bluuebunny/crossref_metadata_2025_split huggingface dataset:
Specific photoreceptor cell fate pathways are differentially altered in NR2E3-associated diseases
Authors: Aísa-Marín Izarbe , Rovira Quirze , Díaz Noelia , Calvo-López Laura , Vaquerizas Juan M. , Marfany Gemma 
Published: June 2023

SUMMARYMutations inNR2E3cause two retinal dystrophies with a distinct phenotype.NR2E3encodes an orphan nuclear transcription factor that contributes to photoreceptor cell fate determination by repressing cone while activating rod genes. To dissect NR2E3 function, we performed scRNA-seq in the retinas of wild type and two differentNr2e3mouse models that show phenotypes similar to patients carryingNR2E3mutations. Our results reveal that rod and cone populations are not homogeneous and can be separated into different sub- classes. We identify a previously unreported cone pathway that generates hybrid cones that co-express both cone- and rod-related genes. In mutant retinas, this hybrid cone subpopulation is more abundant, as it includes a subpopulation of rods transitioning towards a cone cell fate. Hybrid photoreceptors with high misexpression of cone- and rod-related genes are prone to regulated necrosis. Overall, our results shed light on the role of NR2E3 in modulating photoreceptor differentiation towards cone and rod fates and explain how mutations inNR2E3lead to different visual disorders in humans.GRAPHICAL ABSTRACTSYNOPSISMutations in the gene encoding the retinal transcription factorNR2E3cause two different inherited retinal dystrophies: retinitis pigmentosa and enhanced S-cone syndrome.scRNA-seq in retinas of wild type and twoNr2e3mouse models reveal that rod and cone populations are not homogeneous and can be classified into different sub-classes.A previously unreported cone pathway that generates hybrid cones co- expressing both cone- and rod-related genes is identified.Hybrid photoreceptors with high misexpression of cone- and rod-related genes are prone to regulated necrosis.Expression of rod and cone signature genes change in response to differentNR2E3mutations thus providing a frame to understand the molecular basis of distinct NR2E3-associated diseases.
Engineered display of ganglioside-sugars on protein elicits a clonally and structurally constrained B cell response
Authors: Deimel Lachlan P. , Xue Xiaochao , Khan Aziz , Moynie Lucile , Buchanan Charles J. , Sun Guoxuan , McBride Ryan , Schuster Heiko , Gauthier Charles , Saliba Regis , Leonavicus Karolis , Minall Leanne , Bort Guillaume , Russell Rebecca A. , Sezgin Erdinc , Paulson James C. , Anthony Daniel C. , Baldwin Andrew J. , Naismith James , Schiffner Torben , Davis Benjamin G. , Sattentau Quentin J. 
Published: June 2023

AbstractGanglioside sugars, as Tumour-Associated Carbohydrate Antigens (TACAs), are long-proposed targets for vaccination and therapeutic antibody production, but their self-like character imparts immunorecessive characteristics that classical vaccination approaches have to date failed to overcome. One prominent TACA, the glycan component of ganglioside GM3 (GM3g), is over-expressed on diverse tumours. To probe the limits of glycan tolerance, we used protein editing methods to display GM3g in systematically varied non-native presentation modes by attachment to carrier protein lysine sidechains using diverse chemical linkers. We report here that such presentation creates glycoconjugates that are strongly immunogenic in mice and elicit robust antigen-specific IgG responses specific to GM3g. Characterisation of this response by antigen-specific B cell cloning and phylogenetic and functional analyses suggests that such display enables the engagement of a highly restricted naïve B cell class with a defined germline configuration dominated by members of theIGHV2subgroup. Strikingly, structural analysis reveals that glycan features appear to be recognised primarily by antibody CDRH1/2, and despite the presence of an antigen-specific Th response and B cell somatic hypermutation, we found no evidence of affinity maturation towards the antigen. Together these findings suggest a ‘reach-through’ model in which glycans, when displayed in non-self formats of sufficient distance from a conjugate backbone, may engage ‘glycan ready’ V-region motifs encoded in the germline. Structural constraints define why, despite engaging the trisaccharide, antibodies do not bind natively-presented glycans, such as when linked to lipid GM3. Our findings provide an explanation for the long-standing difficulties in raising antibodies reactive with native TACAs, and provide a possible template for rational vaccine design against this and other TACA antigens.HighlightsGM3g synthetically coupled via a longer, orthogonal (from backbone) glycoconjugate (LOG) presentation format (thioethyl-lysyl-amidine) display elicits high-titre IgG responses in mice.The germinal centre experience of LOG glycoconjugate-specific B cell responses is directly influenced by the protein backbone.Structural characterisation of the antibody response to LOGs reveals highly restricted germline-encoded glycan-engaging motifs that mediate GM3g recognition.Failure of antibodies to bind the native trisaccharide highlights barriers to be overcome for the rational design of anti-TACA antibodies.
The VR Billboard Paradigm: Using VR and Eye-tracking to Examine the Exposure-Reception-Retention Link in Realistic Communication Environments
Authors: Schmälzle Ralf , Lim Sue , Cho Hee Jung , Wu Juncheng , Bente Gary 
Published: June 2023

