bluuebunny/crossref_metadata_2025_split huggingface dataset:
Telomerase Reverse Transcriptase Expression Marks a Population of Rare Adipose Tissue Stem Cells
Authors: Lynes Matthew D , Carlone Diana L , Townsend Kristy L , Breault David T , Tseng Yu-Hua 
Published: January 2022

Abstract
In adult tissues such as adipose tissue, post-mitotic cells like adipocytes can be replaced by differentiation of a population of tissue-resident stem cells. Expression of mouse telomerase reverse transcriptase (mTert) is a hallmark of stem cell populations, and previous efforts to identify tissue-resident adult stem cells by measuring mTert expression have increased our understanding of stem cell biology significantly. Here, we used a doxycycline-inducible mouse model to perform longitudinal, live-animal lineage-tracing of mTert-expressing cells for more than 1 year. We identified a rare (&lt;2%) population of stem cells in different fat depots that express putative preadipocyte markers. The adipose-derived mTert-positive cells are capable of self-renewal and possess adipogenic potential. Finally, we demonstrate that high-fat diet (HFD) can initiate differentiation of these cells in vivo. These data identify a population of adipose stem cells that contribute to the depot-specific response to HFD.
Exploring Motor Neuron Diseases Using iPSC Platforms
Authors: Johns Alexandra E , Maragakis Nicholas J 
Published: January 2022

Abstract
The degeneration of motor neurons is a pathological hallmark of motor neuron diseases (MNDs), but emerging evidence suggests that neuronal vulnerability extends well beyond this cell subtype. The ability to assess motor function in the clinic is limited to physical examination, electrophysiological measures, and tissue-based or neuroimaging techniques which lack the resolution to accurately assess neuronal dysfunction as the disease progresses. Spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), hereditary spastic paraplegia (HSP), and amyotrophic lateral sclerosis (ALS) are all MNDs with devastating clinical outcomes that contribute significantly to disease burden as patients are no longer able to carry out normal activities of daily living. The critical need to accurately assess the cause and progression of motor neuron dysfunction, especially in the early stages of those diseases, has motivated the use of human iPSC-derived motor neurons (hiPSC-MN) to study the neurobiological mechanisms underlying disease pathogenesis and to generate platforms for therapeutic discovery and testing. As our understanding of MNDs has grown, so too has our need to develop more complex in vitro models which include hiPSC-MN co-cultured with relevant non-neuronal cells in 2D as well as in 3D organoid and spheroid systems. These more complex hiPSC-derived culture systems have led to the implementation of new technologies, including microfluidics, multielectrode array, and machine learning which offer novel insights into the functional correlates of these emerging model systems.
Mst1/2 Is Necessary for Satellite Cell Differentiation to Promote Muscle Regeneration
Authors: Yang Jingjing , Wang Kezhi , An Yina , Wu Ran , Li Jiangbo , Wang Haidong , Dong Yanjun 
Published: January 2022

Abstract
The diminished ability for muscle to regenerate is associated with aging, diabetes, and cancers. Muscle regeneration depends on the activation and differentiation of satellite cells (SCs). Inactivation of Mst1/2 promotes cell proliferation by activating Yap, and that has been reported as a potential therapeutic target for improving many organ regeneration. However, the function of Mst1/2 in SCs fate decision and that effect on muscle regeneration remain unknown. By using inducible conditional knockout Mst1/2 in the SCs of mice and an inhibitor of Mst1/2, we found that inhibition of Mst1/2 in SCs significantly decrease Yap phosphorylation, thus causing Yap to accumulate in the nucleus and impairing SC differentiation; Mst1/2 were slightly elevated by irisin stimulation during SC differentiation; but inhibiting Mst1/2 in SCs significantly impaired irisin-induced muscle regeneration. These results indicate that Mst1/2 is necessary for SC differentiation and inhibiting Mst1/2 as a therapeutic target has potential risks for muscle regeneration.
Impaired Bone Fracture Healing in Type 2 Diabetes Is Caused by Defective Functions of Skeletal Progenitor Cells
Authors: Figeac Florence , Tencerova Michaela , Ali Dalia , Andersen Thomas L , Appadoo Dan Rémi Christiansen , Kerckhofs Greet , Ditzel Nicholas , Kowal Justyna M , Rauch Alexander , Kassem Moustapha 
Published: January 2022

