airglow height is ~180–300 km). The study employs data from a wide-angle optical system installed at the Geophysical Observatory of the ISTP SB RAS (51°48′ N, 103°04′ E). It describes the algorithm to identify wave disturbances and determine their main parameters in the optical system images. The results obtained due to automatic processing of 2014–2021 data archives are presented. The most probable values of the wave disturbances propagation velocity are about 80 m/s. The horizontal wavelengths and periods are in the range of ~30–400 km and 60–120 min, respectively. The predominant direction of disturbances propagation is to the southwest. The received data of optical and radio observations are compared. We found both similarities and differences in the wavelike structures direction, which are to be investigated in the future.
Single Ionization of He by Energetic Protons in a Parabolic Quasi-Sturmians Approach
Authors: Zaytsev Sergey A. , Zaytsev Alexander S. , Nasyrov Vyacheslav V. , Zaytseva Darya S. , Ancarani Lorenzo U. , Kouzakov Konstantin A.
Published: January 2022

A fully differential cross section for single ionization of helium induced by 1 MeV proton impact is calculated using the parabolic convoluted quasi-Sturmian (CQS) method. In the framework of this approach the transition amplitude is extracted directly from the asymptotic behavior of the solution of an inhomogeneous Schrödinger equation for the Coulomb three-body system (e−,He+,p+). The driven equation is solved numerically by expanding in convolutions of quasi-Sturmians for the two-body proton-He+ and electron-He+ systems. It is found, at least in the high energy limit, that the calculated cross sections within the proposed CQS method converge quickly as the number of terms in the expansions is increased, and are in reasonable agreement with experimental data and other theoretical results.
An Index for Graphs and Graph Groupoids
Authors: Cho Ilwoo , Jorgensen Palle
Published: January 2022

In this paper, we consider certain quantities that arise in the images of the so-called graph-tree indexes of graph groupoids. In text, the graph groupoids are induced by connected finite-directed graphs with more than one vertex. If a graph groupoid GG contains at least one loop-reduced finite path, then the order of G is infinity; hence, the canonical groupoid index G:K of the inclusion K⊆G is either ∞ or 1 (under the definition and a natural axiomatization) for the graph groupoids K of all “parts” K of G. A loop-reduced finite path generates a semicircular element in graph groupoid algebra. Thus, the existence of semicircular systems acting on the free-probabilistic structure of a given graph G is guaranteed by the existence of loop-reduced finite paths in G. The non-semicircularity induced by graphs yields a new index-like notion called the graph-tree index Γ of G. We study the connections between our graph-tree index and non-semicircular cases. Hence, non-semicircularity also yields the classification of our graphs in terms of a certain type of trees. As an application, we construct towers of graph-groupoid-inclusions which preserve the graph-tree index. We further show that such classification applies to monoidal operads.
Computational Experiments with the Roots of Fibonacci-like Polynomials as a Window to Mathematics Research
Authors: Abramovich Sergei , Kuznetsov Nikolay , Leonov Gennady
Published: January 2022

Fibonacci-like polynomials, the roots of which are responsible for a cyclic behavior of orbits of a second-order two-parametric difference equation, are considered. Using Maple and Wolfram Alpha, the location of the largest and the smallest roots responsible for the cycles of period p among the roots responsible for the cycles of periods 2kp (period-doubling) and kp (period-multiplying) has been determined. These purely computational results of experimental mathematics, made possible by the use of modern digital tools, can be used as a motivation for confirmation through not-yet-developed methods of formal mathematics.
Scalable Extended Reality: A Future Research Agenda
Authors: Memmesheimer Vera Marie , Ebert Achim
Published: January 2022

Extensive research has outlined the potential of augmented, mixed, and virtual reality applications. However, little attention has been paid to scalability enhancements fostering practical adoption. In this paper, we introduce the concept of scalable extended reality (XRS), i.e., spaces scaling between different displays and degrees of virtuality that can be entered by multiple, possibly distributed users. The development of such XRS spaces concerns several research fields. To provide bidirectional interaction and maintain consistency with the real environment, virtual reconstructions of physical scenes need to be segmented semantically and adapted dynamically. Moreover, scalable interaction techniques for selection, manipulation, and navigation as well as a world-stabilized rendering of 2D annotations in 3D space are needed to let users intuitively switch between handheld and head-mounted displays. Collaborative settings should further integrate access control and awareness cues indicating the collaborators’ locations and actions. While many of these topics were investigated by previous research, very few have considered their integration to enhance scalability. Addressing this gap, we review related previous research, list current barriers to the development of XRS spaces, and highlight dependencies between them.
DOTA: Deep Learning Optimal Transport Approach to Advance Drug Repositioning for Alzheimer’s Disease
Authors: Chyr Jacqueline , Gong Haoran , Zhou Xiaobo
Published: January 2022

