bluuebunny/crossref_metadata_2025_split huggingface dataset:
Letrozole protects against cadmium-induced inhibition of spermatogenesis via LHCGR and Hsd3b6 to activate testosterone synthesis in mice
Authors: Yao Yao , Wan Yangyang , Shi Xiaoyun , Guo Lan , Jiang Hui , Zhang Xiansheng , Xu Bo , Hua Juan 
Published: March 2022

AbstractThe heavy metal cadmium is proposed to be one of the environmental endocrine disruptors of spermatogenesis. Cadmium-induced inhibition of spermatogenesis is associated with a hormone secretion disorder. Letrozole is an aromatase inhibitor that increases peripheral androgen levels and stimulates spermatogenesis. However, the potential protective effects of letrozole on cadmium-induced reproductive toxicity remain to be elucidated. In this study, male mice were administered CdCl2 (4 mg/kg BW) orally by gavage alone or in combination with letrozole (0.25 mg/kg BW) for 30 days. Cd exposure caused a significant decreases in body weight, sperm count, motility, vitality, and plasma testosterone levels. Histopathological changes revealed extensive vacuolization and decreased spermatozoa in the lumen. However, in the Cd + letrozole group, letrozole treatment compensated for deficits in sperm parameters (count, motility, and vitality) induced by Cd. Letrozole treatment significantly increased serum testosterone levels, which were reduced by Cd. Histopathological studies revealed a systematic array of all germ cells, a preserved basement membrane and relatively less vacuolization. For a mechanistic examination, RNA-seq was used to profile alterations in gene expression in response to letrozole. Compared with that in the Cd-treated group, RNA-Seq analysis showed that 214 genes were differentially expressed in the presence of letrozole. Gene ontology (GO) enrichment analysis and KEGG signaling pathway analysis showed that steroid biosynthetic processes were the processes most affected by letrozole treatment. Furthermore, we found that the expression of the testosterone synthesis-related genes LHCGR (luteinizing hormone/choriogonadotropin receptor) and Hsd3b6 (3 beta- and steroid delta-isomerase 6) was significantly downregulated in Cd‐treated testes, but these genes maintained similar expression levels in letrozole-treated testes as those in the control group. However, the transcription levels of inflammatory cytokines, such as IL-1β and IL-6, and oxidative stress-related genes (Nrf2, Nqo1, and Ho-1) showed no changes. The present study suggests that the potential protective effect of letrozole on Cd-induced reproductive toxicity might be mediated by the upregulation of LHCGR and Hsd3b6, which would beneficially increase testosterone synthesis to achieve optimum protection of sperm quality and spermatogenesis.
Knowledge gaps and national research priorities for COVID-19 in Iran
Authors: Yazdizadeh Bahareh , Ehsani-Chimeh Elham , Zendehdel Kazem , Mobinizadeh Mohammadreza , Mesgarpour Bita , Fakoorfard Zeinab 
Published: March 2022

Abstract
Background
In the present COVID-19 crisis, one of the greatest challenges for research funding at both the international and national level is selecting the best research topic to achieve efficiency and equity in health research and to address the knowledge gap urgently raised due to the event. Despite international recommendations, countries should consider their context-specific situation and define local research priorities. We aimed to exercise a priority-setting activity to identify the knowledge gaps and suggest research priorities in response to the COVID-19 epidemic in Iran.

Methods
First, we tried to identify the contextual knowledge gaps based on an online survey, performing key informant interviews (i.e. health professionals, policy-makers and managers) and media analysis. We also performed a literature review and considered international research priorities for COVID-19. Subsequently, we prepared a list of research questions and challenges to respond to the COVID-19 crisis in Iran using a systems approach. Then we mapped approved COVID-19 research projects in the country to research questions. Finally, we compared the identified research questions (not challenges) with the prioritized research from international organizations and then prioritized them for Iran.

Results
We found risk factors and epidemiological dissemination patterns of the virus and its consequences in an epidemiology domain, implementation of clinical and hygiene in a clinical management domain, genetic studies for targeting prevention and treatment in a candidate treatment and vaccine research and development (R&D) knowledge domain, examination of the manifestations of ethics in society instead of ethics in research in an ethics domain, “care, access and health system” and “public health and participation in response to public health and clinical research” as two sub-domains of a social sciences domain, and finally, no new questions in either the virology, transmission, diagnosis or animal and environmental domain.