AbstractExposure is the cornerstone of media and message effects research. If a health, political, or commercial message is not noticed, no effects can ensue. Yet, existing research in communication, advertising, and related disciplines often fails to measure exposure and demonstrate the causal link between quantified exposure to outcomes because actual exposure (i.e., whether recipients were not only exposed to messages but also took notice of them) is difficult to capture. Here, we harness Virtual Reality (VR) technology integrated with eye tracking to overcome this challenge. While eye-tracking technology alone can capture whether people attend to messages in their communication environment, most eye-tracking research is bound by laboratory-based screen-reading paradigms that are not representative of the broader communication environments in which messages are encountered. Emerging eye-tracking field research suffers from an inability to control and experimentally manipulate key variables. Our solution is to measure eye-tracking within an immersive environment in VR that resembles a realistic message reception context. Specifically, we simulate driving down a highway alongside which billboards are placed and use VR-integrated eye-tracking to measure whether the drivers look at individual billboard messages. This allows us to rigorously quantify the nexus between exposure and reception, and to link our measures to subsequent memory, i.e., whether messages were remembered, forgotten, or not even encoded. We further demonstrate that manipulating drivers’ attention directly impacts gaze behavior and memory. We discuss the large potential of this paradigm to quantify exposure and message reception in realistic communication environments and the equally promising applications in new media contexts (e.g., the Metaverse).
Allosteric activation and inhibition of glycogen phosphorylase share common transient structural features
Authors: Kish Monika , Ivory Dylan P. , Phillips Jonathan J. 
Published: June 2023

ABSTRACTIt remains a major challenge to ascertain the specific structurally dynamic changes that underpin protein functional switching. There is a growing need to complement structural models with the ability to determine the dynamic structural changes that occur as these proteins are regulated and function. The archetypal allosteric enzyme, glycogen phosphorylase is one of the most studied proteins and is a clinical target of much interest to treat type II diabetes and metastatic cancers. However, a lack of understanding of its complex regulation, mediated by dynamic structural changes, hinder its exploitation as a drug target. Here, we precisely locate dynamic structural changes upon allosteric activation and inhibition of glycogen phosphorylase, by developing a time-resolved non-equilibrium millisecond hydrogen/deuterium-exchange mass spectrometry (HDX-MS) approach. We resolved obligate transient changes in localized structure that are absent when directly comparing active/inactive states of the enzyme and show that they are common to allosteric activation by AMP and inhibition by caffeine, operating at different sites. This indicates that opposing allosteric regulation by inhibitor and activator ligands is mediated by pathways that intersect at a common structurally dynamic motif. This approach has broad application to determine the structural kinetic mechanisms by which proteins are regulated.
A deep learning-based drug repurposing screening and validation for anti-SARS-CoV-2 compounds by targeting the cell entry mechanism
Authors: Yao Yingjia , Zhang Yunhan , Li Zexu , Chen Zhisong , Wang Xiaofeng , Li Zihan , Yu Li , Cheng Xiaolong , Li Wei , Jiang Wen-Jie , Wu Hua-Jun , Feng Zezhong , Sun Jinfu , Fei Teng 
Published: June 2023

