bluuebunny/crossref_metadata_2025 huggingface dataset:
Epstein-Barr Functional Mimicry: Pathogenicity of Oncogenic Latent Membrane Protein-1 in Systemic Lupus Erythematosus and Autoimmunity
Authors: Munroe Melissa E. , Anderson Jourdan R. , Gross Timothy F. , Stunz Laura L. , Bishop Gail A. , James Judith A.
Published: February 2021

Systemic lupus erythematosus (SLE) and other autoimmune diseases are propelled by immune dysregulation and pathogenic, disease-specific autoantibodies. Autoimmunity against the lupus autoantigen Sm is associated with cross-reactivity to Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1). Additionally, EBV latent membrane protein-1 (LMP1), initially noted for its oncogenic activity, is an aberrantly active functional mimic of the B cell co-stimulatory molecule CD40. Mice expressing a transgene (Tg) for the mCD40-LMP1 hybrid molecule (containing the cytoplasmic tail of LMP1) have mild autoantibody production and other features of immune dysregulation by 2–3 months of age, but no overt autoimmune disease. This study evaluates whether exposure to the EBV molecular mimic, EBNA-1, stimulates antigen-specific and concurrently-reactive humoral and cellular immunity, as well as lupus-like features. After immunization with EBNA-1, mCD40-LMP1 Tg mice exhibited enhanced, antigen-specific, cellular and humoral responses compared to immunized WT congenic mice. EBNA-1 specific proliferative and inflammatory cytokine responses, including IL-17 and IFN-γ, were significantly increased (p<0.0001) in mCD40-LMP1 Tg mice, as well as antibody responses to amino- and carboxy-domains of EBNA-1. Of particular interest was the ability of mCD40-LMP1 to drive EBNA-1 associated molecular mimicry with the lupus-associated autoantigen, Sm. EBNA-1 immunized mCD40-LMP1 Tg mice exhibited enhanced proliferative and cytokine cellular responses (p<0.0001) to the EBNA-1 homologous epitope PPPGRRP and the Sm B/B’ cross-reactive sequence PPPGMRPP. When immunized with the SLE autoantigen Sm, mCD40-LMP1 Tg mice again exhibited enhanced cellular and humoral immune responses to both Sm and EBNA-1. Cellular immune dysregulation with EBNA-1 immunization in mCD40-LMP1 Tg mice was accompanied by enhanced splenomegaly, increased serum blood urea nitrogen (BUN) and creatinine levels, and elevated anti-dsDNA and antinuclear antibody (ANA) levels (p<0.0001compared to mCD40 WT mice). However, no evidence of immune-complex glomerulonephritis pathology was noted, suggesting that a combination of EBV and genetic factors may be required to drive lupus-associated renal disease. These data support that the expression of LMP1 in the context of EBNA-1 may interact to increase immune dysregulation that leads to pathogenic, autoantigen-specific lupus inflammation.
Abdominal Aortic Aneurysm: Roles of Inflammatory Cells
Authors: Yuan Zhen , Lu Yi , Wei Jia , Wu Jiaqi , Yang Jin , Cai Zhejun
Published: February 2021

Abdominal aortic aneurysms (AAAs) are local dilations of infrarenal segment of aortas. Molecular mechanisms underlying the pathogenesis of AAA remain not fully clear. However, inflammation has been considered as a central player in the development of AAA. In the past few decades, studies demonstrated a host of inflammatory cells, including T cells, macrophages, dendritic cells, neutrophils, B cells, and mast cells, etc. infiltrating into aortic walls, which implicated their crucial roles. In addition to direct cell contacts and cytokine or protease secretions, special structures like inflammasomes and neutrophil extracellular traps have been investigated to explore their functions in aneurysm formation. The above-mentioned inflammatory cells and associated structures may initiate and promote AAA expansion. Understanding their impacts and interaction networks formation is meaningful to develop new strategies of screening and pharmacological interventions for AAA. In this review, we aim to discuss the roles and mechanisms of these inflammatory cells in AAA pathogenesis.
Antibody Responses to Crude Gametocyte Extract Predict Plasmodium falciparum Gametocyte Carriage in Kenya
Authors: Omondi Brian R. , Muthui Michelle K. , Muasya William I. , Orindi Benedict , Mwakubambanya Ramadhan S. , Bousema Teun , Drakeley Chris , Marsh Kevin , Bejon Philip , Kapulu Melissa C.
Published: February 2021

Background

Malaria caused by Plasmodium falciparum remains a serious global public health challenge especially in Africa. Interventions that aim to reduce malaria transmission by targeting the gametocyte reservoir are key to malaria elimination and/or eradication. However, factors that are associated with gametocyte carriage have not been fully explored. Consequently, identifying predictors of the infectious reservoir is fundamental in the elimination campaign.

Methods

We cultured P. falciparum NF54 gametocytes (to stage V) and prepared crude gametocyte extract. Samples from a total of 687 participants (aged 6 months to 67 years) representing two cross-sectional study cohorts in Kilifi, Kenya were used to assess IgG antibody responses by ELISA. We also analyzed IgG antibody responses to the blood-stage antigen AMA1 as a marker of asexual parasite exposure. Gametocytemia and asexual parasitemia data quantified by microscopy and molecular detection (QT-NASBA) were used to determine the relationship with antibody responses, season, age, and transmission setting. Multivariable logistic regression models were used to study the association between antibody responses and gametocyte carriage. The predictive power of the models was tested using the receiver operating characteristic (ROC) curve.

