bluuebunny/crossref_metadata_2025 huggingface dataset:
Studies of Li2Fe0.9M0.1SO Antiperovskite Materials for Lithium–Ion Batteries: The Role of Partial Fe2+ to M2+ Substitution
Authors: Gorbunov Mikhail V. , Carocci Salvatore , Gonzalez Martinez Ignacio G. , Baran Volodymyr , Mikhailova Daria
Published: March 2021

Cubic Li2Fe0.9M0.1SO antiperovskites with M–Co2+, or Mn2+were successfully synthesized by a solid-state technique, and studied as cathode materials in Li-batteries. The influence of the Co, and Mn cation substitution of Fe in Li2FeSO on the resulting electrochemical performance was evaluated by galvanostatic cycling, while the reaction mechanism was explored by applyingoperandoX-ray absorption and X-ray diffraction techniques using synchrotron radiation facilities. Even 10% Fe-substitution by these metals completely changes the structural behavior of the material upon Li-removal and insertion, in comparison to Li2FeSO. The Co-substitution significantly improves cyclability of the material at high current densities in comparison to the non-substituted material, reaching a specific capacity of 250 mAh/g at 1C current density. In contrast, the Mn-substitution leads to deterioration of the electrochemical performance because of the impeded kinetics, which may be caused by the appearance of a second isostructural phase due to formation of Jahn-Teller Mn3+cations upon delithiation.
TRIB3 Promotes the Malignant Progression of Bladder Cancer: An Integrated Analysis of Bioinformatics and in vitro Experiments
Authors: Yang Jieping , Lin Jiaxing , An Jun , Zhao Yongkang , Jing Siyang , Yu Meng , Zhu Yuyan , Yao Yang
Published: March 2021

Background

Bladder cancer is a common malignant tumor characterized by high mortality and high management costs; however, it lacks useful molecular prognostic markers. Tribbles pseudokinase 3 (TRIB3) is a pseudokinase that participates in cell tumor progression and metabolism and whose function in bladder cancer is not precisely known.

Main Methods

We downloaded transcriptome data and clinical data of bladder cancer from associated databases and extracted the expression matrix of TRIB3 for multiple bioinformatics analysis. RT-PCR detected the expression of TRIB3 in bladder cancer cells. After knockdown of TRIB3 with siRNA, we investigated TRIB3 function using CCK8, Cell Cycle and Transwell assays.

Key Findings

Kaplan–Meier analysis of TRIB3 in the four cohorts showed that high expression of TRIB3 correlated with poor outcome. Expression of TRIB3 positively correlated with stage and grade and down-regulation of TRIB3 expression significantly inhibited proliferation, migration and cell cycle of bladder cancer cells.

Significance

TRIB3 is a potential prognostic marker and therapeutic target. It can be used to individualize the treatment of bladder cancer.
Identification of PCBP1 as a Novel Modulator of Mammalian Circadian Clock
Authors: Wu Yaling , Zhao Haijiao , Zhang Eric Erquan , Liu Na
Published: March 2021

The circadian clock governs our daily cycle of behavior and physiology. Previous studies have identified a handful of core clock components and hundreds of circadian modifiers. Here, we report the discovery that poly(C)-binding protein 1 (PCBP1), displaying a circadian expression pattern, was a novel circadian clock regulator. We found that knocking down PCBP1 resulted in period shortening in human U2OS cells, and that manipulations of PCBP1 expression altered the activity of CLOCK/BMAL1 in an E-box-based reporter assay. Further mechanistic study demonstrated that this clock function of PCBP1 appears to work by enhancing the association of Cryptochrome 1 (CRY1) with the CLOCK/BMAL1 complex, thereby negatively regulating the latter’s activation. Co-immunoprecipitation of PCBP1 and core clock molecules confirmed the interactions between PCBP1 and CRY1, and a time-course qPCR assay revealed the rhythmic expression of PCBP1 in mouse hearts in vivo. Given that the RNA interference of mushroom-body expressed (mub), the poly(rC) binding protein (PCBP) homolog of Drosophila, in the clock neurons also led to a circadian phenotype in the locomotor assay, our study deemed PCBP1 a novel clock modifier whose circadian regulatory mechanism is conserved during evolution.
RNA-Associated Co-expression Network Identifies Novel Biomarkers for Digestive System Cancer
Authors: Chen Zheng , Shen Zijie , Zhang Zilong , Zhao Da , Xu Lei , Zhang Lijun
Published: March 2021

Cancers of the digestive system are malignant diseases. Our study focused on colon cancer, esophageal cancer (ESCC), rectal cancer, gastric cancer (GC), and rectosigmoid junction cancer to identify possible biomarkers for these diseases. The transcriptome data were downloaded from the TCGA database (The Cancer Genome Atlas Program), and a network was constructed using the WGCNA algorithm. Two significant modules were found, and coexpression networks were constructed. CytoHubba was used to identify hub genes of the two networks. GO analysis suggested that the network genes were involved in metabolic processes, biological regulation, and membrane and protein binding. KEGG analysis indicated that the significant pathways were the calcium signaling pathway, fatty acid biosynthesis, and pathways in cancer and insulin resistance. Some of the most significant hub genes werehsa-let-7b-3p,hsa-miR-378a-5p,hsa-miR-26a-5p,hsa-miR-382-5p, andhsa-miR-29b-2-5pandSECISBP2 L,NCOA1,HERC1,HIPK3, andMBNL1, respectively. These genes were predicted to be associated with the tumor prognostic reference for this patient population.
Soluble MD-2 and Heme in Sickle Cell Disease Plasma Promote Pro-Inflammatory Signaling in Endothelial Cells
Authors: Zhang Ping , Nguyen Julia , Abdulla Fuad , Nelson Alexander T. , Beckman Joan D. , Vercellotti Gregory M. , Belcher John D.
Published: March 2021

