bluuebunny/crossref_metadata_2025 huggingface dataset:
“The Elephant in the Room”: Exploring Natural Mortality Uncertainty in Statistical Catch at Age Models
Authors: Mannini Alessandro , Pinto Cecilia , Konrad Christoph , Vasilakopoulos Paraskevas , Winker Henning
Published: January 2021

The natural mortality rate (M) of a fish stock is typically highly influential on the outcome of age-structured stock assessment models, but at the same time extremely difficult to estimate. In data-limited stock assessments, M usually relies on a range of empirically or theoretically derived M estimates, which can vary vastly. This article aims at evaluating the impact of this variability in M using seven Mediterranean stocks as case studies of statistical catch-at-age assessments for information-limited fisheries. The two main bodies carrying out stock assessments in the Mediterranean and Black Seas are European Union’s Scientific Technical Economic Committee for Fisheries (STECF) and Food and Agriculture Organization’s General Fisheries Commission for the Mediterranean (GFCM). Current advice in terms of fishing mortality levels is based on a single “best” M assumption which is agreed by stock assessment expert working groups, but uncertainty about M is not taken into consideration. Our results demonstrate that not accounting for the uncertainty surrounding M during the assessment process can lead to strong underestimation or overestimation of fishing mortality, potentially biasing the management process. We recommend carrying out relevant sensitivity analyses to improve stock assessment and fisheries management in data-limited areas such as the Mediterranean basin.
Molecular Responses of Mussel Mytilus galloprovincialis Associated to Accumulation and Depuration of Marine Biotoxins Okadaic Acid and Dinophysistoxin-1 Revealed by Shotgun Proteomics
Authors: Martins José Carlos , Domínguez-Pérez Dany , Azevedo Catarina , Braga Ana Catarina , Costa Pedro Reis , Osório Hugo , Vasconcelos Vitor , Campos Alexandre
Published: January 2021

The molecular pathways behind the toxicity of diarrheic shellfish toxins (DSTs) in bivalves have been scarcely studied. Thus, a shotgun proteomics approach was applied in this work to understand bivalves’ molecular responses to the dinoflagellate Prorocentrum lima (1.0 × 106 cells/L). Protein expression along with toxins levels were analyzed in the gills and digestive gland of the mussel Mytilus galloprovincialis during and after exposure to this toxic strain. Results revealed an accumulation of OA and DTX1 only in the digestive gland with maximum amounts attained at the end of uptake phase (day 5; 2819.2 ± 522.2 μg OA/kg and 1107.1 ± 267.9 μg DTX1/kg). At the end of the depuration phase (day 20), 16% and 47% of total OA and DTX1 concentrations remained in the digestive gland tissues, respectively. The shotgun proteomic analyses yielded 3051 proteins in both organs. A total of 56 and 54 differentially expressed proteins (DEPs) were revealed in the digestive gland and gills, respectively. Both organs presented the same response dynamics along the experiment, although with tissue-specific features. The early response (3 days uptake) was characterized by a high number of DEPs, being more marked in gills, in relation to the latter time points (5 days uptake and depuration). Functional enrichment analysis revealed the up-regulation of carboxylic (GO:0046943) and organic acid transmembrane transporter activity (GO:0005342) pathways after 3 days uptake for digestive gland. Matching to these pathways are a group of proteins related to transmembrane transport and response to toxic substances and xenobiotics, namely P-glycoprotein (ABCB11), Sodium-dependent proline transporter (SLC6A7), and Sideroflexin-1 (SFXN1). According to Clusters of Orthologous Groups (GOs) categories, most of the DEPs found for digestive gland in all time-points were related with “cellular processes and signaling” and involving signal transduction mechanisms, cytoskeleton and post-translational modification, protein turnover, chaperone functions. In gills, the early uptake phase was marked by a balance between DEPs related with “cellular processes and signaling” and “metabolism.” Depuration is clearly marked by processes related with “metabolism,” mainly involving secondary metabolites biosynthesis, transport, and catabolism. Proteomic data are available via ProteomeXchange with identifier PXD022293.
Behavior and Ecology of Silky Sharks Around the Chagos Archipelago and Evidence of Indian Ocean Wide Movement
Authors: Curnick David J. , Andrzejaczek Samantha , Jacoby David M. P. , Coffey Daniel M. , Carlisle Aaron B. , Chapple Taylor K. , Ferretti Francesco , Schallert Robert J. , White Timothy , Block Barbara A. , Koldewey Heather J. , Collen Ben
Published: January 2021

