bluuebunny/crossref_metadata_2025 huggingface dataset:
Negative Regulator Nlrc3-like Maintain the Balanced Innate Immune Response During Mycobacterial Infection in Zebrafish
Authors: Niu Liangfei , Luo Geyang , Liang Rui , Qiu Chenli , Yang Jianwei , Xie Lingling , Zhang Kaile , Tian Yu , Wang Decheng , Song Shu , Takiff Howard E. , Wong Ka-Wing , Fan Xiaoyong , Gao Qian , Yan Bo
Published: May 2022

The NOD-like receptors (NLRs) have been shown to be involved in infection and autoinflammatory disease. Previously, we identified a zebrafish NLR, nlrc3-like, required for macrophage homeostasis in the brain under physiological conditions. Here, we found that a deficiency of nlrc3-like leads to decreased bacterial burden at a very early stage of Mycobacterium marinum infection, along with increased production of pro-inflammatory cytokines, such as il-1β and tnf-α. Interestingly, myeloid-lineage specific overexpression of nlrc3-like achieved the opposite effects, suggesting that the impact of nlrc3-like on the host anti-mycobacterial response is mainly due to its expression in the innate immune system. Fluorescence-activated cell sorting (FACS) and subsequent gene expression analysis demonstrated that inflammasome activation-related genes were upregulated in the infected macrophages of nlrc3-like deficient embryos. By disrupting asc, encoding apoptosis-associated speck-like protein containing a CARD, a key component for inflammasome activation, the bacterial burden increased in asc and nlrc3-like double deficient embryos compared with nlrc3-like single deficient embryos, implying the involvement of inflammasome activation in infection control. We also found extensive neutrophil infiltration in the nlrc3-like deficient larvae during infection, which was associated with comparable bacterial burden but increased tissue damage and death at a later stage that could be alleviated by administration of dexamethasone. Our findings uncovered an important role of nlrc3-like in the negative regulation of macrophage inflammasome activation and neutrophil infiltration during mycobacterial infection. This highlights the importance of a balanced innate immune response during mycobacterial infection and provides a potential molecular basis to explain how anti-inflammatory drugs can improve treatment outcomes in TB patients whose infection is accompanied by a hyperinflammatory response.
Myocardial-Treg Crosstalk: How to Tame a Wolf
Authors: Weiß Emil , Ramos Gustavo Campos , Delgobo Murilo
Published: May 2022

The immune system plays a vital role in maintaining tissue integrity and organismal homeostasis. The sudden stress caused by myocardial infarction (MI) poses a significant challenge for the immune system: it must quickly substitute dead myocardial with fibrotic tissue while controlling overt inflammatory responses. In this review, we will discuss the central role of myocardial regulatory T-cells (Tregs) in orchestrating tissue repair processes and controlling local inflammation in the context of MI. We herein compile recent advances enabled by the use of transgenic mouse models with defined cardiac antigen specificity, explore whole-heart imaging techniques, outline clinical studies and summarize deep-phenotyping conducted by independent labs using single-cell transcriptomics and T-cell repertoire analysis. Furthermore, we point to multiple mechanisms and cell types targeted by Tregs in the infarcted heart, ranging from pro-fibrotic responses in mesenchymal cells to local immune modulation in myeloid and lymphoid lineages. We also discuss how both cardiac-specific and polyclonal Tregs participate in MI repair. In addition, we consider intriguing novel evidence on how the myocardial milieu takes control of potentially auto-aggressive local immune reactions by shaping myosin-specific T-cell development towards a regulatory phenotype. Finally, we examine the potential use of Treg manipulating drugs in the clinic after MI.
Movements and Diving Behavior of the Eastern North Pacific Offshore Killer Whale (Orcinus orca)
Authors: Schorr Gregory S. , Hanson M. Bradley , Falcone Erin A. , Emmons Candice K. , Jarvis Susan M. , Andrews Russel D. , Keen Eric M.
Published: May 2022

The Pacific Offshore killer whale population is currently listed as data deficient on the IUCN Red List and Threatened in Canada. The population is estimated at 300 individuals with a range extending from Southern California to the Aleutian Islands in Alaska. Only 157 encounters with this ecotype have been photo-documented between 1988 and 2014; consequently, movement and behavioral data are limited and restricted to areas commonly surveyed. To better understand movements, habitat use, and diving behavior, we deployed seven dart-attached satellite tags during two encounters with Offshores off California and one encounter off Washington State in 2013. Group size estimates were 6, 9, and 30 whales, respectively. Transmission durations ranged from 6.3 to 147.4 days providing a combined 2,469 location estimates. Whales tagged in Southern California travelled from 30.7°N to 59.3°N degrees latitude, covering a larger latitudinal range in 75 days than all previous sightings (33.5°N to 60.0°N). Within most of the California Current (southern extent of locations up to 48.5°N), Offshores typically used waters deeper than the 200 m isobath. As they approached the northern extent of the California Current and travelled into British Columbia and Alaska, locations were more common near or inside the 200 m isobath. Individuals tagged in the same group disassociated and re-associated within the tracking duration, with animals tagged together separating by as much 1,339 km. Two of the tags also reported summarized diving behavior, and tags captured 1,110 total dives with median dive depths of 41 m and 100 m for each tagged whale; the maximum dive depth was 480 m. Dives were typically short (median = 3.9 and 4.1 min respectively, max = 12.3). A comparison of dive depths and bathymetry suggests that whales typically dove to or near the seafloor in continental shelf habitat. Despite the small number of tag deployments, these data provide new information on social structure, individual ranges, diving behavior, and habitat use of this seldom encountered killer whale ecotype.
Aerial Drones Reveal the Dynamic Structuring of Sea Turtle Breeding Aggregations and Minimum Survey Effort Required to Capture Climatic and Sex-Specific Effects
Authors: Dickson Liam C. D. , Tugwell Hannah , Katselidis Kostas A. , Schofield Gail
Published: May 2022

