bluuebunny/crossref_metadata_2025 huggingface dataset:
MicroRNA-497 Reduction and Increase of Its Family Member MicroRNA-424 Lead to Dysregulation of Multiple Inflammation Related Genes in Synovial Fibroblasts With Rheumatoid Arthritis
Authors: Wang Si , Xu Jing , Guo Yuanxu , Cai Yongsong , Ren Xiaoyu , Zhu Wenhua , Geng Manman , Meng Liesu , Jiang Congshan , Lu Shemin
Published: March 2021

Objectives

Mounting evidence has demonstrated that microRNAs (miRNAs) participate in rheumatoid arthritis (RA). The role of highly conserved miR-15/107 family in RA has not been clarified yet, and hence investigated in this study.

Methods

Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to evaluate the expression of miRNAs and genes. Cell counting kit 8 (CCK-8) and FACS were used to detect proliferation and apoptosis. Protein expression was detected by using Western blotting. mRNA deep sequencing and cytokine antibody array were used to analyze differentially expressed genes, signaling pathways and cytokines.

Results

The expression of miR-15a, miR-103, miR-497, and miR-646 was found decreased, while miR-424 increased in RA patients. MiR-424 and miR-497 were further investigated and the results showed that they could regulate the expression of multiple genes in rheumatoid arthritis synovial fibroblast (RASF) and affect signaling pathways. At the protein level, miR-497 mimic altered all the selected inflammation-related genes while miR-424 inhibitor only affected part of genes. MiR-497 mimic, rather than miR-424 inhibitor, had significant effects on proliferation and apoptosis of RASF. DICER1 was found to positively regulate the expression of miR-424 and miR-497, while DICER1 was also negatively regulated by miR-424. The increase of miR-424 could reduce miR-497 expression, thus forming a loop, which facilitated explaining the dysregulated miR-424 and miR-497 in RA.

Conclusion

The miR-424 and miR-497 of miR-15/107 family affect cell proliferation and apoptosis in RA, and the proposed miR-424-DICER1-miR-497 feedback loop provides a novel insight into regulating miRNA expression and a candidate target for controlling RA.
miR-155 Contributes to the Immunoregulatory Function of Human Mesenchymal Stem Cells
Authors: Pers Yves-Marie , Bony Claire , Duroux-Richard Isabelle , Bernard Laurène , Maumus Marie , Assou Said , Barry Frank , Jorgensen Christian , Noël Danièle
Published: March 2021

Objectives

Mesenchymal stem/stromal cells (MSCs) are widely investigated in regenerative medicine thanks to their immunomodulatory properties. They exert their anti-inflammatory function thanks to the secretion of a number of mediators, including proteins and miRNAs, which can be released in the extracellular environment or in the cargo of extracellular vesicles (EVs). However, the role of miRNAs in the suppressive function of MSCs is controversial. The aim of the study was to identify miRNAs that contribute to the immunomodulatory function of human bone marrow-derived MSCs (BM-MSCs).

Methods

Human BM-MSCs were primed by coculture with activated peripheral blood mononuclear cells (aPBMCs). High throughput miRNA transcriptomic analysis was performed using Human MicroRNA TaqMan® Array Cards. The immunosuppressive function of miRNAs was investigated in mixed lymphocyte reactions and the delayed type hypersensitivity (DTH) murine model.

Results

Upon priming, 21 out of 377 tested miRNAs were significantly modulated in primed MSCs. We validated the up-regulation of miR-29a, miR-146a, miR-155 and the down-regulation of miR-149, miR-221 and miR-361 in additional samples of primed MSCs. We showed that miR-155 significantly reduced the proliferation of aPBMCs in vitro and inflammation in vivo, using the DTH model. Analysis of miRNA-mRNA interactions revealed miR-221 as a potential target gene that is down-regulated by miR-155 both in primed MSCs and in aPBMCs.

Conclusion

Here, we present evidence that miR-155 participates to the immunosuppressive function of human BM-MSCs and down-regulates the expression of miR-221 as a possible inflammatory mediator.
Frontiers of Autoantibodies in Autoimmune Disorders: Crosstalk Between Tfh/Tfr and Regulatory B Cells
Authors: Ding Tingting , Su Rui , Wu Ruihe , Xue Hongwei , Wang Yanyan , Su Ronghui , Gao Chong , Li Xiaofeng , Wang Caihong
Published: March 2021

Balance of Tfh/Tfr cell is critically important for the maintenance of immune tolerance, as evidenced by the fact that T follicular helper (Tfh) cells are central to the autoantibodies generation through providing necessary help for germinal center (GC) B cells, whereas T follicular regulatory (Tfr) cells significantly inhibit autoimmune inflammation process through restraining Tfh cell responses. However, signals underlying the regulation of Tfh and Tfr cells are largely undefined. Regulatory B cells (Bregs) is a heterogeneous subpopulation of B cells with immunosuppressive function. Considerable advances have been made in their functions to produce anti‐inflammatory cytokines and to regulate Th17, Th1, and Treg cells in autoimmune diseases. The recent identification of their correlations with dysregulated Tfr/Tfh cells and autoantibody production makes Bregs an important checkpoint in GC response. Bregs exert profound impacts on the differentiation, function, and distribution of Tfh and Tfr cells in the immune microenvironment. Thus, unraveling mechanistic information on Tfh-Breg and Tfr-Breg interactions will inspire novel implications for the establishment of homeostasis and prevention of autoantibodies in diverse diseases. This review summarizes the dysregulation of Tfh/Tfr cells in autoimmune diseases with a focus on the emerging role of Bregs in regulating the balance between Tfh and Tfr cells. The previously unsuspected crosstalk between Bregs and Tfh/Tfr cells will be beneficial to understand the cellular mechanisms of autoantibody production and evoke a revolution in immunotherapy for autoimmune diseases.
Repurposing Saquinavir for Host-Directed Therapy to Control Mycobacterium Tuberculosis Infection
Authors: Pires David , Valente Sofia , Calado Marta , Mandal Manoj , Azevedo-Pereira José Miguel , Anes Elsa
Published: March 2021

