bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of Phosphodiesterase 5 Promotes the Aromatase-Mediated Estrogen Biosynthesis in Osteoblastic Cells by Activation of cGMP/PKG/SHP2 Pathway
Authors: Wisanwattana Wisanee , Wongkrajang Kanjana , Cao Dong-yi , Shi Xiao-ke , Zhang Zhong-hui , Zhou Zong-yuan , Li Fu , Mei Qing-gang , Wang Chun , Suksamrarn Apichart , Zhang Guo-lin , Wang Fei
Published: March 2021

Mechanical stimulation induces bone growth and remodeling by the secondary messenger, cyclic guanosine 3’, 5’-monophosphate (cGMP), in osteoblasts. However, the role of cGMP in the regulation of estrogen biosynthesis, whose deficiency is a major cause of osteoporosis, remains unclear. Here, we found that the prenylated flavonoids, 3-O-methoxymethyl-7-O-benzylicaritin (13), 7-O-benzylicaritin (14), and 4'-O-methyl-8-isopentylkaempferol (15), which were synthesized using icariin analogs, promoted estrogen biosynthesis in osteoblastic UMR106 cells, with calculated EC50 values of 1.53, 3.45, and 10.57 µM, respectively. 14 and 15 increased the expression level of the bone specific promoter I.4-driven aromatase, the only enzyme that catalyzes estrogen formation by using androgens as substrates, in osteoblastic cells. 14 inhibited phosphodiesterase 5 (PDE5), stimulated intracellular cGMP level and promoted osteoblast cell differentiation. Inhibition of cGMP dependent-protein kinase G (PKG) abolished the stimulatory effect of 14 on estrogen biosynthesis and osteoblast cell differentiation. Further, PKG activation by 14 stimulated the activity of SHP2 (Src homology 2 domain-containing tyrosine phosphatase 2), thereby activating Src and ERK (extracellular signal-regulated kinase) signaling and increasing ERK-dependent aromatase expression in osteoblasts. Our findings reveal a previously unknown role of cGMP in the regulation of estrogen biosynthesis in the bone. These results support the further development of 14 as a PKG-activating drug to mimic the anabolic effects of mechanical stimulation of bone in the treatment of osteoporosis.
Behavioral Variation in the Pygmy Halfbeak Dermogenys collettei: Comparing Shoals With Contrasting Ecologies
Authors: Devigili Alessandro , Fernlund Isaksson Erika , Puniamoorthy Nalini , Fitzpatrick John L.
Published: March 2021

Variation in biotic and abiotic factors among populations affects individual behaviors by transforming the social landscape and shaping mating systems. Consequently, describing behaviors in natural populations requires consideration of the biological and physical factors that different individuals face. Here, we examined variation in socio-sexual and locomotor behaviors in a small, livebearing, freshwater fish, the pygmy halfbeakDermogenys collettei, across natural populations in Singapore. The pygmy halfbeak is a surface feeding fish that spends most of the time near the water surface, making it ideal for non-invasive behavioral observations. We compared behaviors between sexes among 26 shoals while simultaneously accounting for environmental variation. We demonstrated that sexual interactions and locomotor behaviors differed among shoals with varying levels of canopy cover and water flow. Specifically, in areas with greater canopy cover, sexual interactions decreased, whereas time spent in a stationary position increased. Sexual interactions were more numerous in still water, where fish spent less time swimming. Variation in the expression of socio-sexual and locomotor behaviors were not associated with differences in the amount of aquatic vegetation, water depth or halfbeak shoal size. Agonistic interactions were robust to environmental effects, showing little variation among environments. However, there were strong sex effects, with males performing more agonistic behaviors and spending less time in a stationary position compared to females, regardless of the environment. Moreover, sexual interactions, measured as actively performed by males and passively received by females, were on average more frequent in males than in females. Our findings help us explore the proximal causes of intraspecific behavioral variation and suggest that fundamental information on socio-sexual behaviors from wild populations can lead to a better understanding of how sexual selection operates when the strength of natural selection varies across environments.
Land Use Changes Threaten Bird Taxonomic and Functional Diversity Across the Mediterranean Basin: A Spatial Analysis to Prioritize Monitoring for Conservation
Authors: Fusco Johanna , Walker Emily , Papaïx Julien , Debolini Marta , Bondeau Alberte , Barnagaud Jean-Yves
Published: March 2021

Land use changes rank among the highest threats to biodiversity, but assessment of their ecological impact is impaired by data paucity in vast regions of the world. For birds, land use changes may mean habitat loss or fragmentation, changes in resource availability, and disruption of biotic interactions or dispersal pathways. As a result, avian population sizes and assemblage diversity decline in areas subjected to urbanization, agricultural intensification, and land abandonment worldwide. This threat is especially sensitive in hotspots such as the Mediterranean basin, where avifaunas of several biogeographic origins meet, encompassing numerous endemic taxa, and ecological specialists with low resilience to habitat modifications. Here, we correlated several facets of bird taxonomic and functional diversity to a fine-grained land-use change classification, in order to identify priority areas in need for enforced protocoled bird sampling in a conservation prospect. For this, we computed the species richness, functional richness, originality and specificity of 211 bird assemblages based on bird extent-of-occurrence data for 279 species and 10 ecological traits. We used a spatialized regression model to correlate bird diversity patterns with bioclimatic gradients and land use change between 1992 and 2018, assessed from an unsupervised clustering on 2 km resolution data. We showed that species-rich bird assemblages are subjected to agricultural intensification, while functionally diverse assemblages are mainly undergoing desertification and land abandonment. Unfortunately, most of these changes occur in areas where protocoled bird surveys with sufficient spatial and temporal resolution are lacking. In light of these results, we urge for the setting of bird monitoring programs targeted mainly on parts of North-Africa and the Levant, in order to allow a region-level evaluation of the threat posed by recent land use changes on the exceptional avifaunistic diversity of the basin. Fostering such regional-scale evaluations of congruences between human threats and centers of diversity is a necessary preliminary step for a pragmatic response to data deficiencies and ultimately setting appropriate responses to avoid the collapse of avian assemblages.
Composite System of 3D-Printed Polymer and Acellular Matrix Hydrogel to Repair Temporomandibular Joint Disc
Authors: Yi Ping , Liang Jiadi , Huang Futing , Zhao Zuodong , Zhou Xiaohui , Gao Qianya , Huang Min , Chen Baoyi , Guo Zhenzhao , Liu Chang
Published: March 2021

