bluuebunny/crossref_metadata_2025 huggingface dataset:
My Grandmother Drank the Qur'an: Liquid Readings and Permeable Bodies in Bosnia
Authors: HadžiMuhamedović Safet
Published: April 2021

Starting with a curious childhood memory, the author considers the practices of imbibing – or otherwise transforming and internalising – sacred texts as modes of reading in their own right. At the heart of the argument is a call for a receptive apprehension of reading, open to worlds beyond substance dualism and the detachment of text and meaning residing therein. Kaleidoscopic autobiographical elements merge with and extend through a variety of transmutational, syncretic practices, such as the rituals of ‘erasure’ (e.g. kombe) across the African continent, or the magical inscriptions ( zapisi) and the ritual of ‘horror pouring’ ( salivanje strave) in Bosnia. Water appears as a particularly efficacious agent, flowing between humans and more-than-humans and connecting different bodies, religions, and forms of knowledge. Noticing that the recurring motif of such practices is healing, the author wonders if the drinking of text might be a remedy against the political ontology of inter-corporeal distance. A radically intimate engagement with text, it is suggested, requires the kind of trust that allows for permeability – an always-potential openness, a new sort of liquid critical reading.
Intertext as Countertext in Luther's Romans Lectures
Authors: Waller Giles
Published: April 2021

In his article in this issue of CounterText, Brian Cummings develops an account of Luther as a counter-textual reader, in which ‘iconoclastic philology’ reconfigures the relation between divine and human agency, between grace and works. In response, I offer a fresh reading of the opening pages of Luther's seminal (and once long lost) Lectures on Romans, exploring the ways in which for Luther scriptural intertexts become counter-texts, at once interrupting and illuminating one another and Luther's own interpretations of them. I show that this mode of ‘iconoclastic philology’ unites Luther's method of reading and his theological account of grace, with each structured on a pattern of interruption.
Versions of Darkness: Dante and Eckhart (A Dialogue)
Authors: Kirkpatrick Robin
Published: April 2021

This paper does not offer an argument. Indeed, without calling into question the validity of traditional modes of theological and academic discussion (as in journal abstracts), these pages suggest that verse might encourage participation in a theological action. A trialogue is offered here in which extracts from Dante and Eckart are interspersed with choric passages reflecting the darkness in which the writer of this paper operates. And the reader is invited to join in the hermeneutic choreography.
Fair and Square Redistricting
Authors: Fox James
Published: April 2021

Fair maps are the foundation of a representative democracy. Gerrymanderers wish to create an unrepresentative legislature. The counter to gerrymandering is a fair map where voter lean across districts matches voter lean in the state as a whole. This redistricting criterion was recently codified in the Ohio State Constitution. https://www.legislature.ohio.gov/laws/ohio-constitution/section?const=11.06 The following article demonstrates how to construct such maps. Also included is a Guide which presents an overview of the approach written for citizens, advocates and members of redistricting commissions, as well as legislators and judges. As more people become aware of approaches such as this, more are likely to ask, “Why aren’t we using procedures like this to build maps where the districts are compact and the maps are fair?”
The Blockchain That Was Not: The Case of Four Cooperative Agroecological Supermarkets
Authors: Rocas-Royo Marc
Published: April 2021

Blockchain is a technology with many applications derived from its properties. This article analyzes the case of 4 cooperative agroecological supermarkets and in what circumstances blockchain is an exciting technology to adopt. The analysis of the gathered data reveals 10 factors to consider, 5 internal and 5 external. Those factors derive into 6 blockchain domains to develop. The article concludes that in 3 of them, the drawbacks of implementing the technology, although it is theoretically appropriate, are insuperable. The article contributes to demystifying blockchain technology and applying the same business logic we use with other technical options.
Pomegranate Peel Extract as an Inhibitor of SARS-CoV-2 Spike Binding to Human ACE2 Receptor (in vitro): A Promising Source of Novel Antiviral Drugs
Authors: Tito Annalisa , Colantuono Antonio , Pirone Luciano , Pedone Emilia , Intartaglia Daniela , Giamundo Giuliana , Conte Ivan , Vitaglione Paola , Apone Fabio
Published: April 2021

Plant extracts are rich in bioactive compounds, such as polyphenols, sesquiterpenes, and triterpenes, which potentially have antiviral activities. As a consequence of the coronavirus disease 2019 pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus, thousands of scientists have been working tirelessly trying to understand the biology of this new virus and the disease pathophysiology, with the main goal of discovering effective preventive treatments and therapeutic agents. Plant-derived secondary metabolites may play key roles in preventing and counteracting the rapid spread of SARS-CoV-2 infections by inhibiting the activity of several viral proteins, in particular those involved in the virus entry into the host cells and its replication. Using in vitro approaches, we investigated the role of a pomegranate peel extract (PPE) in attenuating the interaction between the SARS-CoV-2 Spike glycoprotein and the human angiotensin-converting enzyme 2 receptor, and on the activity of the virus 3CL protease. Although further studies will be determinant to assess the efficacy of this extract in vivo, our results opened new promising opportunities to employ natural extracts for the development of effective and innovative therapies in the fight against SARS-CoV-2.
A Solid-State Fluorescence Switch Based on Triphenylethene-Functionalized Dithienylethene With Aggregation-Induced Emission
Authors: Zhang Haining , Hu Xiaoxiao , Zhu Huijuan , Shen Limin , Liu Congmin , Zhang Xiaoman , Gao Xinyu , Li Lingmei , Zhu Yan-Ping , Li Ziyong
Published: April 2021