Quantifying how animals use key habitats and resources for their survival allows managers to optimise conservation planning; however, obtaining representative sample sizes of wildlife distributions in both time and space is challenging, particularly in the marine environment. Here, we used unoccupied aircraft systems (UASs) to evaluate temporal and spatial variation in the distribution of loggerhead sea turtles (Caretta caretta) at two high-density breeding aggregations in the Mediterranean, and the effect of varying sample size and survey frequency. In May–June of 2017 to 2019, we conducted 69 surveys, assimilating 10,075 inwater turtle records at the two sites. Optimal time interval between surveys to capture the dynamics of aggregations over the breeding period was <2-week intervals and >500 turtles (from the combined surveys). This minimum threshold was attributed to the core-area use of female turtles shifting across surveys in relation to wind direction to access warmer nearshore waters and male presence. Males were more widely distributed within aggregations than females, particularly in May when mating encounters were high. Most males were recorded swimming and oriented parallel to shore, likely to enhance encounter rates with females. In contrast, most females were generally stationary (resting on the seabed or basking), likely to conserve energy for reproduction, with orientation appearing to shift in relation to male numbers at the breeding area. Thus, by identifying the main factors regulating the movement and distribution of animals, appropriate survey intervals can be selected for appropriate home range analyses. Our study demonstrates the versatility of UASs to capture the fine-scale dynamics of wildlife aggregations and associated factors, which is important for implementing effective conservation.
Theoretical Investigation of Effects of Transition Elements on Phase Stabilities and Elastic Properties of the γ′ Phase in Co–V–Ta Superalloys
Authors: Chen Youheng , Wang Cuiping , Zhang Chi , Yang Chen , Han Jiajia , Liu Xingjun
Published: May 2022

In order to improve the thermal stability and mechanical properties of W-free light-weight Co–V–Ta-based superalloys, the effects of alloying elements including Sc, Ti, Cr, Mn, Fe, Ni, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Hf, W, Re, Os, Ir, and Pt on γ′-Co3(V, Ta) stability and elastic properties were studied. The results from the reaction energy indicate that Sc, Ti, Y, Zr, Nb, Mo, Hf, and W tend to occupy the V site, whereas Cr, Mn, Fe, Ni, Tc, Ru, Rh, Pd, Re, Os, Ir, and Pt prefer to occupy the Co site. It was found that Sc, Ti, Y, Zr, Fe, and Mn stabilize the γ′-Co3(V, Ta) phase by raising the phase-transfer energy. The addition of Mo and W increases the bulk modulus, shear modulus, and Young’s modulus. According to Pugh’s classical criterion, the γ′-Co3(V, Ta) phase is an intrinsically brittle material, and the addition of elements such as Tc and Re significantly enhances the ductility. At finite temperature, the doping of Sc, Ti, Mn, Fe, and Hf enhances the relative stability of the γ′-Co3(V, Ta) phase in the whole temperature range from 0 to 1200 K and are candidates for improving the stability of the γ′-Co3(V, Ta) phase.
Putative Biomarkers in Tears for Diabetic Retinopathy Diagnosis
Authors: Amorim Madania , Martins Beatriz , Caramelo Francisco , Gonçalves Conceição , Trindade Grimalde , Simão Jorge , Barreto Patrícia , Marques Inês , Leal Ermelindo Carreira , Carvalho Eugénia , Reis Flávio , Ribeiro-Rodrigues Teresa , Girão Henrique , Rodrigues-Santos Paulo , Farinha Cláudia , Ambrósio António Francisco , Silva Rufino , Fernandes Rosa
Published: May 2022

Purpose

Tear fluid biomarkers may offer a non-invasive strategy for detecting diabetic patients with increased risk of developing diabetic retinopathy (DR) or increased disease progression, thus helping both improving diagnostic accuracy and understanding the pathophysiology of the disease. Here, we assessed the tear fluid of nondiabetic individuals, diabetic patients with no DR, and diabetic patients with nonproliferative DR (NPDR) or with proliferative DR (PDR) to find putative biomarkers for the diagnosis and staging of DR.

Methods

Tear fluid samples were collected using Schirmer test strips from a cohort with 12 controls and 54 Type 2 Diabetes (T2D) patients, and then analyzed using mass spectrometry (MS)-based shotgun proteomics and bead-based multiplex assay. Tear fluid-derived small extracellular vesicles (EVs) were analyzed by transmission electron microscopy, Western Blotting, and nano tracking.

Results

Proteomics analysis revealed that among the 682 reliably quantified proteins in tear fluid, 42 and 26 were differentially expressed in NPDR and PDR, respectively, comparing to the control group. Data are available via ProteomeXchange with identifier PXD033101. By multicomparison analyses, we also found significant changes in 32 proteins. Gene ontology (GO) annotations showed that most of these proteins are associated with oxidative stress and small EVs. Indeed, we also found that tear fluid is particularly enriched in small EVs. T2D patients with NPDR have higher IL-2/-5/-18, TNF, MMP-2/-3/-9 concentrations than the controls. In the PDR group, IL-5/-18 and MMP-3/-9 concentrations were significantly higher, whereas IL-13 was lower, compared to the controls.

