bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin-16/STAT6 recruits CBP/p300 to upregulate TIMP-3 and promote atherosclerotic plaque stability
Authors: He Hui , Ding Meng , Zhu Yuan , Jiang Tianyu , Dong Doudou , Xu Xiaoting , Ou Hailong 
Published: May 2023

AbstractBackgroundAtherosclerotic plaque rupture increases the risk of ischemic heart disease and stroke and commonly causes sudden death. High levels of circulating or intraplaque interleukin 16 (IL-16) are clinically associated with a reduced incidence of cardiovascular events. Here, we investigated the effects of IL-16 on plaque phenotypic modification and identified the molecules involved in smooth muscle cells (SMCs).MethodsWe deleted IL-16 in ApoE-/- mice to generate IL16-/-ApoE-/- mice, and the double mutant was used for plaque phenotype analysis after a 24-week high-fat diet. RNA sequencing was performed to identify the changes in cellular processes and molecule expression in response to IL-16 defects. Affinity purification-mass spectrometry was used to identify the STAT6 binding protein. Bone marrow transplantation was used to investigate the effects of hematopoietic IL-16 deficiency or reconstitution on plaque stability.ResultsIL-16 deficiency reduced collagen deposition and increased the necrotic core area in the plaques of the brachiocephalic artery and aortic root lesions. Intraplaque TIMP-3 levels were found to be decreased in association with an increase in the proteolytic activity of MMPsinIL16-/-ApoE-/- mice. Next, we demonstrated that IL-16 activates the CD4/JAK2/STAT6 pathway and that STAT6 directly binds the TIMP-3 promoter in SMCs. Furthermore, IL-16 treatment increased the interaction of cAMP-response element binding protein (CBP)/p300 with STAT6, which promoted STAT6 acetylation and increased histone H3 acetylation in the TIMP-3 promoter. Inhibition of CBP/p300 resulted in decreased acetylation of STAT6 and TIMP-3 promoter histone H3 and TIMP-3 expression, suggesting a requirement for CBP/p300 as a coactivator. Finally, we found that hematopoietic-derived IL-16 from ApoE-/- mice or overexpression of TIMP-3 successfully attenuated plaque instability in IL16-/-ApoE-/- mice.ConclusionsIL-6 upregulates TIMP-3 expression and remodels the intraplaque extracellular matrix toward a stable phenotype, suggesting IL-16 as a potential target for intervening in atherosclerosis at later stages.
Genome-wide association study of REM sleep behavior disorder in Parkinson’s disease
Authors: Sosero Yuri L. , Heilbron Karl , Fontanillas Pierre , Norcliffe-Kaufmann Lucy , Yu Eric , Rudakou Uladzislau , Ruskey Jennifer A. , Freeman Kathryn , Asayesh Farnaz , Brolin Kajsa , Swanberg Maria , Morris Huw R , Wu Lesley , Real Raquel , Pihlstrøm Lasse , Tan Manuela , Gasser Thomas , Brockmann Kathrin , Liu Hui , Hu Michele T.M. , Grosset Donald G. , Lewis Simon J.G. , Kwok John B. , Pastor Pau , Alvarez Ignacio , Skorvanek Matej , Lackova Alexandra , Ostrozovicova Miriam , Rizig Mie ,   23andMe Research Team,   The International Parkinson’s Disease Genomics Consortium, Krohn Lynne , Gan-Or Ziv 
Published: May 2023

AbstractObjectiveREM sleep behavior disorder (RBD) is a prodromal synucleinopathy, reported in a subset of Parkinson’s disease (PD) patients, and associated with neuropsychiatric symptoms in PD. We aimed to compare the genetic background of PD patients with probable RBD (PD+RBD) and PD patients without probable RBD (PD-RBD). Furthermore, we examined genetic correlations and potential causal associations between multiple neuropsychiatric traits and PD+RBD.MethodsWe performed a genome-wide association study (GWAS) including 5,403 PD+RBD and 13,020 PD-RBD. To test for genetic correlations and potential causal associations between neuropsychiatric traits and PD+RBD, we used linkage disequilibrium score regression and Mendelian randomization.ResultsTheSNCAlocus was associated with PD+RBD compared to PD-RBD (rs10005233, OR=1.21, 95% CI=1.16-1.27,p=1.81e-15). Further examination of known genetic loci associated with PD from the most recent PD GWAS in Europeans and Asians identified additional variants associated with reduced risk for PD+RBD: two in theSNCAlocus (rs5019538-G, OR=0.85, 95% CI=0.81-0.89,p=2.46E-10; rs356182-G, OR=0.89, 95% CI=0.84-0.95,p=0.0001), and one in theLRRK2locus (rs34637584, p.G2019S, OR=0.41, 95% CI=0.28-0.61,p=1.04E-5). We found a potential genetic correlation between attention deficit hyperactivity disorder (ADHD) and PD+RBD, which was not statistically significant after correction for multiple comparisons. No causative association emerged between PD and neuropsychiatric traits.InterpretationGenetic variants contribute to the occurrence of RBD in PD, further distinguishing between the PD+RBD and PD-RBD subtypes. Understanding the mechanisms underlying these genetic associations could contribute to the development of subtype-specific treatments.
The Notch-Pdgfrβ axis suppresses brown adipocyte progenitor differentiation in early postnatal mice
Authors: Shi Zuoxiao , Xiong Shaolei , Hu Ruoci , Wang Zilai , Park Jooman , Qian Yanyu , Wang Jaden , Bhalla Pratibha , Velupally Nipun , Song Qing , Song Zhenyuan , Layden Brian T. , Jiang Yuwei 
Published: May 2023

