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Loss of Notch signaling in skeletal stem cells enhances bone formation with aging

Bone Research 2023年第4期11卷 737-750页

作者： lindsey h.remark Kevin Leclerc Malissa Ramsukh Ziyan Lin Sooyeon Lee Backialakshmi Dharmalingam Lauren Gillinov Vasudev V.Nayak Paulo El Parente Margaux Sambon Pablo J.Atria Mohamed A.E.Ali Lukasz Witek Alesha B.Castillo Christopher Y.Park Ralf h.Adams Aristotelis Tsirigos Sophie M.Morgani Philipp Leucht Department of Orthopaedic Surgery NYU Robert I.Grossman School of MedicineNew YorkNYUSA Applied Bioinformatics Laboratories NYU Grossman School of MedicineNew YorkNYUSA Institute of Comparative Molecular Endocrinology Ulm UniversityUlmGermany Max Planck Institute for Molecular Biomedicine Department of Tissue Morphogenesisand University of MünsterFaculty of MedicineD-48149 MünsterGermany Department of Biochemistry and Molecular Biology University of Miami Miller School of MedicineMiamiFLUSA Department of Pathology NYU Robert I.Grossman School of MedicineNew YorkNYUSA Biomaterials Division New York University College of DentistryNew YorkNYUSA hansjörg Wyss Department of Plastic Surgery NYU Grossman School of MedicineNew York UniversityNew YorkNYUSA Department of Biomedical Engineering Tandon School of EngineeringNew York UniversityBrooklynNYUSA Department of Cell Biology NYU Robert I.Grossman School of MedicineNew YorkNYUSA

Skeletal stem and progenitor cells(SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.

关键词： Notch skeletal elevated

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Advances in human stem cell therapies:pre-clinical studies and the outlook for central nervous system regeneration

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Neural Regeneration Research 2021年第4期16卷 614-617页

作者： lindsey h.Forbes Melissa R.Andrews Medical Research Council Centre for Reproductive health The Queen’s Medical Research InstituteUniversity of EdinburghEdinburghUK School of Biological Sciences University of SouthamptonSouthamptonUK

Cell transplantation has come to the forefront of regenerative medicine alongside the discovery and application of stem cells in both research and clinical *** are several types of stem cells currently being used for pre-clinical regenerative therapies,each with unique characteristics,benefits and *** brief review will focus on recent basic science advancements made with embryonic stem cells and induced pluripotent stem *** embryonic stem cells and induced pluripotent stem cells provide platforms for new neurons to replace dead and/or dying cells following *** to their capacity for reprogramming and differentiation into any neuronal type,research in preclinical rodent models has shown that embryonic stem cells and induced pluripotent stem cells can integrate,survive and form connections in the nervous system similar to de novo *** forward however,there are some limitations to consider with the use of either stem cell ***,embryonic stem cells are not an ideal source of cells,genetically,induced pluripotent stem cells are not ideal in terms of personalized treatment for those with certain genetic diseases the latter of which may guide regenerative medicine away from personalized stem cell based therapies and into optimized stem cell ***,the potential of these stem cells in central nervous system regenerative therapy is only beginning to be *** example,through genetic modification,stem cells serve as ideal platforms to reintroduce missing or downregulated molecules into the nervous system to further induce regenerative *** this review,we highlight the limitations of stem cell based therapies whilst discussing some of the means of overcoming these limitations.

