bluuebunny/crossref_metadata_2025 huggingface dataset:
A population genetic perspective on the origin, spread and adaptation of the human malaria agents Plasmodium falciparum and Plasmodium vivax
Authors: Rougeron Virginie , Boundenga Larson , Arnathau Céline , Durand Patrick , Renaud François , Prugnolle Franck
Published: September 2021

Malaria is considered one of the most important scourges that humanity has faced during its history, being responsible every year for numerous deaths worldwide. The disease is caused by protozoan parasites, among which two species are responsible of the majority of the burden, Plasmodium falciparum and Plasmodium vivax. For these two parasite species, the questions of their origin (how and when they appeared in humans), of their spread throughout the world, as well as how they have adapted to humans have long been of interest to the scientific community. In this paper we review the existing body of knowledge, including current research dealing with these questions, focusing particularly on genetic and genomic analyses of these parasites and comparison with related Plasmodium species infecting other species of host (such as non-human primates).
Sustainable regeneration in uneven-aged mixed deciduous forests managed by selection silviculture: the role of demographic structure
Authors: Brüllhardt Martin , Rotach Peter , Forrester David I , Bugmann Harald
Published: September 2021

Selection silviculture aims to create and maintain uneven-aged forests with a diameter at breast height (DBH) structure that is balanced at small spatial scales such that the stem number in each DBH class is high enough to replace the harvested and outgrowing trees over time by ingrowth from the next lower class. In these forests, natural regeneration of shade-tolerant species is at an advantage over shade-intolerant species. This is particularly pronounced in continuous-cover stands dominated by European beech (Fagus sylvatica L.), which develops its crown laterally as a reaction to release events. The conditions necessary to sustain a mixture with less shade-tolerant species, e.g. sycamore (Acer pseudoplatanus L.), have been little studied. Therefore, we explored growth patterns and stand structures in mixed deciduous forests with light availability quantified using vegetation height models. Harvesting and growth patterns were derived from inventory data of beech-dominated selection forests in Thuringia, Germany and long-term forest monitoring plot data from four stands in Switzerland. Based on these data, models of stem number distributions confirmed that stand basal area in deciduous forests dominated by beech should not exceed 21–25 m2 ha−1 to maintain a sustainable structure. In these forests, a total of ~90–120 stems per ha are needed in the ingrowth DBH class (DBH 8–11.9 cm) to ensure demographic sustainability. At canopy light transmittance <10 per cent, total stem number required in the thicket stage (DBH < 8 cm) is 800–1700 ha−1. Under such shady conditions, only a small proportion of sycamore was observed (<25 per cent) in the thicket stage, as the species is likely to require canopy gaps >400 m2 (gap diameter > 22.5 m) to recruit successfully. Selection silviculture with shade-intolerant species therefore requires much lower stocking volume and larger canopy openings created by group selection cutting than what is routinely applied in practical forest management using single-tree selection principles.
Phenotypic and Transcriptomic Responses to Stress Differ According to Population Geography in an Invasive Species
Authors: Marin Pierre , Jaquet Angelo , Picarle Justine , Fablet Marie , Merel Vincent , Delignette-Muller Marie-Laure , Ferrarini Mariana Galvão , Gibert Patricia , Vieira Cristina
Published: September 2021

Adaptation to rapid environmental changes must occur within a short-time scale. In this context, studies of invasive species may provide insights into the underlying mechanisms of rapid adaptation as these species have repeatedly encountered and adapted to novel environmental conditions. We investigated how invasive and noninvasive genotypes of Drosophila suzukii deal with oxidative stress at the phenotypic and molecular levels. We also studied the impact of transposable element (TE) insertions on the gene expression in response to stress. Our results show that flies from invasive areas (France and the United States) live longer in natural conditions than the ones from native Japanese areas. As expected, lifespan for all genotypes was significantly reduced following exposure to paraquat, but this reduction varied among genotypes (genotype-by-environment interaction) with invasive genotypes appearing more affected by exposure than noninvasive ones. A transcriptomic analysis of genotypes upon paraquat treatment detected many genes differentially expressed (DE). Although a small core set of genes were DE in all genotypes following paraquat exposure, much of the response of each genotype was unique. Moreover, we showed that TEs were not activated after oxidative stress and DE genes were significantly depleted of TEs. In conclusion, it is likely that transcriptomic changes are involved in the rapid adaptation to local environments. We provide new evidence that in the decade since the invasion from Asia, the sampled genotypes in Europe and the United States of D. suzukii diverged from the ones from the native area regarding their phenotypic and genomic response to oxidative stress.
An Ancient Adenosine Receptor Gains Olfactory Function in Bony Vertebrates
Authors: Kowatschew Daniel , Korsching Sigrun I
Published: September 2021

