bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatiotemporal Transcriptomes of Pig Hearts Reveal Midkine-Mediated Vascularization in a Chronic Myocardial Infarcted Model
Authors: Adusumalli Swarnaseetha , Lim Samantha , Ren Vincent , Chong Li Yen , Tham Roy , Lei Ye , Wang Yibin , Petretto Enrico , Tryggvason Karl , Yap Lynn 
Published: June 2023

ABSTRACTIschemic heart disease is the most prevalent cause of death globally. Regenerative cardiology using stem cell-based therapy is a potential approach to replace infarcted myocardial (MI) heart tissue. We used cardiovascular progenitors (CVPs) derived from human pluripotent embryonic stem cells differentiated to cardiomyocyte progenitors on a laminin 521+221 matrix and transplanted them into acute and chronic MI pig hearts (AMI and CMI). We performed time-series spatial transcriptomics to characterize these human cells at AMI 1- and 2- and at CMI 1-, 4- and 12 weeks post-transplantation. Both models showed high transcriptional reproducibility in the replicates. Furthermore, the human grafts engrafted well, matured, and expressed metabolic, ribosomal, T-tubule, and channel-related genes in the human graft over time. Cell-cell communication analysis revealed Midkine (MDK) signaling as a key pathway that may lead to increased angiogenesis of collaterals in the human graft.
cTBS Over the Left Supplementary Motor Area (lSMA) Does Not Modulate Rhythmic Bimanual Coordination in the Presence and Absence of Visual Cues
Authors: Kaur Jaskanwaljeet , Balasubramaniam Ramesh 
Published: June 2023

AbstractBimanual coordination modes, namely in-phase and anti-phase, represent two distinct movement patterns characterized by simultaneous & symmetrical movements of both hands and alternating complementary actions, respectively. These coordination modes are integral in various activities, such as playing musical instruments, typing, and participating in sports that demand precise hand-eye coordination. The objective of the present experiment was to investigate the impact of continuous theta burst stimulation (cTBS) targeting the left supplementary motor area (lSMA) on bimanual coordination during in/anti-phase coordination modes. To explore this, we utilized a steady-state system of coordination dynamics and evaluated the continuous relative phase (ϕ) and variability of relative phase (SDϕ) during cued and non-cued trials in both pre- and post-transcranial magnetic stimulation (TMS) conditions. The results revealed that visual cues (cued trials) significantly enhanced bimanual coordination performance in both in/anti-phase coordination modes. However, contrary to expectations, the downregulation of lSMA through cTBS did not lead to significant disruptions in movement during in/anti-phase bimanual coordination in pre- and post-TMS stimulation. Potential factors for the lack of observed effects include methodological limitations, individual differences, and functional redundancy within the motor system. Further research is needed to optimize stimulation parameters, increase sample sizes, and explore the interactions between the lSMA, and other brain regions involved in motor control to gain a comprehensive understanding of the contributions of the lSMA in bimanual coordination.
The motor anomalies seen in isolated REM sleep behavior disorder
Authors: Simonet Cristina , Pérez-Carbonell Laura , Huxford Brook FR , Chohan Harneek , Gill Aneet , Leschziner Guy , Lees Andrew J , Schrag Anette , Noyce Alastair J 
Published: June 2023

