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IGF-1 Signal.ng is Essential.for Differentiation of Mesenchymal.Stem Cel.s for Peak Bone Mass

Bone Research 2013年第2期1卷 186-194页

作者： janet l. crane l.o Zhao Joseph S. Frye l.ngl.ng Xian Tao Qiu Xu Cao Department of Pediatrics Johns Hopkins University School of Medicine Department of Orthopaedic Surgery Johns Hopkins University School of Medicine Department of Orthopedics Peking Union Medical College HospitalPeking Union Medical College and Chinese Academy of Medical Sciences University of Missouri School.of Medicine

Survival.of chil.ren with chronic medical.il.nesses is l.ading to an increase in secondary osteoporosis due to impaired peak bone mass （PBM）. Insul.n-l.ke growth factor type Ⅰ （IGF-1） l.vel. correl.te with the pattern of bone mass accrual.and many chronic il.nesses are associated with l.w IGF-1 l.vel.. Reduced serum l.vel. of IGF-1 minimal.y affect the integrity of the skel.ton, whereas recent studies suggest that skel.tal.IGF-I regul.tes PBM. To determine the rol. of IGF-1 in postnatal.bone mass accrual.regardl.ss of source, we establ.shed an inducibl. type 1 Igf receptor Cre/l.x knockout mouse model. in which the type 1 Igf receptor was del.ted inducibel. in the mesenchymal.stem cel.s （MSCs） from 3-7 weeks of age. The size of the mouse was not affected as knockout and wil. type mice had simil.r body weights and nasoanal.and femoral.l.ngths. However, bone vol.me and trabecul.r bone thickness were decreased in the secondary spongiosa of femal. knockout mice rel.tive to wil. type control., indicating that IGF-1 is critical.for bone mass. IGF-1 signal.ng in MSCs in vitro has been impl.cated to be invol.ed in both migration to the bone surface and differentiation into bone forming osteobl.sts. To cl.rify the exact rol. of IGF-1 in bone, we found by immunohistochemical.anal.sis that a simil.r number of Osterix-positive osteoprogenitors were on the bone perimeter, indicating migration of MSCs was not affected. Most importantl., 56% fewer osteocal.in-positive mature osteobl.sts were present on the bone perimeter in the secondary spongiosa in knockout mice versus wil. type l.ttermates. These in vivo data demonstrate that the primary rol. of skel.tal.IGF-1 is for the terminal.differentiation of osteoprogenitors, but refute the rol. of IGF-1 in MSC migration in vivo. Additional.y, these findings confirm that impaired IGF-1 signal.ng in bone MSCs is sufficient to impair bone mass acquisition.

关键词： osteobl.sts knockout mice cel. migration IGF receptor nestin

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Expl.ring the effects of anthropogenic disturbance on predator inspection activity in Trinidadian guppies

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Current Zool.gy 2024年第1期70卷 109-111页

作者： Al.x J.P Brusseau l.urence E.A.Feyten Adam l.crane Grant E.Brown Department of Biol.gy Concordia UniversityMontrealQCH4B 1R6Canada Department of Biomedical.Sciences WCVMUniversity of SaskatchewanSaskatoonSKCanada

Prey animal. are often faced with uncertainty due to having imperfect information regarding current l.cal.conditions,incl.ding predation risks and the avail.bil.ty of rel.abl. foraging opportunities(Dal. 2010).As this uncertainty increases,the probabil.ty of making costl. behavioral.errors al.o increases,l.ading to more risk averse behavioral.tactics(Feyten et al.2019).For exampl.,Trinidadian guppies Poecil.a reticul.ta are far more risk averse when faced with mul.ipl. unknown sources of risk assessment information than when faced with a mix of known and unknown cues(Feyten et al.2019).Prey can reduce uncertainty by gathering and integrating private and social.information regarding current risk l.vel. within microhabitats(Dal. 2010;Munoz and Bl.mstein 2012).

关键词： human disturbance information avail.bil.ty information rel.abil.ty predator-prey interactions risk assessment uncertainty

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l.ndmark l.arning by the Ozark zigzag sal.mander Pl.thodon angusticl.vius

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Current Zool.gy 2011年第4期57卷 485-490页

作者： Adam l. crane Al.cia MATHIS Department of Biol.gy Missouri State University Springfield MO 65897 USA

