bluuebunny/crossref_metadata_2025_split huggingface dataset:
Causal factors in primary open angle glaucoma: a phenome-wide Mendelian randomisation study
Authors: Julian Thomas H , Girach Zain , Sanderson Eleanor , Guo Hui , Yu Jonathan , Cooper-Knock Johnathan , Black Graeme C. , Sergouniotis Panagiotis I 
Published: November 2022

ABSTRACTPrimary open angle glaucoma (POAG) is a chronic, adult-onset optic neuropathy associated with characteristic optic disc and/or visual field changes. With a view to identifying modifiable risk factors for this debilitating condition, we performed a ‘phenome-wide’ univariable Mendelian randomisation (MR) study and analysed the relationship between 9,661 traits and POAG. Data were analysed using the weighted median method, weighted mode based estimation, the Mendelian randomisation (MR) Egger method and the inverse variance weighted approach. Our analysis identified 11 traits related to POAG risk including: serum levels of the angiopoietin-1 receptor (OR [odds ratio] = 1.11, IVW [inverse variance weighted] p= 2.34E-06) and the cadherin 5 protein (OR= 1.06, IVW p= 1.31E-06); intraocular pressure (OR=2.46 - 3.79, MRE IVW p=8.94E-44 - 3.00E-27); diabetes (beta=1.64, IVW p = 9.68E-04); and waist circumference (OR = 0.79, IVW p=1.66E-05). Future research focussing on the effects of diabetes, waist circumference, serum cadherin 5 and serum angiopoietin-1 receptor on POAG development and progression is expected to provide key insights that might inform the provision of lifestyle modification advice and/or the development of novel therapies.
A Mitochondrial Inside-Out Iron-Calcium Signal Reveals Drug Targets for Parkinson’s Disease
Authors: Bharat Vinita , Durairaj Aarooran S. , Vanhauwaert Roeland , Li Li , Muir Colin M. , Chandra Sujyoti , Kwak Chulhwan S. , Guen Yann Le , Nandakishore Pawan , Hsieh Chung-Han , Rensi Stefano E. , Altman Russ B. , Greicius Michael D. , Feng Liang , Wang Xinnan 
Published: November 2022

SummaryDysregulated iron or Ca2+homeostasis has been reported in Parkinson’s disease (PD) models. Here we discover a connection between these two metals at the mitochondria. Elevation of iron levels causes inward mitochondrial Ca2+overflow, through an interaction of Fe2+with Mitochondrial Calcium Uniporter. In PD neurons, iron accumulation-triggered Ca2+influx across the mitochondrial surface leads to spatially confined Ca2+elevation at the outer mitochondrial membrane, which is subsequently sensed by Miro1, a Ca2+-binding protein. A Miro1 blood test distinguishes PD patients from controls and responds to drug treatment. Miro1-based drug screens in PD cells discover FDA-approved T-type Ca2+-channel blockers. Human genetic analysis reveals enrichment of rare variants in T-type Ca2+-channel subtypes associated with PD status. Our results identify a molecular mechanism in PD pathophysiology, and drug targets and candidates coupled with a convenient stratification method.
Practice walking on a treadmill-mounted balance beam modifies beam walking sacral movement and alters performance in other balance tasks
Authors: Symeonidou Evangelia-Regkina , Esposito Nicole M. , Reyes Roehl D. , Ferris Daniel P. 
Published: November 2022

AbstractThe goals of this study were to determine if a single 30-minute session of practice walking on a treadmill-mounted balance beam: 1) altered sacral marker movement kinematics during beam walking, and 2) affected measures of balance during treadmill walking and standing balance. Two groups of young, healthy human subjects practiced walking on a treadmill-mounted balance beam for thirty minutes. One group trained with intermittent visual occlusions and the other group trained with unperturbed vision, providing greater variation in the balance performance outcomes. We hypothesized that the subjects would show changes in sacrum movement kinematics after training and that there would be group differences due to larger improvements in beam walking performance by the visual occlusions group. We also investigated if there was any balance transfer from training on the beam to treadmill walking (margin of stability) and to standing static balance (center of pressure excursion). We found significant differences in sacral marker maximal velocity after training for both groups, but no significant differences between the two groups from training. There was limited evidence of balance transfer from beam walking practice to gait margin of stability for treadmill walking and for single-leg stance balance, but not for tandem stance balance. The number of step-offs while walking on a narrow beam had the largest change with training (partial η2=0.7), in accord with task specificity. Other balance metrics indicative of transfer had lower effect sizes (partial η2<0.5). Given the limited transfer across balance training tasks, future work should examine how intermittent visual occlusions during multi-task training improve real world functional outcomes.
Population genomic evidence of adaptive response during the invasion history ofPlasmodium falciparumin the Americas
Authors: Lefebvre Margaux J. M. , Daron Josquin , Legrand Eric , Fontaine Michael C. , Rougeron Virginie , Prugnolle Franck 
Published: November 2022

