bluuebunny/crossref_metadata_2025 huggingface dataset:
Dissecting the Role of BET Bromodomain Proteins BRD2 and BRD4 in Human NK Cell Function
Authors: Cribbs Adam P. , Filippakopoulos Panagis , Philpott Martin , Wells Graham , Penn Henry , Oerum Henrik , Valge-Archer Viia , Feldmann Marc , Oppermann Udo
Published: February 2021

Natural killer (NK) cells are innate lymphocytes that play a pivotal role in the immune surveillance and elimination of transformed or virally infected cells. Using a chemo-genetic approach, we identify BET bromodomain containing proteins BRD2 and BRD4 as central regulators of NK cell functions, including direct cytokine secretion, NK cell contact-dependent inflammatory cytokine secretion from monocytes as well as NK cell cytolytic functions. We show that both BRD2 and BRD4 control inflammatory cytokine production in NK cells isolated from healthy volunteers and from rheumatoid arthritis patients. In contrast, knockdown of BRD4 but not of BRD2 impairs NK cell cytolytic responses, suggesting BRD4 as critical regulator of NK cell mediated tumor cell elimination. This is supported by pharmacological targeting where the first-generation pan-BET bromodomain inhibitor JQ1(+) displays anti-inflammatory effects and inhibit tumor cell eradication, while the novel bivalent BET bromodomain inhibitor AZD5153, which shows differential activity towards BET family members, does not. Given the important role of both cytokine-mediated inflammatory microenvironment and cytolytic NK cell activities in immune-oncology therapies, our findings present a compelling argument for further clinical investigation.
Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function
Authors: Alatshan Ahmad , Benkő Szilvia
Published: February 2021

Nuclear receptors are important bridges between lipid signaling molecules and transcription responses. Beside their role in several developmental and physiological processes, many of these receptors have been shown to regulate and determine the fate of immune cells, and the outcome of immune responses under physiological and pathological conditions. While NLRP3 inflammasome is assumed as key regulator for innate and adaptive immune responses, and has been associated with various pathological events, the precise impact of the nuclear receptors on the function of inflammasome is hardly investigated. A wide variety of factors and conditions have been identified as modulators of NLRP3 inflammasome activation, and at the same time, many of the nuclear receptors are known to regulate, and interact with these factors, including cellular metabolism and various signaling pathways. Nuclear receptors are in the focus of many researches, as these receptors are easy to manipulate by lipid soluble molecules. Importantly, nuclear receptors mediate regulatory mechanisms at multiple levels: not only at transcription level, but also in the cytosol via non-genomic effects. Their importance is also reflected by the numerous approved drugs that have been developed in the past decade to specifically target nuclear receptors subtypes. Researches aiming to delineate mechanisms that regulate NLRP3 inflammasome activation draw a wide range of attention due to their unquestionable importance in infectious and sterile inflammatory conditions. In this review, we provide an overview of current reports and knowledge about NLRP3 inflammasome regulation from the perspective of nuclear receptors, in order to bring new insight to the potentially therapeutic aspect in targeting NLRP3 inflammasome and NLRP3 inflammasome-associated diseases.
Co-evolution of Immune Response in Multiple Myeloma: Implications for Immune Prevention
Authors: McCachren Samuel S. , Dhodapkar Kavita M. , Dhodapkar Madhav V.
Published: February 2021

Multiple myeloma (MM), a malignant neoplasm of plasma cells that reside in the bone marrow (BM), is universally preceded by a precursor state termed monoclonal gammopathy of undetermined significance (MGUS). Many individuals with MGUS never progress to MM or progress over many years. Therefore, MGUS provides a unique opportunity to surveil changes in the BM tumor microenvironment throughout disease progression. It is increasingly appreciated that MGUS cells carry many of the genetic changes found in MM. Prior studies have also shown that MGUS cells can be recognized by the immune system, leading to early changes in the BM immune environment compared to that of healthy individuals, including alterations in both innate and adaptive immunity. Progression to clinical MM is associated with attrition of T cells with stem memory-like features and instead accumulation of T cells with more terminally differentiated features. Recent clinical studies have suggested that early application of immune-modulatory drugs, which are known to activate both innate and adaptive immunity, can delay the progression to clinical MM. Understanding the biology of how the immune response and tumors coevolve over time is needed to develop novel immune-based approaches to achieve durable and effective prevention of clinical malignancy.
Long-Term Suppressive cART Is Not Sufficient to Restore Intestinal Permeability and Gut Microbiota Compositional Changes
Authors: Ancona Giuseppe , Merlini Esther , Tincati Camilla , Barassi Alessandra , Calcagno Andrea , Augello Matteo , Bono Valeria , Bai Francesca , Cannizzo Elvira S. , d'Arminio Monforte Antonella , Marchetti Giulia
Published: February 2021

Background: We explored the long-term effects of cART on markers of gut damage, microbial translocation, and paired gut/blood microbiota composition, with a focus on the role exerted by different drug classes.