Results

Multivariable logistic regression analysis showed that IgG antibody response to crude gametocyte extract predicted both microscopic (OR=1.81 95% CI: 1.06–3.07, p=0.028) and molecular (OR=1.91, 95% CI: 1.11–3.29, p=0.019) P. falciparum gametocyte carriage. Antibody responses to AMA1 were also associated with both microscopic (OR=1.61 95% CI: 1.08–2.42, p=0.020) and molecular (OR=3.73 95% CI: 2.03–6.74, p<0.001) gametocytemia. ROC analysis showed that molecular (AUC=0.897, 95% CI: 0.868–0.926) and microscopic (AUC=0.812, 95% CI: 0.758–0.865) multivariable models adjusted for gametocyte extract showed very high predictive power. Molecular (AUC=0.917, 95% CI: 0.891–0.943) and microscopic (AUC=0.806, 95% CI: 0.755–0.858) multivariable models adjusted for AMA1 were equally highly predictive.

Conclusion

In our study, it appears that IgG responses to crude gametocyte extract are not an independent predictor of gametocyte carriage after adjusting for AMA1 responses but may predict gametocyte carriage as a proxy marker of exposure to parasites. Serological responses to AMA1 or to gametocyte extract may facilitate identification of individuals within populations who contribute to malaria transmission and support implementation of transmission-blocking interventions.
Pathophysiology of Skin Resident Memory T Cells
Authors: Tokura Yoshiki , Phadungsaksawasdi Pawit , Kurihara Kazuo , Fujiyama Toshiharu , Honda Tetsuya
Published: February 2021

Tissue resident memory T (TRM) cells reside in peripheral, non-lymphoid tissues such as the skin, where they act as alarm-sensor cells or cytotoxic cells. Physiologically, skin TRMcells persist for a long term and can be reactivated upon reinfection with the same antigen, thus serving as peripheral sentinels in the immune surveillance network. CD8+CD69+CD103+ TRM cells are the well-characterized subtype that develops in the epidermis. The local mediators such as interleukin (IL)-15 and transforming growth factor (TGF)-β are required for the formation of long-lived TRMcell population in skin. Skin TRM cells engage virus-infected cells, proliferatein situin response to local antigens and do not migrate out of the epidermis. Secondary TRM cell populations are derived from pre-existing TRM cells and newly recruited TRMprecursors from the circulation. In addition to microbial pathogens, topical application of chemical allergen to skin causes delayed-type hypersensitivity and amplifies the number of antigen-specific CD8+ TRM cells at challenged site. Skin TRMcells are also involved in the pathological conditions, including vitiligo, psoriasis, fixed drug eruption and cutaneous T-cell lymphoma (CTCL). The functions of these TRMcells seem to be different, depending on each pathology. Psoriasis plaques are seen in a recurrent manner especially at the originally affected sites. Upon stimulation of the skin of psoriasis patients, the CD8+CD103+CD49a-TRMcells in the epidermis seem to be reactivated and initiate IL-17A production. Meanwhile, autoreactive CD8+CD103+CD49a+TRM cells secreting interferon-γ are present in lesional vitiligo skin. Fixed drug eruption is another disease where skin TRMcells evoke its characteristic clinical appearance upon administration of a causative drug. Intraepidermal CD8+TRMcells with an effector-memory phenotype resident in the skin lesions of fixed drug eruption play a major contributing role in the development of localized tissue damage. CTCL develops primarily in the skin by a clonal expansion of a transformed TRMcells. CD8+CTCL with the pagetoid epidermotropic histology is considered to originate from epidermal CD8+TRMcells. This review will discuss the current understanding of skin TRMbiology and their contribution to skin homeostasis and diseases.
An Immunological Perspective: What Happened to Pregnant Women After Recovering From COVID-19?
Authors: Zhao Sijia , Xie Ting , Shen Li , Liu Hong , Wang Liling , Ma Xixiang , Wu Jianli , Yuan Shuiqiao , Mor Gil , Liao Aihua
Published: February 2021

The coronavirus disease 2019 (COVID-19) pandemic has been raging around the world since January 2020. Pregnancy places the women in a unique immune scenario which may allow severe COVID‐19 disease. In this regard, the potential unknown effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on mothers and fetuses have attracted considerable attention. There is no clear consistent evidence of the changes in the immune status of pregnant women after recovery from COVID-19. In this study, we use multiparameter flow cytometry and Luminex assay to determine the immune cell subsets and cytokines, respectively, in the peripheral blood and umbilical cord blood from pregnant women recovering from COVID-19 about 3 months (n=5). Our results showed decreased percentages of Tc2, Tfh17, memory B cells, virus-specific NK cells, and increased percentages of naive B cells in the peripheral blood. Serum levels of IL-1ra and MCP-1 showed a decreased tendency in late recovery stage (LRS) patients. Meanwhile, there was no significant difference in immune cell subsets in the umbilical cord blood. The placentas from LRS patients showed increased CD68+ macrophages infiltration and mild hypoxic features. The inflammatory damage of the placenta may be related to the antiviral response. Since the receptors, ACE2 and TMPRSS2, utilized by SARS-CoV-2 are not co-expressed in the placenta, so it is extremely rare for SARS-CoV-2 to cause infection through this route and the impact on the fetus is negligible.
Microscopic and Genetic Characterization of Bacterial Symbionts With Bioluminescent Potential in Pyrosoma atlanticum
Authors: Berger Alexis , Blackwelder Patricia , Frank Tamara , Sutton Tracey T. , Pruzinsky Nina M. , Slayden Natalie , Lopez Jose V.
Published: February 2021

