bluuebunny/crossref_metadata_2025 huggingface dataset:
Early and Late Processes Driving NET Formation, and the Autocrine/Paracrine Role of Endogenous RAGE Ligands
Authors: Tatsiy Olga , de Carvalho Oliveira Vanessa , Mosha Hugo Tshivuadi , McDonald Patrick P.
Published: September 2021

Neutrophil extracellular trap (NET) formation has emerged as an important response against various pathogens; it also plays a role in chronic inflammation, autoimmunity, and cancer. Despite a growing understanding of the mechanisms underlying NET formation, much remains to be elucidated. We previously showed that in human neutrophils activated with different classes of physiological stimuli, NET formation features both early and late events that are controlled by discrete signaling pathways. However, the nature of these events has remained elusive. We now report that PAD4 inhibition only affects the early phase of NET generation, as do distinct signaling intermediates (TAK1, MEK, p38 MAPK). Accordingly, the inducible citrullination of residue R2 on histone H3 is an early neutrophil response that is regulated by these kinases; other arginine residues on histones H3 and H4 do not seem to be citrullinated. Conversely, elastase blockade did not affect NET formation by several physiological stimuli, though it did so in PMA-activated cells. Among belated events in NET formation, we found that chromatin decondensation is impaired by the inhibition of signaling pathways controlling both early and late stages of the phenomenon. In addition to chromatin decondensation, other late processes were uncovered. For instance, unstimulated neutrophils can condition themselves to be poised for rapid NET induction. Similarly, activated neutrophils release endogenous proteic factors that promote and largely mediate NET generation. Several such factors are known RAGE ligands and accordingly, RAGE inbibition largely prevents both NET formation and the conditioning of neutrophils to rapidly generate NETs upon stimulation. Our data shed new light on the cellular processes underlying NET formation, and unveil unsuspected facets of the phenomenon that could serve as therapeutic targets. In view of the involvement of NETs in both homeostasis and several pathologies, our findings are of broad relevance.
Efficacy of Immune Checkpoint Inhibitors in Rare Tumours: A Systematic Review
Authors: Petrelli Fausto , Consoli Francesca , Ghidini Antonio , Perego Gianluca , Luciani Andrea , Mercurio Paola , Berruti Alfredo , Grisanti Salvatore
Published: September 2021

Background

Rare cancers, as defined by the European Union, occur in fewer than 15 out of 100,000 people each year. The International Rare Cancer Consortium defines rare cancer incidence as less than six per 100,000 per year. There is a growing number of reports of the efficacy of immune checkpoint inhibitor (ICI) therapy in patients with rare tumours, and hence, we conducted a comprehensive review to summarise and analyse the available literature.

Methods

A literature search of PubMed was performed on January 31, 2021, using the following ICI names as keywords: ipilimumab, tremelimumab, cemiplimab, nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab. Studies on patients with rare tumours who were being treated with ICIs were included. We plotted the overall response rate against the corresponding median survival across a variety of cancer types using linear regression.

Results

From 1,255 publications retrieved during the primary search, 62 publications were selected (with a total of 4,620 patients). Only four were randomised trials. A minority were first-line studies, while the remaining were studies in which ICIs were delivered as salvage therapy in pretreated patients. There was a good correlation between response rate and overall survival (Spearman R2 >0.9) in skin cancers, mesothelioma, and sarcomas.

Conclusions

Treatment of advanced-stage rare tumours with ICI therapy was found to be associated with significant activity in some orphan diseases (e.g., Merkel cell carcinoma) and hepatocellular carcinoma. Several ongoing prospective clinical trials will expand the knowledge on the safety and efficacy of ICI therapy in patients with these rare cancers.
Timing of Transcriptomic Peripheral Blood Mononuclear Cell Responses of Sheep to Fasciola hepatica Infection Differs From Those of Cattle, Reflecting Different Disease Phenotypes
Authors: Niedziela Dagmara A. , Naranjo-Lucena Amalia , Molina-Hernández Verónica , Browne John A. , Martínez-Moreno Álvaro , Pérez José , MacHugh David E. , Mulcahy Grace
Published: September 2021

Infection with the zoonotic trematode Fasciola hepatica, common in many regions with a temperate climate, leads to delayed growth and loss of productivity in cattle, while infection in sheep can have more severe effects, potentially leading to death. Previous transcriptomic analyses revealed upregulation of TGFB1, cell death and Toll-like receptor signalling, T-cell activation, and inhibition of nitric oxide production in macrophages in response to infection. However, the differences between ovine and bovine responses have not yet been explored. The objective of this study was to further investigate the transcriptomic response of ovine peripheral blood mononuclear cells (PBMC) to F. hepatica infection, and to elucidate the differences between ovine and bovine PBMC responses. Sixteen male Merino sheep were randomly assigned to infected or control groups (n = 8 per group) and orally infected with 120 F. hepatica metacercariae. Transcriptomic data was generated from PBMC at 0, 2 and 16 weeks post-infection (wpi), and analysed for differentially expressed (DE) genes between infected and control animals at each time point (analysis 1), and for each group relative to time 0 (analysis 2). Analysis 2 was then compared to a similar study performed previously on bovine PBMC. A total of 453 DE genes were found at 2 wpi, and 2 DE genes at 16 wpi (FDR < 0.1, analysis 1). Significantly overrepresented biological pathways at 2 wpi included role of PKR in interferon induction and anti-viral response, death receptor signalling and RIG-I-like receptor signalling, which suggested that an activation of innate response to intracellular nucleic acids and inhibition of cellular apoptosis were taking place. Comparison of analysis 2 with the previous bovine transcriptomic study revealed that anti-inflammatory response pathways which were significantly overrepresented in the acute phase in cattle, including IL-10 signalling, Th2 pathway, and Th1 and Th2 activation were upregulated only in the chronic phase in sheep. We propose that the earlier activation of anti-inflammatory responses in cattle, as compared with sheep, may be related to the general absence of acute clinical signs in cattle. These findings offer scope for “smart vaccination” strategies for this important livestock parasite.
Regulatory B Cells: Role in Type 1 Diabetes
Authors: Boldison Joanne , Wong F. Susan
Published: September 2021