AbstractThe recent outbreak of Corona Virus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a severe threat to the global public health and economy, however, effective drugs to treat COVID-19 are still lacking. Here, we employ a deep learning-based drug repositioning strategy to systematically screen potential anti-SARS-CoV-2 drug candidates that target the cell entry mechanism of SARS-CoV-2 virus from 2,635 FDA-approved drugs and 1,062 active ingredients from Traditional Chinese Medicine herbs.In silicomolecular docking analysis validates the interactions between the top compounds and host receptors or viral spike proteins. Using a SARS-CoV-2 pseudovirus system, we further identify several drug candidates including Fostamatinib, Linagliptin, Lysergol and Sophoridine that can effectively block the cell entry of SARS-CoV-2 variants into human lung cells even at a nanomolar scale. These efforts not only illuminate the feasibility of applying deep learning-based drug repositioning for antiviral agents by targeting a specified mechanism, but also provide a valuable resource of promising drug candidates or lead compounds to treat COVID-19.
Adding Different Exercise Training Volumes to a Diet-Induced Weight Loss Facilitates Fat Loss and Maintains Fat-Free Mass in a Dose-Depending Fashion in Persons with Newly Diagnosed Type 2 Diabetes: Secondary Findings from the DOSE-EX Multi-Arm, Parallel-Group, Randomized Trial
Authors: Lyngbæk Mark P.P. , Legaard Grit E. , Nielsen Nina S. , Durrer Cody , Almdal Thomas P. , Lund Morten Asp Vonsild , Liebetrau Benedikte , Ewertsen Caroline , Lauridsen Carsten , Solomon Thomas P.J. , Karstoft Kristian , Pedersen Bente K. , Ried-Larsen Mathias 
Published: June 2023

AbstractOBJECTIVETo assess the dose-response effects of exercise in combination with a diet-induced weight loss on fat mass (FM) percentage (FM%) in persons with diagnosed type 2 diabetes.RESEARCH DESIGN AND METHODSIn this secondary analysis of a four-armed randomized trial (Clinicaltrials.govNCT03769883) 82 persons (35% females, mean age and standard deviation (SD) 58.2 (9.8) years) living with type 2 diabetes were randomly allocated to the control group (N=21, CON), diet control (25% energy restriction;N=20, DCON), diet control and exercise three times/week (two sessions of aerobic and one session combining resistance and aerobic training;N=20, MED), or diet control and exercise six times/week (four sessions of aerobic and two sessions combining resistance and aerobic training;N=21, HED) for 16 weeks. The primary outcome was the change in FM percentage points (pp). Secondary outcomes included fat-free mass and visceral adipose tissue volume.RESULTSType 2 diabetes duration was 4.0 years (interquartile range 1.9 to 5.5), body weight (SD) 101.4 kg (14.6), FM% (SD) 39.4 (6.7). FMpp decreased compared to standard care −3.5 pp (95% CI −5.6 to −1.4) p=0.002, −6.3 pp (CI −8.4 to −4.1) p<0.001, and −8.0 pp (95% CI −10.2 to −5.8) p<0.001, for DCON, MED, and HED, respectively. The difference between HED and MED was −1.8 pp [95% CI −3.9 to 0.4]; p=0.11).CONCLUSIONSAll interventions were superior in reducing FMpp compared to standard care in a dose-dependent manner. Adding three or six sessions of exercise to a low-calorie diet was superior in reducing FM compared to a low-calorie diet alone.Article HighlightsWhy did we undertake this study?Exercise and weight loss are recommended for persons with type 2 diabetes. It is unclear if adding exercise, and which amount of exercise, to a low-calorie diet supports additional fat mass loss.What is the specific question(s) we wanted to answer?What is the dose-response effect of exercise combined with a moderate caloric restriction on changes in fat mass?What did we find?Adding exercise to a diet-induced weight loss reduced fat mass and preserved fat-free mass in a dose-dependent manner.What are the implications of our findings?Adding exercise to a moderate caloric restriction dose-dependently facilitates reductions in fat mass by enlarging weight loss and fat loss.
Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer’s Disease
Authors: Prakash Priya , Manchanda Palak , Paouri Evi , Bisht Kanchan , Sharma Kaushik , Rajpoot Jitika , Wendt Victoria , Hossain Ahad , Wijewardhane Prageeth R. , Randolph Caitlin E. , Chen Yihao , Stanko Sarah , Gasmi Nadia , Gjojdeshi Anxhela , Card Sophie , Fine Jonathan , Jethava Krupal P. , Clark Matthew G. , Dong Bin , Ma Seohee , Crockett Alexis , Thayer Elizabeth A. , Nicolas Marlo , Davis Ryann , Hardikar Dhruv , Allende Daniela , Prayson Richard A. , Zhang Chi , Davalos Dimitrios , Chopra Gaurav 
Published: June 2023

