bluuebunny/crossref_metadata_2025 huggingface dataset:
Nuclear and Mitochondrial Circulating Cell-Free DNA Is Increased in Patients With Inflammatory Bowel Disease in Clinical Remission
Authors: Vrablicova Zuzana , Tomova Kristina , Tothova Lubomira , Babickova Janka , Gromova Barbora , Konecna Barbora , Liptak Robert , Hlavaty Tibor , Gardlik Roman
Published: December 2020

Background:The role of cell-free DNA (cfDNA) in the pathogenesis of inflammatory bowel disease (IBD) has been recently suggested. The aim of this study was to analyze circulating cfDNA and deoxyribonuclease (DNase) activity in IBD patients in clinical remission.

Materials and Methods:Plasma and serum were obtained from 72 patients with Crohn's disease and 28 patients with ulcerative colitis. Total cfDNA, nuclear DNA (ncDNA), mitochondrial DNA (mtDNA) and DNase activity were measured.

Results:IBD patients showed higher levels of both ncDNA and mtDNA compared to healthy controls. Concentration of ncDNA was higher in males compared to females, including patients and healthy controls. However, unlike males higher amount of ncDNA was found in female IBD patients compared to healthy controls. DNase activity was significantly lower in male IBD patients compared with healthy controls. In addition, there was a negative correlation between DNase activity and ncDNA levels in male IBD patients.

Conclusions:Herein we present increased amount of circulating ncDNA and mtDNA in IBD patients in clinical remission. Thus, unlike total cfDNA, circulating ncDNA and mtDNA might not represent the optimal biomarkers of disease activity. This is also the first report on sex difference in circulating ncDNA levels, possibly associated with lower DNase activity in males.
A Digital Innovation for the Personalized Management of Adherence: Analysis of Strengths, Weaknesses, Opportunities, and Threats
Authors: Hein Anna-Elisa , Vrijens Bernard , Hiligsmann Mickael
Published: December 2020

Introduction: Personalized medicine and management of adherence are potential solutions for the suboptimal use of medicines. Digital medication management innovations currently under development combine both aspects. This research aims to investigate facilitators for and barriers to the translation of digital innovations for personalized medicine and adherence management into clinical practice from the policymaker and regulator perspective.

Methods: A mixed-method study was used combining a scoping review to identify main interests, semi-structured interviews (n = 5) with representatives of European health policymaking and regulatory organizations, and a supplementary literature review to investigate key subthemes. The SWOT analysis was used for the qualitative analysis.

Results: The literature reviews and the qualitative interviews suggested that digital solutions can facilitate the personalized management of medications and improve quality and safety, especially as the openness for digital health solutions is increasing. Digital solutions may, on the other hand, add complexity to the treatment, which can be perceived as a potential barrier for their uptake. As more multidisciplinary and participative structures are emerging, digital solutions can promote the implementation of new services. Nevertheless, change progresses slowly in the task-oriented structures of health systems. Integration of digital solutions depends on all stakeholders' willingness and abilities to co-create this change. Patients have different capabilities to self-manage their medical conditions and use digital solutions. Personalization of digital health solutions and integration in existing service structures are crucial to ensure equality among population segments. Developments in the digital infrastructure, although they are partly slow and not well-aligned, enable the implementation of innovations in clinical practice leading to further advances in data generation and usage for future innovations.

Discussion: This study suggests that digital solutions have the potential to facilitate high-quality medication management and improve adherence to medications, enable new service structures, and are essential to drive further innovations in health care. Nevertheless, increasing the self-responsibility of patients can have undesirable effects on health outcomes, especially within vulnerable population segments. Digital health solutions can be an opportunity to optimize the use of medicines and thus their efficiency. Well-conceived development and implementation processes are needed to also realize improvements in equality and solidarity within health systems.
Antimicrobial Efficacy of Aqueous Ozone and Ozone–Lactic Acid Blend on Salmonella-Contaminated Chicken Drumsticks Using Multiple Sequential Soaking and Spraying Approaches
Authors: Megahed Ameer , Aldridge Brian , Lowe James
Published: December 2020

Ozone (O3) is an attractive alternative antimicrobial in the poultry processing industry. The optimal operational conditions of O3 for improving food safety concerns are poorly understood. The main objective of this study was therefore to characterize the microbial killing capacity of aqueous O3 and O3–lactic acid blend (O3–LA) at different operational conditions on chicken drumsticks contaminated with high Salmonella load using sequential soaking and spraying approaches. Four hundred forty-eight chicken drumsticks (280–310 g) were soaked into two-strain Salmonella cocktail, and the initial load on the surface of the skin was 6.9-log10 cell forming unit (CFU)/cm2 [95% confidence interval (CI), 6.8–7.0]. The contaminated drumsticks were then sequentially (10×) soaked and sprayed with aqueous O3 (8 ppm) and O3–LA. Following O3 exposure, quantitative bacterial cultures were performed on the post-soaking and post-spraying water, skin surface, and subcutaneous (SC) of each drumstick using 3MTM PetrifilmTM Rapid Aerobic Count Plate (RAC) and plate reader. The average killing capacity of aqueous O3/cycle on the skin surface was 1.6-log10/cm2 (95% CI, 1.5–1.8-log10/cm2) and 1.2-log10/cm2 (95% CI, 1.0–1.4-log10/cm2), and it was 1.1-log10/cm2 (95% CI, 0.9–1.3-log10/cm2) and 0.9-log10/cm2 (95% CI, 0.7–1.1-log10/cm2) in SC for soaking and spraying approaches, respectively. Six sequential soaking and seven sequential spraying cycles with ozonated water of 8 ppm reduced the heavy Salmonella load below the detectable limit on the skin surface and SC of drumsticks, respectively. Addition of LA seems to increase the microbial killing capacity of aqueous O3 with average differences of 0.3-log10/cm2 (P = 0.08) and 0.2-log10/cm2 (P = 0.12) on the skin surface using soaking and spraying approaches, respectively. Aqueous O3 did not cause any significant changes in the drumstick skin color. The Salmonella load of < 4.5-log10/cm2 was a strong predictor for the reduction rate (P < 0.001, R2 = 0.64). These results provide important information that helps the poultry processing facilities for selecting the optimal operational strategy of O3 as an effective antimicrobial.
Among-Strain Variation in Resistance of Paramecium caudatum to the Endonuclear Parasite Holospora undulata: Geographic and Lineage-Specific Patterns
Authors: Weiler Jared , Zilio Giacomo , Zeballos Nathalie , Nørgaard Louise , Conce Alberto Winiffer D. , Krenek Sascha , Kaltz Oliver , Bright Lydia
Published: December 2020