Recent evidence indicates that hemolysis in sickle cell disease (SCD) promotes inflammation via innate immune signaling through toll-like receptor 4 (TLR4). Free heme released by hemolyzed red blood cells can bind to myeloid differentiation factor-2 (MD-2) and activate TLR4 pro-inflammatory signaling on endothelium to promote vaso-occlusion and acute chest syndrome in murine models of SCD. MD-2 is co-expressed with TLR4 on cell membranes, but in inflammatory conditions, soluble MD-2 (sMD-2) is elevated in plasma. sMD-2 levels were significantly increased in human and murine sickle (SS) plasma as compared to normal (AA) plasma. Human umbilical vein endothelial cells (HUVEC) and human lung microvascular endothelial cells incubated with human SS plasma had significant increases in pro-inflammatory IL-8, IL-6, and soluble VCAM-1 secretion compared to endothelial cells incubated with AA plasma. The increase in HUVEC IL-8 secretion was blocked by depletion of sMD-2 from SS plasma and enhanced by the addition of sMD-2 to AA plasma. The TLR4 signaling inhibitor, TAK-242, inhibited HUVEC IL-8 secretion in response to SS plasma by 85%. Heme-agarose pull-down assays and UV/Vis spectroscopy demonstrated that heme binds to sMD-2. Hemopexin, a high affinity heme-binding protein, inhibited HUVEC IL-8 secretion induced by SS plasma or SS and AA plasma supplemented with sMD-2. These data suggest that sMD-2 bound to heme might play an important role in pro-inflammatory signaling by endothelium in SCD.
EZH2 Inhibition Interferes With the Activation of Type I Interferon Signaling Pathway and Ameliorates Lupus Nephritis in NZB/NZW F1 Mice
Authors: Wu Lingling , Jiang Xiaoyue , Qi Chaojun , Zhang Chunyan , Qu Bo , Shen Nan
Published: March 2021

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase mediating trimethylation of H3K27, which represses gene expression and is critical to immune regulation. Inhibition of EZH2 is proved to have the potential of treating many diseases. However, whether inhibition of EZH2 affects type I interferon (IFN-I) signaling pathway, the abnormality of which is an important pathogenic mechanism for SLE, is still elusive. Here, we report, unexpectedly, a positive regulatory function of EZH2 in IFN-I signaling pathway, which contributes to the overactivation of IFN-I signaling pathway in SLE. We show that the expression of EZH2 was upregulated and positively correlated with the overexpression of interferon stimulated genes (ISGs) in both peripheral blood mononuclear cells and renal tissues of SLE patients. In vitro inhibition of EZH2 by either siRNAs or chemical inhibitors reduced the phosphorylation of STAT1 and the induction of ISGs stimulated by IFN-I. Additionally, inhibition of EZH2 interfered with the in vivo and ex vivo activation of IFN-I signaling pathway elicited by intravenous injection of adenovirus vector expressing mouse IFN-α5 and exogeneous stimulation with IFN-α, respectively. We evaluated the therapeutic effects of EZH2 inhibitor in NZB/NZW F1 mice which depend on IFN-I signaling pathway for the lupus-like disease development. Administration of EZH2 inhibitor prolonged the survival, reduced the levels of anti-dsDNA autoantibodies, and improved lupus nephritis of the mice. What’s more, EZH2 inhibitor attenuated the expression of ISGs in the kidneys of these mice. In summary, we show that excessive EZH2 contributes to the overactivation of IFN-I signaling pathway in SLE. EZH2 inhibitor has the potential to inhibit IFN-I signaling pathway and alleviate lupus nephritis. Additionally, diverse disease driving pathways exist among systemic lupus erythematosus (SLE) patient, and even in the same patients. Common regulators of different pathogenic pathways can be multivalent therapeutic targets. Together with previous studies showing EZH2 is involved in T-cell and B-cell mediated immune responses, EZH2 could be a potent multivalent therapeutic target for SLE.
Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-γ Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome
Authors: Caldarale Francesca , Giacomelli Mauro , Garrafa Emirena , Tamassia Nicola , Morreale Alessia , Poli Piercarlo , Timpano Silviana , Baresi Giulia , Zunica Fiammetta , Cattalini Marco , Moratto Daniele , Chiarini Marco , Cannizzo Elvira Stefania , Marchetti Giulia , Cassatella Marco Antonio , Taddio Andrea , Tommasini Alberto , Badolato Raffaele
Published: March 2021

Background

SARS-CoV-2 occurs in the majority of children as COVID-19, without symptoms or with a paucisymptomatic respiratory syndrome, but a small proportion of children develop the systemic Multi Inflammatory Syndrome (MIS-C), characterized by persistent fever and systemic hyperinflammation, with some clinical features resembling Kawasaki Disease (KD).

Objective

With this study we aimed to shed new light on the pathogenesis of these two SARS-CoV-2-related clinical manifestations.

Methods

We investigated lymphocyte and dendritic cells subsets, chemokine/cytokine profiles and evaluated the neutrophil activity mediators, myeloperoxidase (MPO), and reactive oxygen species (ROS), in 10 children with COVID-19 and 9 with MIS-C at the time of hospital admission.