Silky sharks (Carcharhinus falciformis) represent a major component of global shark catch, both directly and as bycatch, and populations are declining as a result. An improved understanding of their movement ecology is needed to support conservation efforts. We deployed satellite and acoustic tags (2013–2018) and analyzed historical fisheries records (1997–2009), to investigate the spatial ecology of silky sharks in the central Indian Ocean and a large Marine Protected Area (MPA; 640,000 km2) around the Chagos Archipelago. We observed high fidelity to the MPA, and a sustained diurnal association with a seamount complex, with individuals moving off at night and returning at sunrise. Yet, we also observed large-scale divergent movements in two satellite tagged individuals and documented the furthest recorded displacement distance for a satellite tagged silky shark to date, with one individual moving from the MPA to the Kenyan coast—a displacement distance of 3,549 km (track distance ∼4,782 km). Silky sharks undertook diel vertical migrations and oscillatory diving behavior, spending > 99% of their time in the top 100 m, and diving to depths of greater than 300 m, overlapping directly with typical deployments of purse seine and longline sets in the Indian Ocean. One individual was recorded to a depth of 1,112 m, the deepest recorded silky shark dive to date. Individuals spent 96% of their time at liberty within water temperatures between 24 and 30°C. Historic fisheries data revealed that silky sharks were a major component of the shark community around the archipelago, representing 13.69% of all sharks caught by longlines before the fishery closed in 2010. Over half (55.88%) of all individuals caught by longlines and purse seiners were juveniles. The large proportion of juveniles, coupled with the high site fidelity and residence observed in some individuals, suggests that the MPA could provide considerable conservation benefits for silky sharks, particularly during early life-history stages. However, their high mobility potential necessitates that large MPAs need to be considered in conjunction with fisheries regulations and conservation measures in adjacent EEZs and in areas beyond national jurisdiction.
Dabigatran Level Before Reversal Can Predict Hemostatic Effectiveness of Idarucizumab in a Real-World Setting
Authors: Gendron Nicolas , Chocron Richard , Billoir Paul , Brunier Julien , Camoin-Jau Laurence , Tuffigo Marie , Faille Dorothée , Teissandier Dorian , Gay Juliette , de Raucourt Emmanuelle , Suner Ludovic , Bonnet Corentin , Martin Anne-Céline , Lasne Dominique , Ladhari Chayma , Lebreton Aurélien , Bertoletti Laurent , Ajzenberg Nadine , Gaussem Pascale , Morange Pierre-Emmanuel , Le Cam Duchez Véronique , Viallon Alain , Roy Pierre-Marie , Lillo-le Louët Agnès , Smadja David M.
Published: January 2021

Background: Idarucizumab has been included in guidelines for the management of bleeding or surgical procedure in dabigatran-treated patients without need for biological monitoring. The aim of the study was to assess the prognostic value of dabigatran plasma level before reversal to test the hemostatic efficacy of idarucizumab. The secondary objectives were (i) to analyze plasma dabigatran level according to the risk of rebound and (ii) to evaluate the incidence of post-reversal non-favorable clinical outcomes (including thromboembolism, bleeding, antithrombotic, and death) and antithrombotic resumption.

Methods and Results: This was an observational multicentric cohort study, which included all French patients who required idarucizumab for dabigatran reversal. Between May 2016 and April 2019, 87 patients from 21 French centers were enrolled. Patients received idarucizumab for overt bleeding (n = 61), urgent procedures (n = 24), or overdose without bleeding (n = 2). Among patients with major bleeding (n = 57), treatment with idarucizumab was considered effective in 44 (77.2%) of them. Patients who did not achieve effective hemostasis after reversal had a significantly higher mean level of plasma dabigatran at baseline (524.5 ± 386 vs. 252.8 ng/mL ± 235, p = 0.033). Furthermore, patients who did not achieve effective hemostasis after reversal had less favorable outcomes during follow-up (46.2 vs. 81.8%, p = 0.027). ROC curve identified a cutoff of 264 ng/mL for dabigatran level at admission to be predictive of ineffective hemostasis. No plasma dabigatran rebound was observed after reversal in patients with dabigatran plasma level < 264 ng/mL at baseline.

Conclusion: This retrospective study shows that dabigatran level before reversal could predict hemostatic effectiveness and dabigatran plasma rebound after idarucizumab injection.
Insights Into Development and Progression of Idiopathic Pulmonary Fibrosis From Single Cell RNA Studies
Authors: Nemeth Julia , Schundner Annika , Frick Manfred
Published: January 2021

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited therapeutic options. The current model suggests that chronic or repetitive “micro-injuries” of the alveolar epithelium lead to activation and proliferation of fibroblasts and excessive extracellular matrix (ECM) deposition. Disruption of alveolar type II (ATII) epithelial cell homeostasis and the characteristics of mesenchymal cell populations in IPF have received particular attention in recent years. Emerging data from single cell RNA sequencing (scRNAseq) analysis shed novel light on alterations in ATII cell progenitor dysfunction and the diversity of mesenchymal cells within the fibrotic lung. Within this minireview, we summarize the data from most recent human scRNAseq studies. We aim to collate the current knowledge on cellular plasticity and heterogeneity in the development and progression of IPF, effects of drug treatment on transcriptional changes. Finally, we provide a brief outlook on future challenges and promises for large scale sequencing studies in the development of novel therapeutics for IPF.
Symbiotic Associations: Key Factors That Determine Physiology and Lipid Accumulation in Oleaginous Microorganisms
Authors: Deka Deepi , Sonowal Shashanka , Chikkaputtaiah Channakeshavaiah , Velmurugan Natarajan
Published: January 2021