关键词： cell transplantation central nervous system regeneration embryonic stem cells induced pluripotent stem cells spinal cord injury

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Restoring axonal localization and transport of transmembrane receptors to promote repair within the injured CNS: a critical step in CNS regeneration

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Neural Regeneration Research 2017年第1期12卷 27-30页

作者： lindsey h.Forbes Melissa R.Andrews School of Medicine University of St.Andrews Biological Sciences University of Southampton

Each neuronal subtype is distinct in how it develops,responds to environmental cues,and whether it is capable of mounting a regenerative response following *** the adult central nervous system（CNS） does not regenerate,several experimental interventions have been trialled with successful albeit limited instances of axonal *** highlight here some of these approaches including extracellular matrix（ECM） modification,cellular grafting,gene therapy-induced replacement of proteins,as well as application of *** also review the recent report demonstrating the failure of axonal localization and transport of growth-promoting receptors within certain classes of mature *** specifically,we discuss an inability of integrin receptors to localize within the axonal compartment of mature motor neurons such as in the corticospinal and rubrospinal tracts,whereas in immature neurons of those pathways and in mature sensory tracts such as in the optic nerve and dorsal column pathways these receptors readily localize within *** we assert that this failure of axonal localization contributes to the intrinsic inability of axonal *** conclude by highlighting the necessity for both combined therapies as well as a targeted approach specific to both age and neuronal subtype will be required to induce substantial CNS repair.

关键词： axonal transport cellular therapies extracellular matrix gene therapy integrin regeneration viral vectors

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Robotic Assisted Laparoscopic Apical Suspension. Description of a 4 Points Technique (RALAS-4): First Case Reported

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Open Journal of Obstetrics and Gynecology 2017年第9期7卷 944-950页

作者： hugo h Davila lindsey Bruce lindsey Goodman Taryn Gallo Florida healthcare Specialist Urology and Minimally Invasive Surgery Florida Cancer Specialist & Research Institute Sebastian and Vero Beach USA Department of Surgery Division of Urology and Gynecology Sebastian River Medical Center Sebastian USA Florida State University College of Medicine Fort Pierce Campus Fort Pierce USA

The uterosacral ligaments (UTSL), together with the cardinal ligament (CL), hold the upper vagina and cervix over the levator plate. These 2 ligaments provided 4 points support at the apex. here we describe our surgical technique of robotic assisted laparoscopic apical suspension (RALAS) using non-absorbable sutures and describe a new 4 points technique (RALAS-4). 73-year-old Caucasian woman, gravida 5, para 4 had symptomatic pelvic organ prolapse (POP) apical/anterior stage III. At pelvic ultrasound evaluation the uterus was small and normal appearing of adnexa bilaterally. She failed pessaries and was sexually active. The most relevant complaints were vaginal bulging, pressure and urinary incontinence, mainly stress urinary incontinence;she is using 5 - 7 pads/day. Robotic assisted laparoscopic hysterectomy, mid-urthral sling and apical suspension was successfully performed in 125 min. Once we finished with hysterectomy, we proceed with RALAS-4, we used V-Loc 3-0, CV-23 (Covidien) sutures (absorbable) on the right and left uterosacral ligaments (2 points) and theses were reinforced with Gore-Tex 2-0, CV-2 (non-absorbable, Gore Medical). On the right/left anterior apical support we used Gore-Tex 2-0 and these provided the 2 point suspension (UTLS = 2 and anterior vagina = 2). The 2 anterior apical support sutures are taken from the vagina to the transversalis fascia and the obliterated umbilical artery on the anterior abdominal wall. The tension of these anterior sutures was maintained with hem-o-lock (TeleFlex) and LAPRA-TY (Ethicon). In our opinion RALAS-4 may represents an alternative to robotic or laparoscopic sacrocolpopexy. This new approach simulate the natural 4 points support given by uterosacral ligaments and cardinal ligament, with the additional benefit of no mesh and no dissection on the sacrum promontory. With this technique we are chasing the Trifecta: no mesh, no complications and good anatomic support.