Conclusions

Overall, the results show alterations in tear fluid proteins profile in diabetic patients with retinopathy. Promising candidate biomarkers identified need to be validated in a large sample cohort.
A Defined Medium for Cultivation and Exometabolite Profiling of Soil Bacteria
Authors: de Raad Markus , Li Yifan V. , Kuehl Jennifer V. , Andeer Peter F. , Kosina Suzanne M. , Hendrickson Andrew , Saichek Nicholas R. , Golini Amber N. , Han La Zhen , Wang Ying , Bowen Benjamin P. , Deutschbauer Adam M. , Arkin Adam P. , Chakraborty Romy , Northen Trent R.
Published: May 2022

Exometabolomics is an approach to assess how microorganisms alter, or react to their environments through the depletion and production of metabolites. It allows the examination of how soil microbes transform the small molecule metabolites within their environment, which can be used to study resource competition and cross-feeding. This approach is most powerful when used with defined media that enable tracking of all metabolites. However, microbial growth media have traditionally been developed for the isolation and growth of microorganisms but not metabolite utilization profiling through Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). Here, we describe the construction of a defined medium, the Northen Lab Defined Medium (NLDM), that not only supports the growth of diverse soil bacteria but also is defined and therefore suited for exometabolomic experiments. Metabolites included in NLDM were selected based on their presence in R2A medium and soil, elemental stoichiometry requirements, as well as knowledge of metabolite usage by different bacteria. We found that NLDM supported the growth of 108 of the 110 phylogenetically diverse (spanning 36 different families) soil bacterial isolates tested and all of its metabolites were trackable through LC–MS/MS analysis. These results demonstrate the viability and utility of the constructed NLDM medium for growing and characterizing diverse microbial isolates and communities.
Metagenomics Reveals Dominant Unusual Sulfur Oxidizers Inhabiting Active Hydrothermal Chimneys From the Southwest Indian Ridge
Authors: Wang Yong , Bi Hong-Yu , Chen Hua-Guan , Zheng Peng-Fei , Zhou Ying-Li , Li Jiang-Tao
Published: May 2022

The deep-sea hydrothermal vents (DSHVs) in the Southwest Indian Ridge (SWIR) are formed by specific geological settings. However, the community structure and ecological function of the microbial inhabitants on the sulfide chimneys of active hydrothermal vents remain largely unknown. In this study, our analyses of 16S rRNA gene amplicons and 16S rRNA metagenomic reads showed the dominance of sulfur-oxidizing Ectothiorhodospiraceae, Thiomicrorhabdus, Sulfurimonas, and Sulfurovum on the wall of two active hydrothermal chimneys. Compared with the inactive hydrothermal sediments of SWIR, the active hydrothermal chimneys lacked sulfur-reducing bacteria. The metabolic potentials of the retrieved 82 metagenome-assembled genomes (MAGs) suggest that sulfur oxidation might be conducted by Thiohalomonadales (classified as Ectothiorhodospiraceae based on 16S rRNA gene amplicons), Sulfurovaceae, Hyphomicrobiaceae, Thiotrichaceae, Thiomicrospiraceae, and Rhodobacteraceae. For CO2 fixation, the Calvin-Benson-Bassham and reductive TCA pathways were employed by these bacteria. In Thiohalomonadales MAGs, we revealed putative phytochrome, carotenoid precursor, and squalene synthesis pathways, indicating a possible capacity of Thiohalomonadales in adaptation to dynamics redox conditions and the utilization of red light from the hot hydrothermal chimneys for photolithotrophic growth. This study, therefore, reveals unique microbiomes and their genomic features in the active hydrothermal chimneys of SWIR, which casts light on ecosystem establishment and development in hydrothermal fields and the deep biosphere.
Identification of MYH9 Key Domain Involved in the Entry of PRRSV Into Permissive Cells
Authors: Li Liangliang , Sun Weiyao , Hu Qifan , Wang Tongtong , Zhu Guang , Zhao Qin , Zhou En-Min
Published: May 2022

Porcine reproductive and respiratory syndrome virus (PRRSV) is an important pathogen that causes huge losses economically to the pig industry worldwide. Previous research suggested that receptor dependence is necessary for PRRSV infection. MYH9 and CD163 are indispensable for PRRSV entry into a porcine alveolar macrophage. In the present study, human MYH9 (hMYH9) and mouse MYH9 (mMYH9), similar to swine MYH9, could also accelerate PRRSV infection in pCD163-mediated cell lines. Knockdown of MYH9 activity using the specific small interfering RNA or inhibitor (blebbistatin) concomitantly decreased PRRSV infection. C-terminal fragment of MYH9 (PRA) proteins from different mammalian species contains a conserved binding domain (aa1676-1791) for PRRSV binding, since the recombinant MYH91676−1791protein could inhibit the PRRSV infection significantly. Furthermore, the specific polyclonal antibody of MYH91676−1791 could block PRRSV infection in host cells. These data strongly supported that MYH9, a very important cofactor, participated in PRRSV entry into target cells, which may facilitate the development of a new therapeutic agent to control PRRSV infection.
Patterning of the Autotrophic, Mixotrophic, and Heterotrophic Proteomes of Oxygen-Evolving Cyanobacterium Synechocystis sp. PCC 6803
Authors: Muth-Pawlak Dorota , Kreula Sanna , Gollan Peter J. , Huokko Tuomas , Allahverdiyeva Yagut , Aro Eva-Mari
Published: May 2022