Nucleotides are an important class of odorants for aquatic vertebrates such as frogs and fishes, but also have manifold signaling roles in other cellular processes. Recently, an adenosine receptor believed to belong to the adora2 clade has been identified as an olfactory receptor in zebrafish. Here, we set out to elucidate the evolutionary history of both this gene and its olfactory function. We have performed a thorough phylogenetic study in vertebrates, chordates and their sister group, ambulacraria, and show that the origin of the zebrafish olfactory receptor gene can be traced back to the most recent common ancestor of all three groups as a segregate sister clade (adorb) to the adora gene family. Eel, carp, and clawed frog all express adorb in a sparse and distributed pattern within their olfactory epithelium very similar to the pattern observed for zebrafish that is, consistent with a function as olfactory receptor. In sharp contrast, lamprey adorb-expressing cells are absent from the sensory region of the lamprey nose, but form a contiguous domain directly adjacent to the sensory region. Double-labeling experiments confirmed the expression of lamprey adorb in nonneuronal cells and are consistent with an expression in neuronal progenitor cells. Thus, adorb may have undergone a switch of function in the jawed lineage of vertebrates towards a role as olfactory receptor.
Detecting lithospheric discontinuities beneath the Mississippi Embayment using S-wave receiver functions
Authors: Saxena Arushi , Langston Charles Adam
Published: September 2021

Identifying upper-mantle discontinuities in the Central and Eastern US is crucial for verifying models of lithospheric thinning and a low-velocity anomaly structure beneath the Mississippi Embayment. In this study, S-wave receiver functions (SRFs) were used to detect lithospheric boundaries in the embayment region. The viability of SRFs in detecting seismic boundaries was tested before computing them using the earthquake data. A careful analysis using a stochastic noise and coda model on the synthetics revealed that a negative velocity contrast could be detected with certainty at low to moderate noise levels after stacking. A total of 31 518 SRFs from 688 earthquakes recorded at 174 seismic stations including the Northern Embayment Lithospheric Experiment, EarthScope Transportable Array and other permanent networks were used in this study. Common depth point stacks of the SRFs in 1° × 1° bins indicated a continuous and broad S-to-P converted phase (Sp) arrival corresponding to a negative velocity contrast at depths between 50 and 100 km. The observed negative Sp phase is interpreted as a mid-lithospheric discontinuity (MLD), and several possible origins of the velocity drop corresponding to the MLD are explored. After quantitative analysis, a combination of temperature, water content and melt content variations are attributed to explain the observed MLD in this study. The observations and interpretations in this study support the previous claims of an MLD in the Central and Eastern US and provide a possible mechanism for its origin.
Glycomic and glycotranscriptomic profiling of mucin-type O-glycans in planarian Schmidtea mediterranea
Authors: Subramanian Sabarinath Peruvemba , Lakshmanan Vairavan , Palakodeti Dasaradhi , Subramanian Ramaswamy
Published: September 2021