Tissue engineering is a promising approach to restore or replace a damaged temporomandibular joint (TMJ) disc. However, constructing a scaffold that can mimic biomechanical and biological properties of the natural TMJ disc remains a challenge. In this study, three-dimensional (3D) printing technology was used to fabricate polycaprolactone (PCL)/polyurethane (PU) scaffolds and PU scaffolds to imitate the region-specific biomechanical properties of the TMJ disc. The scaffolds were coated with polydopamine (PDA) and combined with a decellularized matrix (dECM). Then, rat costal chondrocytes and mouse L929 fibroblasts, respectively, were suspended on the composite scaffolds and the biological functions of the cells were studied. The properties of the scaffolds were characterized by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), contact angle analysis, and biomechanical testing. To verify the biocompatibility of the scaffolds, the viability, proliferation, and extracellular matrix (ECM) production of the cells seeded on the scaffolds were assessed by LIVE/DEAD staining, Cell Counting Kit-8 assay, biochemical content analysis, immunofluorescence staining, and qRT-PCR. The functionalized hybrid scaffolds were then implanted into the subcutaneous space of nude mice for 6 weeks, and the regenerated tissue was evaluated by histological staining. The biomechanical properties of PCL/PU and PU scaffolds were comparable to that of the central and peripheral zones, respectively, of a native human TMJ disc. The PDA-coated scaffolds displayed superior biomechanical, structural, and functional properties, creating a favorable microenvironment for cell survival, proliferation, ECM production, and tissue regeneration. In conclusion, 3D-printed polymer scaffolds coated with PDA and combined with dECM hydrogel were found to be a promising substitute for TMJ disc tissue engineering.
Fractalkine Is Linked to the Necrosome Pathway in Acute Pulmonary Inflammation
Authors: Ngamsri Kristian-Christos , Gamper-Tsigaras Jutta , Reutershan Jörg , Konrad Franziska M.
Published: March 2021

Acute pulmonary inflammation affects over 10% of intensive care unit (ICU) patients and is associated with high mortality. Fractalkine (CX3CL1) and its receptor, CX3CR1, have been shown to affect pulmonary inflammation, but previous studies have focused on macrophages. In a murine model of acute pulmonary inflammation, we identified inflammatory hallmarks in C57BL/6J and CX3CR1−/− mice. Pulmonary inflammation was significantly enhanced in the CX3CR1−/− animals compared to the C57BL/6J animals, as assessed by microvascular permeability, polymorphonuclear neutrophil (PMN) migration into lung tissue and alveolar space. The CX3CR1−/− mice showed increased levels of apoptotic PMNs in the lungs, and further investigations revealed an increased activation of necrosome-related receptor-interacting serine/threonine-protein kinases 1 (RIPK1), 3 (RIPK3), and mixed-lineage kinase domain-like pseudokinase (MLKL). Phosphorylated MLKL leads to membrane rupture and damage-associated molecular pattern (DAMP) release, which further enhance inflammation. The release of DAMPs was significantly higher in the CX3CR1−/− mice and led to the activation of various cascades, explaining the increased inflammation. RIPK3 and MLKL inhibition improved the inflammatory response in human PMNs in vitro and confirmed our in vivo findings. In conclusion, we linked CX3CL1 to the necrosome complex in pulmonary inflammation and demonstrated a pivotal role of the necrosome complex in human PMNs.
Metabolic Associated Fatty Liver Disease Is Associated With an Increased Risk of Severe COVID-19: A Systematic Review With Meta-Analysis
Authors: Hegyi Péter Jenő , Váncsa Szilárd , Ocskay Klementina , Dembrovszky Fanni , Kiss Szabolcs , Farkas Nelli , Erőss Bálint , Szakács Zsolt , Hegyi Péter , Pár Gabriella
Published: March 2021

Background: The most common pre-existing liver disease, the metabolic dysfunction-associated fatty liver disease (MAFLD) formerly named as non-alcoholic fatty liver disease (NAFLD), may have a negative impact on the severity of COVID-19. This meta-analysis aimed to evaluate if MAFLD or NAFLD are associated with a more severe disease course of COVID-19.

Methods: A systematic search was performed in five databases for studies comparing severity, the rate of intensive care unit (ICU) admission, and mortality of COVID-19 patients with and without MAFLD or NAFLD. In meta-analysis, pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.