Despite the available antibiotics, tuberculosis (TB) has made its return since the 90’s of the last century as a global threat mostly due to co-infection with HIV, to the emergence of drug resistant strains and the lack of an effective vaccine. Host-directed strategies could be exploited to improve treatment efficacy, contain drug-resistant strains, improve immune responses and reduce disease severity. Macrophages in the lungs are often found infected with Mycobacterium tuberculosis (Mtb) and/or with HIV. The long-term survival of lung macrophages infected with Mtb or with HIV, together with their ability to produce viral particles, especially during TB, makes these niches major contributors to the pathogenicity of the infection. Among the available drugs to control HIV infection, protease inhibitors (PIs), acting at post-integrational stages of virus replication cycle, are the only drugs able to interfere with virus production and release from macrophages during chronic infection. For Mtb we recently found that the pathogen induces a general down-regulation of lysosomal proteases, helping bacteria to establish an intracellular niche in macrophages. Here we found that the PI saquinavir, contrary to ritonavir, is able to induce an increase of endolysosomal proteases activity especially of cathepsin S in Mtb infected macrophages and during co-infection with HIV. Our results indicate that saquinavir treatment of infected macrophages led not only to a significant intracellular killing of Mtb but also: (i) to an improved expression of the HLA class II antigen presentation machinery at the cell surface; (ii) to increased T-lymphocyte priming and proliferation; and (iii) to increased secretion of IFN-γ. All together the results indicate saquinavir as a potential host directed therapy for tuberculosis.
Application of a Simple, Low-Cost, Low-Tech Method to Monitor Intertidal Rocky Shore Assemblages on a Broad Geographic Scale
Authors: Livore Juan Pablo , Mendez María M. , Klein Eduardo , Arribas Lorena , Bigatti Gregorio
Published: March 2021

Identifying susceptible regions where biodiversity changes occur at fast rates is essential in order to protect and ameliorate affected areas. Large-scale coastal monitoring programs that focus on long-term variability are scarce, yet the Marine Biodiversity Observation Network Pole to Pole is currently developing a regional collaboration throughout the American continent collecting biodiversity data in coastal habitats with a standardized systematic protocol. The use of photographic methods to collect assemblage data on intertidal rocky shores can be appropriate. The goal of this study was to analyze the performance of a simple, low-cost, non-destructive and low-tech photographic method on a broad geographical scale (∼ 2,000 km) of Atlantic Patagonian coastline. Concurrently, we aimed to identify indicators whose cover, presence or condition can be followed in time and used as beacons of change in biodiversity on these rocky intertidal shores. We also explored the potential relationships between assemblage structure and environmental variables, such as seascape classes. We identified and propose cover of mytilids, Corallina spp. and bare substrate as indicators of change due to their ecological relevance in intertidal assemblages and their visible and rapid response to human stressors or changes in environmental conditions. Finally, we illustrate the practicality and usefulness of remotely accessible environmental data, for instance the seascape classes approach as an integrative tool for large-scale rocky shore studies.
Detecting Regime Shifts in the Portuguese Continental Shelf Ecosystem Within the Last Three Decades
Authors: Szalaj Dorota , Silva Alexandra , Ré Pedro , Cabral Henrique
Published: March 2021

Marine ecosystems are affected by diverse pressures and consequently may undergo significant changes that can be interpreted as regime shifts. In this study we used integrated trend analysis (ITA) that combines multivariate statistics and methodologies to identify abrupt changes in time-series, in order to test a hypothesis about the occurrence of regime shifts in the Portuguese continental shelf ecosystem (PCSE). We used two types of data describing ecosystem drivers (fishing mortality and environmental/climatic indices) and ecosystem state (observed and modelled biomass and ecosystem indices). Modelled biomass and ecosystem indices were outputs of Ecopath with Ecosim temporal model parametrised for PSCE between 1986 and 2017. The analyses indicated that the regime shifts in the PCSE have occurred during three periods in the last three decades: “early regime” until the mid-1990s, followed by “transition regime” in-between and “late regime” since the mid-2010s. The detected regime shifts are characterised by changes in the pelagic community that became more dominant when compared to the demersal community and shifted from sardine, the main fishing resource, abundant in the “early regime”, to other less valuable pelagic fishes such as chub mackerel that dominated the “late regime”. The “early regime” was characterised by high catch, a larger proportion of demersal species, and higher diversity while, the “late regime” was represented by lower catch, an increase in higher trophic level (TL) predatory fish and lower diversity. Moreover, the “late regime” showed lower resilience and reduced maturity when compared to the “early regime”. Changes described in the ecosystem were probably related to (1) the shift in the north Atlantic environmental conditions that affected small pelagic fish (SPF) and lower TLs groups, (2) reduction in fishing pressure, and (3) internal triggers, related to the indirect trophic interactions that might have benefited higher TL fish and impacted the pelagic community. In the context of PCSE management, this study highlighted a need to consider the possibility of regime shifts in the management process. For example, regime specific harvest rates and environmental reference points should be considered when an indication of abrupt change in the ecosystem exists.
Mindfulness as Predictor of Itch Catastrophizing in Patients With Atopic Dermatitis: Results of a Cross-Sectional Questionnaire Study
Authors: Lüßmann Kjell , Montgomery Kerry , Thompson Andrew , Gieler Uwe , Zick Christoph , Kupfer Joerg , Schut Christina
Published: March 2021