关键词： Apical Prolapse Vaginal Prolapse Pelvic Anatomy Robotic Surgery Uterosacral Ligament Cardinal Ligament

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Anatomic Evaluation of Uterosacral and Cardinal Ligament during Robotic and Laparoscopic Surgery for Pelvic Organ Prolapse

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Open Journal of Obstetrics and Gynecology 2017年第12期7卷 1216-1227页

作者： hugo h Davila Renzo Di Natale lindsey Bruce lindsey Goodman Taryn Gallo Florida healthcare Specialist Urology and Minimally Invasive Surgery Florida Cancer Specialist & Research Institute Sebastian and Vero Beach FL USA Department of Surgery Division of Urology and Gynecology Sebastian River Medical Center Sebastian FL USA Florida State University College of Medicine Fort Pierce Campus FL USA

Introduction: It is widely accepted that the uterosacral ligaments (UTSL), together with the cardinal ligament (CL), hold the upper vagina and cervix over the levator plate. The aim of this study is to evaluate the anatomical relationship between the right vs. left CL and UTSL during robotic and laparoscopic utero-sacral ligament suspension (UTSLS) and its implication with the surgical technique during UTSL suspension. Material and Methods: We evaluated 25 women with apical pelvic organ prolapses of stages 2 - 4 and we analyzed 100 uterosacral and cardinal ligaments. They were assigned (non-randomly) to: a) robotic-assisted laparoscopic uterosacral ligament suspension (RAL-UTSLS), b) robotic-assisted single-site utero-sacral ligament suspension (RASS-UTSLS) or laparo-endoscopic single site utero-sacral ligament suspension (LESS-UTSLS). We evaluated the length (distance between origins and insertions) of the aforementioned ligaments using the Da Vinci Si and other laparoscopic instruments like calipers. Results: The mean length of the UTSL in their caudal-cranial extent was 3.5 ± 0.5 cm (right side) and 2.58 ± 0.3 cm (left side). Measurements were performed on the same way for the CL, resulting in 5.1 ± 0.3 cm (both side). The only significant difference was observed when comparing the right vs. left UTSL. This anatomic difference translates to 5 ± 1 suture stitches on the right UTSL vs. 2 ± 1 on the left UTSL. Conclusion: In our evaluation on cardinal and uterosacral ligament, the right UTSL was significantly longer as compared to the left and this allowed us to take 3 additional stitches on the right UTSL vs. left during RAL-UTSLS. Future studies are necessary to compare females with/without POP.

关键词： Apical Prolapse Vaginal Prolapse Pelvic Anatomy Robotic Surgery Pelvic Floor Pelvic Ligaments

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Minimally invasive surgery and transsulcal parafascicular approach in the evacuation of intracerebral haemorrhage

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Stroke & Vascular Neurology 2020年第1期5卷 40-49页

作者： Lina Marenco-hillembrand Paola Suarez-Meade henry Ruiz Garcia Ricardo Murguia-Fuentes Erik h Middlebrooks lindsey Kangas W David Freeman Kaisorn L Chaichana Neurological Surgery Mayo ClinicJacksonvilleFloridaUSA Radiology Neurological SurgeryMayo ClinicJacksonvilleFloridaUSA

Intracerebral haemorrhage(ICh)describes haemorrhage into the brain parenchyma that may result in a decline of the patient’s neurological *** is a common cause of morbidity and mortality *** surgical treatment for ICh has remained controversial as clinical trials have failed to demonstrate substantial improvement in patient outcome and ***,promising mechanical and pharmacological minimally invasive surgery(MIS)techniques for the treatment of ICh have been *** was designed with the objective of reducing morbidity due to complications of surgical *** MIS includes the use of tubular retractors and small diameter instruments for ICh *** methods consist of catheter placement inside the haematoma cavity for the passive drainage of the haematoma over the course of several *** of the most favourable approaches for MIS is the use of natural corridors for reaching the lesion,such as the transsulcal parafascicular *** approach provides an anatomical dissection of the subjacent white matter tracts,causing the least amount of damage while evacuating the haematoma.A detailed description of the currently known MIS techniques and devices is presented in this *** attention is given to the transsulcal parafascicular approach,which has particular benefits to provide a less traumatic MIS with promising overall patient outcome.