Alzheimer’s disease (AD) is the leading cause of age-related dementia, affecting over 5 million people in the United States and incurring a substantial global healthcare cost. Unfortunately, current treatments are only palliative and do not cure AD. There is an urgent need to develop novel anti-AD therapies; however, drug discovery is a time-consuming, expensive, and high-risk process. Drug repositioning, on the other hand, is an attractive approach to identify drugs for AD treatment. Thus, we developed a novel deep learning method called DOTA (Drug repositioning approach using Optimal Transport for Alzheimer’s disease) to repurpose effective FDA-approved drugs for AD. Specifically, DOTA consists of two major autoencoders: (1) a multi-modal autoencoder to integrate heterogeneous drug information and (2) a Wasserstein variational autoencoder to identify effective AD drugs. Using our approach, we predict that antipsychotic drugs with circadian effects, such as quetiapine, aripiprazole, risperidone, suvorexant, brexpiprazole, olanzapine, and trazadone, will have efficacious effects in AD patients. These drugs target important brain receptors involved in memory, learning, and cognition, including serotonin 5-HT2A, dopamine D2, and orexin receptors. In summary, DOTA repositions promising drugs that target important biological pathways and are predicted to improve patient cognition, circadian rhythms, and AD pathogenesis.
Folic Acid, Folinic Acid, 5 Methyl TetraHydroFolate Supplementation for Mutations That Affect Epigenesis through the Folate and One-Carbon Cycles
Authors: Menezo Yves , Elder Kay , Clement Arthur , Clement Patrice
Published: January 2022

Methylation is an essential biochemical mechanism that is central to the transmission of life, and crucially responsible for regulating gametogenesis and continued embryo development. The methylation of DNA and histones drives cell division and regulation of gene expression through epigenesis and imprinting. Brain development and its maturation also depend on correct lipid methylation, and continued neuronal function depends on biogenic amines that require methylation for their synthesis. All methylation processes are carried out via a methyltransferase enzyme and its unique co-factor S-adenosylmethionine (SAM); the transfer of a methyl group to a target molecule results in the release of SAH (SA homocysteine), and then homocysteine (Hcy). Both of these molecules are toxic, inhibiting methylation in a variety of ways, and Hcy recycling to methionine is imperative; this is achieved via the one carbon cycle, supported by the folates cycle. Folate deficiency causes hyperhomocysteinaemia, with several associated diseases; during early pregnancy, deficiency interferes with closure of the neural tube at the fourth week of gestation, and nutraceutical supplementation has been routinely prescribed to prevent neural tube defects, mainly involving B vitamins, Zn and folates. The two metabolic pathways are subject to single nucleotide polymorphisms that alter their activity/capacity, often severely, impairing specific physiological functions including fertility, brain and cardiac function. The impact of three types of nutraceutical supplements, folic acid (FA), folinic acid (FLA) and 5 Methyl THF (MTHF), will be discussed here, with their positive effects alongside potentially hazardous secondary effects. The issue surrounding FA and its association with UMFA (unmetabolized folic acid) syndrome is now a matter of concern, as UMFA is currently found in the umbilical cord of the fetus, and even in infants’ blood. We will discuss its putative role in influencing the acquisition of epigenetic marks in the germline, acquired during embryogenesis, as well as the role of FA in the management of cancerous disease.
Transgenic Mouse Overexpressing Spermine Oxidase in Cerebrocortical Neurons: Astrocyte Dysfunction and Susceptibility to Epileptic Seizures
Authors: Marcoli Manuela , Cervetto Chiara , Amato Sarah , Fiorucci Cristian , Maura Guido , Mariottini Paolo , Cervelli Manuela
Published: January 2022

Polyamines are organic polycations ubiquitously present in living cells. Polyamines are involved in many cellular processes, and their content in mammalian cells is tightly controlled. Among their function, these molecules modulate the activity of several ion channels. Spermine oxidase, specifically oxidized spermine, is a neuromodulator of several types of ion channel and ionotropic glutamate receptors, and its deregulated activity has been linked to several brain pathologies, including epilepsy. The Dach-SMOX mouse line was generated using a Cre/loxP-based recombination approach to study the complex and critical functions carried out by spermine oxidase and spermine in the mammalian brain. This mouse genetic model overexpresses spermine oxidase in the neocortex and is a chronic model of excitotoxic/oxidative injury and neuron vulnerability to oxidative stress and excitotoxic, since its phenotype revealed to be more susceptible to different acute oxidative insults. In this review, the molecular mechanisms underlined the Dach-SMOX phenotype, linked to reactive astrocytosis, neuron loss, chronic oxidative and excitotoxic stress, and susceptibility to seizures have been discussed in detail. The Dach-SMOX mouse model overexpressing SMOX may help in shedding lights on the susceptibility to epileptic seizures, possibly helping to understand the mechanisms underlying epileptogenesis in vulnerable individuals and contributing to provide new molecular mechanism targets to search for novel antiepileptic drugs.
Cognitive Function and Neuropsychiatric Disorders after COVID-19: A Long Term Social and Clinical Problem?
Authors: Ramírez-Moreno José M. , Muñoz-Sanz Agustín , Vaz-Leal Francisco J.
Published: January 2022

SARS-CoV-2 is one more virus that can affect the brain in one way or another. Now, we are only beginning to understand some mechanisms and the degree to which it can impact the nervous system. Considering the rapid accumulation of knowledge about multiple neurological and cognitive symptoms in COVID-19 patients, it seems useful to encourage the development of systematic approaches for the diagnosis, management and treatment of the cognitive aspects of COVID-19. From what is known at this time about the impact of COVID-19 on the brain, the presentation of long-term cognitive sequelae can be expected to be heterogeneous in nature and will depend at least in part on the severity of the disease at the stage acute COVID-19. The long-term essential characteristics of these sequelae will probably be related to a combination of causes and different neuropathological processes in the acute phase. The scope and severity of the current COVID-19 pandemic are unparalleled in modern society. The later implications for neurological function can be just as serious. Although the current focus is on the management of acute diseases, in the near future the focus should be on the long-term consequences of COVID-19 infection and its mitigation, hence the need for the development of systematic approaches for the management of the cognitive and neuropsychiatric aspects of COVID-19.
Genetic Predisposition and Inflammatory Inhibitors in COVID-19: Where Do We Stand?
Authors: Sagris Marios , Theofilis Panagiotis , Antonopoulos Alexios S. , Oikonomou Evangelos , Tsioufis Kostas , Tousoulis Dimitris
Published: January 2022

Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and the resulting coronavirus disease-19 (COVID-19) have led to a global pandemic associated with high fatality rates. COVID-19 primarily manifests in the respiratory system as an acute respiratory distress syndrome following viral entry through the angiotensin-converting enzyme-2 (ACE2) that is present in pulmonary epithelial cells. Central in COVID-19 is the burst of cytokines, known as a “cytokine storm”, and the subsequent widespread endothelial activation, leading to cardiovascular complications such as myocarditis, arrhythmias, and adverse vascular events, among others. Genetic alterations may play an additive, detrimental role in the clinical course of patients with COVID-19, since gene alterations concerning ACE2, major histocompatibility complex class I, and toll-like receptors may predispose patients to a worse clinical outcome. Since the role of inflammation is quintessential in COVID-19, pharmacologic inhibition of various signaling pathways such as the interleukin-1 and -6, tumor necrosis factor-alpha, interferon gamma, Janus kinase-signal transducer and activator of transcription, and granulocyte–macrophage colony-stimulating factor may ameliorate the prognosis following timely administration. Finally, frequently used, non-specific anti-inflammatory agents such as corticosteroids, statins, colchicine, and macrolides represent additional therapeutic considerations.
Gene Expression Profiling in Early Breast Cancer—Patient Stratification Based on Molecular and Tumor Microenvironment Features
Authors: Munkácsy Gyöngyi , Santarpia Libero , Győrffy Balázs
Published: January 2022

Patients with early-stage hormone receptor-positive, human epidermal growth factor receptor 2-negative (HER2−) breast cancer (BC) are typically treated with surgery, followed by adjuvant systemic endocrine therapy with or without adjuvant chemotherapy and radiation therapy. Current guidelines regarding the use of adjuvant systemic therapy depend on clinical and pathological factors, such as the morphological assessment of tumor subtype; histological grade; tumor size; lymphovascular invasion; and lymph node status combined with estrogen receptor, progesterone receptor, and HER2 biomarker profiles assessed using immunohistochemistry and in situ hybridization. Additionally, the prognostic and predictive value of tumor-infiltrating lymphocytes and their composition is emerging as a key marker in triple negative (TNBC) and HER2-enriched molecular breast tumor subtypes. However, all these factors do not necessarily reflect the molecular heterogeneity and complexity of breast cancer. In the last two decades, gene expression signatures or profiling (GEP) tests have been developed to predict the risk of disease recurrence and estimate the potential benefit of receiving adjuvant systemic chemotherapy in patients with luminal breast cancer. GEPs have been utilized to help physicians to refine decision-making process, complementing clinicopathological parameters, and can now be used to classify the risk of recurrence and tailoring personalized treatments. Several clinical trials using GEPs validate the increasing value of such assays in different clinical settings, addressing relevant clinical endpoints. Finally, the recent approval of immune checkpoint inhibitors in TNBC and the increasing use of immunotherapy in different molecular BC populations highlight the opportunity to refine current GEPs by including a variety of immune-related genes that may help to improve predicting drug response and finetune prognosis.
Cardiovascular Disease-Associated MicroRNA Dysregulation during the First Trimester of Gestation in Women with Chronic Hypertension and Normotensive Women Subsequently Developing Gestational Hypertension or Preeclampsia with or without Fetal Growth Restriction
Authors: Hromadnikova Ilona , Kotlabova Katerina , Krofta Ladislav
Published: January 2022