Results

Patients with MIS-C showed higher plasma levels of C reactive protein (CRP), MPO, IL-6, and of the pro-inflammatory chemokines CXCL8 and CCL2 than COVID-19 children. In addition, they displayed higher levels of the chemokines CXCL9 and CXCL10, mainly induced by IFN-γ. By contrast, we detected IFN-α in plasma of children with COVID-19, but not in patients with MIS-C. This observation was consistent with the increase of ISG15 and IFIT1 mRNAs in cells of COVID-19 patients, while ISG15 and IFIT1 mRNA were detected in MIS-C at levels comparable to healthy controls. Moreover, quantification of the number of plasmacytoid dendritic cells (pDCs), which constitute the main source of IFN-α, showed profound depletion of this subset in MIS-C, but not in COVID-19.

Conclusions

Our results show a pattern of immune response which is suggestive of type I interferon activation in COVID-19 children, probably related to a recent interaction with the virus, while in MIS-C the immune response is characterized by elevation of the inflammatory cytokines/chemokines IL-6, CCL2, and CXCL8 and of the chemokines CXCL9 and CXL10, which are markers of an active Th1 type immune response. We believe that these immunological events, together with neutrophil activation, might be crucial in inducing the multisystem and cardiovascular damage observed in MIS-C.
Revisiting Pleiotropic Effects of Type I Interferons: Rationale for Its Prophylactic and Therapeutic Use Against SARS-CoV-2
Authors: Garcia-del-Barco Diana , Risco-Acevedo Daniela , Berlanga-Acosta Jorge , Martos-Benítez Frank Daniel , Guillén-Nieto Gerardo
Published: March 2021

The pandemic distribution of SARS-CoV-2 together with its particular feature of inactivating the interferon-based endogenous response and accordingly, impairing the innate immunity, has become a challenge for the international scientific and medical community. Fortunately, recombinant interferons as therapeutic products have accumulated a long history of beneficial therapeutic results in the treatment of chronic and acute viral diseases and also in the therapy of some types of cancer. One of the first antiviral treatments during the onset of COVID-19 in China was based on the use of recombinant interferon alfa 2b, so many clinicians began to use it, not only as therapy but also as a prophylactic approach, mainly in medical personnel. At the same time, basic research on interferons provided new insights that have contributed to a much better understanding of how treatment with interferons, initially considered as antivirals, actually has a much broader pharmacological scope. In this review, we briefly describe interferons, how they are induced in the event of a viral infection, and how they elicit signaling after contact with their specific receptor on target cells. Additionally, some of the genes stimulated by type I interferons are described, as well as the way interferon-mediated signaling is torpedoed by coronaviruses and in particular by SARS-CoV-2. Angiotensin converting enzyme 2 (ACE2) gene is one of the interferon response genes. Although for many scientists this fact could result in an adverse effect of interferon treatment in COVID-19 patients, ACE2 expression contributes to the balance of the renin-angiotensin system, which is greatly affected by SARS-CoV-2 in its internalization into the cell. This manuscript also includes the relationship between type I interferons and neutrophils, NETosis, and interleukin 17. Finally, under the subtitle of “take-home messages”, we discuss the rationale behind a timely treatment with interferons in the context of COVID-19 is emphasized.
Multivariate Sub-Regional Ocean Indicators in the Mediterranean Sea: From Event Detection to Climate Change Estimations
Authors: Juza Mélanie , Tintoré Joaquín
Published: March 2021

The increasing science and society requests for ocean monitoring from global to regional and local scales, the need for integration and convergence into a globally consistent ocean observing system as well as the need for improvement of access to information are now internationally recognized goals to progress toward the sustainable management of a healthy ocean. To respond to these challenges at regional level, the Balearic Islands Coastal Observing and Forecasting System (SOCIB) is developing a comprehensive set of ocean indicators in the Mediterranean Sea and around the Balearic Islands, key environments that are strongly affected by climate change and human pressure. This new SOCIB value-added product addresses the sub-regional ocean variability from daily (events) to interannual/decadal (climate) scales. A user-friendly interface has been implemented to monitor, visualize and communicate ocean information that is relevant for a wide range of sectors, applications and regional end-users. These sub-regional indicators allowed us to detect specific events in real time. Remarkable events and features identified include marine heat waves, atmospheric storm, extreme river discharge, mesoscale eddy, deep convection among others, all of them being oceanic phenomena that directly impact the ocean circulation and marine ecosystems. The long-term variations, in response to climate change, are also addressed highlighting and quantifying trends in physical and biogeochemical components of the ocean as well as sub-regional differences. At both (sub-) regional, national and international levels, a society-aligned science will have stronger impact on policy decision-makings and will support society to implement specific actions to address worldwide environmental challenges.
High Incidence of Epileptiform Potentials During Continuous EEG Monitoring in Critically Ill COVID-19 Patients
Authors: Schultz Barbara , Krauß Terence , Schmidt Maren , Schultz Michael , Schneider Andrea , Wiesner Olaf , Schmidt Julius J. , Stahl Klaus , David Sascha , Hoeper Marius M. , Busch Markus
Published: March 2021

Objective: To analyze continuous 1- or 2-channel electroencephalograms (EEGs) of mechanically ventilated patients with coronavirus disease 2019 (COVID-19) with regard to occurrence of epileptiform potentials.

Design: Single-center retrospective analysis.

Setting: Intensive care unit of Hannover Medical School, Hannover, Germany.

Patients: Critically ill COVID-19 patients who underwent continuous routine EEG monitoring (EEG monitor: Narcotrend-Compact M) during sedation.

Measurements and Main Results: Data from 15 COVID-19 patients (11 men, four women; age: 19–75 years) were evaluated. Epileptiform potentials occurred in 10 of 15 patients (66.7%).