O-Glycans on cell surfaces play important roles in cell–cell, cell–matrix and receptor–ligand interaction. Therefore, glycan-based interactions are important for tissue regeneration and homeostasis. Free-living flatworm Schmidtea mediterranea, because of its robust regenerative potential, is of great interest in the field of stem cell biology and tissue regeneration. Nevertheless, information on the composition and structure of O-glycans in planaria is unknown. Using mass spectrometry and in silico approaches, we characterized the glycome and the related transcriptome of mucin-type O-glycans of planarian S. mediterranea. Mucin-type O-glycans were composed of multiple isomeric, methylated, and unusually extended mono- and disubstituted O-N-acetylgalactosamine structures. Extensions made of hexoses and 3-O-methyl hexoses were the glycoforms observed. From glycotranscriptomic analysis, 60 genes belonging to five distinct enzyme classes were identified to be involved in mucin-type O-glycan biosynthesis. These genes shared homology with those in other invertebrate systems. Although a majority of the genes involved in mucin-type O-glycan biosynthesis were highly expressed during organogenesis and in differentiated cells, a few select genes in each enzyme class were specifically enriched during early embryogenesis. Our results indicate a unique temporal and spatial role for mucin-type O-glycans during embryogenesis and organogenesis and in adulthood. In summary, this is the first report on O-glycans in planaria. This study expands the structural and biosynthetic possibilities in cellular glycosylation in the invertebrate glycome and provides a framework towards understanding the biological role of mucin-type O-glycans in tissue regeneration using planarians.
The WHO FCTC’s lessons for addressing the commercial determinants of health
Authors: McHardy Juliette
Published: September 2021

The tobacco, alcohol, beverage, processed food, firearms, gambling, fossil fuel and mining industries, inter alia, are implicated in fostering negative commercial determinants of health. They do this by shaping our environments, tastes, knowledge and politics in favour of the unlimited consumption and unencumbered promotion of their deadly and dangerous products. To shift the determinants of health, emphasis should be put on preventing industry actors whose profit lies in harming health from wielding influence over the institutions and actors of global and national governance. The tobacco control experience and the implementation of the WHO Framework Convention on Tobacco Control (WHO FCTC) provide a unique, comprehensive and fully substantiated guide for how this may be done. Just as the tobacco industry was a pathfinder for other harmful industries in developing tactics for expanding the depth and reach of the market for their deadly products, the WHO FCTC experience is the obvious pathfinder for countering the commercial determinants of health across all sectors and industries. Although they are desirable for countering negative commercial determinants of health, the WHO FCTC’s lesson is not that commercially driven epidemics must be tackled with legally binding treaties. Rather, given the challenges to treaty-making, the key lessons are those that show how it is possible to address the harms of other commodities, even in a treaty’s absence. What is needed is the national implementation of measures providing for intersectoral governance and protection from industry interference which will then assist in unlocking measures for reducing the supply of and demand for unhealthy commodities.
Health education for musicians in the UK: a qualitative evaluation
Authors: Matei Raluca , Ginsborg Jane
Published: September 2021

Musical training in higher education music institutions (e.g. conservatoires) has been associated with health-related issues among musicians. The Health Promotion in Schools of Music project in the USA and the Healthy Conservatoires project in the UK have therefore recommended health promotion at conservatoires. Few health education courses have been evaluated to date, however. A 5-month health education programme for first-year undergraduate students at a British conservatoire was introduced as part of the core curriculum in September 2016. The programme, which involved both lectures and seminars, was evaluated using quantitative and qualitative approaches. This article reports only the qualitative evaluation. Twenty semi-structured individual interviews were conducted either face-to-face or via Skype in April 2017. The data were transcribed verbatim and analysed thematically. Five themes were identified: (i) the programme as a catalyst for engagement with health; (ii) behavioural changes; (iii) barriers to engaging with the programme material and initiating changes; (iv) suggestions for improvement; and (v) misinformation. Generally, participants viewed the programme as relevant and informative, particularly appreciating the intimate nature of the seminars. They reported that the programme helped them take a broader perspective on musicianship and that they would welcome sessions that are more practical than theoretical. They also reported instances of change in their behaviours relating to both lifestyle and management of music practice. In conclusion, undergraduate music students viewed this health education programme positively. Their feedback illustrates the complex nature of health promotion in the conservatoire setting.
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