SummarySeveral microglia-expressed genes have emerged as top risk variants for Alzheimer’s disease (AD). Impaired microglial phagocytosis is one of the main proposed outcomes by which these AD-risk genes may contribute to neurodegeneration, but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here we show that microglia form lipid droplets (LDs) upon exposure to amyloid-beta (Aβ), and that their LD load increases with proximity to amyloid plaques in brains from human patients and the AD mouse model 5xFAD. LD formation is dependent on age and disease progression and is prominent in the hippocampus in mice and humans. Despite differences in microglial LD load between brain regions and sexes in mice, LD-laden microglia exhibited a deficit in Aβ phagocytosis. Unbiased lipidomic analysis identified a decrease in free fatty acids (FFAs) and a parallel increase in triacylglycerols (TGs) as the key metabolic transition underlying LD formation. DGAT2, a key enzyme for converting FFAs to TGs, promotes microglial LD formation and is increased in 5xFAD and human AD brains. Inhibition or degradation of DGAT2 improved microglial uptake of Aβ and drastically reduced plaque load in 5xFAD mice, respectively. These findings identify a new lipid-mediated mechanism underlying microglial dysfunction that could become a novel therapeutic target for AD.
Circulating Small Extracellular Vesicle RNA Profiling for the Detection of T1a stage Colorectal Cancer and Precancerous Advanced Adenoma
Authors: Min Li , Bu Fanqin , Meng Jingxin , Liu Xiang , Guo Qingdong , Zhao Libo , Li Zhi , Li Xiangji , Zhu Shengtao , Zhang Shutian 
Published: June 2023

AbstractIt takes more than twenty years for normal colorectal mucosa to develop into metastatic carcinoma. The long time window provides a golden opportunity for early detection to terminate the malignant progression. Here we aim to enable liquid biopsy of T1a stage colorectal cancer (CRC) and precancerous advanced adenoma (AA) by profiling circulating small extracellular vesicle (sEV)-derived RNAs. We exhibited a full RNA landscape for the circulating sEVs isolated from 60 participants. A total of 58,333 annotated RNAs were detected from plasma sEVs, among which 1,615 and 888 sEV-RNAs were found differentially expressed in plasma from T1a stage CRC and AA compared to normal controls (NC). Then we further categorized these sEV-RNAs into 6 modules by a weighted gene coexpression network analysis and constructed a 60-gene t-SNE model consisting of the top 10 RNAs of each module that could well distinguish T1a stage CRC/AA from NC samples. Some sEV-RNAs were also identified as indicators of specific endoscopic and morphological features of different colorectal lesions. The top-ranked biomarkers were further verified by RT-qPCR, proving that these candidate sEV-RNAs successfully identified T1a stage CRC/AA from NC in another cohort of 124 participants. Finally, we adopted different algorithms to improve the performance of RT-qPCR-based models and successfully constructed an optimized classifier with 79.3% specificity and 99.0% sensitivity. In conclusion, circulating sEVs of T1a stage CRC and AA patients have distinct RNA profiles, which successfully enable the detection of both T1a stage CRC and AA via liquid biopsy.
Ryegrass mottle virus complete genome determination and development of infectious cDNA by combining two methods – 3′ RACE and 5′ RACE-seq
Authors: Balke Ina , Silamikelis Ivars , Radovica-Spalvina Ilze , Zeltina Vilija , Resevica Gunta , Fridmanis Davids , Zeltins Andris 
Published: June 2023

AbstractSobemovirus ryegrass mottle virus (RGMoV) is a single-stranded positive virus with a 30 nm viral particle size. It exhibitsT=3symmetry, with 180 coat protein (CP) subunits forming the virus structure. The RGMoV genome comprises five open reading frames, encoding P1, Px, a membrane-anchored 3C-like serine protease, a virus genome-linked protein, P16, an RNA-dependent RNA polymerase, and a coat protein. The RGMoV genome size varies, ranging from 4175 nt (MW411579.1) to 4253 nt (MW411579.1) in deposited sequences. An earlier deposited RGMoV complete genome sequence of 4212 nt length (EF091714.1) was utilized to develop an infectious complementary DNA (icDNA) construct forin vitrogRNA transcription from the T7 promoter. However, when the transcribed gRNA was introduced to oat plants, it failed to induce viral infection. This indicated the potential absence of certain sequences in either the 5’ or 3’ untranslated regions (UTR) or both. To resolve this, the complete sequence of the 3’ UTR was determined through 3’ end RACE, while the 5’ UTR was identified using high-throughput sequencing (HTS) - 5’ RACE-seq. Only the icDNA vector containing both newly identified UTR sequences proved infectious, resulting in classical viral infection symptoms and subsequent propagation of progeny viruses, exhibiting the ability to cause repeated infection in oat plants after at least one passage. The successful generation of the icDNA highlights the synergistic potential of utilizing both methods when one approach alone fails. Furthermore, this study demonstrates the reliability of HTS as a method for determining the complete genome sequence of viral genomes.
Structural basis of EHEP-mediated offense against phlorotannin-induced defense from brown algae to protectakuBGL activity
Authors: Sun Xiaomei , Ye Yuxin , Sakurai Naofumi , Wang Hang , Kato Koji , Yu Jian , Yuasa Keizo , Tsuji Akihiko , Yao Min 
Published: June 2023

