bluuebunny/crossref_metadata_2025 huggingface dataset:
Early Cardiac Injury in Acute Respiratory Distress Syndrome: Comparison of Two Experimental Models
Authors: MIKOLKA P , KOSUTOVA P , BALENTOVA S , CIERNY D , KOPINCOVA J , KOLOMAZNIK M , ADAMKOV M , CALKOVSKA A , MOKRA D
Published: January 2021

Acute respiratory distress syndrome (ARDS) is characterized by diffuse lung damage, inflammation, oedema formation, and surfactant dysfunction leading to hypoxemia. Severe ARDS can accelerate the injury of other organs, worsening the patient´s status. There is an evidence that the lung tissue injury affects the right heart function causing cor pulmonale. However, heart tissue changes associated with ARDS are still poorly known. Therefore, this study evaluated oxidative and inflammatory modifications of the heart tissue in two experimental models of ARDS induced in New Zealand rabbits by intratracheal instillation of neonatal meconium (100 mg/kg) or by repetitive lung lavages with saline (30 ml/kg). Since induction of the respiratory insufficiency, all animals were oxygen-ventilated for next 5 h. Total and differential counts of leukocytes were measured in the arterial blood, markers of myocardial injury [(troponin, creatine kinase - myocardial band (CK-MB), lactate dehydrogenase (LD)] in the plasma, and markers of inflammation [tumour necrosis factor (TNF)α, interleukin (IL)-6], cardiovascular risk [galectin-3 (Gal-3)], oxidative changes [thiobarbituric acid reactive substances (TBARS), 3-nitrotyrosine (3NT)], and vascular damage [receptor for advanced glycation end products (RAGE)] in the heart tissue. Apoptosis of heart cells was investigated immunohistochemically. In both ARDS models, counts of total leukocytes and neutrophils in the blood, markers of myocardial injury, inflammation, oxidative and vascular damage in the plasma and heart tissue, and heart cell apoptosis increased compared to controls. This study indicates that changes associated with ARDS may contribute to early heart damage what can potentially deteriorate the cardiac function and contribute to its failure.
Variability of Peripheral Pulse Wave Velocity in Patients With Diabetes Mellitus Type 2 During Orthostatic Challenge
Authors: SVAČINOVÁ J , HRUŠKOVÁ J , JAKUBÍK J , BUDINSKAYA K , HIDEGOVÁ S , FABŠÍK M , SIEGLOVÁ H , KAŠČÁKOVÁ Z , NOVÁK J , NOVÁKOVÁ Z
Published: January 2021

Diabetes mellitus 2 (DM2) is the seventh cause of death worldwide. One of the reasons is late diagnosis of vascular damage. Pulse wave velocity (PWV) has become an independent marker of arterial stiffness and cardiovascular risk. Moreover, the previous studies have shown the importance of beat-to-beat PWV measurement due to its variability among the heart cycle. However, variability of PWV (PWVv) of the whole body hasn't been examined yet. We have studied a group of DM II and heathy volunteers, to investigate the beat-to-beat mean PWV (PWVm) and PWVv in the different body positions. PWV of left lower and upper extremities were measured in DM2 (7 m/8 f, age 68±10 years, BP 158/90±19/9 mm Hg) and healthy controls (5 m/6 f, age 23±2 years, BP 117/76±9/5 mm Hg). Volunteers were lying in the resting position and of head-up-tilt in 45° (HUT) for 6 min. PWVv was evaluated as a mean power spectrum in the frequency bands LF and HF (0.04-0.15 Hz, 0.15-0.5 Hz). Resting PWVm of upper extremity was higher in DM2. HUT increased lower extremity PWVm only in DM2. Extremities PWVm ratio was significantly lower in DM2 during HUT compared to controls. LF and HF PWVv had the same response to HUT. Resting PWVv was higher in DM2. Lower extremity PWVv increased during HUT in both groups. PWVm and PWVv in DM2 differed between extremities and were significantly influenced by postural changes due to hydrostatic pressure. Increased resting PWVm and PWVv in DM2 is a marker of increased arterial stiffness.
Investigation of Association between Genetic Polymorphisms of MMP2, MMP8, MMP9 and TIMP2 and Development of Varicose Veins in the Slovak Population – Pilot Study
Authors: MAZUCHOVÁ J , HALAŠOVÁ E , MAZUCH J , ŠARLINOVÁ M , VALENTOVÁ V , FRANEKOVÁ M , ZELNÍK Š , KRKOŠKOVÁ K , JAVORKA K , PÉČ M , GRENDÁR M
Published: January 2021

Matrix metalloproteinases (MMPs) are a family of zinc-dependent metalloendopeptidases that degrades extracellular matrix (ECM) components. MMPs are associated with venous wall remodelling, proliferation, migration, phenotypic and functional transformation of vascular smooth muscle cells and ECM organization under the physiological and pathophysiological conditions. We investigated possible association of genetic promoter polymorphisms of MMP2 (rs243866), MMP8 (rs11225395), MMP9 (rs3918242) and TIMP2 (rs8179090) to varicose veins development in the Slovak population. Genomic DNA from 276 Slovak individuals (138 cases, 138 controls) was genotyped for selected SNPs (rs243866, rs11225395, rs3918242 and rs8179090) using the PCR-RFLP analysis. The data were analysed by chi-squared (χ2) test, logistic regression, and Mann-Whitney test. The risk of varicose veins development was evaluated in dominant, codominant and recessive genetic models. The statistical evaluation of selected polymorphisms in patients in all three genetic models has not shown a significant risk of varicose veins development. Our study has not shown the association between selected polymorphisms and increased risk of varicose veins development in Slovak population. More evidence with broaden sample size is needed.
Voltage-Gated Sodium Channels Mediating Conduction in Vagal Motor Fibers Innervating the Esophageal Striated Muscle
Authors: PAVELKOVA N , BROZMANOVA M , JAYANTA PATIL M , KOLLARIK M
Published: January 2021