Regulatory B cells (Bregs) have an anti-inflammatory role and can suppress autoimmunity, by employing both cytokine secretion and cell-contact mediated mechanisms. Numerous Breg subsets have been described and have overlapping phenotypes in terms of their immune expression markers or cytokine production. A hallmark feature of Bregs is the secretion of IL-10, although IL-35 and TGFβ−producing B cells have also been identified. To date, few reports have identified an impaired frequency or function of Bregs in individuals with type 1 diabetes; thus our understanding of the role played by these Breg subsets in the pathogenesis of this condition is limited. In this review we will focus on how regulatory B cells are altered in the development of type 1 diabetes, highlighting both frequency and function and discuss both human and animal studies.
Taxonomic and Functional Patterns of Benthic Communities in Southern Temperate Tidal Flats
Authors: Lam-Gordillo Orlando , Baring Ryan , Dittmann Sabine
Published: September 2021

Coastal ecosystems are vulnerable to anthropogenic disturbances which can cause loss of benthic macrofauna and their ecosystem functioning. Despite the importance of functional assessments for conservation and management, knowledge gaps persist on the generality of how the diversity and functional traits of benthic communities influence ecosystem functioning. We investigated eight sites in three different habitats across ~1,260 km of coastline, to evaluate patterns between taxonomic and functional diversity of benthic macrofauna, and the relationship between benthic macrofauna, functional traits and environmental conditions. A total of 74 benthic macrofauna taxa were identified. Significant differences across sites and season were found for metrics based on taxonomic and functional traits. Multivariate analysis revealed spatial-temporal differences, which were more evident based on taxa than functional traits. Functional diversity also showed spatial and temporal differences and was positively correlated with the number of taxa. The dominant functional traits modalities were deposit feeders, with large (>20 mm) body size, burrowers, bioirrigators, deeper than 3 cm in sediments, and irregular morphology. Novel Generalized Linear Latent Variable Models (GLLVM) uncovered several site-dependent relationships between taxa, traits and environmental conditions. Functional redundancy was lowest in a highly modified lagoon, and highest in a more pristine embayment. The outcomes from this study showed site-dependent patterns of benthic communities based on either taxonomic or functional metrics, highlighting that both perspectives are complementary to obtain a holistic understanding of the functioning in marine sediments under environmental change.
Kidney Function Is Not Related to Brain Amyloid Burden on PET Imaging in The 90+ Study Cohort
Authors: Lau Wei Ling , Fisher Mark , Fletcher Evan , DeCarli Charles , Troutt Hayden , Corrada María M. , Kawas Claudia , Paganini-Hill Annlia
Published: September 2021

Cognitive decline is common in chronic kidney disease (CKD). While the evidence of vascular cognitive impairment in this population is robust, the role of Alzheimer's pathology is unknown. We evaluated serum cystatin C-estimated glomerular filtration rate (eGFR), brain amyloid-β positron emission tomography (PET) imaging, and cognitive function in 166 participants from The 90+ Study. Mean age was 93 years (range 90-107) and 101 (61%) were women; 107 participants had normal cognitive status while 59 participants had cognitive impairment no dementia (CIND) or dementia. Mean ± standard deviation cystatin C was 1.59 ± 0.54 mg/L with eGFR 40.7 ± 18.7 ml/min/1.73m2. Higher amyloid-β burden was associated with dementia, but not with age, diabetes, hypertension, or cardiovascular disease. We found no association between brain amyloid-β burden and cystatin C eGFR. We previously reported that kidney function was associated with cognition and cerebral microbleeds in the same cohort of oldest-old adults (90+ years old). Collectively, these findings suggest that microvascular rather than Alzheimer's pathology drives CKD-associated cognitive dysfunction in this population.
Co-pathogens in Periodontitis and Inflammatory Bowel Disease
Authors: Cai Zhengwen , Zhu Tao , Liu Fengshuo , Zhuang Zixuan , Zhao Lei
Published: September 2021