Symbiosis naturally provides an opportunity for microorganisms to live together by mutual or one-way benefit. In symbiotic relationships, the microorganisms usually overcome the limitations of being free-living. Understanding the symbiotic relationships of oleaginous microorganisms provides potential route for the sustainable production of microbial-based alternative fuels. So far, several studies have been conducted in oleaginous microorganisms for the production of alternative fuels. However, some oleaginous microorganisms require high quantity of nutrients for their growth, and high level of energy and chemicals for harvest and separation of lipid bodies. Symbiotic associations can successfully be applied to address these issues. Of symbiotic associations, lichens and selective species of oleaginous endosymbiotic mucoromycotina have received substantial interest as better models to study the evolutionary relationships as well as single-cell oil production. Construction of artificial lichen system composed of cyanobacteria and oleaginous yeast has been achieved for sustainable production of lipids with minimum energy demand. Recently, endosymbiotic mucoromycotina species have been recognized as potential sources for biofuels. Studies found that endohyphal bacterium influences lipid profiling in endosymbiotic mucoromycotina species. Studies on the genetic factors related to oleaginous characteristics of endosymbiotic mucoromycotina species are scarce. In this regard, this review summarizes the different forms of symbiotic associations of oleaginous microorganisms and how symbiotic relationships are impacting the lipid formation in microorganisms. Further, the review also highlights the importance of evolutionary relationships and benefits of co-culturing (artificial symbiosis) approaches for sustainable production of biofuels.
The Genus Pachyma (Syn. Wolfiporia) Reinstated and Species Clarification of the Cultivated Medicinal Mushroom “Fuling” in China
Authors: Wu Fang , Li Shou-Jian , Dong Cai-Hong , Dai Yu-Cheng , Papp Viktor
Published: January 2021

The fungus “Fuling” has been used in Chinese traditional medicine for more than 2000 years, and its sclerotia have a wide range of biological activities including antitumour, immunomodulation, anti-inflammation, antioxidation, anti-aging etc. This prized medicinal mushroom also known as “Hoelen” is resurrected from a piece of pre-Linnean scientific literature. Fries treated it as Pachyma hoelen Fr. and mentioned that it was cultivated on pine trees in China. However, this name had been almost forgotten, and Poria cocos (syn. Wolfiporia cocos), originally described from North America, and known as “Tuckahoe” has been applied to “Fuling” in most publications. Although Merrill mentioned a 100 years ago that Asian Pachyma hoelen and North American P. cocos are similar but different, no comprehensive taxonomical studies have been carried out on the East Asian Pachyma hoelen and its related species. Based on phylogenetic analyses and morphological examination on both the sclerotia and the basidiocarps which are very seldomly developed, the East Asian samples of Pachyma hoelen including sclerotia, commercial strains for cultivation and fruiting bodies, nested in a strongly supported, homogeneous lineage which clearly separated from the lineages of North American Wolfiporia cocos and other species. So we confirm that the widely cultivated “Fuling” Pachyma hoelen in East Asia is not conspecific with the North American Wolfiporia cocos. Based on the changes in Art. 59 of the International Code of Nomenclature for algae, fungi, and plants, the generic name Pachyma, which was sanctioned by Fries, has nomenclatural priority (ICN, Art. F.3.1), and this name well represents the economically important stage of the generic type. So we propose to use Pachyma rather than Wolfiporia, and subsequently Pachyma hoelen and Pachyma cocos are the valid names for “Fuling” in East Asia and “Tuckahoe” in North America, respectively. In addition, a new combination, Pachyma pseudococos, is proposed. Furthermore, it seems that Pachyma cocos is a species complex, and that three species exist in North America.
The Multi-Fungicide Resistance Status of Aspergillus fumigatus Populations in Arable Soils and the Wider European Environment
Authors: Fraaije Bart , Atkins Sarah , Hanley Steve , Macdonald Andy , Lucas John
Published: January 2021

The evolution and spread of pan-azole resistance alleles in clinical and environmental isolates of Aspergillus fumigatus is a global human health concern. The identification of hotspots for azole resistance development in the wider environment can inform optimal measures to counteract further spread by minimizing exposure to azole fungicides and reducing inoculum build-up and pathogen dispersal. We investigated the fungicide sensitivity status of soil populations sampled from arable crops and the wider environment and compared these with urban airborne populations. Low levels of azole resistance were observed for isolates carrying the CYP51A variant F46Y/M172V/E427K, all belonging to a cluster of related cell surface protein (CSP) types which included t07, t08, t13, t15, t19, and t02B, a new allele. High levels of resistance were found in soil isolates carrying CYP51A variants TR34/L98H and TR46/Y121F/T289A, all belonging to CSP types t01, t02, t04B, or t11. TR46/Y121F/M172V/T289A/G448S (CSP t01) and TR46/Y121F/T289A/S363P/I364V/G448S (CSP t01), a new haplotype associated with high levels of resistance, were isolated from Dutch urban air samples, indicating azole resistance evolution is ongoing. Based on low numbers of pan-azole resistant isolates and lack of new genotypes in soils of fungicide-treated commercial and experimental wheat crops, we consider arable crop production as a coldspot for azole resistance development, in contrast to previously reported flower bulb waste heaps. This study also shows that, in addition to azole resistance, several lineages of A. fumigatus carrying TR-based CYP51A variants have also developed acquired resistance to methyl benzimidazole carbamate, quinone outside inhibitor and succinate dehydrogenase (Sdh) inhibitor fungicides through target-site alterations in the corresponding fungicide target proteins; beta-tubulin (F200Y), cytochrome b (G143A), and Sdh subunit B (H270Y and H270R), respectively. Molecular typing showed that several multi-fungicide resistant strains found in agricultural soils in this study were clonal as identical isolates have been found earlier in the environment and/or in patients. Further research on the spread of different fungicide-resistant alleles from the wider environment to patients and vice versa can inform optimal practices to tackle the further spread of antifungal resistance in A. fumigatus populations and to safeguard the efficacy of azoles for future treatment of invasive aspergillosis.
Organometallic Complex Strongly Impairs Chikungunya Virus Entry to the Host Cells
Authors: Oliveira Débora Moraes de , Santos Igor de Andrade , Martins Daniel Oliveira Silva , Gonçalves Yasmim Garcia , Cardoso-Sousa Léia , Sabino-Silva Robinson , Von Poelhsitz Gustavo , Franca Eduardo de Faria , Nicolau-Junior Nilson , Pacca Carolina Colombelli , Merits Andres , Harris Mark , Jardim Ana Carolina Gomes
Published: January 2021