Conclusions: The results of the evaluation regarding the occurrence of epileptiform potentials show that there is an unusually high percentage of cerebral involvement in patients with severe COVID-19. EEG monitoring can be used in COVID-19 patients to detect epileptiform potentials.
Horizontal Transfer of Different erm(B)-Carrying Mobile Elements Among Streptococcus suis Strains With Different Serotypes
Authors: Chen Li , Huang Jinhu , Huang Xinxin , He Yuping , Sun Junjie , Dai Xingyang , Wang Xiaoming , Shafiq Muhammad , Wang Liping
Published: March 2021

Macrolide-resistant Streptococcus suis is highly prevalent worldwide. The acquisition of the erm(B) gene mediated by mobile genetic elements (MGEs) in particular integrative and conjugative elements (ICEs) is recognized as the main reason for the rapid spread of macrolide-resistant streptococcal strains. However, knowledge about different erm(B)-carrying elements responsible for the widespread of macrolide resistance and their transferability in S. suis remains poorly understood. In the present study, two erm(B)- and tet(O)-harboring putative ICEs, designated as ICESsuYSB17_rplL and ICESsuYSJ15_rplL, and a novel erm(B)- and aadE-spw-like-carrying genomic island (GI), named GISsuJHJ17_rpsI, were identified to be excised from the chromosome and transferred among S. suis strains with different serotypes. ICESsuYSB17_rplL and ICESsuYSJ15_rplL were integrated downstream the rplL gene, a conserve locus of the ICESa2603 family. GISsuJHJ17_rpsI, with no genes belonging to the conjugation module, was integrated into the site of rpsI. All transconjugants did not exhibit obvious fitness cost by growth curve and competition assays when compared with the recipient. The results demonstrate that different erm(B)-carrying elements were presented and highlight the role of these elements in the dissemination of macrolide resistance in S. suis.
Antibiotrophy: Key Function for Antibiotic-Resistant Bacteria to Colonize Soils—Case of Sulfamethazine-Degrading Microbacterium sp. C448
Authors: Billet Loren , Pesce Stéphane , Rouard Nadine , Spor Aymé , Paris Laurianne , Leremboure Martin , Mounier Arnaud , Besse-Hoggan Pascale , Martin-Laurent Fabrice , Devers-Lamrani Marion
Published: March 2021

Chronic and repeated exposure of environmental bacterial communities to anthropogenic antibiotics have recently driven some antibiotic-resistant bacteria to acquire catabolic functions, enabling them to use antibiotics as nutritive sources (antibiotrophy). Antibiotrophy might confer a selective advantage facilitating the implantation and dispersion of antibiotrophs in contaminated environments. A microcosm experiment was conducted to test this hypothesis in an agroecosystem context. The sulfonamide-degrading and resistant bacterium Microbacterium sp. C448 was inoculated in four different soil types with and without added sulfamethazine and/or swine manure. After 1 month of incubation, Microbacterium sp. (and its antibiotrophic gene sadA) was detected only in the sulfamethazine-treated soils, suggesting a low competitiveness of the strain without antibiotic selection pressure. In the absence of manure and despite the presence of Microbacterium sp. C448, only one of the four sulfamethazine-treated soils exhibited mineralization capacities, which were low (inferior to 5.5 ± 0.3%). By contrast, manure addition significantly enhanced sulfamethazine mineralization in all the soil types (at least double, comprised between 5.6 ± 0.7% and 19.5 ± 1.2%). These results, which confirm that the presence of functional genes does not necessarily ensure functionality, suggest that sulfamethazine does not necessarily confer a selective advantage on the degrading strain as a nutritional source. 16S rDNA sequencing analyses strongly suggest that sulfamethazine released trophic niches by biocidal action. Accordingly, manure-originating bacteria and/or Microbacterium sp. C448 could gain access to low-competition or competition-free ecological niches. However, simultaneous inputs of manure and of the strain could induce competition detrimental for Microbacterium sp. C448, forcing it to use sulfamethazine as a nutritional source. Altogether, these results suggest that the antibiotrophic strain studied can modulate its sulfamethazine-degrading function depending on microbial competition and resource accessibility, to become established in an agricultural soil. Most importantly, this work highlights an increased dispersal potential of antibiotrophs in antibiotic-polluted environments, as antibiotics can not only release existing trophic niches but also form new ones.
Taxonomy and Phylogeny of the Fomitopsis pinicola Complex With Descriptions of Six New Species From East Asia
Authors: Liu Shun , Han Mei-Ling , Xu Tai-Min , Wang Yan , Wu Dong-Mei , Cui Bao-Kai
Published: March 2021

Fomitopsis pinicola is a common brown-rot fungal species found in northern hemisphere. It grows on many different gymnosperm and angiosperm trees. Recent studies show that it is a species complex; three species from North America and one species from Europe have been recognized in this complex. In the current study, six new species in the Fomitopsis pinicola complex were discovered from East Asia, based on morphological characters and phylogenetic analyses inferred from the sequence data of the internal transcribed spacer (ITS) regions, the second subunit of RNA polymerase II (RPB2), and the translation elongation factor 1-α gene (TEF). Detailed descriptions of the six new species are provided. Our results also indicates that species of the F. pinicola complex from East Asia usually have limited distribution areas and host specialization.
Venomous Snakes Reveal Ecological and Phylogenetic Factors Influencing Variation in Gut and Oral Microbiomes
Authors: Smith Sierra N. , Colston Timothy J. , Siler Cameron D.
Published: March 2021

