bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engaging people with lived experience on advisory councils of a national not-for-profit: an integrated knowledge translation case study of Heart & Stroke Mission Critical Area Councils
Authors: Lewis Krystina B. , Peter Nedra ,   Heart & Stroke Foundation of Canada, Faubert Christine , Harriman Mary Elizabeth , Lindsay Patrice , Simard Anne , Yip Cindy , Graham Ian D. , Kothari Anita 
Published: May 2022

Abstract
Background
In 2018, the Heart and Stroke Foundation of Canada transformed its approach to organizational strategic planning and priority-setting. The goal was to generate impact from bench to bedside to community, to improve the health of Canadians. It engaged researchers, clinician scientists, health systems leaders, and community members including people with lived experience (PWLE) on six Mission Critical Area (MCA) councils, each of which was co-chaired by a researcher or clinician scientist and a person with lived experience. Together, council members were tasked with providing advice to Heart & Stroke about the most relevant and impactful priorities of our time. The aim of this research was to explore the value of the MCA councils to Heart & Stroke, and to council members themselves. The research questions focused on understanding the process of managing and participating on the councils, the challenges and outcomes.

Methods
Using an integrated knowledge translation approach, we conducted a case study with developmental evaluation over a 2-year time period (2018–2020). We collected qualitative data from various sources (Heart & Stroke team responsible for managing the councils, council co-chairs, council members, and key informants). We collected documents and analysed them for contextual background.

Results
Participants noted that the MCA councils continuously evolved over the 2 years in various ways: from an uncertain direction to a concrete one, better integrating the voice of PWLE, and increased cohesiveness within and across MCA councils. This evolution was achieved in parallel with successes and challenges at three levels: the MCA councils and its members, Heart & Stroke, and Canadians. The MCA councils were disbanded in 2020, yet learnings, developments, initiatives and established partnerships remain as their legacy.

Conclusions
Heart & Stroke’s intended objectives for the MCA councils, to promote engagement and dialogue among community members including PWLE, clinician scientists, and researchers, and to provide advice into Heart & Stroke’s strategic renewal process, were achieved. This collaborative structure and process for PWLE engagement within a community of multidisciplinary clinician scientists and researchers is possible yet requires flexibility, commitment to stakeholder relationship management, and considerable resources. These findings may be helpful for other not-for-profit and funding organizations interested in engaging the public and other stakeholders into their organizational activities.
The future of cancer immunotherapy for brain tumors: a collaborative workshop
Authors: Brown Christine E. , Bucktrout Samantha , Butterfield Lisa H. , Futer Olga , Galanis Evanthia , Hormigo Adilia , Lim Michael , Okada Hideho , Prins Robert , Marr Sara Siebel , Tanner Kirk 
Published: May 2022

AbstractHarnessing the effector mechanisms of the immune system to combat brain tumors with antigen specificity and memory has been in research and clinical testing for many years. Government grant mechanisms and non-profit organizations have supported many innovative projects and trials while biotech companies have invested in the development of needed tools, assays and novel clinical approaches. The National Brain Tumor Society and the Parker Institute for Cancer Immunotherapy partnered to host a workshop to share recent data, ideas and identify both hurdles and new opportunities for harnessing immunotherapy against pediatric and adult brain tumors. Adoptively transferred cell therapies have recently shown promising early clinical results. Local cell delivery to the brain, new antigen targets and innovative engineering approaches are poised for testing in a new generation of clinical trials. Although several such advances have been made, several obstacles remain for the successful application of immunotherapies for brain tumors, including the need for more representative animal models that can better foreshadow human trial outcomes. Tumor and tumor microenvironment biopsies with multiomic analysis are critical to understand mechanisms of response and patient stratification, yet brain tumors are especially challenging for such biopsy collection. These workshop proceedings and commentary shed light on the status of immunotherapy in pediatric and adult brain tumor patients, including current research as well as opportunities for improving future efforts to bring immunotherapy to the forefront in the management of brain tumors.
A crosstalk between gut and brain in sepsis-induced cognitive decline
Authors: Giridharan Vijayasree V. , Generoso Jaqueline S. , Lence Leonardo , Candiotto Gabriela , Streck Emílio , Petronilho Fabricia , Pillai Anilkumar , Sharshar Tarek , Dal-Pizzol Felipe , Barichello Tatiana 
Published: May 2022

Abstract
Background
Sepsis is a potentially fatal disease characterized by acute organ failure that affects more than 30 million people worldwide. Inflammation is strongly associated with sepsis, and patients can experience impairments in memory, concentration, verbal fluency, and executive functioning after being discharged from the hospital. We hypothesize that sepsis disrupts the microbiota–gut–brain axis homeostasis triggering cognitive impairment. This immune activation persists during treatment, causing neurological dysfunction in sepsis survivors.