Chikungunya fever is a disease caused by the Chikungunya virus (CHIKV) that is transmitted by the bite of the female of Aedes sp. mosquito. The symptoms include fever, muscle aches, skin rash, and severe joint pains. The disease may develop into a chronic condition and joint pain for months or years. Currently, there is no effective antiviral treatment against CHIKV infection. Treatments based on natural compounds have been widely studied, as many drugs were produced by using natural molecules and their derivatives. Alpha-phellandrene (α-Phe) is a naturally occurring organic compound that is a ligand for ruthenium, forming the organometallic complex [Ru2Cl4(p-cymene)2] (RcP). Organometallic complexes have shown promising as candidate molecules to a new generation of compounds that presented relevant biological properties, however, there is a lack of knowledge concerning the anti-CHIKV activity of these complexes. The present work evaluated the effects of the RcP and its precursors, the hydrate ruthenium(III) chloride salt (RuCl3⋅xH2O) (Ru) and α-Phe, on CHIKV infection in vitro. To this, BHK-21 cells were infected with CHIKV-nanoluciferase (CHIKV-nanoluc), a viral construct harboring the nanoluciferase reporter gene, at the presence or absence of the compounds for 16 h. Cytotoxicity and impact on infectivity were analyzed. The results demonstrated that RcP exhibited a strong therapeutic potential judged by the selective index > 40. Antiviral effects of RcP on different stages of the CHIKV replicative cycle were investigated; the results showed that it affected early stages of virus infection reducing virus replication by 77% at non-cytotoxic concentrations. Further assays demonstrated the virucidal activity of the compound that completely blocked virus infectivity. In silico molecular docking calculations suggested different binding interactions between aromatic rings of RcP and the loop of amino acids of the E2 envelope CHIKV glycoprotein mainly through hydrophobic interactions. Additionally, infrared spectroscopy spectral analysis indicated interactions of RcP with CHIKV glycoproteins. These data suggest that RcP may act on CHIKV particles, disrupting virus entry to the host cells. Therefore, RcP may represent a strong candidate for the development of anti-CHIKV drugs.
A New Metric Quantifying Chemical and Biological Property of Small Molecule Metabolites and Drugs
Authors: Huang Chuanbo , Zhou Yuan , Yang Jichun , Cui Qinghua , Li Yanhui
Published: January 2021

One prominent class of drugs is chemical small molecules (CSMs), but the majority of CSMs are of very low druggable potential. Therefore, it is quite important to predict drug-related properties (druggable properties) for candidate CSMs. Currently, a number of druggable properties (e.g., logP and pKa) can be calculated by in silico methods; still the identification of druggable CSMs is a high-risk task, and new quantitative metrics for the druggable potential of CSMs are increasingly needed. Here, we present normalized bond energy (NBE), a new metric for the above purpose. By applying NBE to the DrugBank CSMs whose properties are largely known, we revealed that NBE is able to describe a number of critical druggable properties including logP, pKa, membrane permeability, blood–brain barrier penetration, and human intestinal absorption. Moreover, given that the human endogenous metabolites can serve as important resources for drug discovery, we applied NBE to the metabolites in the Human Metabolome Database. As a result, NBE showed a significant difference in metabolites from various body fluids and was correlated with some important properties, including melting point and water solubility.
Hijacking tRNAs From Translation: Regulatory Functions of tRNAs in Mammalian Cell Physiology
Authors: Avcilar-Kucukgoze Irem , Kashina Anna
Published: January 2021

Transfer tRNAs (tRNAs) are small non-coding RNAs that are highly conserved in all kingdoms of life. Originally discovered as the molecules that deliver amino acids to the growing polypeptide chain during protein synthesis, tRNAs have been believed for a long time to play exclusive role in translation. However, recent studies have identified key roles for tRNAs and tRNA-derived small RNAs in multiple other processes, including regulation of transcription and translation, posttranslational modifications, stress response, and disease. These emerging roles suggest that tRNAs may be central players in the complex machinery of biological regulatory pathways. Here we overview these non-canonical roles of tRNA in normal physiology and disease, focusing largely on eukaryotic and mammalian systems.
Abnormal Cingulum Bundle Induced by Type 2 Diabetes Mellitus: A Diffusion Tensor Tractography Study
Authors: Cui Ying , Tang Tian-Yu , Lu Chun-Qiang , Cai Yu , Lu Tong , Wang Yuan-Cheng , Teng Gao-Jun , Ju Shenghong
Published: January 2021

Purpose: In Type 2 diabetes (T2DM), white matter (WM) pathology has been suggested to play an important role in the etiology of T2DM-related cognitive impairment. This study aims to investigate the integrity of the cingulum bundle (CB), a major WM tract, in T2DM patients using diffusion tensor tractography.

Methods: Thirty-seven T2DM patients and 34 age-, sex- and education matched healthy controls were included and underwent diffusion tensor imaging. Tractography of bilateral CB tracts was performed and diffusion measurements were compared between the two groups. Next, brain regions with significant group differences on fractional anisotropy (FA) values were set as the region of interest (ROI), and the CB fibers that passed through were identified. Diffusion measures were extracted from these fibers to investigate their correlations with the cognitive performances and endocrine parameters.