The gastrointestinal tract (GIT) of vertebrates contains a series of organs beginning with the mouth and ending with the anus or cloacal opening. Each organ represents a unique environment for resident microorganisms. Due to their simple digestive anatomy, snakes are good models for studying microbiome variation along the GIT. Cloacal sampling captures the majority of the microbial diversity found in the GIT of snakes—yet little is known about the oral microbiota of snakes. Most research on the snake mouth and gut microbiota are limited to studies of a single species or captive-bred individuals. It therefore remains unclear how a host’s life history, diet, or evolutionary history correlate with differences in the microbial composition within the mouths and guts of wild snakes. We sampled the mouth and gut microbial communities from three species of Asian venomous snakes and utilized 16S rRNA microbial inventories to test if host phylogenetic and ecological differences correlate with distinct microbial compositions within the two body sites. These species occupy three disparate habitat types: marine, semi-arboreal, and arboreal, our results suggest that the diversity of snake mouth and gut microbial communities correlate with differences in both host ecology and phylogeny.
Mining the Selective Remodeling of DNA Methylation in Promoter Regions to Identify Robust Gene-Level Associations With Phenotype
Authors: Quan Yuan , Liang Fengji , Deng Si-Min , Zhu Yuexing , Chen Ying , Xiong Jianghui
Published: March 2021

Epigenetics is an essential biological frontier linking genetics to the environment, where DNA methylation is one of the most studied epigenetic events. In recent years, through the epigenome-wide association study (EWAS), researchers have identified thousands of phenotype-related methylation sites. However, the overlaps of identified phenotype-related DNA methylation sites between various studies are often quite small, and it might be due to the fact that methylation remodeling has a certain degree of randomness within the genome. Thus, the identification of robust gene-phenotype associations is crucial to interpreting pathogenesis. How to integrate the methylation values of different sites on the same gene and to mine the DNA methylation at the gene level remains a challenge. A recent study found that the DNA methylation difference of the gene body and promoter region has a strong correlation with gene expression. In this study, we proposed a Statistical difference of DNA Methylation between Promoter and Other Body Region (SIMPO) algorithm to extract DNA methylation values at the gene level. First, by choosing to smoke as an environmental exposure factor, our method led to significant improvements in gene overlaps (from 5 to 17%) between different datasets. In addition, the biological significance of phenotype-related genes identified by SIMPO algorithm is comparable to that of the traditional probe-based methods. Then, we selected two disease contents (e.g., insulin resistance and Parkinson’s disease) to show that the biological efficiency of disease-related gene identification increased from 15.43 to 44.44% (p-value = 1.20e–28). In summary, our results declare that mining the selective remodeling of DNA methylation in promoter regions can identify robust gene-level associations with phenotype, and the characteristic remodeling of a given gene’s promoter region can reflect the essence of disease.
The Impact of COVID-19 Quarantine on Patients With Dementia and Family Caregivers: A Nation-Wide Survey
Authors: Rainero Innocenzo , Bruni Amalia C. , Marra Camillo , Cagnin Annachiara , Bonanni Laura , Cupidi Chiara , Laganà Valentina , Rubino Elisa , Vacca Alessandro , Di Lorenzo Raffaele , Provero Paolo , Isella Valeria , Vanacore Nicola , Agosta Federica , Appollonio Ildebrando , Caffarra Paolo , Bussè Cinzia , Sambati Renato , Quaranta Davide , Guglielmi Valeria , Logroscino Giancarlo , Filippi Massimo , Tedeschi Gioacchino , Ferrarese Carlo ,   the SINdem COVID-19 Study Group
Published: March 2021

Introduction

Previous studies showed that quarantine for pandemic diseases is associated with several psychological and medical effects. The consequences of quarantine for COVID-19 pandemic in patients with dementia are unknown. We investigated the clinical changes in patients with Alzheimer’s disease and other dementias, and evaluated caregivers’ distress during COVID-19 quarantine.

Methods

The study involved 87 Italian Dementia Centers. Patients with Alzheimer’s Disease (AD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), and Vascular Dementia (VD) were eligible for the study. Family caregivers of patients with dementia were interviewed by phone in April 2020, 45 days after quarantine declaration. Main outcomes were patients’ changes in cognitive, behavioral, and motor symptoms. Secondary outcomes were effects on caregivers’ psychological features.

Results

4913 patients (2934 females, 1979 males) fulfilled the inclusion criteria. Caregivers reported a worsening in cognitive functions in 55.1% of patients, mainly in subjects with DLB and AD. Aggravation of behavioral symptoms was observed in 51.9% of patients. In logistic regression analysis, previous physical independence was associated with both cognitive and behavioral worsening (odds ratio 1.85 [95% CI 1.42–2.39], 1.84 [95% CI 1.43–2.38], respectively). On the contrary, pandemic awareness was a protective factor for the worsening of cognitive and behavioral symptoms (odds ratio 0.74 [95% CI 0.65–0.85]; and 0.72 [95% CI 0.63–0.82], respectively). Approximately 25.9% of patients showed the onset of new behavioral symptoms. A worsening in motor function was reported by 36.7% of patients. Finally, caregivers reported a high increase in anxiety, depression, and distress.

Conclusion

Our study shows that quarantine for COVID-19 is associated with an acute worsening of clinical symptoms in patients with dementia as well as increase of caregivers’ burden. Our findings emphasize the importance to implement new strategies to mitigate the effects of quarantine in patients with dementia.
Factors Associated With the Dilation of Perivascular Space in Healthy Elderly Subjects
Authors: Huang Peiyu , Zhu Zili , Zhang Ruiting , Wu Xiao , Jiaerken Yeerfan , Wang Shuyue , Yu Wenke , Hong Hui , Lian Chunfeng , Li Kaicheng , Zeng Qingze , Luo Xiao , Xu Xiaopei , Yu Xinfeng , Yang Yunjun , Zhang Minming
Published: March 2021

Background: The dilation of perivascular space (PVS) has been widely used to reflect brain degeneration in clinical brain imaging studies. However, PVS characteristics exhibit large differences in healthy subjects. Such variations need to be better addressed before PVS can be used to reflect pathological changes. In the present study, we aim to investigate the potential influence of several related factors on PVS dilation in healthy elderly subjects.