The development of novel dithienylethene-based fluorescence switches in the aggregated state, and the solid state is highly desirable for potential application in the fields of optoelectronics and photopharmacology. In this contribution, three novel triphenylethene-functionalized dithienylethenes (1–3) have been designed and prepared by appending triphenylethene moieties at one end of dithienylethene unit. Their chemical structures are confirmed by 1H NMR, 13C NMR, and HRMS (ESI). They display good photochromic behaviors with excellent fatigue resistance upon irradiation with UV or visible light in Tetrahydrofuran (THF) solution. Before irradiation with UV light, they exhibit Aggregation Induced Emission (AIE) properties and luminescence behaviors in the solid state. Moreover, upon alternating irradiation with UV/visible light, they display effective fluorescent switching behaviors in the aggregated state and the solid state. The experimental results have been validated by the Density Functional Theory (DFT) calculations. Thus, they can be utilized as novel fluorescence switches integrated in smart, solid-state optoelectronic materials and photopharmacology.
Impact of Polypyrrole Functionalization on the Anodic Performance of Boron Nitride Nanosheets: Insights From First-Principles Calculations
Authors: Nnadiekwe Chidera C. , Abdulazeez Ismail , Haroon Muhammad , Peng Qing , Jalilov Almaz , Al-Saadi Abdulaziz
Published: April 2021

Lithium-ion batteries (LIBs) have displayed superior performance compared to other types of rechargeable batteries. However, the depleting lithium mineral reserve might be the most discouraging setback for the LIBs technological advancements. Alternative materials are thus desirable to salvage these limitations. Herein, we have investigated using first-principles DFT simulations the role of polypyrrole, PP functionalization in improving the anodic performance of boron nitride nanosheet, BNNS-based lithium-ion batteries and extended the same to sodium, beryllium, and magnesium ion batteries. The HOMO-LUMO energy states were stabilized by the PP functional unit, resulting in a significantly reduced energy gap of the BNNS by 45%, improved electronic properties, and cell reaction kinetics. The cell voltage, ΔEcell was predicted to improve upon functionalization with PP, especially for Li-ion (from 1.55 to 2.06 V) and Na-ion (from 1.03 to 1.37 V), the trend of which revealed the influence of the size and the charge on the metal ions in promoting the energy efficiency of the batteries. The present study provides an insight into the role of conducting polymers in improving the energy efficiency of metal-ion batteries and could pave the way for the effective design of highly efficient energy storage materials.
Characterization and Follow-Up of Trypanosoma cruzi Natural Populations Refractory to Etiological Chemotherapy in Oral Chagas Disease Patients
Authors: Muñoz-Calderón Arturo , Díaz-Bello Zoraida , Alarcón de Noya Belkisyolé , Noya-González Oscar O. , Schijman Alejandro G.
Published: April 2021

We aimed to characterize the genetic constitution of natural T. cruzi populations involved in an Oral Chagas Disease (OCD) outbreak at a rural school of the community of Chichiriviche de la Costa, Venezuela, which affected patients did not respond to the etiological treatment. Peripheral blood samples and/or hemocultures were obtained from twenty-nine OCD patients at time of diagnosis or along nine years of Post-treatment (Tx) follow-up. The IgG serology, T. cruzi discrete typing units (DTU), satellite DNA-qPCR parasitic loads, and minicircle signatures were determined at Pre-Tx and after Tx. The serological titles and parasitic loads changed after treatment, with a significant decrease of IgG titers (Spearman’s r value= -0.961) and median parasite loads from 2.869 [IQR = 2.113 to 3.720] to 0.105 [IQR = -1.147 to 1.761] log10 par eq. /mL at Pre-Tx and Post-Tx, respectively, suggesting infection evolution from acute to chronic phase, without seroconversion or parasitological eradication, which was indicative of treatment failure. All patients were infected with T. cruzi DTU I populations. At Pre-Tx their median Jaccard genetic distances were 0.775 [IQR = 0.708 to 0.882], decreasing in genetic variability towards the end of follow-up (Mann-Whitney U test p= 0.0031). Interestingly, no Post-Tx minicircle signature was identical to its Pre-Tx counterpart population in a same patient, revealing selection of parasite subpopulations between the primary infection and Post-Tx. The parasitic populations isolated from hemocultures showed a lower number of bands in the minicircle signatures with respect to the signatures obtained directly from the patients’ blood samples, demonstrating a process of parasitic selection and reduction of the population variability that initially infected the patients. Decrease of parasitic loads after treatment as well as Pre- and Post-Tx intra-TcI diversity might be a consequence of both, natural evolution of the acute infection to the chronic phase and persistence of refractory populations due to Tx selection.
Glutaminolysis: A Driver of Vascular and Cardiac Remodeling in Pulmonary Arterial Hypertension
Authors: Mprah Richard , Adzika Gabriel Komla , Gyasi Yusif I. , Ndzie Noah Marie Louise , Adu-Amankwaah Joseph , Adekunle Adebayo O. , Duah Maxwell , Wowui Prosperl Ivette , Weili Qiao
Published: April 2021