The pelagic tunicate pyrosome,Pyrosoma atlanticum, is known for its brilliant bioluminescence, but the mechanism causing this bioluminescence has not been fully characterized. This study identifies the bacterial bioluminescent symbionts ofP. atlanticumcollected in the northern Gulf of Mexico using several methods such as light and electron microscopy, as well as molecular genetics. The bacteria are localized within the pyrosome light organs. Greater than 50% of the bacterial taxa present in the tunicate samples were the bioluminescent symbiotic bacteria Vibrionaceae as determined by utilizing current molecular genetics methodologies. A total of 396K MiSeq16S rRNA reads provided total pyrosome microbiome profiles to determine bacterial symbiont taxonomy. After comparing with the Silva rRNA database, aPhotobacteriumsp. r33-like bacterium (which we refer to as “PhotobacteriumPa-1”) matched at 99% sequence identity as the most abundant bacteria withinPyrosoma atlanticumsamples. Specifically designed 16S rRNA V4 probes for fluorescencein situhybridization (FISH) verified thePhotobacteriumPa-1 location as internally concentrated along the periphery of each dual pyrosome luminous organ. While searching for bacterialluxgenes in two tunicate samples, we also serendipitously generated a draft tunicate mitochondrial genome that can be used forPyrosoma atlanticumidentification. Scanning (SEM) and transmission (TEM) electron microscopy confirmed the presence of intracellular rod-like bacteria in the light organs. This intracellular localization of bacteria may represent bacteriocyte formation reminiscent of other invertebrates.
Bottom–Up Impacts of Forecasted Climate Change on the Eastern Bering Sea Food Web
Authors: Whitehouse George A. , Aydin Kerim Y. , Hollowed Anne B. , Holsman Kirstin K. , Cheng Wei , Faig Amanda , Haynie Alan C. , Hermann Albert J. , Kearney Kelly A. , Punt André E. , Essington Timothy E.
Published: February 2021

Recent observations of record low winter sea-ice coverage and warming water temperatures in the eastern Bering Sea have signaled the potential impacts of climate change on this ecosystem, which have implications for commercial fisheries production. We investigate the impacts of forecasted climate change on the eastern Bering Sea food web through the end of the century under medium- and high-emissions climate scenarios in combination with a selection of fisheries management strategies by conducting simulations using a dynamic food web model. The outputs from three global earth system models run under two greenhouse gas emission scenarios were dynamically downscaled using a regional ocean and biogeochemical model to project ecosystem dynamics at the base of the food web. Four fishing scenarios were explored: status quo, no fishing, and two scenarios that alternatively assume increased fishing emphasis on either gadids or flatfishes. Annual fishery quotas were dynamically simulated by combining harvest control rules based on model-simulated stock biomass, while incorporating social and economic tradeoffs induced by the Bering Sea’s combined groundfish harvest cap. There was little predicted difference between the status quo and no fishing scenario for most managed groundfish species biomasses at the end of the century, regardless of emission scenario. Under the status quo fishing scenario, biomass projections for most species and functional groups across trophic levels showed a slow but steady decline toward the end of the century, and most groups were near or below recent historical (1991–2017) biomass levels by 2080. The bottom–up effects of declines in biomass at lower trophic levels as forecasted by the climate-enhanced lower trophic level modeling, drove the biomass trends at higher trophic levels. By 2080, the biomass projections for species and trophic guilds showed very little difference between emission scenarios. Our method for climate-enhanced food web projections can support fisheries managers by informing strategic guidance on the long-term impacts of ecosystem productivity shifts driven by climate change on commercial species and the food web, and how those impacts may interact with different fisheries management scenarios.
Is Metagenomic Analysis an Effective Way to Analyze Fish Feeding Habits? A Case of the Yellowfin Sea Bream Acanthopagrus latus (Houttuyn) in Daya Bay
Authors: Pan Wanni , Qin Chuanxin , Zuo Tao , Yu Gang , Zhu Wentao , Ma Hongmei , Xi Shigai
Published: February 2021

Yellowfin seabream, Acanthopagrus latus, is one of the most important species in terms of stock enhancement in China. However, using metagenomic techniques to explore the feeding habits and stomach microbiome of yellowfin seabream is still rare. The objective of this work was to study the feeding habits and stomach microbiome of yellowfin sea bream from Daya Bay through metagenomic analysis of different weight classes (≤50, 50–100, and >100 g). Whole-metagenome shotgun sequencing and morphological observation were used to investigate the stomach contents. The dietary composition and the community composition of the stomach microbiome of A. latus were examined. In this study, 153 species were detected in the eukaryotic composition of the stomach contents of yellowfin sea bream. At the species level, Mytilus edulis was the only species identified by both metagenomic analysis and morphological observation. The proportion of fish and bivalves was over 98%, but the diet changed little with body size. Larimichthys crocea, Scophthalmus maximus, and Seriola dumerili were the most abundant species among all samples. In total, 285 species were identified in the stomach microbiome of yellowfin sea bream. Bacterium 2013Ark19i, bacterium 2013Arg42i and Acinetobacter baumannii, first reported in the stomach contents of yellowfin sea bream, were the most abundant species of the stomach microbiomes. There was no difference in the biodiversity of the stomach microbiomes among the different body sizes. Overall, the composition of the yellowfin sea bream diet mainly consists of fish and bivalves. The use of metagenomics techniques is a promising approach for assessing the feeding habits of yellowfin sea bream. The results derived from this study can provide important information for evaluating the feeding ecology of yellowfin sea bream in Daya Bay.
Medicine Shortages: From Assumption to Evidence to Action - A Proposal for Using the FMD Data Repositories for Shortages Monitoring
Authors: Bouvy François , Rotaru Mihai
Published: February 2021