AbstractBackgroundIsolated REM sleep behavior disorder (iRBD) is known to be an early feature in some PD patients. Quantitative tools are needed to detect early motor anomalies in iRBD.MethodsA motor battery was used to compare iRBD patients with controls. This included two online keyboard-based tests, the BRadykineisa Akinesia INcoordination (BRAIN) test and the Distal Finger Tapping (DFT) test, a timed handwriting task and two motor assessments (10-meter walking and finger tapping) carried out both alone and during a mental task. This battery was compared with the motor section of the MDS-MDS-UPDRS-III. ROC analyses were used to measure diagnostic accuracy.ResultsWe included 33 patients with video-PSG-confirmed iRBD and 29 age and sex matched controls. The iRBD group performed the BRAIN test and DFT test more slowly (p<0.001, p=0.020 respectively) and erratically (p<0.001, p=0.009 respectively) than controls. Handwriting speed was 10 seconds slower in iRBDs than controls (p=0.004). Unlike controls, under a mental task the iRBD group decreased their walking pace (p<0.001) and had a smaller amplitude (p=0.001) and slower (p=0.007) finger tapping than tasks in isolation. The combination of BRAIN & DFT tests with the effect of mental tasks on walking and finger tapping showed 90.3% sensitivity for 89.3% specificity (AUC 0.94, 95% CI 0.88-0.99), which was higher than the MDS-UPDRS-III (minus action tremor) (69.7% sensitivity, 72.4% specificity; AUC 0.81, 95% CI 0.71-0.91) for detecting motor abnormalities.ConclusionThis study suggests that speed, incoordination, and dual task motor deterioration might be accurate indicators of incipient PD in iRBD.
Combined near infrared photoacoustic imaging and ultrasound detects vulnerable atherosclerotic plaque
Authors: Schneider Martin Karl , Wang James , Kare Aris , Adkar Shaunak S. , Salmi Darren , Bell Caitlin F. , Alsaigh Tom , Wagh Dhananjay , Coller John , Mayer Aaron , Snyder Sarah J. , Borowsky Alexander D. , Long Steven R. , Lansberg Maarten G. , Steinberg Gary K. , Heit Jeremy J. , Leeper Nicholas J. , Ferrara Katherine W. 
Published: June 2023

AbstractAtherosclerosis is an inflammatory process resulting in the deposition of cholesterol and cellular debris, narrowing of the vessel lumen and clot formation. Characterization of the morphology and vulnerability of the lesion is essential for effective clinical management. Photoacoustic imaging has sufficient penetration and sensitivity to map and characterize human atherosclerotic plaque. Here, near infrared photoacoustic imaging is shown to detect plaque components and, when combined with ultrasound imaging, to differentiate stable and vulnerable plaque. In anex vivostudy of photoacoustic imaging of excised plaque from 25 patients, 88.2% sensitivity and 71.4% specificity were achieved using a clinically-relevant protocol. In order to determine the origin of the near-infrared auto-photoacoustic (NIRAPA) signal, immunohistochemistry, spatial transcriptomics and proteomics were applied to adjacent sections of the plaque. The highest NIRAPA signal was spatially correlated with bilirubin and associated blood-based residue and inflammatory macrophages bearing CD74, HLA-DR, CD14 and CD163 markers. In summary, we establish the potential to apply the NIRAPA-ultrasound imaging combination to detect vulnerable carotid plaque.Graphical Abstract
Quality of Refractive Error Care in Cambodia: An Unannounced Standardised Patient Study
Authors: Burnett Anthea , Meng Ngy , Seiha Do , Kong Neath , Chea Seila , Dean Malis , Horm Piseth , Meas Kim San , Varga Beatrice , Ho Suit May , McGuinness Myra , Lee Ling 
Published: June 2023

AbstractPurposeQuality-of-care in refractive error services is essential, as it directly affects vision outcomes, wellbeing, educational attainment, and workforce participation. In Cambodia, uncorrected refractive error is a leading cause of mild and moderate vision impairment in adults. We evaluated the quality of refractive error care in Cambodia by estimating the proportion of prescribed and dispensed spectacles appropriate for people’s refractive error needs and factors associated with spectacle quality.MethodsA cross-sectional protocol was employed with 18 Khmer-speaking adult participants observing testing procedures in 156 optical services across six provinces in 2022. A total of 496 dispensed spectacles were assessed against spectacle quality indicators.ResultsThe analysis revealed that 35.1% of dispensed spectacles were of optimal quality. The most common error observed in sub-optimal spectacles was the presence of horizontal prism outside of tolerance limits. The study also found that 44.0% of emmetrope visits involved unnecessary prescription spectacle recommendations, and 18.3% of written prescriptions did not correspond with dispensed spectacles. Sex differences were observed, with men predominantly providing refractive error care and women more likely to be unnecessarily recommended prescription spectacles.ConclusionThe findings highlight the importance of prioritizing quality-of-care in refractive error services. A key recommendation is to consider regulatory mechanisms to ensure optical services employ appropriately qualified staff. Additionally, efforts should be made to eliminate unnecessary prescriptions –– especially for emmetropes and females –– standardize written prescriptions, ensure consistent pupil distance measurements, reduce reliance on autorefraction, and address the gender imbalance in the refractive error workforce.
Tobacco usage among general Indian population: A meta-analysis of evidence drawn from regional studies between 2010 - 2022
Authors: Pahari Shubhajit , Barman Diplina , Talukdar Rounik 
Published: June 2023