Pulmonary arterial hypertension (PAH) is a decimating ailment described by chronic precapillary pulmonary hypertension, an elevated mean pulmonary arterial pressure with a normal pulmonary capillary wedge pressure, and a raised pulmonary vascular resistance resulting in increased right ventricular afterload culminating in heart failure and death. Current PAH treatments regulate the vasodilatory/vasoconstrictory balance of pulmonary vessels. However, these treatment options are unable to stop the progression of, or reverse, an already established disease. Recent studies have advanced a metabolic dysregulation, featuring increased glutamine metabolism, as a mechanism driving PAH progression. Metabolic dysregulation in PAH leads to increased glutaminolysis to produce substrate to meet the high-energy requirement by hyperproliferative and apoptosis-resistant pulmonary vascular cells. This article explores the role of glutamate metabolism in PAH and how it could be targeted as an anti-remodeling therapeutic strategy.
NP-59 Adrenal Scintigraphy as an Imaging Biomarker to Predict KCNJ5 Mutation in Primary Aldosteronism Patients
Authors: Lu Ching-Chu , Yen Ruoh-Fang , Peng Kang-Yung , Huang Jei-Yie , Wu Kwan-Dun , Chueh Jeff S. , Lin Wan-Yu
Published: April 2021

Purpose

Somatic KCNJ5 mutation occurs in half of unilateral primary aldosteronism (PA) and is associated with more severe phenotype. Mutation status can only be identified by tissue sample from adrenalectomy. NP-59 adrenal scintigraphy is a noninvasive functional study for disease activity assessment. This study aimed to evaluate the predictive value of NP-59 adrenal scintigraphy in somatic KCNJ5 mutation among PA patients who received adrenalectomy.

Methods

Sixty-two PA patients who had NP-59 adrenal scintigraphy before adrenalectomy with available KCNJ5 mutation status were included. Two semiquantitative parameters, adrenal to liver ratio (ALR) and lesion to contralateral ratio of bilateral adrenal glands (CON) derived from NP-59 adrenal scintigraphy, of mutated and wild-type patients were compared. Cutoff values calculated by receiver-operating characteristic (ROC) analysis were used as a predictor of KCNJ5 mutation.

Results

Twenty patients had KCNJ5 mutation and 42 patients were wild type. Patients harboring KCNJ5 mutation had both higher ALR and CON (p = 0.0031 and 0.0833, respectively) than wild-type patients. With ALR and CON cutoff of 2.10 and 1.95, the sensitivity and specificity to predict KCNJ5 mutation were 85%, 57% and 45%, 93%, respectively. Among 20 patients with KCNJ5 mutation, 16 showed G151R point mutation (KCNJ5- G151R) and 4 showed L168R point mutation (KCNJ5-L168R), which former one had significantly lower ALR (p=0.0471).

Conclusion

PA patients harboring somatic KCNJ5 mutation had significantly higher NP-59 uptake regarding to ALR and CON than those without mutation. APAs with KCNJ5-L168R point mutation showed significantly higher ALR than those with KCNJ5-G151R point mutation.
The Characteristics of Northeast China Cold Vortex With Different Active Paths in June and Their Relationship With Precipitation and Pre-SST
Authors: Fang Yi-He , Zhang Meng-Meng , Zhao Chun-Yu , Gong Zhi-Qiang , Zhou Xiao-Yu , Zhang Wei-Qi
Published: April 2021

In this study, a K-means clustering (KMC) method was used to identify the paths of the Northeast China (NEC) Cold Vortex (NCCV). The NCCV was divided into four types according to the identified active paths: (1) Eastward movement type (EM); (2) Southeastward long-distance movement type (SLM); (3) Eastward short-distance movement type (ESM); and (4) Southward short-distance movement type (SSM). The characteristics of the four types of the NCCV, along with their impacts on the precipitation during early summer in NEC, were studied. The results showed that the KMC method can effectively divide the NCCV events into four different types. The maintaining days of these four types of the NCCV were found to have obvious interannual and interdecadal variation features. For example, the maintaining days of the EM and ESM types were mainly characterized by interannual variability, while the SLM and SSM types have the obvious 10–13a interdecadal variation along with interannual variability. In terms of the spatial distributions and impacts on precipitation, the EM type was found to appear in the majority of the areas located in NEC, the SLM type mainly occurred in the northwestern region of NEC and the highest rain center was located in the south-central portion, while the ESM type and SSM type were observed precipitation only appear in a small portion of the northeastern region. In addition, it is also observed the distribution of the sea-surface temperature (SST) anomalies had close relationship with the formation of these four types of the NCCV. The tripole distributions of the SST anomalies in the Atlantic Ocean corresponded to the EM type of the NCCV, the positive anomalies of SST in the eastern equatorial Pacific Ocean and negative anomalies in the western equatorial Pacific corresponded to the SLM type, the positive SSTs in the Northwest Pacific correspond to the ESM type, while negative anomalies SST in the western equatorial Pacific Ocean corresponded to the SSM type of the NCCV.
Multiallelic, Targeted Mutagenesis of Magnesium Chelatase With CRISPR/Cas9 Provides a Rapidly Scorable Phenotype in Highly Polyploid Sugarcane
Authors: Eid Ayman , Mohan Chakravarthi , Sanchez Sara , Wang Duoduo , Altpeter Fredy
Published: April 2021