Results: T2DM patients exhibited decreased FA in bilateral CB, increased mean diffusion (MD) in the right CB, and decreased length in the left CB. Through voxel-wise comparison, the most prominent FA difference was identified in the posterior segment of the CB and the reconstructed tract was part of the retrosplenial component. Importantly, the diffusion measurements of the tract were significantly correlated with the impaired performance in executive functioning and elevated insulin resistance (IR) in the T2DM group, instead of the control group.

Conclusions: The diffusion measurements in bilateral CB were altered in T2DM patients, which might reflect important neuropathologic changes in the fibers. Our study adds to knowledge about how the cingulum changes structurally along its entire length in T2DM and highlights the relationship between WM and cognitive performance. Besides, IR might be an important risk factor that warrants further exploration.
Neural Correlates of Age-Related Changes in Precise Grip Force Regulation: A Combined EEG-fNIRS Study
Authors: Berger Alisa , Steinberg Fabian , Thomas Fabian , Doppelmayr Michael
Published: January 2021

Motor control is associated with suppression of oscillatory activity in alpha (8–12 Hz) and beta (12–30 Hz) ranges and elevation of oxygenated hemoglobin levels in motor-cortical areas. Aging leads to changes in oscillatory and hemodynamic brain activity and impairments in motor control. However, the relationship between age-related changes in motor control and brain activity is not yet fully understood. Therefore, this study aimed to investigate age-related and task-complexity-related changes in grip force control and the underlying oscillatory and hemodynamic activity. Sixteen younger [age (mean ± SD) = 25.4 ± 1.9, 20–30 years] and 16 older (age = 56.7 ± 4.7, 50–70 years) healthy men were asked to use a power grip to perform six trials each of easy and complex force tracking tasks (FTTs) with their right dominant hand in a randomized within-subject design. Grip force control was assessed using a sensor-based device. Brain activity in premotor and primary motor areas of both hemispheres was assessed by electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS). Older adults showed significantly higher inaccuracies and higher hemodynamic activity in both FTTs than did young adults. Correlations between grip force control owing to task complexity and beta activity were different in the contralateral premotor cortex (PMC) between younger and older adults. Collectively, these findings suggest that aging leads to impairment of grip force control and an increase in hemodynamic activity independent of task complexity. EEG beta oscillations may represent a task-specific neurophysiological marker for age-related decline in complex grip force control and its underlying compensation strategies. Further EEG-fNIRS studies are necessary to determine neurophysiological markers of dysfunctions underlying age-related motor disabilities for the improvement of individual diagnosis and therapeutic approaches.
Electrophysiological Profile Remodeling via Selective Suppression of Voltage-Gated Currents by CLN1/PPT1 Overexpression in Human Neuronal-Like Cells
Authors: Demontis Gian Carlo , Pezzini Francesco , Margari Elisa , Bianchi Marzia , Longoni Biancamaria , Doccini Stefano , Lalowski Maciej Maurycy , Santorelli Filippo Maria , Simonati Alessandro
Published: January 2021

CLN1 disease (OMIM #256730) is an inherited neurological disorder of early childhood with epileptic seizures and premature death. It is associated with mutations in CLN1 coding for Palmitoyl-Protein Thioesterase 1 (PPT1), a lysosomal enzyme which affects the recycling and degradation of lipid-modified (S-acylated) proteins by removing palmitate residues. Transcriptomic evidence from a neuronal-like cellular model derived from differentiated SH-SY5Y cells disclosed the potential negative roles of CLN1 overexpression, affecting the elongation of neuronal processes and the expression of selected proteins of the synaptic region. Bioinformatic inquiries of transcriptomic data pinpointed a dysregulated expression of several genes coding for proteins related to voltage-gated ion channels, including subunits of calcium and potassium channels (VGCC and VGKC). In SH-SY5Y cells overexpressing CLN1 (SH-CLN1 cells), the resting potential and the membrane conductance in the range of voltages close to the resting potential were not affected. However, patch-clamp recordings indicated a reduction of Ba2+ currents through VGCC of SH-CLN1 cells; Ca2+ imaging revealed reduced Ca2+ influx in the same cellular setting. The results of the biochemical and morphological investigations of CACNA2D2/α2δ-2, an accessory subunit of VGCC, were in accordance with the downregulation of the corresponding gene and consistent with the hypothesis that a lower number of functional channels may reach the plasma membrane. The combined use of 4-AP and NS-1643, two drugs with opposing effects on Kv11 and Kv12 subfamilies of VGKC coded by the KCNH gene family, provides evidence for reduced functional Kv12 channels in SH-CLN1 cells, consistent with transcriptomic data indicating the downregulation of KCNH4. The lack of compelling evidence supporting the palmitoylation of many ion channels subunits investigated in this study stimulates inquiries about the role of PPT1 in the trafficking of channels to the plasma membrane. Altogether, these results indicate a reduction of functional voltage-gated ion channels in response to CLN1/PPT1 overexpression in differentiated SH-SY5Y cells and provide new insights into the altered neuronal excitability which may underlie the severe epileptic phenotype of CLN1 disease. It remains to be shown if remodeling of such functional channels on plasma membrane can occur as a downstream effect of CLN1 disease.
Sevoflurane-Induced Neuroapoptosis in Rat Dentate Gyrus Is Activated by Autophagy Through NF-κB Signaling on the Late-Stage Progenitor Granule Cells
Authors: Tong Dongyi , Ma Zhongliang , Su Peng , Wang Shuai , Xu Ying , Zhang Li Min , Wu Ziyi , Liu Kun , Zhao Ping
Published: January 2021

Objective

The mechanisms by which exposure of the late-stage progenitor cells to the anesthesia sevoflurane alters their differentiation are not known. We seek to query whether the effects of sevoflurane on late-stage progenitor cells might be regulated by apoptosis and/or autophagy.