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

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

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

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

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

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

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

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

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

Intellectual 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

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

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.
Chronic Medical Conditions as Predictors of the Likelihood of PTSD among Black Adults: Preparing for the Aftermath of COVID-19
Authors: Archibald Paul , Thorpe Roland
Published: September 2021

The relationship between chronic medical conditions and PTSD within-race in Black adults is not well understood and there exists a dearth of empirical research investigating the gender differences. Cross-sectional data from the National Survey of American Life were used to examine the relationship between PTSD and obesity, hypertension, diabetes, heart disease, and asthma (five of the most commonly identified COVID-19 underlying medical conditions) among Black adults in the United States. Results from modified Poisson regression analyses revealed that Black adults across all three groups (overall, male, and female samples) who reported two or more chronic medical conditions had a higher prevalence of PTSD than those who reported zero or one. Black men with obesity, diabetes, or heart disease and Black women with asthma had a higher prevalence of PTSD than those who did not report obesity, diabetes, heart disease, or asthma. Findings from this study underscore the need to alert social workers to the potential relationship between obesity, diabetes, or heart disease and PTSD for Black men and asthma and PTSD for Black women to help develop culturally appropriate biopsychosocial–spiritual assessments, with a measured focus on Black men based on their comparatively worse health status.
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

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

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

Genetic 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.
Effects of the award of public service contracts on the performance and payroll of winning firms
Authors: Ravenda Diego , Valencia-Silva Maika Melina , Argiles-Bosch Josep Maria , García-Blandón Josep
Published: September 2021

We investigate the effects of an exogenous demand shock arising from the award of public service contracts by Italian public administrations in 2015 on a sample of 1782 winning small and medium firms that were not awarded any contract during the previous 3 years. Using a difference-in-differences model with continuous treatments estimated on a propensity score matched sample, our results reveal that higher awarded values enhance various performance dimensions of the winning firms as well as their average payroll per employee. Nonetheless, higher winning rebates moderate the positive effects of the award on payroll by inducing the winning firms to downward manage both salaries and social security contributions per employee to maintain their desired level of performance. The effects are mostly significant for smaller microenterprises. In addition, winning rebates negatively affect the performance of firms in the construction industry by leading these firms to downward manage the payroll of their employees more aggressively than firms in other industries. Our findings provide novel insights for the implementation of industrial policies aimed at achieving sustainable macroeconomic and social goals, within the business fabric, through the effective management of public service procurement.
Surface habitat modification through industrial tuna fishery practices
Authors: Dupaix Amaël , Capello Manuela , Lett Christophe , Andrello Marco , Barrier Nicolas , Viennois Gaëlle , Dagorn Laurent
Published: September 2021

Natural floating objects (FOBs) have always been a major component of the habitat of pelagic species. Since the 1990s, the number of FOBs in the open ocean has increased greatly as a result of the introduction of fish aggregating devices (FADs) by the industrial tropical tuna purse seine vessels. These changes, and their potential impacts on the species that associate with FOBs, remain poorly understood. Using fisheries observer data, data from satellite-linked tracking buoys attached to FOBs and Lagrangian simulations, this study quantifies the temporal changes in the density and spatial distribution of FOBs due to the use of FADs in the Indian Ocean (IO) between 2006 and 2018. From 2012 to 2018, the entire western IO is impacted, with FADs representing more than 85% of the overall FOBs, natural FOBs less than 10%, and objects originating from pollution 5%. Results also suggest that both FADs and natural FOBs densities are lower in the eastern IO, but this initial investigation highlights the need for further studies. Our study confirms that FADs have greatly modified the density and spatial distribution of FOBs, which highlights the need to investigate potential consequences on the ecology of associated species.
Extended, virtual and augmented reality in thoracic surgery: a systematic review
Authors: Arjomandi Rad Arian , Vardanyan Robert , Thavarajasingam Santhosh G , Zubarevich Alina , Van den Eynde Jef , Sá Michel Pompeu B O , Zhigalov Konstantin , Sardiari Nia Peyman , Ruhparwar Arjang , Weymann Alexander
Published: September 2021

OBJECTIVES

Extended reality (XR), encompassing both virtual reality (VR) and augmented reality, allows the user to interact with a computer-generated environment based on reality. In essence, the immersive nature of VR and augmented reality technology has been warmly welcomed in all aspects of medicine, gradually becoming increasingly feasible to incorporate into everyday practice. In recent years, XR has become increasingly adopted in thoracic surgery, although the extent of its applications is unclear. Here, we aim to review the current applications of XR in thoracic surgery.