Resistance is a key determinant in interactions between hosts and their parasites. Understanding the amount and distribution of variation in this trait between strains can provide insights into (co)evolutionary processes and their potential to shape patterns of diversity in natural populations. Using controlled inoculation in experimental mass cultures, we investigated the quantitative variation in resistance to the bacterial parasiteHolospora undulataacross a worldwide collection of strains of its ciliate hostParamecium caudatum. We combined the observed variation with available information on the phylogeny and biogeography of the strains. We found substantial variation in resistance among strains, with upper-bound values of broad-sense heritability >0.5 (intraclass correlation coefficients). Strain estimates of resistance were repeatable between laboratories and ranged from total resistance to near-complete susceptibility. Early (1 week post inoculation) measurements provided higher estimates of resistance heritability than did later measurements (2–3 weeks), possibly due to diverging epidemiological dynamics in replicate cultures of the same strains. Genetic distance (based on a neutral marker) was positively correlated with the difference in resistance phenotype between strains (r= 0.45), essentially reflecting differences between highly divergent clades (haplogroups) within the host species. Haplogroup A strains, mostly European, were less resistant to the parasite (49% infection prevalence) than non-European haplogroup B strains (28%). At a smaller geographical scale (within Europe), strains that are geographically closer to the parasite origin (Southern Germany) were more susceptible to infection than those from further away. These patterns are consistent with a picture of local parasite adaptation. Our study demonstrates ample natural variation in resistance on which selection can act and hints at symbiont adaptation producing signatures in geographic and lineage-specific patterns of resistance in this model system.
More Than a Methanotroph: A Broader Substrate Spectrum for Methylacidiphilum fumariolicum SolV
Authors: Picone Nunzia , Mohammadi Sepehr S. , Waajen Annemiek C. , van Alen Theo A. , Jetten Mike S. M. , Pol Arjan , Op den Camp Huub J. M.
Published: December 2020

Volcanic areas emit a number of gases including methane and other short chain alkanes, that may serve as energy source for the prevailing microorganisms. The verrucomicrobial methanotroph Methylacidiphilum fumariolicum SolV was isolated from a volcanic mud pot, and is able to grow under thermoacidophilic conditions on different gaseous substrates. Its genome contains three operons encoding a particulate methane monooxygenase (pMMO), the enzyme that converts methane to methanol. The expression of two of these pmo operons is subjected to oxygen-dependent regulation, whereas the expression of the third copy (pmoCAB3) has, so far, never been reported. In this study we investigated the ability of strain SolV to utilize short-chain alkanes and monitored the expression of the pmo operons under different conditions. In batch cultures and in carbon-limited continuous cultures, strain SolV was able to oxidize and grow on C1–C3 compounds. Oxidation of ethane did occur simultaneously with methane, while propane consumption only started once methane and ethane became limited. Butane oxidation was not observed. Transcriptome data showed that pmoCAB1 and pmoCAB3 were induced in the absence of methane and the expression of pmoCAB3 increased upon propane addition. Together the results of our study unprecedently show that a pMMO-containing methanotroph is able to co-metabolize other gaseous hydrocarbons, beside methane. Moreover, it expands the substrate spectrum of verrucomicrobial methanotrophs, supporting their high metabolic flexibility and adaptation to the harsh and dynamic conditions in volcanic ecosystems.
Responses of Free-Living Vibrio Community to Seasonal Environmental Variation in a Subtropical Inland Bay
Authors: Chen Xing , Zhao Huaxian , Jiang Gonglingxia , Tang Jinli , Xu Qiangsheng , Huang Lengjinghua , Chen Si , Zou Shuqi , Dong Ke , Li Nan
Published: December 2020