Results: Altogether, we included nine studies in our quantitative and qualitative synthesis. MAFLD was associated with an increased risk of severe COVID-19 compared to the non-MAFLD group (28 vs. 13%, respectively; OR = 2.61, CI: 1.75–3.91). Similarly, in the NAFLD vs. non-NAFLD comparison, NAFLD proved to be a risk factor as well (36 vs. 12%, respectively; OR = 5.22, CI: 1.94–14.03). On the other hand, NAFLD was not associated with an increased risk of ICU admission (24 vs. 7%, respectively; OR = 2.29, CI: 0.79–6.63). We were unable to perform meta-analysis to investigate the association of MAFLD with the rate of ICU admission and with mortality.

Conclusion: In conclusion, patients with MAFLD and NAFLD showed a more severe clinical picture in COVID-19. Our results support the importance of close monitoring of COVID-19 patients with MAFLD. Further research is needed to explore the cause of increased severity of COVID-19 in MAFLD.
Procalcitonin and C-Reactive Protein/Procalcitonin Ratio as Markers of Infection in Patients With Solid Tumors
Authors: Vassallo Matteo , Michelangeli Celine , Fabre Roxane , Manni Sabrina , Genillier Pierre L. , Weiss Nicolas , Blanchouin Elea , Saudes Laurence , Kaphan Regis , Puchois Annick , Pradier Christian , Montagne Nathalie
Published: March 2021

Objectives: The roles of procalcitonin (PCT) and C-reactive protein (CRP) in febrile cancer patients is currently unclear. Our aim was to assess these in febrile patients with solid tumors and to identify cut-off values for ruling out infection.

Methods: We retrospectively evaluated patients with solid tumors admitted to hospital due to fever. They were divided into those with Fever with microbiologically documented infection (FMDI), Fever with clinically documented infection (FCDI) and Tumor-related fever (TRF). PCT and CRP levels were compared. Receiver-operating curves were plotted to define the best cut-off values for discriminating between infection-related and cancer-related fever.

Results: Between January 2015 to November 2018, 131 patients were recorded (mean age 68 years, 67% male, 86% with metastasis). Patients with FMDI or FCDI had significantly higher baseline levels of PCT and lower CRP/PCT than those with TRF. A PCT cut-off value of 0.52 ng/mL for discriminating between infection and cancer-associated fever yielded 75% sensitivity, 55% specificity, 77% positive predictive value (PPV), and 52% negative predictive value (NPV). A CRP/PCT ratio with a cut-off value of 95 showed 56% sensitivity, 70% specificity, 79% NPV, and 44% PPV.

Discussion: PCT is a sensitive marker of sepsis or localized infection in patients with solid tumors, but its specificity is poor. The CRP/PCT ratio improves specificity, thus providing a reliable means of ruling out infection for values above 95.
SARS-CoV-2 Testing of 11,884 Healthcare Workers at an Acute NHS Hospital Trust in England: A Retrospective Analysis
Authors: Hanrath Aidan T. , Schim van der Loeff Ina , Lendrem Dennis W. , Baker Kenneth F. , Price David A. , McDowall Peter , McDowall Kiera , Cook Susan , Towns Peter , Schwab Ulrich , Evans Adam , Dixon Jill , Collins Jennifer , Burton-Fanning Shirelle , Saunders David , Harwood Jayne , Samuel Julie , Schmid Matthias L. , Pareja-Cebrian Lucia , Hunter Ewan , Murphy Elizabeth , Taha Yusri , Payne Brendan A. I. , Duncan Christopher J. A.
Published: March 2021

Healthcare workers (HCWs) are known to be at increased risk of infection with SARS-CoV-2, although whether these risks are equal across all roles is uncertain. Here we report a retrospective analysis of a large real-world dataset obtained from 10 March to 6 July 2020 in an NHS Foundation Trust in England with 17,126 employees. 3,338 HCWs underwent symptomatic PCR testing (14.4% positive, 2.8% of all staff) and 11,103 HCWs underwent serological testing for SARS-CoV-2 IgG (8.4% positive, 5.5% of all staff). Seropositivity was lower than other hospital settings in England but higher than community estimates. Increased test positivity rates were observed in HCWs from BAME backgrounds and residents in areas of higher social deprivation. A multiple logistic regression model adjusting for ethnicity and social deprivation confirmed statistically significant increases in the odds of testing positive in certain occupational groups, most notably domestic services staff, nurses, and health-care assistants. PCR testing of symptomatic HCWs appeared to underestimate overall infection levels, probably due to asymptomatic seroconversion. Clinical outcomes were reassuring, with only a small minority of HCWs with COVID-19 requiring hospitalization (2.3%) or ICU management (0.7%) and with no deaths. Despite a relatively low level of HCW infection compared to other UK cohorts, there were nevertheless important differences in test positivity rates between occupational groups, robust to adjustment for demographic factors such as ethnic background and social deprivation. Quantitative and qualitative studies are needed to better understand the factors contributing to this risk. Robust informatics solutions for HCW exposure data are essential to inform occupational monitoring.
AMRmap: An Interactive Web Platform for Analysis of Antimicrobial Resistance Surveillance Data in Russia
Authors: Kuzmenkov Alexey Y. , Trushin Ivan V. , Vinogradova Alina G. , Avramenko Andrey A. , Sukhorukova Marina V. , Malhotra-Kumar Surbhi , Dekhnich Andrey V. , Edelstein Mikhail V. , Kozlov Roman S.
Published: March 2021