Itch and worry about itch are predominant symptoms in atopic dermatitis (AD). Mindfulness refers to paying attention in a certain way, non-judgementally and on purpose. In patients with chronic pain, which shares several similarities with chronic itch, a significant relationship between pain intensity, mindfulness and pain catastrophizing has been found. The aim of this study was to investigate whether itch intensity and mindfulness are related to itch catastrophizing in AD patients. Participants receiving treatment for AD (n= 155; 58 male; mean age: 46.5 ± 12 years) completed measures of itch-related catastrophizing (Itch Cognitions Questionnaire; ICQ) and mindfulness (Comprehensive Inventory of Mindfulness; CHIME) during their stay at a rehabilitation center in Borkum, Germany. In addition to other variables, their average itch intensity during the last 2 weeks was assessed by means of a visual analog scale. A positive relationship between itch intensity and itch catastrophizing was found (r= 0.409;p< 0.01). Moreover, the mindfulness scales “acting with awareness,” “accepting and non-judgemental orientation,” and “non-reactive orientation” were negatively related to itch catastrophizing. A linear regression analysis revealed that itch intensity in combination with “acting with awareness” was able to explain more than 27 % (correctedR2= 0.274;p< 0.001) of the variance of itch catastrophizing. Thus, itch intensity and certain facets of mindfulness were associated with itch catastrophizing in AD patients. Psychological interventions aiming to increase acting with awareness might have a buffering effect on itch catastrophizing, which in turn could lead to lower itch intensity in patients with AD. Future RCTs should test this hypothesis.
Genome-Wide Analysis of Staphylococcus aureus Sequence Type 72 Isolates Provides Insights Into Resistance Against Antimicrobial Agents and Virulence Potential
Authors: Batool Nayab , Shamim Amen , Chaurasia Akhilesh Kumar , Kim Kyeong Kyu
Published: March 2021

Staphylococcus aureus sequence type 72 (ST72) is a major community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) that has rapidly entered the hospital setting in Korea, causing mild superficial skin wounds to severe bloodstream infections. In this study, we sequenced and analyzed the genomes of one methicillin-resistant human isolate and one methicillin-sensitive human isolate of ST72 from Korea, K07-204 and K07-561, respectively. We used a subtractive genomics approach to compare these two isolates to other 27 ST72 isolates to investigate antimicrobial resistance (AMR) and virulence potential. Furthermore, we validated genotypic differences by phenotypic characteristics analysis. Comparative and subtractive genomics analysis revealed that K07-204 contains methicillin (mecA), ampicillin (blaZ), erythromycin (ermC), aminoglycoside (aadD), and tetracycline (tet38, tetracycline efflux pump) resistance genes while K07-561 has ampicillin (blaZ) and tetracycline (tet38) resistance genes. In addition to antibiotics, K07-204 was reported to show resistance to lysostaphin treatment. K07-204 also has additional virulence genes (adsA, aur, hysA, icaABCDR, lip, lukD, sdrC, and sdrE) compared to K07-561, which may explain the differential virulence potential of these human isolates of ST72. Unexpectedly, the virulence potential of K07-561 was higher in an in vivo wax-worm infection model than that of K07-204, putatively due to the presence of a 20-fold higher staphyloxanthin concentration than K07-204. Comprehensive genomic analysis of these two human isolates, with 27 ST72 isolates, and S. aureus USA300 (ST8) suggested that acquisition of both virulence and antibiotics resistance genes by ST72 isolates might have facilitated their adaptation from a community to a hospital setting where the selective pressure imposed by antibiotics selects for more resistant and virulent isolates. Taken together, the results of the current study provide insight into the genotypic and phenotypic features of various ST72 clones across the globe, delivering more options for developing therapeutics and rapid molecular diagnostic tools to detect resistant bacteria.
Comparative Study of the Rhizosphere and Root Endosphere Microbiomes of Cholistan Desert Plants
Authors: Mukhtar Salma , Mehnaz Samina , Malik Kauser Abdulla
Published: March 2021