AbstractThe mechanisms of obesity and type 2 diabetes (T2D)-associated impaired fracture healing are poorly studied. In a murine model of T2D reflecting both hyperinsulinemia induced by high-fat diet and insulinopenia induced by treatment with streptozotocin, we examined bone healing in a tibia cortical bone defect. A delayed bone healing was observed during hyperinsulinemia as newly formed bone was reduced by –28.4 ± 7.7% and was associated with accumulation of marrow adipocytes at the defect site +124.06 ± 38.71%, and increased density of SCA1+ (+74.99 ± 29.19%) but not Runx2+ osteoprogenitor cells. We also observed increased in reactive oxygen species production (+101.82 ± 33.05%), senescence gene signature (≈106.66 ± 34.03%), and LAMIN B1- senescent cell density (+225.18 ± 43.15%), suggesting accelerated senescence phenotype. During insulinopenia, a more pronounced delayed bone healing was observed with decreased newly formed bone to –34.9 ± 6.2% which was inversely correlated with glucose levels (R2 = 0.48, P &lt; .004) and callus adipose tissue area (R2 = .3711, P &lt; .01). Finally, to investigate the relevance to human physiology, we observed that sera from obese and T2D subjects had disease state-specific inhibitory effects on osteoblast-related gene signatures in human bone marrow stromal cells which resulted in inhibition of osteoblast and enhanced adipocyte differentiation. Our data demonstrate that T2D exerts negative effects on bone healing through inhibition of osteoblast differentiation of skeletal stem cells and induction of accelerated bone senescence and that the hyperglycemia per se and not just insulin levels is detrimental for bone healing.
L-DOPA-Induced Neurogenesis in the Hippocampus Is Mediated Through GPR143, a Distinct Mechanism of Dopamine
Authors: Kasahara Yuka , Masukawa Daiki , Kobayashi Kenta , Yamasaki Miwako , Watanabe Masahiko , Goshima Yoshio 
Published: January 2022

AbstractNeurogenesis occurs in the hippocampus throughout life and is implicated in various physiological brain functions such as memory encoding and mood regulation. L-3,4-dihydroxyphenylalanine (L-DOPA) has long been believed to be an inert precursor of dopamine. Here, we show that L-DOPA and its receptor, GPR143, the gene product of ocular albinism 1, regulate neurogenesis in the dentate gyrus (DG) in a dopamine-independent manner. L-DOPA at concentrations far lower than that of dopamine promoted proliferation of neural stem and progenitor cells in wild-type mice under the inhibition of its conversion to dopamine; this effect was abolished in GPR143 gene-deficient (Gpr143−/y) mice. Hippocampal neurogenesis decreased during development and adulthood, and exacerbated depression-like behavior was observed in adult Gpr143−/y mice. Replenishment of GPR143 in the DG attenuated the impaired neurogenesis and depression-like behavior. Our findings suggest that L-DOPA through GPR143 modulates hippocampal neurogenesis, thereby playing a role in mood regulation in the hippocampus.
Hoxb1 Regulates Distinct Signaling Pathways in Neuromesodermal and Hindbrain Progenitors to Promote Cell Survival and Specification
Authors: Pazur Kristijan , Giannios Ioannis , Lesche Mathias , Rodriguez-Aznar Eva , Gavalas Anthony 
Published: January 2022

Abstract
Hox genes play key roles in the anterior-posterior (AP) specification of all 3 germ layers during different developmental stages. It is only partially understood how they function in widely different developmental contexts, particularly with regards to extracellular signaling, and to what extent their function can be harnessed to guide cell specification in vitro. Here, we addressed the role of Hoxb1 in 2 distinct developmental contexts; in mouse embryonic stem cells (mES)-derived neuromesodermal progenitors (NMPs) and hindbrain neural progenitors.
We found that Hoxb1 promotes NMP survival through the upregulation of Fgf8, Fgf17, and other components of Fgf signaling as well as the repression of components of the apoptotic pathway. Additionally, it upregulates other anterior Hox genes suggesting that it plays an active role in the early steps of AP specification. In neural progenitors, Hoxb1 synergizes with shh to repress anterior and dorsal neural markers, promote the expression of ventral neural markers and direct the specification of facial branchiomotorneuron (FBM)-like progenitors. Hoxb1 and shh synergize in regulating the expression of diverse signals and signaling molecules, including the Ret tyrosine kinase receptor. Finally, Hoxb1 synergizes with exogenous Glial cell line-derived neurotrophic factor (GDNF) to strengthen Ret expression and further promote the generation of FBM-like progenitors. Facial branchiomotorneuron-like progenitors survived for at least 6 months and differentiated into postmitotic neurons after orthotopic transplantation near the facial nucleus of adult mice. These results suggested that the patterning activity of Hox genes in combination with downstream signaling molecules can be harnessed for the generation of defined neural populations and transplantations with implications for neurodegenerative diseases.
CTGF-D4 Amplifies LRP6 Signaling to Promote Grafts of Adult Epicardial-derived Cells That Improve Cardiac Function After Myocardial Infarction
Authors: Rao Krithika S , Kloppenburg Jessica E , Marquis Taylor , Solomon Laura , McElroy-Yaggy Keara L , Spees Jeffrey L 
Published: January 2022