ABSTRACTDe novo brown adipogenesis holds potential in combating the epidemics of obesity and diabetes. However, the identity of brown adipocyte progenitor cells (APCs) and their regulation have not been extensively studied. Here throughin vivolineage tracing, we observed that PDGFRβ+ pericytes give rise to developmental brown adipocytes, but not to those in adult homeostasis. In contrast, TBX18+ pericytes contribute to brown adipogenesis throughout both developmental and adult stages, though in a depot-specific manner. Mechanistically, Notch inhibition in PDGFRβ+ pericytes promotes brown adipogenesis through the downregulation of PDGFRβ. Furthermore, inhibition of Notch signaling in PDGFRβ+ pericytes mitigates HFHS (high-fat, high-sucrose) induced glucose and metabolic impairment in both developmental and adult stages. Collectively, these findings show that the Notch/PDGFRβ axis negatively regulates developmental brown adipogenesis, and its repression promotes brown adipose tissue expansion and improves metabolic health.HighlightsPDGFRβ+ pericytes act as an essential developmental brown APC.TBX18+ pericytes contribute to brown adipogenesis in a depot-specific manner.Inhibiting Notch-Pdgfrβ axis promotes brown APC adipogenesis.Enhanced postnatal brown adipogenesis improves metabolic health in adult stage.
Cross-Protection Induced by Highly Conserved Human B, CD4+,and CD8+T Cell Epitopes-Based Coronavirus Vaccine Against Severe Infection, Disease, and Death Caused by Multiple SARS-CoV-2 Variants of Concern
Authors: Prakash Swayam , Dhanushkodi Nisha R. , Zayou Latifa , Ibraim Izabela Coimbra , Quadiri Afshana , Coulon Pierre Gregoire , Tifrea Delia F , Suzler Berfin , Amin Mohamed , Chilukuri Amruth , Edwards Robert A , Vahed Hawa , Nesburn Anthony B , Kuppermann Baruch D , Ulmer Jeffrey B. , Gil Daniel , Jones Trevor M. , BenMohamed Lbachir 
Published: May 2023

ABSTRACTBackgroundThe Coronavirus disease 2019 (COVID-19) pandemic has created one of the largest global health crises in almost a century. Although the current rate of SARS-CoV-2 infections has decreased significantly; the long-term outlook of COVID-19 remains a serious cause of high death worldwide; with the mortality rate still surpassing even the worst mortality rates recorded for the influenza viruses. The continuous emergence of SARS-CoV-2 variants of concern (VOCs), including multiple heavily mutated Omicron sub-variants, have prolonged the COVID-19 pandemic and outlines the urgent need for a next-generation vaccine that will protect from multiple SARS-CoV-2 VOCs.MethodsIn the present study, we designed a multi-epitope-based Coronavirus vaccine that incorporated B, CD4+, and CD8+T cell epitopes conserved among all known SARS-CoV-2 VOCs and selectively recognized by CD8+and CD4+T-cells from asymptomatic COVID-19 patients irrespective of VOC infection. The safety, immunogenicity, and cross-protective immunity of this pan-Coronavirus vaccine were studied against six VOCs using an innovative triple transgenic h-ACE-2-HLA-A2/DR mouse model.ResultsThe Pan-Coronavirus vaccine: (i) is safe; (ii) induces high frequencies of lung-resident functional CD8+and CD4+TEMand TRMcells; and (iii) provides robust protection against virus replication and COVID-19-related lung pathology and death caused by six SARS-CoV-2 VOCs: Alpha (B.1.1.7), Beta (B.1.351), Gamma or P1 (B.1.1.28.1), Delta (lineage B.1.617.2) and Omicron (B.1.1.529).Conclusions: A multi-epitope pan-Coronavirus vaccine bearing conserved human B and T cell epitopes from structural and non-structural SARS-CoV-2 antigens induced cross-protective immunity that cleared the virus, and reduced COVID-19-related lung pathology and death caused by multiple SARS-CoV-2 VOCs.
Growth factor-free, peptide-functionalized gelatin hydrogel promotes arteriogenesis and attenuates tissue damage in a murine model of critical limb ischemia
Authors: Curry Corinne W. , Sturgeon Sarah M. , O’Grady Brian J. , Yates Alexis K. , Kjar Andrew , Paige Hayden A. , Mowery Lucas S. , Katdare Ketaki A. , Patel Riya V. , Mlouk Kate , Stiefbold Madison R. , Vafaie-Partin Sidney , Kawabata Atsuyuki , McKee Rachel M. , Lotridge Stephanie Moore- , Hawkes Adrienne , Kusunose Jiro , Gibson-Corley Katherine N. , Schmeckpeper Jeffrey , Schoenecker Jonathan G. , Caskey Charles F. , Lippmann Ethan S. 
Published: May 2023