Surveillance of antimicrobial resistance (AMR) is crucial for identifying trends in resistance and developing strategies for prevention and treatment of infections. Globally, AMR surveillance systems differ in terms of organizational principles, comprehensiveness, accessibility, and usability of data presentation. Until recently, the data on AMR in Russia were scarcely available, especially to international community, despite the fact that the large prospective multicenter surveillance in Russia was conducted and data were accumulated for over 20 years. We describe the source of data, structure, and functionality of a new-generation web platform, called AMRmap (https://amrmap.net/), for analysis of AMR surveillance data in Russia. The developed platform currently comprises susceptibility data of >40,000 clinical isolates, and the data on abundance of key resistance determinants, including acquired carbapenemases in gram-negatives, are updated annually with information on >5,000 new isolates. The AMRmap allows smart data filtration by multiple parameters and provides interactive data analysis and visualization tools: MIC and S/I/R distribution plots, time-trends and regression plots, associated resistance plots, prevalence maps, statistical significance graphs, and tables.
Gene Expression, Biochemical Characterization of a sn-1, 3 Extracellular Lipase From Aspergillus niger GZUF36 and Its Model-Structure Analysis
Authors: Xing Shuqi , Zhu Ruonan , Cheng Kai , Cai Yangyang , Hu Yuedan , Li Cuiqin , Zeng Xuefeng , Zhu Qiujin , He Laping
Published: March 2021

In this study, a sn-1, 3 extracellular lipases from Aspergillus niger GZUF36 (PEXANL1) was expressed in Pichia pastoris, characterized, and the predicted structural model was analyzed. The optimized culture conditions of P. pastoris showed that the highest lipase activity of 66.5 ± 1.4 U/mL (P < 0.05) could be attained with 1% methanol and 96 h induction time. The purified PEXANL1 exhibited the highest activity at pH 4.0 and 40°C temperature, and its original activity remained unaltered in the majority of the organic solvents (20% v/v concentration). Triton X-100, Tween 20, Tween 80, and SDS at a concentration of 0.01% (w/v) enhanced, and all the metal ions tested inhibited activity of purified PEXANL. The results of ultrasound-assisted PEXANL1 catalyzed synthesis of 1,3-diaglycerides showed that the content of 1,3-diglycerides was rapidly increased to 36.90% with 25 min of ultrasound duration (P < 0.05) and later decreased to 19.93% with 35 min of ultrasound duration. The modeled structure of PEXANL1 by comparative modeling showed α/β hydrolase fold. Structural superposition and molecular docking results validated that Ser162, His274, and Asp217 residues of PEXANL1 were involved in the catalysis. Small-angle X-ray scattering analysis indicated the monomer properties of PEXANL1 in solution. The ab initio model of PEXANL1 overlapped with its modeling structure. This work presents a reliable structural model of A. niger lipase based on homology modeling and small-angle X-ray scattering. Besides, the data from this study will benefit the rational design of suitable crystalline lipase variants in the future.
Metataxonomic Profiling of Native and Starter Microbiota During Ripening of Gouda Cheese Made With Listeria monocytogenes-Contaminated Unpasteurized Milk
Authors: Salazar Joelle K. , Gonsalves Lauren J. , Fay Megan , Ramachandran Padmini , Schill Kristin M. , Tortorello Mary Lou
Published: March 2021

Unpasteurized milk is used to produce aged artisanal cheeses, which presents a safety concern due to possible contamination with foodborne pathogens, especially Listeria monocytogenes. The objective of this study was to examine the composition of the bacterial community in unpasteurized milk used to prepare Gouda cheese artificially contaminated with L. monocytogenes (~1 log CFU/ml) and assess the community dynamics and their potential interaction with L. monocytogenes during a 90-day ripening period using targeted 16S rRNA sequencing. The diversity of bacterial taxa in three batches of unpasteurized milk was not significantly different, and the microbiomes were dominated by species of Lactococcus, Streptomyces, Staphylococcus, and Pseudomonas. The highest relative abundances were observed for Pseudomonas fluorescens (31.84–78.80%) and unidentified operational taxonomic units (OTUs) of Pseudomonas (7.56–45.27%). After manufacture, both with and without L. monocytogenes-contaminated unpasteurized milk, Gouda cheese was dominated by starter culture bacteria (including Lactococcus lactis subsp. cremoris, lactis, lactis bv. diacetylactis, and Streptococcus thermophilus), in addition to unassigned members in the taxa L. lactis and Streptococcus. During ripening there was an overall decrease in L. lactis abundance and an increase in the number of taxa with relative abundances >0.1%. After 90-day ripening, a total of 82 and 81 taxa were identified in the Gouda cheese with and without L. monocytogenes, respectively. Of the identified taxa after ripening, 31 (Gouda cheese with L. monocytogenes) and 56 (Gouda cheese without L. monocytogenes) taxa had relative abundances >0.1%; 31 were shared between the two types of Gouda cheese, and 25 were unique to the Gouda cheese without added L. monocytogenes. No unique taxa were identified in the Gouda cheese with the added L. monocytogenes. This study provides information on the dynamics of the bacterial community in Gouda cheese during ripening, both with and without the addition of L. monocytogenes.
Computational Analysis of Residue-Specific Binding Free Energies of Androgen Receptor to Ligands
Authors: Shao Guangfeng , Bao Jingxiao , Pan Xiaolin , He Xiao , Qi Yifei , Zhang John Z. H.
Published: March 2021