Microbial communities associated with the rhizosphere and roots of desert halophytes play an important role in plants’ growth and development. Very limited information has been available on the microbial diversity of arid environments of Pakistan. Hence in the current study, the microbial diversity of rhizosphere and root endosphere of desert halophytes, Zygophyllum simplex, Haloxylon salicoricum, Aerva javanica, and Capparis decidua was evaluated. The rhizosphere and root endosphere samples of desert halophytes collected from the three geographic sites of Cholistan desert, Punjab, Pakistan were analyzed by using 16S rRNA based Illumina sequencing. The results showed that Proteobacteria were more abundant in the rhizospheric soils while Actinobacteria were more dominant in the root endosphere of halophytes. Bacteroidetes, Firmicutes, and Deinococcus-Thermus were identified from all rhizospheric soils and roots across the three sites, with variable percentage. Bacillus, Kocuria, Pseudomonas, Halomonas, and Flavobacterium were commonly identified from the rhizosphere and root endosphere of halophytes across all the three sites. At the genus level, microbial diversity from Haloxylon showed the greatest variations between the rhizosphere and root endosphere from the site 2. This study revealed that microbial diversity analysis can be used to study how changes in abiotic factors such as soil moisture content and salinity affect the microbial communities associated with the rhizospheric soils and root endosphere of halophytes across the three sites. This study will also help in the discovery of potential inoculants for crops growing in arid and semi-arid regions of Pakistan.
Purification, Structural Characteristics, and Biological Activities of Exopolysaccharide Isolated From Leuconostoc mesenteroides SN-8
Authors: Wu Junrui , Yan Danli , Liu Yumeng , Luo Xue , Li Yang , Cao Chengxu , Li Mo , Han Qi , Wang Cong , Wu Rina , Zhang Lanwei
Published: March 2021

In this study, a novel exopolysaccharide (EPS) was extracted from Leuconostoc mesenteroides Shen Nong’s (SN)-8 which can be obtained from Dajiang. After the purification step, EPS-8-2 was obtained with molecular weights of 1.46 × 105 Da. The structural characterization of EPS indicated that the EPS belonged to the class polysaccharide, mainly composed of glucan and also contained certain mannose residues that were found to be connected by α-1,6 glycosidic bonds. Moreover, the results demonstrated that EPS displayed a significant capacity to scavenge free radical to some extent, and this anti-oxidant potential was found to be concentration dependent. The results further revealed that EPS displayed a significant inhibitory potential on the growth of HepG2 cells by promoting apoptosis and induced cell cycle arrest in G1 and G2 phases. Overall, these results suggested that EPS can be explored as a possible anti-cancer agent.
Succession of Bacterial Community During the Initial Aerobic, Intense Fermentation, and Stable Phases of Whole-Plant Corn Silages Treated With Lactic Acid Bacteria Suspensions Prepared From Other Silages
Authors: Sun Lin , Bai Chunsheng , Xu Haiwen , Na Na , Jiang Yun , Yin Guomei , Liu Sibo , Xue Yanlin
Published: March 2021

The present study was aimed at investigating the bacterial community in lactic acid bacteria (LAB) suspensions prepared from whole-plant corn silage (LAB suspension-CS) and Elymus sibiricus silage (LAB suspension-ES) and the bacterial community succession of whole-plant corn silages inoculated with LAB suspension-CS or LAB suspension-ES during initial aerobic phase, intense fermentation phase, and stable phase. The LAB suspensions were cultured in sterile Man, Rogosa, Sharpe broth at 37°C for 24 h and used as inoculants for ensiling. The chopped whole-plant corn was treated with distilled water (CK), LAB suspension-CS (CSL), or LAB suspension-ES (ESL) and then ensiled in vacuum-sealed plastic bags containing 500 g of fresh forage. Silages were sampled at 0 h, anaerobic state (A), 3 h, 5 h, 10 h, 24 h, 2 days, 3 days, 10 days, 30 days, and 60 days of ensiling with four replicates for each treatment. The results showed that Lactobacillus, Weissella, and Lachnoclostridium_5 dominated the bacterial community in LAB suspension-CS; Lactobacillus was the most predominant bacterial genus in LAB suspension-ES. During the initial aerobic phase (from 0 h to A) of whole-plant corn silage, the pH and the abundances of Pantoea, Klebsiella, Rahnella, Erwinia, and Serratia increased. During the intense fermentation phase (from A to 3 days), the pH decreased rapidly, and the microbial counts increased exponentially; the most predominant bacterial genus shifted from Pantoea to Weissella, and then to Lactobacillus; inoculating LAB suspensions promoted the bacterial succession and the fermentation process, and LAB suspension-CS was more effective than LAB suspension-ES. During the stable phase (from 3 to 60 days), the pH and the microbial counts decreased, and Lactobacillus dominated the bacterial community with a little decrease. The results also confirmed the existence of LAB fermentation relay during fermentation process, which was reflected by Weissella, Lactococcus, and Leuconostoc in the first 5 h; Weissella, Lactococcus, Leuconostoc, Lactobacillus, and Pediococcus between 5 and 24 h; and Lactobacillus from 24 h to 60 days.
Mining TCGA Data for Key Biomarkers Related to Immune Microenvironment in Endometrial cancer by Immune Score and Weighted Correlation Network Analysis
Authors: Guo Chengbin , Tang Yuqin , Zhang Yongqiang , Li Gen
Published: March 2021

Background: Endometrial cancer (EC) is one of the most lethal gynecological cancers around the world. The aim of this study is to identify the potential immune microenvironment-related biomarkers associated with the prognosis for EC.

