bluuebunny/crossref_metadata_2025_split huggingface dataset:
Smek1 deficiency exacerbates experimental autoimmune encephalomyelitis by activating proinflammatory microglia and suppressing the IDO1-AhR pathway
Authors: Duan Ruo-Nan , Yang Chun-Lin , Du Tong , Liu Ai , Wang An-Ran , Sun Wen-Jie , Li Xi , Li Jiang-Xia , Yan Chuan-Zhu , Liu Qi-Ji 
Published: June 2021

Abstract
Background
Experimental autoimmune encephalomyelitis (EAE) is an animal disease model of multiple sclerosis (MS) that involves the immune system and central nervous system (CNS). However, it is unclear how genetic predispositions promote neuroinflammation in MS and EAE. Here, we investigated how partial loss-of-function of suppressor of MEK1 (SMEK1), a regulatory subunit of protein phosphatase 4, facilitates the onset of MS and EAE.

Methods
C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) to establish the EAE model. Clinical signs were recorded and pathogenesis was investigated after immunization. CNS tissues were analyzed by immunostaining, quantitative polymerase chain reaction (qPCR), western blot analysis, and enzyme-linked immunosorbent assay (ELISA). Single-cell analysis was carried out in the cortices and hippocampus. Splenic and lymph node cells were evaluated with flow cytometry, qPCR, and western blot analysis.

Results
Here, we showed that partial Smek1 deficiency caused more severe symptoms in the EAE model than in controls by activating myeloid cells and that Smek1 was required for maintaining immunosuppressive function by modulating the indoleamine 2,3-dioxygenase (IDO1)-aryl hydrocarbon receptor (AhR) pathway. Single-cell sequencing and an in vitro study showed that Smek1-deficient microglia and macrophages were preactivated at steady state. After MOG35-55 immunization, microglia and macrophages underwent hyperactivation and produced increased IL-1β in Smek1-/+ mice at the peak stage. Moreover, dysfunction of the IDO1-AhR pathway resulted from the reduction of interferon γ (IFN-γ), enhanced antigen presentation ability, and inhibition of anti-inflammatory processes in Smek1-/+ EAE mice.

Conclusions
The present study suggests a protective role of Smek1 in autoimmune demyelination pathogenesis via immune suppression and inflammation regulation in both the immune system and the central nervous system. Our findings provide an instructive basis for the roles of Smek1 in EAE and broaden the understanding of the genetic factors involved in the pathogenesis of autoimmune demyelination.
Characterisation of a highly potent and near pan-neutralising anti-HIV monoclonal antibody expressed in tobacco plants
Authors: Moore Catherine M. , Grandits Melanie , Grünwald-Gruber Clemens , Altmann Friedrich , Kotouckova Maria , Teh Audrey Y.-H. , Ma Julian K.-C. 
Published: June 2021

Abstract
Background
HIV remains one of the most important health issues worldwide, with almost 40 million people living with HIV. Although patients develop antibodies against the virus, its high mutation rate allows evasion of immune responses. Some patients, however, produce antibodies that are able to bind to, and neutralise different strains of HIV. One such ‘broadly neutralising’ antibody is ‘N6’. Identified in 2016, N6 can neutralise 98% of HIV-1 isolates with a median IC50 of 0.066 µg/mL. This neutralisation breadth makes N6 a very promising therapeutic candidate.

Results
N6 was expressed in a glycoengineered line of N. benthamiana plants (pN6) and compared to the mammalian cell-expressed equivalent (mN6). Expression at 49 mg/kg (fresh leaf tissue) was achieved in plants, although extraction and purification are more challenging than for most plant-expressed antibodies. N-glycoanalysis demonstrated the absence of xylosylation and a reduction in α(1,3)-fucosylation that are typically found in plant glycoproteins. The N6 light chain contains a potential N-glycosylation site, which was modified and displayed more α(1,3)-fucose than the heavy chain. The binding kinetics of pN6 and mN6, measured by surface plasmon resonance, were similar for HIV gp120. pN6 had a tenfold higher affinity for FcγRIIIa, which was reflected in an antibody-dependent cellular cytotoxicity assay, where pN6 induced a more potent response from effector cells than that of mN6. pN6 demonstrated the same potency and breadth of neutralisation as mN6, against a panel of HIV strains.