Androgen receptor (AR) is an important therapeutic target for the treatment of diseases such as prostate cancer, hypogonadism, muscle wasting, etc. In this study, the complex structures of the AR ligand-binding domain (LBD) with fifteen ligands were analyzed by molecular dynamics simulations combined with the alanine-scanning-interaction-entropy method (ASIE). The quantitative free energy contributions of the pocket residues were obtained and hotspot residues are quantitatively identified. Our calculation shows that that these hotspot residues are predominantly hydrophobic and their interactions with binding ligands are mainly van der Waals interactions. The total binding free energies obtained by summing over binding contributions by individual residues are in good correlation with the experimental binding data. The current quantitative analysis of binding mechanism of AR to ligands provides important insight on the design of future inhibitors.
The Functions and Mechanisms of PR-DUB in Malignancy
Authors: Cao Lei , Li Rui , Wu Xudong
Published: March 2021

The interplay between cancer genome and deregulated epigenomic control is critical for cancer initiation and progression.ASXL1(Additional Sex combs-like 1) is frequently mutated in tumors especially myeloid malignancies. However, there remains a debate whether the mutations are loss or gain-of-function. Mechanistically, ASXL1 forms a complex with BAP1 for the erasure of mono-ubiquitylation at lysine 119 on Histone H2A (H2AK119ub1), a well-known histone mark associated with transcription repression. Unexpectedly, this de-ubiquitylation complex has been genetically defined as a Polycomb Repressive complex though the regulatory mechanisms are elusive. In this review, we will discuss about the functions of ASXL1 in malignancies and reconcile seemingly paradoxical effects of ASXL1 or BAP1 loss on transcription regulation.
Pericytes Across the Lifetime in the Central Nervous System
Authors: Bennett Hannah C. , Kim Yongsoo
Published: March 2021

The pericyte is a perivascular cell type that encapsulates the microvasculature of the brain and spinal cord. Pericytes play a crucial role in the development and maintenance of the blood-brain barrier (BBB) and have a multitude of important functions in the brain. Recent evidence indicates that pericyte impairment has been implicated in neurovascular pathology associated with various human diseases such as diabetes mellitus, Alzheimer’s disease (AD), and stroke. Although the pericyte is essential for normal brain function, knowledge about its developmental trajectory and anatomical distribution is limited. This review article summarizes the scientific community’s current understanding of pericytes’ regional heterogeneity in the brain and their changes during major life stages. More specifically, this review article focuses on pericyte differentiation and migration during brain development, regional population differences in the adult brain, and changes during normal and pathological aging. Most of what is known about pericytes come from studies of the cerebral cortex and hippocampus. Therefore, we highlight the need to expand our understanding of pericyte distribution and function in the whole brain to better delineate this cell type’s role in the normal brain and pathological conditions.
Inhibition of 14-3-3 Proteins Alters Neural Oscillations in Mice
Authors: Jones Zachary B. , Zhang Jiajing , Wu Yuying , Zhou Yi
Published: March 2021

Accumulating evidence suggests that schizophrenia is a disorder of the brain’s communication, a result of functional and structural dysconnectivities. Patients with schizophrenia exhibit irregular neuronal circuit and network activity, but the causes and consequences of such activity remain largely unknown. Inhibition of 14-3-3 proteins in the mouse brain leads to the expression of multiple schizophrenia endophenotypes. Here we investigated how 14-3-3 inhibition alters neuronal network activity in the mouse hippocampus (HPC) and prefrontal cortex (PFC), key brain regions implicated in schizophrenia pathophysiology. We implanted monopolar recording electrodes in these two regions to record local field potentials both at rest and during a cognitive task. Through our assessment of band power, coherence, and phase-amplitude coupling, we found that neural oscillations in the theta and gamma frequency ranges were altered as a result of 14-3-3 dysfunction. Utilizing transgenic and viral mouse models to assess the effects of chronic and acute 14-3-3 inhibition on oscillatory activities, respectively, we observed several fundamental similarities and differences between the two models. We localized viral mediated 14-3-3 protein inhibition to either the HPC or PFC, allowing us to assess the individual contributions of each region to the observed changes in neural oscillations. These findings identify a novel role of 14-3-3 proteins in neural oscillations that may have implications for our understanding of schizophrenia neurobiology.
Cerebrospinal Fluid Cavitation as a Mechanism of Blast-Induced Traumatic Brain Injury: A Review of Current Debates, Methods, and Findings
Authors: Marsh Jenny L. , Bentil Sarah A.
Published: March 2021

Cavitation has gained popularity in recent years as a potential mechanism of blast-induced traumatic brain injury (bTBI). This review presents the most prominent debates on cavitation; how bubbles can form or exist within the cerebrospinal fluid (CSF) and brain vasculature, potential mechanisms of cellular, and tissue level damage following the collapse of bubbles in response to local pressure fluctuations, and a survey of experimental and computational models used to address cavitation research questions. Due to the broad and varied nature of cavitation research, this review attempts to provide a necessary synthesis of cavitation findings relevant to bTBI, and identifies key areas where additional work is required. Fundamental questions about the viability and likelihood of CSF cavitation during blast remain, despite a variety of research regarding potential injury pathways. Much of the existing literature on bTBI evaluates cavitation based off its prima facie plausibility, while more rigorous evaluation of its likelihood becomes increasingly necessary. This review assesses the validity of some of the common assumptions in cavitation research, as well as highlighting outstanding questions that are essential in future work.
Remedial Training of the Less-Impaired Arm in Chronic Stroke Survivors With Moderate to Severe Upper-Extremity Paresis Improves Functional Independence: A Pilot Study
Authors: Maenza Candice , Wagstaff David A. , Varghese Rini , Winstein Carolee , Good David C. , Sainburg Robert L.
Published: March 2021