Methods: RNA-seq data and clinical information of EC patients were derived from The Cancer Genome Atlas (TCGA). The immune score of each EC sample was obtained by ESTIMATE algorithm. Weighted gene co-expression network analysis (WGCNA) was used to identify the interesting module and potential key genes concerning the immune score. The expression patterns of the key genes were then verified via the GEPIA database. Finally, CIBERSORT was applied to evaluate the relative abundances of 22 immune cell types in EC.

Results: Immune scores were significantly associated with tumor grade and histology of EC, and high immune scores may exert a protective influence on the survival outcome for EC. WGCNA indicated that the black module was significantly correlated with the immune score. Function analysis revealed it mainly involved in those terms related to immune regulation and inflammatory response. Moreover, 11 key genes (APOL3, C10orf54, CLEC2B, GIMAP1, GIMAP4, GIMAP6, GIMAP7, GIMAP8, GYPC, IFFO1, TAGAP) were identified from the black module, validated by the GEPIA database, and revealed strong correlations with infiltration levels of multiple immune cell types, as was the prognosis of EC.

Conclusion: In this study, 11 key genes showed abnormal expressions and strong correlations with immune infiltration in EC, most of which were significantly associated with the prognosis of EC. These findings made them promising therapeutic targets for the treatment of EC.
Modality-Dependent Brain Activation Changes Induced by Acquiring a Second Language Abroad
Authors: Sakai Kuniyoshi L. , Kuwamoto Tatsuro , Yagi Satoma , Matsuya Kyohei
Published: March 2021

The dynamic nature of cortical activation changes during language acquisition, including second-language learning, has not been fully elucidated. In this study, we administered two sets of reading and listening tests (Pre and Post) to participants who had begun to learn Japanese abroad. The two sets were separated by an interval of about 2 months of Japanese language training. We compared the results of longitudinal functional MRI experiments between the two time-points and obtained the following major findings. First, the left-dominant language areas, as well as bilateral visual and auditory areas, were activated, demonstrating the synergistic effects of multiple modalities. There was also significant activation in the bilateral hippocampi, indicating the expected involvement of memory-related processes. Second, consistent with the behavioral improvements from Pre to Post, the brain activations decreased in the left inferior and middle frontal gyri during the listening tests, as well as in the visual areas (the bilateral inferior and superior parietal lobules, and left inferior and middle occipital gyri) during the reading tests, while activations in the right superior and middle temporal gyri increased during the listening tests. These modality-dependent activation changes could not be explained by domain-general cognitive factors, such as habituation or familiarization, because we used completely different test sets for Pre and Post. Third, the posterior hippocampus showed a main effect of the hemisphere, whereas the anterior hippocampus showed a significant main effect of the event (i.e., specific to first listening events), reflecting initial encoding of auditory information alone. In summary, activation changes from Pre to Post indicate functional changes in modality-dependent networks over a short period of staying abroad, which would enable effective acquisition of a second language.
Clinical Application of a Neurosurgical Robot in Intracranial Ommaya Reservoir Implantation
Authors: Liu Huan-Guang , Liu De-Feng , Zhang Kai , Meng Fan-Gang , Yang An-Chao , Zhang Jian-Guo
Published: March 2021

Background: The Ommaya reservoir implantation technique allows for bypass of the blood-brain barrier. It can be continuously administered locally and be used to repeatedly flush the intracranial cavity to achieve the purpose of treatment. Accurate, fast, and minimally invasive placement of the drainage tube is essential during the Ommaya reservoir implantation technique, which can be achieved with the assistance of robots.

Methods: We retrospectively analyzed a total of 100 patients undergoing Ommaya reservoir implantation, of which 50 were implanted using a robot, and the remaining 50 were implanted using conventional surgical methods. We then compared the data related to surgery between the two groups and calculated the accuracy of the drainage tube of the robot-assisted group.

Results: The average operation time of robot-assisted surgery groups was 41.17 ± 11.09 min, the bone hole diameter was 4.1 ± 0.5 mm, the intraoperative blood loss was 11.1 ± 3.08 ml, and the average hospitalization time was 3.9 ± 1.2 days. All of the Ommaya reservoirs were successful in one pass, and there were no complications such as infection or incorrect placement of the tube. In the conventional Ommaya reservoir implantation group, the average operation time was 65 ± 14.32 min, the bone hole diameter was 11.3 ± 0.3 mm, the intraoperative blood loss was 19.9 ± 3.98 ml, and the average hospitalization time was 4.1 ± 0.5 days. In the robot-assisted surgery group, the radial error was 2.14 ± 0.99 mm and the axial error was 1.69 ± 1.24 mm.

