bluuebunny/crossref_metadata_2025 huggingface dataset:
Interleukin-6 and indoleamine-2,3-dioxygenase as potential adjuvant targets for Papillomavirus-related tumors immunotherapy
Authors: Pagni Roberta Liberato , Souza Patrícia da Cruz , Pegoraro Rafael , Porchia Bruna Felício Milazzotto Maldonado , da Silva Jamile Ramos , Aps Luana Raposo de Melo Moraes , Silva Mariângela de Oliveira , Rodrigues Karine Bitencourt , Sales Natiely Silva , Ferreira Luís Carlos de Souza , Moreno Ana Carolina Ramos
Published: November 2022

High-risk Human papillomavirus (HPV) infections represent an important public health issue. Nearly all cervical malignancies are associated with HPV, and a range of other female and male cancers, such as anogenital and oropharyngeal. Aiming to treat HPV-related tumors, our group developed vaccines based on the genetic fusion of the HSV-1 glycoprotein D (gD) with the HPV-16 E7 oncoprotein (gDE7 vaccines). Despite the promising antitumor results reached by gDE7 vaccines in mice, combined therapies may increase the therapeutic effects by improving antitumor responses and halting immune suppressive mechanisms elicited by tumor cells. Considering cancer immunosuppressive mechanisms, indoleamine-2,3-dioxygenase (IDO) enzyme and interleukin-6 (IL-6) stand out in HPV-related tumors. Since IL-6 sustained the constitutive IDO expression, here we evaluated the therapeutic outcomes achieved by the combination of active immunotherapy based on a gDE7 protein-based vaccine with adjuvant treatments involving blocking IDO, either by use of IDO inhibitors or IL-6 knockout mice. C57BL/6 wild-type (WT) and transgenic IL-6-/- mice were engrafted with HPV16-E6/E7-expressing TC-1 cells and treated with 1-methyl-tryptophan isoforms (D-1MT and DL-1MT), capable to inhibit IDO. In vitro, the 1MT isoforms reduced IL-6 gene expression and IL-6 secretion in TC-1 cells. In vivo, the multi-targeted treatment improved the antitumor efficacy of the gDE7-based protein vaccine. Although the gDE7 immunization achieves partial tumor mass control in combination with D-1MT or DL-1MT in WT mice or when administered in IL-6-/- mice, the combination of gDE7 and 1MT in IL-6-/- mice further enhanced the antitumor effects, reaching total tumor rejection. The outcome of the combined therapy was associated with an increased frequency of activated dendritic cells and decreased frequencies of intratumoral polymorphonuclear myeloid-derived suppressor cells and T regulatory cells. In conclusion, the present study demonstrated that IL-6 and IDO negatively contribute to the activation of immune cells, particularly dendritic cells, reducing gDE7 vaccine-induced protective immune responses and, therefore, opening perspectives for the use of combined strategies based on inhibition of IL-6 and IDO as immunometabolic adjuvants for immunotherapies against HPV-related tumors.
Targeted proteomics identifies circulating biomarkers associated with active COVID-19 and post-COVID-19
Authors: Zoodsma Martijn , de Nooijer Aline H. , Grondman Inge , Gupta Manoj Kumar , Bonifacius Agnes , Koeken Valerie A. C. M. , Kooistra Emma , Kilic Gizem , Bulut Ozlem , Gödecke Nina , Janssen Nico , Kox Matthijs , Domínguez-Andrés Jorge , van Gammeren Adriaan J. , Ermens Anton A. M. , van der Ven Andre J. A. M. , Pickkers Peter , Blasczyk Rainer , Behrens Georg M. N. , van de Veerdonk Frank L. , Joosten Leo A. B. , Xu Cheng-Jian , Eiz-Vesper Britta , Netea Mihai G. , Li Yang
Published: November 2022

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic is caused by the highly infectious Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). There is an urgent need for biomarkers that will help in better stratification of patients and contribute to personalized treatments. We performed targeted proteomics using the Olink platform and systematically investigated protein concentrations in 350 hospitalized COVID-19 patients, 186 post-COVID-19 individuals, and 61 healthy individuals from 3 independent cohorts. Results revealed a signature of acute SARS-CoV-2 infection, which is represented by inflammatory biomarkers, chemokines and complement-related factors. Furthermore, the circulating proteome is still significantly affected in post-COVID-19 samples several weeks after infection. Post-COVID-19 individuals are characterized by upregulation of mediators of the tumor necrosis (TNF)-α signaling pathways and proteins related to transforming growth factor (TGF)-ß. In addition, the circulating proteome is able to differentiate between patients with different COVID-19 disease severities, and is associated with the time after infection. These results provide important insights into changes induced by SARS-CoV-2 infection at the proteomic level by integrating several cohorts to obtain a large disease spectrum, including variation in disease severity and time after infection. These findings could guide the development of host-directed therapy in COVID-19.
The effect and underlying mechanism of yeast β-glucan on antiviral resistance of zebrafish against spring viremia of carp virus infection
Authors: Liang Hui , Li Yu , Li Ming , Zhou Wei , Chen Jie , Zhang Zhen , Yang Yalin , Ran Chao , Zhou Zhigang
Published: November 2022