Genome editing with sequence-specific nucleases, such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), is revolutionizing crop improvement. Developing efficient genome-editing protocols for highly polyploid crops, including sugarcane (x = 10–13), remains challenging due to the high level of genetic redundancy in these plants. Here, we report the efficient multiallelic editing of magnesium chelatase subunit I (MgCh) in sugarcane. Magnesium chelatase is a key enzyme for chlorophyll biosynthesis. CRISPR/Cas9-mediated targeted co-mutagenesis of 49 copies/alleles of magnesium chelatase was confirmed via Sanger sequencing of cloned PCR amplicons. This resulted in severely reduced chlorophyll contents, which was scorable at the time of plant regeneration in the tissue culture. Heat treatment following the delivery of genome editing reagents elevated the editing frequency 2-fold and drastically promoted co-editing of multiple alleles, which proved necessary to create a phenotype that was visibly distinguishable from the wild type. Despite their yellow leaf color, the edited plants were established well in the soil and did not show noticeable growth retardation. This approach will facilitate the establishment of genome editing protocols for recalcitrant crops and support further optimization, including the evaluation of alternative RNA-guided nucleases to overcome the limitations of the protospacer adjacent motif (PAM) site or to develop novel delivery strategies for genome editing reagents.
SARS-CoV-2-Seronegative Subjects Target CTL Epitopes in the SARS-CoV-2 Nucleoprotein Cross-Reactive to Common Cold Coronaviruses
Authors: Schmidt Katja G. , Nganou-Makamdop Krystelle , Tenbusch Matthias , El Kenz Boutaina , Maier Clara , Lapuente Dennis , Überla Klaus , Spriewald Bernd , Bergmann Silke , Harrer Ellen G. , Harrer Thomas
Published: April 2021

The beta-coronavirus SARS-CoV-2 induces severe disease (COVID-19) mainly in elderly persons with risk factors, whereas the majority of patients experience a mild course of infection. As the circulating common cold coronaviruses OC43 and HKU1 share some homologous sequences with SARS-CoV-2, beta-coronavirus cross-reactive T-cell responses could influence the susceptibility to SARS-CoV-2 infection and the course of COVID-19. To investigate the role of beta-coronavirus cross-reactive T-cells, we analyzed the T-cell response against a 15 amino acid long peptide (SCoV-DP15: DLSPRWYFYYLGTGP) from the SARS-CoV-2 nucleoprotein sequence with a high homology to the corresponding sequence (QLLPRWYFYYLGTGP) in OC43 and HKU1. SCoV-DP15-specific T-cells were detected in 4 out of 23 (17.4%) SARS-CoV-2-seronegative healthy donors. As HIV-1 infection is a potential risk factor for COVID-19, we also studied a cohort of HIV-1-infected patients on antiretroviral therapy. 44 out of these 116 HIV-1-infected patients (37.9%) showed a specific recognition of the SCoV-DP15 peptide or of shorter peptides within SCoV-DP15 by CD4+ T-cells and/or by CD8+ T-cells. We could define several new cross-reactive HLA-I-restricted epitopes in the SARS-CoV-2 nucleoprotein such as SPRWYFYYL (HLA-B*07, HLA-B*35), DLSPRWYFYY (HLA-A*02), LSPRWYFYY (HLA-A*29), WYFYYLGTGP and WYFYYLGT. Epitope specific CD8+ T-cell lines recognized corresponding epitopes within OC43 and HKU1 to a similar degree or even at lower peptide concentrations suggesting that they were induced by infection with OC43 or HKU1. Our results confirm that SARS-CoV-2-seronegative subjects can target SARS-CoV-2 not only by beta-coronavirus cross-reactive CD4+ T-cells but also by cross-reactive CD8+ cytotoxic T-cells (CTL). The delineation of cross-reactive T-cell epitopes contributes to an efficient epitope-specific immunomonitoring of SARS-CoV-2-specific T-cells. Further prospective studies are needed to prove a protective role of cross-reactive T-cells and their restricting HLA alleles for control of SARS-CoV-2 infection. The frequent observation of SARS-CoV-2-reactive T-cells in HIV-1-infected subjects could be a reason that treated HIV-1 infection does not seem to be a strong risk factor for the development of severe COVID-19.
SARS-CoV-2 Induces Lymphocytopenia by Promoting Inflammation and Decimates Secondary Lymphoid Organs
Authors: Xiang Qun , Feng Zeqing , Diao Bo , Tu Chao , Qiao Qinghua , Yang Han , Zhang Yi , Wang Gang , Wang Huiming , Wang Chenhui , Liu Liang , Wang Changsong , Liu Longding , Chen Rong , Wu Yuzhang , Chen Yongwen
Published: April 2021

While lymphocytopenia is a common characteristic of coronavirus disease 2019 (COVID-19), the mechanisms responsible for this lymphocyte depletion are unclear. Here, we retrospectively reviewed the clinical and immunological data from 18 fatal COVID-19 cases, results showed that these patients had severe lymphocytopenia, together with high serum levels of inflammatory cytokines (IL-6, IL-8 and IL-10), and elevation of many other mediators in routine laboratory tests, including C-reactive protein, lactate dehydrogenase, α-hydroxybutyrate dehydrogenase and natriuretic peptide type B. The spleens and hilar lymph nodes (LNs) from six additional COVID-19 patients with post-mortem examinations were also collected, histopathologic detection showed that both organs manifested severe tissue damage and lymphocyte apoptosis in these six cases. In situ hybridization assays illustrated that SARS-CoV-2 viral RNA accumulates in these tissues, and transmission electronic microscopy confirmed that coronavirus-like particles were visible in the LNs. SARS-CoV-2 Spike and Nucleocapsid protein (NP) accumulated in the spleens and LNs, and the NP antigen restricted in angiotensin-converting enzyme 2 (ACE2) positive macrophages and dendritic cells (DCs). Furthermore, SARS-CoV-2 triggered the transcription of Il6, Il8 and Il1b genes in infected primary macrophages and DCs in vitro, and SARS-CoV-2-NP+ macrophages and DCs also manifested high levels of IL-6 and IL-1β, which might directly decimate human spleens and LNs and subsequently lead to lymphocytopenia in vivo. Collectively, these results demonstrated that SARS-CoV-2 induced lymphocytopenia by promoting systemic inflammation and direct neutralization in human spleen and LNs.
Taxonomy and Phylogeny of Rust Fungi on Hamamelidaceae
Authors: Liu Yun , Cao Bin , Tian Chengming , Ono Yoshitaka , Lin Weiwei , Liang Yingmei
Published: April 2021