Medicine shortages may negatively impact patient care and the patient experience. Shortages should be a priority of industry, supply chain stakeholders and national competent authorities, and deserve more than empathy or “lip-service” but serious engagement and action. Under the overarching principle that without correct measurements in place there cannot be any improvement in overall performance (1), stakeholders in the pharmaceutical supply chain, notably pharmaceutical manufacturers have made the call for all relevant sources of information to be used in order to provide additional intelligence about the root causes and drivers of shortages, including the identification of bottlenecks in the supply chain. This paper outlines a proposal for using the data stored in the interoperable network of national repositories being set up in the context of the Falsified Medicines Directive (Directive 2011/62/EU) and its Delegated Regulation 2016/161/EU on safety features for providing additional intelligence in monitoring shortages. The paper analyses the potential feasibility and readiness of using this data for monitoring shortages as well as the strengths and weaknesses of the approach. We explore also what are some of the other complementary data sources that could be analyzed in conjunction with the data in the repository system to sharpen the overall analysis. Lastly, we provide a theoretical but concrete use case for using the abovementioned data for better informing decisions to prevent and mitigate shortages. In doing so, we explain the interlink between patient needs at country level, demand from economic actors, intra-EU parallel trade and manufacturer-imposed supply quotas and propose a mechanism for collaboration between national competent authorities and supply chain stakeholders for early detection and action to prevent medicine shortages from occurring.
Induction of Krüppel-Like Factor 4 Mediates Polymorphonuclear Neutrophil Activation in Streptococcus pneumoniae Infection
Authors: Bhattacharyya Aritra , Herta Toni , Conrad Claudia , Frey Doris , García Pedro , Suttorp Norbert , Hippenstiel Stefan , Zahlten Janine
Published: February 2021

The recruitment and activation of polymorphonuclear neutrophils (PMNs) are of central importance for the elimination of pathogens in bacterial infections. We investigated theStreptococcus pneumoniae-dependent induction of the transcription factor Krüppel-like factor (KLF) 4 in PMNs as a potential regulator of PMN activation. We found that KLF4 expression is induced in human blood-derived PMNs in a time- and dose-dependent manner by wild-typeS. pneumoniaeand capsule knockout mutants. Unencapsulated knockout mutants induced stronger KLF4 expression than encapsulated wild types. The presence of autolysin LytA-competent (thus viable) pneumococci and LytA-mediated bacterial autolysis were required for KLF4 induction in human and murine PMNs. LyzMcre-mediated knockdown of KLF4 in murine blood-derived PMNs revealed that KLF4 influences pneumococci killing and increases the release of the proinflammatory cytokines tumor necrosis factor α and keratinocyte chemoattractant and decreases the release of the anti-inflammatory cytokine interleukin-10. Thus,S. pneumoniaeinduces KLF4 expression in PMNs, which contributes to PMN activation inS. pneumoniaeinfection.
Temporal Characteristics of the Oropharyngeal and Nasal Microbiota Structure in Crewmembers Stayed 180 Days in the Controlled Ecological Life Support System
Authors: Chen Yanwu , Xu Chong , Zhong Chongfa , Lyu Zhitang , Liu Junlian , Chen Zhanghuang , Dun Huanhuan , Xin Bingmu , Xie Qiong
Published: February 2021

Confined experiments are carried out to simulate the closed environment of space capsule on the ground. The Chinese Controlled Ecological Life Support System (CELSS) is designed including a closed-loop system supporting 4 healthy volunteers surviving for 180 days, and we aim to reveal the temporal characteristics of the oropharyngeal and nasal microbiota structure in crewmembers stayed 180 days in the CELSS, so as to accumulate the information about microbiota balance associated with respiratory health for estimating health risk in future spaceflight. We investigated the distribution of microorganisms and their dynamic characteristics in the nasal cavity and oropharynx of occupants with prolonged confinement. Based on the 16S rDNA v3–v4 regions using Illumina high-throughput sequencing technology, the oropharyngeal and nasal microbiota were monitored at eight time points during confinement. There were significant differences between oropharyngeal and nasal microbiota, and there were also individual differences among the same site of different volunteers. Analysis on the structure of the microbiota showed that, in the phylum taxon, the nasal bacteria mainly belonged to Actinobacteria, Firmicutes, Proteobacteria, Bacteroidetes, etc. In addition to the above phyla, in oropharyngeal bacteria Fusobacterial accounted for a relatively high proportion. In the genus taxon, the nasal and oropharyngeal bacteria were independent. Corynebacterium and Staphylococcus were dominant in nasal cavity, and Corynebacterium, Streptococcus, and Neisseria were dominant in oropharynx. With the extension of the confinement time, the abundance of Staphylococcus in the nasal cavity and Neisseria in the oropharynx increased, and the index Chao fluctuated greatly from 30 to 90 days after the volunteers entered the CELSS.