AbstractObjectivesThe purpose of this review is to generate a national and zonal pooled estimate of Current Tobacco Usage (CTU) in any form, as well as stratified gender and tobacco type (smokeless & smoke) specific estimates among the general Indian population, utilizing evidence from 2010 to 2022.MethodPubMed, Scopus, Science Direct, CINAHL and Google Scholar databases were searched for articles on tobacco use among Indian adults published between January 2010 and October 2022. The NIH Quality Assessment Tool was used to assess study quality, and a random-effects inverse-variance method was used to attain a pooled estimate of usage. Heterogeneity was estimated through I2statistics and prediction intervals, and further subgroup analysis and meta-regression were conducted. To estimate publication bias egger’s test was performed and a leave-one-out analysis was done to establish the sensitivity of our overall pooled estimate.ResultsCTU of any form amongst the Indian population irrespective of age group was 35.25% (Confidence Interval (CI) 25.27 - 45.92, I2= 99.7, P-value < 0.001) between the years 2010 - 2022, whereas through 2016 – 2022 regionally drawn estimate was 44.38% (CI 30.57 – 58.64, I2= 99.8, P-value < 0.01). The region-wise highest prevalence was found in the East zone (55.43%) followed by North – East with 51.88% consumption. Though residual heterogeneity was present after subgroup analysis, Variability in estimates was statistically significant by administrative zones and gender-wise consumption (test of subgroup difference P value <0.0001). Leave-one-out analysis proved consistency in our overall CTU estimate.ConclusionThe differences between national-level surveys and regional estimates are highlighted in this review and thereby warrant more regionally representative surveys of tobacco usage for tailor-making prevention efforts alongside, increased regional efforts, improved community-level advocacy, and more coordinated and stringent tobacco prevention policy implementation at national and state levels.
The broad impact of cell death genes on the human disease phenome
Authors: Rich Abigail , Lin Phillip , Gamazon Eric , Zinkel Sandra 
Published: June 2023

ABSTRACTApoptotic, necroptotic, and pyroptotic cell death pathways are attractive and druggable targets for many human diseases, however the tissue specificity of these pathways and the relationship between these pathways and human disease is poorly characterized. Understanding the impact of modulating cell death gene expression on the human phenome could inform clinical investigation of cell death pathway-modulating therapeutics in human disorders by identifying novel trait associations and by detecting tissue-specific side effect profiles. We analyzed the expression profiles of an array of 44 cell death genes across somatic tissues in GTEx v8 and investigated the relationship between tissue-specific genetically determined expression of 44 cell death genes and the human phenome using summary statistics-based transcriptome wide association studies (TWAS) on human traits in the UK Biobank V3 (n ∼500,000). We evaluated 513 traits encompassing ICD-10 defined diagnoses and hematologic traits (blood count labs). Our analysis revealed hundreds of significant (FDR<0.05) associations between cell death gene expression and diverse human phenotypes, which were independently validated in another large-scale biobank. Cell death genes were highly enriched for significant associations with blood traits versus non-cell-death genes, with apoptosis-associated genes enriched for leukocyte and platelet traits and necroptosis gene associations enriched for erythroid traits (e.g., Reticulocyte count, FDR=0.004). This suggests that immunogenic cell death pathways play an important role in regulating erythropoiesis and reinforces the paradigm that apoptosis pathway genes are critical for white blood cell and platelet development. Of functionally analogous genes, for instance pro-survival BCL2 family members, trait/direction-of-effect relationships were heterogeneous across blood traits. Overall, these results suggest that even functionally similar and/or orthologous cell death genes playdistinctroles in their contribution to human phenotypes, and that cell death genes influence a diverse array of human traits.
Genetic and immune determinants ofE. coliliver abscess formation
Authors: Hullahalli Karthik , Dailey Katherine G. , Hasegawa Yuko , Suzuki Masataka , Zhang Hailong , Threadgill David W. , Waldor Matthew K. 
Published: June 2023