β-glucan has been used as immunostimulant for fish. However, the effect of yeast β-glucan on viral infections has been less studied in fish. In this study, we investigated the effects of β-glucan on the resistance of zebrafish against spring viraemia of carp virus (SVCV) and elucidated the underlying mechanisms. Zebrafish were fed with a control diet or diet supplemented with 0.01% and 0.025% β-glucan for 2 weeks, and were challenged by SVCV. Zebrafish embryonic fibroblast (ZF4) cells were treated with 5 μg/mL β-glucan and were infected by SVCV. We further investigated the effect of β-glucan on autophagy level post SVCV infection. The intestinal microbiota was evaluated by 16S rRNA gene pyrosequencing. Results showed that dietary supplementation of 0.025% β-glucan significantly increased survival rate of zebrafish compared with control group after SVCV challenge (P < 0.05). Dietary β-glucan significantly increased the expression of genes related to type I IFN antiviral immune pathway in the spleen of zebrafish after viral infection, including type I IFN genes (ifnφ1, ifnφ2, ifnφ3), IFN-stimulated genes (mxb, mxc), as well as other genes involved in the IFN signaling pathway, including tlr7, rig1, mavs, irf3 and irf7. Morpholino knockdown of type I IFN receptors dampened the antiviral effect of β-glucan in zebrafish larvae, indicating that β-glucan-mediated antiviral function was at least partially dependent on IFN immune response. Furthermore, β-glucan can inhibit the replication of SVCV in ZF4 cells. However, β-glucan did not stimulate type I IFN antiviral response in ZF4 cells, and the antiviral effect of β-glucan in ZF4 was independent of Myd88. Interestingly, β-glucan induced autophagy in ZF4 cells after SVCV infection. Inhibition of autophagy blocked the antiviral effect of β-glucan in ZF4 cells. Lastly, dietary β-glucan changed the composition of intestinal microbiota in zebrafish, with reduced abundance of Proteobacteria and an enrichment of Fusobacteria and Firmicutes. To sum up, our results indicate that the β-glucan enhanced resistance of zebrafish against SVCV and the mechanism involved stimulation of type I IFN antiviral immune response of fish after viral infection.
The role of immune profile in predicting outcomes in cancer patients treated with immunotherapy
Authors: Botticelli Andrea , Pomati Giulia , Cirillo Alessio , Scagnoli Simone , Pisegna Simona , Chiavassa Antonella , Rossi Ernesto , Schinzari Giovanni , Tortora Giampaolo , Di Pietro Francesca Romana , Cerbelli Bruna , Di Filippo Alessandra , Amirhassankhani Sasan , Scala Alessandro , Zizzari Ilaria Grazia , Cortesi Enrico , Tomao Silverio , Nuti Marianna , Mezi Silvia , Marchetti Paolo
Published: November 2022

Background

Despite the efficacy of immunotherapy, only a small percentage of patients achieves a long-term benefit in terms of overall survival. The aim of this study was to define an immune profile predicting the response to immune checkpoint inhibitors (ICIs).

Methods

Patients with advanced solid tumors, who underwent ICI treatment were enrolled in this prospective study. Blood samples were collected at the baseline. Thirteen soluble immune checkpoints, 3 soluble adhesion molecules, 5 chemokines and 11 cytokines were analyzed. The results were associated with oncological outcomes.

Results

Regardless of tumor type, patients with values of sTIM3, IFNα, IFNγ, IL1β, IL1α, IL12p70, MIP1β, IL13, sCD28, sGITR, sPDL1, IL10 and TNFα below the median had longer overall survival (p<0.05). By using cluster analysis and grouping the patients according to the trend of the molecules, two clusters were found. Cluster A had a significantly higher mean progression free survival (Cluster A=11.9 months vs Cluster B=3.5 months, p<0.01), a higher percentage of disease stability (Cluster A=34.5% vs. Cluster B=0%, p<0.05) and a lower percentage of disease progression (Cluster A=55.2% vs. Cluster B = 94.4%, p=0.04).

Conclusion

The combined evaluation of soluble molecules, rather than a single circulating factor, may be more suitable to represent the fitness of the immune system status in each patient and could allow to identify two different prognostic and predictive outcome profiles.
Seasonal variations in microbial diversity and metabolite profiles of the gut of sea cucumber (Apostichopus japonicus)
Authors: Deng Beini , Ru Xiaoshang , Wang Ting , Zhang Chenxi , Sun Wanhui , Lu Songchong , Zhang Libin
Published: November 2022

The sea cucumber (Apostichopus japonicus) is the main economic species in China and has a significant role in aquaculture. Gut microbiome composition is closely related to external environments. In this study, we identified the effects of seasonal changes on the composition and main metabolites of symbiotic microorganisms in the intestine of A. japonicus. We used 16S rRNA sequencing to identify the composition of symbiotic microorganisms in different seasons. Intestinal metabolites were determined using liquid chromatography with tandem mass spectrometry, which linked symbiotic microorganisms to intestinal metabolites. Analyzing changes in intestinal microbial composition across different seasons. The results showed that seasonal changes of intestinal microorganisms were significant, A. japonicus were infected by Vibrio easily in summer, Stigmasterol and sitosterol could affect the growth of body wall of A. japonicus. It is vital importance for A. japonicus that the results benefit for the growth, immunity and aquaculture.
Frailty trajectory over one year among residential aged care (nursing home) residents
Authors: Lim Renly , Kelly Thu-Lan , Andrade Andre Q. , Kalisch Ellett Lisa M. , Bilton Rebecca , Dorj Gereltuya , Pratt Nicole L. , Roughead Elizabeth E.
Published: November 2022

Objectives

Large population-based studies examining frailty trajectory found a linear increase in frailty over time. The pattern in which frailty changes over time for an individual person is less well-described. We examined the frailty trajectory of older adults living in aged-care in Australia.