Methods: We enrolled 41 cART naïve HIV-infected subjects, undergoing blood and fecal sampling prior to cART (T0) and after 12 (T12) and 24 (T24) months of therapy. Fifteen HIV-uninfected individuals were enrolled as controls. We analyzed: (i) T-cell homeostasis (flow cytometry); (ii) microbial translocation (sCD14, EndoCab, 16S rDNA); (iii) intestinal permeability and damage markers (LAC/MAN, I-FABP, fecal calprotectin); (iv) plasma and fecal microbiota composition (alpha- and beta-diversity, relative abundance); (v) functional metagenome predictions (PICRUSt).

Results: Twelve and twenty four-month successful cART resulted in a rise in EndoCAb (p = 0.0001) and I-FABP (p = 0.039) vis-à-vis stable 16S rDNA, sCD14, calprotectin and LAC/MAN, along with reduced immune activation in the periphery. Furthermore, cART did not lead to substantial modifications of microbial composition in both plasma and feces and metabolic metagenome predictions. The stratification according to cART regimens revealed a feeble effect on microbiota composition in patients on NNRTI-based or INSTI-based regimens, but not PI-based regimens.

Conclusions: We hereby show that 24 months of viro-immunological effective cART, while containing peripheral hyperactivation, exerts only minor effects on the gastrointestinal tract. Persistent alteration of plasma markers indicative of gut structural and functional impairment seemingly parallels enduring fecal dysbiosis, irrespective of drug classes, with no effect on metabolic metagenome predictions.
Causes of Mortality of Northern Sea Otters (Enhydra lutris kenyoni) in Alaska From 2002 to 2012
Authors: Burek Huntington Kathleen Ann , Gill Verena Ann , Berrian Amanda M. , Goldstein Tracey , Tuomi Pam , Byrne Barbara A. , Worman Kristin , Mazet Jonna
Published: February 2021

Most of the world’s sea otters reside in Alaska, but there has never been an assessment of long-term mortality patterns for this keystone predator. We examined data collected from 780 northern sea otter (Enhydra lutris kenyoni)carcasses recovered in Alaska from 2002 to 2012 to evaluate the causes of mortality and risk factors associated with death. A smaller group (n= 144, 18%) of fresh non-frozen carcasses were included in a more detailed mortality analysis. Forty-four% of the fresh dead otters were determined to have died from infectious endocarditis, meningoencephalitis, and/or septicemia due to systemic streptococcosis (“Strepsyndrome”).Streptococcus lutetiensis, a member of theStreptococcus bovis/equinus(SB/E) group was most commonly isolated, although other members of the SB/E group were identified. There were fewer cases whereS. phocaeand other streptococci were isolated. A regression analysis revealed age and location risk factors forStrepsyndrome. Subadults were the highest risk age group, and otters recovered from the Kachemak Bay region were 3.6 times (95% CI: 2.2–5.9) more likely to die fromStrepsyndrome than otters recovered elsewhere. Diagnosis of thisStrepsyndrome had not been reported in other marine mammals in Alaska. Sporadic cases of septicemia and infectious endocarditis due toS. lutetiensishave been seen in the southern sea otter population in California. Other causes of death for the fresh otters included neurologic diseases (10%), trauma (8%), nutritional diseases (7%), cardiovascular diseases (7%), gastrointestinal diseases /parasites (6%), undetermined (5%), septicemia (3%), and neoplasia (3%). All other causes of death (oiling, hepatobiliary, fungal, marine biotoxins, pulmonary) were at or below 1%. Twenty percent of fresh animals were positive for phocine distemper virus (PDV) by polymerase chain reaction (PCR, 11/55), 18% seropositive for PDV (7/38), and paramyxovirus-like particles were demonstrated by electron microscopy within inclusion bodies from one animal. Low concentrations of the harmful algal bloom toxins domoic acid and saxitoxin were also detected in 26% and 22% of fresh animals, respectively. Protozoal disease was rare. These patterns of disease differ from sea otters in other regions and possible reasons are discussed.
Flame Retarded Rigid Polyurethane Foams Composites Modified by Aluminum Diethylphosphinate and Expanded Graphite
Authors: Hu Yuxiang , Zhou Zijian , Li Shuisheng , Yang Dong , Zhang Shui , Hou Yakang
Published: February 2021

Rigid polyurethane foam (RPUF) was an organic porous material, which was applied in many fields for excellent thermal insulation and mechanical properties, especially in building insulation. However, the poor fire performance significantly suppresses its further application. In this work, aluminum diethylphosphinate (ADP) combined with expanded graphite (EG) to form a synergistic flame retarded system, which was introduced to fabricate flame retarded rigid polyurethane foam composites (FR-RPUF) by one-step water-blown method. Furthermore, thermal insulation, thermal stability, fire performance, and decomposition products of RPUF and FR-RPUF composites were systematically investigated. It was found that FR-RPUF composites possessed LOI of 25.9 vol% with V-1 rating in UL-94 test when 10 php of ADP and 20 php of EG were added, which were better than RPUF composites with ADP or EG added alone. MCC test showed that RPUF/ADP24/EG6 had the lowest PHRR value of 159.85 W/g, which was 52.01 W/g lower than that of pure RPUF. Gas phase products investigation implied that the combination of ADP and EG could decrease toxic and combustible gases intensities, thus significantly enhancing fire safety of FR-RPUF composites. SEM test indicated that ADP and EG promoted the formation of dense and continuous char residue, which significantly inhibited heat and substance transfer in combustion, thus significantly enhancing fire performance of FR-RPUF composites.
Effect of Vacuum Heat Treatment on Microstructures and Mechanical Properties of 7A52 Aluminum Alloy-Al2O3 Ceramic Brazed Joints
Authors: Zhang Deku , Qian Xusheng , Li Xiaopeng , Wang Kehong
Published: February 2021