The vagal motor fibers innervating the esophageal striated muscle are essential for esophageal motility including swallowing and vomiting. However, it is unknown which subtypes of voltage-gated sodium channels (NaV1s) regulate action potential conduction in these efferent nerve fibers. The information on the NaV1s subtypes is necessary for understanding their potential side effects on upper gut, as novel inhibitors of NaV1s are developed for treatment of pain. We used isolated superfused (35 °C) vagally-innervated mouse esophagus striated muscle preparation (mucosa removed) to measure isometric contractions of circular striated muscle evoked by electrical stimulation of the vagus nerve. NaV1 inhibitors were applied to the de-sheathed segment of the vagus nerve. Tetrodotoxin (TTX) applied to the vagus nerve completely abolished electrically evoked contractions. The selective NaV1.7 inhibitor PF-05089771 alone partially inhibited contractions and caused a >3-fold rightward shift in the TTX concentration-inhibition curve. The NaV1.1, NaV1.2 and NaV1.3 group inhibitor ICA-121431 failed to inhibit contractions, or to alter TTX concentration-inhibition curves in the absence or in the presence of PF-05089771. RT-PCR indicated lack of NaV1.4 expression in nucleus ambiguus and dorsal motor nucleus of the vagus nerve, which contain motor and preganglionic neurons projecting to the esophagus. We conclude that the action potential conduction in the vagal motor fibers to the esophageal striated muscle in the mouse is mediated by TTX-sensitive voltage gated sodium channels including NaV1.7 and most probably NaV1.6. The role of NaV1.6 is supported by ruling out other TTX-sensitive NaV1s (NaV1.1-1.4) in the NaV1.7-independent conduction.
Religiosity and Reproductive Decisions in Europe
Authors:   , Bein Christoph
Published: January 2021

Religiosity has strongly declined in Europe since the 1960s. This is part of a broader trend towards secularization and individualization. We know from prior studies that religiosity still continues to be an important determinant of fertility. Yet, the mechanisms behind this relationship, as well as the cross-national differences are not well understood. In this thesis, the relationship between religiosity and reproductive decisions is approached from different angles, using data from the Generations and Gender Survey and the pairfam. Three key results emerge from the analysis. First, it is found that religiosity is positively related to the planning to have children (fertility intentions), in the same way as previous studies found for fertility behaviour. It was also revealed that this relationship between religiosity and fertility intentions vary across countries. Second, there is also evidence for gender-specific differences in the mechanisms of how religiosity translates into higher fertility. Specifically, highly religious women do not base their childbearing decisions on perceived costs of having children, contrary to less religious women and all men. Third, the results suggest that religiosity is a rather independent variable in the fertility decision making process, in particular it does not interact with variables related to gender roles and gender equity. All in all this thesis demonstrates that religiosity is still a powerful determinant of reproductive decisions in a secularizing Europe and likely continues to shape population dynamics across the continent.
Fermentative Production of l-2-Hydroxyglutarate by Engineered Corynebacterium glutamicum via Pathway Extension of l-Lysine Biosynthesis
Authors: Prell Carina , Burgardt Arthur , Meyer Florian , Wendisch Volker F.
Published: January 2021

l-2-hydroxyglutarate (l-2HG) is a trifunctional building block and highly attractive for the chemical and pharmaceutical industries. The natural l-lysine biosynthesis pathway of the amino acid producer Corynebacterium glutamicum was extended for the fermentative production of l-2HG. Since l-2HG is not native to the metabolism of C. glutamicum metabolic engineering of a genome-streamlined l-lysine overproducing strain was required to enable the conversion of l-lysine to l-2HG in a six-step synthetic pathway. To this end, l-lysine decarboxylase was cascaded with two transamination reactions, two NAD(P)-dependent oxidation reactions and the terminal 2-oxoglutarate-dependent glutarate hydroxylase. Of three sources for glutarate hydroxylase the metalloenzyme CsiD from Pseudomonas putida supported l-2HG production to the highest titers. Genetic experiments suggested a role of succinate exporter SucE for export of l-2HG and improving expression of its gene by chromosomal exchange of its native promoter improved l-2HG production. The availability of Fe2+ as cofactor of CsiD was identified as a major bottleneck in the conversion of glutarate to l-2HG. As consequence of strain engineering and media adaptation product titers of 34 ± 0 mM were obtained in a microcultivation system. The glucose-based process was stable in 2 L bioreactor cultivations and a l-2HG titer of 3.5 g L−1 was obtained at the higher of two tested aeration levels. Production of l-2HG from a sidestream of the starch industry as renewable substrate was demonstrated. To the best of our knowledge, this study is the first description of fermentative production of l-2HG, a monomeric precursor used in electrochromic polyamides, to cross-link polyamides or to increase their biodegradability.
Interactions Between 2D Materials and Living Matter: A Review on Graphene and Hexagonal Boron Nitride Coatings
Authors: Santos João , Moschetta Matteo , Rodrigues João , Alpuim Pedro , Capasso Andrea
Published: January 2021