Materials and methods

This secondary study used data from a randomised controlled trial involving 39 aged-care facilities in Australia. The trial intervention was an on-going pharmacist-led intervention occurring every 8 weeks over 12 months aimed at preventing medicine-induced deterioration and adverse reactions. Frailty was assessed using the Frailty Index. Participants were categorised as non-frail, pre-frail and frail. Individual frailty trajectory over 12 months was visualised using the alluvial plot. Case notes were examined to explore reasons for any rapid transitions in frailty status.

Results

A total of 248 participants was included. At baseline, 40.3% were non-frail and 59.7% were pre-frail. The proportion of participants who were non-frail and pre-frail decreased over time; 15.7% were frail at 6 months and 23.4% were frail at 12 months. Overall, twenty different combinations of frailty transitions were identified over 12 months. Retrospective analysis of case notes suggest that death or transition from non-frail to frail was often preceded by hospitalisation, falls, medication change or clinically significant deterioration in grip strength or cognition.

Conclusion

The degree of frailty increased over time, but there were variations in the individual trajectories. Regular monitoring of events that precede changes in frailty status is needed to identify strategies to prevent further deterioration in residents’ conditions.
Administration of granulocyte-macrophage colony-stimulating factor enhanced chimeric antigen receptor T-cell expansion and cellular immunity recovery without inducing cytokine release syndrome
Authors: Jiang Ying , Feng Dan , Wang Chun , Zhang Yanlei , Zhao Chuxian , Li Su , Qin Youwen , Chang Alex H. , Zhu Jun
Published: November 2022

Background

Neutropenia and cytokine release syndrome (CRS) are two major toxicities of chimeric antigen receptor (CAR)-T cell therapy. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an ideal candidate treatment for neutropenia except for its potential aggravation of CRS. We hypothesized that the optimal timing of supplemental with GM-CSF in a shortage of host immunity and CAR T-cell was chosen as avoidance of CRS. In the study we evaluated the safety and efficacy of GM-CSF intervention post-CAR T-cell therapy while circulating CAR T-cell declined.

Materials and methods

Nine patients received GM-CSF therapy who displayed moderate neutropenia with absolute neutrophil counts (ANC) < 1,500 cells/mm3 with concomitant declination of circulating CAR T-cell.

Results

The median duration of GM-CSF intervention was 15 days (4–30). CAR T-cell expansion was observed in peripheral blood (PB) of seven patients (7/9). The median baseline and peak CAR T cells count in PB of the seven patients with CAR T-cell expansion were 0.85 × 106/L (0–50.9) and 6.06 × 106/L (1.43–112.55). And the peaks of CAR T-cell levels in PB appeared in day 7 (2–11) following the initiation of GM-CSF administration with increases of 2.84 × 106/L (0.38–61.65). Also, increased white blood cells in PB were observed in all patients. The median onset and duration time of WBC recovery were 9 (1–14) and 17 (3–53) days. Moreover, the increment of WBC, neutrophil, lymphocyte and CD3-CD16 + CD56 + natural killer cell in PB was observed. In addition, no CRS or fatal infection occurred during GM-CSF treatment.

Conclusion

This study provides evidence for the clinical feasibility of combining CAR T-cell therapy with the GM-CSF to treat neutropenia patients with concomitant declination of circulating CAR T-cell.
Progression to lung fibrosis in severe COVID-19 patients: A morphological and transcriptomic study in postmortem samples
Authors: Pérez-Mies Belén , Caniego-Casas Tamara , Bardi Tommaso , Carretero-Barrio Irene , Benito Amparo , García-Cosío Mónica , González-García Irene , Pizarro David , Rosas Marta , Cristóbal Eva , Ruano Yolanda , Garrido María Concepción , Rigual-Bobillo Juan , de Pablo Raúl , Galán Juan Carlos , Pestaña David , Palacios José
Published: November 2022

The development of lung fibrosis is a major concern in patients recovered from severe COVID-19 pneumonia. This study aimed to document the evolution of diffuse alveolar damage (DAD) to the fibrosing pattern and define the transcriptional programs involved. Morphological, immunohistochemical and transcriptional analysis were performed in lung samples obtained from autopsy of 33 severe COVID-19 patients (median illness duration: 36 days). Normal lung and idiopathic pulmonary fibrosis (IPF) were used for comparison. Twenty-seven patients with DAD and disease evolution of more than 2 weeks had fibrosis. Pathways and genes related with collagen biosynthesis and extracellular matrix (ECM) biosynthesis and degradation, myofibroblastic differentiation and epithelial to mesenchymal transition (EMT) were overexpressed in COVID-19. This pattern had similarities with that observed in IPF. By immunohistochemistry, pathological fibroblasts (pFBs), with CTHRC1 and SPARC expression, increased in areas of proliferative DAD and decreased in areas of mature fibrosis. Immunohistochemical analysis demonstrated constitutive expression of cadherin-11 in normal epithelial cells and a similar pattern of cadherin and catenin expression in epithelial cells from both normal and COVID-19 samples. Transcriptomic analysis revealed downregulation of the Hippo pathway, concordant with the observation of YAP overexpression in hyperplastic alveolar epithelial cells. Progression to fibrosis in severe COVID-19 is associated with overexpression of fibrogenic pathways and increased in CTHRC1- and SPARC-positive pFBs. Whereas the Hippo pathway seemed to be implicated in the response to epithelial cell damage, EMT was not a major process implicated in COVID-19 mediated lung fibrosis.
Stemphylium lycopersici and Stemphylium solani improved antioxidant system of soybean under chromate stress
Authors: Husna Husna , Hussain Anwar , Shah Mohib , Hamayun Muhammad , Iqbal Amjad , Qadir Muhammad , Asim Syed , Lee In-Jung
Published: November 2022