Vibrio are widely distributed in aquatic environments and strongly associated with eutrophic environments and human health through the consumption of contaminated seafood. However, the response of the Vibrio community to seasonal variation in eutrophic environments is poorly understood. In this study, we used a Vibrio-specific 16S rRNA sequencing approach to reveal the seasonal distribution pattern and diversity of the Vibrio community in the Maowei Sea, Beibu Gulf of China. The Shannon diversity of the Vibrio community was highest in the summer, while β-diversity analysis showed that Vibrio community structures were significantly different between seasons. Distance-based redundancy analysis (dbRDA) and Mantel test analysis suggested that total dissolved nitrogen (TDN), total dissolved phosphorus (TDP), dissolved inorganic nitrogen (DIN), salinity, and temperature were the key environmental factors shaping the Vibrio community structure, indicating a strong filtering effect of trophic condition on Vibrio communities. Furthermore, through random forest analysis, V. fluvialis, V. alginolyticus, V. proteolyticus, V. splendidus, and the other eight Vibrio species were more sensitive to eutrophic changes. This study revealed seasonal changes in Vibrio communities and the influence of environmental variation on Vibrio community composition, contributing to a better understanding of their potential ecological roles in a subtropical inland bay.
Influence of Dietary Long-Chain Polyunsaturated Fatty Acids and ω6 to ω3 Ratios on Head Kidney Lipid Composition and Expression of Fatty Acid and Eicosanoid Metabolism Genes in Atlantic Salmon (Salmo salar)
Authors: Katan Tomer , Xue Xi , Caballero-Solares Albert , Taylor Richard G. , Rise Matthew L. , Parrish Christopher C.
Published: December 2020

The interaction of dietary eicosapentaenoic acid and docosahexaenoic acid (EPA+DHA) levels with omega-6 to omega-3 ratios (ω6:ω3), and their impact on head kidney lipid metabolism in farmed fish, are not fully elucidated. We investigated the influence of five plant-based diets (12-week exposure) with varying EPA+DHA levels (0.3, 1.0, or 1.4%) and ω6:ω3 (high ω6, high ω3, or balanced) on tissue lipid composition, and transcript expression of genes involved in fatty acid and eicosanoid metabolism in Atlantic salmon head kidney. Tissue fatty acid composition was reflective of the diet with respect to C18 PUFA and MUFA levels (% of total FA), and ω6:ω3 (0.5–1.5). Fish fed 0.3% EPA+DHA with high ω6 (0.3% EPA+DHA↑ω6) had the highest increase in proportions (1.7–2.3-fold) and in concentrations (1.4-1.8-fold) of arachidonic acid (ARA). EPA showed the greatest decrease in proportion and in concentration (by ~½) in the 0.3% EPA+DHA↑ω6 fed fish compared to the other treatments. However, no differences were observed in EPA proportions among salmon fed the high ω3 (0.3 and 1.0% EPA+DHA) and balanced (1.4% EPA+DHA) diets, and DHA proportions were similar among all treatments. Further, the transcript expression of elovl5a was lowest in the 0.3% EPA+DHA↑ω6 fed fish, and correlated positively with 20:3ω3, 20:4ω3 and EPA:ARA in the head kidney. This indicates that high dietary 18:3ω3 promoted the synthesis of ω3 LC-PUFA. Dietary EPA+DHA levels had a positive impact on elovl5a, fadsd5 and srebp1 expression, and these transcripts positively correlated with tissue ΣMUFA. This supported the hypothesis that LC-PUFA synthesis is positively influenced by tissue MUFA levels in Atlantic salmon. The expression of pparaa was higher in the 0.3% EPA+DHA↑ω6 compared to the 0.3% EPA+DHA↑ω3 fed fish. Finally, significant correlations between head kidney fatty acid composition and the expression of eicosanoid synthesis-related transcripts (i.e., 5loxa, 5loxb, cox1, cox2, ptges2, ptges3, and pgds) illustrated the constitutive relationships among fatty acids and eicosanoid metabolism in salmon.
Imaging Subthreshold Voltage Oscillation With Cellular Resolution in the Inferior Olive in vitro
Authors: Dorgans Kevin , Kuhn Bernd , Uusisaari Marylka Yoe
Published: December 2020

Voltage imaging with cellular resolution in mammalian brain slices is still a challenging task. Here, we describe and validate a method for delivery of the voltage-sensitive dye ANNINE-6plus (A6+) into tissue for voltage imaging that results in higher signal-to-noise ratio (SNR) than conventional bath application methods. The not fully dissolved dye was injected into the inferior olive (IO) 0, 1, or 7 days prior to acute slice preparation using stereotactic surgery. We find that the voltage imaging improves after an extended incubation period in vivo in terms of labeled volume, homogeneous neuropil labeling with saliently labeled somata, and SNR. Preparing acute slices 7 days after the dye injection, the SNR is high enough to allow single-trial recording of IO subthreshold oscillations using wide-field (network-level) as well as high-magnification (single-cell level) voltage imaging with a CMOS camera. This method is easily adaptable to other brain regions where genetically-encoded voltage sensors are prohibitively difficult to use and where an ultrafast, pure electrochromic sensor, like A6+, is required. Due to the long-lasting staining demonstrated here, the method can be combined, for example, with deep-brain imaging using implantable GRIN lenses.
Correlative Magnetic Resonance Imaging and Histopathology in Small Ruminant Listeria Rhombencephalitis
Authors: Precht Christina , Vermathen Peter , Henke Diana , Staudacher Anne , Lauper Josiane , Seuberlich Torsten , Oevermann Anna , Schweizer-Gorgas Daniela
Published: December 2020

Background: Listeria rhombencephalitis, infection of the brainstem with Listeria monocytogenes, occurs mainly in humans and farmed ruminants and is associated with high fatality rates. Small ruminants (goats and sheep) are a large animal model due to neuropathological similarities. The purpose of this study was to define magnetic resonance imaging (MRI) features of listeria rhombencephalitis in naturally infected small ruminants and correlate them with histopathology. Secondly, the purpose of this study was to compare the results with MRI findings reported in humans.