Conclusions
In the event of global health crises like COVID-19, prioritization of research questions can be done globally, but some of the research priorities are context-specific and may vary by regional needs. To better manage research resources, researchers must respond to the challenges faced in each country based on its political, economic, social and cultural characteristics, and to make evidence-informed decisions, global knowledge gaps must be customized in each country.
The mechanisms of mutual relationship between malignant hematologic cells and mesenchymal stem cells: Does it contradict the nursing role of mesenchymal stem cells?
Authors: Goodarzi Alireza , Valikhani Mohsen , Amiri Fatemeh , Safari Armita 
Published: March 2022

AbstractMesenchymal stem/stromal cells (MSCs) are known as the issue in biology because of some unpredictable characteristics in the different microenvironments especially in their bone marrow niche. MSCs are used in the regenerative medicine because of their unique potentials for trans-differentiation, immunomodulation, and paracrine capacity. But, their pathogenic and pro-survival effects in tumors/cancers including hematologic malignancies are indisputable. MSCs and/or their derivatives might be involved in tumor growth, metastasis and drug resistance in the leukemias. One of important relationship is MSCs and hematologic malignancy-derived cells which affects markedly the outcome of disease. The communication between these two cells may be contact-dependent and/or contact-independent. In this review, we studied the crosstalk between MSCs and malignant hematologic cells which results the final feedback either the progression or suppression of blood cell malignancy.
Graphical abstract
Perceptions of physical activity and sedentary behaviour guidelines among end-users and stakeholders: a systematic review
Authors: Hollman Heather , Updegraff John A. , Lipkus Isaac M. , Rhodes Ryan E. 
Published: March 2022

Abstract
Background
Many of the world’s population, across all age groups and abilities, are not meeting or even aware of internationally recommended physical activity (PA) and sedentary behaviour (SB) guidelines. In order to enhance awareness and uptake, guidelines should be perceived positively by targeted users. The purpose of this study was to review the literature on end-user and stakeholder perceptions of PA and SB guidelines.

Methods
The electronic databases APA PsycInfo, CINAHL, MEDLINE, and SPORTDiscus, using EBSCOhost Research Platform, and Web of Science were searched from inception to June, 2021 with keyword synonyms for “perceptions”, “PA guidelines”, and “SB guidelines”. Studies of any design that collected stakeholder and/or end-user responses to a PA and/or SB guideline were included and assessed for risk of bias. The PA and/or SB guideline could be any type of official form (e.g., national documents, organizational guidelines, expert consensus statements, etc.) from any country, that targets individuals at the regional, provincial/statewide, national, or international level, and includes all types of guidelines (e.g., strength, aerobic, clinical, nonclinical, screen-time, sitting, etc.). Data were extracted and analyzed using thematic synthesis.

Results
After screening 1399 abstracts and applying citation screening, 304 full-texts were retrieved. A total of 31 articles met the inclusion criteria. End-users and stakeholders for PA guidelines across all age groups expressed the need for simplified language with more definitions, relatable examples and imagery, and quantification of PA behaviours. There was concern for the early years and child PA guidelines leading to guilt amongst parents and the SB guidelines, particularly the recommendations to limit screen-time, being unrealistic. General age group PA guidelines were not perceived as usable to populations with differing abilities, clinical conditions, and socioeconomic status. Guidelines that targeted clinical populations, such as persons with multiple sclerosis and persons with spinal cord injury, were well received.