Ecologists around the world are giving great attention to the metal pollution of agronomic soil. Recently, several techniques have been employed to remediate heavy metals, but the use of microorganisms is cheap, less time-consuming, and easily available. In the current study, the endophytic strains, Cp1 and Cp2 were isolated from sterilized 1–5 cm long root and leaf segments of Chlorophytum comosum using Hagem media. To get pure colonies, the strains were repeatedly cultured on potato dextrose agar (PDA) media. The strains Cp1 and CP2 were identified as Stemphylium lycopersici and Stemphylium solani based on ITS sequencing and neighbor joining (NJ) method. Both strains showed a growth-promoting potential in soybean seedlings exposed to chromate (Cr) stress. Moreover, S. lycopersici and S. solani improved the Indole-3-acetic acid (IAA), flavonoids, phenolics, protein, and proline contents, whereas, lowered Salicylic acid (SA) production in the seedlings. The selected endophytic fungal strains also promoted the antioxidant system of soybean seedlings through enhanced production of ascorbic acid oxidase (AAO), catalases (CAT), peroxidase, and free radical scavenging enzymes. Both strains bio-transformed the toxic Cr-VI to less toxic Cr-III in the cultural filtrate as well as host plants. In fact, efficient uptake of Cr and its conversion by the isolated endophytic fungal strains could be used as a viable tool to remediate Cr contamination in agricultural soils.
Phenotypic and genomic assessment of the potential threat of human spaceflight-relevant Staphylococcus capitis isolates under stress conditions
Authors: Siems Katharina , Runzheimer Katharina , Rehm Anna , Schwengers Oliver , Heidler von Heilborn David , Kaser Liv , Arndt Franca , Neidhöfer Claudio , Mengel Jan Philipp , Parcina Marijo , Lipski André , Hain Torsten , Moeller Ralf
Published: November 2022

Previous studies have reported that spaceflight specific conditions such as microgravity lead to changes in bacterial physiology and resistance behavior including increased expression of virulence factors, enhanced biofilm formation and decreased susceptibility to antibiotics. To assess if spaceflight induced physiological changes can manifest in human-associated bacteria, we compared three spaceflight relevant Staphylococcus capitis isolates (DSM 111179, ISS; DSM 31028, clean room; DSM 113836; artificial gravity bedrest study) with the type strain (DSM 20326T). We tested the three strains regarding growth, colony morphology, metabolism, fatty acid and polar lipid pattern, biofilm formation, susceptibility to antibiotics and survival in different stress conditions such as treatment with hydrogen peroxide, exposure to desiccation, and irradiation with X-rays and UV-C. Moreover, we sequenced, assembled, and analyzed the genomes of all four strains. Potential genetic determinants for phenotypic differences were investigated by comparative genomics. We found that all four strains show similar metabolic patterns and the same susceptibility to antibiotics. All four strains were considered resistant to fosfomycin. Physiological differences were mainly observed compared to the type strain and minor differences among the other three strains. The ISS isolate and the bedrest study isolate exhibit a strong delayed yellow pigmentation, which is absent in the other two strains. Pigments were extracted and analyzed by UV/Vis spectroscopy showing characteristic carotenoid spectra. The ISS isolate showed the highest growth rate as well as weighted average melting temperature (WAMT) of fatty acids (41.8°C) of all strains. The clean room isolate showed strongest biofilm formation and a high tolerance to desiccation. In general, all strains survived desiccation better in absence of oxygen. There were no differences among the strains regarding radiation tolerance. Phenotypic and genomic differences among the strains observed in this study are not inevitably indicating an increased virulence of the spaceflight isolate. However, the increased growth rate, higher WAMT and colony pigmentation of the spaceflight isolate are relevant phenotypes that require further research within the human spaceflight context. We conclude that combining genetic analysis with classical microbiological methods allows the detailed assessment of the potential threat of bacteria in highly regulated and extreme environments such as spaceflight environments.
Leukocyte metabolism in obese type 2 diabetic individuals associated with COVID-19 severity
Authors: Lobato Tiago Bertola , Gennari-Felipe Matheus , Pauferro Janaína Ribeiro Barbosa , Correa Ilana Souza , Santos Beatriz Ferreira , Dias Beatriz Belmiro , de Oliveira Borges João Carlos , dos Santos Camila Soares , de Sousa Santos Elvirah Samantha , de Araújo Maria Janaína Leite , Ferreira Liliane Araújo , Pereira Sara Araujo , Serdan Tamires Duarte Afonso , Levada-Pires Adriana Cristina , Hatanaka Elaine , Borges Leandro , Cury-Boaventura Maria Fernanda , Vinolo Marco Aurélio Ramirez , Pithon-Curi Tania Cristina , Masi Laureane Nunes , Curi Rui , Hirabara Sandro Massao , Gorjão Renata
Published: November 2022