Methods: One-hundred and three subjects (mean age = 59.5) were retrospectively included from a prospectively collected community cohort. Multi-modal high-resolution magnetic resonance imaging and cognitive assessments were performed on each subject. Machine-learning based segmentation methods were employed to quantify PVS volume and white matter hyperintensity (WMH) volume. Multiple regression analysis was performed to reveal the influence of demographic factors, vascular risk factors, intracranial volume (ICV), major brain artery diameters, and brain atrophy on PVS dilation.

Results: Multiple regression analysis showed that age was positively associated with the basal ganglia (BG) (standardized beta = 0.227, p = 0.027) and deep white matter (standardized beta = 0.220, p = 0.029) PVS volume. Hypertension was positively associated with deep white matter PVS volume (standardized beta = 0.234, p = 0.017). Furthermore, we found that ICV was strongly associated with the deep white matter PVS volume (standardized beta = 0.354, p < 0.001) while the intracranial artery diameter was negatively associated with the deep white matter PVS volume (standardized beta = −0.213, p = 0.032).

Conclusions: Intracranial volume has significant influence on deep white matter PVS volume. Future studies on PVS dilation should include ICV as an important covariate.
The Role of Parvalbumin Interneuron GIRK Signaling in the Regulation of Affect and Cognition in Male and Female Mice
Authors: Anderson Eden M. , Demis Skyler , D’Acquisto Hunter , Engelhardt Annabel , Hearing Matthew
Published: March 2021

Pathological impairments in the regulation of affect (i.e., emotion) and flexible decision-making are commonly observed across numerous neuropsychiatric disorders and are thought to reflect dysfunction of cortical and subcortical circuits that arise in part from imbalances in excitation and inhibition within these structures. Disruptions in GABA transmission, in particular, that from parvalbumin-expressing interneurons (PVI), has been highlighted as a likely mechanism by which this imbalance arises, as they regulate excitation and synchronization of principle output neurons. G protein-gated inwardly rectifying potassium ion (GIRK/Kir3) channels are known to modulate excitability and output of pyramidal neurons in areas like the medial prefrontal cortex and hippocampus; however, the role GIRK plays in PVI excitability and behavior is unknown. Male and female mice lacking GIRK1 in PVI (Girk1flox/flox:PVcre) and expressing td-tomato in PVI (Girk1flox/flox:PVCre:PVtdtom) exhibited increased open arm time in the elevated plus-maze, while males showed an increase in immobile episodes during the forced swim test (FST). Loss of GIRK1 did not alter motivated behavior for an appetitive reward or impair overall performance in an operant-based attention set-shifting model of cognitive flexibility; however it did alter types of errors committed during the visual cue test. Unexpectedly, baseline sex differences were also identified in these tasks, with females exhibiting overall poorer performance compared to males and distinct types of errors, highlighting potential differences in task-related problem-solving. Interestingly, reductions in PVI GIRK signaling did not correspond to changes in membrane excitability but did increase action potential (AP) firing at higher current injections in PVI of males, but not females. This is the first investigation on the role that PVI GIRK-signaling has on membrane excitability, AP firing, and their role on affect and cognition together increasing the understanding of PVI cellular mechanisms and function.
Exposure to Blue Wavelength Light Is Associated With Increases in Bidirectional Amygdala-DLPFC Connectivity at Rest
Authors: Alkozei Anna , Dailey Natalie S. , Bajaj Sahil , Vanuk John R. , Raikes Adam C. , Killgore William D. S.
Published: March 2021

Blue wavelength light has been used successfully as a treatment method for certain mood disorders, but, the underlying mechanisms behind the mood enhancing effects of light remain poorly understood. We investigated the effects of a single dose of 30 min of blue wavelength light (n = 17) vs. amber wavelength light (n = 12) exposure in a sample of healthy adults on subsequent resting-state functional and directed connectivity, and associations with changes in state affect. Individuals who received blue vs. amber wavelength light showed greater positive connectivity between the right amygdala and a region within the left dorsolateral prefrontal cortex (DLPFC). In addition, using granger causality, the findings showed that individuals who received blue wavelength light displayed greater bidirectional information flow between these two regions relative to amber light. Furthermore, the strength of amygdala-DLPFC functional connectivity was associated with greater decreases in negative mood for the blue, but not the amber light condition. Blue light exposure may positively influence mood by modulating greater information flow between the amygdala and the DLPFC, which may result in greater engagement of cognitive control strategies that are needed to perceive and regulate arousal and mood.
Clinical and Prognostic Analysis of Autoantibody-Associated CNS Demyelinating Disorders in Children in Southwest China
Authors: Li Ziyan , Sun Hong , Fan Xiao , Yuan Ping , Jiang Yan , Wu Peng , Zhong Min , Ma Jiannan , Jiang Li , Li Xiujuan
Published: March 2021

Objective: To analyze the positive and recurrence rates of different autoantibody-associated demyelination disorders in children in Southwest China, and describe the clinical, radiological, and prognostic features of the myelin oligodendrocyte glycoprotein antibody (MOG-ab) and aquaporin-4 antibody (AQP4-ab) associated disease. This study also summarizes steroid maintenance therapy approaches for MOG-ab-positive children.