Two-dimensional material (2DM) coatings exhibit complex and controversial interactions with biological matter, having shown in different contexts to induce bacterial cell death and contribute to mammalian cell growth and proliferation in vitro and tissue differentiation in vivo. Although several reports indicate that the morphologic and electronic properties of the coating, as well as its surface features (e.g., crystallinity, wettability, and chemistry), play a key role in the biological interaction, these kinds of interactions have not been fully understood yet. In this review, we report and classify the cellular interaction mechanisms observed in graphene and hexagonal boron nitride (hBN) coatings. Graphene and hBN were chosen as study materials to gauge the effect of two atomic-thick coatings with analogous lattice structure yet dissimilar electrical properties upon contact with living matter, allowing to discern among the observed effects and link them to specific material properties. In our analysis, we also considered the influence of crystallinity and surface roughness, detailing the mechanisms of interaction that make specific coatings of these 2DMs either hostile toward bacterial cells or innocuous for mammalian cells. In doing this, we discriminate among the material and surface properties, which are often strictly connected to the 2DM production technique, coating deposition and post-processing method. Building on this knowledge, the selection of 2DM coatings based on their specific characteristics will allow to engineer desired functionalities and devices. Antibacterial coatings to prevent biofouling, biocompatible platforms suitable for biomedical applications (e.g., wound healing, tissue repairing and regeneration, and novel biosensing devices) could be realized in the next future. Overall, a clear understanding on how the 2DM coating’s properties may modulate a specific bacterial or cellular response is crucial for any future innovation in the field.
Application of TonB-Dependent Transporters in Vaccine Development of Gram-Negative Bacteria
Authors: Wang Jia , Xiong Kun , Pan Qu , He Weifeng , Cong Yanguang
Published: January 2021

Multiple scarce nutrients, such as iron and nickel, are essential for bacterial growth. Gram-negative bacteria secrete chelators to bind these nutrients from the environment competitively. The transport of the resulting complexes into bacterial cells is mediated by TonB-dependent transporters (TBDTs) located at the outer membrane in Gram-negative bacteria. The characteristics of TBDTs, including surface exposure, protective immunogenicity, wide distribution, inducible expression in vivo, and essential roles in pathogenicity, make them excellent candidates for vaccine development. The possible application of a large number of TBDTs in immune control of the corresponding pathogens has been recently investigated. This paper summarizes the latest progresses and current major issues in the application.
Electric Mode Excitation in the Atmosphere by Magnetospheric Impulses and ULF Waves
Authors: Pilipenko V. A. , Fedorov E. N. , Martines-Bedenko V. A. , Bering E. A.
Published: January 2021

Variations of vertical atmospheric electric field Ez have been attributed mainly to meteorological processes. On the other hand, the theory of electromagnetic waves in the atmosphere, between the bottom ionosphere and earth’s surface, predicts two modes, magnetic H (TE) and electric E (TH) modes, where the E-mode has a vertical electric field component, Ez. Past attempts to find signatures of ULF (periods from fractions to tens of minutes) disturbances in Ez gave contradictory results. Recently, study of ULF disturbances of atmospheric electric field became feasible thanks to project GLOCAEM, which united stations with 1 sec measurements of potential gradient. These data enable us to address the long-standing problem of the coupling between atmospheric electricity and space weather disturbances at ULF time scales. Also, we have reexamined results of earlier balloon-born electric field and ground magnetic field measurements in Antarctica. Transmission of storm sudden commencement (SSC) impulses to lower latitudes was often interpreted as excitation of the electric TH0 mode, instantly propagating along the ionosphere–ground waveguide. According to this theoretical estimate, even a weak magnetic signature of the E-mode ∼1 nT must be accompanied by a burst of Ez well exceeding the atmospheric potential gradient. We have examined simultaneous records of magnetometers and electric field-mills during >50 SSC events in 2007–2019 in search for signatures of E-mode. However, the observed Ez disturbance never exceeded background fluctuations ∼10 V/m, much less than expected for the TH0 mode. We constructed a model of the electromagnetic ULF response to an oscillating magnetospheric field-aligned current incident onto the realistic ionosphere and atmosphere. The model is based on numerical solution of the full-wave equations in the atmospheric-ionospheric collisional plasma, using parameters that were reconstructed using the IRI model. We have calculated the vertical and horizontal distributions of magnetic and electric fields of both H- and E-modes excited by magnetospheric field-aligned currents. The model predicts that the excitation rate of the E-mode by magnetospheric disturbances is low, so only a weak Ez response with a magnitude of ∼several V/m will be produced by ∼100 nT geomagnetic disturbance. However, at balloon heights (∼30 km), electric field of the E-mode becomes dominating. Predicted amplitudes of horizontal electric field in the atmosphere induced by Pc5 pulsations and travelling convection vortices, about tens of mV/m, are in good agreement with balloon electric field and ground magnetometer observations.
200 Years of Research on Himalayan Biodiversity: Trends, Gaps, and Policy Implications
Authors: Rana Suresh K. , Rawal Ranbeer S. , Dangwal Bhawana , Bhatt Indra D. , Price Trevor D.
Published: January 2021