Conclusions
There is a clear need to balance the evidence base with the pragmatic needs of translation and uptake so that the guidelines are not ignored or act as a barrier to actual engagement.
Evaluation of neuroprotective and immunomodulatory properties of mesenchymal stem cells in an ex vivo retinal explant model
Authors: Reboussin Élodie , Buffault Juliette , Brignole-Baudouin Françoise , Réaux-Le Goazigo Annabelle , Riancho Luisa , Olmiere Céline , Sahel José-Alain , Mélik Parsadaniantz Stéphane , Baudouin Christophe 
Published: March 2022

Abstract
Background
Glaucoma is a blinding degenerative neuropathy in which the death of retinal ganglion cells (RGCs) causes progressive loss of visual field and eventually vision. Neuroinflammation appears to be a key event in the progression and spread of this disease. Thus, microglial immunomodulation represents a promising therapeutic approach in which mesenchymal stem cells (MSCs) might play a crucial role. Their neuroprotective and regenerative potentials have already raised hope in animal models. Yet no definitive treatment has been developed, and some safety concerns have been reported in human trials. In the present study, we investigated the neuroprotective and immunomodulatory properties as well as the safety of MSCs in an ex vivo neuroretina explant model.

Methods
Labeled rat bone marrow MSCs were placed in coculture with rat retinal explants after optic nerve axotomy. We analyzed the neuroprotective effect of MSCs on RGC survival by immunofluorescence using RBPMS, Brn3a, and NeuN markers. Gliosis and retinal microglial activation were measured by using GFAP, CD68, and ITGAM mRNA quantification and GFAP, CD68, and Iba1 immunofluorescence stainings. We also analyzed the mRNA expression of both ‘M1’ or classically activated state inflammatory cytokines (TNFα, IL1β, and IL6), and ‘M2’ or alternatively activated state microglial markers (Arginase 1, IL10, CD163, and TNFAIP6).

Results
The number of RGCs was significantly higher in retinal explants cultured with MSCs compared to the control group at Day 7 following the optic nerve axotomy. Retinal explants cultured with MSCs showed a decrease in mRNA markers of gliosis and microglial activations, and immunostainings revealed that GFAP, Iba1, and CD68 were limited to the inner layers of the retina compared to controls in which microglial activation was observed throughout the retina. In addition, MSCs inhibited the M1 phenotype of the microglia. However, edema of the explants was observed in presence of MSCs, with an increase in fibronectin labeling at the surface of the explant corresponding to an epiretinal membrane-like phenotype.

Conclusion
Using an ex vivo neuroretina model, we demonstrated a neuroprotective and immunomodulatory effect of MSCs on RGCs. Unfortunately, the presence of MSCs also led to explant edema and epiretinal membrane formation, as described in human trials. Using the MSC secretome might offer the beneficial effects of MSCs without their potential adverse effects, through paracrine signaling.
Microglial VPS35 deficiency impairs Aβ phagocytosis and Aβ-induced disease-associated microglia, and enhances Aβ associated pathology
Authors: Ren Xiao , Yao Lingling , Wang YongGang , Mei Lin , Xiong Wen-Cheng 
Published: March 2022

Abstract
Background
Vacuolar sorting protein 35 (VPS35), a key component of the retromer, plays an essential role in selectively retrieval of transmembrane proteins from endosomes to trans-Golgi networks. Dysfunctional retromer is a risk factor for neurodegenerative disorders, including Alzheimer’s disease (AD). Microglial VPS35 deficiency is found in AD patients’ brain; however, it remains unclear if and how microglial VPS35-loss contributes to AD development.

Methods
We used mice with VPS35 cKO (conditional knockout) in microglial cells in 5XFAD, an AD mouse model. The AD related brain pathology (Aβ and glial activation), behavior, and phagocytosis of Aβ were accessed by a combination of immunofluorescence staining analyses and neurological behavior tests.

Results
A decrease in learning and memory function, but increases in insoluble, fibrillar, and plaques of β-amyloids (Aβ), dystrophic neurites, and reactive astrocytes are observed in microglial VPS35 deficient 5XFAD mice. Further examining microglial phenotype demonstrates necessity of microglial VPS35 in disease-associated microglia (DAM) development and microglial uptake of Aβ, revealing a tight association of microglial Aβ uptake with DAM development.