Conclusions
The successful expression of N6 in tobacco supports the prospect of developing a low-cost, low-tech production platform for a monoclonal antibody cocktail to control HIV in low-to middle income countries.

Graphic abstract
Impact of joint management of a COVID-19 mother and her newborn on the virus transmission: a case report
Authors: De Nardo Maria Chiara , Bellomo Anna Rita , Perfetti Francesca , Battaglia Francesco Antonino , Lichtner Miriam , Lubrano Riccardo 
Published: June 2021

Abstract
Background
Since last year, COVID-19, the disease caused by the novel Sars-Cov-2 virus, has been globally spread to all the world. COVID-19 infection among pregnant women has been described. However, transplacental transmission of Sars-Cov-2 virus from infected mother to the newborn is not yet established. The appropriate management of infants born to mothers with confirmed or suspected COVID-19 and the start of early breastfeeding are being debated.

Case presentation
We report a case of the joint management of a healthy neonate with his mother tested positive for Covid-19 before the delivery and throughout neonatal follow-up. The infection transmission from the mother to her baby is not described, even after a long period of contact between them and breastfeeding.

Conclusion
It may consider an appropriate practice to keep mother and her newborn infant together in order to facilitate their contact and to encourage breastfeeding, although integration with infection prevention measures is needed.
Expression of miR-195 and its target gene Bcl-2 in human intervertebral disc degeneration and their effects on nucleus pulposus cell apoptosis
Authors: Lin Xue-Lin , Zheng Zhao-Yun , Zhang Qing-Shan , Zhang Zhen , An You-Zhi 
Published: June 2021

Abstract
Objective
To investigate the expression of miR-195 and its target gene Bcl-2 in intervertebral disc degeneration (IVDD) and its effect on nucleus pulposus (NP) cell apoptosis.

Methods
The expressions of miR-195 and Bcl-2 in NP tissues of IVDD patients were quantified by qRT-PCR and western blotting, respectively. NP cells were divided into blank group, TNF-α group, TNF-α + miR-NC group, TNF-α + siBcl-2 group, and TNF-α + miR-195 inhibitors + siBcl-2 group. Cell proliferation was detected by MTT assay, cell apoptosis evaluated by flow cytometry, and mitochondrial membrane potential (MMP) tested by JC-1 staining. Moreover, the function of miR-195 on IVDD in vivo was investigated using a puncture-induced IVDD rat model.

Results
IVDD patients had significantly increased miR-195 expression and decreased Bcl-2 protein expression in NP tissues. The expression of miR-195 was negatively correlated with the expression of Bcl-2 in IVDD patients. Dual-luciferase reporter gene assay indicated that Bcl-2 was a target gene of miR-195. In comparison with blank group, TNF-α group showed decreased cell proliferation and MMP, increased cell apoptosis, upregulated expression of miR-195, Bax, and cleaved caspase 3, and downregulated Bcl-2 protein, while these changes were attenuated by miR-195 inhibitors. Additionally, siBcl-2 can reverse the protective effect of miR-195 inhibitors on TNF-α-induced NP cells. Besides, inhibition of miR-195 alleviated IVDD degeneration and NP cell apoptosis in the rat model.

Conclusion
MiR-195 was significantly upregulated in NP tissues of IVDD patients, and inhibition of miR-195 could protect human NP cells from TNF-α-induced apoptosis via upregulation of Bcl-2.
Knockdown of long noncoding RNA HOTAIR inhibits osteoarthritis chondrocyte injury by miR-107/CXCL12 axis
Authors: Lu Jipeng , Wu Zhongxiong , Xiong Ying 
Published: June 2021

Abstract
Background
Osteoarthritis (OA) is a joint disease characterized via destruction of cartilage. Chondrocyte damage is associated with cartilage destruction during OA. Long noncoding RNAs (lncRNAs) are implicated in the regulation of chondrocyte damage in OA progression. This study aims to investigate the role and underlying mechanism of lncRNA homeobox antisense intergenic RNA (HOTAIR) in OA chondrocyte injury.