This study investigated the interface morphology, microstructure composition and connection strength of 7A52 aluminum alloy-Al2O3 ceramic brazed joints under heat treatment conditions. Alumina ceramics were first treated with electroless nickel plating, followed by vacuum heat treatment at different temperatures. Then an Al-Si-Mg intermediate layer was placed between the treated alumina ceramic and 7A52 aluminum alloy for brazing under the conditions of welding temperature 590, holding time 1h, pressure 2 MPa. Results showed that when heat treatment was performed at 350°C and below, the nickel-plated metal had an amorphous structure, and when performed at 400°C, the nickel-plated layer had a crystalline structure and the brittle phase Ni3P was precipitated. When the heat treatment temperature was 350°C, the joint shear strength reached the maximum, which was 68.7 MPa.
Photoresponsive Piezoelectrics
Authors: Bai Yang
Published: February 2021

Most piezoelectric materials are not interactive with visible light, meaning that their band gaps are beyond the photon energies of the visible part of the light spectrum. The first narrow band gap (1.1 eV, the same as silicon) ferroelectric material based on the oxide perovskite structure has been achieved by doping Ni on the B-sites of KNbO3 and paring the Ni2+ ions with oxygen vacancies to form defect dipoles to ease the band-band transition. This band gap engineered ferroelectric material has also been proved to be piezoelectric. The Ni-doping strategy for band gap engineering has been successfully applied to other perovskite compositions. As a result, several materials with simultaneously good piezoelectricity and a visible-range band gap have been developed. Such photoresponsive piezoelectrics have potential applications in opto-electrical dual-source actuators, single-material multi-sensors and multi-source energy harvesters. This mini review focuses on the works of simultaneous tuning of piezoelectricity and band gap, which have not previously been discussed as an individual topic in existing reviews. Pioneer works on the applications of photoresponsive piezoelectrics are also presented. Since most of such materials are built on the frame of lead-free perovskite oxides, their band gap (without degrading the piezoelectricity) provides an additional benefit to environmentally friendly lead-free piezoelectrics (compared to lead-based counterparts such as PZT [Pb(Zr,Ti)O3)]. This review aims to draw the attention of piezoelectric scientists and device engineers, so that potential applications of photoresponsive piezoelectrics can be comprehensively investigated, as well as more material options that can be offered in future works.
Comparative Genomic and Transcriptomic Analysis Reveals Specific Features of Gene Regulation in Kluyveromyces marxianus
Authors: Yu Yao , Mo Wenjuan , Ren Haiyan , Yang Xianmei , Lu Wanlin , Luo Tongyu , Zeng Junyuan , Zhou Jungang , Qi Ji , Lu Hong
Published: February 2021

Kluyveromyces marxianus is a promising host for producing bioethanol and heterologous proteins. It displays many superior traits to a conventional industrial yeast species, Saccharomyces cerevisiae, including fast growth, thermotolerance and the capacity to assimilate a wider variety of sugars. However, little is known about the mechanisms underlying the fast-growing feature of K. marxianus. In this study, we performed a comparative genomic analysis between K. marxianus and other Saccharomycetaceae species. Genes involved in flocculation, iron transport, and biotin biosynthesis have particularly high copies in K. marxianus. In addition, 60 K. marxianus specific genes were identified, 45% of which were upregulated during cultivation in rich medium and these genes may participate in glucose transport and mitochondrion related functions. Furthermore, the transcriptomic analysis revealed that under aerobic condition, normalized levels of genes participating in TCA cycles, respiration chain and ATP biosynthesis in the lag phase were higher in K. marxianus than those in S. cerevisiae. Levels of highly copied genes, genes involved in the respiratory chain and mitochondrion assembly, were upregulated in K. marxianus, but not in S. cerevisiae, in later time points during cultivation compared with those in the lag phase. Notably, during the fast-growing phase, genes involved in the respiratory chain, ATP synthesis and glucose transport were co-upregulated in K. marxianus. A few shared motifs in upstream sequences of relevant genes might result in the co-upregulation. Specific features in the co-regulations of gene expressions might contribute to the fast-growing phenotype of K. marxianus. Our study underscores the importance of genome-wide rewiring of the transcriptional network during evolution.
Evolution of Bacterial Tolerance Under Antibiotic Treatment and Its Implications on the Development of Resistance
Authors: Sulaiman Jordy Evan , Lam Henry
Published: February 2021

Recent laboratory evolution studies have shown that upon repetitive antibiotic treatments, bacterial populations will adapt and eventually became tolerant and resistant to the drug. Drug tolerance rapidly evolves upon frequent, intermittent antibiotic treatments, and such emerging drug tolerance seems to be specific to the treatment conditions, complicating clinical practice. Moreover, it has been shown that tolerance often promotes the development of resistance, which further reinforces the need of clinical diagnostics for antibiotic tolerance to reduce the occurrence of acquired resistance. Here, we discuss the laboratory evolution studies that were performed to track the development of tolerance in bacterial populations, and highlight the urgency of developing a comprehensive knowledge base of various tolerance phenotypes and their detection in clinics. Finally, we propose future directions for basic research in this growing field.
Insect Derived Lauric Acid as Promising Alternative Strategy to Antibiotics in the Antimicrobial Resistance Scenario
Authors: Borrelli Luca , Varriale Lorena , Dipineto Ludovico , Pace Antonino , Menna Lucia F. , Fioretti Alessandro
Published: February 2021