Abstract
Transplantation of stem/progenitor cells holds promise for cardiac regeneration in patients with myocardial infarction (MI). Currently, however, low cell survival and engraftment after transplantation present a major barrier to many forms of cell therapy. One issue is that ligands, receptors, and signaling pathways that promote graft success remain poorly understood. Here, we prospectively isolate uncommitted epicardial cells from the adult heart surface by CD104 (β-4 integrin) and demonstrate that C-terminal peptide from connective tissue growth factor (CTGF-D4), when combined with insulin, effectively primes epicardial-derived cells (EPDC) for cardiac engraftment after MI. Similar to native epicardial derivatives that arise from epicardial EMT at the heart surface, the grafted cells migrated into injured myocardial tissue in a rat model of MI with reperfusion. By echocardiography, at 1 month after MI, we observed significant improvement in cardiac function for animals that received epicardial cells primed with CTGF-D4/insulin compared with those that received vehicle-primed (control) cells. In the presence of insulin, CTGF-D4 treatment significantly increased the phosphorylation of Wnt co-receptor LRP6 on EPDC. Competitive engraftment assays and neutralizing/blocking studies showed that LRP6 was required for EPDC engraftment after transplantation. Our results identify LRP6 as a key target for increasing EPDC engraftment after MI and suggest amplification of LRP6 signaling with CTGF-D4/insulin, or by other means, may provide an effective approach for achieving successful cellular grafts in regenerative medicine.
Lactate Enhances Mouse ES Cell Differentiation Toward XEN Cells In Vitro
Authors: Gatie Mohamed I , Cooper Tyler T , Khazaee Reza , Lajoie Gilles A , Kelly Gregory M 
Published: January 2022

Abstract
Metabolism plays a crucial role for cell survival and function; however, recent evidence has implicated it in regulating embryonic development. In the embryo, the inner cell mass undergoes orchestrated cellular divisions resulting in the formation of pluripotent epiblast stem cells and primitive endoderm cells. However, both lineages can be captured in vitro as embryonic stem (ES) cells and extraembryonic endoderm (XEN) cells. Concomitantly, changes in the metabolic profile occurs during development, and are well documented in the embryonic lineages. However, a comprehensive multi-omic analysis of these features in XEN cells remains lacking. We observed that mouse XEN cells exhibited high sensitivity to glycolytic inhibition in addition to maintaining elevated intra- and extracellular lactate levels in vitro. Extraembryonic endoderm cells maintain high lactate levels by increased LDHA activity, and re-routing pyruvate away from the mitochondria resulting in reduced mitochondrial activity due to disruptions in electron transport chain stoichiometry. Importantly, exogenous lactate supplementation or promoting intracellular lactate accumulation enhances XEN differentiation in vitro. These results highlight how lactate contributes to XEN differentiation in vitro and may serve to enhance reprogramming efficiency of cells used for regenerative medicine.
ROR2 Downregulation Activates the MSX2/NSUN2/p21 Regulatory Axis and Promotes Dental Pulp Stem Cell Senescence
Authors: He Xin , Yang Zhan , Chu Xiao-Yang , Li Yun-Xia , Zhu Biao , Huang Yan-Xia , Wang Wei , Gao Chun-Yan , Chen Xu , Zheng Chun-Yan , Yang Kai , Zhang Dong-Liang 
Published: January 2022