Proteomes of an oxygenic photosynthetic cyanobacterium, Synechocystis sp. PCC 6803, were analyzed under photoautotrophic (low and high CO2, assigned as ATLC and ATHC), photomixotrophic (MT), and light-activated heterotrophic (LAH) conditions. Allocation of proteome mass fraction to seven sub-proteomes and differential expression of individual proteins were analyzed, paying particular attention to photosynthesis and carbon metabolism–centered sub-proteomes affected by the quality and quantity of the carbon source and light regime upon growth. A distinct common feature of the ATHC, MT, and LAH cultures was low abundance of inducible carbon-concentrating mechanisms and photorespiration-related enzymes, independent of the inorganic or organic carbon source. On the other hand, these cells accumulated a respiratory NAD(P)H dehydrogenase I (NDH-11) complex in the thylakoid membrane (TM). Additionally, in glucose-supplemented cultures, a distinct NDH-2 protein, NdbA, accumulated in the TM, while the plasma membrane-localized NdbC and terminal oxidase decreased in abundance in comparison to both AT conditions. Photosynthetic complexes were uniquely depleted under the LAH condition but accumulated under the ATHC condition. The MT proteome displayed several heterotrophic features typical of the LAH proteome, particularly including the high abundance of ribosome as well as amino acid and protein biosynthesis machinery-related components. It is also noteworthy that the two equally light-exposed ATHC and MT cultures allocated similar mass fractions of the total proteome to the seven distinct sub-proteomes. Unique trophic condition-specific expression patterns were likewise observed among individual proteins, including the accumulation of phosphate transporters and polyphosphate polymers storing energy surplus in highly energetic bonds under the MT condition and accumulation under the LAH condition of an enzyme catalyzing cyanophycin biosynthesis. It is concluded that the rigor of cell growth in the MT condition results, to a great extent, by combining photosynthetic activity with high intracellular inorganic carbon conditions created upon glucose breakdown and release of CO2, besides the direct utilization of glucose-derived carbon skeletons for growth. This combination provides the MT cultures with excellent conditions for growth that often exceeds that of mere ATHC.
Key Genes Associated With Non-Alcoholic Fatty Liver Disease and Polycystic Ovary Syndrome
Authors: Chen Yong , Ma Leikai , Ge Zhouling , Pan Yizhao , Xie Lubin
Published: May 2022

Background: Polycystic ovary syndrome (PCOS) is the most common metabolic and endocrinopathies disorder in women of reproductive age and non-alcoholic fatty liver (NAFLD) is one of the most common liver diseases worldwide. Previous research has indicated potential associations between PCOS and NAFLD, but the underlying pathophysiology is still not clear. The present study aims to identify the differentially expressed genes (DEGs) between PCOS and NAFLD through the bioinformatics method, and explore the associated molecular mechanisms.

Methods: The microarray datasets GSE34526 and GSE63067 were downloaded from Gene Expression Omnibus (GEO) database and analyzed to obtain the DEGs between PCOS and NAFLD with the GEO2R online tool. Next, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for the DEGs were performed. Then, the protein-protein interaction (PPI) network was constructed and the hub genes were identified using the STRING database and Cytoscape software. Finally, NetworkAnalyst was used to construct the network between the targeted microRNAs (miRNAs) and the hub genes.

Results: A total of 52 genes were identified as DEGs in the above two datasets. GO and KEGG enrichment analysis indicated that DEGs are mostly enriched in immunity and inflammation related pathways. In addition, nine hub genes, including TREM1, S100A9, FPR1, NCF2, FCER1G, CCR1, S100A12, MMP9, and IL1RN were selected from the PPI network by using the cytoHubba and MCODE plug-in. Then, four miRNAs, including miR-20a-5p, miR-129-2-3p, miR-124-3p, and miR-101-3p, were predicted as possibly the key miRNAs through the miRNA-gene network construction.

Conclusion: In summary, we firstly constructed a miRNA-gene regulatory network depicting interactions between the predicted miRNA and the hub genes in NAFLD and PCOS, which provides novel insights into the identification of potential biomarkers and valuable therapeutic leads for PCOS and NAFLD.
Ceramide Aminoethylphosphonate as a New Molecular Target for Pore-Forming Aegerolysin-Based Protein Complexes
Authors: Balbi Teresa , Trenti Francesco , Panevska Anastasija , Bajc Gregor , Guella Graziano , Ciacci Caterina , Canonico Barbara , Canesi Laura , Sepčić Kristina
Published: May 2022

Ostreolysin A6 (OlyA6) is a 15 kDa protein produced by the oyster mushroom (Pleurotus ostreatus). It belongs to the aegerolysin family of proteins and binds with high affinity to the insect-specific membrane sphingolipid, ceramide phosphoethanolamine (CPE). In concert with its partnering protein with the membrane-attack-complex/perforin domain, pleurotolysin B (PlyB), OlyA6 can form bicomponent 13-meric transmembrane pores in artificial and biological membranes containing the aegerolysin lipid receptor, CPE. This pore formation is the main underlying molecular mechanism of potent and selective insecticidal activity of OlyA6/PlyB complexes against two economically important coleopteran plant pests: the western corn rootworm and the Colorado potato beetle. In contrast to insects, the main sphingolipid in cell membranes of marine invertebrates (i.e., molluscs and cnidarians) is ceramide aminoethylphosphonate (CAEP), a CPE analogue built on a phosphono rather than the usual phosphate group in its polar head. Our targeted lipidomic analyses of the immune cells (hemocytes) of the marine bivalve, the mussel Mytilus galloprovincialis, confirmed the presence of 29.0 mol% CAEP followed by 36.4 mol% of phosphatidylcholine and 34.6 mol% of phosphatidylethanolamine. Further experiments showed the potent binding of OlyA6 to artificial lipid vesicles supplemented with mussel CAEP, and strong lysis of these vesicles by the OlyA6/PlyB mixture. In Mytilus haemocytes, short term exposure (max. 1 h) to the OlyA6/PlyB mixture induced lysosomal membrane destabilization, decreased phagocytic activity, increased Annexin V binding and oxyradical production, and decreased levels of reduced glutathione, indicating rapid damage of endo-lysosomal and plasma membranes and oxidative stress. Our data suggest CAEP as a novel high-affinity receptor for OlyA6 and a target for cytolytic OlyA6/PlyB complexes.
A Novel Key Features Screening Method Based on Extreme Learning Machine for Alzheimer’s Disease Study
Authors: Lu Jia , Zeng Weiming , Zhang Lu , Shi Yuhu
Published: May 2022