Methods: Twenty small ruminants (13 sheep and 7 goats) with listeria rhombencephalitis were prospectively enrolled and underwent in vivo MRI of the brain, including T2-weighted, fluid attenuation inversion recovery, and T1-weighted sequences pre- and post-contrast administration and postmortem histopathology. In MRI, lesions were characterized by location, extent, border definition, signal intensity, and contrast enhancement. In histopathology, the location, cell type, severity, and chronicity of inflammatory infiltrates and signs of vascular damage were recorded. In addition, histopathologic slides were matched to MRIs, and histopathologic and MRI features were compared.

Results: Asymmetric T2-hyperintense lesions in the brainstem were observed in all animals and corresponded to the location and pattern of inflammatory infiltrates in histopathology. Contrast enhancement in the brainstem was observed in 10 animals and was associated with vessel wall damage and perivascular fibrin accumulation in 8 of 10 animals. MRI underestimated the extension into rostral brain parts and the involvement of trigeminal ganglia and meninges.

Conclusion: Asymmetric T2-hyperintense lesions in the brainstem with or without contrast enhancement can be established as criteria for the diagnosis of listeria rhombencephalitis in small ruminants. Brainstem lesions were similar to human listeria rhombencephalitis in terms of signal intensity and location. Different from humans, contrast enhancement was a rare finding, and abscessation was not observed.
Relation Between Reading Performance and White-Matter Alteration and Reorganization in Neurosurgical Patients
Authors: Cargnelutti Elisa , Maieron Marta , Ius Tamara , Skrap Miran , Tomasino Barbara
Published: December 2020

Reading abilities and diffusion tensor imaging (DTI) parameters were retrospectively analyzed in a group of neurosurgical patients to investigate (Study 1) the role of white matter—in particular the arcuate fasciculus (AF)—in preserved vs. impaired reading; 4 months after surgery, we explored the plasticity processes (Study 2). Study 1 involved 40 patients with brain glioma (23 low-grade and 17 high-grade gliomas). We compared preoperative DTI parameters of language-related fascicles between patients who developed a reading impairment after surgery (n = 23) and patients with preserved reading (n = 17). Besides lower fractional anisotropy (FA), patients with impaired reading also displayed lower number and density of streamlines of a direct (i.e., directly connecting temporal and frontal lobes) AF segment. In Study 2, we longitudinally tested at follow-up-when reading performance had generally improved-13 patients diagnosed with low-grade glioma. The most relevant finding was a significant increase in length of streamlines of the direct AF segments in both hemispheres. From a neurosurgical perspective, our preliminary findings suggest the clinical importance of sparing direct AF segments for the involvement they showed in reading; however, the results also suggest the reorganization potential of these segments, possibly compensating of the right homologs as well.
Active Video Games and Low-Cost Virtual Reality: An Ideal Therapeutic Modality for Children With Physical Disabilities During a Global Pandemic
Authors: Demers Marika , Martinie Ophélie , Winstein Carolee , Robert Maxime T.
Published: December 2020

Current guidelines against spread of coronavirus (COVID-19) interrupt non-essential rehabilitation services. Thus, individuals with physical disabilities such as children with cerebral palsy can no longer benefit from physical rehabilitation during this undetermined period. Using either a synchronous or asynchronous format, in collaboration with a therapist via telerehabilitation, we suggest that active video games and low-cost virtual reality are a promising delivery mode for at-home rehabilitation in the context of a global pandemic. This therapeutic modality, incorporated into an at-home individualized treatment plan, provides a means to lessen the impact of an interruption in rehabilitation services while not loosing the pre-pandemic, in-person physical activity gains. Growing evidence supports active video games and low-cost virtual reality as viable therapeutic interventions for children with physical disabilities. These technologies are especially well-accepted by pediatric populations for the ludic and motivating features that lend themselves to nearly seamless incorporation into telerehabilitation. Advantages for rehabilitation of active video games and low-cost virtual reality include a rich, challenging, multi-modal training environment in which high numbers of movement repetitions can be accomplished, and a unique opportunity to foster engaged practice actions that go beyond household activities. We offer suggestions for the clinician about how to adopt active video games and low-cost virtual reality into your practice during a global pandemic.
Efficacy and Safety of Rituximab in Chinese Children With Refractory Anti-NMDAR Encephalitis
Authors: Dou Xiangjun , Li Dongjing , Wu Yan , Wang Zhijing , Yang Le , Ma Nan , Wang Dong , Li Xia
Published: December 2020

Purpose: To assess the efficacy and safety of rituximab treatment as second-line immunotherapy in pediatric cases of anti-NMDA receptor (NMDAR) encephalitis.

Methods: We retrospectively recruited 8 patients with anti-NMDAR encephalitis who were treated with rituximab as second-line immunotherapy. We evaluated the clinical features, laboratory examination results and treatment protocols of the Chinese children and defined good outcomes based on the modified Rankin scale (mRS) score (0–2) at the last follow-up.

Results: A total of eight pediatric patients (median age 6.7 years; four female) with refractory anti-NMDAR encephalitis were recruited to the study. Rituximab was given after a median duration of disease of 57 days (range 50.5–113.75 days). The use of rituximab led to a significant reduction in the mRS and CD19+ B-cells compared to before rituximab infusion (P < 0.05). Five patients (62.5%) had a good outcome (mRS ≤ 2) including four patients (50%) who showed complete recovery (mRS = 0) at the last follow-up. Transient infusion adverse events were recorded in 2 patients (25%). Two patients (25%) had severe infectious adverse events (AEs) and two patients with grade 5 (death). None of the patients developed progressive multifocal leukoencephalopathy (PML).