AbstractPlasmodium falciparum, the most virulent agent of human malaria, spread from Africa to all continents following the out-of-Africa human migrations. During the transatlantic slave trade between the 16thand 19thcenturies, it was introduced twice independently to the Americas where it adapted to new environmental conditions (new human populations and mosquito species). Here, we analyzed the genome-wide polymorphisms of 2,635 isolates across the currentP. falciparumdistribution range in Africa, Asia, Oceania, and the Americas to investigate its genetic structure, invasion history, and selective pressures associated with its adaptation to the American environment. We confirmed that American populations originated from Africa with at least two independent introductions that led to two genetically distinct clusters, one in the North (Haiti and Columbia) and one in the South (French Guiana and Brazil), and the admixed Peruvian group. Genome scans revealed recent and more ancient signals of positive selection in the American populations. Particularly, we detected positive selection signals in genes involved in interactions with host (human and mosquito) cells and in genes involved in resistance to malaria drugs in both clusters. We found that some genes were under selection in both clusters. Analyses suggested that for five genes, adaptive introgression between clusters or selection on standing variation was at the origin of this repeated evolution. This study provides new genetic evidence onP. falciparumcolonization history and on its local adaptation in the Americas.
High-Throughput Library Transgenesis inCaenorhabditis elegansvia Transgenic Arrays Resulting in Diversity of Integrated Sequences (TARDIS)
Authors: Stevenson Zachary C. , Moerdyk-Schauwecker Megan J. , Banse Stephen A. , Patel Dhaval S. , Lu Hang , Phillips Patrick C. 
Published: November 2022

AbstractHigh-throughput transgenesis using synthetic DNA libraries is a powerful method for systematically exploring genetic function. Diverse synthesized libraries have been used for protein engineering, identification of protein-protein interactions, characterization of promoter libraries, developmental and evolutionary lineage tracking, and various other exploratory assays. However, the need for library transgenesis has effectively restricted these approaches to single-cell models. Here we present Transgenic Arrays Resulting in Diversity of Integrated Sequences (TARDIS), a simple yet powerful approach to large-scale transgenesis that overcomes typical limitations encountered in multicellular systems. TARDIS splits the transgenesis process into a two-step process: creation of individuals carrying experimentally introduced sequence libraries, followed by inducible extraction and integration of individual sequences/library components from the larger library cassette into engineered genomic sites. Thus, transformation of a single individual, followed by lineage expansion and functional transgenesis, gives rise to thousands of genetically unique transgenic individuals. We demonstrate the power of this system using engineered, split selectable TARDIS sites in Caenorhabditis elegans to generate (1) a large set of individually barcoded lineages and (2) transcriptional reporter lines from pre-defined promoter libraries. We find that this approach increases transformation yields up to approximately 1000-fold over current single-step methods. While we demonstrate the utility of TARDIS using C. elegans, in principle the process is adaptable to any system where experimentally generated genomic loci landing pads and diverse, heritable DNA elements can be generated.
The undue influence of genetic information on medical students’ treatment decisions
Authors: Lane Andrew S. , Lynch Kate E. , Arnold Mark , Dar-Nimrod Ilan , Morandini James , Gawronski Stefan A. , Griffiths Paul E. 
Published: November 2022