Methods: A total of 160 children presenting with acquired demyelinating syndromes (ADS) between January 2016 and December 2019 were tested for MOG-ab and AQP4-ab. Clinical data, MRI scans, and survival analyses were compared between MOG-ab-positive and AQP4-ab-positive children. Evolution of serologic status and treatment response to immunosuppressants were collected in MOG-ab-positive children.

Results: Of the 160 included children, the MOG-ab positivity rate (47.4%) was significantly higher than the AQP4-ab (5%) positivity rate. The recurrence rate for AQP4-ab disease (71.4%) was higher than that of MOG-ab disease (30.1%). For 135 children with both MOG-ab and AQP4-ab tested, the median age at onset was 7 (interquartile range [IQR] 5–10) years, and the median follow-up period was 19 (IQR 13–27.5) months. MOG-ab-positive children more frequently presented with acute disseminated encephalomyelitis, had deep gray matter lesions on MRI, had a better clinical and radiological recovery, and were less likely to have sustained disability than AQP4-ab-positive children. In MOG-ab-positive and AQP4-ab-positive children, maintenance therapy was a protective factor for recurrence, but presenting optic neuritis was a predictor of earlier relapse. A high Expanded Disability Status Scale score at onset was associated with sustained disability. Steroid maintenance therapy longer than 6 months after the initial attack was associated with a lower risk of a second relapse in MOG-ab-positive children. On serial serum MOG antibody analysis, clinical relapse occurred in 34.6% of children with persistent seropositivity, but none of the children who converted to seronegative status experienced relapse.

Conclusion: The MOG antibody is more common in children with ADS than the AQP4 antibody. MOG-ab-positive children are characterized by distinct clinical and radiological features. Although some MOG-ab-positive children experience relapsing courses or have persistently seropositive status, they still predict a better outcome than AQP4-ab-positive children.
The Usefulness of Diffusion Tensor Tractography in Diagnosing Neuropathic Pain: A Narrative Review
Authors: Yang Seoyon , Kwon SuYeon , Chang Min Cheol
Published: March 2021

Diffusion tensor tractography (DTT) is derived from diffusion tensor imaging. It has allowed visualization and estimation of neural tract injury, which may be associated with the pathogenesis of neuropathic pain (NP). The aim of the present study was to review DTT studies that demonstrated the relationship between neural injuries and NP and to describe the potential use of DTT in the evaluation of neural injuries that are involved in the pathophysiological process of NP. A PubMed search was conducted for articles published until July 3, 2020, which used DTT to investigate the association between neural injuries and NP. The key search phrase for identifying potentially relevant articles was (diffusion tensor tractography AND pain). The following inclusion criteria were applied for article selection: (1) studies involving patients with NP and (2) studies in which DTT was applied for the evaluation of NP. Review articles were excluded. Altogether, 108 potentially relevant articles were identified. After reading the titles and abstracts and assessment of eligibility based on the full-text articles, 46 publications were finally included in our review. The results of the included studies suggested that DTT may be beneficial in identifying the pathophysiological mechanism of NP of various origins including central pain caused by brain injuries, trigeminal neuralgia, sciatica, and some types of headache. Further studies are needed to validate the efficacy of DTT in investigating the pathophysiology of other types of NP.
Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain
Authors: Cochard Loïc M. , Levros Louis-Charles , Joppé Sandra E. , Pratesi Federico , Aumont Anne , Fernandes Karl J. L.
Published: March 2021

The ventricular-subventricular zone (V-SVZ) is the principal neurogenic niche in the adult mammalian forebrain. Neural stem/progenitor cell (NSPC) activity within the V-SVZ is controlled by numerous of extrinsic factors, whose downstream effects on NSPC proliferation, survival and differentiation are transduced via a limited number of intracellular signaling pathways. Here, we investigated the relationship between age-related changes in NSPC output and activity of signaling pathways downstream of the epidermal growth factor receptor (EGFR), a major regulator of NSPC activity. Biochemical experiments indicated that age-related decline of NSPC activity in vivo is accompanied by selective deficits amongst various EGFR-induced signal pathways within the V-SVZ niche. Pharmacological loss-of-function signaling experiments with cultured NSPCs revealed both overlap and selectivity in the biological functions modulated by the EGFR-induced PI3K/AKT, MEK/ERK and mTOR signaling modules. Specifically, while all three modules promoted EGFR-mediated NSPC proliferation, only mTOR contributed to NSPC survival and only MEK/ERK repressed NSPC differentiation. Using a gain-of-function in vivo genetic approach, we electroporated a constitutively active EGFR construct into a subpopulation of quiescent, EGFR-negative neural stem cells (qNSCs); this ectopic activation of EGFR signaling enabled qNSCs to divide in 3-month-old early adult mice, but not in mice at middle-age or carrying familial Alzheimer disease mutations. Thus, (i) individual EGFR-induced signaling pathways have dissociable effects on NSPC proliferation, survival, and differentiation, (ii) activation of EGFR signaling is sufficient to stimulate qNSC cell cycle entry during early adulthood, and (iii) the proliferative effects of EGFR-induced signaling are dominantly overridden by anti-proliferative signals associated with aging and Alzheimer’s disease.
Ultra-Processed Food Consumption Among Chilean Preschoolers Is Associated With Diets Promoting Non-communicable Diseases
Authors: Araya C. , Corvalán C. , Cediel G. , Taillie L. S. , Reyes M.
Published: March 2021

Introduction: In adults, intake of ultra-processed foods (UPF) has been linked with poor diets and adverse health outcomes. In young children, evidence is scarcer but suggests a higher dietary share of UPF.