Localized inflammatory lesions in one area of the body may affect other distant organs through various modes of transmission thus initiating secondary inflammatory infections. Periodontal disease (PD) and inflammatory bowel disease (IBD) have been shown to coexist. Periodontitis is a multifactorial inflammatory disease, and dental plaque is considered to be the initial risk factor. Individuals with genetic susceptibility are more likely to develop periodontitis when exposed to external stimuli. IBD is affected by host genetics, immunoregulation, daily diet, and the gut microbiota, and its risk factors appear to be shared with those of PD. However, the key etiologies of both diseases remain unclear, thus hindering the exploration of possible links between IBD and PD. Recent studies and systematic reviews have focused on evidence-based statistics of the prevalence and clinical manifestations of both diseases, but discussions of the microbial etiological correlation between periodontitis and intestinal inflammation are scarce. Here, we summarize the potential common pathogenic microorganisms that may serve as bridges between the two diseases. Studies have shown that invasive microorganisms such asPorphyromonas gingivalis, Fusobacterium nucleatum, Klebsiellaspp. andCampylobacterspp. play key roles in the comorbidity of PD and IBD.
When Origin Matters: Properties of Mesenchymal Stromal Cells From Different Sources for Clinical Translation in Kidney Disease
Authors: Calcat-i-Cervera Sandra , Sanz-Nogués Clara , O'Brien Timothy
Published: September 2021

Advanced therapy medicinal products (ATMPs) offer new prospects to improve the treatment of conditions with unmet medical needs. Kidney diseases are a current major health concern with an increasing global prevalence. Chronic renal failure appears after many years of impairment, which opens a temporary window to apply novel therapeutic approaches to delay or halt disease progression. The immunomodulatory, anti-inflammatory, and pro-regenerative properties of mesenchymal stromal cells (MSCs) have sparked interest for their use in cell-based regenerative therapies. Currently, several early-phase clinical trials have been completed and many are ongoing to explore MSC safety and efficacy in a wide range of nephropathies. However, one of the current roadblocks to the clinical translation of MSC therapies relates to the lack of standardization and harmonization of MSC manufacturing protocols, which currently hinders inter-study comparability. Studies have shown that cell culture processing variables can have significant effects on MSC phenotype and functionality, and these are highly variable across laboratories. In addition, heterogeneity within MSC populations is another obstacle. Furthermore, MSCs may be isolated from several sources which adds another variable to the comparative assessment of outcomes. There is now a growing body of literature highlighting unique and distinctive properties of MSCs according to the tissue origin, and that characteristics such as donor, age, sex and underlying medical conditions may alter the therapeutic effect of MSCs. These variables must be taken into consideration when developing a cell therapy product. Having an optimal scale-up strategy for MSC manufacturing is critical for ensuring product quality while minimizing costs and time of production, as well as avoiding potential risks. Ideally, optimal scale-up strategies must be carefully considered and identified during the early stages of development, as making changes later in the bioprocess workflow will require re-optimization and validation, which may have a significant long-term impact on the cost of the therapy. This article provides a summary of important cell culture processing variables to consider in the scale-up of MSC manufacturing as well as giving a comprehensive review of tissue of origin-specific biological characteristics of MSCs and their use in current clinical trials in a range of renal pathologies.
Enhanced Efficacy of Some Antibiotics in Presence of Silver Nanoparticles Against Multidrug Resistant Pseudomonas aeruginosa Recovered From Burn Wound Infections
Authors: Khalil Maha A. , El Maghraby Gamal M. , Sonbol Fatma I. , Allam Nanis G. , Ateya Perihan S. , Ali Sameh S.
Published: September 2021

Burn wound infections with multidrug-resistant (MDR) bacteria are shown in many countries as severe widespread health threats. Consequently, attention has been devoted to new nanoparticle-based materials in the field of antimicrobial chemotherapy for burn wound infections. This study aimed to evaluate both in vitro and in vivo efficacies of nanoparticle–antibiotic combinations as new classes of materials subjected against MDR Pseudomonas aeruginosa. Out of 40 Gram-negative isolates, 23 P. aeruginosa were recovered from patients with burn wound infections attending different hospitals in Tanta, Egypt. The susceptibility test revealed that 95.7% of P. aeruginosa isolates were MDR with a high incidence of resistance against carbenicillin. Antibacterial activities of silver nanoparticles (Ag-NPs) against the isolates examined showed various inhibition zone diameters ranging from 11 to 17 mm. Strong synergistic efficacy of neomycin was reported in combination with Ag-NPs against MDR P. aeruginosa P8 and P14 isolates. The in vivo effectiveness of various pharmaceutical formulations prepared from a combination of neomycin antibiotic with Ag-NPs in the treatment of induced bacterially infected mice burns showed that maximum healing activity along with faster wound contraction reported with the combination of neomycin-Ag-NPs in the spray formulation. Generally, data indicated that incorporating Ag-NPs in combination with certain antibiotics may be a new, promising application for wound treatments, especially burns infected with MDR P. aeruginosa.
Age-Related Changes in the Ruminal Microbiota and Their Relationship With Rumen Fermentation in Lambs
Authors: Yin Xuejiao , Ji Shoukun , Duan Chunhui , Tian Peizhi , Ju Sisi , Yan Hui , Zhang Yingjie , Liu Yueqin
Published: September 2021