Conclusions: Robot-assisted stereotactic Ommaya reservoir implantation is quick, effective, and minimally invasive. The technique effectively negates the inefficiencies of craniotomy and provides a novel treatment for intracranial lesions.
The Role of Inflammation and Infection in Age-Related Neurodegenerative Diseases: Lessons From Bacterial Meningitis Applied to Alzheimer Disease and Age-Related Macular Degeneration
Authors: Too Lay Khoon , Hunt Nicholas , Simunovic Matthew P.
Published: March 2021

Age-related neurodegenerative diseases, such as Alzheimer disease (AD) and age-related macular degeneration (AMD), are multifactorial and have diverse genetic and environmental risk factors. Despite the complex nature of the diseases, there is long-standing, and growing, evidence linking microbial infection to the development of AD dementia, which we summarize in this article. Also, we highlight emerging research findings that support a role for parainfection in the pathophysiology of AMD, a disease of the neurosensory retina that has been shown to share risk factors and pathological features with AD. Acute neurological infections, such as Bacterial Meningitis (BM), trigger inflammatory events that permanently change how the brain functions, leading to lasting cognitive impairment. Neuroinflammation likewise is a known pathological event that occurs in the early stages of chronic age-related neurodegenerative diseases AD and AMD and might be triggered as a parainfectious event. To date, at least 16 microbial pathogens have been linked to the development of AD; on the other hand, investigation of a microbe-AMD relationship is in its infancy. This mini-review article provides a synthesis of existing evidence indicating a contribution of parainfection in the aetiology of AD and of emerging findings that support a similar process in AMD. Subsequently, it describes the major immunopathological mechanisms that are common to BM and AD/AMD. Together, this evidence leads to our proposal that both AD and AMD may have an infectious aetiology that operates through a dysregulated inflammatory response, leading to deleterious outcomes. Last, it draws fresh insights from the existing literature about potential therapeutic options for BM that might alleviate neurological disruption associated with infections, and which could, by extension, be explored in the context of AD and AMD.
Effects of Hearing Aid Noise Reduction on Early and Late Cortical Representations of Competing Talkers in Noise
Authors: Alickovic Emina , Ng Elaine Hoi Ning , Fiedler Lorenz , Santurette Sébastien , Innes-Brown Hamish , Graversen Carina
Published: March 2021

Objectives

Previous research using non-invasive (magnetoencephalography, MEG) and invasive (electrocorticography, ECoG) neural recordings has demonstrated the progressive and hierarchical representation and processing of complex multi-talker auditory scenes in the auditory cortex. Early responses (<85 ms) in primary-like areas appear to represent the individual talkers with almost equal fidelity and are independent of attention in normal-hearing (NH) listeners. However, late responses (>85 ms) in higher-order non-primary areas selectively represent the attended talker with significantly higher fidelity than unattended talkers in NH and hearing–impaired (HI) listeners. Motivated by these findings, the objective of this study was to investigate the effect of a noise reduction scheme (NR) in a commercial hearing aid (HA) on the representation of complex multi-talker auditory scenes in distinct hierarchical stages of the auditory cortex by using high-density electroencephalography (EEG).

Design

We addressed this issue by investigating early (<85 ms) and late (>85 ms) EEG responses recorded in 34 HI subjects fitted with HAs. The HA noise reduction (NR) was either on or off while the participants listened to a complex auditory scene. Participants were instructed to attend to one of two simultaneous talkers in the foreground while multi-talker babble noise played in the background (+3 dB SNR). After each trial, a two-choice question about the content of the attended speech was presented.

Results

Using a stimulus reconstruction approach, our results suggest that the attention-related enhancement of neural representations of target and masker talkers located in the foreground, as well as suppression of the background noise in distinct hierarchical stages is significantly affected by the NR scheme. We found that the NR scheme contributed to the enhancement of the foreground and of the entire acoustic scene in the early responses, and that this enhancement was driven by better representation of the target speech. We found that the target talker in HI listeners was selectively represented in late responses. We found that use of the NR scheme resulted in enhanced representations of the target and masker speech in the foreground and a suppressed representation of the noise in the background in late responses. We found a significant effect of EEG time window on the strengths of the cortical representation of the target and masker.

Conclusion

Together, our analyses of the early and late responses obtained from HI listeners support the existing view of hierarchical processing in the auditory cortex. Our findings demonstrate the benefits of a NR scheme on the representation of complex multi-talker auditory scenes in different areas of the auditory cortex in HI listeners.
Prognostic Impact of PCK1 Protein Kinase Activity-Dependent Nuclear SREBP1 Activation in Non-Small-Cell Lung Carcinoma
Authors: Shao Fei , Bian Xueli , Wang Juhong , Xu Daqian , Guo Wei , Jiang Hongfei , Zhao Gaoxiang , Zhu Lei , Wang Shuai , Xing Dongming , Gao Yibo , He Jie , Lu Zhimin
Published: March 2021

Metabolic enzymes can perform non-metabolic functions and play critical roles in the regulation of a variety of important cellular activities. Phosphoenolpyruvate carboxykinase 1 (PCK1), a gluconeogenesis enzyme, was recently identified as an AKT-regulated protein kinase that phosphorylates INSIG1/2 to promote nuclear SREBP1-dependent lipogenesis. However, the relationship of this regulation with the progression of non-small-cell lung carcinoma (NSCLC) is unclear. Here, we demonstrate that epidermal growth factor receptor (EGFR) activation induces AKT-dependent PCK1 pS90, PCK1-mediated INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 accumulation in NSCLC cells. In addition, the expression levels of AKT pS473, PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 are higher in 451 analyzed human NSCLC specimens than in their adjacent normal tissues and positively correlated with each other in the tumor specimens. Furthermore, the expression levels of PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 are associated with TNM stage and progression in NSCLC. Importantly, levels of PCK1 pS90 or INSIG1 pS207/INSIG2 pS151 are positively correlated with poor prognosis in NSCLC patients, and the combined expression value of the PCK1 and INSIG1/2 phosphorylation has a better prognostic value than that of each individual protein phosphorylation value and is an independent prognostic marker for NSCLC. These findings reveal the role of PCK1-mediated nuclear SREBP1 activation in NSCLC progression and highlight the potential to target the protein kinase activity of PCK1 for the diagnosis and treatment of human NSCLC.
A Positive Feedback Loop of Long Noncoding RNA LINC00152 and KLF5 Facilitates Breast Cancer Growth
Authors: Li Qiang , Wang Xiao , Zhou Liheng , Jiang Mingyun , Zhong Guansheng , Xu Shuguang , Zhang Minjun , Zhang Yigan , Liang Xiaodong , Zhang Lei , Tang Jianming , Zhang Haibo
Published: March 2021