Methods
Twenty-three OA patients and healthy controls without OA were recruited. Chondrocytes were isolated from OA cartilage tissues. HOTAIR, microRNA-107 (miR-107) and C-X-C motif chemokine ligand 12 (CXCL12) levels were measured by quantitative real-time polymerase chain reaction and western blot. Cell proliferation, apoptosis and extracellular matrix (ECM) degradation were measured using cell counting kit-8, flow cytometry and western blot. The target interaction was explored by bioinformatics, luciferase reporter and RNA immunoprecipitation assays.

Results
HOTAIR expression was enhanced, and miR-107 level was reduced in OA cartilage samples. HOTAIR overexpression inhibited cell proliferation, but induced cell apoptosis and ECM degradation in chondrocytes. HOTAIR knockdown caused an opposite effect. MiR-107 was sponged and inhibited via HOTAIR, and knockdown of miR-107 mitigated the effect of HOTAIR silence on chondrocyte injury. CXCL12 was targeted by miR-107. CXCL12 overexpression attenuated the roles of miR-107 overexpression or HOTAIR knockdown in the proliferation, apoptosis and ECM degradation. CXCL12 expression was decreased by HOTAIR silence, and restored by knockdown of miR-107.

Conclusion
HOTAIR knockdown promoted chondrocyte proliferation, but inhibited cell apoptosis and ECM degradation in OA chondrocytes by regulating the miR-107/CXCL12 axis.
RETRACTED ARTICLE: Tree species diversity predicts aboveground carbon storage through functional diversity and functional dominance in the dry evergreen Afromontane forest of Hararghe highland, Southeast Ethiopia
Authors: Wondimu Mengistu Teshome , Nigussie Zebene Asfaw , Yusuf Muktar Mohammed 
Published: June 2021

AbstractBackgroundRegarding the most important ecological challenges, scientists are increasingly debating the relationship between biodiversity and ecosystem function. Despite this, several experimental and theoretical researches have shown inconsistencies in biodiversity and ecosystem function relationships, supporting either the niche complementarity or selection effect hypothesis. The relationship between species diversity, functional diversity, and aboveground biomass carbon was investigated in this study employing standing aboveground carbon (AGC) stock as a proxy measure for ecosystem function. We hypothesized that (i) effects of diversity on AGC can be transmitted through functional diversity and functional dominance; (ii) effects of diversity on AGC would be greater for functional dominance than functional diversity; and (iii) effects of functional diversity and functional dominance on carbon stock varied with metrics and functional traits. Community-weighted means (CWM) of functional traits (wood density, specific leaf area, and maximum plant height) were calculated to assess functional dominance (selection effects). As for functional diversity (complementarity effects), multi-trait functional diversity (selection effects) indices were computed. We tested the first hypothesis using structural equation modeling. For the second hypothesis, the effects of environmental variables such as slope, aspect, and elevation were tested first, and separate linear mixed-effects models were fitted afterward for functional diversity, functional dominance, and the two together.ResultsResults revealed that slope had a significant effect on aboveground carbon storage. Functional diversity and functional dominance were significant predictors of the aboveground carbon storage (22.4%) in the dry evergreen Afromontane forest. The effects of species richness on aboveground carbon storage were mediated by functional diversity and functional dominance of species. This shows that both the selection effects and the niche complementarity are important for aboveground carbon storage prediction. However, the functional diversity effects (niche complementarity) were greater than functional dominance effects (selection effects).ConclusionsLinking diversity and biodiversity components to aboveground carbon provides better insights into the mechanisms that explain variation in aboveground carbon storage in natural forests, which may help improve the prediction of ecosystem functions.
Masticatory performances and maximum occlusal forces of immediate and conventional loaded two-implant supported overdentures retained by magnetic attachments: preliminary study of randomized controlled clinical trial
Authors: Katheng Awutsadaporn , Kanazawa Manabu , Komagamine Yuriko , Miyayasu Anna , Uehara Yoko , Sato Daisuke , Minakuchi Shunsuke 
Published: June 2021