The rumen microbiota is vital for the health and growth performance of the host animal, mainly due to its role in the fermentation of ingested feed within the rumen. Attaining a better understanding of the development of the bacterial community and fermentation in the rumen can provide the theoretical basis for regulating feed utilization. This study analyzed the development of rumen bacteria in lambs from birth to 4 months of age using 16S-rRNA amplicon sequencing data and studied its relationship with ruminal fermentation. Serum levels of metabolites were monitored at 30, 60, 90, and 120 days of age, and the RandomForest approach was used to determine age-related changes in rumen bacteria. Levels of blood metabolites, ruminal fermentation, the rumen bacterial community and its functions were all affected by the age of the lambs (P < 0.05). Based on the Bray-Curtis distance within the age groups of the rumen microbiota, the similarity increased sharply after the lambs were weaned at 60 days of age (P < 0.05). The similarity between the samples collected from birth to 90 days of age and those collected at 120 days of age, increased after 20 days of age, reaching a maximum at 90 days vs. 120 days (P < 0.05). Some age-associated changes in the microbial genera were correlated with changes in the concentrations of volatile fatty acids and the levels of microbial crude protein in the rumen, including positive correlations between main volatile fatty acids and the genera of Prevotella 1, Lachnospiraceae NK3A20 group, Ruminococcus gauvreauii group, Ruminococcaceae UCG-014, and Ruminococcus 2 (P < 0.05). These results indicated that the microbial community and the function of rumen was not well-established before 20 days of age, so there is a degree of plasticity in the rumen bacterial community during the first 20 days of post-natal development in lambs, and this might provide an opportunity for interventions to improve rumen fermentation and, thus, increase their growth performance.
The Different Response to an Acid Shock of Two Salmonella Strains Marks Their Resistance to Thermal Treatments
Authors: Clemente-Carazo Marta , Leal José-Juan , Huertas Juan-Pablo , Garre Alberto , Palop Alfredo , Periago Paula M.
Published: September 2021

Microbial cells respond to sub-lethal stresses with several physiological changes to increase their chance of survival. These changes are of high relevance when combined treatments (hurdle technology) are applied during food production, as the cells surviving the first hurdle may have greater resistance to subsequent treatments than untreated cells. In this study, we analyzed if Salmonella develops increased resistance to thermal treatments after the application of an acid shock. We compared the heat resistance of acid-shocked (pH 4.5 achieved with citric acid) Salmonella cells with that of cells maintained at pH 7 (control cells). Thermal treatments were performed between 57.5 and 65°C. We observed a differential response between the two strains studied. Acid-shocked cells of Salmonella Senftenberg exhibited reduced heat resistance, e.g., for a treatment at 60.0°C and pH 7.0 the time required to reduce the population by 3 log cycles was lowered from 10.75 to 1.98min with respect to control cells. Salmonella Enteritidis showed a different response, with acid-shocked cells having similar resistance than untreated cells (the time required to reduce 3 log cycles at 60.0°C and pH 7.0 was 0.30min for control and 0.31min for acid-shock cells). Based on results by differential plating (with or without adding the maximum non-inhibitory concentration of NaCl to the recovery medium), we hypothesize that the differential response between strains can be associated to sub-lethal damage to the cell membrane of S. Senftenberg caused by the acid shock. These results provide evidence that different strains of the same species can respond differently to an acid shock and highlight the relevance of cross-resistances for microbial risk assessment.
Overexpression of mqsR in Xylella fastidiosa Leads to a Priming Effect of Cells to Copper Stress Tolerance
Authors: Carvalho Isis Gabriela Barbosa , Merfa Marcus Vinicius , Teixeira-Silva Natália Sousa , Martins Paula Maria Moreira , Takita Marco Aurélio , de Souza Alessandra Alves
Published: September 2021

Copper-based compounds are widely used in agriculture as a chemical strategy to limit the spread of multiple plant diseases; however, the continuous use of this heavy metal has caused environmental damage as well as the development of copper-resistant strains. Thus, it is important to understand how the bacterial phytopathogens evolve to manage with this metal in the field. The MqsRA Toxin–Antitoxin system has been recently described for its function in biofilm formation and copper tolerance in Xylella fastidiosa, a plant-pathogen bacterium responsible for economic damage in several crops worldwide. Here we identified differentially regulated genes by X. fastidiosa MqsRA by assessing changes in global gene expression with and without copper. Results show that mqsR overexpression led to changes in the pattern of cell aggregation, culminating in a global phenotypic heterogeneity, indicative of persister cell formation. This phenotype was also observed in wild-type cells but only in the presence of copper. This suggests that MqsR regulates genes that alter cell behavior in order to prime them to respond to copper stress, which is supported by RNA-Seq analysis. To increase cellular tolerance, proteolysis and efflux pumps and regulator related to multidrug resistance are induced in the presence of copper, in an MqsR-independent response. In this study we show a network of genes modulated by MqsR that is associated with induction of persistence in X. fastidiosa. Persistence in plant-pathogenic bacteria is an important genetic tolerance mechanism still neglected for management of phytopathogens in agriculture, for which this work expands the current knowledge and opens new perspectives for studies aiming for a more efficient control in the field.
Comparison of the Fermentation Activities and Volatile Flavor Profiles of Chinese Rice Wine Fermented Using an Artificial Starter, a Traditional JIUYAO and a Commercial Starter
Authors: Chen Chen , Liu Zheng , Zhou Wenya , Tian Huaixiang , Huang Juan , Yuan Haibin , Yu Haiyan
Published: September 2021