Global mountains, including the Himalaya, are highly vulnerable ecosystems, especially given climate and land-use changes. Here, we compile the literature on Himalayan biodiversity in order to assess spatial and taxonomic trends in research during the past 200 years. We identified 35,316 research outputs, including 28,120 journal articles, 3,725 doctoral theses, and 3,471 books. Nepal contributes the largest volume of published literature, followed by west Himalayan Indian states, with relatively few studies on the most biodiverse region lying to the east of Nepal. Publications on Himalayan biodiversity research have increased annually, especially after 1970, with an acceleration since 2000. Among the major taxonomic groups, the largest number of publications is on seed plants (angiosperms), followed by invertebrates (especially arthropods) and vertebrates. Some groups of organisms, notably fungi, bacteria, algae, bryophytes, pteridophytes, etc., are clearly understudied. Among various research disciplines, ecology is the most dominant field followed by agriculture, ethnobiology, and paleontology. Some newer disciplines, including molecular biology and climate change, have contributed to the growth in the number of papers appearing during the last two decades. Despite an encouraging and rapid increase in research papers during this century, they are largely in low-impact-factor journals, likely to be subject to poor peer review, and many doctoral theses remain unpublished. The Government of India's development initiative emphasizes the importance of research in the Himalaya, which can be enhanced by improved quality of peer review and local journals registering in global indexing services.
Identification of Amino Acid Residues in Human IgM Fc Receptor (FcµR) Critical for IgM Binding
Authors: Skopnik Christopher M. , Al-Qaisi Khlowd , Calvert Rosaleen A. , Enghard Philipp , Radbruch Andreas , Sutton Brian J. , Kubagawa Hiromi
Published: January 2021

Both non-immune “natural” and antigen-induced “immune” IgM are important for protection against infections and for regulation of immune responses to self-antigens. The roles of its Fc receptor (FcµR) in these IgM effector functions have begun to be explored. In the present study, by taking advantage of the difference in IgM-ligand binding of FcµRs of human (constitutive binding) and mouse (transient binding), we replaced non-conserved amino acid residues of human FcµR with mouse equivalents before establishment of cell lines stably expressing mutant or wild-type (WT) receptors. The resultant eight-different mutant FcµR-bearing cells were compared with WT receptor-bearing cells for cell-surface expression and IgM-binding by flow cytometric assessments using receptor-specific mAbs and IgM paraproteins as ligands. Three sites Asn66, Lys79-Arg83, and Asn109, which are likely in the CDR2, DE loop and CDR3 of the human FcµR Ig-like domain, respectively, were responsible for constitutive IgM binding. Intriguingly, substitution of Glu41 and Met42 in the presumed CDR1 with the corresponding mouse residues Gln and Leu, either single or more prominently in combination, enhanced both the receptor expression and IgM binding. A four-aa stretch of Lys24-Gly27 in the predicted A ß-strand of human FcµR appeared to be essential for maintenance of its proper receptor conformation on plasma membranes because of reduction of both receptor expression and IgM-binding potential when these were mutated. Results from a computational structural modeling analysis were consistent with these mutational data and identified a possible mode of binding of FcµR with IgM involving the loops including Asn66, Arg83 and Asn109 of FcµR interacting principally with the Cµ4 domain including Gln510 and to a lesser extent Cµ3 domain including Glu398, of human IgM. To our knowledge, this is the first experimental report describing the identification of amino acid residues of human FcµR critical for binding to IgM Fc.
Inactivation of the PD-1-Dependent Immunoregulation in Mice Exacerbates Contact Hypersensitivity Resembling Immune-Related Adverse Events
Authors: Ashoori Matin Dokht , Suzuki Kensuke , Tokumaru Yosuke , Ikuta Naoko , Tajima Masaki , Honjo Tasuku , Ohta Akio
Published: January 2021

Blockade of PD-1, an indispensable physiological immunoregulatory mechanism, enhances immune activities and is widely used in the immunotherapy of cancer. This treatment often accompanies inflammatory complication called immune-related adverse events (irAE), most frequently in the skin. To analyze how skin inflammation develops by the blockade of PD-1-dependent immunoregulation, we studied the exacerbation of oxazolone-induced contact hypersensitivity by PD-L1 blockade. The inactivation of PD-1 signaling enhanced swelling of the skin with massive CD8+T cell infiltration. Among PD-1-expressing cells, T cells were the predominant targets of anti-PD-L1 mAb treatment since PD-L1 blockade did not affect skin inflammation in RAG2-/-mice. PD-L1 blockade during immunization with oxazolone significantly promoted the development of hapten-reactive T cells in the draining lymph nodes. The enhancement of local CD8+T cell-dominant immune responses by PD-L1 blockade was correlated with the upregulation of CXCL9 and CXCL10. Challenges with a low dose of oxazolone did not demonstrate any significant dermatitis; however, the influence of PD-L1 blockade on T cell immunity was strong enough to cause the emergence of notable dermatitis in this suboptimal dosing, suggesting its relevance to dermal irAE development. In the low-dose setting, the blockade of CXCR3, receptor of CXCL9/10, prevented the induction of T cell-dominant inflammation by anti-PD-L1 mAb. This experimental approach reproduced CD8+T cell-dominant form of cutaneous inflammation by the blockade of PD-L1 that has been observed in dermal irAE in human patients.
Very High Resolution Tools for the Monitoring and Assessment of Environmental Hazards in Coastal Areas
Authors: García-Sánchez Guillermo , Mancho Ana M. , Ramos Antonio G. , Coca Josep , Pérez-Gómez Begoña , Álvarez-Fanjul Enrique , Sotillo Marcos G. , García-León Manuel , García-Garrido Víctor J. , Wiggins Stephen
Published: January 2021