The Extreme Learning Machine (ELM) is a simple and efficient Single Hidden Layer Feedforward Neural Network(SLFN) algorithm. In recent years, it has been gradually used in the study of Alzheimer’s disease (AD). When using ELM to diagnose AD based on high-dimensional features, there are often some features that have no positive impact on the diagnosis, while others have a significant impact on the diagnosis. In this paper, a novel Key Features Screening Method based on Extreme Learning Machine (KFS-ELM) is proposed. It can screen for key features that are relevant to the classification (diagnosis). It can also assign weights to key features based on their importance. We designed an experiment to screen for key features of AD. A total of 920 key functional connections screened from 4005 functional connections. Their weights were also obtained. The results of the experiment showed that: (1) Using all (4,005) features to diagnose AD, the accuracy is 95.33%. Using 920 key features to diagnose AD, the accuracy is 99.20%. The 3,085 (4,005 - 920) features that were screened out had a negative effect on the diagnosis of AD. This indicates the KFS-ELM is effective in screening key features. (2) The higher the weight of the key features and the smaller their number, the greater their impact on AD diagnosis. This indicates that the KFS-ELM is rational in assigning weights to the key features for their importance. Therefore, KFS-ELM can be used as a tool for studying features and also for improving classification accuracy.
Parallel Spinal Pathways for Transmitting Reflexive and Affective Dimensions of Nocifensive Behaviors Evoked by Selective Activation of the Mas-Related G Protein-Coupled Receptor D-Positive and Transient Receptor Potential Vanilloid 1-Positive Subsets of Nociceptors
Authors: Wang Liang-Biao , Su Xiao-Jing , Wu Qiao-Feng , Xu Xiang , Wang Xin-Yue , Chen Mo , Ye Jia-Reng , Maimaitiabula Abasi , Liu Xiao-Qing , Sun Wen , Zhang Yan
Published: May 2022

The high incidence of treatment-resistant pain calls for the urgent preclinical translation of new analgesics. Understanding the behavioral readout of pain in animals is crucial for efficacy evaluation when developing novel analgesics. Mas-related G protein-coupled receptor D-positive (Mrgprd+) and transient receptor potential vanilloid 1-positive (TRPV1+) sensory neurons are two major non-overlapping subpopulations of C-fiber nociceptors. Their activation has been reported to provoke diverse nocifensive behaviors. However, what kind of behavior reliably represents subjectively conscious pain perception needs to be revisited. Here, we generated transgenic mice in which Mrgprd+ or TRPV1+ sensory neurons specifically express channelrhodopsin-2 (ChR2). Under physiological conditions, optogenetic activation of hindpaw Mrgprd+ afferents evoked reflexive behaviors (lifting, etc.), but failed to produce aversion. In contrast, TRPV1+ afferents activation evoked marked reflexive behaviors and affective responses (licking, etc.), as well as robust aversion. Under neuropathic pain conditions induced by spared nerve injury (SNI), affective behaviors and avoidance can be elicited by Mrgprd+ afferents excitation. Mechanistically, spinal cord-lateral parabrachial nucleus (lPBN) projecting neurons in superficial layers (lamina I–IIo) were activated by TRPV1+ nociceptors in naïve conditions or by Mrgprd+ nociceptors after SNI, whereas only deep spinal cord neurons were activated by Mrgprd+ nociceptors in naïve conditions. Moreover, the excitatory inputs from Mrgprd+ afferents to neurons within inner lamina II (IIi) are partially gated under normal conditions. Altogether, we conclude that optogenetic activation of the adult Mrgprd+ nociceptors drives non-pain-like reflexive behaviors via the deep spinal cord pathway under physiological conditions and drives pain-like affective behaviors via superficial spinal cord pathway under pathological conditions. The distinct spinal pathway transmitting different forms of nocifensive behaviors provides different therapeutic targets. Moreover, this study appeals to the rational evaluation of preclinical analgesic efficacy by using comprehensive and suitable behavioral assays, as well as by assessing neural activity in the two distinct pathways.
MRI-Based Demonstration of the Normal Glymphatic System in a Human Population: A Systematic Review
Authors: Lee Min Kyoung , Cho Se Jin , Bae Yun Jung , Kim Jong-Min
Published: May 2022

Background

The glymphatic system has been described as one that facilitates the exchange between the cerebrospinal fluid (CSF) and interstitial fluid, and many recent studies have demonstrated glymphatic flow based on magnetic resonance imaging (MRI). We aim to systematically review the studies demonstrating a normal glymphatic flow in a human population using MRI and to propose a detailed glymphatic imaging protocol.

Methods

We searched the MEDLINE and EMBASE databases to identify studies with human participants involving MRI-based demonstrations of the normal glymphatic flow. We extracted data on the imaging sequence, imaging protocol, and the targeted anatomical structures on each study.

Results

According to contrast-enhanced MRI studies, peak enhancement was sequentially detected first in the CSF space, followed by the brain parenchyma, the meningeal lymphatic vessel (MLV), and, finally, the cervical lymph nodes, corresponding with glymphatic flow and explaining the drainage into the MLV. Non-contrast flow-sensitive MRI studies revealed similar glymphatic inflow from the CSF space to the brain parenchyma and efflux of exchanged fluid from the brain parenchyma to the MLV.