Methods
To test our hypothesis, adult Wistar rats were subjected to cecal–ligation and perforation (CLP) or sham (non-CLP) surgeries. The animals were subjected to the [11C]PBR28 positron emission tomography (PET)/computed tomography (CT) imaging at 24 h and 10 days after CLP and non-CLP surgeries. At 24 h and 10 days after surgery, we evaluated the gut microbiome, bacterial metabolites, cytokines, microglia, and astrocyte markers. Ten days after sepsis induction, the animals were subjected to the novel object recognition (NOR) and the Morris water maze (MWM) test to assess their learning and memory.

Results
Compared to the control group, the 24-h and 10-day CLP groups showed increased [11C]PBR28 uptake, glial cells count, and cytokine levels in the brain. Results show that sepsis modulates the gut villus length and crypt depth, alpha and beta microbial diversities, and fecal short-chain fatty acids (SCFAs). In addition, sepsis surviving animals showed a significant cognitive decline compared with the control group.

Conclusions
Since several pharmacological studies have failed to prevent cognitive impairment in sepsis survivors, a better understanding of the function of glial cells and gut microbiota can provide new avenues for treating sepsis patients.
Poly-γ-glutamic acid/Alum adjuvanted pH1N1 vaccine-immunized aged mice exhibit a significant increase in vaccine efficacy with a decrease in age-associated CD8+ T cell proportion in splenocytes
Authors: Yang Jihyun , Kim Jaemoo , Kwak Chaewon , Poo Haryoung 
Published: May 2022

Abstract
Background
Highly contagious respiratory diseases caused by viral infections are a constantly emerging threat, particularly the elderly with the higher risk of developing serious complications. Vaccines are the best strategy for protection against influenza-related diseases. However, the elderly has lower vaccine efficacy than young population and the age-driven decline of the influenza vaccine efficacy remains unresolved.

Objectives
This study investigates the effect of an adjuvant, poly-γ-glutamic acid and alum (PGA/Alum) on vaccine efficacy in aged mice (18-months) and its mechanism is investigated using ovalbumin as a model antigen and a commercial pandemic H1N1 (pH1N1) flu vaccine. Antigen trafficking, dendritic cell (DC) activation, and the DC-mediated T cell activation were analyzed via in vivo imaging and flow cytometry. Antigen-specific humoral and cellular immune responses were evaluated in sera and splenocytes from the vaccinated mice. Also, we analyzed gene expression profiles of splenocytes from the vaccinated mice via single-cell transcriptome sequencing and evaluated the protective efficacy against pH1N1 virus challenge.

Results
Aged mice had lower antigen trafficking and DC activation than younger mice (6-weeks), which was ameliorated by PGA/Alum with increased antigen uptake and DC activation leading to improved antigen-specific IFN-γ+CD8+ T lymphocyte frequencies higher in the vaccinated aged mice, to a similar extent as PGA/Alum adjuvanted vaccine-immunized young mice. The results of single-cell transcriptome sequencing display that PGA/Alum also reduced the proportion of age-associated CD8+ T cell subsets and gene levels of inhibitory regulators in CD8+ T cells, which may play a role in the recovery of CD8+ T cell activation. Finally, PGA/Alum adjuvanted pH1N1 vaccine-immunized aged mice were completely protected (100% survival) compared to aged mice immunized with vaccine only (0% survival) after pH1N1 virus challenge, akin to the efficacy of the vaccinated young mice (100% survival).

Conclusions
PGA/Alum adjuvanted pH1N1 vaccine-immunized aged mice showed a significant increase in vaccine efficacy compared to aged mice administered with vaccine only. The enhanced vaccine efficacy by PGA/Alum is associated with significant increases of activation of DCs and effector CD8+ T cells and a decrease in age-associated CD8+ T cell proportion of splenocytes. Collectively, PGA/Alum adjuvanted flu vaccine may be a promising vaccine candidate for the elderly.
In vitro anti-influenza assessment of anionic compounds ascorbate, acetate and citrate
Authors: Shokouhi Targhi Hadiseh , Mehrbod Parvaneh , Fotouhi Fatemeh , Amininasab Mehriar 
Published: May 2022

Abstract
Background
Influenza A virus (IAV) infection remains a serious public health threat. Due to drug resistance and side effects of the conventional antiviral drugs, repurposing the available natural compounds with high tolerability and fewer side effects has attracted researchers’ attention. The aim of this study was to screen in vitro anti-influenza activity of three anionic compounds ascorbate, acetate, and citrate.