The ipsilesional arm of stroke patients often has functionally limiting deficits in motor control and dexterity that depend on the side of the brain that is lesioned and that increase with the severity of paretic arm impairment. However, remediation of the ipsilesional arm has yet to be integrated into the usual standard of care for upper limb rehabilitation in stroke, largely due to a lack of translational research examining the effects of ipsilesional-arm intervention. We now ask whether ipsilesional-arm training, tailored to the hemisphere-specific nature of ipsilesional-arm motor deficits in participants with moderate to severe contralesional paresis, improves ipsilesional arm performance and generalizes to improve functional independence. We assessed the effects of this intervention on ipsilesional arm unilateral performance [Jebsen–Taylor Hand Function Test (JHFT)], ipsilesional grip strength, contralesional arm impairment level [Fugl–Meyer Assessment (FM)], and functional independence [Functional independence measure (FIM)] (N = 13). Intervention occurred over a 3 week period for 1.5 h/session, three times each week. All sessions included virtual reality tasks that targeted the specific motor control deficits associated with either left or right hemisphere damage, followed by graded dexterity training in real-world tasks. We also exposed participants to 3 weeks of sham training to control for the non-specific effects of therapy visits and interactions. We conducted five test-sessions: two pre-tests and three post-tests. Our results indicate substantial improvements in the less-impaired arm performance, without detriment to the paretic arm that transferred to improved functional independence in all three posttests, indicating durability of training effects for at least 3 weeks. We provide evidence for establishing the basis of a rehabilitation approach that includes evaluation and remediation of the ipsilesional arm in moderately to severely impaired stroke survivors. This study was originally a crossover design; however, we were unable to complete the second arm of the study due to the COVID-19 pandemic. We report the results from the first arm of the planned design as a longitudinal study.
Subject-Independent Functional Near-Infrared Spectroscopy-Based Brain–Computer Interfaces Based on Convolutional Neural Networks
Authors: Kwon Jinuk , Im Chang-Hwan
Published: March 2021

Functional near-infrared spectroscopy (fNIRS) has attracted increasing attention in the field of brain–computer interfaces (BCIs) owing to their advantages such as non-invasiveness, user safety, affordability, and portability. However, fNIRS signals are highly subject-specific and have low test-retest reliability. Therefore, individual calibration sessions need to be employed before each use of fNIRS-based BCI to achieve a sufficiently high performance for practical BCI applications. In this study, we propose a novel deep convolutional neural network (CNN)-based approach for implementing a subject-independent fNIRS-based BCI. A total of 18 participants performed the fNIRS-based BCI experiments, where the main goal of the experiments was to distinguish a mental arithmetic task from an idle state task. Leave-one-subject-out cross-validation was employed to evaluate the average classification accuracy of the proposed subject-independent fNIRS-based BCI. As a result, the average classification accuracy of the proposed method was reported to be 71.20 ± 8.74%, which was higher than the threshold accuracy for effective BCI communication (70%) as well as that obtained using conventional shrinkage linear discriminant analysis (65.74 ± 7.68%). To achieve a classification accuracy comparable to that of the proposed subject-independent fNIRS-based BCI, 24 training trials (of approximately 12 min) were necessary for the traditional subject-dependent fNIRS-based BCI. It is expected that our CNN-based approach would reduce the necessity of long-term individual calibration sessions, thereby enhancing the practicality of fNIRS-based BCIs significantly.
Compassion Is Not a Benzo: Distinctive Associations of Heart Rate Variability With Its Empathic and Action Components
Authors: Di Bello Maria , Ottaviani Cristina , Petrocchi Nicola
Published: March 2021

Recent studies have linked compassion with higher vagally mediated heart rate variability (vmHRV), a measure of parasympathetic activity, and meta-analytic evidence confirmed significant and positive associations. Compassion, however, is not to be confused with soothing positive emotions: in order to engage in actions aimed to alleviate (self or others) suffering, the pain should resonate, and empathic sensitivity should be experienced first. The present study examined the association between vmHRV and the empathic sensitivity and action components of trait and state compassion. To do so, several dispositional questionnaires were administered and two videos inducing empathic sensitivity (video 1) and compassionate actions (video 2) were shown, while the ECG was continuously recorded, and momentary affect was assessed. Results showed that (i) scores on subscales assessing the empathic component of trait compassion were inversely related to resting vmHRV; (ii) vmHRV decreased after video 1 but significantly increased after video 2. As to momentary affect, video 1 was accompanied with an increase in sadness and a decrease in positive affect, whereas video 2 was characterized by an increase in anger, a parallel decrease in sadness, and an increase (although non-significant) in positive affect. Overall, present findings support the notion that it is simplistic to link compassion with higher vmHRV. Compassion encompasses increased sensitivity to emotional pain, which is naturally associated with lower vmHRV, and action to alleviate others’ suffering, which is ultimately associated with increased vmHRV. The importance of adopting a nuanced perspective on the complex physiological regulation that underlies compassionate responding to suffering is discussed.
Possible Involvement of MyD88 in Regulating Stress Response in Mice
Authors: Hosoi Toru , Yamawaki Yosuke , Kimura Hitomi , Honda Shoko , Ozawa Koichiro
Published: March 2021