Abstract
Cellular senescence severely limits the research and the application of dental pulp stem cells (DPSCs). A previous study conducted by our research group revealed a close implication of ROR2 in DPSC senescence, although the mechanism underlying the regulation of ROR2 in DPSCs remains poorly understood so far. In the present study, it was revealed that the expression of the ROR2-interacting transcription factor MSX2 was increased in aging DPSCs. It was demonstrated that the depletion of MSX2 inhibits the senescence of DPSCs and restores their self-renewal capacity, and the simultaneous overexpression of ROR2 enhanced this effect. Moreover, MSX2 knockdown suppressed the transcription of NOP2/Sun domain family member 2 (NSUN2), which regulates the expression of p21 by binding to and causing the 5-methylcytidine methylation of the 3ʹ- untranslated region of p21 mRNA. Interestingly, ROR2 downregulation elevated the levels of MSX2 protein, and not the MSX2 mRNA expression, by reducing the phosphorylation level of MSX2 and inhibiting the RNF34-mediated MSX2 ubiquitination degradation. The results of the present study demonstrated the vital role of the ROR2/MSX2/NSUN2 axis in the regulation of DPSC senescence, thereby revealing a potential target for antagonizing DPSC aging.
Toll-Like Receptor 5 Promotes the Neurogenesis From Embryonic Stem Cells and Adult Hippocampal Neural Stem Cells in Mice
Authors: Seong Kyung-Joo , Choi Seungho , Lee Hyun-Gwan , Rhee Joon Haeng , Lee Jin Ho , Koh Jeong-Tae , Kim Sun-Hun , Choi Won-Seok , Jung Ji-Yeon , Kim Won-Jae 
Published: January 2022

Abstract
Toll-like receptors (TLRs) make a crucial contribution to the innate immune response. TLR5 was expressed in embryoid body derived from mouse embryonic stem cells (mESCs) and βIII-tubulin-positive cells under all-trans retinoic acid-treated condition. TLR5 was upregulated during neural differentiation from mESCs and augmented the neural differentiation of mESCs via nuclear factor-κB and interleukin 6/CREB pathways. Besides, TLR5 was expressed in SOX2- or doublecortin-positive cells in the subgranular zone of the hippocampal dentate gyrus where adult neurogenesis occurs. TLR5 inhibited the proliferation of adult hippocampal neural stem cells (NSCs) by regulating the cell cycle and facilitated the neural differentiation from the adult hippocampal NSCs via JNK pathway. Also, TLR5 deficiency impaired fear memory performance in mice. Our data suggest that TLR5 is a crucial modulator of neurogenesis from mESCs and adult hippocampal NSCs in mice and represents a new therapeutic target in neurological disorders related to cognitive function.
Neural Stem Cell-Derived Extracellular Vesicles Counteract Insulin Resistance-Induced Senescence of Neurogenic Niche
Authors: Natale Francesca , Leone Lucia , Rinaudo Marco , Sollazzo Raimondo , Barbati Saviana Antonella , La Greca Francesco , Spinelli Matteo , Fusco Salvatore , Grassi Claudio 
Published: January 2022

Abstract
Neural stem and progenitor cell (NSPC) depletion may play a crucial role in the cognitive impairment observed in many age-related non-communicable diseases. Insulin resistance affects brain functions through a plethora of mechanisms that remain poorly understood. In an experimental model of insulin resistant NSPCs, we identified a novel molecular circuit relying on insulin receptor substrate-1 (IRS-1)/ Forkhead box O (FoxO) signaling cascade and inhibiting the recruitment of transcription factors FoxO1 and FoxO3a on the promoters of genes regulating proliferation and self-renewal. Insulin resistance also epigenetically increased the expression of cyclin-dependent kinase inhibitor 1 (p21) and accelerated NSPC senescence. Of note, we found that stimulation of NSPCs with NSPC-derived exosomes (exo-NSPC) rescued IRS-1/FoxO activation and counteracted both the reduced proliferation and senescence of stem cells. Accordingly, intranasal administration of exo-NSPC counteracted the high-fat diet-dependent impairment of adult hippocampal neurogenesis in mice by restoring the balance between proliferating and senescent NSPCs in the hippocampus. Our findings suggest a novel mechanism underlying the metabolic control of NSPC fate potentially involved in the detrimental effects of metabolic disorders on brain plasticity. In addition, our data highlight the role of extracellular vesicle-mediated signals in the regulation of cell fate within the adult neurogenic niche.
Estimating the direct Disability-Adjusted Life Years (DALYs) associated with SARS-CoV-2 (COVID-19) in the Republic of Ireland: The first full year
Authors: Moran Declan , Pires Sara Montero , Wyper Grant , Devleesschauwer Brecht , Cuschieri Sarah , Kabir Zubair 
Published: January 2022