The aim of the study was to assess if cardiovascular disease-associated microRNAs would be able to predict during the early stages of gestation (within 10 to 13 weeks) subsequent onset of hypertensive pregnancy-related complications: gestational hypertension (GH) or preeclampsia (PE). Secondly, the goal of the study was to assess if cardiovascular disease-associated microRNAs would be able to detect the presence of chronic hypertension in early pregnancies. The retrospective study was performed on whole peripheral blood samples collected from singleton Caucasian pregnancies within the period November 2012 to March 2020. The case control study, nested in a cohort, involved all women with chronic hypertension (n = 29), all normotensive women that later developed GH (n = 83) or PE with or without fetal growth restriction (FGR) (n = 66), and 80 controls selected on the base of equal sample storage time. Whole peripheral blood profiling was performed with the selection of 29 cardiovascular disease-associated microRNAs using real-time RT-PCR. Upregulation of miR-1-3p (51.72% at 10.0% FPR) was observed in patients with chronic hypertension only. Upregulation of miR-20a-5p (44.83% and 33.33% at 10.0% FPR) and miR-146a-5p (65.52% and 42.42% at 10.0% FPR) was observed in patients with chronic hypertension and normotensive women with later occurrence of PE. Upregulation of miR-181a-5p was detected in normotensive women subsequently developing GH (22.89% at 10.0% FPR) or PE (40.91% at 10.0% FPR). In a part of women with subsequent onset of PE, upregulation of miR-143-3p (24.24% at 10.0% FPR), miR-145-5p (21.21% at 10.0% FPR), and miR-574-3p (27.27% at 10.0% FPR) was also present. The combination of microRNA biomarkers (miR-20a-5p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-181a-5p, and miR-574-3p) can predict the later occurrence of PE in 48.48% of pregnancies at 10.0% FPR in early stages of gestation. The combination of upregulated microRNA biomarkers (miR-1-3p, miR-20a-5p, and miR-146a-5p) is able to identify 72.41% of pregnancies with chronic hypertension at 10.0% FPR in early stages of gestation. Cardiovascular disease-associated microRNAs represent promising biomarkers with very good diagnostical potential to be implemented into the current first trimester screening program to predict later occurrence of PE with or without FGR. The comparison of the predictive results of the routine first trimester screening for PE and/or FGR based on the criteria of the Fetal Medicine Foundation and the first trimester screening for PE wo/w FGR using a panel of six cardiovascular disease-associated microRNAs only revealed that the detection rate of PE increased 1.45-fold (48.48% vs. 33.33%).
FAM111A Is a Novel Molecular Marker for Oocyte Aging
Authors: Yang Huixia , Kolben Thomas , Kessler Mirjana , Meister Sarah , Paul Corinna , van Dorp Julia , Eren Sibel , Kuhn Christina , Rahmeh Martina , Herbst Cornelia , Fink Sabine Gabriele , Weimer Gabriele , Mahner Sven , Jeschke Udo , von Schönfeldt Viktoria
Published: January 2022

Aging is the main cause of decline in oocyte quality, which can further trigger the failure of assisted reproductive technology (ART). Exploring age-related genes in oocytes is an important way to investigate the molecular mechanisms involved in oocyte aging. To provide novel insight into this field, we performed a pooled analysis of publicly available datasets, using the overlapping results of two statistical methods on two Gene Expression Omnibus (GEO) datasets. The methods utilized in the current study mainly include Spearman rank correlation, the Wilcoxon signed-rank test, t-tests, Venn diagrams, Gene Ontology (GO), Protein–Protein Interaction (PPI), Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and receiver operating characteristic (ROC) curve analysis. We identified hundreds of age-related genes across different gene expression datasets of in vitro maturation-metaphase II (IVM-MII) oocytes. Age-related genes in IVM-MII oocytes were involved in the biological processes of cellular metabolism, DNA replication, and histone modifications. Among these age-related genes, FAM111A expression presented a robust correlation with age, seen in the results of different statistical methods and different datasets. FAM111A is associated with the processes of chromosome segregation and cell cycle regulation. Thus, this enzyme is potentially an interesting novel marker for the aging of oocytes, and warrants further mechanistic study.
Incidence and Risk Factors for Acute Kidney Injury after Allogeneic Stem Cell Transplantation: A Prospective Study
Authors: Andronesi Andreea , Sorohan Bogdan , Burcea Andreea , Lipan Lavinia , Stanescu Cristina , Craciun Oana , Stefan Laura , Ranete Adela , Varady Zsofia , Ungureanu Oana , Lupusoru Gabriela , Agrigoroaei Gabriela , Andronesi Danut , Iliuta Luminita , Obrisca Bogdan , Tanase Alina
Published: January 2022

(1) Background: Acute kidney injury (AKI) is a serious complication of hematopoietic stem cell transplantation (HSCT). (2) Methods: The aim was to identify the incidence, severity, and risk factors for AKI during the first 100 days after allo-HSCT; we performed a prospective observational study on 135 consecutive patients. (3) Results: The mean age was 38.3 ± 11.9 years (50.6% females), AKI developed in 93 patients (68.9%), the median time of appearance was 28 days, and the mean serum creatinine at the time of AKI was 1.8 ± 0.8 mg/dL. A total of 36 (38.7%) patients developed stage 1 AKI, 33 (35.5%) patients developed stage 2, and 24 (25.8%) patients developed stage 3; eight (8.6%) patients required temporary hemodialysis, and the mortality rate in these patients was 87.5%. Death was twice as frequent in the AKI subgroup, without statistical significance. Cyclosporine overdose (HR = 2.36, 95% CI: 1.45–3.85, p = 0.001), tacrolimus overdose (HR = 4.72, 95% CI: 2.22–10.01, p < 0.001), acute graft-versus-host disease (aGVHD) (HR = 1.96, 95% CI: 1.13–3.40, p = 0.01), and CRP level (HR = 1.009, 95% CI: 1.007–1.10, p < 0.001) were independent risk factors for AKI. Sepsis (HR = 5.37, 95% CI: 1.75–16.48, p = 0.003) and sinusoidal obstruction syndrome (HR = 5.10, 95% CI: 2.02–12.85, p = 0.001) were found as independent risk factors for AKI stage 3. (4) Conclusions: AKI occurs with high incidence and increased severity after allo-HSCT. Careful monitoring of calcineurin inhibitors and proper management of sepsis may reduce this risk.
Stable Gastric Pentadecapeptide BPC 157 May Counteract Myocardial Infarction Induced by Isoprenaline in Rats
Authors: Barisic Ivan , Balenovic Diana , Udovicic Mario , Bardak Darija , Strinic Dean , Vlainić Josipa , Vranes Hrvoje , Smoday Ivan Maria , Krezic Ivan , Milavic Marija , Sikiric Suncana , Uzun Sandra , Zivanovic Posilovic Gordana , Strbe Sanja , Vukoja Ivan , Lovric Eva , Lozic Marin , Sever Marko , Lovric Bencic Martina , Boban Blagaic Alenka , Skrtic Anita , Seiwerth Sven , Sikiric Predrag
Published: January 2022