Conclusion: The structure and diversity of the nasal and oropharyngeal microbiota changed in the CELSS, and there was the phenomenon of migration between occupants, suggesting that the microbiota structure and health of the respiratory tract could be affected by living in a closed environment for a long time.
Antibacterial Activity of Chrysanthemum buds Crude Extract Against Cronobacter sakazakii and Its Application as a Natural Disinfectant
Authors: Chang Yunhe , Xing Min , Hu Xinying , Feng Hongxia , Wang Yao , Guo Bingrui , Sun Maocheng , Ma Lizhi , Fei Peng
Published: February 2021

Cronobacter sakazakii is an opportunistic food-borne pathogen that endangers the health of neonates and infants. This study aims to elucidate the antibacterial activity and mechanism of Chrysanthemum buds crude extract (CBCE) against C. sakazakii and its application as a natural disinfectant. The antibacterial activity was evaluated by the determination of the diameter of inhibition zone (DIZ), minimum inhibitory concentration (MIC), and minimum bactericide concentration (MBC). The antibacterial mechanism was explored based on the changes of growth curve assay, intracellular ATP concentration, membrane potential, intracellular pH (pHin), content of soluble protein and nucleic acid, and cell morphology. Finally, the inactivation effects of CBCE against C. sakazakii in biofilm on stainless steel tube, tinplate, glass, and polystyrene were evaluated. The results showed that the DIZ, MIC, and MBC of CBCE against C. sakazakii were 14.55 ± 0.44–14.84 ± 0.38 mm, 10 mg/mL, and 20 mg/mL, respectively. In the process of CBCE acting on C. sakazakii, the logarithmic growth phase of the tested bacteria disappeared, and the concentrations of intracellular ATP, pHin, bacterial protein, and nucleic acid were reduced. Meanwhile, CBCE caused the cell membrane depolarization and leakage of cytoplasm of C. sakazakii. In addition, about 6.5 log CFU/mL of viable C. sakazakii in biofilm on stainless steel tube, tinplate, glass, and polystyrene could be inactivated after treatment with 1 MIC of CBCE for 30 min at 25°C. These findings reveal the antibacterial activity and mechanism of CBCE against C. sakazakii and provide a possibility of using a natural disinfectant to kill C. sakazakii in the production environment, packaging materials, and utensils.
Endophytic Bacteria From the Roots of the Medicinal Plant Alkanna tinctoria Tausch (Boraginaceae): Exploration of Plant Growth Promoting Properties and Potential Role in the Production of Plant Secondary Metabolites
Authors: Rat Angélique , Naranjo Henry D. , Krigas Nikos , Grigoriadou Katerina , Maloupa Eleni , Alonso Alicia Varela , Schneider Carolin , Papageorgiou Vassilios P. , Assimopoulou Andreana N. , Tsafantakis Nikolaos , Fokialakis Nikolas , Willems Anne
Published: February 2021

Alkannin and shikonin (A/S) are enantiomeric naphthoquinones produced in the roots of certain plants from the Boraginaceae family such as Lithospermum spp. and Alkanna spp. They possess antimicrobial, anti-tumoral and wound healing properties. The production of secondary metabolites by Alkanna tinctoria might be influenced by its endomicrobiome. To study the interaction between this medicinal plant and its bacterial endophytes, we isolated bacteria from the roots of wild growing Alkanna tinctoria collected near to Athens and Thessaloniki in Greece. Representative strains selected by MALDI-TOF mass spectrometry were identified by partial 16S rRNA gene sequence analysis. In total, 197 distinct phylotypes of endophytic bacteria were detected. The most abundant genera recovered were Pseudomonas, Xanthomonas, Variovorax, Bacillus, Inquilinus, Pantoea, and Stenotrophomonas. Several bacteria were then tested in vitro for their plant growth promoting activity and the production of cell-wall degrading enzymes. Strains of Pseudomonas, Pantoea, Bacillus and Inquilinus showed positive plant growth properties whereas those of Bacteroidetes and Rhizobiaceae showed pectinase and cellulase activity in vitro. In addition, bacterial responses to alkannin and shikonin were investigated through resistance assays. Gram negative bacteria were found to be resistant to the antimicrobial properties of A/S, whereas the Gram positives were sensitive. A selection of bacteria was then tested for the ability to induce A/S production in hairy roots culture of A. tinctoria. Four strains belonging to Chitinophaga sp., Allorhizobium sp., Duganella sp., and Micromonospora sp., resulted in significantly more A/S in the hairy roots than the uninoculated control. As these bacteria can produce cell-wall degrading enzymes, we hypothesize that the A/S induction may be related with the plant-bacteria interaction during colonization.
Local Electric Field Controls Fluorescence Quantum Yield of Red and Far-Red Fluorescent Proteins
Authors: Drobizhev Mikhail , Molina Rosana S. , Callis Patrik R. , Scott J. Nathan , Lambert Gerard G. , Salih Anya , Shaner Nathan C. , Hughes Thomas E.
Published: February 2021