Antibiotic misuse is greatly contributing to an increase in antimicrobial resistance (AMR) in humans and animals. Natural and synthetic alternative strategies are being investigated in human and veterinary medicine, but little attention is paid to the antimicrobial effects of edible lipids, such as medium-chain fatty acids (MCFAs) and monoglycerides. Among MCFAs, lauric acid (LA) and its monoglyceride derivative, glycerol monolaurate (GML), exhibit the strongest antimicrobial activity. Coconut and palm kernel oils are considered the main sources of LA. On the other hand, some edible insects (e.g., Hermetia illucens) are gaining interest as novel feed ingredients, due to the high amount of LA they contain as well as their numerous bioactive components, which provide many additional benefits to animal health. Although the beneficial effect of both MCFAs and LA is gradually being recognized, their high content within insects and, consequently, their possible role as antimicrobials, has not been well-reported. This mini review focuses on the anti-infective effects of the insect-derived MCFAs LA and its derivatives. We emphasize the potential of insect lipids, compared to the other vegetable sources, in the current global scenario where a sustainable and circular economy is required. Finally, we critically discuss the use and the benefits of edible insects such as favorable options as feed and food from the perspective of animal and human nutrition.
Pre-weaning Ruminal Administration of Differentially-Enriched, Rumen-Derived Inocula Shaped Rumen Bacterial Communities and Co-occurrence Networks of Post-weaned Dairy Calves
Authors: Park Tansol , Cersosimo Laura M. , Li Wenli , Radloff Wendy , Zanton Geoffrey I.
Published: February 2021

Adult rumen fluid inoculations have been considered to facilitate the establishment of rumen microbiota of pre-weaned dairy calves. However, the sustained effects of the inoculations remain to be explored. In our previous study, 20 pre-weaned dairy calves had been dosed with four types of adult rumen inoculums [autoclaved rumen fluid, bacterial-enriched rumen fluid (BE), protozoal-enriched (PE), and BE + PE] weekly at 3 to 6 weeks of age. To verify the sustained effect of adult rumen inoculation, the rumen bacterial communities, fermentation characteristics, and animal performance measurements were measured after sacrifice from 20 post-weaned dairy bull calves (9 weeks of age). Ruminal pH tended to be lower in BE treated calves (n= 10). All PE treated calves had rumen ciliates (>104cells per ml of rumen fluid). PE treated calves had greater VFA concentrations (P= 0.052), lower molar proportions of isobutyrate (P= 0.073), and butyrate (P= 0.019) compared to those of control calves. No treatment differences were found in all animal performance measurements. Both PE and BE inocula increased bacterial species richness, Faith’s phylogenetic diversity, and Shannon’s index in rumen liquid fractions. However, the relative proportion of those bacterial taxa possibly transferred from the donor’s rumen was minor. Microbial network analysis showed different co-occurrence and mutually exclusive interactions between treatments of microbial inoculations. Collectively, adult rumen inoculations in pre-weaned dairy calves slightly altered the rumen bacteriome of post-weaned calves without changing fermentation and animal performance.
Characterization of Sulfurimonas hydrogeniphila sp. nov., a Novel Bacterium Predominant in Deep-Sea Hydrothermal Vents and Comparative Genomic Analyses of the Genus Sulfurimonas
Authors: Wang Shasha , Jiang Lijing , Hu Qitao , Cui Liang , Zhu Bitong , Fu Xiaoteng , Lai Qiliang , Shao Zongze , Yang Suping
Published: February 2021

Bacteria of the genus Sulfurimonas within the class Campylobacteria are predominant in global deep-sea hydrothermal environments and widespread in global oceans. However, only few bacteria of this group have been isolated, and their adaptations for these extreme environments remain poorly understood. Here, we report a novel mesophilic, hydrogen- and sulfur-oxidizing bacterium, strain NW10T, isolated from a deep-sea sulfide chimney of Northwest Indian Ocean.16S rRNA gene sequence analysis showed that strain NW10T was most closely related to the vent species Sulfurimonas paralvinellae GO25T with 95.8% similarity, but ANI and DDH values between two strains were only 19.20 and 24.70%, respectively, indicating that strain NW10 represents a novel species. Phenotypic characterization showed strain NW10T is an obligate chemolithoautotroph utilizing thiosulfate, sulfide, elemental sulfur, or molecular hydrogen as energy sources, and molecular oxygen, nitrate, or elemental sulfur as electron acceptors. Moreover, hydrogen supported a better growth than reduced sulfur compounds. During thiosulfate oxidation, the strain can produce extracellular sulfur of elemental α-S8 with an unknown mechanism. Polyphasic taxonomy results support that strain NW10T represents a novel species of the genus Sulfurimonas, and named as Sulfurimonas hydrogeniphila sp. nov. Genome analyses revealed its diverse energy metabolisms driving carbon fixation via rTCA cycling, including pathways of sulfur/hydrogen oxidation, coupled oxygen/sulfur respiration and denitrification. Comparative analysis of the 11 available genomes from Sulfurimonas species revealed that vent bacteria, compared to marine non-vent strains, possess unique genes encoding Type V Sqr, Group II, and Coo hydrogenase, and are selectively enriched in genes related to signal transduction and inorganic ion transporters. These phenotypic and genotypic features of vent Sulfurimonas may explain their thriving in hydrothermal environments and help to understand the ecological role of Sulfurimonas bacteria in hydrothermal ecosystems.
Effects of Citric Acid and Lactobacillus plantarum on Silage Quality and Bacterial Diversity of King Grass Silage
Authors: Zi Xuejuan , Li Mao , Chen Yeyuan , Lv Renlong , Zhou Hanlin , Tang Jun
Published: February 2021