We revealed that the stable gastric pentadecapeptide BPC 157, a useful peptide therapy against isoprenaline myocardial infarction, as well as against isoprenaline myocardial reinfarction, may follow the counteraction of the recently described occlusion-like syndrome, induced peripherally and centrally, which was described for the first time in isoprenaline-treated rats. BPC 157 (10 ng/kg, 10 µg/kg i.p.), L-NAME (5 mg/kg i.p.), and L-arginine (200 mg/kg i.p.) were given alone or together at (i) 30 min before or, alternatively, (ii) at 5 min after isoprenaline (75 or 150 mg/kg s.c.). At 30 min after isoprenaline 75 mg/kg s.c., we noted an early multiorgan failure (brain, heart, lung, liver, kidney and gastrointestinal lesions), thrombosis, intracranial (superior sagittal sinus) hypertension, portal and caval hypertension, and aortal hypotension, in its full presentation (or attenuated by BPC 157 therapy (given at 5 min after isoprenaline) via activation of the azygos vein). Further, we studied isoprenaline (75 or 150 mg/kg s.c.) myocardial infarction (1 challenge) and reinfarction (isoprenaline at 0 h and 24 h, 2 challenges) in rats (assessed at the end of the subsequent 24 h period). BPC 157 reduced levels of all necrosis markers, CK, CK-MB, LDH, and cTnT, and attenuated gross (no visible infarcted area) and histological damage, ECG (no ST-T ischemic changes), and echocardiography (preservation of systolic left ventricular function) damage induced by isoprenaline. Its effect was associated with a significant decrease in oxidative stress parameters and likely maintained NO system function, providing that BPC 157 interacted with eNOS and COX2 gene expression in a particular way and counteracted the noxious effect of the NOS-blocker, L-NAME.
CD14 Is Involved in the Interferon Response of Human Macrophages to Rubella Virus Infection
Authors: Schilling Erik , Pfeiffer Lukas , Hauschildt Sunna , Koehl Ulrike , Claus Claudia
Published: January 2022

Macrophages (MΦ) as specialized immune cells are involved in rubella virus (RuV) pathogenesis and enable the study of its interaction with the innate immune system. A similar replication kinetics of RuV in the two human MΦ types, the pro-inflammatory M1-like (or GM-MΦ) and anti-inflammatory M2-like (M-MΦ), was especially in M-MΦ accompanied by a reduction in the expression of the innate immune receptor CD14. Similar to RuV infection, exogenous interferon (IFN) β induced a loss of glycolytic reserve in M-MΦ, but in contrast to RuV no noticeable influence on CD14 expression was detected. We next tested the contribution of CD14 to the generation of cytokines/chemokines during RuV infection of M-MΦ through the application of anti-CD14 blocking antibodies. Blockage of CD14 prior to RuV infection enhanced generation of virus progeny. In agreement with this observation, the expression of IFNs was significantly reduced in comparison to the isotype control. Additionally, the expression of TNF-α was slightly reduced, whereas the chemokine CXCL10 was not altered. In conclusion, the observed downmodulation of CD14 during RuV infection of M-MΦ appears to contribute to virus-host-adaptation through a reduction of the IFN response.
Study Designs for Evaluation of Combination Treatment: Focus on Individual Patient Benefit
Authors: Michel Martin C. , Staskin David
Published: January 2022

Combination treatment, i.e., the use of two or more drugs for the same condition, is frequent in medicine if monotherapy yields an insufficient therapeutic response. We review and challenge clinical study designs and formats of reporting outcomes for the evaluation of the benefit/risk ratio of combination treatment over monotherapy. We demonstrate that benefits of combination treatment at the group level overestimate the probability of benefit at the single patient level based on outcome simulations under almost any imaginable setting. Based on these findings, we propose that studies testing combination treatment should always report on percentages of responders to monotherapy and combination treatment. We provide equations that allow the calculation of the percentage of patients truly benefitting from combination (responders to both monotherapies) and that of patients exposed to risk of harm from adverse effects without a reasonable expectation of individual benefit. These considerations are explained based on real clinical data, mostly from the field of functional urology (male lower urinary tract symptoms).
Reducing the Pill Burden: Immunosuppressant Adherence and Safety after Conversion from a Twice-Daily (IR-Tac) to a Novel Once-Daily (LCP-Tac) Tacrolimus Formulation in 161 Liver Transplant Patients
Authors: Maurer Max M. , Ibach Marius , Plewe Julius , Winter Axel , Ritschl Paul , Globke Brigitta , Öllinger Robert , Lurje Georg , Schöning Wenzel , Pratschke Johann , Eurich Dennis
Published: January 2022