AbstractSystemic infections can yield distinct outcomes in different tissues. In mice, intravenous inoculation ofE.colileads to bacterial replication within liver abscesses while other organs such as the spleen largely clear the pathogen. Abscesses are macroscopic necrotic regions that comprise the vast majority of the bacterial burden in the animal, yet little is known about the processes underlying their formation. Here, we characterizeE. coliliver abscesses and identify host determinants of abscess susceptibility. Spatial transcriptomics revealed that liver abscesses are associated with heterogenous immune cell clusters comprised of macrophages, neutrophils, dendritic cells, innate lymphoid cells, and T-cells that surround necrotic regions of the liver. Susceptibility to liver abscesses is heightened in the C57BL/6 lineage, particularly in C57BL/6N females. Backcross analyses demonstrated that abscess susceptibility is a polygenic trait inherited in a sex-dependent manner without direct linkage to sex chromosomes. As early as one day post infection, the magnitude ofE. colireplication in the liver distinguishes abscess-susceptible and abscess-resistant strains of mice, suggesting that the immune pathways that regulate abscess formation are induced within hours. We characterized the early hepatic response with single-cell RNA sequencing and found that mice with reduced activation of early inflammatory responses, such as those lacking the LPS receptor TLR4, are resistant to abscess formation. Experiments with barcodedE. colirevealed that TLR4 mediates a tradeoff between abscess formation and bacterial clearance. Together, our findings define hallmarks ofE. coliliver abscess formation and suggest that hyperactivation of the hepatic innate immune response drives liver abscess susceptibility.ImportanceAnimal models of disseminating bacterial infections are critical for developing therapeutic interventions. Following systemic dissemination in mice,E. coliundergo dramatic replication within abscesses in the liver but not in other organs. Although liver abscesses are the largest reservoir of bacteria within the animal, the processes that lead to abscess formation are not known. Here, we characterizeE. coliliver abscess formation and identify several determinants of abscess susceptibility, including sex, mouse genotype, and innate immune factors. By combining spatial and single-cell transcriptomics with genetic and phenotypic analyses, we delineate critical host pathways that underlie abscess formation. Our findings define several avenues for future studies to unravel how abscess susceptibility determinants interact to modulate clearance of systemic infections and govern tissue-specific bacterial replication.
Hypothalamic neuronal activation in primates drives naturalistic goal-directed eating behavior
Authors: Ha Leslie Jaesun , Yeo Hyeon-Gu , Kim Yu Gyeong , Baek Inhyeok , Baeg Eunha , Lee Young Hee , Won Jinyoung , Jung Yunkyo , Park Junghyung , Jeon Chang-Yeop , Kim Keonwoo , Min Jisun , Song Youngkyu , Park Jeong-Heon , Nam Kyung Rok , Son Sangkyu , Michael Yoo Seng Bum , Park Sung-hyun , Choi Won Seok , Lim Kyung Seob , Choi Jae Yong , Cho Jee-Hyun , Lee Youngjeon , Choi Hyung Jin 
Published: June 2023

AbstractEating addiction is the primary cause of modern obesity. Although the causal role of the lateral hypothalamic area (LHA) for eating is demonstrated in rodents, there is no evidence in primates regarding naturalistic eating behaviors. We investigated the role of LHA GABAergic (LHAGABA) neurons in eating by chemogenetics in three macaques. LHAGABAneuron activation significantly increased naturalistic goal-directed behaviors and food motivation, which was specific for palatable food. PET and MRS validated the chemogenetic activation. Rs-fMRI result revealed that functional connectivity (FC) between the LHA and frontal areas was increased, while the FC between the frontal cortices was decreased after the LHAGABAneuron activation. Thus, our study elucidates the role of LHAGABAneurons in eating and obesity therapeutics for primates and humans.
The distress context of social calls evokes a fear response in the batPipistrellusabramus
Authors: Yoshino-Hashizawa Kazuki , Nishiuchi Yuna , Hiragochi Midori , Kihara Motoki , Kobayasi Kohta I , Hiryu Shizuko 
Published: June 2023