To better understand the mechanism underlying the citric acid (CA)-regulated silage fermentation, we investigated the bacterial community and fermentation quality of king grass (KG) ensiled without (CK) or with Lactobacillus plantarum (L), CA and the combination of L and CA (CAL). The bacterial community was characterized by using the 16Sr DNA sequencing technology. The L and CA treatments altered the silage bacterial community of KG, showing reduced bacterial diversity, while the abundance of desirable genus Lactobacillus was increased, and the abundances of undesirable genus Dysgonomonas and Pseudomonas were decreased. The additives also significantly raised the lactic acid content, dropped the pH, and reduced the contents of acetic acid, propionic acid, and ammonia-N in ensiled KG (P < 0.01). Besides, the combination treatment was more effective on silage fermentation with the highest pH and lactic acid content, while the contents of acetic acid, propionic acid, and ammonia-N were the lowest (P < 0.01). Moreover, CAL treatment exerted a notable influence on the bacterial community, with the lowest operational taxonomic unit (OTU) number and highest abundance of Lactobacillus. Furthermore, the bacterial community was significantly correlated with fermentation characteristics. These results proved that L and CA enhanced the KG silage quality, and the combination had a beneficial synergistic effect.
Characterizing Hydropathy of Amino Acid Side Chain in a Protein Environment by Investigating the Structural Changes of Water Molecules Network
Authors: Di Rienzo Lorenzo , Miotto Mattia , Bò Leonardo , Ruocco Giancarlo , Raimondo Domenico , Milanetti Edoardo
Published: February 2021

Assessing the hydropathy properties of molecules, like proteins and chemical compounds, has a crucial role in many fields of computational biology, such as drug design, biomolecular interaction, and folding prediction. Over the past decades, many descriptors were devised to evaluate the hydrophobicity of side chains. In this field, recently we likewise have developed a computational method, based on molecular dynamics data, for the investigation of the hydrophilicity and hydrophobicity features of the 20 natural amino acids, analyzing the changes occurring in the hydrogen bond network of water molecules surrounding each given compound. The local environment of each residue is complex and depends on the chemical nature of the side chain and the location in the protein. Here, we characterize the solvation properties of each amino acid side chain in the protein environment by considering its spatial reorganization in the protein local structure, so that the computational evaluation of differences in terms of hydropathy profiles in different structural and dynamical conditions can be brought to bear. A set of atomistic molecular dynamics simulations have been used to characterize the dynamic hydrogen bond network at the interface between protein and solvent, from which we map out the local hydrophobicity and hydrophilicity of amino acid residues.
Apolipoprotein E ε4 Allele-Based Differences in Brain Volumes Are Largely Uniform Across Late Middle Aged and Older Hispanic/Latino- and Non-Hispanic/Latino Whites Without Dementia
Authors: Stickel Ariana M. , McKinnon Andrew C. , Matijevic Stephanie , Grilli Matthew D. , Ruiz John , Ryan Lee
Published: February 2021

Hispanics/Latinos are at an equal or a greater risk for Alzheimer's disease (AD), yet risk factors remain more poorly characterized as compared to non-Hispanic/Latino Whites. Among non-Hispanic/Latino White cohorts, the apolipoprotein E (APOE) ε4 allele is one of the strongest risk factors for AD with subtle declines in episodic memory and brain volumes detectable in the preclinical stages. We examined whether the APOE ε4 status had a differential impact on cognition and brain volumes among cognitively healthy and mild cognitively impaired Hispanics/Latinos (n = 86; ε4 n = 23) compared to a well-matched group of non-Hispanic/Latino Whites (n = 92; ε4 n = 29). Neither the APOE ε4 status nor the interaction between the ε4 status and ethnicity was associated with cognitive performance. The APOE ε4 status was associated with white matter and not with gray matter volumes. APOE ε4 carriers had a significantly smaller total brain white matter volumes, as well as smaller right middle temporal and left superior temporal volumes. The Hispanics/Latinos had significantly smaller left middle frontal gray matter volumes, yet marginally larger overall white matter volumes, than the non-Hispanic/Latino Whites. Exploratory analysis within the Hispanic/Latino sample found that those people whose primary language was Spanish had larger total brain white matter volumes compared primarily to the English speakers. Importantly, primary language differences only held for Hispanic/Latino ε4 carriers and did not differentiate Hispanic/Latino non-carriers, underscoring the need for further investigation into the impacts of language and acculturation on cognitive aging among the fastest growing ethnic minority group in the United States.
Traditional Chinese Medicine Monomers: Novel Strategy for Endogenous Neural Stem Cells Activation After Stroke
Authors: Wang Ju , Hu Jun , Chen Xuezhu , Lei Xuejiao , Feng Hua , Wan Feng , Tan Liang
Published: February 2021