Non-adherence to immunosuppressant therapy reduces long-term graft and patient survival after solid organ transplantation. The objective of this 24-month prospective study was to determine adherence, efficacy and safety after conversion of stable liver transplant (LT) recipients from a standard twice-daily immediate release Tacrolimus (IR-Tac) to a novel once-daily life cycle pharma Tacrolimus (LCP-Tac) formulation. We converted a total of 161 LT patients at baseline, collecting Tacrolimus trough levels, laboratories, physical examination data and the BAASIS© questionnaire for self-reported adherence to immunosuppression at regular intervals. With 134 participants completing the study period (17% dropouts), the overall adherence to the BAASIS© increased by 57% until month 24 compared to baseline (51% vs. 80%). Patients who required only a morning dose of their concomitant medications reported the largest improvement in adherence after conversion. The intra-patient variability (IPV) of consecutive Tacrolimus trough levels after conversion did not change significantly compared to pre-conversion levels. Despite reducing the daily dose by 30% at baseline as recommended by the manufacturer, Tac-trough levels remained stable, reflected by an increase in the concentration-dose (C/D) ratio. No episodes of graft rejection or loss occurred. Our data suggest that the use of LCP-Tac in liver transplant patients is safe and can increase adherence to immunosuppression compared to conventional IR-Tac.
Genetic Complementation of ATP Synthase Deficiency Due to Dysfunction of TMEM70 Assembly Factor in Rat
Authors: Marković Aleksandra , Tauchmannová Kateřina , Šimáková Miroslava , Mlejnek Petr , Kaplanová Vilma , Pecina Petr , Pecinová Alena , Papoušek František , Liška František , Šilhavý Jan , Mikešová Jana , Neckář Jan , Houštěk Josef , Pravenec Michal , Mráček Tomáš
Published: January 2022

Mutations of the TMEM70 gene disrupt the biogenesis of the ATP synthase and represent the most frequent cause of autosomal recessive encephalo-cardio-myopathy with neonatal onset. Patient tissues show isolated defects in the ATP synthase, leading to the impaired mitochondrial synthesis of ATP and insufficient energy provision. In the current study, we tested the efficiency of gene complementation by using a transgenic rescue approach in spontaneously hypertensive rats with the targeted Tmem70 gene (SHR-Tmem70ko/ko), which leads to embryonic lethality. We generated SHR-Tmem70ko/ko knockout rats expressing the Tmem70 wild-type transgene (SHR-Tmem70ko/ko,tg/tg) under the control of the EF-1α universal promoter. Transgenic rescue resulted in viable animals that showed the variable expression of the Tmem70 transgene across the range of tissues and only minor differences in terms of the growth parameters. The TMEM70 protein was restored to 16–49% of the controls in the liver and heart, which was sufficient for the full biochemical complementation of ATP synthase biogenesis as well as for mitochondrial energetic function in the liver. In the heart, we observed partial biochemical complementation, especially in SHR-Tmem70ko/ko,tg/0 hemizygotes. As a result, this led to a minor impairment in left ventricle function. Overall, the transgenic rescue of Tmem70 in SHR-Tmem70ko/ko knockout rats resulted in the efficient complementation of ATP synthase deficiency and thus in the successful genetic treatment of an otherwise fatal mitochondrial disorder.
Tipping the Balance: Vitamin D Inadequacy in Children Impacts the Major Gut Bacterial Phyla
Authors: Singh Parul , Rawat Arun , Saadaoui Marwa , Elhag Duaa , Tomei Sara , Elanbari Mohammed , Akobeng Anthony K. , Mustafa Amira , Abdelgadir Ibtihal , Udassi Sharda , Hendaus Mohammed A. , Al Khodor Souhaila
Published: January 2022

Vitamin D inadequacy appears to be on the rise globally, and it has been linked to an increased risk of osteoporosis, as well as metabolic, cardiovascular, and autoimmune diseases. Vitamin D concentrations are partially determined by genetic factors. Specific single nucleotide polymorphisms (SNPs) in genes involved in vitamin D transport, metabolism, or binding have been found to be associated with its serum concentration, and these SNPs differ among ethnicities. Vitamin D has also been suggested to be a regulator of the gut microbiota and vitamin D deficiency as the possible cause of gut microbial dysbiosis and inflammation. This pilot study aims to fill the gap in our understanding of the prevalence, cause, and implications of vitamin D inadequacy in a pediatric population residing in Qatar. Blood and fecal samples were collected from healthy subjects aged 4–14 years. Blood was used to measure serum metabolite of vitamin D, 25-hydroxycholecalciferol 25(OH)D. To evaluate the composition of the gut microbiota, fecal samples were subjected to 16S rRNA gene sequencing. High levels of vitamin D deficiency/insufficiency were observed in our cohort with 97% of the subjects falling into the inadequate category (with serum 25(OH)D < 75 nmol/L). The CT genotype in rs12512631, an SNP in the GC gene, was associated with low serum levels of vitamin D (ANOVA, p = 0.0356) and was abundant in deficient compared to non-deficient subjects. Overall gut microbial community structure was significantly different between the deficient (D) and non-deficient (ND) groups (Bray Curtis dissimilarity p = 0.049), with deficient subjects also displaying reduced gut microbial diversity. Significant differences were observed among the two major gut phyla, Firmicutes (F) and Bacteroidetes (B), where deficient subjects displayed a higher B/F ratio (p = 0.0097) compared to ND. Vitamin D deficient children also demonstrated gut enterotypes dominated by the genus Prevotella as opposed to Bacteroides. Our findings suggest that pediatric vitamin D inadequacy significantly impacts the gut microbiota. We also highlight the importance of considering host genetics and baseline gut microbiome composition in interpreting the clinical outcomes related to vitamin D deficiency as well as designing better personalized strategies for therapeutic interventions.
Relationship between Cognitive Dysfunction and Age-Related Variability in Oxidative Markers in Isolated Mitochondria of Alzheimer’s Disease Transgenic Mouse Brains
Authors: Yoshida Naoki , Kato Yugo , Takatsu Hirokatsu , Fukui Koji
Published: January 2022