Conclusion: Our study provides evidence that rituximab can efficiently improve the clinical symptoms of anti-NMDAR encephalitis in children. However, due to the risk of adverse infections, rituximab should be restricted in pediatric patients with high rates of mortality and disability.
The Effects of Stochastic Galvanic Vestibular Stimulation on Body Sway and Muscle Activity
Authors: Matsugi Akiyoshi , Oku Kosuke , Mori Nobuhiko
Published: December 2020

Objective: This study aimed to investigate whether galvanic vestibular stimulation with stochastic noise (nGVS) modulates the body sway and muscle activity of the lower limbs, depending on visual and somatosensory information from the foot using rubber-foam.

Methods: Seventeen healthy young adults participated in the study. Each subject maintained an upright standing position on a force plate with/without rubber-foam, with their eyes open/closed, to measure the position of their foot center of pressure. Thirty minutes after baseline measurements under four possible conditions (eyes open/closed with/without rubber-foam) performed without nGVS (intensity: 1 mA, duration: 40 s), the stimulation trials (sham-nGVS/real-nGVS) were conducted under the same conditions in random order, which were then repeated a week or more later. The total center of pressure (COP) path length movement (COP-TL) and COP movement velocity in the mediolateral (Vel-ML) and anteroposterior (Vel-AP) directions were recorded for 30 s during nGVS. Furthermore, electromyography activity of the right tibial anterior muscle and soleus muscle was recorded for the same time and analyzed.

Results: Three-way analysis of variance and post-hoc multiple comparison revealed a significant increment in COP-related parameters by nGVS, and a significant increment in soleus muscle activity on rubber. There was no significant effect of eye condition on any parameter.

Conclusions: During nGVS (1 mA), body sway and muscle activity in the lower limb may be increased depending not on the visual condition, but on the foot somatosensory condition.
Fisetin Regulates Gut Microbiota and Exerts Neuroprotective Effect on Mouse Model of Parkinson’s Disease
Authors: Chen Tian-Jiao , Feng Ya , Liu Te , Wu Ting-Ting , Chen Ya-Jing , Li Xuan , Li Qing , Wu Yun-Cheng
Published: December 2020

Previous studies have reported the anti-oxidant, anti-inflammatory, and anti-cancer effects of fisetin. However, the therapeutic efficacy of fisetin in Parkinson’s disease (PD) is unclear. In this study, we demonstrated that fisetin could markedly alleviate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration in mice. To confirm the reported correlation between gut microbiota and PD, the bacterial DNA in the fresh feces of mice from each group was subjected to 16S rRNA (V3 and V4 regions) sequencing. The results revealed that fisetin changed the number, diversity, and distribution of gut microbiota in MPTP-induced mice model of PD. The alpha and beta diversity analyses showed that the fisetin intervented MPTP group gut microbiota exhibited a significantly higher abundance of Lachnospiraceae and a significantly lower abundance of uncultured_bacterium_g_Escherichia-Shigella and uncultured_bacterium_g_Bacillus than the MPTP group gut microbiota. These findings indicated that fisetin exerts a neuroprotective effect on neurodegeneration by altering the composition and diversity of gut microbiota. Thus, fisetin could be a potential novel therapeutic for PD.
Mutual Information of Multiple Rhythms for EEG Signals
Authors: Ibáñez-Molina Antonio José , Soriano María Felipa , Iglesias-Parro Sergio
Published: December 2020

Electroencephalograms (EEG) are one of the most commonly used measures to study brain functioning at a macroscopic level. The structure of the EEG time series is composed of many neural rhythms interacting at different spatiotemporal scales. This interaction is often named as cross frequency coupling, and consists of transient couplings between various parameters of different rhythms. This coupling has been hypothesized to be a basic mechanism involved in cognitive functions. There are several methods to measure cross frequency coupling between two rhythms but no single method has been selected as the gold standard. Current methods only serve to explore two rhythms at a time, are computationally demanding, and impose assumptions about the nature of the signal. Here we present a new approach based on Information Theory in which we can characterize the interaction of more than two rhythms in a given EEG time series. It estimates the mutual information of multiple rhythms (MIMR) extracted from the original signal. We tested this measure using simulated and real empirical data. We simulated signals composed of three frequencies and background noise. When the coupling between each frequency component was manipulated, we found a significant variation in the MIMR. In addition, we found that MIMR was sensitive to real EEG time series collected with open vs. closed eyes, and intra-cortical recordings from epileptic and non-epileptic signals registered at different regions of the brain. MIMR is presented as a tool to explore multiple rhythms, easy to compute and withouta prioriassumptions.
Progranulin Adsorbs to Polypropylene Tubes and Disrupts Functional Assays: Implications for Research, Biomarker Studies, and Therapeutics
Authors: Gururaj Sushmitha , Sampognaro Paul J. , Argouarch Andrea R. , Kao Aimee W.
Published: December 2020

Progranulin (PGRN) is a tightly regulated, secreted glycoprotein involved in a wide range of biological processes that is of tremendous interest to the scientific community due to its involvement in neoplastic, neurodevelopmental, and neurodegenerative diseases. In particular, progranulin haploinsufficiency leads to frontotemporal dementia. While performing experiments with a HIS-tagged recombinant human (rh) PGRN protein, we observed a measurable depletion of protein from solution due to its adsorption onto polypropylene (PPE) microcentrifuge tubes. In this study, we have quantified the extent of rhPGRN adsorption to PPE tubes while varying experimental conditions, including incubation time and temperature. We found that ∼25–35% of rhPGRN becomes adsorbed to the surface of PPE tubes even after a short incubation period. We then directly showed the deleterious impact of PGRN adsorption in functional assays and have recommended alternative labware to minimize these effects. Although the risk of adsorption of some purified proteins and peptides to polymer plastics has been characterized previously, this is the first report of rhPGRN adsorption. Moreover, since PGRN is currently being studied and utilized in both basic science laboratories to performin vitrostudies and translational laboratories to survey PGRN as a quantitative dementia biomarker and potential replacement therapy, the reported observations here are broadly impactful and will likely significantly affect the design and interpretation of future experiments centered on progranulin biology.
A Sextuple Knockout Cell Line System to Study the Differential Roles of CRY, PER, and NR1D in the Transcription-Translation Feedback Loop of the Circadian Clock
Authors: Chiou Yi-Ying , Li Tzu-Ying , Yang Yanyan , Sancar Aziz
Published: December 2020