Stem cell therapy, which has become a potential regenerative medical treatment and a promising approach for treating brain injuries induced by different types of cerebrovascular disease, has various application methods. Activation of endogenous neural stem cells (NSCs) can enable infarcted neuron replacement and promote neural networks’ regeneration without the technical and ethical issues associated with the transplantation of exogenous stem cells. Thus, NSC activation can be a feasible strategy to treat central nervous system (CNS) injury. The potential molecular mechanisms of drug therapy for the activation of endogenous NSCs have gradually been revealed by researchers. Traditional Chinese medicine monomers (TCMs) are active components extracted from Chinese herbs, and some of them have demonstrated the potential to activate proliferation and neurogenesis of NSCs in CNS diseases. Ginsenoside Rg1, astragaloside IV (AST), icariin (ICA), salvianolic acid B (Sal B), resveratrol (RES), curcumin, artesunate (ART), and ginkgolide B (GB) have positive effects on NSCs via different signaling pathways and molecules, such as the Wingless/integrated/β-catenin (Wnt/β-catenin) signaling pathway, the sonic hedgehog (Shh) signaling pathway, brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1). This article may provide further motivation for researchers to take advantage of TCMs in studies on CNS injury and stem cell therapy.
Non-vitamin K Oral Anticoagulants and Anti-seizure Medications: A Retrospective Cohort Study
Authors: Ho Chen-Jui , Chen Shih-Hsuan , Lin Chih-Hsiang , Lu Yan-Ting , Hsu Che-Wei , Tsai Meng-Han
Published: February 2021

Purpose: Concerns of drug–drug interactions (DDIs) between anti-seizure medications (ASMs) and non-vitamin K oral anticoagulants (NOACs) have emerged in recent case reports and guidelines. Theoretically, the induction of hepatic cytochrome P450 3A4 (CYP3A4) enzyme and permeability glycoprotein (P-GP) efflux transporter protein systems may reduce the effect of NOACs. We aimed to investigate whether such DDIs are clinically relevant in a real-world situation.

Methods: We retrospectively reviewed 320 ischemic stroke patients with atrial fibrillation (Af) and grouped them according to different potential interactions with CYP3A4 and P-GP. Ischemic stroke events, transient ischemic attack (TIA) events, follow-up duration, baseline characteristics, concomitant ASMs, and stroke risk factors were collected. Statistical analysis included Kaplan–Meier survival curves and the log-rank test.

Results: Overall, 320 ischemic stroke with Af patients received NOACs. Among the NOAC users, 75 also took ASMs, including 56 that have potential DDIs: 43 (13.4%) were categorized as potential CYP and P-GP DDIs and 13 (4.1%) as P-GP-only DDIs. The remaining 264 (82.5%) patients were used as controls including 19 exposed to nonsignificant DDI ASMs and 245 patients without ASM exposure. The incidence rates of recurrent stroke/TIA events in both CYP3A4 and P-GP DDIs, P-GP DDIs only, and no DDIs were 7.5, 2.1, and 8.4/100 person-years, respectively. Kaplan–Meier survival curves and the log-rank test did not show significant differences among the groups.

Conclusions: The recurrent stroke rate of NOAC users with potential DDIs was not higher than in those without potential DDIs in this single-institute study. Our results suggest that theoretical interactions between ASMs and NOACs may not be as severe as previously thought in a real-world situation.
Fast Open-Source Toolkit for Water T2 Mapping in the Presence of Fat From Multi-Echo Spin-Echo Acquisitions for Muscle MRI
Authors: Santini Francesco , Deligianni Xeni , Paoletti Matteo , Solazzo Francesca , Weigel Matthias , de Sousa Paulo Loureiro , Bieri Oliver , Monforte Mauro , Ricci Enzo , Tasca Giorgio , Pichiecchio Anna , Bergsland Niels
Published: February 2021