Conclusion

We may recommend T1-weighted contrast-enhanced MRI for visualizing glymphatic flow. Our result can increase understanding of the glymphatic system and may lay the groundwork for establishing central nervous system fluid dynamic theories and developing standardized imaging protocols.
Guillain-Barré Syndrome in Patient With SARS-CoV-2 PCR Positivity Treated Successfully With Therapeutic Exchange Plasma: A First Case Report From Vietnam
Authors: Duong-Quy Sy , Huynh-Truong-Anh Duc , Nguyen-Thi-Kim Thanh , Nguyen-Quang Tien , Nguyen-Chi Thanh , Tran-Xuan Quynh , Nguyen-Nhu Vinh , Ngo Carine , Craig Timothy
Published: May 2022

Since the first case of Guillain-Barré syndrome (GBS)-associated SARS-CoV-2 (COVID-19) infection reported in 2020, a series of cases have been published in some countries. In this case report, we present a young patient with GBS, whose clinical and laboratory data were appropriate for the diagnosis of GBS due to COVID-19 infection. Neurological examination revealed the muscular weakness of lower limbs with Medical Research Council (MRC) scale of 2/5 associated with diminished reflexes. Laboratory studies showed the positive nasal swab RT-PCR test for COVID-19, leukopenia, increased ferritin and LDH levels, normal electrolyte and liver and kidney function, and normal chest X-ray. The result of cerebrospinal fluid showed the albuminocytologic dissociation. The patient was treated with remdesivir, dexamethasone, anticoagulation, and therapeutic plasma exchange (TPE). Patient's muscle weakness was significantly improved after 1 week of admission. He was discharged at 23rd days of hospitalization and followed-up in the out-patients department.
Investigating Serum sHLA-G Cooperation With MRI Activity and Disease-Modifying Treatment Outcome in Relapsing-Remitting Multiple Sclerosis
Authors: Amoriello Roberta , Rizzo Roberta , Mariottini Alice , Bortolotti Daria , Gentili Valentina , Bonechi Elena , Aldinucci Alessandra , Carnasciali Alberto , Peruzzi Benedetta , Repice Anna Maria , Massacesi Luca , Fainardi Enrico , Ballerini Clara
Published: May 2022

Relapsing-remitting multiple sclerosis (RRMS) is a demyelinating disease in which pathogenesis T cells have a major role. Despite the unknown etiology, several risk factors have been described, including a strong association with human leukocyte antigen (HLA) genes. Recent findings showed that HLA class I-G (HLA-G) may be tolerogenic in MS, but further insights are required. To deepen the HLA-G role in MS inflammation, we measured soluble HLA-G (sHLA-G) and cytokines serum level in 27 patients with RRMS at baseline and after 12 and 24 months of natalizumab (NTZ) treatment. Patients were divided into high (sHLA-G>20 ng/ml), medium (sHLA-G between 10 and 20 ng/ml), and low (sHLA-G <10 ng/ml) producers. Results showed a heterogeneous distribution of genotypes among producers, with no significant differences between groups. A significant decrease of sHLA-G was found after 24 months of NTZ in low producers carrying the +3142 C/G genotype. Finally, 83.3% of high and 100% of medium producers were MRI-activity free after 24 months of treatment, compared to 63.5% of low producers. Of note, we did not find any correlation of sHLA-G with peripheral cell counts or cytokines level. These findings suggest that serum sHLA-G level may partly depend on genotype rather than peripheral inflammation, and that may have impacted on MRI activity of patients over treatment.
A Riemannian Revisiting of Structure–Function Mapping Based on Eigenmodes
Authors: Deslauriers-Gauthier Samuel , Zucchelli Mauro , Laghrissi Hiba , Deriche Rachid
Published: May 2022

Understanding the link between brain structure and function may not only improve our knowledge of brain organization, but also lead to better quantification of pathology. To quantify this link, recent studies have attempted to predict the brain's functional connectivity from its structural connectivity. However, functional connectivity matrices live in the Riemannian manifold of the symmetric positive definite space and a specific attention must be paid to operate on this appropriate space. In this work we investigated the implications of using a distance based on an affine invariant Riemannian metric in the context of structure–function mapping. Specifically, we revisit previously proposed structure–function mappings based on eigendecomposition and test them on 100 healthy subjects from the Human Connectome Project using this adapted notion of distance. First, we show that using this Riemannian distance significantly alters the notion of similarity between subjects from a functional point of view. We also show that using this distance improves the correlation between the structural and functional similarity of different subjects. Finally, by using a distance appropriate to this manifold, we demonstrate the importance of mapping function from structure under the Riemannian manifold and show in particular that it is possible to outperform the group average and the so–called glass ceiling on the performance of mappings based on eigenmodes.
Brain-Derived Neurotrophic Factor: A Connecting Link Between Nutrition, Lifestyle, and Alzheimer’s Disease
Authors: Xue Bin , Waseem Shah Mohammad Abbas , Zhu Zhixin , Alshahrani Mohammed A. , Nazam Nazia , Anjum Farah , Habib Alaa Hamed , Rafeeq Misbahuddin M. , Nazam Fauzia , Sharma Monika
Published: May 2022