AbstractBats primarily use sound information, including echolocation, for social communication. Bats under stressful conditions, for example when confronted by a predator, will emit aggressive social calls. The presentation of aggressive social calls, including distress calls (DCs), is known to increase heart rate (HR), but how this change in HR is related to the bat’s sound perception and how this evokes behaviors such as the fear response is unknown. Herein, we show that the perception of a distress context induces freezing behavior as a fear response in bats. We found that bats responded by freezing and displayed increased HRs when they were presented with a conspecific donor bat in a distress situation evoked by gentle poking with a cotton swab. In addition, when we presented two types of auditory oddball paradigms with different probabilities of DCs and echolocation calls (ECs), the bats’ HRs increased when DCs were presented as deviant or control stimuli within standard ECs but did not increase when DCs were presented as standard stimuli. These results suggest that the situational context created by the frequency of sound presentation, rather than simply a single sound feature, induces HR increases and freezing as fear responses in bats.Summary statementWe investigated the electrocardiograms of captivePipistrellus abramusand found that their heart rate increased as a fear response when the bats heard sounds with a distress context.
Improved Production of Taxol® Precursors inS. cerevisiaeusing Combinatorialin silicoDesign and Metabolic Engineering
Authors: Malcı Koray , Santibáñez Rodrigo , Jonguitud-Borrego Nestor , Santoyo-Garcia Jorge H. , Kherkoven Eduard J. , Rios-Solis Leonardo 
Published: June 2023

ABSTRACTIntegrated metabolic engineering approaches combining system and synthetic biology tools allow the efficient designing of microbial cell factories to synthesize high-value products. In the present study,in silicodesign algorithms were used on the latest yeast genome-scale model 8.5.0 to predict potential genomic modifications that could enhance the production of early-step Taxol® in previously engineeredSaccharomyces cerevisiaecells. The solution set containing genomic modification candidates was narrowed down by employing the COnstraints Based Reconstruction and Analysis (COBRA) methods. 17 genomic modifications consisting of nine gene deletions and eight gene overexpression were screened using wet-lab studies to determine whether these modifications can increase the production yield of taxadiene, the first metabolite in the Taxol® through the mevalonate pathway. Depending on the cultivation condition, most of the single genomic modifications resulted in higher taxadiene production. The best-performing strain, named KM32, contained four overexpressed genes,ILV2, TRR1, ADE13andECM31, from the branched-chain amino acid biosynthesis, thioredoxin system,de novopurine synthesis, and the pantothenate pathway, respectively. Using KM32, taxadiene production was increased by 50%, reaching 215 mg/L of taxadiene. The engineered strain also produced 43.65 mg/L of taxa-4(20),11-dien-5α-ol (T5α-ol), and 26.2 mg/L of taxa-4(20),11-dien-5-α-yl acetate (T5αAc) which are the highest productions of these early-step Taxol® metabolites reported until now inS. cerevisiae. The findings of this study highlight that the use of computational and integrated approaches can ensure determining promising modifications that are difficult to estimate intuitively to develop yeast cell factories.
PP2A-B55SUR-6promotes nuclear envelope breakdown inC. elegansembryos
Authors: Kapoor Sukriti , Adhikary Kuheli , Kotak Sachin 
Published: June 2023

AbstractNuclear envelope (NE) disassembly during mitosis is critical to ensure faithful segregation of the genetic material. NE disassembly is a phosphorylation-dependent process wherein mitotic kinases hyper-phosphorylate lamina and nucleoporins to initiate nuclear envelope breakdown (NEBD). In this study, we uncover an unexpected role of the PP2A phosphatase B55SUR-6in NEBD during the first embryonic division ofCaenorhabditis elegansembryo. B55SUR-6depletion delays NE permeabilization and stabilizes lamina and nucleoporins. As a result, the merging of parental genomes and chromosome segregation is impaired. This NEBD defect upon B55SUR-6depletion is not due to delayed mitotic onset or mislocalization of mitotic kinases. Importantly, we demonstrate that microtubule-dependent mechanical forces synergize with B55SUR-6for efficient NE disassembly. Finally, our data suggest that the lamin LMN-1 is likely a bona fide target of PP2A-B55SUR-6. These findings establish a model highlighting biochemical cross-talk between kinases, PP2A-B55SUR-6phosphatase, and microtubule-generated mechanical forces in timely NE dissolution.