Hamamelidaceae is composed of woody plant taxa of important economic value; however, reports on diseases affecting these plants are rare. Three kinds of rusts were studied, of which the first one is characterized by catenulate spores in peridiate columnar sori onSycopsis sinensis, the second one produces two-celled pedicellate teliospores in pulvinate sori onS. sinensisandCorylopsisspp., and the last one produces aeciospores in cup-shaped aecia onHamamelisspp. Phylogenetic analyses indicated that the three species belong to the same genus in Pucciniaceae. The first fungus is distinct in teliospore morphology, producing one-celled catenulate spores in peridiate columnar sori and molecular phylogeny from species of other genera. Thus, it is described herein as a new genus and speciesNovopuccinia sycopsis-sinensisin Pucciniaceae. The latter two species were reported asPuccinia corylopsidisandAecidium hamamelidis, respectively. However, phylogenetic analysis usingITSand28Sgenes has revealed that these are closely related to the new genus and species. By combining host, distribution, and evolutionary hypothesis of rust fungi with endocyclic life cycle, these are reclassified asN. corylopsidisandN. hamamelidis. Taxonomic descriptions, illustrations, and a key to rust fungal species occurring in Hamamelidaceae in Asia are provided.
TRPM4 Expression During Postnatal Developmental of Mouse CA1 Pyramidal Neurons
Authors: Riquelme Denise , Cerda Oscar , Leiva-Salcedo Elias
Published: April 2021

TRPM4 is a non-selective cation channel activated by intracellular calcium and permeable to monovalent cations. This channel participates in the control of neuronal firing, neuronal plasticity, and neuronal death. TRPM4 depolarizes dendritic spines and is critical for the induction of NMDA receptor-dependent long-term potentiation in CA1 pyramidal neurons. Despite its functional importance, no subcellular localization or expression during postnatal development has been described in this area. To examine the localization and expression of TRPM4, we performed duplex immunofluorescence and patch-clamp in brain slices at different postnatal ages in C57BL/6J mice. At P0 we found TRPM4 is expressed with a somatic pattern. At P7, P14, and P35, TRPM4 expression extended from the soma to the apical dendrites but was excluded from the axon initial segment. Patch-clamp recordings showed a TRPM4-like current active at the resting membrane potential from P0, which increased throughout the postnatal development. This current was dependent on intracellular Ca2+ (ICAN) and sensitive to 9-phenanthrol (9-Ph). Inhibiting TRPM4 with 9-Ph hyperpolarized the membrane potential at P14 and P35, with no effect in earlier stages. Together, these results show that TRPM4 is expressed in CA1 pyramidal neurons in the soma and apical dendrites and associated with a TRPM4-like current, which depolarizes the neurons. The expression, localization, and function of TRPM4 throughout postnatal development in the CA1 hippocampal may underlie an important mechanism of control of membrane potential and action potential firing during critical periods of neuronal development, particularly during the establishment of circuits.
Long-Term Consequence of Non-neurotropic H3N2 Influenza A Virus Infection for the Progression of Alzheimer’s Disease Symptoms
Authors: Hosseini Shirin , Michaelsen-Preusse Kristin , Schughart Klaus , Korte Martin
Published: April 2021

Influenza viruses until today are a leading cause of worldwide severe pandemics and represent a major threat to human and animal health. Although the primary target of influenza viruses is the lung, infection may manifest with acute and even chronic neurological complications (e.g., status epilepticus, encephalopathies, and encephalitis) potentially increasing the long-term risk for neurodegenerative diseases. We previously described that a peripheral influenza A virus (IAV) infection caused by non-neurotropic H3N2 (maHK68) variant leads to long-term neuroinflammation and synapse loss together with impaired memory formation in young adult mice. Processes of neuroinflammation have been associated with neurodegenerative diseases such as Alzheimer’s disease (AD) and prolonged or excessive innate immune responses are considered a risk factor for AD. Here, the role of purely peripheral IAV infection for the development and progression of AD in a transgenic mouse model (APP/PS1) was investigated. At 2 months of age, mice were infected with H3N2 IAV and the detailed analysis of microglia morphology revealed neuroinflammation in the hippocampus already of 6 months old non-infected APP/PS1 mice together with impaired spatial learning, however, microglia activation, amyloid-β plaques load and cognitive impairments were even more pronounced in APP/PS1 mice upon H3N2 infection. Moreover, CA1 hippocampal dendritic spine density was reduced even at 120 dpi compared to wild-type and also to non-infected APP/PS1 mice, whereas neuronal cells number was not altered. These findings demonstrate that non-neurotropic H3N2 IAV infection as a peripheral immune stimulation may exacerbate AD symptoms possibly by triggering microglial hyperactivation.
Review of Multi-Modal Imaging in Urea Cycle Disorders: The Old, the New, the Borrowed, and the Blue
Authors: Sen Kuntal , Anderson Afrouz A. , Whitehead Matthew T. , Gropman Andrea L.
Published: April 2021