Methods
The non-cytotoxic concentration of the compounds was determined by MTT assay and examined for the activity against IAV in simultaneous, pre-, and post-penetration combination treatments over 1 h incubation on Madin-Darby Canine Kidney (MDCK) cell line. The virus titer and viral load were determined using hemagglutination assay (HA) and qPCR, respectively. Few pro-inflammatory and anti-inflammatory cytokines were evaluated at RNA and protein levels by qPCR and ELISA, respectively.

Results
The non-cytotoxic concentrations of the ascorbate (200 mg/ml), acetate and citrate (both 3 mg/ml) reduced the viral titer by 6.5, 4.5, and 1.5 logs in the simultaneous combination treatment. The M protein gene copy number decreased significantly in simultaneous treatment (P < 0.01). The expression of cytokines was also affected by the treatment of these compounds.

Conclusions
These anionic compounds could affect the influenza virus load, thereby reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines levels.
Robust network topologies for temperature-inducible bioswitches
Authors: Wu Di , Wang Hongli , Ouyang Qi 
Published: May 2022

Abstract
Background
Thermoinducible bioswitches are unique in that the all-or-none switch response is triggered by temperature, which is a global factor that impacts all biochemical reaction processes. To date, temperature-inducible bioswitches rely exclusively on special thermal sensing biomolecules of DNA, RNA, proteins and lipids whose conformations are critically temperature dependent.

Method
This paper extends the traditional thermal switch by utilizing purposely designed network topologies of biomolecular interactions to achieve the switching function. By assuming the general Arrhenius law for biochemical reactions, we explore the full space of all three-node genetic interaction networks to screen topologies capable of thermal bioswitches. Three target bioswitches, i.e., thermal-inducible Off–On, cold-inducible On–Off, and hybrid Off–On-Off double switches, are considered separately.

Conclusions
We identify the minimal and core network skeletons that are basic and essential for building robust high-performance bioswitches: three Off–On motifs, three On–Off motifs, and an incoherent feedforward motif for an Off–On-Off double switch. Functional topologies are implicitly preferential in choosing parameter values to achieve the target functions. The scenario of the topology-based bioswitch we propose here is an extension of molecule-based bioswitches and would be valuable in aiding the rational design and synthesis of efficient high-performance thermal bioswitches.
Circulating Th2 cell reduction and Th1/Th2 imbalance are correlated with primary Sjogren’s syndrome-associated interstitial lung disease
Authors: Shi Lei , Wang Jia , Guo Hong-Xia , Han Xiao-Lei , Tang Yu-Ping , Liu Guang-Ying 
Published: May 2022

Abstract
Objective
Primary Sjogren’s syndrome (pSS) is a heterogeneous chronic autoimmune disorder characterized by lymphocyte infiltration of the exocrine glands and the involvement and dysfunction of multiple organs and tissues. Interstitial lung disease (ILD) is the most common type of respiratory system damage. This study ascertained the factors related to ILD in patients with pSS (pSS-ILD), such as altered levels of circulating lymphocyte subtypes.

Methods
Eighty healthy controls and 142 patients diagnosed with pSS were included. The pSS patients were classified into groups with pSS-ILD or pSS without ILD (pSS-non-ILD). Baseline clinical and laboratory data were collected for all subjects, including the levels of lymphocytes measured by modified flow cytometry.

Results
The pSS-ILD patients were older, had higher ESSDAI scores, had higher positivity rates for anti-SSB and anti-Ro52 antibodies, and had more frequent symptoms of respiratory system involvement than pSS-non-ILD patients. pSS-ILD patients had the lowest Th2 cell counts among the three groups. Although the absolute numbers of Treg and NK cells were lower in pSS patients with and without ILD than in the healthy controls, there was no significant difference between the two pSS groups. The Th1/Th2 ratio was significantly higher in patients with ILD than in patients without ILD. Further analysis showed that older age (OR=1.084), lower Th2 count (OR=0.947), higher Th1/Th2 ratio (OR=1.021), and positivity for anti-SSB (OR=3.620) and anti-Ro52 (OR=5.184) antibodies were associated with the occurrence of ILD in patients with pSS.