The transcription-translation feedback loop (TTFL) is the core mechanism of the circadian rhythm. In mammalian cells, CLOCK-BMAL1 proteins activate the downstream genes by binding on the E-box sequence of the clock-controlled genes. Among these gene products, CRY1, CRY2, PER1, PER2, NR1D1, and NR1D2 can regulate the CLOCK-BMAL1-mediated transcription to form the feedback loop. However, the detailed mechanism of the TTFL is unclear because of the complicated inter-regulation of these proteins. Here, we generated a cell line lacking CRY1, CRY2, PER1, PER2, NR1D1, and NR1D2 (Cry/Per/Nr1d_KO) to study TTFL. We compared the Dbp transcription after serum-shock and dexamethasone-shock between Cry/Per/Nr1d_KO cells and cells expressing endogenous CRY (Per/Nr1d_KO) or NR1D (Cry/Per_KO). Furthermore, we found that CRY1-mediated repression of Dbp could persist more than 24 h in the absence of other proteins in the negative limb of the TTFL. Our Cry/Per/Nr1d_KO cells is a suitable system for the studying of differential roles of CRY, PER, and NR1D in the TTFL.
Modulation of Gut Microbiota and Oxidative Status by β-Carotene in Late Pregnant Sows
Authors: Yuan Xupeng , Yan Jiahao , Hu Ruizhi , Li Yanli , Wang Ying , Chen Hui , Hou De-Xing , He Jianhua , Wu Shusong
Published: December 2020

Recent evidences suggest that gut microbiota plays an important role in regulating physiological and metabolic activities of pregnant sows, and β-carotene has a potentially positive effect on reproduction, but the impact of β-carotene on gut microbiota in pregnant sows remains unknown. This study aimed to explore the effect and mechanisms of β-carotene on the reproductive performance of sows from the aspect of gut microbiota. A total of 48 hybrid pregnant sows (Landrace × Yorkshire) with similar parity were randomly allocated into three groups (n= 16) and fed with a basal diet or a diet containing 30 or 90 mg/kg of β-carotene from day 90 of gestation until parturition. Dietary supplementation of 30 or 90 mg/kg β-carotene increased the number of live birth to 11.82 ± 1.54 and 12.29 ± 2.09, respectively, while the control group was 11.00 ± 1.41 (P= 0.201). Moreover, β-carotene increased significantly the serum nitric oxide (NO) level and glutathione peroxidase (GSH-Px) activity (P< 0.05). Characterization of fecal microbiota revealed that 90 mg/kg β-carotene increased the diversity of the gut flora (P< 0.05). In particular, β-carotene decreased the relative abundance of Firmicutes includingLachnospiraceaeAC2044 group,LachnospiraceaeNK4B4 group andRuminococcaceaeUCG-008, but enriched Proteobacteria includingBilophilaandSutterella, and Actinobacteria includingCorynebacteriumandCorynebacterium1 which are related to NO synthesis. These data demonstrated that dietary supplementation of β-carotene may increase antioxidant enzyme activity and NO, an important vasodilator to promote the neonatal blood circulation, through regulating gut microbiota in sows.
Performance Evaluation of SHOX2 and RASSF1A Methylation for the Aid in Diagnosis of Lung Cancer Based on the Analysis of FFPE Specimen
Authors: Shi Juanhong , Chen Xue , Zhang Long , Fang Xia , Liu Yuting , Zhu Xuyou , Zhang Haoyang , Fan Lichao , Gu Jun , Zhang Suxia , She Bin , Han Hongxiu , Yi Xianghua
Published: December 2020

Emerging molecular diagnostic methods are more sensitive and objective, which can overcome the intrinsic failings of morphological diagnosis. Here, a RT-PCR-based in vitro diagnostic test kit (LungMe®) was developed and characterized to simultaneously quantify the DNA methylation of SHOX2 and RASSF1A in FFPE tissue specimens. The clinical manifestations were evaluated in 251 FFPE samples with specificity and sensitivity of 90.4 and 89.8%, respectively. Furthermore, the quantitative analysis shows that the degree of SHOX2 methylation was correlated with the stages of lung cancer, but not in the case of RASSF1A. Our observation indicated that the DNA methylation of SHOX2 and RASSF1A may play different roles in cancer development. Comparison of the methylation levels of SHOX2 and RASSF1A between cancer and cancer-adjacent specimens (n = 30), showed they have “epigenetic field defect”. As additional clinical validation, the hypermethylation of SHOX2 and RASSF1A was detected not only in surgical operative specimens, but also in histopathological negative puncture biopsies. SHOX2 and RASSF1A methylation detection can be used to increase sensitivity and NPV, which provide us with a more accurate method of differential diagnosis and are likely to be rapidly applied in clinical examinations.
Dibenzazepine Attenuates Against Cisplatin-Induced Nephrotoxicity in Rats: Involvement of NOTCH Pathway
Authors: Abd El-Rhman Rana H. , El-Naga Reem N. , Gad Amany M. , Tadros Mariane G. , Hassaneen Sherifa K.
Published: December 2020