AbstractCritical limb ischemia (CLI) occurs when blood flow is restricted through the arteries, resulting in ulcers, necrosis, and chronic wounds in the downstream extremities. The development of collateral arterioles (i.e. arteriogenesis), either by remodeling of pre-existing vascular networks orde novogrowth of new vessels, can prevent or reverse ischemic damage, but it remains challenging to stimulate collateral arteriole development in a therapeutic context. Here, we show that a gelatin-based hydrogel, devoid of growth factors or encapsulated cells, promotes arteriogenesis and attenuates tissue damage in a murine CLI model. The gelatin hydrogel is functionalized with a peptide derived from the extracellular epitope of Type 1 cadherins. Mechanistically, these “GelCad” hydrogels promote arteriogenesis by recruiting smooth muscle cells to vessel structures in bothex vivoandin vivoassays. In a murine femoral artery ligation model of CLI, delivery ofin situcrosslinking GelCad hydrogels was sufficient to restore limb perfusion and maintain tissue health for 14 days, whereas mice treated with gelatin hydrogels had extensive necrosis and autoamputated within 7 days. A small cohort of mice receiving the GelCad hydrogels were aged out to 5 months and exhibited no decline in tissue quality, indicating durability of the collateral arteriole networks. Overall, given the simplicity and off-the-shelf format of the GelCad hydrogel platform, we suggest it could have utility for CLI treatment and potentially other indications that would benefit from arteriole development.
POMBOX: a fission yeast toolkit for molecular and synthetic biology
Authors: Hebra Téo , Smrčková Helena , Elkatmis Büsra , Převorovský Martin , Pluskal Tomáš 
Published: May 2023

AbstractSchizosaccharomyces pombeis a popular model organism in molecular biology and cell physiology. With its ease of genetic manipulation and growth, supported by in-depth functional annotation in the PomBase database and genome-wide metabolic models,S. pombeis an attractive option for synthetic biology applications. However,S. pombecurrently lacks modular tools for generating genetic circuits with more than one transcriptional unit. We have developed a toolkit to address this issue. Adapted from the MoClo- YTK plasmid kit forSaccharomyces cerevisiaeand using the same Golden Gate grammar, our POMBOX toolkit is designed to facilitate the fast, efficient and modular construction of genetic circuits inS. pombe. It allows for interoperability when working with DNA sequences that are functional in bothS. cerevisiaeandS. pombe(e.g. protein tag, antibiotic resistance cassette, coding sequences). Moreover, POMBOX enables the modular assembly of multi-gene pathways and increases possible pathway length from 6 to 12 transcriptional units. We also adapted the stable integration vector homology arms to Golden Gate assembly and tested the genomic integration success rate depending on different sequence sizes, from four to twenty-four kilobases. We included fourteenS. pombepromoters that we characterized for two fluorescent proteins, in both minimal defined media (EMM2) and complex media (YES). Then we tested sixS. cerevisiaeand six synthetic terminators inS. pombe. Finally, we used the POMBOX kit for a synthetic biology application in metabolic engineering and expressed plant enzymes inS. pombeto produce specialized metabolite precursors, namely methylxanthine, amorpha-4,11-diene and cinnamic acid from the purine, mevalonate and amino acid pathways.
Experimental evolution of hybrid populations to identify Dobzhansky-Muller incompatibility loci
Authors: Szabo Nicole , Cutter Asher D. 
Published: May 2023