Abstract
Background
The appropriate loading protocol to improve masticatory performance (MP) is still unclear in elderly patients and two-implant overdentures (2-IODs) wearers. This study aimed to compare the long-term MP and maximum occlusal force of immediate loading (IL) and conventional loading (CL) of 2-IODs retained by magnetic attachments. Nineteen edentulous patients were randomly assigned to either an IL (n=10) or CL group (n = 9). In the IL group, the implant was loaded on the same day as insertion, whereas it was loaded 3 months after insertion in the CL group. Magnetic attachments were used to retain all overdentures to the implants. MP, measured by a piece of color-changeable chewing gum and a gummy jelly test, and maximum occlusal force, measured using an occlusal force measuring device, were assessed in both groups at baseline and at 3-, 4-, and 5-year follow-ups.

Results
No significant differences were observed in the MP and the maximum occlusal force between the IL and CL groups at any time point. However, a significantly higher MP was observed at the 3-year time point in the IL group (P = 0.036). The maximum occlusal force revealed a significant correlation with MP, both with the color-changeable chewing gum and gummy jelly at 5 years.

Conclusion
After long-term observation, no significant differences in MP and maximum occlusal force were observed between the IL and CL groups. However, compared to pre-implant insertion of the complete denture, the MP in the IL group significantly improved at 3 years. Furthermore, the maximum occlusal force was significantly correlated with MP at 5 years.

Trial registration
UMIN, UMIN000009889. Registered on 28 January 2013.
Quality of life and its predictors in adults with tuberous sclerosis complex (TSC): a multicentre cohort study from Germany
Authors: Zöllner Johann Philipp , Conradi Nadine , Sauter Matthias , Knuf Markus , Knake Susanne , Kurlemann Gerhard , Mayer Thomas , Hertzberg Christoph , Bertsche Astrid , Immisch Ilka , Klein Karl Martin , Marquard Klaus , Meyer Sascha , Noda Anna H. , von Podewils Felix , Schäfer Hannah , Thiels Charlotte , Zukunft Bianca , Schubert-Bast Susanne , Grau Janina , Willems Laurent M. , Rosenow Felix , Reese Jens-Peter , Strzelczyk Adam 
Published: June 2021

AbstractBackgroundTuberous sclerosis complex (TSC) is a monogenetic, multisystemic disease characterised by the formation of benign tumours that can affect almost all organs, caused by pathogenic variations inTSC1orTSC2. In this multicentre study from Germany, we investigated the influence of sociodemographic, clinical, and therapeutic factors on quality of life (QoL) among individuals with TSC.MethodsWe assessed sociodemographic and clinical characteristics and QoL among adults with TSC throughout Germany using a validated, three-month, retrospective questionnaire. We examined predictors of health-related QoL (HRQoL) using multiple linear regression analysis and compared the QoL among patients with TSC with QoL among patients with other chronic neurological disorders.ResultsWe enrolled 121 adults with TSC (mean age: 31.0 ± 10.5 years; range: 18–61 years, 45.5% [n = 55] women). Unemployment, a higher grade of disability, a higher number of organ manifestations, the presence of neuropsychiatric manifestations or active epilepsy, and a higher burden of therapy-related adverse events were associated with worse QoL, as measured by two QoL instruments (EuroQoL-5 dimensions [EQ-5D] and Quality of Life in Epilepsy Patients [QOLIE-31]). Neuropsychiatric and structural nervous system manifestations, the number of affected organs, and therapy-related adverse events were also associated with higher depression, as measured by the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). In multiple regression analysis, more severe therapy-related adverse events (large effect,p < 0.001), active epilepsy (large effect,p < 0.001), and neuropsychiatric manifestations (medium effect,p = 0.003) were independently associated with worse HRQoL, explaining 65% of the variance (p < 0.001). The HRQoL among patients with active TSC-associated epilepsy was worse than that among patients with drug-refractory mesial temporal lobe epilepsy (p < 0.001), and the generic QoL among patients with more than three TSC organ manifestations was similar to those of patients with severe migraine and uncontrolled asthma.ConclusionsActive epilepsy, neuropsychiatric manifestations (such as anxiety and depression), and therapy-related adverse events are important independent predictors of worse quality of life among adults with TSC. Generic quality of life in TSC with several manifestations is similar to uncontrolled severe chronic diseases and significantly negatively correlates with TSC severity.Trial registrationDRKS,DRKS00016045. Registered 01 March 2019.
Uncovering trends in training progression for a national cohort of psychiatry trainees: discrete-time survival analysis
Authors: Silkens Milou E.W.M. , Sarker Shah-Jalal , Medisauskaite Asta 
Published: June 2021