AbstractObjectivesBurden of Disease frameworks facilitate estimation of the health impact of diseases to be translated into a single measure, such as the Disability-Adjusted-Life-Year (DALY).MethodsDALYs were calculated as the sum of Years of Life Lost (YLL) and Years Lived with Disability (YLD) directly associated with COVID-19 in the Republic of Ireland (RoI) from March 01, 2020, to February 28, 2021. Life expectancy is based on the Global Burden of Disease (GBD) Study life tables for 2019.ResultsThere were 220,273 confirmed cases with a total of 4,500 deaths as a direct result of COVID-19. DALYs were estimated to be 51,532.1 (95% Uncertainty Intervals [UI] 50,671.6, 52,294.3). Overall, YLL contributed to 98.7% of the DALYs. Of total symptomatic cases, 6.5% required hospitalisation and of those hospitalised 10.8% required intensive care unit treatment. COVID-19 was likely to be the second highest cause of death over our study’s duration.ConclusionEstimating the burden of a disease at national level is useful for comparing its impact with other diseases in the population and across populations. This work sets out to standardise a COVID-19 BoD methodology framework for the RoI and comparable nations in the EU.
A Web-based Spatial Decision Support System of Wastewater Surveillance for COVID-19 Monitoring: A Case Study of a University Campus
Authors: Tang Wenwu , Chen Tianyang , Slocum Zachery , Lan Yu , Delmelle Eric , Chen Don , Mittal Neha , Rice-Boayue Jacelyn , Shukla Tarini , Lin Sophia , Akella Srinivas , Schlueter Jessica , Munir Mariya , Gibas Cynthia 
Published: January 2022

AbstractThe ongoing COVID-19 pandemic has produced substantial impacts on our society. Wastewater surveillance has increasingly been introduced to support the monitoring, and thus mitigation, of COVID-19 outbreaks and transmission. Monitoring of buildings and sub-sewershed areas via a wastewater surveillance approach has been a cost-effective strategy for mass testing of residents in congregate living situations such as universities. A series of spatial and spatiotemporal data are involved with wastewater surveillance, and these data must be interpreted and integrated with other information to better serve as guidance on response to a positive wastewater signal. The management and analysis of these data poses a significant challenge, in particular, for the need of supporting timely decision making. In this study, we present a web-based spatial decision support system framework to address this challenge. Our study area is the main campus of the University of North Carolina at Charlotte. We develop a spatiotemporal data model that facilitates the management of space-time data related to wastewater surveillance. We use spatiotemporal analysis and modeling to discover spatio-temporal patterns of COVID-19 virus abundance at wastewater collection sites that may not be readily apparent in wastewater data as they are routinely collected. Web-based GIS dashboards are implemented to support the automatic update and sharing of wastewater testing results. Our web-based SDSS framework enables the efficient and automated management, analytics, and sharing of spatiotemporal data of wastewater testing results for our study area. This framework provides substantial support for informing critical decisions or guidelines for the prevention of COVID-19 outbreak and the mitigation of virus transmission on campus.
Convalescent plasma improves overall survival in patients with B-cell lymphoid malignancies and COVID-19: a longitudinal cohort and propensity score analysis
Authors: Hueso Thomas , Godron Anne-Sophie , Lanoy Emilie , Pacanowski Jérôme , Levi Laura I. , Gras Emmanuelle , Surgers Laure , Guemriche Amina , Meynard Jean-Luc , Pirenne France , Idri Salim , Tiberghien Pierre , Morel Pascal , Besson Caroline , Duléry Rémy , Lamure Sylvain , Hermine Olivier , Gagneux-Brunon Amandine , Freymond Nathalie , Grabar Sophie , Lacombe Karine ,   the HEMOPLASM Study Group
Published: January 2022

AbstractPatients with hematological malignancies and COVID-19 display a high mortality rate. In such patients, immunosuppression due to underlying disease and previous specific treatment impair humoral response, limiting viral clearance. Thus, COVID-19 convalescent plasma (CCP) therapy appears as a promising approach through the transfer of neutralizing antibodies specific to SARS-CoV-2.We report the effect of CCP in a cohort of 112 patients with hematological malignancies and COVID-19 and a propensity score analysis on subgroups of patients with B-cell lymphoid disease treated (n=81) or not (n=120) with CCP between 1 May 2020 and 1 April 2021. The overall survival of the whole cohort was 65% [56–74.9] and 77.5% [68.5–87.7] for patients with B-cell neoplasm. Prior anti-CD20 monoclonal antibodies therapy was associated with better overall survival whereas age, high blood pressure, and COVID-19 severity were associated with a poor outcome. After an inverse probability of treatment weighting approach, we observed in anti-CD20–exposed patients with B-cell lymphoid disease a decreased mortality of 63% (95% CI=31%–80%) in the CCP-treated group compared to the CCP-untreated subgroup, confirmed in the other sensitivity analyses.Convalescent plasma may be beneficial in COVID-19 patients with B-cell neoplasm who are unable to mount a humoral immune response.