Myeloid differentiation primary response 88 (MyD88) is an adapter protein of the toll-like receptor (TLR) family that regulates innate immune function. Here, we identified a novel role of MyD88 in regulating stress response. MyD88 deficiency decreased immobility time in the forced swim test without affecting locomotor activity in mice. Immobilization stress-induced production of serum corticosterone was also completely inhibited by MyD88 deficiency. Stress induced decrease in glucocorticoid receptor in the hippocampus. On the other hand, stress exposure in MyD88 deficient mice did not cause decrease in its level in the hippocampus. Furthermore, immobilization stress-induced reduction of brain-derived neurotrophic factor (BDNF) levels in the hippocampus was ameliorated by MyD88 deficiency. These results suggest that MyD88 deficiency attenuates depression-like behavior by regulating corticosterone and BDNF levels. Overall, these results indicate the key role of MyD88 in regulating stress response in mice.
Polo-Like Kinase 4’s Critical Role in Cancer Development and Strategies for Plk4-Targeted Therapy
Authors: Zhang Xiaoyang , Wei Cheng , Liang Hao , Han Lei
Published: March 2021

Polo-like kinases (Plks) are critical regulatory molecules during the cell cycle process. This family has five members: Plk1, 2, 3, 4, and 5. Plk4 has been identified as a master regulator of centriole replication, and its aberrant expression is closely associated with cancer development. In this review, we depict the DNA, mRNA, and protein structure of Plk4, and the regulation of Plk4 at a molecular level. Then we list the downstream targets of Plk4 and the hallmarks of cancer associated with these targets. The role of Plk4 in different cancers is also summarized. Finally, we review the inhibitors that target Plk4 in the hope of discovering effective anticancer drugs. From authors’ perspective, Plk4 might represent a valuable tumor biomarker and critical target for cancer diagnosis and therapy.
Association of Maternal Body Mass Index With Risk of Infant Mortality: A Dose-Response Meta-Analysis
Authors: Huo Nana , Zhang Kun , Wang Li , Wang Lina , Lv Wenhui , Cheng Wenke , Jia GuangZhu
Published: March 2021

Objective: This study presumed that a high or low body mass index (BMI) might increase the risk of infant mortality. Therefore, a meta-analysis was performed to systematically assess the association between maternal BMI and the risk of infant mortality.

Methods: The electronic databases, including Pubmed, Embase database, and Cochrane Library, were systemically searched by two investigators from inception to November 26th, 2020, with no language restriction. In parallel, a dose-response was assessed.

Results: Finally, 22 cohort studies involving 13,532,293 participants were included into this paper, which showed that compared with normal BMI, maternal overweight significantly increased the risks of infant mortality [risk ratio (RR), 1.16; 95% confidence interval (CI), 1.13–1.19], neonatal mortality (RR, 1.23; 95% CI, 1.08–1.39), early neonatal mortality (RR, 1.55; 95% CI, 1.26–1.92) and post-neonatal mortality (RR, 1.18; 95% CI, 1.07–1.29). Similarly, maternal obesity significantly increased the risk of infant mortality (RR, 1.55; 95% CI, 1.41–1.70), neonatal mortality (RR, 1.55; 95% CI, 1.28–1.67), early neonatal mortality (RR, 1.37; 95% CI, 1.13–1.67), and post-neonatal mortality (RR, 1.30; 95% CI, 1.03–1.65), whereas maternal underweight potentially decreased the risk of infant mortality (RR, 0.93; 95% CI, 0.88–0.98). In the dose-response analysis, the risk of infant mortality significantly increased when the maternal BMI was >25 kg/m2.

Conclusions: Maternal overweight or obesity significantly increases the risks of infant mortality, neonatal mortality, early neonatal mortality, and post-neonatal mortality compared with normal BMI in a dose-dependent manner. Besides, maternal underweight will not increase the risk of infant mortality, neonatal mortality, early neonatal mortality, or postneonatal mortality; instead, it tends to decrease the risk of infant mortality. Early weight management may provide potential benefits to infants, and more large-scale prospective studies are needed to verify this finding in the future.
Pyr1-Mediated Pharmacological Inhibition of LIM Kinase Restores Synaptic Plasticity and Normal Behavior in a Mouse Model of Schizophrenia
Authors: Gory-Fauré Sylvie , Powell Rebecca , Jonckheere Julie , Lanté Fabien , Denarier Eric , Peris Leticia , Nguyen Chi Hung , Buisson Alain , Lafanechère Laurence , Andrieux Annie
Published: March 2021

The search for effective treatments for neuropsychiatric disorders is ongoing, with progress being made as brain structure and neuronal function become clearer. The central roles played by microtubules (MT) and actin in synaptic transmission and plasticity suggest that the cytoskeleton and its modulators could be relevant targets for the development of new molecules to treat psychiatric diseases. In this context, LIM Kinase - which regulates both the actin and MT cytoskeleton especially in dendritic spines, the post-synaptic compartment of the synapse - might be a good target. In this study, we analyzed the consequences of blocking LIMK1 pharmacologically using Pyr1. We investigated synaptic plasticity defects and behavioral disorders in MAP6 KO mice, an animal model useful for the study of psychiatric disorders, particularly schizophrenia. Our results show that Pyr1 can modulate MT dynamics in neurons. In MAP6 KO mice, chronic LIMK inhibition by long-term treatment with Pyr1 can restore normal dendritic spine density and also improves long-term potentiation, both of which are altered in these mice. Pyr1 treatment improved synaptic plasticity, and also reduced social withdrawal and depressive/anxiety-like behavior in MAP6 KO mice. Overall, the results of this study validate the hypothesis that modulation of LIMK activity could represent a new therapeutic strategy for neuropsychiatric diseases.
In-vitro Study for Cerenkov Luminescence Imaging Application in Hepatic Metastasectomy
Authors: Ciarrocchi Esther , Saponaro Sara , Bartoli Francesco , Cataldi Angela Gabriella , Vitali Sara , Erba Paola Anna , Belcari Nicola
Published: March 2021