Imaging has become a valuable tool in the assessment of neuromuscular diseases, and, specifically, quantitative MR imaging provides robust biomarkers for the monitoring of disease progression. Quantitative evaluation of fat infiltration and quantification of the T2 values of the muscular tissue's water component (wT2) are two of the most essential indicators currently used. As each voxel of the image can contain both water and fat, a two-component model for the estimation of wT2 must be used. In this work, we present a fast method for reconstructing wT2 maps obtained from conventional multi-echo spin-echo (MESE) acquisitions and released as Free Open Source Software. The proposed software is capable of fast reconstruction thanks to extended phase graphs (EPG) simulations and dictionary matching implemented on a general-purpose graphic processing unit. The program can also perform more conventional biexponential least-squares fitting of the data and incorporate information from an external water-fat acquisition to increase the accuracy of the results. The method was applied to the scans of four healthy volunteers and five subjects suffering from facioscapulohumeral muscular dystrophy (FSHD). Conventional multi-slice MESE acquisitions were performed with 17 echoes, and additionally, a 6-echo multi-echo gradient-echo (MEGE) sequence was used for an independent fat fraction calculation. The proposed reconstruction software was applied on the full datasets, and additionally to reduced number of echoes, respectively, to 8, 5, and 3, using EPG and biexponential least-squares fitting, with and without incorporating information from the MEGE acquisition. The incorporation of external fat fraction maps increased the robustness of the fitting with a reduced number of echoes per datasets, whereas with unconstrained fitting, the total of 17 echoes was necessary to retain an independence of wT2 from the level of fat infiltration. In conclusion, the proposed software can successfully be used to calculate wT2 maps from conventional MESE acquisition, allowing the usage of an optimized protocol with similar precision and accuracy as a 17-echo acquisition. As it is freely released to the community, it can be used as a reference for more extensive cohort studies.
Muscle Characteristics in Pediatric Hereditary Spastic Paraplegia vs. Bilateral Spastic Cerebral Palsy: An Exploratory Study
Authors: De Beukelaer Nathalie , Bar-On Lynn , Hanssen Britta , Peeters Nicky , Prinsen Sandra , Ortibus Els , Desloovere Kaat , Van Campenhout Anja
Published: February 2021

Hereditary spastic paraplegia (HSP) is a neurological, genetic disorder that predominantly presents with lower limb spasticity and muscle weakness. Pediatric pure HSP types with infancy or childhood symptom onset resemble in clinical presentation to children with bilateral spastic cerebral palsy (SCP). Hence, treatment approaches in these patient groups are analogous. Altered muscle characteristics, including reduced medial gastrocnemius (MG) muscle growth and hyperreflexia have been quantified in children with SCP, using 3D-freehand ultrasound (3DfUS) and instrumented assessments of hyperreflexia, respectively. However, these muscle data have not yet been studied in children with HSP. Therefore, we aimed to explore these MG muscle characteristics in HSP and to test the hypothesis that these data differ from those of children with SCP and typically developing (TD) children. A total of 41 children were retrospectively enrolled including (1) nine children with HSP (ages of 9–17 years with gross motor function levels I and II), (2) 17 age-and severity-matched SCP children, and (3) 15 age-matched typically developing children (TD). Clinically, children with HSP showed significantly increased presence and severity of ankle clonus compared with SCP (p = 0.009). Compared with TD, both HSP and SCP had significantly smaller MG muscle volume normalized to body mass (p ≤ 0.001). Hyperreflexia did not significantly differ between the HSP and SCP group. In addition to the observed pathological muscle activity for both the low-velocity and the change in high-velocity and low-velocity stretches in the two groups, children with HSP tended to present higher muscle activity in response to increased stretch velocity compared with those with SCP. This exploratory study is the first to reveal MG muscle volume deficits in children with HSP. Moreover, high-velocity-dependent hyperreflexia and ankle clonus is observed in children with HSP. Instrumented impairment assessments suggested similar altered MG muscle characteristics in pure HSP type with pediatric onset compared to bilateral SCP. This finding needs to be confirmed in larger sample sizes. Hence, the study results might indicate analogous treatment approaches in these two patient groups.
Effects of Emotional Stimulations on the Online Operation of a P300-Based Brain–Computer Interface
Authors: Kim Minju , Kim Jongsu , Heo Dojin , Choi Yunjoo , Lee Taejun , Kim Sung-Phil
Published: February 2021

Using P300-based brain–computer interfaces (BCIs) in daily life should take into account the user’s emotional state because various emotional conditions are likely to influence event-related potentials (ERPs) and consequently the performance of P300-based BCIs. This study aimed at investigating whether external emotional stimuli affect the performance of a P300-based BCI, particularly built for controlling home appliances. We presented a set of emotional auditory stimuli to subjects, which had been selected for each subject based on individual valence scores evaluated a priori, while they were controlling an electric light device using a P300-based BCI. There were four conditions regarding the auditory stimuli, including high valence, low valence, noise, and no sound. As a result, subjects controlled the electric light device using the BCI in real time with a mean accuracy of 88.14%. The overall accuracy and P300 features over most EEG channels did not show a significant difference between the four auditory conditions (p > 0.05). When we measured emotional states using frontal alpha asymmetry (FAA) and compared FAA across the auditory conditions, we also found no significant difference (p > 0.05). Our results suggest that there is no clear evidence to support a hypothesis that external emotional stimuli influence the P300-based BCI performance or the P300 features while people are controlling devices using the BCI in real time. This study may provide useful information for those who are concerned with the implementation of a P300-based BCI in practice.
Is Reconsolidation a General Property of Memory?
Authors: Kim Gayoung , Kwon Minjae , Kang Wonjun , Lee Sue-Hyun
Published: February 2021

Memory reconsolidation holds great hope for memory modification approaches and clinical treatments of mental disorders associated with maladaptive memories. However, it remains controversial as to whether reconsolidation is a general property of all types of memory. Especially, discrepancies have been reported in research focusing on whether declarative memory undergoes reconsolidation, and whether old memories can be reorganized after retrieval. Here, we discuss how these inconsistent results can be reconciled and what information we need to uncover for the general use of reconsolidation.
Beta Electroencephalographic Oscillation Is a Potential GABAergic Biomarker of Chronic Peripheral Neuropathic Pain
Authors: Teixeira Micael , Mancini Christian , Wicht Corentin Aurèle , Maestretti Gianluca , Kuntzer Thierry , Cazzoli Dario , Mouthon Michael , Annoni Jean-Marie , Chabwine Joelle Nsimire
Published: February 2021