Recent studies show that the metabolic characteristics of different leukocytes, such as, lymphocytes, neutrophils, and macrophages, undergo changes both in the face of infection with SARS-CoV-2 and in obesity and type 2 diabetes mellitus (DM2) condition. Thus, the objective of this review is to establish a correlation between the metabolic changes caused in leukocytes in DM2 and obesity that may favor a worse prognosis during SARS-Cov-2 infection. Chronic inflammation and hyperglycemia, specific and usual characteristics of obesity and DM2, contributes for the SARS-CoV-2 replication and metabolic disturbances in different leukocytes, favoring the proinflammatory response of these cells. Thus, obesity and DM2 are important risk factors for pro-inflammatory response and metabolic dysregulation that can favor the occurrence of the cytokine storm, implicated in the severity and high mortality risk of the COVID-19 in these patients.
Sennoside A inhibits quorum sensing system to attenuate its regulated virulence and pathogenicity via targeting LasR in Pseudomonas aeruginosa
Authors: Han Xiaofeng , Nan Mengyue , Cai Xinyu , Qiao Boling , Chen Lin , Shen Lixin
Published: November 2022

Pseudomonas aeruginosa is an important opportunistic pathogen, and the emergence of drug resistance greatly increased the difficulty of treating its infection. Cell density-dependent quorum sensing (QS) system not only regulates the virulence but also associates with the drug resistance of P. aeruginosa. Screening for agents targeting QS to inhibit bacterial virulence and pathogenicity is considered a promising strategy to combat P. aeruginosa infection. In the present study, sennoside A was found to be able to inhibit the QS expression of P. aeruginosa at subinhibitory concentrations. The QS-regulated virulence factors, including protease, elastase, rhamnolipid, and pyocyanin, were also inhibited by sennoside A at both transcriptional and translational levels. Moreover, sennoside A could suppress the motility of twitching, swimming, and swarming as well as the biofilm formation, which is associated with the acute and chronic infections of P. aeruginosa in a dose-dependent manner. The attenuated pathogenicity of P. aeruginosa by sennoside A was further verified by Chinese cabbage, Drosophila melanogaster, and Caenorhabditis elegans infection analysis. Further study found that sennoside A might target the las system, mainly LasR, to interfere with QS. All the results indicate that sennoside A could inhibit the QS system to attenuate its regulated virulence and pathogenicity via mainly targeting LasR in P. aeruginosa and further research to identify its anti-QS activity for other Gram-negative bacteria is warranted.
Biochemical, genomic and structural characteristics of the Acr3 pump in Exiguobacterium strains isolated from arsenic-rich Salar de Huasco sediments
Authors: Castro-Severyn Juan , Pardo-Esté Coral , Araya-Durán Ingrid , Gariazzo Valentina , Cabezas Carolina , Valdés Jorge , Remonsellez Francisco , Saavedra Claudia P.
Published: November 2022

Arsenic is a highly toxic metalloid of major concern for public safety. However, microorganisms have several resistance mechanisms, particularly the expression of arsenic pumps is a critical component for bacterial ability to expel it and decrease intracellular toxicity. In this study, we aimed to characterize the biochemical, structural, and genomic characteristics of the Acr3 pump among a group of Exiguobacterium strains isolated from different sites of the arsenic-rich Salar de Huasco (SH) ecosystem. We also determined whether the differences in As(III) resistance levels presented by the strains could be attributed to changes in the sequence or structure of this protein. In this context, we found that based on acr3 sequences the strains isolated from the SH grouped together phylogenetically, even though clustering based on gene sequence identity did not reflect the strain’s geographical origin. Furthermore, we determined the genetic context of the acr3 sequences and found that there are two versions of the organization of acr3 gene clusters, that do not reflect the strain’s origin nor arsenic resistance level. We also contribute to the knowledge regarding structure of the Acr3 protein and its possible implications on the functionality of the pump, finding that although important and conserved components of this family of proteins are present, there are several changes in the amino acidic sequences that may affect the interactions among amino acids in the 3D model, which in fact are evidenced as changes in the structure and residues contacts. Finally, we demonstrated through heterologous expression that the Exiguobacterium Acr3 pump does indeed improve the organisms As resistance level, as evidenced in the complemented E. coli strains. The understanding of arsenic detoxification processes in prokaryotes has vast biotechnological potential and it can also provide a lot of information to understand the processes of evolutionary adaptation.
Antimicrobial resistance and genomic characterization of Salmonella enterica serovar Senftenberg isolates in production animals from the United States
Authors: Srednik Mariela E. , Morningstar-Shaw Brenda R. , Hicks Jessica A. , Mackie Tonya A. , Schlater Linda K.
Published: November 2022

In the USA, Salmonella enterica subspecies enterica serovar Senftenberg is among the top five serovars isolated from food and the top 11 serovars isolated from clinically ill animals. Human infections are associated with exposure to farm environments or contaminated food. The objective of this study was to characterize S. Senftenberg isolates from production animals by analyzing phenotypic antimicrobial resistance profiles, genomic features and phylogeny.

Salmonella Senftenberg isolates (n = 94) from 20 US states were selected from NVSL submissions (2014–2017), tested against 14 antimicrobial drugs, and resistance phenotypes determined. Resistance genotypes were determined using whole genome sequencing analysis with AMRFinder and the NCBI and ResFinder databases with ABRicate. Plasmids were detected using PlasmidFinder. Integrons were detected using IntFinder and manual alignment with reference genes. Multilocus-sequence-typing (MLST) was determined using ABRicate with PubMLST database, and phylogeny was determined using vSNP.