In this study, an artificial starter culture was prepared using the core microbial species of JIUYAO to produce Chinese rice wine (CRW). The fermentation activity and flavor profiles of CRW samples fermented with traditional JIUYAO, a commercial starter culture, and our artificial starter culture were compared. The optimal protectant combination for lyophilization of the artificial starter was established as 15.09% skim milk, 4.45% polyethylene glycol, 1.96% sodium glutamate, and 11.81% maltodextrin. A comparative analysis revealed that the ethanol content of the three CRW samples was similar. The total acid content of the CRW sample fermented with the artificial starter (7.10 g/L) was close to that of the sample fermented with JIUYAO (7.35 g/L), but higher than that of the sample fermented with the commercial starter (5.40 g/L). An electronic nose analysis revealed that the olfactory fingerprints of the CRW samples fermented with JIUYAO and the artificial starter resembled each other. For both above mentioned samples, the flavor profiles determined by gas chromatography–mass spectrometry indicated some differences in the variety and content of the aroma compounds, but the key odorants (odor activity values ≥1), such as isoamyl acetate, ethyl acetate, phenyl alcohol, and isoamyl alcohol, were similar.
Chronic Aerobic Training at Different Volumes in the Modulation of Macrophage Function and in vivo Infection of BALB/c Mice by Leishmania major
Authors: Guimarães T. T. , Gomes S. M. R. , Albuquerque R. A. A. C. , Lima A. K. C. , Braga G. F. , Souza J. B. , Assis M. , Brito A. C. S. , Santos R. F. , Da Silva T. , Siqueira L. M. , Ventura B. D. , Rodrigues L. S. , Terra R. , Da Silva S. A. G. , Dutra P. M. L.
Published: September 2021

Physical inactivity is one of the main causes of chronic diseases; however, strenuous exercise can induce immunosuppression. Several studies suggest that moderate amounts of exercise lead to a Th1 response, favoring the resolution of infections caused by intracellular microorganisms, while high volumes of exercise tend to direct the response to Th2, favoring infection by them. Leishmaniasis is a parasitic disease promoted by parasites of theLeishmaniagenus, with clinical manifestations that vary according to the species of the parasite and the immune response of the host. The experimentalLeishmania major–BALB/C mouse model provides a good model for the resistance (Th1 response) or susceptibility (Th2 response) that determines the progression of this infection. The aim of this study was to evaluate the effect of aerobic training at different volumes on modulation ofin vitromacrophage infection byL. major, as well as to assess the effect of high volume (HV) aerobic training on the development ofL. major in vivoin BALB/c mice. Uninfected animals were submitted to various exercise volumes: none (SED), light (LV), moderate (MV), high (HV), very high (VHV), and tapering (TAP). The macrophages of these animals were infected byL. majorand the LV and MV groups showed a decrease in the infection factor, while the VHV showed an increase in the infection factor, when treated with LPS. The cytokine concentration pattern measured in the supernatants of these macrophages suggested a predominant Th1 response profile in the LV and MV groups, while the Th2 profile predominated in the VHV and TAP groups. Groups of BALB/C mice infected withL. majorwere subjected to high volume (iHV) or non-periodized high volume (iNPHV) exercise or kept sedentary (iSED). The exercised animals suffered a significant increase in injuries caused by the parasites. The animals in the group submitted to high volume exercise (iHV) showed visceralization of the infection. These data strongly suggest that a very high volume of aerobic training increased the susceptibility of BALB/C mice toL. majorinfection, while moderate distribution of training loads promoted immunological balance, better controlling the infection by this parasite.
Delivery of Anti-miRNA-221 for Colorectal Carcinoma Therapy Using Modified Cord Blood Mesenchymal Stem Cells-Derived Exosomes
Authors: Han Siqi , Li Guangchao , Jia Meng , Zhao Yulu , He Chenglong , Huang Mengxi , Jiang Longwei , Wu Meijuan , Yang Jiahe , Ji Xiaoqin , Liu Xiaobei , Chen Cheng , Chu Xiaoyuan
Published: September 2021

Background: Exosomes, as natural intercellular information carriers, have great potential in the field of drug delivery. Many studies have focused on modifying exosome surface proteins to allow drugs to specifically target cancer cells.

Methods: In this study, human cord blood mesenchymal stromal cell-derived exosomes were used in the delivery of anti-miRNA oligonucleotides so as to be specifically ingested by tumor cells to perform anti-tumor functions. Mesenchymal stem cells modified by the fusion gene iRGD-Lamp2b were constructed to separate and purify exosomes, and the anti-miRNA-221 oligonucleotide (AMO) was loaded into the exosomes by electroporation.

Results: The AMO-loaded exosomes (AMO-Exos) effectively inhibited the proliferation and clonal formation of colon cancer cells in vitro, and it was further found that AMO-Exos was taken up by tumor cells through interaction with the NRP-1 protein. The results of a xenograft tumor model also showed that iRGD-modified exosomes were obviously enriched in tumor sites, exerting excellent anti-tumor efficacy. In vivo imaging showed that exosomes were mainly distributed in liver, spleen, and lung tissues.

Conclusion: Our results suggest that genetically modified exosomes could be an ideal natural nanostructure for anti-miRNA oligonucleotide delivery.
Leisure Activities, APOE ε4, and Cognitive Decline: A Longitudinal Cohort Study
Authors: Zhang Yun , Fu Shihui , Ding Ding , Lutz Michael W. , Zeng Yi , Yao Yao
Published: September 2021

Background: Both leisure activities and the ε4 allele of the apolipoprotein E (APOE ε4) have been shown to affect cognitive health. We aimed to determine whether engagement in leisure activities protects against APOE ε4-related cognitive decline.