Recently, new steps have been taken for the development of operational applications in coastal areas which require very high resolutions both in modeling and remote sensing products. In this context, this work describes a complete monitoring of an oil spill: we discuss the performance of high resolution hydrodynamic models in the area of Gran Canaria and their ability for describing the evolution of a real-time event of a diesel fuel spill, well-documented by port authorities and tracked with very high resolution remote sensing products. Complementary information supplied by different sources enhances the description of the event and supports their validation.
Risk Factors for Intestinal Barrier Impairment in Patients With Essential Hypertension
Authors: Li Cao , Xiao Ping , Lin Da , Zhong Hao-Jie , Zhang Ran , Zhao Zhi-gang , He Xing-Xiang
Published: January 2021

Background: Previous studies have indicated an association between hypertension and intestinal barrier dysfunction in mice models. The present study aims to investigate the association between hypertension and intestinal barrier impairment in humans and identify the novel potential risk factors for hypertension.

Methods: Medical data from consecutive inpatients were retrospectively pooled from patient records. We compared intestinal barrier serum markers [diamine oxidase (DAO), lipopolysaccharide (LPS), and D-lactate] between those patients with and without hypertension. Moreover, the associations between intestinal barrier markers and cardiovascular risk, hypertension history, blood pressure control, hypertensive complications, and antihypertensive medication history were also analyzed.

Results: Overall, 106 hypertensive and 251 normotensive subjects were included. Patients with hypertension had a higher level of DAO (28.30 vs. 18.73%, P = 0.044) and LPS (22.64 vs. 11.16%, P = 0.005). In hypertensive patients, multivariate logistic regression analyses showed that long hypertension history (≥20 years), poor control of diastolic blood pressure, cardiac and renal complications, and use of multiple antihypertensive medications were risk factors for elevated DAO, while the use of multiple antihypertensive medications was a risk factor for elevated D-lactate (P < 0.05).

Conclusions: Hypertension is associated with impairment of intestinal barrier, especially in patients with long duration, poor blood pressure control, cardiac and renal complications, and use of multiple antihypertensive medications. The current study indicates that intestinal barrier dysfunction might be a potential predictor of hypertension.
Residue-Level Contact Reveals Modular Domain Interactions of PICK1 Are Driven by Both Electrostatic and Hydrophobic Forces
Authors: Stevens Amy O. , He Yi
Published: January 2021

PICK1 is a multi-domain scaffolding protein that is uniquely comprised of both a PDZ domain and a BAR domain. While previous experiments have shown that the PDZ domain and the linker positively regulate the BAR domain and the C-terminus negatively regulates the BAR domain, the details of internal regulation mechanisms are unknown. Molecular dynamics (MD) simulations have been proven to be a useful tool in revealing the intramolecular interactions at atomic-level resolution. PICK1 performs its biological functions in a dimeric form which is extremely computationally demanding to simulate with an all-atom force field. Here, we use coarse-grained MD simulations to expose the key residues and driving forces in the internal regulations of PICK1. While the PDZ and BAR domains do not form a stable complex, our simulations show the PDZ domain preferentially interacting with the concave surface of the BAR domain over other BAR domain regions. Furthermore, our simulations show that the short helix in the linker region can form interactions with the PDZ domain. Our results reveal that the surface of the βB-βC loop, βC strand, and αA-βD loop of the PDZ domain can form a group of hydrophobic interactions surrounding the linker helix. These interactions are driven by hydrophobic forces. In contrast, our simulations reveal a very dynamic C-terminus that most often resides on the convex surface of the BAR domain rather than the previously suspected concave surface. These interactions are driven by a combination of electrostatic and hydrophobic interactions.
Drug Resistance in Glioblastoma: The Two Faces of Oxidative Stress
Authors: Olivier Christophe , Oliver Lisa , Lalier Lisenn , Vallette François M.
Published: January 2021

Glioblastomas (GBM) are the most common primary brain tumor with a median survival of 15 months. A population of cells with stem cell properties (glioblastoma stem cells, GSCs) drives the initiation and progression of GBM and is localized in specialized microenvironments which support their behavior. GBM are characterized as extremely resistant to therapy, resulting in tumor recurrence. Reactive oxygen species (ROS) control the cellular stability by influencing different signaling pathways. Normally, redox systems prevent cell oxidative damage; however, in gliomagenesis, the cellular redox mechanisms are highly impaired. Herein we review the dual nature of the redox status in drug resistance. ROS generation in tumor cells affects the cell cycle and is involved in tumor progression and drug resistance in GBM. However, excess ROS production has been found to induce cell death programs such as apoptosis and autophagy. Since GBM cells have a high metabolic rate and produce high levels of ROS, metabolic adaptation in these cells plays an essential role in resistance to oxidative stress-induced cell death. Finally, the microenvironment with the stromal components participates in the enhancement of the oxidative stress to promote tumor progression and drug resistance.
Establish a Nomogram to Predict Falls in Spinocerebellar Ataxia Type 3
Authors: Lin Junyu , Zhang Lingyu , Cao Bei , Wei Qianqian , Ou Ruwei , Hou Yanbing , Xu Xinran , Liu Kuncheng , Gu Xiaojing , Shang Huifang
Published: January 2021

Purpose: Falls are common and are frequently accompanied by injuries in patients with spinocerebellar ataxias type 3 (SCA3). We explored which factors could predict falls in a cohort of patients with SCA3 and developed a nomogram model to predict the first fall in non-fallen patients with SCA3.

