bluuebunny/crossref_metadata_2025_split huggingface dataset:
Occupational sitting time, its determinants and intervention strategies in Malaysian office workers: a mixed-methods study
Authors: Suhaimi Saiful Adli , Müller Andre Matthias , Hafiz Eliza , Khoo Selina 
Published: September 2021

Abstract
Adults who accumulate a lot of sedentary time per day are at an increased risk of metabolic syndrome, type 2 diabetes, and hypertension. Prolonged sitting is also associated with depression, anxiety, bipolar disorder and schizophrenia. With the increase in desk-based office work, many office workers spend long hours sitting at the workplace. The aim of this study was to assess occupational sitting time in Malaysian government office workers, and investigate determinants of occupational sitting time and potential strategies to interrupt sitting time. We conducted a mixed-methods study consisting of a survey and focus group discussions (FGDs). A total of 1338 office workers from 24 Malaysian ministries completed the Occupational Sitting and Physical Activity Questionnaire. Twenty-nine office workers who spent at least 7 h per day sitting at work participated in FGDs. We enquired about knowledge, awareness and perceptions related to prolonged sitting time, barriers and facilitators to sitting time at work, and potential intervention strategies. Mean daily sitting time at work was 5.96 h (standard deviation = 1.37 h). FDGs confirmed barriers and facilitators to sitting time in accordance with the social-ecological model for health. Intrapersonal, social and physical environmental factors as well as organizational culture and organizational policy were mentioned to affect occupational sitting time. The results show that Malaysian government office workers spent a significant amount of time sitting at work and we identified multi-level factors influencing sitting time. A smartphone-based intervention to interrupt sitting time at work was suggested and is currently being tested.
Recommendations for breast cancer education for African American women below screening age
Authors: Huq M R , Woodard N , Okwara L , McCarthy S , Knott C L 
Published: September 2021

Abstract
Although statistically unlikely, early-onset breast cancer tends to be more aggressive and leads to greater mortality than breast cancer among women of screening age. Young African American women are disproportionately impacted by early-onset breast cancer compared to women of other races. Given the racial disparities and because young women are typically not the primary audience for breast cancer educational messaging, there is a need to identify recommendations for age-appropriate breast cancer education for African American women below mammogram eligibility. Through N = 30 key informant interviews with young African American breast cancer survivors, family members of young survivors, community organization leaders and healthcare providers, we identified breast cancer educational message content and communication channels relevant for these women. Participants recommended that message content should emphasize the need to address family cancer history and self-advocacy in healthcare encounters in addition to concerns about loss of womanhood, financial costs and opportunity costs associated with preventive healthcare visits. Breast cancer messages for this audience should consider the influences of earlier life stage, culture and race. Recommended communication channels highlighted use of social media and videos. Findings will inform future age-appropriate educational messaging aimed at eliminating early-onset breast cancer disparities disproportionately impacting young African American women.
The Zaran company in the Holy Land: an unknown fourth crusade charter from Acre
Authors: Lippiatt G E M 
Published: September 2021

Abstract
This article publishes and examines a newly discovered charter drafted in the Holy Land during the time of the fourth crusade, bringing the number of such original documents to four. In addition to shedding light on the nature of donations made by minor crusaders to the Templars while in Outremer, the witness list also reveals for the first time documentary evidence of the progress of a group of crusaders who departed from the main host of the fourth crusade after the attack on Zara and their connections with wider events such as the Grandmontine crisis and the conquest of Normandy.
The novel potent GSK3 inhibitor AF3581 reverts fragile X syndrome phenotype
Authors: Porceddu Pier Francesca , Ciampoli Mariasole , Romeo Elisa , Garrone Beatrice , Durando Lucia , Milanese Claudio , Di Giorgio Francesco Paolo , Reggiani Angelo 
Published: September 2021