Genetically encoded probes with red-shifted absorption and fluorescence are highly desirable for imaging applications because they can report from deeper tissue layers with lower background and because they provide additional colors for multicolor imaging. Unfortunately, red and especially far-red fluorescent proteins have very low quantum yields, which undermines their other advantages. Elucidating the mechanism of nonradiative relaxation in red fluorescent proteins (RFPs) could help developing ones with higher quantum yields. Here we consider two possible mechanisms of fast nonradiative relaxation of electronic excitation in RFPs. The first, known as the energy gap law, predicts a steep exponential drop of fluorescence quantum yield with a systematic red shift of fluorescence frequency. In this case the relaxation of excitation occurs in the chromophore without any significant changes of its geometry. The second mechanism is related to a twisted intramolecular charge transfer in the excited state, followed by an ultrafast internal conversion. The chromophore twisting can strongly depend on the local electric field because the field can affect the activation energy. We present a spectroscopic method of evaluating local electric fields experienced by the chromophore in the protein environment. The method is based on linear and two-photon absorption spectroscopy, as well as on quantum-mechanically calculated parameters of the isolated chromophore. Using this method, which is substantiated by our molecular dynamics simulations, we obtain the components of electric field in the chromophore plane for seven different RFPs with the same chromophore structure. We find that in five of these RFPs, the nonradiative relaxation rate increases with the strength of the field along the chromophore axis directed from the center of imidazolinone ring to the center of phenolate ring. Furthermore, this rate depends on the corresponding electrostatic energy change (calculated from the known fields and charge displacements), in quantitative agreement with the Marcus theory of charge transfer. This result supports the dominant role of the twisted intramolecular charge transfer mechanism over the energy gap law for most of the studied RFPs. It provides important guidelines of how to shift the absorption wavelength of an RFP to the red, while keeping its brightness reasonably high.
Differential Patterns of Gyral and Sulcal Morphological Changes During Normal Aging Process
Authors: Lin Hsin-Yu , Huang Chu-Chung , Chou Kun-Hsien , Yang Albert C. , Lo Chun-Yi Zac , Tsai Shih-Jen , Lin Ching-Po
Published: February 2021

The cerebral cortex is a highly convoluted structure with distinct morphologic features, namely the gyri and sulci, which are associated with the functional segregation or integration in the human brain. During the lifespan, the brain atrophy that is accompanied by cognitive decline is a well-accepted aging phenotype. However, the detailed patterns of cortical folding change during aging, especially the changing age-dependencies of gyri and sulci, which is essential to brain functioning, remain unclear. In this study, we investigated the morphology of the gyral and sulcal regions from pial and white matter surfaces using MR imaging data of 417 healthy participants across adulthood to old age (21–92 years). To elucidate the age-related changes in the cortical pattern, we fitted cortical thickness and intrinsic curvature of gyri and sulci using the quadratic model to evaluate their age-dependencies during normal aging. Our findings show that comparing to gyri, the sulcal thinning is the most prominent pattern during the aging process, and the gyrification of pial and white matter surfaces were also affected differently, which implies the vulnerability of functional segregation during aging. Taken together, we propose a morphological model of aging that may provide a framework for understanding the mechanisms underlying gray matter degeneration.
Pyramidal Neurons of the Zebrafish Tectum Receive Highly Convergent Input From Torus Longitudinalis
Authors: DeMarco Elisabeth , Tesmer Alexander L. , Hech Bruna , Kawakami Koichi , Robles Estuardo
Published: February 2021

The torus longitudinalis (TL) is a midbrain structure unique to ray finned fish. Although previously implicated in orienting behaviors elicited by changes in ambient lighting, the role of TL in visual processing is not well-understood. TL is reciprocally connected to tectum and is the only known source of synaptic input to the stratum marginalis (SM) layer of tectal neuropil. Conversely, tectal pyramidal neurons (PyrNs) are the only identified tectal neuron population that forms a dendrite in SM. In this study we describe a zebrafish gal4 transgenic that labels TL neurons that project to SM. We demonstrate that the axonal TL projection to SM in zebrafish is glutamatergic. Consistent with these axons synapsing directly onto PyrNs, SM-targeted dendrites of PyrNs contain punctate enrichments of the glutamatergic post-synaptic marker protein PSD95. Sparse genetic labeling of individual TL axons and PyrN dendrites enabled quantitative morphometric analysis that revealed (1) large, sparsely branched TL axons in SM and (2) small, densely innervated PyrN dendrites in SM. Together this unique combination of morphologies support a wiring diagram in which TL inputs to PyrNs exhibit a high degree of convergence. We propose that this convergence functions to generate large, compound visual receptive fields in PyrNs. This quantitative anatomical data will instruct future functional studies aimed at identifying the precise contribution of TL-PyrN circuitry to visual behavior.
A Long-Term Enriched Environment Ameliorates the Accelerated Age-Related Memory Impairment Induced by Gestational Administration of Lipopolysaccharide: Role of Plastic Mitochondrial Quality Control
Authors: Zhuang Zhan-Qiang , Zhang Zhe-Zhe , Zhang Yue-Ming , Ge He-Hua , Sun Shi-Yu , Zhang Ping , Chen Gui-Hai
Published: February 2021