Methods: We used the cohort data from the Chinese Longitudinal Healthy Longevity Survey. A total of 3,017 participants (mean age of 77.0 years, SD = 9.0; 49.3% female) from 23 provinces of China were recruited in 2008 and were reinterviewed in 2014. We assessed cognitive function using the Mini-Mental State Examination (MMSE). We calculated cognitive decline using subtraction of the MMSE score of each participant in 2008 and 2014. We genotyped a number of APOE ε4 alleles for each participant at baseline and determined the Index of Leisure Activities (ILAs) by summing up the frequency of nine types of typical activities in productive, social, and physical domains. We used ordinal logistic regression models to estimate the effects of leisure activities, APOE ε4, and their interaction on cognitive decline, statistically adjusted for a range of potential confounders.

Results: There were significant associations between APOE ε4 and faster cognitive decline, independent of potential confounders, and between leisure activities and mitigated cognitive decline. The odds ratios were 1.25 (95% CI: 1.03, 1.53) and 0.93 (95% CI: 0.89, 0.97), respectively. We found significant interactions of APOE ε4 with leisure activities with a P-value of 0.018. We also observed interactive effects of subtypes of leisure activities: participants who regularly engaged in productive activities were more likely to reduce the risk of APOE ε4-related cognitive decline.

Conclusion: Our findings provide support for the indication that participating in leisure activities reduces the risk of APOE ε4-related cognitive decline.
Changes in the Number and Morphology of Dendritic Spines in the Hippocampus and Prefrontal Cortex of the C58/J Mouse Model of Autism
Authors: Barón-Mendoza Isabel , Maqueda-Martínez Emely , Martínez-Marcial Mónica , De la Fuente-Granada Marisol , Gómez-Chavarin Margarita , González-Arenas Aliesha
Published: September 2021

Autism spectrum disorder (ASD) has a broad range of neurobiological characteristics, including alterations in dendritic spines, where approximately 90% of excitatory synapses occur. Therefore, changes in their number or morphology would be related to atypical brain communication. The C58/J inbred mouse strain displays low sociability, impaired communication, and stereotyped behavior; hence, it is considered among the animal models suitable for the study of idiopathic autism. Thus, this study aimed to evaluate the dendritic spine differences in the hippocampus and the prefrontal cortex of C58/J mice. We found changes in the number of spines and morphology in a brain region-dependent manner: a subtle decrease in spine density in the prefrontal cortex, higher frequency of immature phenotype spines characterized by filopodia-like length or small morphology, and a lower number of mature phenotype spines with mushroom-like or wide heads in the hippocampus. Moreover, an in silico analysis showed single nucleotide polymorphisms (SNPs) at genes collectively involved in regulating structural plasticity with a likely association with ASD, including MAP1A (Microtubule-Associated Protein 1A), GRM7 (Metabotropic Glutamate Receptor, 7), ANKRD11 (Ankyrin Repeat Domain 11), and SLC6A4 (Solute Carrier Family 6, member 4), which might support the relationship between the C58/J strain genome, an autistic-like behavior, and the observed anomalies in the dendritic spines.
Seizure Forecasting: Patient and Caregiver Perspectives
Authors: Grzeskowiak Caitlin L. , Dumanis Sonya B.
Published: September 2021

Accurate seizure forecasting is emerging as a near-term possibility due to recent advancements in machine learning and EEG technology improvements. Large-scale data curation and new data element collection through consumer wearables and digital health tools such as longitudinal seizure diary data has uncovered new possibilities for personalized algorithm development that may be used to predict the likelihood of future seizures. The Epilepsy Foundation recognized the unmet need for development in seizure forecasting following a 2016 survey where an overwhelming majority of respondents across all seizure types and frequencies reported that unpredictability of seizures had the strongest impact on their life while living with or caring for someone living with epilepsy. In early 2021, the Epilepsy Foundation conducted an updated survey among those living with epilepsies and/or their caregivers to better understand the use-cases that best suit the needs of our community as seizure forecast research advances. These results will provide researchers with insight into user-acceptance of using a forecasting tool and incorporation into their daily life. Ultimately, this input from people living with epilepsy and caregivers will provide timely feedback on what the community needs are and ensure researchers and companies first and foremost consider these needs in seizure forecasting tools/product development.
Microsurgical Treatment Strategy of Vertebral Artery Fusiform Aneurysm—From the Standpoint of Hemodynamic Integrity and Perforator Preservation
Authors: Tsunoda Sho , Inoue Tomohiro
Published: September 2021

During treatment of vertebral artery (VA) fusiform aneurysms, it is critical to preserve peripheral perforators and anterograde blood flow of the VA and to reduce hemodynamic load to the contralateral VA. Even in the era of endovascular treatment, there are still many benefits to using microsurgical treatments with appropriate clip application and preservation of the perforators around the aneurysm, in conjunction with various bypass techniques. The ideal microsurgical technique involves reconstructive clipping that obliterates the aneurysm but preserves anterograde blood flow of the VA, followed by isolation of the aneurysm and VA reconstruction. If these two methods are unavailable, proximal clipping of the aneurysm combined with flow-augmentation bypass to the distal branch can be considered as an alternative surgical management. We discuss the microsurgical treatment of unruptured VA fusiform aneurysms in our surgical cases on the basis of a review of the current literature.
Clinical Characteristics of Predominantly Unilateral Oral Cenesthopathy With and Without Neurovascular Contact
Authors: Watanabe Kazuya , Watanabe Motoko , Takao Chihiro , Hong Chaoli , Liu Zhenyan , Suga Takayuki , Tu Trang Thi Huyen , Sakamoto Junichiro , Umezaki Yojiro , Yoshikawa Tatsuya , Takenoshita Miho , Uezato Akihito , Motomura Haruhiko , Kurabayashi Tohru , Abiko Yoshihiro , Toyofuku Akira
Published: September 2021