Many neurodegenerative disorders, including Alzheimer’s disease (AD), are strongly associated with the accumulation of oxidative damage. Transgenic animal models are commonly used to elucidate the pathogenic mechanism of AD. Beta amyloid (Aβ) and tau hyperphosphorylation are very famous hallmarks of AD and well-studied, but the relationship between mitochondrial dysfunction and the onset and progression of AD requires further elucidation. In this study we used transgenic mice (the strain name is 5xFAD) at three different ages (3, 6, and 20 months old) as an AD model. Cognitive impairment in AD mice occurred in an age-dependent manner. Aβ1-40 expression significantly increased in an age-dependent manner in all brain regions with or without AD, and Aβ1-42 expression in the hippocampus increased at a young age. In a Western blot analysis using isolated mitochondria from three brain regions (cerebral cortex, cerebellum, and hippocampus), NMNAT-3 expression in the hippocampi of aged AD mice was significantly lower than that of young AD mice. SOD-2 expression in the hippocampi of AD mice was lower than for the age-matched controls. However, 3-NT expression in the hippocampi of AD mice was higher than for the age-matched controls. NQO-1 expression in the cerebral cortex of AD mice was higher than for the age-matched controls at every age that we examined. However, hippocampal NQO-1 expression in 6-month-old AD mice was significantly lower than in 3-month-old AD mice. These results indicate that oxidative stress in the hippocampi of AD mice is high compared to other brain regions and may induce mitochondrial dysfunction via oxidative damage. Protection of mitochondria from oxidative damage may be important to maintain cognitive function.
Pseudoprogression in Glioblastoma: Role of Metabolic and Functional MRI-Systematic Review
Authors: Sidibe Ingrid , Tensaouti Fatima , Roques Margaux , Cohen-Jonathan-Moyal Elizabeth , Laprie Anne
Published: January 2022

Background: Glioblastoma is the most frequent malignant primitive brain tumor in adults. The treatment includes surgery, radiotherapy, and chemotherapy. During follow-up, combined chemoradiotherapy can induce treatment-related changes mimicking tumor progression on medical imaging, such as pseudoprogression (PsP). Differentiating PsP from true progression (TP) remains a challenge for radiologists and oncologists, who need to promptly start a second-line treatment in the case of TP. Advanced magnetic resonance imaging (MRI) techniques such as diffusion-weighted imaging, perfusion MRI, and proton magnetic resonance spectroscopic imaging are more efficient than conventional MRI in differentiating PsP from TP. None of these techniques are fully effective, but current advances in computer science and the advent of artificial intelligence are opening up new possibilities in the imaging field with radiomics (i.e., extraction of a large number of quantitative MRI features describing tumor density, texture, and geometry). These features are used to build predictive models for diagnosis, prognosis, and therapeutic response. Method: Out of 7350 records for MR spectroscopy, GBM, glioma, recurrence, diffusion, perfusion, pseudoprogression, radiomics, and advanced imaging, we screened 574 papers. A total of 228 were eligible, and we analyzed 72 of them, in order to establish the role of each imaging modality and the usefulness and limitations of radiomics analysis.
Bacterial-Specific Induction of Inflammatory Cytokines Significantly Decreases upon Dual Species Infections of Implant Materials with Periodontal Pathogens in a Mouse Model
Authors: Rahim Muhammad Imran , Winkel Andreas , Ingendoh-Tsakmakidis Alexandra , Lienenklaus Stefan , Falk Christine S. , Eisenburger Michael , Stiesch Meike
Published: January 2022

Cytokine profiles are often perturbed after infections of medical implants. With a non-invasive in vivo imaging system, we report in a mouse model that interferon expression after infection of subcutaneous implants with Streptococcus oralis, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Treponema denticola (alone or as a combination) was species-specific, persisted longer in the presence of implants, and notably decreased upon dual species infections. This type I interferon expression disappeared within two weeks; however, histology of implant–tissue interface indicated high recruitment of immune cells even after three weeks. This was suggestive that biomaterial-associated infections could have prolonged effects, including the systemic stimulation of inflammatory cytokines. The present study investigated the systemic impact of this chronic peri-implant inflammation on the systemic expression of inflammatory cytokines (23) using a multiplex assay. Initially, the cytokine measurement in murine fibroblasts exposed to periodontal pathogens remained limited to the expression of five cytokines, namely, IL-6, G-CSF, CXCL-1/KC, MCP-1 (MCAF), and IL-12 (p40). The systemic determination of cytokines in mice increased to 19 cytokines (IL-1α, IL-2, IL-3, IL-5, IL-6, IL-9, IL-12 (p40), IL-12 (p70), IL-13, IL-17A, CCL-11/Eotaxin, G-CSF, IFN-γ, CXCL1/KC, MCP-1 (MCAF), MIP-1α/CCL3, MIP-1β/CCL4, CCL5/RANTES, and TNF-α). Systemic induction of cytokines was species-specific in the mouse model. The cytokine induction from infected implants differed significantly from sole tissue infections and sterile implants. Notably, systemic cytokine induction decreased after infections with dual species compared to single species infections. These findings describe the systemic effect of chronic peri-implant inflammation on the systemic induction of inflammatory cytokines, and this effect was strongly correlated to the type and composition of initial infection. Systemic modulations in cytokine expression upon dual species infections exhibit an exciting pattern that might explain the complications associated with biomaterial-related infection in patients. Moreover, these findings validate the requirement of multispecies infections for pre-clinical studies involving animal models.
Biomimicry for Energy-Efficient Building Design: A Bibliometric Analysis
Authors: Varshabi Niloufar , Arslan Selçuk Semra , Mutlu Avinç Güneş
Published: January 2022