Brain-derived neurotrophic factor (BDNF) involving tropomyosin kinase B and low affinity p75 neurotropin receptors is the most abundant and researched neurotropins in mammal’s brain. It is one of the potential targets for therapeutics in Alzheimer’s disease (AD) owing to its key role in synaptic plasticity. Low levels of BDNF are implicated in the pathophysiology of neurological diseases including AD. However, a healthy lifestyle, exercise, and dietary modifications are shown to positively influence insulin regulation in the brain, reduce inflammation, and up-regulate the levels of BDNF, and are thus expected to have roles in AD. In this review, the relationship between BDNF, mental health, and AD is discussed. Insights into the interrelationships between nutrition, lifestyle, and environment with BDNF and possible roles in AD are also provided in the review. The review sheds light on the possible new therapeutic targets in neurodegenerative diseases.
Association of the Weight-Adjusted-Waist Index With Risk of All-Cause Mortality: A 10-Year Follow-Up Study
Authors: Cai Shuang , Zhou Lin , Zhang Yue , Cheng Bokai , Zhang Anhang , Sun Jin , Li Man , Su Yongkang , Bao Qiligeer , Zhang Yan , Ma Shouyuan , Zhu Ping , Wang Shuxia
Published: May 2022

Background

To explore the relationship between weight-adjusted-waist index (WWI) and the risk of all-cause mortality in one urban community-dwelling population in China.

Methods

This is a prospective cohort study with a sample of 1,863 older adults aged 60 years or over in Beijing who completed baseline examinations in 2009–2010 and a 10-year follow-up in 2020. WWI was calculated as waist circumference (cm) divided by the square root of weight (kg). Cox regression analysis was performed to investigate the significance of the association of WWI with all-cause mortality. The area under the receiver operating characteristic (ROC) curves were used to compare the ability of each obesity index to predict mortality.

Results

During a median follow-up of 10.8 years (1.0 to 11.3 years), 339 deaths occurred. After adjusted for covariates, the hazard ratios (HRs) for all-cause mortality progressively increased across the tertile of WWI. Compared with the lowest WWI category (tertile1 <10.68 cm/√kg), with WWI 10.68 to 11.24cm/√kg, and≥11.25 cm/√kg, the HRs (95% confidence intervals (CIs)) for all-cause mortality were 1.58 (1.12–2.22), and 2.66 (1.80–3.92), respectively. In stratified analyses, the relationship between WWI and the risk of all-cause mortality persisted. The area under ROC for WWI was higher for all-cause mortality than BMI, WHtR, and WC.

Conclusion

WWI was associated with a higher risk for all-cause mortality, and the association was more robust with the highest WWI category.
Efficacy and Safety of Placebo During the Maintenance Therapy of Ovarian Cancer in Randomized Controlled Trials: A Systematic Review and Meta-analysis
Authors: Wang Jin-feng , Zhao Lan-bo , Bin Ya-di , Zhang Kai-lu , Sun Chao , Wang Yi-ran , Feng Xue , Ji Jing , He Li-song , Chen Fang-yao , Li Qi-ling
Published: May 2022

Introduction

This meta-analysis evaluated the efficacy and safety of placebo during the maintenance therapy of ovarian cancer (OC) patients in randomized controlled trials (RCTs).

Methods

A comprehensive literature review was performed for RCTs published up to and including August 2020 from four electronic databases. We analyzed the efficacy and safety in the control arms of the maintenance therapy in advanced OC patients. Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) of progression-free survival (PFS) and overall survival (OS) were estimated in the placebo arms and the observation arms, respectively, using the Frequency Framework method. We also calculated the incidences of common adverse effects (AEs) in the placebo arms.

Results

In total, 41 articles with 20,099 (4,787 in the placebo arms, 3,420 in the observation arms, and 11,892 in the experiment arms) patients were included in this meta-analysis. Compared with observation, placebo did not improve or reduce PFS (HR, 1.02; 95% CI, 0.87–1.20; P = 0.81) and OS (HR, 1.02; 95% CI, 0.89–1.16; P = 0.76) of OC patients, while other treatments, except for radiotherapy, significantly improved PFS and OS (all P < 0.05). The incidences of AEs produced by placebo were 94.03% in all grades and 20.22% in grade ≥3. The incidences of AEs were 29.75% in fatigue, 26.38% in nausea, 24.34% in abdominal pain, 18.92% in constipation, 16.65% in diarrhea, 14.55% in vomiting, 13.89% in hypertension, and 13.14% in headache.

Conclusions

Placebo did not improve or reduce the PFS and OS benefits of OC patients in RCTs but increased the incidences of AEs.
Integrin-Linked Kinase Expression Characterizes the Immunosuppressive Tumor Microenvironment in Colorectal Cancer and Regulates PD-L1 Expression and Immune Cell Cytotoxicity
Authors: Almasabi Saleh , Boyd Richard , Ahmed Afsar U. , Williams Bryan R. G.
Published: May 2022

Integrin-linked kinase (ILK) has been implicated as a molecular driver and mediator in both inflammation and tumorigenesis of the colon. However, a role for ILK in the tumor microenvironment (TME) and immune evasion has not been investigated. Here, we show a correlation of ILK expression with the immunosuppressive TME and cancer prognosis. We also uncover a role for ILK in the regulation of programmed death-ligand 1 (PD-L1) expression and immune cell cytotoxicity. Interrogation of web-based data-mining platforms, showed upregulation of ILK expression in tumors and adjacent-non tumor tissue of colorectal cancer (CRC) associated with poor survival and advanced stages. ILK expression was correlated with cancer-associated fibroblast (CAFs) and immunosuppressive cell infiltration including regulatory T cells (Treg) and M2 macrophages (M2) in addition to their gene markers. ILK expression was also significantly correlated with the expression of different cytokines and chemokines. ILK expression showed pronounced association with different important immune checkpoints including PD-L1. Deletion of the ILK gene in PD-L1 positive CRC cell lines using a doxycycline inducible-CRISPR/Cas9, resulted in suppression of both the basal and IFNγ-induced PD-L1 expression via downregulating NF-κB p65. This subsequently sensitized the CRC cells to NK92 immune cell cytotoxicity. These findings suggest that ILK can be used as a biomarker for prognosis and immune cell infiltration in colon cancer. Moreover, ILK could provide a therapeutic target to prevent immune evasion mediated by the expression of PD-L1.
TRAF4 Inhibits the Apoptosis and Promotes the Proliferation of Breast Cancer Cells by Inhibiting the Ubiquitination of Spindle Assembly-Associated Protein Eg5
Authors: Hao Miaomiao , Zhang Jie , Sun Mingfang , Diao Kexin , Wang Jian , Li Shiping , Cao Qixue , Dai Shundong , Mi Xiaoyi
Published: May 2022