The urea cycle disorders (UCD) are rare genetic disorder due to a deficiency of one of six enzymes or two transport proteins that act to remove waste nitrogen in form of ammonia from the body. In this review, we focus on neuroimaging studies in OTCD and Arginase deficiency, two of the UCD we have extensively studied. Ornithine transcarbamylase deficiency (OTCD) is the most common of these, and X-linked. Hyperammonemia (HA) in OTCD is due to deficient protein handling. Cognitive impairments and neurobehavioral disorders have emerged as the major sequelae in Arginase deficiency and OTCD, especially in relation to executive function and working memory, impacting pre-frontal cortex (PFC). Clinical management focuses on neuroprotection from HA, as well as neurotoxicity from other known and yet unclassified metabolites. Prevention and mitigation of neurological injury is a major challenge and research focus. Given the impact of HA on neurocognitive function of UCD, neuroimaging modalities, especially multi-modality imaging platforms, can bring a wealth of information to understand the neurocognitive function and biomarkers. Such information can further improve clinical decision making, and result in better therapeutic interventions. In vivo investigations of the affected brain using multimodal neuroimaging combined with clinical and behavioral phenotyping hold promise. MR Spectroscopy has already proven as a tool to study biochemical aberrations such as elevated glutamine surrounding HA as well as to diagnose partial UCD. Functional Near Infrared Spectroscopy (fNIRS), which assesses local changes in cerebral hemodynamic levels of cortical regions, is emerging as a non-invasive technique and will serve as a surrogate to fMRI with better portability. Here we review two decades of our research using non-invasive imaging and how it has contributed to an understanding of the cognitive effects of this group of genetic conditions.
Comparative Analysis of Trigeminal Neuralgia Caused by Sole Arterial and Venous Compression: Clinical Features and Surgical Outcomes From 222 Cases
Authors: Wang Junwen , Niu Hongquan , Zhao Kai , Shu Kai , Lei Ting
Published: April 2021

Background: Compared with trigeminal neuralgia (TN) caused by arterial neurovascular conflict (NVC), the clinical characteristics and managements for TN with venous NVC are not well-established. This study aims to comparatively summarize the clinical features and surgical outcomes of microvascular decompression (MVD) for patients with TN caused by sole arterial and venous compression, with a particular focus on the morphological features of posterior cranial fossa (PCF).

Methods: A total of 222 patients with TN caused by sole arterial NVC (188/84.7%) and venous NVC (34/15.3%) underwent MVD in our department from January 2014 to December 2018. The patient data were analyzed retrospectively. Particularly, we focused on the potential impact of PCF on surgical outcomes.

Results: Compared with arterial NVC, V3 branch of the trigeminal nerve was more frequently involved in venous NVC (p = 0.009). The most common compression site was root entry zone for arterial NVC (68.6%) and midcisternal segment for venous NVC (76.5%) (p < 0.001). No serious post-operative complication was observed in the two groups. Both short- and long-term outcomes were relatively worse in venous NVC cases compared with arterial NVC cases (p = 0.001 and p = 0.030, respectively); and a dominantly higher rate of delayed cure was demonstrated in venous NVC cases (p < 0.001). TN patients with venous NVC revealed a more flat-shaped PCF than those with arterial NVC. Moreover, flat-shaped PCF morphometry was negatively correlated with surgical outcomes of TN patients with arterial NVC, but not with those of venous NVC cases.

Conclusions: MVD is an effective and safe treatment for patients with TN caused by either arterial or venous NVC. Patients with a more flat-shaped PCF might be vulnerable to venous compression. Our study demonstrated that PCF morphometry only affected the surgical outcomes of patients with TN caused by arterial NVC, but not the outcomes of those with venous NVC.
Microbial Pathogenesis and Pathophysiology of Alzheimer's Disease: A Systematic Assessment of Microorganisms' Implications in the Neurodegenerative Disease
Authors: Ekundayo Temitope Cyrus , Olasehinde Tosin Abiola , Okaiyeto Kunle , Okoh Anthony I.
Published: April 2021

Microbial infections have been linked to the pathogenesis and pathophysiology of Alzheimer's disease (AD) and other neurodegenerative diseases. The present study aimed to synthesise and assess global evidence of microbial pathogenesis and pathophysiology in AD (MPP-AD) and associated neurodegenerative conditions using integrated science mapping and content analytics to explore the associated research landscape. Relevant MPP-AD documents were retrieved from Web of Science and Scopus according to PRISMA principles and analysed for productivity/trend linked to authors/countries, thematic conceptual framework, and international collaborative networks. A total of 258 documents published from 136 sources to 39.42 average citations/document were obtained on MPP-AD. The co-authors per document were 7.6, and the collaboration index was 5.71. The annual research outputs increased tremendously in the last 6 years from 2014 to 2019, accounting for 66% compared with records in the early years from 1982 to 1990 (16%). The USA (n = 71, freq. = 30.34%), United Kingdom (n = 32, freq. = 13.68%) and China (n = 27, 11.54%) ranked in first three positions in term of country's productivity. Four major international collaboration clusters were found in MPP-AD research. The country collaboration network in MPP-AD was characteristic of sparse interaction and acquaintanceship (density = 0.11, diameter = 4). Overall, international collaboration is globally inadequate [centralisation statistics: degree (40.5%), closeness (4%), betweenness (23%), and eigenvector (76.7%)] against the robust authors' collaboration index of 5.71 in MPP-AD research. Furthermore, four conceptual thematic frameworks (CTF) namely, CTF#1, roles of microbial/microbiome infection and dysbiosis in cognitive dysfunctions; CTF#2, bacterial infection specific roles in dementia; CTF#3, the use of yeast as a model system for studying MPP-AD and remediation therapy; and CFT#4, flow cytometry elucidation of amyloid-beta and aggregation in Saccharomyces cerevisiae model. Finally, aetiology-based mechanisms of MPP-AD, namely, gut microbiota, bacterial infection, and viral infection, were comprehensively discussed. This study provides an overview of MPP-AD and serves as a stepping stone for future preparedness in MPP-AD-related research.
Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease
Authors: Zhang Xin , Alshakhshir Nadine , Zhao Liqin
Published: April 2021