关键词： approach surgery cavity

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具有亲油性及近红外光吸收特性的金属细菌卟吩的合成与表征

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高等学校化学学报 2013年第4期34卷 776-781页

作者：孙二军陈志源 lindsey Jonathan S. 长春师范学院化学学院长春130032 Department of Chemistry North Carolina State Universityraleigh276958204

在四氢呋喃中加入金属卟吩、强碱(无水氢化钠)和金属盐MXn(M=Cu,Ni,Pd),合成了细菌卟吩的5种过渡金属配合物,该方法减少了反应时间,提高了反应产率.通过紫外-可见光谱、核磁共振氢谱、质谱等方法对所合成的化合物进行了表征,并研究了其... 详细信息

在四氢呋喃中加入金属卟吩、强碱(无水氢化钠)和金属盐MXn(M=Cu,Ni,Pd),合成了细菌卟吩的5种过渡金属配合物,该方法减少了反应时间,提高了反应产率.通过紫外-可见光谱、核磁共振氢谱、质谱等方法对所合成的化合物进行了表征,并研究了其光学性质.结果表明,细菌卟吩在近红外区有明显的吸收峰,且具有较高的强度,相比于细菌卟吩配体,金属配合物吸收光谱中的Qx和Qy带均发生了明显的红移.细菌卟吩配体与锌配合物具有发光性质,为Qy(0,0)荧光,而铜、镍等金属配合物并没有检测到荧光峰。

关键词：细菌卟吩金属配合物吸收光谱

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Strategies for PET imaging of the receptor for advanced glycation endproducts(RAGE)

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Journal of Pharmaceutical Analysis 2020年第5期10卷 452-465页

作者： lindsey R.Drake Allen F.Brooks Jenelle Stauff Phillip S.Sherman Janna Arteaga Robert A.Koeppe Aimee Reed Timothy J.Montavon Marc B.Skaddan Peter J.h.Scott Department of Radiology University of MichiganAnn ArborMI48109USA Department of Medicinal Chemistry University of MichiganAnn ArborMI48109USA AbbVie Process Chemistry North ChicagoIL60064USA AbbVie Centralized Medicinal Chemistry North ChicagoIL60064USA AbbVie Translational Imaging North ChicagoIL60064USA

The implication of the receptor for advanced glycation end-products(RAGE)in numerous diseases and neurodegenerative disorders makes it interesting both as a therapeutic target and as an inflammatory *** the context of investigating RAGE as a biomarker,there is interest in developing radiotracers that will enable quantification of RAGE using positron emission tomography(PET)*** have synthesized potential small molecule radiotracers for both the intracellular([18F]InRAGER)and extracellular([18F]RAGER)domains of *** we report preclinical evaluation of both using in vitro(lead panel screens)and in vivo(rodent and nonhuman primate PET imaging)*** radiotracers have high affinity for RAGE and show good brain uptake,but suffer from off-target *** source of the off-target PET signal is not attributable to binding to melatonin receptors,but remains *** have also investigated use of lipopolysaccharide(LPS)-treated mice as a possible animal model with upregulated RAGE for evaluation of new imaging *** of the mouse brain sections revealed increases in RAGE in the male cohorts,but no difference in the female ***,it proves challenging to quantify the changes in RAGE due to off-target binding of the ***,they are appropriate lead scaffolds for future development of 2nd generation RAGE PET radiotracers because of their high affinity for the receptor and good CNS penetration.

关键词： RAGE Neuroimaging Positron emission tomography Radiochemistry Neuroinflammation

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Are Northeastern U.S. forests vulnerable to extreme drought?

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Ecological Processes 2017年第1期6卷 351-363页

作者： Adam P.Coble Matthew A.Vadeboncoeur Z.Carter Berry Katie A.Jennings Cameron D.McIntire John L.Campbell lindsey E.Rustad Pamela h.Templer heidi Asbjornsen Department of Natural Resources and the Environment University of New Hampshire56 College Rd.114 James HallDurhamNH 03824USA. Earth Systems Research Center University of New Hampshire8 College RoadDurhamNH 03824USA. Northern Research Station USDA Forest Service271 Mast RoadDurhamNH 03824USA. Department of Biology Boston University5 Cummington MallBostonMA 02215USA.