Methods

To address the short-term impact of sevoflurane exposure on granule cell differentiation, we used 5-bromo-2-deoxyuridine (BrdU) to identify the labeled late-stage progenitor granule cells. Male or female rats were exposed to 3% sevoflurane for 4 h when the labeled granule cells were 2 weeks old. Differentiation of the BrdU-labeled granule cells was quantified 4 and 7 days after exposure by double immunofluorescence. The expression of apoptosis and autophagy in hippocampal dentate gyrus (DG) was determined by western blot and immunofluorescence. Western blot for the expression of NF-κB was used to evaluate the mechanism. Morris water maze (MWM) test was performed to detect cognitive function in the rats on postnatal 28–33 days.

Results

Exposure to sevoflurane decreased the differentiation of the BrdU-labeled late-stage progenitor granule cells, but increased the expression of caspase-3, autophagy, and phosphorylated-P65 in the hippocampus of juvenile rats and resulted in cognitive deficiency. These damaging effects of sevoflurane could be mitigated by inhibitors of autophagy, apoptosis, and NF-κB. The increased apoptosis could be alleviated by pretreatment with the autophagy inhibitor 3-MA, and the increased autophagy and apoptosis could be reduced by pretreatment with NF-κB inhibitor BAY 11-7085.

Conclusion

These findings suggest that a single, prolonged sevoflurane exposure could impair the differentiation of late-stage progenitor granule cells in hippocampal DG and cause cognitive deficits possibly via apoptosis activated by autophagy through NF-κB signaling. Our results do not preclude the possibility that the affected differentiation and functional deficits may be caused by depletion of the progenitors pool.
Comparing Theories for the Maintenance of Late LTP and Long-Term Memory: Computational Analysis of the Roles of Kinase Feedback Pathways and Synaptic Reactivation
Authors: Smolen Paul , Baxter Douglas A. , Byrne John H.
Published: January 2021

A fundamental neuroscience question is how memories are maintained from days to a lifetime, given turnover of proteins that underlie expression of long-term synaptic potentiation (LTP) or “tag” synapses as eligible for LTP. A likely solution relies on synaptic positive feedback loops, prominently including persistent activation of Ca2+/calmodulin kinase II (CaMKII) and self-activated synthesis of protein kinase M ζ (PKMζ). Data also suggest positive feedback based on recurrent synaptic reactivation within neuron assemblies, or engrams, is necessary to maintain memories. The relative importance of these mechanisms is controversial. To explore the likelihood that each mechanism is necessary or sufficient to maintain memory, we simulated maintenance of LTP with a simplified model incorporating persistent kinase activation, synaptic tagging, and preferential reactivation of strong synapses, and analyzed implications of recent data. We simulated three model variants, each maintaining LTP with one feedback loop: autonomous, self-activated PKMζ synthesis (model variant I); self-activated CamKII (model variant II); and recurrent reactivation of strengthened synapses (model variant III). Variant I predicts that, for successful maintenance of LTP, either 1) PKMζ contributes to synaptic tagging, or 2) a low constitutive tag level persists during maintenance independent of PKMζ, or 3) maintenance of LTP is independent of tagging. Variant II maintains LTP and suggests persistent CaMKII activation could maintain PKMζ activity, a feedforward interaction not previously considered. However, we note data challenging the CaMKII feedback loop. In Variant III synaptic reactivation drives, and thus predicts, recurrent or persistent activation of CamKII and other necessary kinases, plausibly contributing to persistent elevation of PKMζ levels. Reactivation is thus predicted to sustain recurrent rounds of synaptic tagging and incorporation of plasticity-related proteins. We also suggest (model variant IV) that synaptic reactivation and autonomous kinase activation could synergistically maintain LTP. We propose experiments that could discriminate these maintenance mechanisms.
PKA-Dependent Membrane Surface Recruitment of CI-AMPARs Is Crucial for BCP-Mediated Protection Against Post-acute Ischemic Stroke Cognitive Impairment
Authors: Chen Sha , Wang Yuchun , Wang Xuhui , He Meng , Zhang Lu , Dong Zhi
Published: January 2021