Abstract
Glycogen-synthase kinase 3 (GSK3) is a kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK3 has been linked to several disease conditions such as fragile X syndrome (FXS). Recent evidences demonstrating an increased activity of GSK3 in murine models of FXS, suggest that dysregulation/hyperactivation of the GSK3 path should contribute to FXS development. A likely possibility could be that in FXS there is a functional impairment of the upstream inhibitory input over GSK3 thus making overactive the kinase. Since GSK3 signaling is a central regulatory node for critical neurodevelopmental pathways, understanding the contribution of GSK3 dysregulation to FXS, may provide novel targets for therapeutic interventions for this disease. In this study we used AF3581, a potent GSK3 inhibitor that we recently discovered, in an in vivo FXS mouse model to elucidate the crucial role of GSK3 in specific behavioral patterns (locomotor activity, sensorimotor gating and social behavior) associated with this disease. All the behavioral alterations manifested by Fmr1 knockout mice were reverted after a chronic treatment with our GSK3 inhibitor, confirming the importance of this pathway as a therapeutic target.
Assessing the genetic relationship between gastro-esophageal reflux disease and risk of COVID-19 infection
Authors: Ong Jue-Sheng , Gharahkhani Puya , Vaughan Thomas L , Whiteman David , Kendall Bradley J , MacGregor Stuart 
Published: September 2021

Abstract
Symptoms related with gastro-esophageal reflux disease (GERD) were previously shown to be linked with increased risk for the 2019 coronavirus disease (COVID-19). We aim to interrogate the possibility of a shared genetic basis between GERD and COVID-19 outcomes. Using published GWAS data for GERD (78 707 cases; 288 734 controls) and COVID-19 susceptibility (up to 32 494 cases; 1.5 million controls), we examined the genetic relationship between GERD and three COVID-19 outcomes: risk of developing severe COVID-19, COVID-19 hospitalization and overall COVID-19 risk. We estimated the genetic correlation between GERD and COVID-19 outcomes followed by Mendelian randomization (MR) analyses to assess genetic causality. Conditional analyses were conducted to examine whether known COVID-19 risk factors (obesity, smoking, type-II diabetes, coronary artery disease) can explain the relationship between GERD and COVID-19. We found small to moderate genetic correlations between GERD and COVID-19 outcomes (rg between 0.06 and 0.24). MR analyses revealed a OR of 1.15 (95% CI: 0.96–1.39) for severe COVID-19; 1.16 (1.01–1.34) for risk of COVID-19 hospitalization; 1.05 (0.97–1.13) for overall risk of COVID-19 per doubling of odds in developing GERD. The genetic correlation/associations between GERD and COVID-19 showed mild attenuation towards the null when obesity and smoking was adjusted for. Susceptibility for GERD and risk of COVID-19 hospitalization were genetically correlated, with MR findings supporting a potential causal role between the two. The genetic association between GERD and COVID-19 was partially attenuated when obesity is accounted for, consistent with obesity being a major risk factor for both diseases.
MCU-complex-mediated mitochondrial calcium signaling is impaired in Barth syndrome
Authors: Ghosh Sagnika , Zulkifli Mohammad , Joshi Alaumy , Venkatesan Manigandan , Cristel Allen , Vishnu Neelanjan , Madesh Muniswamy , Gohil Vishal M 
Published: September 2021