Among 94 isolates, 60.6% were resistant to at least one antimicrobial and 39.4% showed multidrug resistance. The most prevalent resistance findings were for streptomycin (44.7%), tetracycline (42.6%), ampicillin (36.2%) and sulfisoxazole (32.9%). The most commonly found antimicrobial resistance genes were aac(6′)-Iaa (100%), aph(3″)-Ib and aph(6)-Id (29.8%) for aminoglycosides, followed by blaTEM-1 (26.6%) for penicillins, sul1 (25.5%) and sul2 (23.4%) for sulfonamides and tetA (23.4%) for tetracyclines. Quinolone-resistant isolates presented mutations in gyrA and/or parC genes. Class 1 integrons were found in 37 isolates. Thirty-six plasmid types were identified among 77.7% of the isolates. Phylogenetic analysis identified two distinct lineages of S. Senftenberg that correlated with the MLST results. Isolates were classified into two distinct sequence types (ST): ST14 (97.9%) and ST 185 (2.1%). The diversity of this serotype suggests multiple introductions into animal populations from outside sources.

This study provided antimicrobial susceptibility and genomic characteristics of S. Senftenberg clinical isolates from production animals in the USA during 2014 to 2017. This study will serve as a base for future studies focused on the phenotypic and molecular antimicrobial characterization of S. Senftenberg isolates in animals. Monitoring of antimicrobial resistance to detect emergence of multidrug-resistant strains is critical.
Intercellular communication analysis of the human retinal pigment epithelial and choroidal cells predicts pathways associated with aging, cellular senescence and age-related macular degeneration
Authors: Dhirachaikulpanich Dhanach , Lagger Cyril , Chatsirisupachai Kasit , de Magalhães João Pedro , Paraoan Luminita
Published: November 2022

The retinal pigment epithelium (RPE) and the choroid are ocular tissues with fundamental roles in supporting neuroretinal function. The pathogenesis of age-related macular degeneration (AMD), a leading cause of irreversible blindness for which aging is the highest risk factor is closely linked with progressive impairment of various functions of these tissues. Cellular senescence, marked by cell cycle arrest and secretion of proinflammatory factors, is known to be associated with aging and has been proposed as a potential driver of AMD. Here, we investigated the role played by intercellular communication in the RPE/choroid within the context of aging, senescence and AMD. We inferred cell–cell interactions in the RPE/choroid by applying CellChat and scDiffCom on a publicly available scRNA-seq dataset from three human donors with and without AMD. We identified age-regulated ligand and receptor genes by using limma on a separate publicly available bulk microarray dataset providing RPE/choroid samples at multiple time points. Cellular senescence was investigated by assigning a score to each cell and each sample of these scRNA-seq and microarray datasets, respectively, based on the expression of key signature genes determined by a previous senescence meta-analysis. We identified VEGF-, BMP-and tenascin-mediated pathways supporting some of the strongest cell–cell interactions between RPE cells, fibroblasts and choroidal endothelial cells and as strong intercellular communication pathways related to both aging and senescence. Their signaling strength was enhanced between subpopulations of cells having high senescence scores. Predominant ligands of these pathways were upregulated with age whereas predominant receptors were downregulated. Globally, we also observed that cells from AMD samples presented slightly bigger senescence scores than normal cells and that the senescence score positively correlated with age in bulk samples (R = 0.26, value of p < 0.01). Hence, our analysis provides novel information on RPE/choroid intercellular communication that gives insights into the connection between aging, senescence and AMD.
Moderating effect of cognitive reserve on brain integrity and cognitive performance
Authors: Nelson Monica E. , Veal Britney M. , Andel Ross , Martinkova Julie , Veverova Katerina , Horakova Hana , Nedelska Zuzana , Laczó Jan , Vyhnalek Martin , Hort Jakub
Published: November 2022

Background

Dementia syndrome is one of the most devastating conditions in older adults. As treatments to stop neurodegeneration become available, accurate and timely diagnosis will increase in importance. One issue is that cognitive performance sometimes does not match the corresponding level of neuropathology, affecting diagnostic accuracy. Cognitive reserve (CR), which can preserve cognitive function despite underlying neuropathology, explains at least some variability in cognitive performance. We examined the influence of CR proxies (education and occupational position) on the relationship between hippocampal or total gray matter volume and cognition.

Methods

We used data from the Czech Brain Aging Study. Participants were clinically confirmed to be without dementia (n = 457, including subjective cognitive decline and amnestic mild cognitive impairment) or with dementia syndrome (n = 113).

Results

For participants without dementia, higher education magnified the associations between (a) hippocampal volume and executive control (b = 0.09, p = 0.033), (b) total gray matter volume and language (b = 0.12, p < 0.001), and (c) total gray matter volume and memory (b = 0.08, p = 0.018). Similarly, higher occupational position magnified the association between total gray matter volume and (a) attention/working memory (b = 0.09, p = 0.009), (b) language (b = 0.13, p = 0.002), and (c) memory (b = 0.10, p = 0.013). For participants with dementia, the associations between hippocampal (b = –0.26, p = 0.024) and total gray matter (b = –0.28, p = 0.024) volume and visuospatial skills decreased in magnitude with higher education.