AbstractIntroductionKnowledge of the genetic basis of health conditions can influence how the public perceives their own and others’ health. When there are known genetic associations for such conditions, genetic essentialist biases facilitate deterministic thinking and an over-emphasis of genetic causality. This study investigates the role that genetic essentialist biases play in medical decision making.MethodsThird- and fourth- year medical students (N = 102) read a scenario in which a patient presents with gastroenterological symptoms. Half of the students were told that the patient tested positive for HLADQ2 – a gene implicated in, but not deterministic of, coeliac disease. The other half received no genetic information. Students were assessed on their recommendations for investigation and management using a multiple-choice questionnaire. Twenty-two of these students participated in a qualitative follow-up which used semi-structured interviews to explore the reasoning behind students’ responses.ResultsManagement recommendations differed between the two groups, with those receiving genetic information more likely to recommend a gluten free diet. Recommendations for further investigation did not differ significantly between groups. Interviews suggested that these findings arose despite the students’ good understanding of the common non-deterministic nature of genes, such as HLADQ2. Differences in management recommendations suggest that the inclusion of genetic information unduly biased students towards a premature diagnosis of a serious health condition–coeliac disease. Follow-up interviews introduce the possibility that observed manipulation-based differences may have been based on anticipated expectations of examiners. Thus, research in clinical settings is needed to ascertain whether genetic essentialist biases are implicitly influencing medical students under examination conditions or whether they react to the assumptive genetic biases of examiners.ConclusionThe present findings indicate that genetic essentialist biases may affect clinical decision making of senior medical students. While the findings may also arise as an artifact of a conscious exam-taking strategy, there are substantial arguments against this interpretation.
Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma
Authors: Recouvreux Maria Victoria , Galapate Cheska Marie , Grenier Shea , Esparza Edgar , Zhang Yijuan , Maganti Swetha , Naeem Razia , Scott David A. , Lowy Andrew M. , Tiriac Hervé , Commisso Cosimo 
Published: November 2022

ABSTRACTIn pancreatic ductal adenocarcinoma (PDAC), glutamine is a critical nutrient that drives a wide array of metabolic and biosynthetic processes that support tumor growth. Despite this established dependency, the targeting of specific enzymes involved in glutamine metabolism is yet to yield any clinical benefit. Here, we have examined the therapeutic potential of 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist that broadly inhibits glutamine metabolism. We found that DON treatment significantly blocks PDAC tumor growth and attenuates metastasis. Interestingly, we link the effectiveness of DON in PDAC to asparagine (Asn) metabolism. By inhibiting asparagine synthetase (ASNS), DON significantly reduces intracellular Asn production and Asn supplementation rescues the anti-proliferative effects of DON. We discern that PDAC cells upregulate expression of ASNS as a metabolic adaptation and that modulating ASNS levels can impact DON efficacy. Strikingly, in patient-derived organoids, DON responsiveness is inversely correlated with ASNS expression, a feature that is not observed for other metabolic enzymes targeted by DON. We find that treatment with L-asparaginase (ASNase), an enzyme that catabolizes free Asn, synergizes with DON to impact the viability of PDAC cells. Finally, we identify that a combination therapy of DON and ASNase has a significant impact on metastasis. These results shed light on the mechanisms that drive the effects of glutamine mimicry and point to the utility of co-targeting adaptive responses to control PDAC progression.
Reconstitution of human adrenocortical specification and steroidogenesis using induced pluripotent stem cells
Authors: Sakata Yuka , Cheng Keren , Mayama Michinori , Seita Yasunari , Detlefsen Andrea J. , Mesaros Clementina A. , Penning Trevor M. , Shishikura Kyosuke , Yang Wenli , Auchus Richard J. , Strauss Jerome F. , Sasaki Kotaro 
Published: November 2022

AbstractThe mechanisms leading to adrenal cortex development and steroid synthesis in humans remain poorly understood due to the paucity of model systems. Herein, we faithfully recapitulate human fetal adrenal cortex specification processes through stepwise induction of human induced pluripotent stem cells through posterior intermediate mesoderm-like and adrenal progenitor-like states to ultimately generate fetal zone adrenal cortex-like cells (FZLCs), as evidenced by histomorphological, ultrastructural, and transcriptome features and adrenocorticotropic hormone (ACTH)-independent Δ5 steroid biosynthesis. Furthermore, FZLC generation is promoted by SHH and inhibited by NOTCH, ACTIVIN and WNT signaling, and that steroid synthesis is amplified by ACTH/PKA signaling and blocked by inhibitors of Δ5 steroid synthesis enzymes. Finally, NR5A1 promotes FZLC survival and steroidogenesis. Together, these findings provide a framework for understanding and reconstituting human adrenocortical development in vitro paving the way for cell-based therapies of adrenal insufficiency.
RSV-induced Expanded Ciliated Cells Contribute to Bronchial Wall Thickening
Authors: Talukdar Sattya N. , Osan Jaspreet , Ryan Ken , Grove Bryon , Perley Danielle , Kumar Bony D. , Yang Shirley , Dallman Sydney , Hollingsworth Lauren , Bailey Kristina L. , Mehedi Masfique 
Published: November 2022