This preliminary investigation aimed to assess beta (β) oscillation, a marker of the brain GABAergic signaling, as a potential objective pain marker, hence contributing at the same time to the mechanistic approach of pain management. This case–control observational study measured β electroencephalographic (EEG) oscillation in 12 right-handed adult male with chronic neuropathic pain and 10 matched controls (∼55 years). Participants were submitted to clinical evaluation (pain visual analog scale, Hospital Anxiety, and Depression scale) and a 24-min high-density EEG recording (BIOSEMI). Data were analyzed using the EEGlab toolbox (MATLAB), SPSS, and R. The global power spectrum computed within the low (Lβ, 13–20 Hz) and the high (Hβ, 20–30 Hz) β frequency sub-bands was significantly lower in patients than in controls, and accordingly, Lβ was negatively correlated to the pain visual analog scale (R = −0.931, p = 0.007), whereas Hβ correlation was at the edge of significance (R = −0.805; p = 0.053). Patients’ anxiety was correlated to pain intensity (R = 0.755; p = 0.003). Normalization of the low and high β global power spectrum (GPS) to the GPS of the full frequency range, while confirming the significant Lβ power decrease in chronic neuropathic pain patients, vanished the significance of the Hβ decrease, as well as the correlation between Lβ power and pain intensity. Our results suggest that the GABAergic Lβ EEG oscillation is affected by chronic neuropathic pain. Confirming the Lβ GPS decrease and the correlation with pain intensity in larger studies would open new opportunities for the clinical application of gamma-aminobutyric acid-modifying therapies.
Neuromodulation of the Pudendal Nerve Assisted by 3D Printed: A New Method of Neuromodulation for Lower Urinary Tract Dysfunction
Authors: Gu Yinjun , Lv Tingting , Jiang Chen , Lv Jianwei
Published: February 2021

Electrical stimulation of peripheral nerves by implanted electrodes is an effective treatment for certain pelvic floor diseases. As well as intravesical electrical stimulation, this predominantly includes stimulation of the sacral nerve, tibial nerve, and pudendal nerve. The pudendal nerve is one of the main nerves that stimulate pelvic floor muscles, external urethral meatus, and the anal sphincter and pelvic organs, and it may have effects on frequent urination, urgency, dysuria, and perineal pain. It is difficult to locate because of its anatomical course, however, leading to difficulties fixing the electrode, which increases the difficulty of pudendal nerve electrical stimulation in clinical practice. In the current study 3D printed navigation was used to solve these problems. Combined with autopsy data and patient pelvic and nerve data, a personalized design was generated. Neural modulation of the pudendal nerve was achieved by implanting the lead with the guidance of 3D printed navigation. 3D printed navigation can maximize the phase II conversion rate, reduce the difficulty of surgery, shorten the operation time, reduce damage to additional organs and blood vessels, and increase the accuracy of electrode implantation, and it can be performed while the patient is awake. It is an accurate, reversible, efficient, and minimally invasive surgery.
Integration of Nutrient Sensing in Fish Hypothalamus
Authors: Soengas José L.
Published: February 2021

The knowledge regarding hypothalamic integration of metabolic and endocrine signaling resulting in regulation of food intake is scarce in fish. Available studies pointed to a network in which the activation of the nutrient-sensing (glucose, fatty acid, and amino acid) systems would result in AMP-activated protein kinase (AMPK) inhibition and activation of protein kinase B (Akt) and mechanistic target of rapamycin (mTOR). Changes in these signaling pathways would control phosphorylation of transcription factors cAMP response-element binding protein (CREB), forkhead box01 (FoxO1), and brain homeobox transcription factor (BSX) leading to food intake inhibition through changes in the expression of neuropeptide Y (NPY), agouti-related peptide (AgRP), pro-opio melanocortin (POMC), and cocaine and amphetamine-related transcript (CART). The present mini-review summarizes information on the topic and identifies gaps for future research.
Physical and Chemical Interplay Between the Membrane and a Prototypical Potassium Channel Reconstituted on a Lipid Bilayer Platform
Authors: Iwamoto Masayuki , Oiki Shigetoshi
Published: February 2021

Once membrane potential changes or ligand binding activates the ion channel, the activity of the channel is finely modulated by the fluctuating membrane environment, involving local lipid composition and membrane tension. In the age of post-structural biology, the factors in the membrane that affect the ion channel function and how they affect it are a central concern among ion channel researchers. This review presents our strategies for elucidating the molecular mechanism of membrane effects on ion channel activity. The membrane’s diverse and intricate effects consist of chemical and physical processes. These elements can be quantified separately using lipid bilayer methods, in which a membrane is reconstructed only from the components of interest. In our advanced lipid bilayer platform (contact bubble bilayer, CBB), physical features of the membrane, such as tension, are freely controlled. We have elucidated how the specific lipid or membrane tension modulates the gating of a prototypical potassium channel, KcsA, embedded in the lipid bilayer. Our results reveal the molecular mechanism of the channel for sensing and responding to the membrane environment.