Conclusion
Decreased circulating Th2 cells and an elevated Th1/Th2 ratio may be the immunological mechanism underlying the development of ILD in pSS patients.
DNA methylation and expression profiles of placenta and umbilical cord blood reveal the characteristics of gestational diabetes mellitus patients and offspring
Authors: Lu Sha , Wang Jiahao , Kakongoma Nisile , Hua Wen , Xu Jiahui , Wang Yunfei , He Shutao , Gu Hongcang , Shi Jiantao , Hu Wensheng 
Published: May 2022

Abstract
Background
Gestational diabetes mellitus (GDM) is a common pregnancy-specific disease and is growing at an alarming rate worldwide, which can negatively affect the health of pregnant women and fetuses. However, most studies are limited to one tissue, placenta or umbilical cord blood, usually with one omics assay. It is thus difficult to systematically reveal the molecular mechanism of GDM and the key influencing factors on pregnant women and offspring.

Results
We recruited a group of 21 pregnant women with GDM and 20 controls without GDM. For each pregnant woman, reduced representation bisulfite sequencing and RNA-seq were performed using the placenta and paired neonatal umbilical cord blood specimens. Differentially methylated regions (DMRs) and differentially expressed genes (DEGs) were identified with body mass index as a covariate. Through the comparison of GDM and control samples, 2779 and 141 DMRs, 1442 and 488 DEGs were identified from placenta and umbilical cord blood, respectively. Functional enrichment analysis showed that the placenta methylation and expression profiles of GDM women mirrored the molecular characteristics of “type II diabetes” and “insulin resistance.” Methylation-altered genes in umbilical cord blood were associated with pathways “type II diabetes” and “cholesterol metabolism.” Remarkably, both DMRs and DEGs illustrated significant overlaps among placenta and umbilical cord blood samples. The overlapping DMRs were associated with “cholesterol metabolism.” The top-ranking pathways enriched in the shared DEGs include “growth hormone synthesis, secretion and action” and “type II diabetes mellitus.”

Conclusions
Our research demonstrated the epigenetic and transcriptomic alternations of GDM women and offspring. Our findings emphasized the importance of epigenetic modifications in the communication between pregnant women with GDM and offspring, and provided a reference for the prevention, control, treatment, and intervention of perinatal deleterious events of GDM and neonatal complications.
Cross talk between acetylation and methylation regulators reveals histone modifier expression patterns posing prognostic and therapeutic implications on patients with colon cancer
Authors: Zhou Rui , Xie Fuli , Liu Kuncai , Zhou Xuee , Chen Xuemei , Chen Jinzhang , Xi Shaoyan , Huang Zhenhua , Rong Xiaoxiang 
Published: May 2022

Abstract
Background
Alterations in histone modifications have been reported to be related to tumorigenicity and tumor progression. However, whether histone modification can aid the classification of patients or influence clinical behavior in patients with colon cancer remains unclear. Therefore, this study aimed to evaluate histone modifier expression patterns using the unsupervised clustering of the transcriptomic expressions of 88 histone acetylation and methylation regulators.

Results
In this study, by consensus clustering analysis based on the transcriptome data of 88 histone modification regulators, we identified four distinct expression patterns of histone modifiers associated with different prognoses, intrinsic fluorouracil sensitivities, biological pathways, and tumor microenvironment characteristics among 1372 colon cancer samples. In these four clusters, the HMC4 cluster represented a stroma activation phenotype characterized by both the worst prognosis and lowest response rates to fluorouracil treatment. Then, we established a scoring scheme comprising 155 genes designated as “HM_score” by using the Boruta algorithm to distinguish colon cancer patients within the HMC4 cluster. Patients with a high HM_score were considered to have high stromal pathway activation, high stromal fraction, and an unfavorable prognosis. Further analyses indicated that a high HM_score also correlated with reduced therapeutic benefits from fluorouracil chemotherapy. Moreover, through CRISPR library screening, ZEB2 was found to be a critical driver gene that mediates fluorouracil resistance, which is associated with histone modifier expression patterns.