Alzheimer’s disease (AD) is the most common form of age-related dementia. Despite decades of research, the etiology and pathogenesis of AD are not well understood. Brain glucose hypometabolism has long been recognized as a prominent anomaly that occurs in the preclinical stage of AD. Recent studies suggest that glycolytic metabolism, the cytoplasmic pathway of the breakdown of glucose, may play a critical role in the development of AD. Glycolysis is essential for a variety of neural activities in the brain, including energy production, synaptic transmission, and redox homeostasis. Decreased glycolytic flux has been shown to correlate with the severity of amyloid and tau pathology in both preclinical and clinical AD patients. Moreover, increased glucose accumulation found in the brains of AD patients supports the hypothesis that glycolytic deficit may be a contributor to the development of this phenotype. Brain hyperglycemia also provides a plausible explanation for the well-documented link between AD and diabetes. Humans possess three primary variants of the apolipoprotein E (ApoE) gene – ApoE∗ϵ2, ApoE∗ϵ3, and ApoE∗ϵ4 – that confer differential susceptibility to AD. Recent findings indicate that neuronal glycolysis is significantly affected by human ApoE isoforms and glycolytic robustness may serve as a major mechanism that renders an ApoE2-bearing brain more resistant against the neurodegenerative risks for AD. In addition to AD, glycolytic dysfunction has been observed in other neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, strengthening the concept of glycolytic dysfunction as a common pathway leading to neurodegeneration. Taken together, these advances highlight a promising translational opportunity that involves targeting glycolysis to bolster brain metabolic resilience and by such to alter the course of brain aging or disease development to prevent or reduce the risks for not only AD but also other neurodegenerative diseases.
Fyn Kinase-Mediated PKCδ Y311 Phosphorylation Induces Dopaminergic Degeneration in Cell Culture and Animal Models: Implications for the Identification of a New Pharmacological Target for Parkinson’s Disease
Authors: Saminathan Hariharan , Ghosh Anamitra , Zhang Danhui , Song Chunjuan , Jin Huajun , Anantharam Vellareddy , Kanthasamy Arthi , Kanthasamy Anumantha G.
Published: April 2021

Oxidative stress, neuroinflammation and apoptosis are some of the key etiological factors responsible for dopamin(DA)ergic degeneration during Parkinson’s disease (PD), yet the downstream molecular mechanisms underlying neurodegeneration are largely unknown. Recently, a genome-wide association study revealed the FYN gene to be associated with PD, suggesting that Fyn kinase could be a pharmacological target for PD. In this study, we report that Fyn-mediated PKCδ tyrosine (Y311) phosphorylation is a key event preceding its proteolytic activation in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinsonism. MPP+/MPTP induced Fyn kinase activation in N27 DAergic neuronal cells and the mouse substantia nigra. PKCδ-Y311 phosphorylation by activated Fyn initiates the apoptotic caspase-signaling cascade during DAergic degeneration. Pharmacological attenuation of Fyn activity protected DAergic neurons from MPP+-induced degeneration in primary mesencephalic neuronal cultures. We further employed Fyn wild-type and Fyn knockout (KO) mice to confirm whether Fyn is a valid pharmacological target of DAergic neurodegeneration. Primary mesencephalic neurons from Fyn KO mice were greatly protected from MPP+-induced DAergic cell death, neurite loss and DA reuptake loss. Furthermore, Fyn KO mice were significantly protected from MPTP-induced PKCδ-Y311 phosphorylation, behavioral deficits and nigral DAergic degeneration. This study thus unveils a mechanism by which Fyn regulates PKCδ′s pro-apoptotic function and DAergic degeneration. Pharmacological inhibitors directed at Fyn activation could prove to be a novel therapeutic target in the delay or halting of selective DAergic degeneration during PD.
Protein Kinases Mediate Anti-Inflammatory Effects of Cannabidiol and Estradiol Against High Glucose in Cardiac Sodium Channels
Authors: Fouda Mohamed A. , Ruben Peter C.
Published: April 2021

Background: Cardiovascular anomalies are predisposing factors for diabetes-induced morbidity and mortality. Recently, we showed that high glucose induces changes in the biophysical properties of the cardiac voltage-gated sodium channel (Nav1.5) that could be strongly correlated to diabetes-induced arrhythmia. However, the mechanisms underlying hyperglycemia-induced inflammation, and how inflammation provokes cardiac arrhythmia, are not well understood. We hypothesized that inflammation could mediate the high glucose-induced biophyscial changes on Nav1.5 through protein phosphorylation by protein kinases A and C. We also hypothesized that this signaling pathway is, at least partly, involved in the cardiprotective effects of cannabidiol (CBD) and 17β-estradiol (E2).