The long noncoding RNA (lncRNA) LINC00152, also known as CYTOR, displays aberrant expression in various cancers. However, its clinical value and functional mechanisms in breast cancer remain insufficiently understood. Our study found that LINC00152 is significantly upregulated in breast cancer, and that it acts as an indicator of poor survival prognosis. Further studies revealed that LINC00152 knockdown suppresses cell proliferation and tumorigenicity in vitro and in vivo. Mechanistic analyses demonstrated that LINC00152 directly binds to KLF5 protein and increases KLF5 stability. Moreover, LINC00152 is also a KLF5-responsive lncRNA, and KLF5 activates LINC00152 transcription by directly binding to its promoter. Our study suggests that LINC00152 promotes tumor progression by interacting with KLF5. LINC00152 may be a valuable prognostic predictor for breast cancer, and the positive feedback loop of LINC00152-KLF5 could be a therapeutic target in pharmacological strategies.
Lymphocyte-to-Monocyte Ratio Is the Independent Prognostic Marker of Progression in Patients Undergoing BCG-Immunotherapy for Bladder Cancer
Authors: Adamkiewicz Mateusz , Bryniarski Piotr , Kowalik Maksymilian , Burzyński Bartłomiej , Rajwa Paweł , Paradysz Andrzej
Published: March 2021

Introduction

Transurethral resection of bladder tumor with subsequent BCG immunotherapy is the current gold standard in the treatment of high risk and some medium-risk non-muscle invasive bladder cancer. Clinical factors like stage, grade, age and gender are well-know predictors of progression to muscle-invasive bladder cancer. In recent years novel hematological biomarkers were shown to be independent predictors of progression. This study aimed to evaluate which of these novel markers has the highest prognostic value of progression in patients with bladder cancer receiving BCG immunotherapy.

Materials and methods

We retrospectively analyzed the data of 125 patients with non-muscle invasive bladder cancer who received BCG immunotherapy. Of these, 61 progressed to muscle-invasive disease or had high-grade recurrence. These patients were compared with the group who did not progress (n = 64). Clinical data including stage, grade, age, gender, smoking status and observational time was collected. Besides, information on blood count analysis was obtained from ambulatory digital charts. On this basis neutrophil-to-lymphocyte ratio (NLR), platelet-to lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) was counted and compared between groups.

Results

NLR, PLR and LMR were shown to be independent prognostic markers of progression in multivariable analysis. The model with stage, grade, age, gender, smoking status and LMR had the highest prognostic values of all models (area under curve [AUC] = 0.756). The cut-off point according to ROC curves for LMR was 3.25. Adding LMR to the baseline model including clinical variables significantly increased area under curve by 0.08 (p = 0.001). NLR and PLR did not increase areas under curve significantly to baseline model.

Conclusions

LMR outperformed NLR and PLR for prediction of progression in patients with non-muscle-invasive bladder cancer receiving BCG immunotherapy. LMR, as an easily obtainable biomarker, should be incorporated to the present risk stratification models.
First Bites—Why, When, and What Solid Foods to Feed Infants
Authors: Borowitz Stephen M.
Published: March 2021

Humans are the only mammals who feed our young special complementary foods before weaning and we are the only primates that wean our young before they can forage independently. There appears to be a sensitive period in the first several months of life when infants readily accept a wide variety of tastes and this period overlaps with a critical window for oral tolerance. As a result, infants should be exposed to a wide variety of flavors while mother is pregnant, while mother is nursing and beginning at an early age. There also appears to be a sensitive period between 4 and 9 months when infants are most receptive to different food textures. There remains debate about when it is best to begin introducing solid foods into an infant's diet however, the available evidence suggests that provided the water and food supply are free of contamination, and the infant is provided adequate nutrition, there are no clear contraindications to feeding infants complementary foods at any age. There is emerging evidence that introduction of solid foods into an infant's diet by 4 months may increase their willingness to eat a variety of fruits and vegetables later in life, decrease their risk of having feeding problems later in life, and decrease their risk of developing food allergies, and the early introduction of solid foods into an infant's diet does not appear to increase their risk of obesity later in childhood.
Comparison of Local and Systemic DTPA Treatment Efficacy According to Actinide Physicochemical Properties Following Lung or Wound Contamination in the Rat
Authors: Griffiths Nina M. , Van der Meeren Anne , Grémy Olivier
Published: March 2021