Oral cenesthopathy (OC) is characterized by unusual oral discomfort without corresponding evidence, and it has often been categorized as “delusional disorder, somatic type”. Regarding possible causative factors of OC, involvement of neurovascular contact (NVC) of the trigeminal nerve, which transmits not only pain but also thermal, tactile, and pressure sensations, has never been observed yet. This study aimed to investigate the relationship between clinical characteristics of unilateral OC and the presence of trigeminal nerve NVC. This is a retrospective comparative study that involved 48 patients having predominantly unilateral OC who visited the Psychosomatic Dentistry Clinic of Tokyo Medical and Dental University between April 2016 and February 2019. Magnetic resonance imaging was performed to assess NVC presence. The Oral Dysesthesia Rating Scale (Oral DRS) was used to assess the various oral sensations and functional impairments besides psychometric questionnaires. Clinical characteristics were retrospectively obtained from the patients' medical charts. NVC was present in 45.8% (22/48) of the patients. There was no significant difference in sex, age, psychiatric history, oral psychosomatic comorbidity, and psychometric questionnaire scores between patients with and without NVC. However, compared to the patients with NVC, the patients without NVC had significantly higher scores for overall subjective severity of OC symptoms (p = 0.008). Moreover, patients having predominantly unilateral OC without NVC showed significantly higher scores in symptom severity and functional impairment of the following parameters: movement (p = 0.030), work (p = 0.004), and social activities (p = 0.010). In addition, compared with the patients with NVC, the patients without NVC showed significantly higher averages of the total symptom severity scale (SSS) and functional impairment scale (FIS) scores in the Oral DRS (p = 0.015 and p = 0.031, respectively). Furthermore, compared with the patients with NVC, the patients without NVC had significantly higher numbers of corresponding symptoms in both the SSS and FIS (p = 0.041 and p = 0.007, respectively). While NVC may be involved in the indescribable subtle OC symptoms, more complex mechanisms may also exist in OC patients without NVC, which yield varying and more unbearable oral symptoms.
Graphene Nanoplatelets Render Poly(3-Hydroxybutyrate) a Suitable Scaffold to Promote Neuronal Network Development
Authors: Moschetta Matteo , Chiacchiaretta Martina , Cesca Fabrizia , Roy Ipsita , Athanassiou Athanassia , Benfenati Fabio , Papadopoulou Evie L. , Bramini Mattia
Published: September 2021

The use of composite biomaterials as innovative bio-friendly neuronal interfaces has been poorly developed so far. Smart strategies to target neuro-pathologies are currently exploiting the mixed and complementary characteristics of composite materials to better design future neural interfaces. Here we present a polymer-based scaffold that has been rendered suitable for primary neurons by embedding graphene nanoplatelets (GnP). In particular, the growth, network formation, and functionality of primary neurons on poly(3-hydroxybutyrate) [P(3HB)] polymer supports functionalized with various concentrations of GnP were explored. After growing primary cortical neurons onto the supports for 14 days, all specimens were found to be biocompatible, revealing physiological growth and maturation of the neuronal network. When network functionality was investigated by whole patch-clamp measurements, pure P(3HB) led to changes in the action potential waveform and reduction in firing frequency, resulting in decreased neuronal excitability. However, the addition of GnP to the polymer matrix restored the electrophysiological parameters to physiological values. Interestingly, a low concentration of graphene was able to promote firing activity at a low level of injected current. The results indicate that the P(3HB)/GnP composites show great potential for electrical interfacing with primary neurons to eventually target central nervous system disorders.
State-Dependent Synchrony and Functional Connectivity in the Primary and Secondary Whisker Somatosensory Cortices
Authors: Khateb Mohamed , Schiller Jackie , Schiller Yitzhak
Published: September 2021

Synchronized activity plays an important role in sensory coding and memory and is a hallmark of functional network connectivity. However, the effect of sensory activation on synchronization and cortical functional connectivity is largely unknown. In this study, we investigated the effect of whisker activation on synchronization and functional connectivity of the primary (wS1) and secondary (wS2) whisker somatosensory cortices at the single-cell level. The results showed that during the spontaneous pre-stimulus state, neurons tended to be functionally connected with nearby neurons which shared similar tuning characteristics. Whisker activation using either ramp-and-hold stimulation or artificial whisking against sandpaper has significantly reduced the average overall pairwise synchronization and functional connectivity within the wS1 barrel and wS2 cortices. Whisker stimulation disconnected approximately a third of neuronal pairs that were functionally connected during the unstimulated state. Nearby neurons with congruent tuning properties were more likely to remain functionally connected during whisker activation. The findings of this study indicated that cortical somatosensory networks are organized in non-random small world networks composed of neurons sharing relatively similar tuning properties. Sensory whisker activation intensifies these properties and further subdivides the cortical network into smaller more functionally uniform subnetworks, which possibly serve to increase the computational capacity of the network.
Dynamic Analysis of Major Components in the Different Developmental Stages of Tenebrio molitor
Authors: Yu Xiao , He Qiang , Wang Dun
Published: September 2021