AbstractEpistatic interactions between loci that reduce fitness in inter-species hybrids, Dobzhansky-Muller incompatibilities (DMIs), contribute genetically to the inviability and infertility within hybrid populations. It remains a challenge, however, to identify the loci that contribute to DMIs as causes of reproductive isolation between species. Here, we assess through forward simulation the power of evolve and resequence experimental evolution of hybrid populations to map DMI loci. We document conditions under which such a mapping strategy may be most feasible and demonstrate how mapping power is sensitive to biologically relevant parameters such as one-way versus two-way incompatibility type, selection strength, recombination rate, and dominance interactions. We also assess the influence of parameters under direct control of an experimenter, including duration of experimental evolution and number of replicate populations. We conclude that an evolve and re-sequence strategy for mapping DMI loci, and other cases of epistasis, can be a viable option under some circumstances for study systems with short generation times likeCaenorhabditisnematodes.
CA3 circuit model compressing sequential information in theta oscillation and replay
Authors: Kuroki Satoshi , Mizuseki Kenji 
Published: May 2023

AbstractThe hippocampus compresses the sequential information in a theta oscillation cycle and short-term sequential activities during sharp-wave ripple while sleeping or resting; these processes are known as theta sequence and replay, respectively. The theta sequence is based on theta phase precession patterns of individual neurons. However, how these sequential neuronal activities are generated and how they store information about the outside environment remains unknown. We developed a hippocampal cornu ammonis (CA)3 computational model based on the biological CA3 circuit’s anatomical and electrophysiological evidence to address these. The model comprises theta rhythm inhibition, place input, and CA3-CA3 plastic recurrent connection. The model could compress the sequence of the external inputs and reproduce theta phase precession and replay, learn additional sequences, and reorganize previously learned sequences. A gradual increase in synaptic inputs, controlled by interactions between theta-paced inhibition and place inputs, explained the mechanism for sequence acquisition. This model highlights the crucial role of plasticity in the CA3 recurrent connection and theta oscillational dynamics, and hypothesizes how the CA3 circuit acquires, compresses, and replays sequential information.
Tempered IL-2 Signals Program PD-1 Checkpoint Blockade-Responsive Stem-like Exhausted T Cells During Priming
Authors: Kalia Vandana , Reed Jim , Khanna Asheema , Toumi Ryma , Xiao Hanxi , Pulliam Thomas , Deo Rucha , Nghiem Paul , Sarkar Surojit 
Published: May 2023

ABSTRACTStem-like progenitor exhausted CD8 T cells are critical for maintaining long-term resistance during chronic infections and cancer, and represent an important checkpoint blockade immunotherapy target for functional reinvigoration and disease control. Hence, there is vigorous interest in understanding the ontogenesis of TCF-1Histem-like exhausted CD8 T cells, and in defining the signals that promote their development. Here, we show that virus-specific TCF1HiGzmBLoCD8 T cells develop during early stages of chronic viral infection, and are progressively deprogrammed from the stem-like lineage towards terminal differentiation by strong IL-2 signals. In vivo fate-tracking studies show that strong T cell-intrinsic IL-2 signals through the high affinity heterotrimeric IL-2Rα/β/γ receptor drive skewed development of terminally differentiated TCF-1LoGzmBHicells, which largely die in chronic antigenic environment. In contrast, tempered IL-2 signals through the intermediate affinity IL-2Rβ/γ heterodimer, or delayed priming in diminished IL-2 milieu support preferential development of TCF-1Histem-like exhausted CD8 T cells, capable of long-term persistence and potent responsiveness to PD-1 therapy in later stages of chronic viral infection. In human tumors as well, single cell RNA-seq analyses of tumor infiltrating lymphocytes from melanoma, human papillomavirus+ head and neck cancer and lung cancer patients revealed an inverse relationship between IL-2 signaling signature and T cell stemness. Moreover, melanoma patients with enriched IL-2 signaling signature showed poor responses to checkpoint blockade immunotherapy. Collectively, these findings bear relevance to clinical immunotherapies of chronic viral infections and cancers, and support exogenous IL-2 signal manipulation prior to therapy as a strategy for augmenting long-term clinical outcomes.ONE SENTENCE SUMMARYProgramming of exhausted T cell fates by differential IL-2
Vocational training support and innovation at SMEs
Authors: Hlasny Vladimir 
Published: May 2023

Purpose
While the value of human capital for technological innovation is well acknowledged, literature on the role of vocational training in corporate innovation is notably scarce. The purpose of this study is to assess the effect of government support for small and medium-sized enterprise (SME) competencies on Korean firms’ innovation. The author investigates SMEs’ patent applications (supported by the government to varying degrees) while accounting for firms’ market position, ownership and management structure, as well as prior changes in firms’ technologies, products, processes and other characteristics. Alternative hypotheses about management motivation – the “lazy manager”, “career concerns” and “special East Asian institutional constraints” hypotheses – are also evaluated.