Post-acute ischemic stroke cognitive impairment frequently occurs and seriously affects patients daily activities. Recruitment of GluA2-containing Ca2+-impermeable AMPA receptors (CI-AMPARs) to hippocampal synaptic membrane surfaces was shown to trigger synaptic plasticity. Currently, the effect of CI-AMPAR trafficking on acute ischemic stroke remains poorly understood. β-Caryophyllene (BCP) has been shown to ameliorate cognitive impairment. However, the mechanism has not been characterized. In this study, a 60-min temporary middle cerebral artery occlusion (MCAO) model was established to simulate the pathology of acute ischemic stroke. BCP reduced neurologic deficits, cerebral infarct volume, and pathological damage in MCAO mice and caused CI-AMPARs to translocate to synaptic membranes in the hippocampus; surface expression of CI-AMPARs was also decreased in MCAO mice. Furthermore, this study also showed that BCP treatment significantly activated the cAMP/PKA pathway, which is consistent with the synaptic membrane expression of CI-AMPARs. To better understand the underlying mechanisms, the PKA inhibitor H-89 was used to study the role of BCP in MCAO mice. Interestingly, H-89 treatment significantly disrupted the BCP-mediated facilitation of CI-AMPAR translocation to the synaptic membrane surface and substantially attenuated BCP-induced protection against acute ischemic stroke. Additionally, inhibition the cAMP/PKA pathway not only reduced BCP-induced inhibition of AMPAR-mediated excitatory postsynaptic currents in the hippocampal CA1 region but also decreased the effect of BCP-mediated protection against post-acute ischemic stroke cognitive impairment. Taken together, these data indicate that PKA-dependent synaptic membrane surface recruitment of CI-AMPARs is crucial for the neuroprotective effect of BCP against acute ischemic stroke and protection against post-acute ischemic stroke cognitive impairment.
Contributions of Robotics to the Safety and Efficacy of Invasive Monitoring With Stereoelectroencephalography
Authors: Faraji Amir H. , Remick Madison , Abel Taylor J.
Published: January 2021

The purpose of this review is to provide a discussion of the history and utility of robotics in invasive monitoring for epilepsy surgery using stereoelectroencephalography (sEEG). The authors conducted a literature review of available sources to describe how the advent of surgical robotics has improved the efficacy and ease of performing sEEG surgery. The sEEG method integrates anatomic, electrographic, and clinical information to test hypotheses regarding the localization of the epileptogenic zone (EZ) and has been used in Europe since the 1950s. One of the primary benefits of robot-assisted sEEG implantation techniques is the ability to seamlessly transition between both orthogonal and oblique trajectory types using a single technique. Based on available information, it is our view that, when applied appropriately, robotic sEEG can have a low rate of complications and many advantages over both non-robotic sEEG implantation and traditional craniotomy-based invasive monitoring methods.
Preliminary Study of Subclinical Brain Alterations in Patients With Asymptomatic Carotid Vulnerable Plaques Using Intravoxel Incoherent Motion Imaging by Voxelwise Comparison: A Study of Whole-Brain Imaging Measures
Authors: Guo Jiuqing , OuYang Lirong , Wang Xiaoyi , Liao Weihua , Huang Qing , He Wei , Zhou Gaofeng , Yang Shuai
Published: January 2021

Objective

To preliminarily explore subclinical brain alterations in an asymptomatic carotid vulnerable plaque group based on intravoxel incoherent motion (IVIM) imaging through voxelwise comparison in the whole brain.

Materials and Methods

Forty-nine elderly participants underwent multi-b-value DWI, of whom 24 participants with asymptomatic carotid vulnerable plaques and <50% stenosis served as the test group, while the rest served as the healthy control group. After fitting the double-exponential model, slow ADC (Ds) and the fraction of fast ADC (f) values of the whole brain were obtained, which then were compared in a voxelwise manner by two-sample t-test. Multiple comparisons were corrected by the family-wise error (FWE) method with a corrected threshold of P < 0.05. Pearson correlations between IVIM parameters in altered brain regions and blood pressure, glucose, lipid, and homocysteine were calculated.

Results

For the test group, the Z-normalized Ds values were significantly higher in the left median cingulate and paracingulate gyrus (DCG.L), posterior cingulate gyrus (PCG. L), and left precuneus gyrus (PCUN.L) (cluster size = 156) and in the left middle frontal gyrus (MFG.L), orbital middle frontal gyrus (ORBmid.L), and superior frontal gyrus (SFG.L) (cluster size = 165); the Z-normalized Ds values were significantly lower in the right middle temporal gyrus (MTG.R) and inferior temporal gyrus (ITG.R) (cluster size = 116); and the Z-normalized f-values were significantly lower in the MTG.R and ITG.R (cluster size = 85) (p < 0.05, FWE correction). LDL-C was negatively correlated with the Z-normalized Ds values in the DCG.L, PCG.L, and PCUN.L (r = 0.601, p = 0.002). LDL-C was positively correlated with the Z-normalized f-value in the MTG.R and ITG.R (r = 0.405, p = 0.05). Systolic blood pressure was positively correlated with the Z-normalized Ds values in the MFG.L, ORBmid.L, and SFG.L (r = 0.433, p = 0.035).

Conclusion

This study was the first to detect subclinical brain alterations in asymptomatic carotid vulnerable plaque group through IVIM using whole-brain voxelwise comparisons, which were partially correlated with blood pressure and lipids. Thus, IVIM might be utilized as a noninvasive biomarker of microvascular and microstructural brain changes in the asymptomatic carotid vulnerable plaque group.
Deep Neural Network Model of Hearing-Impaired Speech-in-Noise Perception
Authors: Haro Stephanie , Smalt Christopher J. , Ciccarelli Gregory A. , Quatieri Thomas F.
Published: January 2021