The yellow mealworm, Tenebrio molitor, is an important resource insect with a high protein percentage that is widely farmed in many countries. In this study, the content dynamics for protein, fat, chitin, and other components in the whole development process of yellow mealworms were analyzed by sampling from different instars and combining with their growth conditions. The results of the component dynamic analyses in the different development stages showed that the percentages of protein, fat, and chitin were the highest in the larval stage, pupal stage, and adult stage, respectively. The results of amino acid composition dynamic analysis also indicated comparatively higher essential amino acids in the earlier instar (e.g., before the 9th instar) larvae. Therefore, we found that the earlier instar is better than the final instar as the insect farming harvest time. Furthermore, the larvae in the earlier instar consumed dramatically less feed and could effectively reduce the farming costs of insect farmers. This finding provides an alternative option to farm insects for different purposes and in an economic way.
Parental Adherence to Ideal Cardiovascular Health Status Was Associated With a Substantially Lower Prevalence of Overweight and Obesity in Their Offspring Aged 6–18 Years
Authors: Li Yanhui , Gao Di , Yang Zhaogeng , Ma Ying , Chen Manman , Ma Jun , Dong Yanhui , Dong Bin
Published: September 2021

Background: Parental health status had a potential influence on offspring health. This study aimed to investigate the separate associations between paternal and maternal cardiovascular health statuses and the prevalence of childhood overweight and obesity in the offspring.

Methods: Data were from a cross-sectional study conducted in seven provinces or cities of China in 2013. A total of 29,317 children aged 6–18 years old and their parents, making up 9,585 father-offspring pairs and 19,732 mother-offspring pairs, were included in the final analysis. Information on parental cardiovascular health status factors (dietary behaviors, body mass index (BMI), smoking, physical activity, hypertension, and diabetes mellitus) was obtained from the structured self-administrated questionnaires. Based on the health status factors, we then generated an ideal cardiovascular health (iCVH) score. The overweight and obesity of children were defined using age- and sex-specific cutoffs based on the International Obesity Task Force criteria. A multilevel log-binomial regression model was used to assess the association between parental cardiovascular health status and prevalence of childhood overweight and obesity in the offspring.

Results: The prevalence of pediatric overweight and obesity was 22.0% in the father-offspring subset and 23.8% in the mother-offspring subset, respectively. Fathers with ideal BMI, non-smoking, and absence of hypertension and diabetes, and mothers with ideal BMI, ideal physical activity, and absence of hypertension and diabetes were found to be associated with lower prevalence of overweight and obesity in the offspring. The prevalence of offspring overweight and obesity was significantly decreased with the parental iCVH scores increased. Each additional increase in paternal and maternal iCVH factor was associated with a 30% and 27% lower prevalence of overweight and obesity in the offspring. Compared with children whose parental iCVH scores ≤ 3, offspring whose fathers or mothers met all six iCVH factors had 67% [prevalence ratio (PR): 0.33, 95%CI: 0.25–0.42] and 58% (PR: 0.42, 95%CI: 0.29–0.62) lower prevalence of overweight and obesity, respectively.

Conclusions: Parental adherence to iCVH status was associated with a lower prevalence of pediatric overweight and obesity in offspring. Our findings support the intervention strategy that parents should involve in the obesity intervention program for children.
Immune Checkpoint Inhibitors Plus Single-Agent Chemotherapy for Advanced Non-Small-Cell Lung Cancer After Resistance to EGFR-TKI
Authors: Deng Haiyi , Lin Xinqing , Xie Xiaohong , Yang Yilin , Wang Liqiang , Wu Jianhui , Liu Ming , Xie Zhanhong , Qin Yinyin , Zhou Chengzhi
Published: September 2021

Purpose

Platinum-based chemotherapy remains the classic treatment option for patients with advanced non-small-cell lung cancer (NSCLC) who progress while receiving treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). In this study, we analyzed real-world outcomes of treatment with immune checkpoint inhibitors (ICIs) combined with platinum-free chemotherapy in patients with NSCLC after developing resistance to EGFR-TKIs.

Methods

This retrospective study included patients with mutation-positive NSCLC after developing resistance to EGFR-TKIs. Patients who received chemotherapy alone plus ICIs with or without anti-angiogenic drugs (cohort A) or platinum-based chemotherapy (cohort B) between February 2019 and August 2020 were enrolled. Clinical characteristics, EGFR mutation status, response to therapy, and adverse events (AEs) were retrospectively analyzed.

Results

Seventeen patients were eligible and included in the analysis, including 8 in cohort A and 9 in cohort B. After a median follow-up of 7.6 months, the median progression-free survival was 6.5 months [95% confidence interval (CI), 6.1 to 7.0] in cohort A and 3.6 months (95% CI, 1.3–5.8) in cohort B (hazard ratios, 0.22; 95% CI, 0.05–0.93; P = 0.039). The overall response and disease control rates were 50% and 100% in cohort A, and 22% and 89% in cohort B, respectively. Adverse events of grade 3 or higher occurred in 25% of the patients in cohort A and in 33.3% of the patients in cohort B.

Conclusion

ICIs plus platinum-free, single-agent chemotherapy provides promising progression-free survival and overall response rate benefit, along with a low rate of severe AEs in patients with EGFR-TKI-resistant advanced NSCLC.