Method: We conducted a prospective cohort study. Forty-four non-fallen patients with SCA3 were followed up until the first fall or November 5, 2020, whichever came first. Univariate and multivariate Cox proportional hazard regression analyses were applied to explore the predictive factors of falls in patients with SCA3. A nomogram model predicting the no-fall probabilities at 3, 6, 12, and 24 months was formulated based on the results of the multivariate Cox analysis. Internal validation was conducted to assess the discrimination and calibration of the final model using bootstrapping with 1,000 resamples.

Results: Multivariate Cox proportional hazard regression showed that the presence of dystonia, hyperreflexia, urinary incontinence, and hidrosis and the number of abnormal eye movements predicted a more rapid progression to falls in patients with SCA3. The nomogram model showed good discrimination with a concordance index of 0.83 and good calibration.

Conclusion: Patients with dystonia, hyperreflexia, urinary incontinence, and hidrosis, and more types of abnormal eye movement had a more rapid progression to falls in SCA3.
Standard vs. Modified Antiplatelet Therapy Based on Thromboelastography With Platelet Mapping for Preventing Bleeding Events in Patients Undergoing Stent-Assisted Coil for a Ruptured Intracranial Aneurysm
Authors: Li Yuanshu , Zhang Xiaodong , Guo Zongduo , Zhu Ji , Xu Rui , He Zhaohui , Sun Xiaochuan
Published: January 2021

Background and Purpose: Stent-assisted coiling (SAC) of intracranial aneurysms is usually treated with antiplatelet therapy to reduce the risk of postoperative ischemic events. However, using the same antiplatelet therapy for all patients may increase the risk of bleeding in patients with aneurysmal subarachnoid hemorrhage (aSAH). Thromboelastography-platelet mapping (TEG-PM) measures platelet function, which reflects the effect of antiplatelet drugs. This study aimed to evaluate the benefits of individualized antiplatelet regimens based on TEG-PM parameters for patients with aSAH who underwent SAC.

Methods: We retrospectively included patients with aSAH who treated with SAC during the period from June 2012 to December 2019. Patients were divided into two groups: patients whose antiplatelet therapy adjusted by TEG-PM parameters after surgery (adjustment group) and patients who were treated with standard dual antiplatelet therapy without TEG-PM test (control group). The occurrence of major/minor bleeding events, major/minor thromboembolic events, and favorable outcome (modified Rankin scale <3) were compared in both groups during hospitalization.

Results: Of 188 aSAH patients considered for this study, 145 met the criteria for inclusion and were included in the analysis (93 patients in the adjustment group and 52 patients in the control group). The risks of minor bleeding events (1.1 vs. 9.6%, p = 0.02) were significantly lower in patients in the adjustment group. However, there was no significant difference in the rate of major bleeding events at discharge between adjustment and control groups (p = 0.35). The rates of thromboembolic events and favorable outcome were similar in both groups (22.6 vs. 28.8%, p = 0.42, 95.7 vs. 96.2%, p = 1.00). Furthermore, the minor thromboembolic events rate was significantly lower in the patients treated with treatment plan C (p = 0.02 for treatment plan C vs. treatment A, p = 0.03 for treatment plan C vs. treatment plan B). However, there was no significant difference in the rate of other mentioned above complications and favorable outcomes among patients treated with different antiplatelet regimens.

Conclusions: Individualized antiplatelet therapy based on TEG-PM parameters might positively impact the bleeding risk of aSAH patients, without increasing the risk for clinically relevant thromboembolic events.
Is This Within Reach? Left but Not Right Brain Damage Affects Affordance Judgment Tendencies
Authors: Randerath Jennifer , Finkel Lisa , Shigaki Cheryl , Burris Joe , Nanda Ashish , Hwang Peter , Frey Scott H.
Published: January 2021

The ability to judge accurately whether or not an action can be accomplished successfully is critical for selecting appropriate response options that enable adaptive behaviors. Such affordance judgments are thought to rely on the perceived fit between environmental properties and knowledge of one's current physical capabilities. Little, however, is currently known about the ability of individuals to judge their own affordances following a stroke, or about the underlying neural mechanisms involved. To address these issues, we employed a signal detection approach to investigate the impact of left or right hemisphere injuries on judgments of whether a visual object was located within reach while remaining still (i.e., reachability). Regarding perceptual sensitivity and accuracy in judging reachability, there were no significant group differences between healthy controls (N = 29), right brain damaged (RBD, N = 17) and left brain damaged stroke patients (LBD, N = 17). However, while healthy controls and RBD patients demonstrated a negative response criterion and thus overestimated their reach capability, LBD patients' average response criterion converged to zero, indicating no judgment tendency. Critically, the LBD group's judgment tendency pattern is consistent with previous findings in this same sample on an affordance judgment task that required estimating whether the hand can fit through apertures (Randerath et al., 2018). Lesion analysis suggests that this loss of judgment tendency may be associated with damage to the left insula, the left parietal and middle temporal lobe. Based on these results, we propose that damage to the left ventro-dorsal stream disrupts the retrieval and processing of a stable criterion, leading to stronger reliance on intact on-line body-perceptive processes computed within the preserved bilateral dorsal network.
Stimulus Intervals Modulate the Balance of Brain Activity in the Human Primary Somatosensory Cortex: An ERP Study
Authors: Liu Yang , Dong Bo , Yang Jiajia , Ejima Yoshimichi , Wu Jinglong , Wu Qiong , Zhang Ming
Published: January 2021