Abstract
Calcium signaling via mitochondrial calcium uniporter (MCU) complex coordinates mitochondrial bioenergetics with cellular energy demands. Emerging studies show that the stability and activity of the pore-forming subunit of the complex, MCU, is dependent on the mitochondrial phospholipid, cardiolipin (CL), but how this impacts calcium-dependent mitochondrial bioenergetics in CL-deficiency disorder like Barth syndrome (BTHS) is not known. Here we utilized multiple models of BTHS including yeast, mouse muscle cell line, as well as BTHS patient cells and cardiac tissue to show that CL is required for the abundance and stability of the MCU-complex regulatory subunit MICU1. Interestingly, the reduction in MICU1 abundance in BTHS mitochondria is independent of MCU. Unlike MCU and MICU1/MICU2, other subunit and associated factor of the uniporter complex, EMRE and MCUR1, respectively, are not affected in BTHS models. Consistent with the decrease in MICU1 levels, we show that the kinetics of MICU1-dependent mitochondrial calcium uptake is perturbed and acute stimulation of mitochondrial calcium signaling in BTHS myoblasts fails to activate pyruvate dehydrogenase, which in turn impairs the generation of reducing equivalents and blunts mitochondrial bioenergetics. Taken together, our findings suggest that defects in mitochondrial calcium signaling could contribute to cardiac and skeletal muscle pathologies observed in BTHS patients.
Systemic complement levels in patients with age-related macular degeneration carrying rare or low-frequency variants in the CFH gene
Authors: de Jong Sarah , de Breuk Anita , Volokhina Elena B , Bakker Bjorn , Garanto Alejandro , Fauser Sascha , Katti Suresh , Hoyng Carel B , Lechanteur Yara T E , van den Heuvel Lambert P , den Hollander Anneke I 
Published: September 2021

Abstract
Age-related macular degeneration (AMD) is a major cause of vision loss among the elderly in the Western world. Genetic variants in the complement factor H (CFH) gene are associated with AMD, but the functional consequences of many of these variants are currently unknown. In this study, we aimed to determine the effect of 64 rare and low-frequency variants in the CFH gene on systemic levels of factor H (FH) and complement activation marker C3bBbP using plasma samples of 252 carriers and 159 non-carriers. Individuals carrying a heterozygous nonsense, frameshift or missense variant in CFH presented with significantly decreased FH levels and significantly increased C3bBbP levels in plasma compared to non-carrier controls. FH and C3bBbP plasma levels were relatively stable over time in samples collected during follow-up visits. Decreased FH and increased C3bBbP concentrations were observed in carriers compared to non-carriers of CFH variants among different AMD stages, with the exception of C3bBbP levels in advanced AMD stages, which were equally high in carriers and non-carriers. In AMD families, FH levels were decreased in carriers compared to non-carriers, but C3bBbP levels did not differ. Rare variants in the CFH gene can lead to reduced FH levels or reduced FH function as measured by increased C3bBbP levels. The effects of individual variants in the CFH gene reported in this study will improve the interpretation of rare and low-frequency variants observed in AMD patients in clinical practice.
De novo missense variants in FBXO11 alter its protein expression and subcellular localization
Authors: Gregor Anne , Meerbrei Tanja , Gerstner Thorsten , Toutain Annick , Lynch Sally Ann , Stals Karen , Maxton Caroline , Lemke Johannes R , Bernat John A , Bombei Hannah M , Foulds Nicola , Hunt David , Kuechler Alma , Beygo Jasmin , Stöbe Petra , Bouman Arjan , Palomares-Bralo Maria , Santos-Simarro Fernando , Garcia-Minaur Sixto , Pacio-Miguez Marta , Popp Bernt , Vasileiou Georgia , Hebebrand Moritz , Reis André , Schuhmann Sarah , Krumbiegel Mandy , Brown Natasha J , Sparber Peter , Melikyan Lyusya , Bessonova Liudmila , Cherevatova Tatiana , Sharkov Artem , Shcherbakova Natalia , Dabir Tabib , Kini Usha , Schwaibold Eva M C , Haack Tobias B , Bertoli Marta , Hoffjan Sabine , Falb Ruth , Shinawi Marwan , Sticht Heinrich , Zweier Christiane 
Published: September 2021

Abstract
Recently, others and we identified de novo FBXO11 (F-Box only protein 11) variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data, our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs.
Genomic editing of metformin efficacy-associated genetic variants in SLC47A1 does not alter SLC47A1 expression
Authors: Kalamajski Sebastian , Huang Mi , Dalla-Riva Jonathan , Keller Maria , Dawed Adem Y , Hansson Ola , Pearson Ewan R ,   MetGen Plus Consortium, Mulder Hindrik , Franks Paul W 
Published: September 2021