AbstractViral infection, particularly respiratory syncytial virus (RSV), causes inflammation in the bronchiolar airways (bronchial wall thickening, also known as bronchiolitis), reducing airflow through the bronchioles. This bronchial wall thickening is a common pathophysiological feature in RSV infection, but it causes more fatalities in infants than in children and adults. However, the molecular mechanism of RSV-induced bronchial wall thickening remains unknown, particularly in healthy adults. RSV infection in the airway epithelium of healthy adult bronchial cells reveals RSV-infects primarily ciliated cells. RSV infection expands the cell cytoskeleton substantially without compromising epithelial membrane integrity and ciliary functions. The RSV-induced actin cytoskeleton expansion increases ununiformly epithelial height, and cytoskeletal (actin polymerization), immunological (INF-L1, TNF-α, IP10/CXCL10), and viral (NS2) factors are probably responsible. Interestingly, RSV-infected cell cytoskeleton’s expansion resembles a noncanonical inflammatory phenotype, which contributes to bronchial wall thickening, and is termed cytoskeletal inflammation.Author SummaryRSV infects everyone. Although RSV-induced fatal pathophysiology (e.g., bronchiolitis) is more common in infants than adults, this bronchiolitis (or bronchial wall thickening) is common in the lower respiratory tract due to RSV infection in all ages. To determine the molecular mechanism of RSV-induced bronchial wall thickening, we infectedin vitroadult airway epithelium with RSV. We found that RSV-infection induced a substantial actin-cytoskeleton expansion, consequently increased the height of the epithelium. We identified actin polymerization, secretion of proinflammatory cytokines and chemokines, and viral proteins contribute to the RSV-induced cytoskeletal expansion. Our results suggest that RSV-induces a novel noncanonical epithelial host response termed cytoskeletal inflammation, which may contribute to bronchial wall thickening.
Structural basis of Irgb6 inactivation byToxoplasma gondiithrough the phosphorylation of switch I
Authors: Okuma Hiromichi , Saijo-Hamano Yumiko , Sherif Aalaa Alrahman , Hashizaki Emi , Sakai Naoki , Kato Takaaki , Imasaki Tsuyoshi , Nitta Eriko , Sasai Miwa , Maniwa Yoshimasa , Kosako Hidetaka , Standley Daron M , Yamamoto Masahiro , Nitta Ryo 
Published: November 2022

AbstractUpon infection withToxoplasma gondii, host cells produce immune-related GTPases (IRGs) to kill the parasite.T. gondiicounters this response by releasing ROP18 kinase, which inactivates IRG GTPases and inhibits their recruitment to theT. gondiiparasitophorous vacuole (PV). However, the molecular mechanisms of this process are entirely unknown. Here we report the atomic structures of Irgb6 with a phosphomimetic mutation by ROP18. The mutant has lower GTPase activity and is not recruited to the PV membrane (PVM). The crystal structure shows the mutant exhibit a distinct conformation from the physiological nucleotide-free form, thus preventing GTPase cycling. This change allosterically modifies the conformation of the membrane-binding interface, preventing physiological PVM-binding. Docking simulation of PI5P also supports the impaired binding of the mutant to PVM. We thus demonstrate the structural basis forT. gondiiescape from host cell-autonomous defense, and provide a structural model for regulating enzymatic activity by phosphorylation.
An optimised method for the recovery of laboratory generated SARS-CoV-2 aerosols by plaque assay
Authors: Byrne Rachel L , Gould Susan , Edwards Thomas , Wooding Dominic , Atkinson Barry , Moore Ginny , Collings Kieran , Boisdon Cedric , Maher Simon , Biagini Giancarlo , Adams Emily R , Fletcher Tom , Pennington Shaun H 
Published: November 2022