Neuronal excitation and inhibition occur in the brain at the same time, and brain activation reflects changes in the sum of excitation and inhibition. This principle has been well-established in lower-level sensory systems, including vision and touch, based on animal studies. However, it is unclear how the somatosensory system processes the balance between excitation and inhibition. In the present ERP study, we modified the traditional spatial attention paradigm by adding double stimuli presentations at short intervals (i.e., 10, 30, and 100 ms). Seventeen subjects participated in the experiment. Five types of stimulation were used in the experiment: a single stimulus (one raised pin for 40 ms), standard stimulus (eight pins for 40 ms), and double stimuli presented at intervals of 10, 30, and 100 ms. The subjects were asked to attend to a particular finger and detect whether the standard stimulus was presented to that finger. The results showed a clear attention-related ERP component in the single stimulus condition, but the suppression components associated with the three interval conditions seemed to be dominant in somatosensory areas. In particular, we found the strongest suppression effect in the ISI-30 condition (interval of 30 ms) and that the suppression and enhancement effects seemed to be counterbalanced in both the ISI-10 and ISI-100 conditions (intervals of 10 and 100 ms, respectively). This type of processing may allow humans to easily discriminate between multiple stimuli on the same body part.
Mechanisms and Applications of Neuromodulation Using Surface Acoustic Waves—A Mini-Review
Authors: Peng Danli , Tong Wei , Collins David J. , Ibbotson Michael R. , Prawer Steven , Stamp Melanie
Published: January 2021

The study of neurons is fundamental for basic neuroscience research and treatment of neurological disorders. In recent years ultrasound has been increasingly recognized as a viable method to stimulate neurons. However, traditional ultrasound transducers are limited in the scope of their application by self-heating effects, limited frequency range and cavitation effects during neuromodulation. In contrast, surface acoustic wave (SAW) devices, which are producing wavemodes with increasing application in biomedical devices, generate less self-heating, are smaller and create less cavitation. SAW devices thus have the potential to address some of the drawbacks of traditional ultrasound transducers and could be implemented as miniaturized wearable or implantable devices. In this mini review, we discuss the potential mechanisms of SAW-based neuromodulation, including mechanical displacement, electromagnetic fields, thermal effects, and acoustic streaming. We also review the application of SAW actuation for neuronal stimulation, including growth and neuromodulation. Finally, we propose future directions for SAW-based neuromodulation.
Insights Into the Delivery of Personalized Nutrition: Evidence From Face-To-Face and Web-Based Dietary Interventions
Authors: Al-Awadhi Balquees , Fallaize Rosalind , Zenun Franco Rodrigo , Hwang Faustina , Lovegrove Julie A.
Published: January 2021

Prevention strategies for non-communicable diseases (NCDs) are a global priority as it has been estimated that NCDs will account for around 73% of worldwide mortality by the year 2020. The adoption of diets that are low in saturated fat, free sugars, and red and processed meats and higher in unsaturated fats, wholegrains, fruit, and vegetables have been shown to reduce the risk of NCDs. With increasing internet use, several nutrition interventions are now being conducted online as well as face-to-face, however it is unclear which delivery method is most effective. Although a consumer preference toward face-to-face dietary advice delivery has been identified previously, interest in delivering web-based dietary advice, and in particular personalized nutrition (PN), has been rising, as internet delivery may be less costly and more scalable. This review compares published face-to-face and web-based dietary interventions to give insight into which dietary method might be more effective for PN. In total, 19 peer-reviewed randomized controlled trials were identified for inclusion in the review. The majority of face-to-face nutrition interventions were successful at facilitating dietary change. Results from web-based nutrition interventions suggested that personalized web-based nutrition interventions may be successful at inducing short-term dietary change compared to standardized dietary interventions, however, minimal evidence of long-term impact has been found across both delivery methods. Results of a trial that compared face-to-face with web-based diet intervention found significantly greater dietary changes in the face-to-face group compared to web-based and control groups. Further controlled comparative studies and cost-benefit analysis are needed to assess whether web-based methods can be used in place of face-to-face interventions for achieving dietary change.
High Serum Estradiol Reduces Acute Hepatotoxicity Risk Induced by Epirubicin Plus Cyclophosphamide Chemotherapy in Premenopausal Women with Breast Cancer
Authors: Huang Shunmin , Liu Maobai , Fu Fangmeng , Liu Hangmin , He Baochang , Xiao Danni , Yang Jing
Published: January 2021

Aim: We evaluated whether acute drug-induced liver injury (DILI) caused by adjuvant chemotherapy with epirubicin plus cyclophosphamide for early breast cancer was associated with estradiol (E2), luteinizing hormone (LH), and follicle-stimulating hormone (FSH).