BackgroundThe global rise in mental health issues calls for a strong psychiatry workforce. Yet, psychiatry training worldwide is facing recruitment challenges, causing unfilled consultant posts and possibly threatening the quality of patient care. An in-depth understanding of trainees’ progression through training is warranted to explore what happens to recruited trainees during training.AimsTo uncover current trends in psychiatry trainees’ progression through training in the UK.MethodThis national retrospective cohort study with data from the UK Medical Education Database used discrete-time survival analysis to analyse training progression for those trainees who started their core psychiatry post in 2012–2017 (2820 trainees; 59.6% female, 67.6% UK graduates (UKGs)). The impact of sociodemographic characteristics on training progression were also investigated.ResultsThe overall probability of completing training in 6 years (minimum years required to complete psychiatry training in the UK) was 17.2% (ranging from 4.8% for non-UKG females to 29% for UKG males). The probability to not progress was highest (57.1%) from core to specialty training. For UKGs, trainees from ethnicities other than White, trainees with a disability, and trainees who had experienced childhood social deprivation (measured as entitlement to free school meals) had a significantly (P≤ 0.02) lower probability of completing training in 6 years.ConclusionsLess than one in five psychiatry trainees are likely to complete training in 6 years and this probability varies across groups of doctors. Completing psychiatry training in 6 years is, therefore, the exception rather than the norm and this has important implications for trainees, those planning psychiatry workforces or responsible for psychiatry training.
Development and Pilot Implementation of the Genomic Risk Assessment for Cancer Implementation and Sustainment (GRACIAS) Intervention in Mexico
Authors: Blazer Kathleen R. , Chavarri-Guerra Yanin , Villarreal Garza Cynthia , Nehoray Bita , Mohar Alejandro , Daneri-Navarro Adrian , del Toro Azucena , Aguilar Dione , Arteaga Jazmin , Álvarez Rosa Maria , Mejia Rosa , Herzog Josef , Castillo Danielle , Fernandez Maria , Weitzel Jeffrey N. 
Published: June 2021

PURPOSEGenomic cancer risk assessment (GCRA) is standard-of-care practice that uses genomic tools to identify individuals with increased cancer risk, enabling screening for early detection and cancer prevention interventions. GCRA is not available in most of Mexico, where breast cancer (BC) is the leading cause of cancer death and ovarian cancer has a high mortality rate.METHODSGuided by an implementation science framework, we piloted the Genomic Risk Assessment for Cancer Implementation and Sustainment (GRACIAS) intervention, combining GCRA training, practice support, and low-cost BRCA1/ 2 ( BRCA) gene testing at four centers in Mexico. The RE-AIM model was adapted to evaluate GRACIAS intervention outcomes, including reach, the proportion of new patients meeting adapted National Comprehensive Cancer Network criteria who participated in GCRA. Barriers to GCRA were identified through roundtable sessions and semistructured interviews.RESULTSEleven clinicians were trained across four sites. Mean pre-post knowledge score increased from 60% to 67.2% (range 53%-86%). GCRA self-efficacy scores increased by 31% (95% CI, 6.47 to 55.54; P = .02). Participant feedback recommended Spanish content to improve learning. GRACIAS promoted reach at all sites: 77% in Universidad de Guadalajara, 86% in Instituto Nacional de Cancerología, 90% in Tecnológico de Monterrey, and 77% in Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Overall, a pathogenic BRCA variant was identified in 15.6% (195 of 1,253) of patients. All trainees continue to provide GCRA and address barriers to care.CONCLUSIONWe describe the first project to use implementation science methods to develop and deliver an innovative multicomponent implementation intervention, combining low-cost BRCA testing, comprehensive GCRA training, and practice support in Mexico. Scale-up of the GRACIAS intervention will promote risk-appropriate care, cancer prevention, and reduction in related mortality.