Conclusion

We found that the association between brain volume and cognitive performance varies based on CR, with greater CR related to a stronger link between brain volume and cognition before, and a weaker link after, dementia diagnosis.
Characterizing cortical responses to short-term multidisciplinary intensive rehabilitation treatment in patients with Parkinson’s disease: A transcranial magnetic stimulation and electroencephalography study
Authors: Pei Guangying , Liu Xinting , Huang Qiwei , Shi Zhongyan , Wang Li , Suo Dingjie , Funahashi Shintaro , Wu Jinglong , Zhang Jian , Fang Boyan
Published: November 2022

Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) is a powerful non-invasive tool for qualifying the neurophysiological effects of interventions by recording TMS-induced cortical activation with high temporal resolution and generates reproducible and reliable waves of activity without participant cooperation. Cortical dysfunction contributes to the pathogenesis of the clinical symptoms of Parkinson’s disease (PD). Here, we examined changes in cortical activity in patients with PD following multidisciplinary intensive rehabilitation treatment (MIRT). Forty-eight patients with PD received 2 weeks of MIRT. The cortical response was examined following single-pulse TMS over the primary motor cortex by 64-channel EEG, and clinical symptoms were assessed before and after MIRT. TMS-evoked potentials were quantified by the global mean field power, as well as oscillatory power in theta, alpha, beta, and gamma bands, and their clinical correlations were calculated. After MIRT, motor and non-motor symptoms improved in 22 responders, and only non-motor function was enhanced in 26 non-responders. Primary motor cortex stimulation reduced global mean field power amplitudes in responders but not significantly in non-responders. Oscillations exhibited attenuated power in the theta, beta, and gamma bands in responders but only reduced gamma power in non-responders. Associations were observed between beta oscillations and motor function and between gamma oscillations and non-motor symptoms. Our results suggest that motor function enhancement by MIRT may be due to beta oscillatory power modulation and that alterations in cortical plasticity in the primary motor cortex contribute to PD recovery.
Molar loss further exacerbates 2-VO-induced cognitive impairment associated with the activation of p38MAPK/NFκB pathway
Authors: Lu Yunping , Pang Qian , Wu Qianqian , Luo Bin , Tang Xiaofei , Jiang Qingsong
Published: November 2022

Background

Vascular dementia is characterized by reduced cognitive function due to chronic cerebral hypoperfusion and has become a significant public health challenge as the global population ages. Recent studies suggested that molar loss, a common problem among the elderly, may trigger the development of cognitive decline. Our previous study found that the molar loss affected cognitive dysfunction, and the astrocytes in the hippocampus of chronic cerebral ischemia rats were affected, but the underlying mechanism is unclear.

Methods

In this study, we established the animal model of molar loss with 2-VO rats and the Morris water maze was used to test the cognitive ability of rats in each group. The damage to neurons was observed via Nissl staining, and neuronal apoptosis was analyzed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay in the hippocampus of the rats. Quantitative Real-Time PCR and immunohistochemistry and histology (IHC) were used to detect the expression of p38MAPK, NFκB, caspase 3, and iNOS in the hippocampus. The astrocytes were detected by IHC and Immunofluorescence analysis for GFAP. After 2-VO MO surgery, rats were administered DMSO or p38MAPK inhibitor (SB203580) by intrathecal injection.

Results

The Morris water maze test showed that the molar loss aggravated spatial memory learning ability with chronic cerebral ischemia decreased in the rats. The neuronal damage and more apoptotic cells were observed in the hippocampus of 2-VO rats. After the molar loss, the mRNA and protein expression of iNOS, p38MAPK, NFκB, and caspase 3 were further upregulated in 2-VO rats. Molar loss upregulated GFAP expression, and the p38MAPK-positive cells were labeled with the astrocyte marker GFAP. SB203580 reduced cognitive impairment and apoptosis of hippocampal neurons in 2-VO rats following the molar loss.

Conclusion

Molar loss can aggravate cognitive impairment in 2-VO rats to a certain extent. The mechanism of molar loss exacerbating the cognitive decline in 2-VO rats may be associated with the activation of the p38MAPK-NFκB-caspase 3 signaling pathway, which induces neuronal apoptosis.
Mediating effect of lower extremity muscle strength on the relationship between mobility and cognitive function in Chinese older adults: A cross-sectional study
Authors: Chen Yaoxin , Zhan Yijun , Wang Hong , Zhang Hui , Cai Yiwen , Wang Liaoyao , Zhu Wenyan , Shen Haiyue , Pei Jian
Published: November 2022

Aging is a multifactorial process associated with irreversible decline in mobility and cognitive function. However, the mechanisms underlying the relationship between mobility and cognitive function remain elusive. In specific, the mediating effect of muscle strength, which is essential to maintain mobility, on this relationship has yet to be clarified. Accordingly, we performed a cross-sectional study involving Chinese older adults to understand the role of muscle strength in the relationship between mobility and cognitive function. The cognitive function and physical performance of 657 community-dwelling participants aged over 65 years old were observed. Cognitive function was assessed using the Mini-Mental State Examination, whereas physical performance, including mobility and muscle strength, was measured via Timed Up-and-Go Test and knee extension strength measurement. Data were statistically analyzed using PROCESS Model 4 developed by Hayes, and 595 complete data were finally included. Physical performance (mobility and muscle strength) was significantly correlated with cognitive function (p < 0.01). Muscle strength was negatively correlated with mobility (r = −0.273, p < 0.001) and positively correlated with cognitive function (r = 0.145, p < 0.001). Muscle strength accounted for 20.1% of the total mediating effects on the relationship between mobility and cognitive function, which revealed the partial mediating role of lower extremity muscle strength in this relationship.
A review of the preclinical and clinical studies on the role of the gut microbiome in aging and neurodegenerative diseases and its modulation
Authors: Hashim Haslin Madihah , Makpol Suzana
Published: November 2022