Design/methodology/approach
Censored and count data analysis methods are used on a panel of 595 Korean firms covering 2005–2015 from the Korean Human Capital Corporate Survey, Intellectual Property Office and National Investment Commission. A regression discontinuity estimator accounts for potential endogeneity because of support for vocational training at firms.

Findings
Firms receiving training support are more innovative than firms without support, but latent effects may play a role. The regression-discontinuity model suggests that firms that succeeded only marginally in obtaining support had higher innovative output than non-recipients near the eligibility threshold.

Originality/value
The findings of this study establish that government support had the intended effect on SMEs’ technological capacity. This cannot be discounted as a simple crowding-out effect. The author also establishes that management–ownership separation within firms was conducive to innovation, that product competition had an inverse U-shaped effect and that management–ownership separation had a substitutable relationship with competition in overcoming managers’ effort avoidance. The findings support the “lazy manager” hypothesis over the “career concerns” and the “special East Asian institutional constraints” hypotheses.
Uniformly convergent computational method for singularly perturbed time delayed parabolic differential-difference equations
Authors: Mohapatra Jugal , Priyadarshana Sushree , Raji Reddy Narahari 
Published: May 2023

PurposeThe purpose of this work is to introduce an efficient, global second-order accurate and parameter-uniform numerical approximation for singularly perturbed parabolic differential-difference equations having a large lag in time.Design/methodology/approachThe small delay and advance terms in spatial direction are handled with Taylor's series approximation. The Crank–Nicholson scheme on a uniform mesh is applied in the temporal direction. The derivative terms in space are treated with a hybrid scheme comprising the midpoint upwind and the central difference scheme at appropriate domains, on two layer-resolving meshes namely, the Shishkin mesh and the Bakhvalov–Shishkin mesh. The computational effectiveness of the scheme is enhanced by the use of the Thomas algorithm which takes less computational time compared to the usual Gauss elimination.FindingsThe proposed scheme is proved to be second-order accurate in time and to be almost second-order (up to a logarithmic factor) uniformly convergent in space, using the Shishkin mesh. Again, by the use of the Bakhvalov–Shishkin mesh, the presence of a logarithmic effect in the spatial-order accuracy is prevented. The detailed analysis of the convergence of the fully discrete scheme is thoroughly discussed.Research limitations/implicationsThe use of second-order approximations in both space and time directions makes the complete finite difference scheme a robust approximation for the considered class of model problems.Originality/valueTo validate the theoretical findings, numerical simulations on two different examples are provided. The advantage of using the proposed scheme over some existing schemes in the literature is proved by the comparison of the corresponding maximum absolute errors and rates of convergence.
Innovation comes with responsibility: a dual moderation model of taking charge and innovative job performance
Authors: Liu Pingqing , Yuan Yunyun , Yang Lifeng , Liu Bin , Xu Shuang 
Published: May 2023

PurposeThe aim of this study is to examine the relationships between taking charge, bootlegging innovation and innovative job performance, and to explore the moderating roles of felt responsibility for constructive change (FRCC) and creative self-efficacy (CSE).Design/methodology/approachData for this research was collected from 503 employees working in a chain company. Through a longitudinal study design, a three-wave survey with 397 valid data provided support for the proposed theoretical model.FindingsThe results maintain a positive association between taking charge, bootlegging innovation and innovative job performance, indicating the mediating effect of bootlegging innovation. Additionally, both the FRCC and CSE facilitate the indirect effect of taking charge on innovative job performance through bootlegging innovation. Furthermore, the integrated moderated mediation model analysis suggested that FRCC is more vital in improving employees' innovative job performance.Originality/valueThis research aims to break the black box between taking charge and innovative job performance, which has been relatively unexplored. Drawing from self-determination theory (SDT) and the proactive motivation model, the authors verify the bridge-building role of bootlegging innovation and the dual-facilitating effects of FRCC and CSE while employees conduct taking charge. This study’s results provide new insight for managers to foster, encourage and support employees' proactive behavior.