Conclusions
Together, these results uncovered a mechanism by which microglial VPS35-deficiency precipitates AD pathology in 5XFAD mice likely by impairing DAM development and DAM mediated Aβ uptake and clearance, and thus accelerating the cognition decline.
Psychometric study of the SF-36v2 in hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE)
Authors: Palao-Ocharan Paola , Prior Nieves , Pérez-Fernández Elia , Caminoa Magdalena ,   DV-HAE-QoL Study Group, Aberer W. , Betschel S. , Bygum A. , Campos R. A. , Csuka D. , Farkas H. , Gómez-Traseira C. , Grumach A. S. , Leibovich I. , Malbran A. , Moldovan D. , Mihaly E. , Obtulowicz K. , Porebski G. , Reshef A. , Staubach P. , Caballero Teresa 
Published: March 2022

Abstract
Background
The generic 36-item Short-Form Health Survey (SF-36v2) has been used to assess health related quality of life in adult patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) even though it has not yet been validated for use in this specific disease.

Objective
This study aims to validate the SF-36v2 for use in adult patients with C1-INH-HAE.

Results
There was a very low item non-response rate (1–3.4%), with a high ceiling effect in 25/35 items and a low floor effect in 3/35 items. A moderate ceiling effect was observed in 5/8 dimensions of the SF-36v2, whereas no floor effect was noticed in any of the dimensions. Internal consistency was good to excellent with Cronbach's alpha coefficient ranging between 0.82 and 0.93 for the different dimensions. Construct validity was good: seven out of the 8 hypotheses defined on clinical criteria were confirmed, discriminant validity assessment showed significant differences among patients with different C1-INH-HAE severity, convergent validity showed a good correlation among the physical and mental component summaries of the SF-36v2 and the HAE-QoL total score (0.45 and 0.64 respectively, P < 0.001). Test–retest reliability was high with intraclass correlation coefficient varying from 0.758 to 0.962. The minimal clinically important difference was calculated by distribution methods and small differences in the domain scores and in the component summaries scores were shown to be meaningful.

Conclusions
The psychometric properties of the SF-36v2 show it can be a useful tool to assess HRQoL in adult patients with C1-INH-HAE, although with some content validity limitation.

Methods
The psychometric properties of the SF-36v2 were evaluated in an international setting based on responses from 290 adult C1-INH-HAE patients in 11 countries.
Establishing and boosting communication in the European Reference Network for Rare Neurological Diseases (ERN-RND): the impact of offering free educational webinars
Authors: Brunelle Praschberger Alicia , Post Annemarie E. M. , Hermanns Sanja , Graessner Holm 
Published: March 2022

Abstract
Background
Since it first started operating in 2017, the European Reference Network for Rare Neurological Diseases (ERN-RND) implemented a multi-channel communication strategy to effectively reach its target audience: healthcare professionals, patients, researchers, industry representatives and the general public. We first created a website containing useful and up to date information, followed by social media accounts. Here, the analytical data collected about the ERN-RND website and social media channels was compared (Twitter, Facebook, YouTube) during two periods: October 2018 to September 2019, and the year after the ERN-RND free educational webinars were launched: from October 2019 to September 2020. This allowed us to quantify the impact of offering a tangible product (webinars) on the communication strategy.

Results
The analytical data obtained from October 2018 to September 2019 and from October 2019 to September 2020 clearly shows a significant increase in traffic and followers since the launch of the ERN-RND webinars in November 2019. We also created a communication survey which was disseminated between February and June 2021. We collected responses from 61 people: 38 healthcare professionals, 11 scientists, 10 patients (advocates), 2 industry representatives, 1 patient association, 1 charity representative, 1 resident and 1 master student. Most respondents answered “webinars” as the number one reason when asked about which content they look for on the ERN-RND website.

Conclusions
Offering a tangible product—such as the webinars presented in this report—to a specific target group (healthcare professionals) supported our communication strategy by driving traffic to ERN-RND communication channels. It has also successfully tackled ERN-RND’s general aim: by enabling the flow of knowledge on rare neurological and movement disorders to the medical community in hospitals treating patients with these rare and complex conditions, patients ultimately benefit from improved and faster diagnosis, care, and treatment. We aim to set up similar strategies to effectively reach other or the same target groups. For healthcare professionals, organising eConsultations via the Clinical Patient Management System or disseminating standards of care such as diagnostic and therapeutic algorithms as well as clinical practice guidelines might offer potential. For the patient community, organising customised and multilingual webinars could also work.
In-depth biological analysis of alteration in Plasmodium knowlesi-infected red blood cells using a noninvasive optical imaging technique
Authors: Firdaus Moh Egy Rahman , Muh Fauzi , Park Ji-Hoon , Lee Seong-Kyun , Na Sung-Hun , Park Won-Sun , Ha Kwon-Soo , Han Jin-Hee , Han Eun-Taek 
Published: March 2022