Conclusions
This study highlights that characterizing histone modifier expression patterns may help better understand the epigenetic mechanisms underlying tumor heterogeneity in patients with colon cancer and provide more personalized therapeutic strategies.
Genome-wide promoter methylation profiling in a cellular model of melanoma progression reveals markers of malignancy and metastasis that predict melanoma survival
Authors: Rius Flávia E. , Papaiz Debora D. , Azevedo Hatylas F. Z. , Ayub Ana Luísa P. , Pessoa Diogo O. , Oliveira Tiago F. , Loureiro Ana Paula M. , Andrade Fernando , Fujita André , Reis Eduardo M. , Mason Christopher E. , Jasiulionis Miriam G. 
Published: May 2022

AbstractThe epigenetic changes associated with melanoma progression to advanced and metastatic stages are still poorly understood. To shed light on the CpG methylation dynamics during melanoma development, we analyzed the methylome profiles of a four-stage cell line model of melanoma progression: non-tumorigenic melanocytes (melan-a), premalignant melanocytes (4C), non-metastatic melanoma cells (4C11−), and metastatic melanoma cells (4C11+). We identified 540 hypo- and 37 hypermethylated gene promoters that together characterized a malignancy signature, and 646 hypo- and 520 hypermethylated promoters that distinguished a metastasis signature. Differentially methylated genes from these signatures were correlated with overall survival using TCGA-SKCM methylation data. Moreover, multivariate Cox analyses with LASSO regularization identified panels of 33 and 31 CpGs, respectively, from the malignancy and metastasis signatures that predicted poor survival. We found a concordant relationship between DNA methylation and transcriptional levels for genes from the malignancy (Pyroxd2 and Ptgfrn) and metastasis (Arnt2, Igfbp4 and Ptprf) signatures, which were both also correlated with melanoma prognosis. Altogether, this study reveals novel CpGs methylation markers associated with malignancy and metastasis that collectively could improve the survival prediction of melanoma patients.
Plasma neuregulin 1 as a synaptic biomarker in Alzheimer’s disease: a discovery cohort study
Authors: Vrillon Agathe , Mouton-Liger François , Martinet Matthieu , Cognat Emmanuel , Hourregue Claire , Dumurgier Julien , Bouaziz-Amar Elodie , Brinkmalm Ann , Blennow Kaj , Zetterberg Henrik , Hugon Jacques , Paquet Claire 
Published: May 2022

AbstractBackgroundSynaptic dysfunction is an early core feature of Alzheimer’s disease (AD), closely associated with cognitive symptoms. Neuregulin 1 (NRG1) is a growth and differentiation factor with a key role in the development and maintenance of synaptic transmission. Previous reports have shown that changes in cerebrospinal fluid (CSF) NRG1 concentration are associated with cognitive status and biomarker evidence of AD pathology. Plasma biomarkers reflecting synaptic impairment would be of great clinical interest.ObjectiveTo measure plasma NRG1 concentration in AD patients in comparison with other neurodegenerative disorders and neurological controls (NC) and to study its association with cerebrospinal fluid (CSF) core AD and synaptic biomarkers.MethodsThis retrospective study enrolled 127 participants including patients with AD at mild cognitive impairment stage (AD-MCI,n= 27) and at dementia stage (n= 35), non-AD dementia (n= 26, Aβ-negative), non-AD MCI (n= 19), and neurological controls (n=20). Plasma and CSF NRG1, as well as CSF core AD biomarkers (Aβ 42/Aβ 40 ratio, phospho-tau, and total tau), were measured using ELISA. CSF synaptic markers were measured using ELISA for GAP-43 and neurogranin and through immunoprecipitation mass spectrometry for SNAP-25.ResultsPlasma NRG1 concentration was higher in AD-MCI and AD dementia patients compared with neurological controls (respectivelyP =0.005 andP< 0.001). Plasma NRG1 differentiated AD MCI patients from neurological controls with an area under the curve of 88.3%, and AD dementia patients from NC with an area under the curve of 87.3%. Plasma NRG1 correlated with CSF NRG1 (β= 0.372,P= 0.0056, adjusted on age and sex). Plasma NRG1 was associated with AD CSF core biomarkers in the whole cohort and in Aβ-positive patients (β= −0.197–0.423). Plasma NRG1 correlated with CSF GAP-43, neurogranin, and SNAP-25 (β= 0.278–0.355). Plasma NRG1 concentration correlated inversely with MMSE in the whole cohort and in Aβ-positive patients (all,β= −0.188,P= 0.038; Aβ+:β= −0.255,P= 0.038).ConclusionPlasma NRG1 concentration is increased in AD patients and correlates with CSF core AD and synaptic biomarkers and cognitive status. Thus, plasma NRG1 is a promising non-invasive biomarker to monitor synaptic impairment in AD.