Objective: To quantify the intake of UPF and its association with the nutrient composition of the diet in a sample of preschoolers in Santiago, Chile.

Methods: Cross-sectional analysis of dietary data (24-h recall survey) from 960 preschoolers. Foods were categorized according to the extent and purpose of processing (NOVA classification) and participants were classified in quintiles of UPF intake. We explored the associations between UPF intake (% of the total energy) and intake of nutrients of concern for non-communicable disease development (carbohydrates, total sugars, fats, and sodium), and nutrients for promotion (proteins, polyunsaturated fats, iron, calcium, zinc, vitamins A, D, C, and B12, folate, and fiber) using multivariate regression after controlling for covariates.

Results: UPF constituted 49% of the total energy intake. Preschoolers with higher intake consumed more energy, saturated and monounsaturated fats, carbohydrates, total sugars, and vitamin D, compared to preschoolers in the lowest quintile of UPF intake. In contrast, UPF intake was negatively associated with the consumption of proteins, polyunsaturated fats, fiber, zinc, vitamin A, and sodium (p < 0.05).

Conclusion: In Chilean preschoolers, UPF was the primary source of energy intake. The dietary share of UPF was associated with the nutrient composition of the diet. Improving children's diet should consider not only promoting healthy food consumption but also limiting UPF consumption.
The Spectrum, Tendency and Predictive Value of PIK3CA Mutation in Chinese Colorectal Cancer Patients
Authors: Fu Xinhui , Lin Hanjie , Fan Xinjuan , Zhu Yaxi , Wang Chao , Chen Zhiting , Tan Xiaoli , Huang Jinglin , Cai Yacheng , Huang Yan
Published: March 2021

Background

PIK3CA is a high-frequency mutation gene in colorectal cancer, while its prognostic value remains unclear. This study evaluated the mutation tendency, spectrum, prognosis power and predictive power in cetuximab treatment of PIK3CA in Chinese CRC cohort.

Methods

The PIK3CA exon 9 and 20 status of 5763 CRC patients was detected with Sanger sequencing and a high-resolution melting test. Clinicopathological characteristics of 5733 patients were analyzed. Kaplan-Meier method and nomogram were used to evaluate the overall survival curve and disease recurrence, respectively.

Results

Fifty-eight types of mutations in 13.4% (771/5733) of the patients were detected. From 2014 to 2018, the mutation rate of PIK3CA increased from 11.0% to 13.5%. At stage IV, exon 20 mutated patients suffered shorter overall survival time than wild-type patients (multivariate COX regression analysis, HR = 2.72, 95% CIs = 1.47-5.09; p-value = 0.012). At stage III, PIK3CA mutated patients were more likely to relapse (multivariate Logistic regression analysis, exon 9: OR = 2.54, 95% CI = 1.34-4.73, p = 0.003; exon 20: OR = 3.89, 95% CI = 1.66-9.10, p = 0.002). The concordance index of the nomogram for predicting the recurrence risk of stage III patients was 0.685. After cetuximab treatment, the median PFS of PIK3CA exon 9 wild-type patients (n = 9) and mutant patients (n = 5) did not reach a significant difference (3.6 months vs. 2.3 months, Log-rank test, p-value = 0.513).

Conclusions

We found that PIK3CA mutation was an adverse predictive marker for the overall survival of stage IV patients and recurrence of stage III patients, respectively. Further more, we suggested that PIK3CA exon 9 mutations are not negative predictors of cetuximab treatment in KRAS, NRAS, and BRAF wild-type mCRC patients.
Comprehensive Association Analysis of 21-Gene Recurrence Score and Obesity in Chinese Breast Cancer Patients
Authors: Tong Yiwei , Gao Weiqi , Wu Jiayi , Zhu Siji , Huang Ou , He Jianrong , Zhu Li , Chen Weiguo , Li Yafen , Shen Kunwei , Chen Xiaosong
Published: March 2021

Purpose

A center-specific 21-gene recurrence score (RS) assay has been validated in Luminal-like, HER2-, pN0-1 Chinese breast cancer patients with both predictive and prognostic value. The association between RS and host factors such as obesity remains unclear. The objectives of the current study are to comprehensively analyze the distribution, single gene expression, and prognostic value of RS among non-overweight, overweight and obese patients.

Patients and methods

Luminal-like patients between January 2009 and December 2018 were retrospectively reviewed. Association and subgroup analysis between BMI and RS were conducted. Single-gene expression in RS panel was compared according to BMI status. Disease-free survival (DFS) and overall survival (OS) were calculated according to risk category and BMI status.

Results

Among 1876 patients included, 124 (6.6%), 896 (47.8%) and 856 (45.6%) had RS < 11, RS 11-25, and RS ≥ 26, respectively. Risk category was significantly differently distributed by BMI status (P=0.033). Obese patients were more likely to have RS < 11 (OR 2.45, 95% CI 1.38-4.35, P=0.002) compared with non-overweight patients. The effect of BMI on RS significantly varied according to menstruation (P<0.05). Compared to non-overweight patients, obese ones presented significantly higher ER, PR, CEGP1, Ki67, CCNB1 and GSTM1 (all P<0.05) mRNA expression, and such difference was mainly observed in postmenopausal population. After a median follow-up of 39.40 months (range 1.67-119.53), RS could significantly predict DFS in whole population (P=0.001). RS was associated with DFS in non-overweight (P=0.046), but not in overweight (P=0.558) or obese (P=0.114) population.

Conclusions

RS was differently distributed among different BMI status, which interacted with menopausal status. Estrogen receptor and proliferation group genes were more expressed in obese patients, especially in postmenopausal population.