Abstract
Background
Imaging techniques are commonly used to understand disease mechanisms and their biological features in the microenvironment of the cell. Many studies have added to our understanding of the biology of the malaria parasite Plasmodium knowlesi from functional in vitro and imaging analysis using serial block-face scanning electron microscopy (SEM). However, sample fixation and metal coating during SEM analysis can alter the parasite membrane.

Methods
In this study, we used noninvasive diffraction optical tomography (DOT), also known as holotomography, to explore the morphological, biochemical, and mechanical alterations of each stage of P. knowlesi-infected red blood cells (RBCs). Each stage of the parasite was synchronized using Nycodenz and magnetic-activated cell sorting (MACS) for P. knowlesi and P. falciparum, respectively. Holotomography was applied to measure individual three-dimensional refractive index tomograms without metal coating, fixation, or additional dye agent.

Results
Distinct profiles were found on the surface area and hemoglobin content of the two parasites. The surface area of P. knowlesi-infected RBCs showed significant expansion, while P. falciparum-infected RBCs did not show any changes compared to uninfected RBCs. In terms of hemoglobin consumption, P. falciparum tended to consume hemoglobin more than P. knowlesi. The observed profile of P. knowlesi-infected RBCs generally showed similar results to other studies, proving that this technique is unbiased.

Conclusions
The observed profile of the surface area and hemoglobin content of malaria infected-RBCs can potentially be used as a diagnostic parameter to distinguish P. knowlesi and P. falciparum infection. In addition, we showed that holotomography could be used to study each Plasmodium species in greater depth, supporting strategies for the development of diagnostic and treatment strategies for malaria.

Graphical Abstract
Development of microsatellite markers for population genetics of biting midges and a potential tool for species identification of Culicoides sonorensis Wirth & Jones
Authors: Shults Phillip , Moran Megan , Blumenfeld Alexander J. , Vargo Edward L. , Cohnstaedt Lee W. , Eyer Pierre-Andre 
Published: March 2022

Abstract
Background
Proper vector surveillance relies on the ability to identify species of interest accurately and efficiently, though this can be difficult in groups containing cryptic species. Culicoides Latreille is a genus of small biting flies responsible for the transmission of numerous pathogens to a multitude of vertebrates. Regarding pathogen transmission, the C. variipennis species complex is of particular interest in North America. Of the six species within this group, only C. sonorensis Wirth & Jones is a proven vector of bluetongue virus and epizootic hemorrhagic disease virus. Unfortunately, subtle morphological differences, cryptic species, and mitonuclear discordance make species identification in the C. variipennis complex challenging. Recently, single-nucleotide polymorphism (SNP) analysis enabled discrimination between the species of this group; however, this demanding approach is not practical for vector surveillance.

Methods
The aim of the current study was to develop a reliable and affordable way of distinguishing between the species within the C. variipennis complex, especially C. sonorensis. Twenty-five putative microsatellite markers were identified using the C. sonorensis genome and tested for amplification within five species of the C. variipennis complex. Machine learning was then used to determine which markers best explain the genetic differentiation between species. This led to the development of a subset of four and seven markers, which were also tested for species differentiation.

Results
A total of 21 microsatellite markers were successfully amplified in the species tested. Clustering analyses of all of these markers recovered the same species-level identification as the previous SNP data. Additionally, the subset of seven markers was equally capable of accurately distinguishing between the members of the C. variipennis complex as the 21 microsatellite markers. Finally, one microsatellite marker (C508) was found to be species-specific, only amplifying in the vector species C. sonorensis among the samples tested.

Conclusions
These microsatellites provide an affordable way to distinguish between the sibling species of the C. variipennis complex and could lead to a better understanding of the species dynamics within this group. Additionally, after further testing, marker C508 may allow for the identification of C. sonorensis with a single-tube assay, potentially providing a powerful new tool for vector surveillance in North America.

Graphical Abstract