AbstractWe present an optimised method for the recovery of laboratory generated SARS-CoV-2 virus by plaque assay. This method allows easy incorporation into existing standard operating procedures of biological containment level 3 (BCL3) laboratories.
Identifying the best PCR enzyme for library amplification in NGS
Authors: Quail Michael A , Corton Craig , Uphill James , Keane Jacqueline , Gu Yong 
Published: November 2022

AbstractBackgroundPCR amplification is a necessary step in many next generation sequencing (NGS) library preparation methods[1] [2]. Whilst many PCR enzymes are developed to amplify single targets efficiently, accurately and with specificity, few are developed to meet the challenges imposed by NGS PCR, namely unbiased amplification of a wide range of different sizes and GC content. As a result PCR amplification during NGS library prep often results in bias toward GC neutral and smaller fragments. As NGS has matured, optimised NGS library prep kits and polymerase formulations have emerged and in this study we have tested a wide selection of available enzymes for both short read Illumina library preparation and long fragment amplification ahead of long-read sequencing.ResultsWe tested over 20 different Hi-fidelity PCR enzymes/NGS amplification mixes on a range of Illumina library templates of varying GC content and composition, and find that both yield and genome coverage uniformity characteristics of the commercially available enzymes varied dramatically. Three enzymes Quantabio RepliQa Hifi Toughmix, Watchmaker Library Amplification Hot Start Master Mix (2X) “Equinox” and Takara Ex Premier were found to give a consistent performance, over all genomes, that mirrored closely that observed for PCR free datasets. We also test a range of enzymes for long read sequencing by amplifying size fractionated S. cerevisiae DNA of average size 21.6 and 13.4kb respectively.ConclusionThe enzymes of choice for short read (Illumina) library fragment amplification are Quantabio RepliQa Hifi Toughmix, Watchmaker Library Amplification Hot Start Master Mix (2X) “Equinox” and Takara Ex Premier, with RepliQa also being the best performing enzyme from the enzymes tested for long fragment amplification prior to long read sequencing.
Chronological aging impacts abundance, function and microRNA content of extracellular vesicles produced by human epidermal keratinocytes
Authors: Nedachi Taku , Bonod Christelle , Rorteau Julie , Chinoune Wafae , Ishiuchi Yuri , Hughes Sandrine , Gillet Benjamin , Sigaudo-Roussel Dominique , Lamartine Jérôme 
Published: November 2022

AbstractThe disturbance of intercellular communication is one of the hallmarks of aging. The goal of this study is to clarify the impact of chronological aging on extracellular vesicles (EVs), a key mode of communication in mammalian tissues. We focused on epidermal keratinocytes, the main cells of the outer protective layer of the skin which is strongly impaired in the skin of elderly. EVs were purified from conditioned medium of primary keratinocytes isolated from infant or aged adult skin. A significant increase of the relative number of EVs released from aged keratinocytes was observed whereas their size distribution was not modified. By small RNA sequencing, we described a specific microRNA (miRNA) signature of aged EVs with an increase abundance of miR-30a, a key regulator of barrier function in human epidermis. EVs from aged keratinocytes were found to be able to reduce the proliferation of young keratinocytes, to impact their organogenesis properties in a reconstructed epidermis model and to slow down the early steps of skin wound healing in mice, three features observed in aged epidermis. This work reveals that intercellular communication mediated by EVs is modulated during aging process in keratinocytes and might be involved in the functional defects observed in aged skin.
Topological benchmarking of algorithms to infer Gene Regulatory Networks from Single-Cell RNA-seq Data
Authors: Popp Niclas , Stock Marco , Fiorentino Jonathan , Scialdone Antonio 
Published: November 2022

AbstractIn recent years, many algorithms for inferring gene regulatory networks from single-cell transcriptomic data have been published. Several studies have evaluated their accuracy in estimating the presence of an interaction between pairs of genes. However, these benchmarking analyses do not quantify the algorithms’ ability to capture structural properties of networks, which are fundamental, for example, for studying the robustness of a gene network to external perturbations. Here, we devise a three-step benchmarking pipeline called STREAMLINE that quantifies the ability of algorithms to capture topological properties of networks and identify hubs. To this aim, we use data simulated from different types of networks as well as experimental data from three different organisms. We apply our benchmarking pipeline to four algorithms and provide guidance on which algorithm should be used depending on the global network property of interest.