Studies have shown that gestational inflammation accelerates age-related memory impairment in mother mice. An enriched environment (EE) can improve age-related memory impairment, whereas mitochondrial dysfunction has been implicated in the pathogenesis of brain aging. However, it is unclear whether an EE can counteract the accelerated age-related memory impairment induced by gestational inflammation and whether this process is associated with the disruption of mitochondrial quality control (MQC) processes. In this study, CD-1 mice received daily intraperitoneal injections of lipopolysaccharide (LPS, 50 μg/kg) or normal saline (CON group) during gestational days 15–17 and were separated from their offspring at the end of normal lactation. The mothers that received LPS were divided into LPS group and LPS plus EE (LPS-E) treatment groups based on whether the mice were exposed to an EE until the end of the experiment. At 6 and 18 months of age, the Morris water maze test was used to evaluate spatial learning and memory abilities. Quantitative reverse transcription polymerase chain reaction and Western blot were used to measure the messenber RNA (mRNA) and protein levels of MQC-related genes in the hippocampus, respectively. The results showed that all the aged (18 months old) mice underwent a striking decline in spatial learning and memory performances and decreased mRNA/protein levels related to mitochondrial dynamics (Mfn1/Mfn2, OPA1, and Drp1), biogenesis (PGC-1α), and mitophagy (PINK1/parkin) in the hippocampi compared with the young (6 months old) mice. LPS treatment exacerbated the decline in age-related spatial learning and memory and enhanced the reduction in the mRNA and protein levels of MQC-related genes but increased the levels of PGC-1α in young mice. Exposure to an EE could alleviate the accelerated decline in age-related spatial learning and memory abilities and the accelerated changes in MQC-related mRNA or protein levels resulting from LPS treatment, especially in aged mice. In conclusion, long-term exposure to an EE can counteract the accelerated age-related spatial cognition impairment modulated by MQC in CD-1 mother mice that experience inflammation during pregnancy.
Neuroimaging Patterns and Function in Cerebral Palsy—Application of an MRI Classification
Authors: Himmelmann Kate , Horber Veronka , Sellier Elodie , De la Cruz Javier , Papavasiliou Antigone , Krägeloh-Mann Ingeborg ,   The Surveillance of Cerebral Palsy in Europe (SCPE) Collaboration
Published: February 2021

Background: Cerebral palsy (CP) is a disorder of movement and posture and every child with CP has a unique composition of neurological symptoms, motor severity, and associated impairments, constituting the functional profile. Although not part of the CP definition, magnetic resonance imaging (MRI) sheds light on the localization, nature, and severity of brain compromise. The MRI classification system (MRICS), developed by the Surveillance of Cerebral Palsy in Europe (SCPE), describes typical MRI patterns associated with specific timing of vulnerability in different areas of the brain. The classification has proven to be reliable and easy to use.

Aims: The aim of this study is to apply the MRICS on a large dataset and describe the functional profile associated with the different MRI patterns of the MRICS.

Materials and Methods: Data on children with CP born in 1999–2009 with a post-neonatal MRI from 20 European registers in the JRC-SCPE Central Registry was included. The CP classification and the MRICS was applied, and The Gross Motor Function Classification (GMFCS) and the Bimanual Fine Motor Function (BFMF) classification were used. The following associated impairments were documented: intellectual impairment, active epilepsy, visual impairment, and hearing impairment. An impairment index was used to characterize severity of impairment load.

Results: The study included 3,818 children with post-neonatal MRI. Distribution of CP type, motor, and associated impairments differed by neuroimaging patterns. Functional profiles associated with neuroimaging patterns were described, and the impairment index showed that bilateral findings were associated with a more severe outcome both regarding motor impairment and associated impairments than unilateral compromise. The results from this study, particularly the differences in functional severity regarding uni- and bilateral brain compromise, may support counseling and service planning of support of children with CP.
Case Report: Findings Suggestive of Paraclinical Progressive Multifocal Leukoencephalopathy and Lung Cancer-Derived Brain Metastases in an MS Patient Treated With Fingolimod
Authors: Maass Fabian , von Gottberg Philipp , Franz Jonas , Stadelmann Christine , Bähr Mathias , Weber Martin S.
Published: February 2021

Fingolimod represents a highly effective disease-modifying drug in patients with active relapsing-remitting multiple sclerosis (RRMS). Its immunosuppressive effects can mediate adverse events like increased risk of cancer development or appearance of opportunistic infections. Progressive multifocal leukoencephalopathy (PML)–representing a severe opportunistic infection–has been only infrequently described during Fingolimod treatment. Here, we present a case of a 63-year-old women with pre-diagnosed RRMS who presented with new multiple cerebral lesions in a routine MRI scan, also including a tumefactive lesion in the left parietal lobe, eventually leading to the diagnosis of brain metastases derived by an adenocarcinoma of the lung. Additionally, a JCV-DNA-PCR in the cerebrospinal fluid revealed positive results, corresponding to a paraclinical progressive multifocal leukoencephalopathy. In conclusion, adverse events potentially associated with immunosuppression can occur during Fingolimod treatment. In this context, the occurrence of cancer and opportunistic infections should be carefully monitored. Here, we report a case in which JCV-DNA-PCR in the cerebrospinal fluid suggests asymptomatic PML and simultaneously lung cancer brain metastases developed. While it is rather unlikely that either event occurred as an adverse event of fingolimod treatment, a contributing effect cannot be formally excluded.
Case Report: Neuropsychological Findings in IgLON5 Antibody Disorder
Authors: El Shazly Jasmin , Juenemann Martin , Gerriets Tibo , Tschernatsch Marlene
Published: February 2021