Abstract
Several pharmacogenetics studies have identified an association between a greater metformin-dependent reduction in HbA1c levels and the minor A allele at rs2289669 in intron 10 of SLC47A1, encoding multidrug and toxin extrusion 1 (MATE1), a presumed metformin transporter. It is currently unknown if the rs2289669 locus is a cis-eQTL, which would validate its role as predictor of metformin efficacy. We looked at association between common genetic variants in the SLC47A1 gene region and HbA1c reduction after metformin treatment using locus-wise meta-analysis from the MetGen consortium. CRISPR-Cas9 was applied to perform allele editing of, or genomic deletion around, rs2289669 and of the closely linked rs8065082 in HepG2 cells. The genome-edited cells were evaluated for SLC47A1 expression and splicing. None of the common variants including rs2289669 showed significant association with metformin response. Genomic editing of either rs2289669 or rs8065082 did not alter SLC47A1 expression or splicing. Experimental and in silico analyses show that the rs2289669-containing haploblock does not appear to carry genetic variants that could explain its previously reported association with metformin efficacy.
Deficiency of the neurodevelopmental disorder-associated geneCyfip2alters the retinal ganglion cell properties and visual acuity
Authors: Chaya Taro , Ishikane Hiroshi , Varner Leah R , Sugita Yuko , Maeda Yamato , Tsutsumi Ryotaro , Motooka Daisuke , Okuzaki Daisuke , Furukawa Takahisa 
Published: September 2021

AbstractIntellectual disability (ID) is a neurodevelopmental disorder affecting approximately 0.5–3% of the population in the developed world. Individuals with ID exhibit deficits in intelligence, impaired adaptive behavior and often visual impairments. Cytoplasmic fragile X mental retardation 1 (FMR1)-interacting protein 2 (CYFIP2) is an interacting partner of the FMR protein, whose loss results in fragile X syndrome, the most common inherited cause of ID. Recently, CYFIP2 variants have been found in patients with early-onset epileptic encephalopathy, developmental delay and ID. Such individuals often exhibit visual impairments; however, the underlying mechanism is poorly understood. In the present study, we investigated the role of Cyfip2 in retinal and visual functions by generating and analyzing Cyfip2 conditional knockout (CKO) mice. While we found no major differences in the layer structures and cell compositions between the control and Cyfip2 CKO retinas, a subset of genes associated with the transporter and channel activities was differentially expressed in Cyfip2 CKO retinas than in the controls. Multi-electrode array recordings showed more sustained and stronger responses to positive flashes of the ON ganglion cells in the Cyfip2 CKO retina than in the controls, although electroretinogram analysis revealed that Cyfip2 deficiency unaffected the photoreceptor and ON bipolar cell functions. Furthermore, analysis of initial and late phase optokinetic responses demonstrated that Cyfip2 deficiency impaired the visual function at the organismal level. Together, our results shed light on the molecular mechanism underlying the visual impairments observed in individuals with CYFIP2 variants and, more generally, in patients with neurodevelopmental disorders, including ID.
Epilepsy-causing Reelin mutations result in impaired secretion and intracellular degradation of mutant proteins
Authors: Dazzo Emanuela , Nobile Carlo 
Published: September 2021

Abstract
Autosomal dominant lateral temporal epilepsy (ADLTE) is a genetically heterogeneous neurologic disorder clinically characterized by focal seizures with auditory symptoms and/or aphasia. About 20% of ADLTE families segregate disease-causing heterozygous mutations in RELN, a brain-expressed gene encoding the secreted protein Reelin. Using a cell-based secretion assay, we show that pathogenic RELN mutations abolish or significantly reduce secretion of mutant proteins and that this secretion defect results from impaired trafficking of mutant Reelin along the secretory pathway. Confocal immunofluorescence analysis of transiently transfected cells shows that Reelin mutant proteins are degraded by the autophagy system, as revealed by increased formation of autophagosomes immunoreacting with the autophagy markers p62 and LC3. In addition, LC3 immunoblotting shows a significant increase of autophagy flux due to mutant overexpression. Finally, we show that the secretion defect of mutant proteins can be partially rescued by small-molecule correctors. Altogether, these results suggest that Reelin mutant proteins are not properly secreted and that they are degraded through the autophagy pathway.
The European Human Rights System and the Right to Life Seen through Suicide Prevention in Places of Detention: Between Risk Management and Punishment
Authors: Cliquennois Gaëtan , Snacken Sonja , van Zyl Smit Dirk 
Published: September 2021