Cisplatin is one of the standard anti-cancer agents that are used to treat variety of solid tumors. Nevertheless, due to the accumulation of cisplatin in the renal epithelial cells, nephrotoxicity was found to be the main side effect that limits its clinical use. The current study was conducted to assess the potential nephroprotective effect of dibenzazepine, a Notch inhibitor, against cisplatin-induced nephrotoxicity in rats as well as the possible mechanisms underlying this nephroprotection. The rats were pre-treated with 2 mg/kg dibenzazepine for 7 days before giving a single nephrotoxic dose of cisplatin (7 mg/kg). Cisplatin induced acute nephrotoxicity, where blood urea nitrogen and serum creatinine levels were significantly increased. Besides, lipid peroxidation was markedly elevated and the levels of reduced glutathione and catalase were significantly reduced. Also, the tissue levels of the pro-inflammatory mediators; IL-1β, TNF-α, and NF-kB, were significantly increased in the cisplatin group. The pre-treatment with dibenzazepine significantly mitigated the nephrotoxic effects of cisplatin, the oxidative stress and inflammatory status as well as decreased caspase-3 expression, as compared to the cisplatin group. Furthermore, the up-regulation of Notch-1 and Hes-1 was found to be involved in cisplatin-induced nephrotoxicity and their expression was significantly reduced by dibenzazepine. The nephroprotective effect of dibenzazepine was further confirmed by the histopathological assessment. Moreover, dibenzazepine pre-treatment of hela and PC3 cellsin vitrodid not antagonize the cisplatin anti-cancer activity. In conclusion, these findings show that dibenzazepine provides protection against cisplatin-induced nephrotoxicity. Moreover, the up-regulation of the Notch pathway was shown to play a role in the pathogenesis of cisplatin-induced renal injury.
The Efficacy of Beta-Blockers in Patients With Long QT Syndrome 1–3 According to Individuals’ Gender, Age, and QTc Intervals: A Network Meta-analysis
Authors: Han Lu , Liu Fuxiang , Li Qing , Qing Tao , Zhai Zhenyu , Xia Zirong , Li Juxiang
Published: December 2020

Long QT syndrome (LQTS) is an arrhythmic heart disease caused by congenital genetic mutations, and results in increased occurrence rates of polymorphic ventricular tachyarrhythmias and sudden cardiac death (SCD). Clinical evidence from numerous previous studies suggested that beta blockers (BBs), including atenolol, propranolol, metoprolol, and nadolol, exhibit different efficacies for reducing the risk of cardiac events (CEs), such as syncope, arrest cardiac arrest (ACA), and SCD, in patients with LQTS. In this study, we identified relevant studies in MEDLINE, PubMed, embase, and Cochrane databases and performed a meta-analysis to assess the relationship between the rate of CEs and LQTS individuals with confounding variables, including different gender, age, and QTc intervals. Moreover, a network meta-analysis was not only established to evaluate the effectiveness of different BBs, but also to provide the ranked efficacies of BBs treatment for preventing the recurrence of CEs in LQT1 and LQT2 patients. In conclusion, nadolol was recommended as a relatively effective strategy for LQT2 in order to improve the prognosis of patients during a long follow-up period.
Toward Regulatory Effects of Curcumin on Transforming Growth Factor-Beta Across Different Diseases: A Review
Authors: Ashrafizadeh Milad , Zarrabi Ali , Hushmandi Kiavash , Zarrin Vahideh , Moghadam Ebrahim Rahmani , Hashemi Farid , Makvandi Pooyan , Samarghandian Saeed , Khan Haroon , Hashemi Fardin , Najafi Masoud , Mirzaei Hamed
Published: December 2020

Immune response, proliferation, migration and angiogenesis are juts a few of cellular events that are regulated by transforming growth factor-β (TGF-β) in cells. A number of studies have documented that TGF-β undergoes abnormal expression in different diseases, e.g., diabetes, cancer, fibrosis, asthma, arthritis, among others. This has led to great fascination into this signaling pathway and developing agents with modulatory impact on TGF-β. Curcumin, a natural-based compound, is obtained from rhizome and roots of turmeric plant. It has a number of pharmacological activities including antioxidant, anti-inflammatory, anti-tumor, anti-diabetes and so on. Noteworthy, it has been demonstrated that curcumin affects different molecular signaling pathways such as Wnt/β-catenin, Nrf2, AMPK, mitogen-activated protein kinase and so on. In the present review, we evaluate the potential of curcumin in regulation of TGF-β signaling pathway to corelate it with therapeutic impacts of curcumin. By modulation of TGF-β (both upregulation and down-regulation), curcumin ameliorates fibrosis, neurological disorders, liver disease, diabetes and asthma. Besides, curcumin targets TGF-β signaling pathway which is capable of suppressing proliferation of tumor cells and invading cancer cells.
A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Ascending Dose and Food Effect Study to Evaluate the Tolerance, Pharmacokinetics of Jaktinib, a New Selective Janus Kinase Inhibitor in Healthy Chinese Volunteers
Authors: Liu Jingrui , Lv Binhua , Yin Hewen , Zhu Xiaoxue , Wei Haijing , Ding Yanhua
Published: December 2020

Background: Jaktinib is a novel selective janus kinase 1/2 inhibitor. The phase I first-in-human study evaluated the tolerance and pharmacokinetics of jaktinib in healthy Chinese subjects.