Many individuals struggle to understand speech in listening scenarios that include reverberation and background noise. An individual's ability to understand speech arises from a combination of peripheral auditory function, central auditory function, and general cognitive abilities. The interaction of these factors complicates the prescription of treatment or therapy to improve hearing function. Damage to the auditory periphery can be studied in animals; however, this method alone is not enough to understand the impact of hearing loss on speech perception. Computational auditory models bridge the gap between animal studies and human speech perception. Perturbations to the modeled auditory systems can permit mechanism-based investigations into observed human behavior. In this study, we propose a computational model that accounts for the complex interactions between different hearing damage mechanisms and simulates human speech-in-noise perception. The model performs a digit classification task as a human would, with only acoustic sound pressure as input. Thus, we can use the model's performance as a proxy for human performance. This two-stage model consists of a biophysical cochlear-nerve spike generator followed by a deep neural network (DNN) classifier. We hypothesize that sudden damage to the periphery affects speech perception and that central nervous system adaptation over time may compensate for peripheral hearing damage. Our model achieved human-like performance across signal-to-noise ratios (SNRs) under normal-hearing (NH) cochlear settings, achieving 50% digit recognition accuracy at −20.7 dB SNR. Results were comparable to eight NH participants on the same task who achieved 50% behavioral performance at −22 dB SNR. We also simulated medial olivocochlear reflex (MOCR) and auditory nerve fiber (ANF) loss, which worsened digit-recognition accuracy at lower SNRs compared to higher SNRs. Our simulated performance following ANF loss is consistent with the hypothesis that cochlear synaptopathy impacts communication in background noise more so than in quiet. Following the insult of various cochlear degradations, we implemented extreme and conservative adaptation through the DNN. At the lowest SNRs (<0 dB), both adapted models were unable to fully recover NH performance, even with hundreds of thousands of training samples. This implies a limit on performance recovery following peripheral damage in our human-inspired DNN architecture.
Brain Functional Interaction of Acupuncture Effects in Diarrhea-Dominant Irritable Bowel Syndrome
Authors: Ma Kai , Liu Yongkang , Shao Wei , Sun Jianhua , Li Jing , Fang Xiaokun , Li Jing , Wang Zhongqiu , Zhang Daoqiang
Published: January 2021

Acupuncture is a traditional Chinese medicine treatment that has widely been used to modulate gastrointestinal dysfunction caused by irritable bowel syndrome (IBS) and to alleviate the resulting pain. Recent studies have shown that gastrointestinal dysfunction caused by IBS is associated with dysregulation of the brain's central and peripheral nervous system, while functional magnetic resonance imaging (fMRI) helps explore functional abnormality of the brain. However, previous studies rarely used fMRI to study the correlations between brain functional connection, interaction, or segregation (e.g., network degree and clustering coefficient) and acupuncture stimulation in IBS. To bridge this knowledge gap, we study the changed brain functional connection, interaction, and segregation before and after acupuncture stimulation for diarrhea-dominant IBS (IBS-D) with the help of complex network methods based on fMRI. Our results indicate that the abnormal functional connections (FCs) in the right hippocampus, right superior occipital gyrus, left lingual gyrus, left middle occipital gyrus, and the cerebellum, and abnormal network degree in right middle occipital gyrus, where normal controls are significantly different from IBS-D patients, are improved after acupuncture stimulation. These changed FCs and the network degree before and after acupuncture stimulation have significant correlations with the changed clinical information including IBS symptom severity score (r = −0.54, p = 0.0065) and IBS quality of life (r = 0.426, p = 0.038). We conclude that the changes of the brain functional connection, interaction, and segregation in the hippocampus, middle and superior occipital gyrus, cerebellum, and the lingual gyrus may be related to acupuncture stimulation. The abnormal functional connection, interaction, and segregation in IBS-D may be improved after acupuncture stimulation.
Preventing Neurodegeneration by Controlling Oxidative Stress: The Role of OXR1
Authors: Volkert Michael R. , Crowley David J.
Published: January 2021

Parkinson’s disease, diabetic retinopathy, hyperoxia induced retinopathy, and neuronal damage resulting from ischemia are among the notable neurodegenerative diseases in which oxidative stress occurs shortly before the onset of neurodegeneration. A shared feature of these diseases is the depletion of OXR1 (oxidation resistance 1) gene products shortly before the onset of neurodegeneration. In animal models of these diseases, restoration of OXR1 has been shown to reduce or eliminate the deleterious effects of oxidative stress induced cell death, delay the onset of symptoms, and reduce overall severity. Moreover, increasing OXR1 expression in cells further increases oxidative stress resistance and delays onset of disease while showing no detectable side effects. Thus, restoring or increasing OXR1 function shows promise as a therapeutic for multiple neurodegenerative diseases. This review examines the role of OXR1 in oxidative stress resistance and its impact on neurodegenerative diseases. We describe the potential of OXR1 as a therapeutic in light of our current understanding of its function at the cellular and molecular level and propose a possible cascade of molecular events linked to OXR1’s regulatory functions.
Molecular Imaging of Tau Protein: New Insights and Future Directions
Authors: Pizzarelli Rocco , Pediconi Natalia , Di Angelantonio Silvia
Published: January 2021

Tau is a microtubule-associated protein (MAPT) that is highly expressed in neurons and implicated in several cellular processes. Tau misfolding and self-aggregation give rise to proteinaceous deposits known as neuro-fibrillary tangles. Tau tangles play a key role in the genesis of a group of diseases commonly referred to as tauopathies; notably, these aggregates start to form decades before any clinical symptoms manifest. Advanced imaging methodologies have clarified important structural and functional aspects of tau and could have a role as diagnostic tools in clinical research. In the present review, recent progresses in tau imaging will be discussed. We will focus mainly on super-resolution imaging methods and the development of near-infrared fluorescent probes.