IgLON5 antibody encephalopathy is a rare but increasingly recognized disorder with a variety of clinical signs. Typical symptoms are sleep disorder, gait disturbances, signs of bulbar dysfunction and a variety of neurological symptoms like oculomotor abnormalities and movement disorders. In addition, cognitive decline can be a prominent symptom. So far, there are only a few studies that have dealt with the course and possible treatment options of IgLON5 antibody encephalopathy. In this study the clinical case of a female patient with IgLON5 antibody disease and the response to treatment is described. Here we report on the case of a 67-year-old female patient who showed cognitive deterioration, gait difficulties, and chronic obstructive sleep disorder. The diagnostic course showed a positive anti-IgLON5 serum and anti-IgLON5 IgG antibodies in cerebrospinal fluid. The patient was subsequently treated with high dosage i.v. methylprednisolone, i.v. immunoglobulins and plasmapheresis. Neuropsychological tests showed cognitive deficits in different domains, including verbal and visual memory. Both, neuropsychological deficits and antibody titer, showed an improvement after plasmapheresis. The presented case shows that IgLON5 disease can present with rapidly progressing cognitive deterioration as the prominent symptom, adding to the variety of clinical signs in this disorder. Testing for IgLON5-antibodies should be considered in patients with progressing cognitive decline, especially if accompanied by sleep disorders or neurological symptoms like oculomotor abnormalities, dysautonomia or bulbar signs.
Functional Effects of Bilateral Dorsolateral Prefrontal Cortex Modulation During Sequential Decision-Making: A Functional Near-Infrared Spectroscopy Study With Offline Transcranial Direct Current Stimulation
Authors: Schommartz Iryna , Dix Annika , Passow Susanne , Li Shu-Chen
Published: February 2021

The ability to learn sequential contingencies of actions for predicting future outcomes is indispensable for flexible behavior in many daily decision-making contexts. It remains open whether such ability may be enhanced by transcranial direct current stimulation (tDCS). The present study combined tDCS with functional near-infrared spectroscopy (fNIRS) to investigate potential tDCS-induced effects on sequential decision-making and the neural mechanisms underlying such modulations. Offline tDCS and sham stimulation were applied over the left and right dorsolateral prefrontal cortex (dlPFC) in young male adults (N = 29, mean age = 23.4 years, SD = 3.2) in a double-blind between-subject design using a three-state Markov decision task. The results showed (i) an enhanced dlPFC hemodynamic response during the acquisition of sequential state transitions that is consistent with the findings from a previous functional magnetic resonance imaging (fMRI) study; (ii) a tDCS-induced increase of the hemodynamic response in the dlPFC, but without accompanying performance-enhancing effects at the behavioral level; and (iii) a greater tDCS-induced upregulation of hemodynamic responses in the delayed reward condition that seems to be associated with faster decision speed. Taken together, these findings provide empirical evidence for fNIRS as a suitable method for investigating hemodynamic correlates of sequential decision-making as well as functional brain correlates underlying tDCS-induced modulation. Future research with larger sample sizes for carrying out subgroup analysis is necessary in order to decipher interindividual differences in tDCS-induced effects on sequential decision-making process at the behavioral and brain levels.
CRISPR-dCas9-Based Artificial Transcription Factors to Improve Efficacy of Cancer Treatment With Drug Repurposing: Proposal for Future Research
Authors: Martinez-Escobar Alejandro , Luna-Callejas Benjamín , Ramón-Gallegos Eva
Published: February 2021

Due to the high resistance that cancer has shown to conventional therapies, it is difficult to treat this disease, particularly in advanced stages. In recent decades, treatments have been improved, being more specific according to the characteristics of the tumor, becoming more effective, less toxic, and invasive. Cancer can be treated by the combination of surgery, radiation therapy, and/or drug administration, but therapies based on anticancer drugs are the main cancer treatment. Cancer drug development requires long-time preclinical and clinical studies and is not cost-effective. Drug repurposing is an alternative for cancer therapies development since it is faster, safer, easier, cheaper, and repurposed drugs do not have serious side effects. However, cancer is a complex, heterogeneous, and highly dynamic disease with multiple evolving molecular constituents. This tumor heterogeneity causes several resistance mechanisms in cancer therapies, mainly the target mutation. The CRISPR-dCas9-based artificial transcription factors (ATFs) could be used in cancer therapy due to their possibility to manipulate DNA to modify target genes, activate tumor suppressor genes, silence oncogenes, and tumor resistance mechanisms for targeted therapy. In addition, drug repurposing combined with the use of CRISPR-dCas9-based ATFs could be an alternative cancer treatment to reduce cancer mortality. The aim of this review is to describe the potential of the repurposed drugs combined with CRISPR-dCas9-based ATFs to improve the efficacy of cancer treatment, discussing the possible advantages and disadvantages.
Radiotherapy and Immunotherapy for Head and Neck Cancer: Current Evidence and Challenges
Authors: Qian Jack M. , Schoenfeld Jonathan D.
Published: February 2021

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment over the past decade. However, although the immune landscape suggests a strong rationale for the use of these agents in patients with head and neck squamous cell carcinoma, the available clinical evidence indicates that most patients currently do not respond to ICI monotherapy. Radiotherapy is a primary treatment modality for many patients with locally advanced head and neck cancer. While ionizing radiation traditionally has been thought to act in a purely cytotoxic fashion, a growing body of preclinical studies have demonstrated additional profound immunomodulatory effects. Consequently, there has been a surge of interest in the potential synergy between radiotherapy and immunotherapy, both the potential for radiotherapy to augment the systemic anti-tumor immune response and the potential for immunotherapy to improve in-field tumor response to radiation. In this review, we summarize the current preclinical and clinical evidence for radioimmunotherapy, with a particular focus on studies directly relevant to head and neck squamous cell carcinoma, as well as existing challenges and future directions for this emerging field.