With the development of the biomimicry approach, new and creative ideas have been established to solve problems in architectural design. In the designs based on this process, “nature” is used as a diverse data source for the transfer of these data to various processes, functions, materials, and structures. The primary purpose of this paper is to explore the development of biomimicry as an architectural approach, with a bibliometric review of research related to biomimicry and energy efficiency. Emphasis on the importance of the need for biomimicry in modern designs is another goal of this study. In this study, articles published in the Web of Science database (2010–2021) were analyzed. VOSviewer and SankeyMATIC software were used to represent the analysis results graphically. According to the results of this study, in addition to the inadequacy of biomimicry research, the need for further research became apparent. This review can serve as a reference for future studies to transfer natural phenomena to architecture in order to solve the problem of efficient energy consumption.
Multi-Functional Silver Nanoparticles for High-Throughput Endospore Sensing
Authors: Ikeno Shinya , Maekawa Takahiro , Hara Noriyasu
Published: January 2022

In spore-forming bacteria such as Bacillus and Clostridium, the vegetative cells form highly durable hard shells called endospores inside the bacteria to survive as the growth environment deteriorates. Because of these properties, endospores can cause food poisoning and medical accidents if they contaminate food, medicine, or other products, and it is required for technology to detect the spores at the manufacturing site. In this study, we focused on the surface-enhanced Raman scattering (SERS) method for the sensitive detection of dipicolinic acid (DPA), a molecular marker of endospores. We constructed Fe3O4/Ag core–shell functional silver nanoparticles that specifically bind to DPA, and investigated a method for the qualitative detection of DPA by SERS and the quantitative detection of DPA by fluorescence method using a terbium complex formed on the surface. As a result, the concentration of the functional silver nanoparticles constructed could detect spore-derived DPA by fluorescence detection method, and SERS was several tens of nM. The functionalized nanoparticles can detect DPA quantitatively and qualitatively, and are expected to be applied to detection technology in the production of food and pharmaceuticals.
Non-Destructive Genotyping of Cultivars and Strains of Sesame through NIR Spectroscopy and Chemometrics
Authors: Panero Francisco dos Santos , Smiderle Oscar , Panero João S. , Faria Fernando S. D. V. , Panero Pedro dos S. , Rodriguez Anselmo F. R.
Published: January 2022

The differentiation of cultivars is carried out by means of morphological descriptors, in addition to molecular markers. In this work, near-infrared spectroscopy (NIR) and chemometric techniques were used to develop classification models for two different commercial sesame cultivars (Sesamum indicum) and 3 different strains. The diffuse reflectance spectra were recorded in the region of 700 to 2500 nm. Based on the application of chemometric techniques: principal component analysis—PCA, hierarchical cluster analysis—HCA, k-nearest neighbor—KNN and the flexible independent modeling of class analogy—SIMCA, from the infrared spectra in the near region, it was possible to perform the genotyping of two sesame cultivars (BRS Seda and BRS Anahí), and to classify these cultivars with 3 different sesame strains, obtaining 100% accurate results. Due to the good results obtained with the implemented models, the potential of the methods for a possible realization of forensic, fast and non-destructive authentication, in intact sesame seeds was evident.
Detection of Liver Dysfunction Using a Wearable Electronic Nose System Based on Semiconductor Metal Oxide Sensors
Authors: Voss Andreas , Schroeder Rico , Schulz Steffen , Haueisen Jens , Vogler Stefanie , Horn Paul , Stallmach Andreas , Reuken Philipp
Published: January 2022

The purpose of this exploratory study was to determine whether liver dysfunction can be generally classified using a wearable electronic nose based on semiconductor metal oxide (MOx) gas sensors, and whether the extent of this dysfunction can be quantified. MOx gas sensors are attractive because of their simplicity, high sensitivity, low cost, and stability. A total of 30 participants were enrolled, 10 of them being healthy controls, 10 with compensated cirrhosis, and 10 with decompensated cirrhosis. We used three sensor modules with a total of nine different MOx layers to detect reducible, easily oxidizable, and highly oxidizable gases. The complex data analysis in the time and non-linear dynamics domains is based on the extraction of 10 features from the sensor time series of the extracted breathing gas measurement cycles. The sensitivity, specificity, and accuracy for distinguishing compensated and decompensated cirrhosis patients from healthy controls was 1.00. Patients with compensated and decompensated cirrhosis could be separated with a sensitivity of 0.90 (correctly classified decompensated cirrhosis), a specificity of 1.00 (correctly classified compensated cirrhosis), and an accuracy of 0.95. Our wearable, non-invasive system provides a promising tool to detect liver dysfunctions on a functional basis. Therefore, it could provide valuable support in preoperative examinations or for initial diagnosis by the general practitioner, as it provides non-invasive, rapid, and cost-effective analysis results.