In the Northeastern U.S.,drought is expected to increase in frequency over the next century,and therefore,the responses of trees to drought are important to *** is recent debate about whether land-use change or moisture availability is the primary driver of changes in forest species composition in this *** argue that fire suppression from the early twentieth century to present has resulted in an increase in shade-tolerant and pyrophobic tree species that are drought intolerant,while others suggest precipitation variability as a major driver of species *** this debate,an emerging hypothesis is that mesophication and increases in the abundance of mesophytic genera(e.g.,Acer,Betula,and Fagus)resulted in forests that are more vulnerable to *** review examines the published literature and factors that contribute to drought vulnerability of Northeastern *** assessed two key concepts related to drought vulnerability,including drought tolerance(ability to survive drought)and sensitivity(short-term responses to drought),with a focus on Northeastern *** assessed drought-tolerance classifications for species,which revealed both consistencies and inconsistencies,as well as contradictions when compared to actual observations,such as higher mortality for drought-tolerant *** to drought sensitivity,recent work has focused on isohydric/anisohydric regulation of leaf water ***,based on the review of the literature,we conclude that drought sensitivity should be viewed in terms of multiple variables,including leaf abscission,stomatal sensitivity,turgor pressure,and dynamics of non-structural *** considered drought sensitive(e.g.,Acer,Betula,and Liriodendron)may actually be less prone to drought-induced mortality and dieback than previously considered because stomatal regulation and leaf abscission in these species are effective at preventing water potential from reaching critica

关键词： Acer Betula Drought sensitivity Drought tolerance Quercus Northeastern U.S. Temperate deciduous

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Is the Photosuturing Agent, Rose Bengal, a Mutagen?

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Journal of Cosmetics, Dermatological Sciences and Applications 2014年第1期4卷 24-30页

作者： lindsey hunter-Ellul Shuguang Wang Jeffrey Wickliffe Michael Wilkerson Department of Dermatology The University of Texas Medical Branch Galveston Texas USA Department of Global Environmental health Sciences School of Public Health and Tropical Medicine Tulane University New Orleans Louisiana USA

Rose Bengal (RB) is a potential photosuturing agent that may improve standard dermatologic surgical closure techniques. however, RB produces reactive oxygen species with photoactivation and its photomutagenic potential must be considered in clinical application. We investigated cytotoxicity, mutagenicity, and singlet oxygen (SO) production of RB on epithelial Chinese hamster ovary cell line. Cells were exposed to RB concentrations: 0.1%, 0.01%, 0.001%, 0.0001%, 0.00001%;irradiated for 400 s using a high-intensity visible wavelength lamp or maintained in the dark. Cell viability was assessed by XTT assay, mutagenicity by hPRT gene mutation assay, and SO production by Sensor Green reagent. RB > 0.001% was significantly cytotoxic. Viabilities were uninfluenced by ≤0.0001% RB controls, or 30-min incubation. 49% of irradiated cells died after 24-h in 0.0001% RB. At ≥0.001% RB, >90% of cells died. Irradiating 0.00001% - 0.001% RB increased SO;levels dropped significantly between 0.01% - 0.1%. Controls exhibited negligible SO production. hPRT suggested that RB was not mutagenic (0.0001%, 0.00001%);SO induction increased between 0.00001% - 0.001%, with reduced production at higher concentrations. Pilot studies suggested irradiated 0.0001% RB is mutagenic in vitro;current data suggest RB is not photomutagenic. The contribution of RB’s cytotoxicity on observed clinical improvement of scars and mutagenic potential remains unclear, necessitating further study.

关键词： Rose Bengal Photochemical Tissue Bonding Mutagenicity Cytotoxicity Wound healing Dermatological Surgery

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