Tumor necrosis factor receptor associated factor 4 (TRAF4) is a RING domain E3 ubiquitin ligase that mediates the ubiquitination of various proteins and plays an important role in driving tumor progression. By studying the relationship between TRAF4 and Eg5, a member of the kinesin family that plays a critical role in spindle assembly, we demonstrated that TRAF4 regulated Eg5 ubiquitination and contributed to Eg5-mediated breast cancer proliferation and inhibited breast cancer apoptosis. TRAF4 and Eg5 were both highly expressed in breast cancer and their protein level was positively correlated. Relying on its Zinc fingers domain, TRAF4 interacted with Eg5 in the cytoplasm of breast cancer cells. TRAF4 was a mitosis-related protein, and by up-regulating the protein level of Eg5 TRAF4 participated in spindle assembly. Loss of TRAF4 resulted in monopolar spindles formation, but loss of function could be rescued by Eg5. Relying on its RING domain, TRAF4 up-regulated Eg5 protein levels by inhibition of Eg5 ubiquitination, thus stabilizing Eg5 protein level during mitosis. Furthermore, we found that Smurf2, a TRAF4-targeted ubiquitination substrate, mediated the regulation of Eg5 ubiquitination by TRAF4. TRAF4 inhibited the interaction between Smurf2 and Eg5, and down-regulated the protein level of Smurf2 by promoting its ubiquitination, thereby inhibited the Smurf2-catalyzed ubiquitination of Eg5 and up-regulated Eg5 protein levels. We also demonstrate that TRAF4 plays an important role in promoting cell proliferation and in inhibiting cell apoptosis induced by Eg5. In summary, our study suggests a new direction for investigating the role of TRAF4 in driving breast cancer progression.
The Comparative Outcomes of Particulate Versus Coil Preoperative Embolization for Carotid Body Tumors
Authors: Huang Xun , Wang Lin , Chen Yangjing , Liu Jianlin , Liu Yamin , Yang Lin
Published: May 2022

Till now, the effect of different embolic materials (particulate vs coil) on pre-embolization of carotid body tumors remains poorly understood. The aim of this study was to explore the comparative results between particulate and coil embolization for carotid body tumors. Thirty-seven patients with carotid body tumors who underwent embolization before surgical resection were reviewed and analyzed in this retrospective study between 2008 and 2020. Twenty-one patients were included in the particulate group, while 16 patients were included in the coil group. All procedure-related details, complications and 5-year follow-up data were collected in the study. The preoperative embolization time was obviously longer in the particulate group than in the coil group (42.6 ± 12.3 min vs. 33.7 ± 10.1 min, P =.02), and the fluo time of the procedure (864.5 ± 240.9 s vs. 729.6 ± 251.5 s) and cumulative air kerma (634.6 ± 188.4 mGy vs. 486.7 ± 164.7 mGy) value were higher in the particulate group (P =.01). The incidences of total adverse events in both groups were not significantly different (28.6% vs. 25.0%, P >.05); however, two cases of ectopic embolization only occurred in the particulate group. Interestingly, medical expenditure was higher in the particulate group than in the coil group (P =.02). For the 3-year follow-up evaluation, recurrence and all-cause mortality were similar in both groups (P >.05). Preoperative embolization with coils could be relatively safe, have a lower radiation dosage and be cost-effective for the treatment of carotid body tumors.
Fibrillary Glomerulonephritis and Monoclonal Gammopathy: Potential Diagnostic Challenges
Authors: Da Yi , Goh Giap Hean , Lau Titus , Chng Wee Joo , Soekojo Cinnie Yentia
Published: May 2022

Fibrillary glomerulonephritis (FGN) is a rare glomerular disease featured by the randomly arranged 12- to 24-nm fibrils under electron microscopy (EM). Up to 10% of FGN patients have monoclonal gammopathy. However, distinguishing between FGN as monoclonal gammopathy of renal significance (MGRS) and FGN from other causes with incidental monoclonal gammopathy of undetermined significance (MGUS) can be challenging, as the current way of demonstrating monoclonality is flawed due to (1) the suboptimal sensitivity of kappa staining by immunofluorescence in frozen tissue (IF-F) as compared to pronase-digested paraffin sections (IF-P), causing incorrect labeling of light chain restriction; (2) the unavailability of immunoglobulin G (IgG) subtyping in some centers; and (3) the unavailability of tests demonstrating the monoclonality of highly variable VH or VL domains in immunoglobulin structures in clinical use. The discovery of DnaJ homolog subfamily B member 9 (DNAJB9) allows diagnosis for FGN with less reliance on EM, and the summary of recent studies revealed that genuine MGRS is extremely rare among FGN. Further research integrating IF-P, IgG subtyping, VH or VL domain monoclonality confirmation, and DNAJB9 as diagnostic modalities, with corresponding clinical data including treatment response and prognosis, is required for a better understanding of this subject.