Abstract
This paper analyses the shortcomings of European suicide prevention policy in places of detention, a topic that has been neglected in the European legal literature. Four interrelated characteristics of the suicide prevention policies developed by the European Court of Human Rights (ECtHR) are responsible for the failures of these policies. First, the risk-based approach relies on individual risk calculations by national detention authorities to the detriment of environmental factors and a holistic approach. Second, there is an unacknowledged tension in the jurisprudence of the ECtHR between the right to life of detainees and the right to life of potential victims of terrorism and other serious crimes. Third, the jurisprudence on state liability, with its individual risk-based approach, has been translated into highly restrictive death avoidance national practices, which infringe human dignity and reinforce detainees’ willingness to commit suicide. Finally, the right to life does not effectively limit the inherent punitiveness of suicide prevention policies.
Comparing endometriotic lesions with eutopic endometrium: time to shift focus?
Authors: Colgrave Eliza M , Keast Janet R , Bittinger Sophie , Healey Martin , Rogers Peter A W , Holdsworth-Carson Sarah J , Girling Jane E 
Published: September 2021

ABSTRACT
Endometriosis is a heterogeneous disease in terms of patient symptoms, treatment responsiveness and the presentation of endometriotic lesions. This article explores the histological features of endometriotic lesions, highlighting their sometimes underappreciated heterogeneity. We note the variability in evidence for and against the menstrual cycle responsiveness of lesions and consider the utility of drawing parallels between endometriotic lesions and eutopic endometrium. We ask whether histopathologic features beyond just the presence/absence of endometrial-like glands and/or stroma could help improve disease stratification. At the same time, we acknowledge the desire of many clinicians and patients to avoid invasive surgery thereby limiting the ability to histologically phenotype lesions. The ability to derive clinically useful histological information from endometriotic lesions, in association with patient data, would be invaluable to clinicians to help improve treatment options in such a diverse group of patients. However, in suggesting that a shift in focus may enable the development of a better patient stratification system, we recognise that our wish for a single comprehensive stratification system may be beyond reach for a disease of such diverse presentation.
Women and Stews: the Social and Material History of Prostitution in the late medieval Southern Low Countries
Authors: Haemers Jelle 
Published: September 2021

Abstract
This article explores the social background and material culture of an understudied medieval brothel, the private ‘stew’, the most common type of brothel in the Southern Low Countries, where public brothels were rare. The fifteenth-century lease contracts of private stews contain information about the stew's size, economic value, and ambiance, suggesting the advantageous social position of some of the women who sold sex and providing inspiration to English brothel keepers. The absence of public brothels in the Low Countries reflected both a tolerance for prostitution and the relative freedom enjoyed by women in this region.
Influence of genetic factors and institutional environment on entrepreneurial activity: evidence from a twin study in Italy
Authors: Zunino Diego 
Published: September 2021

AbstractGenetic factors influence entrepreneurial activity, but we know little about how genetic factors influence entrepreneurial activity when the institutional environment is favorable. Two theories from behavioral genetics explain the gene–environment interaction. One theory argues that a favorable environment favors the development of genetic factors and their influence. An alternative theory posits that unfavorable environment triggers the development of genetic factors and their influence. I test these two competing theories with a twin study based in Italy. I compare the influence of genetic factors in provinces where the institutional environment favors entrepreneurial activity with provinces where the institutional environment is unfavorable to entrepreneurial activity. I found consistent evidence that genetic factors exert a larger influence in favorable institutional environments, suggesting that favorable institutional environments complement genetic factors.