Cerenkov luminescence imaging (CLI) has been recently proposed as a method to visualize surgical margins in the operating theater, immediately after resection, to allow refining surgery in a single procedure. Our group is preparing a pilot clinical study to evaluate the impact of CLI during hepatic metastasectomy, using 18F-FDG and 68Ga-DOTATOC. Currently, we are optimizing the clinical protocol in terms of patient inclusion criteria, activity to inject, maximum allowed delay for imaging, and radiation monitoring. This paper describes a preliminary study we have performed to define the clinical protocol. The study is composed of two branches: 1) an in-vitro study to predict the typical signals and optical attenuation in the liver with 18F and 68Ga, 2) an analysis of clinical PET/CT data to determine typical values of relevant parameters, such as uptake and lesion dimension. The combined information by these two branches gives us an indication of the feasibility of CLI for margin assessment in liver metastasectomy. For 68Ga, we obtained detection limits ranging from 0.55 to 3.5 kBq/cc, to be compared with minimum and mean clinical uptakes of 1.6 and 7 kBq/cc, respectively. For 18F, the detection limits ranged from 12 to 145 kBq/cc, and the minimum and mean clinical uptakes were 5 and 11 kBq/cc, respectively. From these values, we expect CLI with 68Ga to be able to detect surgical margins in most patients, while with 18F the activities to inject for sufficient signal-to-noise ratio should be larger than standards, or the time delay between injection and imaging largely reduced. The results reported here can be useful also more in general, for studies dedicated to other CLI applications in the liver.
The Impact of Public Deliberation on Climate Change Opinions Among U.S. Citizens
Authors: Ghimire Rajiv , Anbar Nathaniel , Chhetri Netra B.
Published: March 2021

Governance of climate change has become a major global environmental issue in the 21st century, and in the absence of wider citizen engagement poses risks of global proportions. Much of the current climate governance debate, unfortunately, is limited to scientists, politicians, and interest groups. With few exceptions, everyday citizens are spectators at best, their views, if not absent, are dismally represented in policy processes. To close the widening gap between citizens and policymakers, thereby increasing the sense of ownership of environmental policies by ordinary people, several methods of citizen engagement for global environmental governance have emerged. The effectiveness of these methods, however, relies upon the ability of citizens to deliberate meaningfully, especially in issues such as climate change. We conducted a study in conjunction with World Wide Views on Climate and Energy, a global citizen consultation that aims to solicit carefully considered public views on pressing issues, to determine whether American citizens are receptive to deliberation, and to ascertain what effect it had on their opinions, if any, could be observed. Along with the descriptive analysis, we performed a non-parametric Wilcoxon signed-rank test of selected pre-and post-event opinions of the participants from the US. Our study revealed that providing US citizens with the opportunity to engage in deliberation resulted in increased awareness regarding climate change and greater trust in science, technology, and international agreements. The change in opinion was more pronounced among people whose political orientation titled to the right or who considered themselves as neutral. Citizen’s opinions, especially after the event, resulted in less polarized views towards the global consensus on climate change. This finding suggests that US citizens are receptive to scientific information if it is communicated in an appropriate manner – a characteristic necessary for the creation of deliberative democratic governance on socially contested issues.
Psychometric Properties of the German Version of the Self-Regulation of Eating Behavior Questionnaire
Authors: Schmalbach Ileana , Schmalbach Bjarne , Zenger Markus , Petrowski Katja , Beutel Manfred , Hilbert Anja , Brähler Elmar
Published: March 2021

Background: The Self-Regulation of Eating Behavior Questionnaire (SREBQ) is an economical way of assessing an individual's self-regulatory abilities regarding eating behavior. Such scales are needed in the German population; therefore, the purpose of the present study was the translation and validation of a German version of the SREBQ.

Method: First, we conducted a pilot study (Study 1; N = 371) after the translation procedure. Second, we assessed the final scale in a representative sample of the German population (Sample 2; N = 2,483) and its underlying factor structure. Further, we tested for measurement invariance and evaluated the SREBQ's associations with related scales to explore convergent and discriminant validity. Finally, we considered differences in SREBQ based on sociodemographic variables and provided derived reference scores (norm values).

Results: Factor analysis revealed deficiencies in the original model. Thus, we shortened the scale based on statistical considerations and the adapted version showed improved fit in Confirmatory Factor Analysis and reliability. We also found evidence for partial strict invariance, which means the measure is equivalent for the tested groups of age and gender. Item and scale psychometric properties of the shortened version were satisfactory. In terms of diagnostic validity, it was shown that individuals with higher body mass index (kg/m2) have worse self-regulation of eating behavior than those with lower.

Conclusion: In sum, the SREBQ evidenced good validity and reliability and is suitable for application in medical, psychological, and nutritional research.