Methods: A randomized, double-blind, placebo-controlled study were designed. A total of 126 healthy subjects were enrolled into the single ascending dose, multiple ascending dose and food effect study. Safety endpoints included adverse events, abnormal vital signs, 12-lead ECGs, abdominal ultrasound, chest x-ray, physical examination and clinical laboratory tests. Blood, urine and feces samples were collected at predetermined time points for pharmacokinetic analysis of jaktinib, the metabolites ZG0244 and ZG0245, which are formed by oxidation or hydrolysis metabolic pathway, respectively.

Results: Jaktinib was absorbed with a median time to peak plasma concentration of 1.25–3.5 h and was eliminated with a half-life of 2.952–9.040 h. Linear pharmacokinetic characteristic was presented over the dose range from 25 to 400 mg. No obvious accumulation was observed after multiple doses for 10 days. Administration after a high-fat breakfast significantly increased the absorption of jaktinib. The accumulated fraction of jaktinib and the determined metabolites excreted in urine and feces was 19.478%. Jaktinib was well tolerated in all single dose cohorts. In multiple dose cohorts, 200 mg q24 h method was evaluated as maximally tolerated dose. Neutropenia, diarrhea, dizziness and headache were the most frequently reported treatment related adverse events. No deaths, serious or Grade ≥4 adverse events was developed.

Conclusion: Jaktinib was well tolerated when single dose ranging from 25 to 400 mg and multiple dose up to 200 mg q24 h. The safety and pharmacokinetic characteristics support the next trial in myelofibrosis patients.
The Relationship Between Anti-Hypertensive Drugs and Cancer: Anxiety to be Resolved in Urgent
Authors: Yang Rong , Zhang Yonggang , Liao Xiaoyang , Yao Yi , Huang Chuanying , Liu Lixia
Published: December 2020

Hypertension is the prevailing independent risk factor for cardiovascular disease worldwide. Anti-hypertensive drugs are the common and effective cure for lowering blood pressure in patients with hypertension. However, some large-scale clinical studies have pointed out that long-term ingestion of some oral anti-hypertensive drugs was associated with risks of incident cancer and the survival time. In contrast, other studies argue that anti-hypertensive drugs are not related to the occurrence of cancer, even as a complementary therapy of tumor treatment. To resolve the dispute, numerous recent mechanistic studies using animal models have tried to find the causal link between cancer and different anti-hypertensive drugs. However, the results were often contradictory. Such uncertainties have taken a toll on hypertensive patients. In this review, we will summarize advances of longitudinal studies in the association between anti-hypertensive drugs and related tumor risks that have helped to move the field forward from associative to causative conclusions, in hope of providing a reference for more rigorous and evidence-based clinical research on the topic to guide the clinical decision making.
Machine Learning Techniques for Soybean Charcoal Rot Disease Prediction
Authors: Khalili Elham , Kouchaki Samaneh , Ramazi Shahin , Ghanati Faezeh
Published: December 2020

Early prediction of pathogen infestation is a key factor to reduce the disease spread in plants. Macrophomina phaseolina (Tassi) Goid, as one of the main causes of charcoal rot disease, suppresses the plant productivity significantly. Charcoal rot disease is one of the most severe threats to soybean productivity. Prediction of this disease in soybeans is very tedious and non-practical using traditional approaches. Machine learning (ML) techniques have recently gained substantial traction across numerous domains. ML methods can be applied to detect plant diseases, prior to the full appearance of symptoms. In this paper, several ML techniques were developed and examined for prediction of charcoal rot disease in soybean for a cohort of 2,000 healthy and infected plants. A hybrid set of physiological and morphological features were suggested as inputs to the ML models. All developed ML models were performed better than 90% in terms of accuracy. Gradient Tree Boosting (GBT) was the best performing classifier which obtained 96.25% and 97.33% in terms of sensitivity and specificity. Our findings supported the applicability of ML especially GBT for charcoal rot disease prediction in a real environment. Moreover, our analysis demonstrated the importance of including physiological featured in the learning. The collected dataset and source code can be found in https://github.com/Elham-khalili/Soybean-Charcoal-Rot-Disease-Prediction-Dataset-code.
Attention-Based Recurrent Neural Network for Plant Disease Classification
Authors: Lee Sue Han , Goëau Hervé , Bonnet Pierre , Joly Alexis
Published: December 2020

Plant diseases have a significant impact on global food security and the world's agricultural economy. Their early detection and classification increase the chances of setting up effective control measures, which is why the search for automatic systems that allow this is of major interest to our society. Several recent studies have reported promising results in the classification of plant diseases from RGB images on the basis of Convolutional Neural Networks (CNN). These studies have been successfully experimented on a large number of crops and symptoms, and they have shown significant advantages in the support of human expertise. However, the CNN models still have limitations. In particular, CNN models do not necessarily focus on the visible parts affected by a plant disease to allow their classification, and they can sometimes take into account irrelevant backgrounds or healthy plant parts. In this paper, we therefore develop a new technique based on a Recurrent Neural Network (RNN) to automatically locate infected regions and extract relevant features for disease classification. We show experimentally that our RNN-based approach is more robust and has a greater ability to generalize to unseen infected crop species as well as to different plant disease domain images compared to classical CNN approaches. We also analyze the focus of attention as learned by our RNN and show that our approach is capable of accurately locating infectious diseases in plants. Our approach, which has been tested on a large number of plant species, should thus contribute to the development of more effective means of detecting and classifying crop pathogens in the near future.