METHODS

A systematic database search was conducted of original articles that explored the use of VR and/or augmented reality in thoracic surgery in EMBASE, MEDLINE, Cochrane database and Google Scholar, from inception to December 2020.

RESULTS

Our search yielded 1494 citations, of which 21 studies published from 2007 to 2019 were included in this review. Three main areas were identified: (i) the application of XR in thoracic surgery training; (ii) preoperative planning of thoracic procedures; and (iii) intraoperative assistance. Overall, XR could produce progression along the learning curve, enabling trainees to reach acceptable standards before performing in the operating theatre. Preoperatively, through the generation of 3D-renderings of the thoracic cavity and lung anatomy, VR increases procedural accuracy and surgical confidence through familiarization of the patient’s anatomy. XR-assisted surgery may have therapeutic use particularly for complex cases, where conventional methods would yield inadequate outcomes due to inferior accuracy.

CONCLUSION

XR represents a salient step towards improving thoracic surgical training, as well as enhancing preoperative planning and intraoperative guidance.
Impact of coronary calcification assessed by coronary CT angiography on treatment decision in patients with three-vessel CAD: insights from SYNTAX III trial
Authors: Andreini Daniele , Takahashi Kuniaki , Mushtaq Saima , Conte Edoardo , Modolo Rodrigo , Sonck Jeroen , De Mey Johan , Ravagnani Paolo , Schoors Danny , Maisano Francesco , Kaufmann Philipp , Lindeboom Wietze , Morel Marie-angele , Doenst Torsten , Teichgräber Ulf , Pontone Gianluca , Pompilio Giulio , Bartorelli Antonio , Onuma Yoshinobu , Serruys Patrick W ,   the Syntax III Revolution Investigators
Published: September 2021

OBJECTIVES

The aim of this study was to determine Syntax scores based on coronary computed tomography angiography (CCTA) and invasive coronary angiography (ICA) and to assess whether heavy coronary calcification significantly limits the CCTA evaluation and the impact of severe calcification on heart team’s treatment decision and procedural planning in patients with three-vessel coronary artery disease (CAD) with or without left main disease.

METHODS

SYNTAX III was a multicentre, international study that included patients with three-vessel CAD with or without left main disease. The heart teams were randomized to either assess coronary arteries with coronary CCTA or ICA. We stratified the patients based on the presence of at least 1 lesion with heavy calcification defined as arc of calcium >180° within the lesion using CCTA. Agreement on the anatomical SYNTAX score and treatment decision was compared between patients with and without heavy calcifications.

RESULTS

Overall, 222 patients with available CCTA and ICA were included in this trial subanalysis (104 with heavy calcification, 118 without heavy calcification). The mean difference in the anatomical SYNTAX score (CCTA derived—ICA derived) was lower in patients without heavy calcifications [mean (−1.96 SD; +1.96 SD) = 1.5 (−19.3; 22.4) vs 5.9 (−17.5; +29.3), P = 0.004]. The agreement on treatment decision did not differ between patients with (Cohen’s kappa 0.79) or without coronary calcifications (Cohen’s kappa 0.84). The agreement on the treatment planning did not differ between patients with (concordance 80.3%) or without coronary calcifications (concordance 82.8%).

CONCLUSIONS

An overall good correlation between CCTA- and ICA-derived Syntax score was found. The presence of heavy coronary calcification moderately influenced the agreement between CCTA and ICA on the anatomical SYNTAX score. However, agreement on the treatment decision and planning was high and irrespective of the presence of calcified lesions.