Methods and Results: To test these ideas, we used Chinese hamster ovarian (CHO) cells transiently co-transfected with cDNA encoding human Nav1.5 α-subunit under control, a cocktail of inflammatory mediators or 100 mM glucose conditions (for 24 h). We used electrophysiological experiments and action potential modeling. Inflammatory mediators, similar to 100 mM glucose, right shifted the voltage dependence of conductance and steady-state fast inactivation and increased persistent current leading to computational prolongation of action potential (hyperexcitability) which could result in long QT3 arrhythmia. We also used human iCell cardiomyocytes derived from inducible pluripotent stem cells (iPSC-CMs) as a physiologically relevant system, and they replicated the effects produced by inflammatory mediators observed in CHO cells. In addition, activators of PK-A or PK-C replicated the inflammation-induced gating changes of Nav1.5. Inhibitors of PK-A or PK-C, CBD or E2 mitigated all the potentially deleterious effects provoked by high glucose/inflammation.

Conclusion: These findings suggest that PK-A and PK-C may mediate the anti-inflammatory effects of CBD and E2 against high glucose-induced arrhythmia. CBD, via Nav1.5, may be a cardioprotective therapeutic approach in diabetic postmenopausal population.
Evaluation of the Biodistribution of Mesenchymal Stem Cells in a Pre-clinical Renal Tuberculosis Model by Non-linear Magnetic Response Measurements
Authors: Yudintceva Natalia , Mikhailova Natalia , Bobkov Danila , Yakovleva Liudmila , Nikolaev Boris , Krasavina Darya , Muraviov Alexandr , Vinogradova Tatiana , Yablonskiy Petr , Samusenko Igor , Ryzhov Vyacheslav , Deriglazov Vladimir , Marchenko Yaroslav , Multhoff Gabriele , Klapproth Alexander P. , Li Wei Bo , Nayak Barsa , Sonawane Avinash , Shevtsov Maxim
Published: April 2021

Bone-marrow derived mesenchymal stem cells (MSCs) exert anti-tuberculosis effects due to their potential to repair damaged tissues and modulate inflammatory immune responses. MSCs were reported to be recruited to the Mycobacterium tuberculosis (Mtb) affected sites in the organism. However, due to limitations of presently applied in vivo imaging techniques the trafficking and biodistribution of MSCs in Mtb-infected organisms is not possible. In the current study MSCs were labeled with superparamagnetic iron oxide nanoparticles (SPIONs) as a negative MR contrast agent for imaging the biodistribution of MSCs in vivo. Trafficking of SPIONs-labeled MSCs was analyzed in a preclinical model of renal tuberculosis in male Chinchilla rabbits (n = 18) following intravenous administration on the days 0, 2, 3, and 7 employing a highly sensitive method of non-linear longitudinal magnetic response (NLR-M2) measurements. Within 48 h after injection, nanoparticle-labeled MSCs accumulated predominantly in lung, spleen, liver tissues, and paratracheal lymph nodes with subsequent decrease over the observation period of 7 days. The recruitment of MSCs to Mtb-affected organs was further proven by immunohistological analysis. NLR-M2 allowed the detection of SPIONs-labeled cells at low concentrations in different organs and tissues giving insights of in vivo mesenchymal stem cells trafficking in organism after TB infection.
CD36 Senses Dietary Lipids and Regulates Lipids Homeostasis in the Intestine
Authors: Zhao Lei , Li Yuqi , Ding Qiuying , Li Yanping , Chen Yaxi , Ruan Xiong Z.
Published: April 2021

Dietary lipids absorbed in the intestine are closely related to the development of metabolic syndrome. CD36 is a multi-functional scavenger receptor with multiple ligands, which plays important roles in developing hyperlipidemia, insulin resistance, and metabolic syndrome. In the intestine, CD36 is abundant on the brush border membrane of the enterocytes mainly localized in proximal intestine. This review recapitulates the update and current advances on the importance of intestinal CD36 in sensing dietary lipids and regulating intestinal lipids uptake, synthesis and transport, and regulating intestinal hormones secretion. However, further studies are still needed to demonstrate the complex interactions between intestinal CD36 and dietary lipids, as well as its importance in diet associated metabolic syndrome.
Targeted Enrichment of rRNA Gene Tandem Arrays for Ultra-Long Sequencing by Selective Restriction Endonuclease Digestion
Authors: McKinlay Anastasia , Fultz Dalen , Wang Feng , Pikaard Craig S.
Published: April 2021

Large regions of nearly identical repeats, such as the 45S ribosomal RNA (rRNA) genes of Nucleolus Organizer Regions (NORs), can account for major gaps in sequenced genomes. To assemble these regions, ultra-long sequencing reads that span multiple repeats have the potential to reveal sets of repeats that collectively have sufficient sequence variation to unambiguously define that interval and recognize overlapping reads. Because individual repetitive loci typically represent a small proportion of the genome, methods to enrich for the regions of interest are desirable. Here we describe a simple method that achieves greater than tenfold enrichment of Arabidopsis thaliana 45S rRNA gene sequences among ultra-long Oxford Nanopore Technology sequencing reads. This method employs agarose-embedded genomic DNA that is subjected to restriction endonucleases digestion using a cocktail of enzymes predicted to be non-cutters of rRNA genes. Most of the genome is digested into small fragments that diffuse out of the agar plugs, whereas rRNA gene arrays are retained. In principle, the approach can also be adapted for sequencing other repetitive loci for which gaps exist in a reference genome.