Methods: Reproductive hormone test results of breast cancer patients were collected in the first chemotherapy cycle. E2, LH, and FSH levels were loge-transformed to normally distributed variables and were assessed using Student’s t-test to determine significant differences between the case and control groups. Hormone levels were classified according to the interquartile range and analyzed by logistic regression to determine their association with DILI caused by chemotherapy.

Results: Among the 915 enrolled patients (DILI group: 204; control group: 711), menopausal status, along with serum E2, LH, and FSH levels, did not substantially differ between case and control groups. However, in the premenopause subgroup (n = 483), we found a significant difference in the E2 level between the case and control groups (p = 0.001). After adjusting for age and body mass index, premenopausal patients with 152–2,813 pg/mL E2 showed a lower risk of chemotherapy-induced DILI than patients with ≤20 pg/mL E2 (odds ratio: 0.394; 95% confidence interval: 0.207–0.748). The linear trend χ2 test revealed that E2 levels in premenopausal patients with breast cancer were inversely associated with the development of DILI.

Conclusion: High serum E2 levels are associated with a reduced DILI risk in premenopausal patients with breast cancer undergoing epirubicin plus cyclophosphamide adjuvant chemotherapy.
Calming the Storm: Natural Immunosuppressants as Adjuvants to Target the Cytokine Storm in COVID-19
Authors: Peter Angela E. , Sandeep B. V. , Rao B. Ganga , Kalpana V. Lakshmi
Published: January 2021

The COVID-19 pandemic has caused a global health crisis, with no specific antiviral to treat the infection and the absence of a suitable vaccine to prevent it. While some individuals contracting the SARS-CoV-2 infection exhibit a well coordinated immune response and recover, others display a dysfunctional immune response leading to serious complications including ARDS, sepsis, MOF; associated with morbidity and mortality. Studies revealed that in patients with a dysfunctional immune response, there is a massive cytokine and chemokine release, referred to as the ‘cytokine storm’. As a result, such patients exhibit higher levels of pro-inflammatory/modulatory cytokines and chemokines like TNFα, INFγ, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-17, G-CSF, GM-CSF, MCSF, HGF and chemokines CXCL8, MCP1, IP10, MIP1α and MIP1β. Targeting this cytokine storm is a novel, promising treatment strategy to alleviate this excess influx of cytokines observed at the site of infection and their subsequent disastrous consequences. Natural immunosuppressant compounds, derived from plant sources like curcumin, luteolin, piperine, resveratrol are known to inhibit the production and release of pro-inflammatory cytokines and chemokines. This inhibitory effect is mediated by altering signal pathways like NF-κB, JAK/STAT, MAPK/ERK that are involved in the production and release of cytokines and chemokines. The use of these natural immunosuppressants as adjuvants to ameliorate the cytokine storm; in combination with antiviral agents and other treatment drugs currently in use presents a novel, synergistic approach for the treatment and effective cure of COVID-19. This review briefly describes the immunopathogenesis of the cytokine storm observed in SARS-CoV-2 infection and details some natural immunosuppressants that can be used as adjuvants in treating COVID-19 disease.
Adverse Cardiovascular Effects of Phenylephrine Eye Drops Combined With Intravenous Atropine
Authors: Li Qingyu , Pang Jianxin , Deng Yang , Zhang Shaochong , Wang Yong , Gao Yang , Yuan Xiaoyong , Wei Yantao , Zhang Hongbin , Tan Junlian , Chi Wei , Guo Wenjun
Published: January 2021

Background:Phenylephrine and atropine can cause serious adverse effects when applied in combination. We investigated the effect of phenylephrine eye drops combined with intravenous atropine on the cardiovascular system in patients under general anesthesia undergoing intraocular surgery.

Methods:The effects of the drugs were observed through clinical study. Thirteen patients undergoing intraocular surgery under general anesthesia were observed in this study; all were injected intravenously with atropine due to the oculocardiac reflex during surgery. To study the combination of drugs, anin vivostudy was performed on rats. Seventy-two standard deviation rats that received phenylephrine eye drops and intravenous atropine treatment under general anesthesia were assessed, of which 18 treated with these drugs simultaneously were administered normal saline, neostigmine or esmolol. Blood pressure and heart rate were recorded and analyzed.

Findings:The age of the patients ranged from seven to 14 years old with an average age of 10.7 years old, and 11 patients were male. In patients, 5% phenylephrine eye drops combined with intravenous atropine led to a significant heart rate increase and the increase lasted 20 min. The significant increase in diastolic blood pressure and systolic blood pressure lasted for 15 and 25 min, respectively. From five to 25 min after intravenous atropine treatment, the systolic blood pressure and diastolic blood pressure were both more than 20% higher than that at baseline. In rats, the changes in blood pressure and heart rate were independent of the phenylephrine and atropine administration sequence but were related to the administration time interval. The neostigmine group showed a significant decrease in blood pressure after the increase from the administration of phenylephrine and atropine.

Interpretation:Phenylephrine eye drops combined with intravenous atropine have obvious cardiovascular effects that can be reversed by neostigmine. This drug combination should be used carefully for ophthalmic surgery, especially in patients with cardio-cerebrovascular diseases.