As the world population ages, the burden of age-related health problems grows, creating a greater demand for new novel interventions for healthy aging. Advancing aging is related to a loss of beneficial mutualistic microbes in the gut microbiota caused by extrinsic and intrinsic factors such as diet, sedentary lifestyle, sleep deprivation, circadian rhythms, and oxidative stress, which emerge as essential elements in controlling and prolonging life expectancy of healthy aging. This condition is known as gut dysbiosis, and it affects normal brain function via the brain-gut microbiota (BGM) axis, which is a bidirectional link between the gastrointestinal tract (GIT) and the central nervous system (CNS) that leads to the emergence of brain disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Here, we reviewed the role of the gut microbiome in aging and neurodegenerative diseases, as well as provided a comprehensive review of recent findings from preclinical and clinical studies to present an up-to-date overview of recent advances in developing strategies to modulate the intestinal microbiome by probiotic administration, dietary intervention, fecal microbiota transplantation (FMT), and physical activity to address the aging process and prevent neurodegenerative diseases. The findings of this review will provide researchers in the fields of aging and the gut microbiome design innovative studies that leverage results from preclinical and clinical studies to better understand the nuances of aging, gut microbiome, and neurodegenerative diseases.
17O-labeled water distribution in the human inner ear: Insights into lymphatic dynamics and vestibular function
Authors: Yoshida Tadao , Naganawa Shinji , Kobayashi Masumi , Sugimoto Satofumi , Katayama Naomi , Nakashima Tsutomu , Kato Yutaka , Ichikawa Kazushige , Yamaguchi Hiroshi , Nishida Kazuki , Sone Michihiko
Published: November 2022

We evaluated the inner ear distribution of 17O-labeled saline administered to the human tympanic cavity. Magnetic resonance imaging was performed after intratympanic administration in five healthy volunteers and one patient with cochlear endolymphatic hydrops. In all volunteers, 17O-labeled water permeated the cochlear basal turn and vestibule at 30 min and disappeared gradually within 2–4 h. All participants experienced positional vertigo lasting a few hours to a few days. Visualization of 17O-labeled water distribution in the endolymphatic space of the posterior ampulla showed indistinct separation of endolymph and perilymph in the cochlea and most of the vestibule in all participants. Intralabyrinthine distribution of 17O-labeled water differed from that in previous reports of intratympanically administered gadolinium-based contrast agent. 17O-labeled water in the endolymphatic space may cause heavier endolymph and positional vertigo. These results of this study may add new insights for investigating the distribution and the effects of molecules in the inner ear after the intratympanic administration in living humans.
Age-related hearing loss was accelerated by apoptosis of spiral ganglion and stria vascularis cells in ApoE KO mice with hyperglycemia and hyperlipidemia
Authors: Nguyen Phuong Thi Thanh , Song Hayoung , Kim Boyoung , Kim Yoo Yeon , Kim Chulho , Lee Jun Ho , Suh Jun Gyo
Published: November 2022

Age-related hearing loss (ARHL) is associated with diabetes and/or dyslipidemia in humans. However, the detailed mechanism for the development of ARHL by diabetes and/or dyslipidemia has not been elucidated. In this study, we investigated the etiology of ARHL in apolipoprotein E (ApoE)-deficient mice with diabetes and dyslipidemia. The atherosclerotic CD-STZ (mice fed with a control diet and received an STZ injection), WD-con (mice fed with a western diet), and WD-STZ (mice fed with a western diet and received an STZ injection) mice showed a 2.4-, 4.9-, and 6.8-fold larger area, respectively, occupied by lesions throughout the aorta compared with the CD-con mice. A significantly larger area under the curve (AUC) was observed in the STZ-treated groups than in the non-treated groups based on the oral glucose tolerance test (OGTT). At 20 weeks of age, HbA1c levels were significantly higher in the CD-STZ and WD-STZ mice than in the CD-con and WD-con mice. In all the groups, the auditory brainstem response (ABR) thresholds of the 16-week-old mice were significantly higher compared with those of the 8-week-old mice. In particular, in the WD-STZ mice, the ABR thresholds of the left and right ears reached the maximum decibel peak equivalent sound pressure levels (130 dBpeSPL), which is a sign of deafness. The apoptotic spiral ganglion neurons (SGNs) of the WD-STZ mice were significantly increased compared with those of the other three groups, indicating that SGN apoptosis resulted in hearing loss in STZ-induced diabetic ApoE KO mice fed with a WD. A significant loss of the stria vascularis cells was observed in the WD-STZ group compared with the CD-con mice. In the organ of Corti, few apoptotic hair cells were found in all the groups; however, no significant difference was observed. Therefore, we consider that the reduced hearing ability in the STZ-treated and WD-fed groups was attributed to the damage to the SGN and stria vascularis in the cochlea. Thus, our results indicated that ototoxicity by diabetes and/or dyslipidemia accelerated ARHL in ApoE KO mice, thereby suggesting the importance of appropriate treatment of patients with diabetes and/or dyslipidemia to prevent ARHL.
Cognitive dysfunctions in high myopia: An overview of potential neural morpho-functional mechanisms
Authors: Li Kaixiu , Wang Qun , Wang Liqiang , Huang Yifei
Published: November 2022

Dementia and cognitive impairment (CIM) carry high levels of mortality. Visual impairment (VI) is linked with CIM risk. High myopia (HM) is a chronic disease frequently leading to irreversible blindness. Current opinion has shifted from retinal injury as the cause of HM to the condition being considered an eye-brain disease. However, the pathogenesis of this disease and the manner in which neural structures are damaged are poorly understood. This review comprehensively discusses the relationship between HM, the central nervous system, and CIM, together with the novel concept of three visual pathways, and possible research perspectives.