AbstractThe defensive-offensive associations between algae and herbivores determine marine ecology. Brown algae utilize phlorotannin as their chemical defense against the predatorAplysia kurodai, which uses β-glucosidase (akuBGL) to digest the laminarin in algae to glucose. Moreover,A. kurodaiemploysEiseniahydrolysis-enhancing protein (EHEP) as an offense to protectakuBGL activity from phlorotannin inhibition by precipitating phlorotannin. To underpin the molecular mechanism of this digestive-defensive-offensive system, we determined the structures of apo and tannic-acid (TNA, a phlorotannin-analog) bound form of EHEP, as well as apoakuBGL. EHEP consisted of three peritrophin-A domains formed in a triangle and bound TNA in the center without significant conformational changes. Structural comparison between EHEP and EHEP–TNA led us to find that EHEP can be resolubilized from phlorotannin-precipitation at an alkaline pH, which reflects a requirement in the digestive tract.akuBGL contained two GH1 domains, only one of which conserved the active site. Combining docking analysis, we propose the mechanisms by which phlorotannin inhibitsakuBGL by occupying the substrate-binding pocket, and EHEP protectsakuBGL against the inhibition by binding with phlorotannin to free theakuBGL pocket.
Mitral Annular Disjunction in Out-of-Hospital Cardiac Arrest Patients – a Retrospective Cardiac MRI Study
Authors: Troger Felix , Klug Gert , Poskaite Paulina , Tiller Christina , Lechner Ivan , Reindl Martin , Holzknecht Magdalena , Fink Priscilla , Brunnauer Eva-Maria , Gizewski Elke R. , Metzler Bernhard , Reinstadler Sebastian , Mayr Agnes 
Published: June 2023

AbstractBackgroundMitral annular disjunction (MAD), defined as defective attachment of the mitral annulus to the ventricular myocardium, has recently been linked to malignant arrhythmias. However, its role and prognostic significance in patients requiring cardio-pulmonary resuscitation (CPR) remains unknown. This retrospective analysis aimed to describe prevalence and significance of MAD by cardiac magnetic resonance (CMR) imaging, in out-of-hospital cardiac arrest (OHCA) patients.MethodsEighty-six patients with OHCA and a CMR scan 5 days after CPR (interquartile range (IQR): 49 days before – 9 days after) were consecutively enrolled. MAD was defined as disjunction-extent ≥1mm in CMR long-axis cine-images. Medical records were screened for laboratory parameters, comorbidities and prior arrhythmias.ResultsIn 34 patients (40%), no underlying cause for OHCA was found during hospitalization despite profound diagnostics. Unknown-cause OHCA patients showed a higher prevalence of MAD compared to definite-cause patients (56% vs. 10%, p<0.001) and had a MAD-extent of 6.3mm (IQR: 4.4-10.3); moreover, these patients were significantly younger (43 years vs. 61 years, p<0.001), more often female (74% vs. 21%, p<0.001) and had fewer comorbidities (hypertension, hypercholesterolemia, coronary artery disease, all p<0.005). By logistic regression analysis, presence of MAD remained significantly associated with OHCA of unknown cause (odds ratio: 8.49, 95% confidence interval: 2.37-30.41, p=0.001) after adjustment for age, presence of hypertension and hypercholesterolemia.ConclusionsMAD is rather common in OHCA patients without definitive aetiology undergoing CMR. Presence of MAD remains independently associated to OHCA without identifiable trigger. Further research is needed to understand the exact role of MAD in OHCA patients.Clinical PerspectivesThis study showed that MAD is apparently a common finding in cardiac arrest patients without underlying trigger and was associated with it independently of age, concomitant hypertension and hypercholesterolemia.In clinical routine, MAD should be considered as potential arrhythmogenic substrate especially in those cardiac arrest patients, in which eventually no clear etiology can be found.However, future studies need to further explore the role of MAD in these patients and investigate the true arrhythmogenic potential of this anatomical variant.