Purpose: In cases of occupational accidents in nuclear facilities or subsequent to terrorist activities, the most likely routes of internal contamination with alpha-particle emitting actinides, such as plutonium (Pu) and americium (Am), are by inhalation or following wounding. Following contamination, actinide transfer to the circulation and subsequent deposition in skeleton and liver depends primarily on the physicochemical nature of the compound. The treatment remit following internal contamination is to decrease actinide retention and in consequence potential health risks, both at the contamination site and in systemic retention organs as well as to promote elimination. The only approved drug for decorporation of Pu and Am is the metal chelator diethylenetriaminepentaacetic acid (DTPA). However, a limited efficacy of DTPA has been reported following contamination with insoluble actinides, irrespective of the contamination route. The objectives of this work are to evaluate the efficacy of prompt local and/or systemic DTPA treatment regimens following lung or wound contamination by actinides with differing solubility. The conclusions are drawn from retrospective analysis of experimental studies carried out over 10 years.

Materials and Methods: Rat lungs or wounds were contaminated either with poorly soluble Mixed OXide (U, Pu O2) or more soluble forms of Pu (nitrate or citrate). DTPA treatment was administered promptly after contamination, locally to lungs by insufflation of a powder or inhalation of aerosolized solution or by injection directly into the wound site. Intravenous injections of DTPA were given either once or repeated in combination with the local treatment. Doses ranged from 1 to 30 µmol/kg. Animals were euthanized from day 7–21 and alpha activity levels were measured in urine, lungs, wound, bone and liver for determination of decorporation efficacy.

Results: Different experiments confirmed that whatever the route of contamination, most of the activity is retained at the entry site after insoluble MOX contamination as compared with contamination with more soluble forms which results in very low activities reaching the systemic compartment and subsequent retention in bone and liver. Several DTPA treatment regimens were evaluated that had no significant effect on either lung or wound levels compared with untreated animals. In contrast, in all cases systemic retention (skeleton and liver) was reduced and urinary excretion were enhanced irrespective of the contamination route or DTPA treatment regimen.

Conclusion: The present study demonstrates that despite limitation of retention in systemic organs, different DTPA protocols were ineffective in removing insoluble actinides deposited in lungs or wound site. For moderately soluble actinides, local or intravenous DTPA treatment reduced activity levels both at contamination and at systemic sites.
Identification of Plitidepsin as Potent Inhibitor of SARS-CoV-2-Induced Cytopathic Effect After a Drug Repurposing Screen
Authors: Rodon Jordi , Muñoz-Basagoiti Jordana , Perez-Zsolt Daniel , Noguera-Julian Marc , Paredes Roger , Mateu Lourdes , Quiñones Carles , Perez Carles , Erkizia Itziar , Blanco Ignacio , Valencia Alfonso , Guallar Víctor , Carrillo Jorge , Blanco Julià , Segalés Joaquim , Clotet Bonaventura , Vergara-Alert Júlia , Izquierdo-Useros Nuria
Published: March 2021

There is an urgent need to identify therapeutics for the treatment of Coronavirus disease 2019 (COVID-19). Although different antivirals are given for the clinical management of SARS-CoV-2 infection, their efficacy is still under evaluation. Here, we have screened existing drugs approved for human use in a variety of diseases, to compare how they counteract SARS-CoV-2-induced cytopathic effect and viral replication in vitro. Among the potential 72 antivirals tested herein that were previously proposed to inhibit SARS-CoV-2 infection, only 18 % had an IC50 below 25 µM or 102 IU/ml. These included plitidepsin, novel cathepsin inhibitors, nelfinavir mesylate hydrate, interferon 2-alpha, interferon-gamma, fenofibrate, camostat along the well-known remdesivir and chloroquine derivatives. Plitidepsin was the only clinically approved drug displaying nanomolar efficacy. Four of these families, including novel cathepsin inhibitors, blocked viral entry in a cell—type specific manner. Since the most effective antivirals usually combine therapies that tackle the virus at different steps of infection, we also assessed several drug combinations. Although no particular synergy was found, inhibitory combinations did not reduce their antiviral activity. Thus, these combinations could decrease the potential emergence of resistant viruses. Antivirals prioritized herein identify novel compounds and their mode of action, while independently replicating the activity of a reduced proportion of drugs which are mostly approved for clinical use. Combinations of these drugs should be tested in animal models to inform the design of fast track clinical trials.
The Myotendinous Junction—A Vulnerable Companion in Sports. A Narrative Review
Authors: Jakobsen Jens Rithamer , Krogsgaard Michael Rindom
Published: March 2021

The incidence of strain injuries continues to be high in many popular sports, especially hamstring strain injuries in football, despite a documented important effect of eccentric exercise to prevent strains. Studies investigating the anatomical properties of these injuries in humans are sparse. The majority of strains are seen at the interface between muscle fibers and tendon: the myotendinous junction (MTJ). It has a unique morphology with a highly folded muscle membrane filled with invaginations of collagen fibrils from the tendon, establishing an increased area of force transmission between muscle and tendon. There is a very high rate of remodeling of the muscle cells approaching the MTJ, but little is known about how the tissue adapts to exercise and which structural changes heavy eccentric exercise may introduce. This review summarizes the current knowledge about the anatomy, composition and adaptability of the MTJ, and discusses reasons why strain injuries can be prevented by eccentric exercise.