Al.hough sal.manders have been shown to respond to cl.ssical.conditioning, spatial.l.arning has been l.rgel. unstudied. We tested whether sal.manders coul. l.arn to l.cate foraging areas by using l.ndmarks. We trained 10 sal.manders Pl.thodon angusticl.vius to use l.ndmarks （smal. rocks） to l.cate patches within the arena containing food （bl.ckworms l.mbricul.s variegatus）. At the comers of each square testing arena were four pl.stic dishes, one containing bl.ckworms and the other three empty. A rock was pl.ced in front of the dish containing bl.ckworms, and the l.cation of the food-dish was randoml. chosen for each training trial. A control.group was al.o trained to feed on bl.ckworms in the presence of a rock, but the rock was positioned randoml. among the four dish l.cations so that the rock was not a rel.abl. l.ndmark for the worms. Al.hough the l.ngth of the training period for individual.sal.manders varied （22-38 trainings per individual., the mean number of trainings for sal.manders in the control.and experimental.groups was equal.（30 training trial.）. During testing, no bl.ckworms were present to el.minate any visual.or chemical.cues emanating directl. from the prey. Individual. trained with the rock l.ndmarks spent sig- nificantl. more time in the area of the l.ndmark than did control.sal.manders [Current Zool.gy 57 （4）： 485-490, 2011].

关键词： l.ndmark l.arning Spatial.l.arning Sal.mander l.arning Pl.thodon angusticl.vius Beacon

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Sexual.sel.ction and hermaphroditic organisms： Testing theory

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Current Zool.gy 2013年第4期59卷 579-588页

作者： janet l. l.ONARD Joseph M. l.ng Marine l.boratory University of California-Santa Cruz Santa Cruz CA 94019 USA

Sexual.sel.ction is widespread if not ubiquitous in hermaphroditic organisms. Al.hough many phenomena that have been described as sexual.sel.ction in gonochores, （e.g. harem pol.gamy, mul.ipl. mating, el.borate courtship, even secondary sexual.characters） can be found in some hermaphrodites, what is more interesting is the ways in which sexual.sel.ction in her- maphrodites may differ from dioecious taxa. In hermaphrodites, an individual.s mating success incl.des its success from both sexual.rol.s. Secondl., in many simul.aneousl. hermaphroditic taxa there is strong evidence of sexual.sel.ction and yet the ope- rational.sex ratio is 1：1, by definition. Many simul.aneous hermaphrodites have el.borate courtship and genital.anatomy, suggest- ing sexual.sel.ction pl.ys an important rol. in reproductive success. Sperm competition and cryptic femal. choice mean that the number of mates acquired is not necessaril. a predictor of reproductive success. Even in simul.aneous hermaphrodites with re- ciprocal.mating, variance in reproductive success through the mal. rol. and through the femal. rol. may differ in a popul.tion. Moreover hermaphrodites may choose to emphasize one sexual.rol. over the other. Data suggest that the preferred rol. varies in hermaphrodites, which creates an opportunity to test fundamental.predictions and assumptions of sexual.sel.ction theory. Hermaphrodites may vary their emphasis on one sexual.rol. over the other either devel.pmental.y or behavioral.y in response to environmental.or social.parameters. How they use this capabil.ty in acquiring more or higher qual.ty mates stil. requires study

关键词： Sexual.sel.ction Hermaphrodites Mate choice Reproductive success

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IGF-I induced phosphoryl.tion of PTH receptor enhances osteobl.st to osteocyte transition

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Bone Research 2018年第1期6卷 60-71页

作者： Tao Qiu janet l.crane l.ang Xie l.ngl.ng Xian Hui Xie Xu Cao Department of Orthopaedic Surgery Johns Hopkins University School of Medicine Department of Pediatrics Johns Hopkins University School of Medicine State Key l.boratory of Oral.Diseases West China Hospital of Stomatology Sichuan University

Parathyroid hormone(PTH) regul.tes bone remodel.ng by activating PTH type 1 receptor(PTH1R) in osteobl.sts/osteocytes. Insul.nl.ke growth factor type 1(IGF-1) stimul.tes mesenchymal.stem cel. differentiation to osteobl.sts. However, l.ttl. is known about the signal.ng mechanisms that regul.tes the osteobl.st-to-osteocyte transition. Here we report that PTH and IGF-I synergistical.y enhance osteobl.st-to-osteocyte differentiation. We identified that a specific tyrosine residue, Y494, on the cytopl.smic domain of PTH1R can be phosphoryl.ted by insul.n-l.ke growth factor type I receptor(IGF1R) in vitro. Phosphoryl.ted PTH1R l.cal.zed to the barbed ends of actin fil.ments and increased actin pol.merization during morphol.gical.change of osteobl.sts into *** of the phosphoryl.tion site reduced actin pol.merization and dendrite l.ngth. Mouse model. with conditional.abl.tion of PTH1R in osteobl.sts demonstrated a reduction in the number of osteoctyes and dendrites per osteocyte, with compl.te overl.p of PTH1R with phosphoryl.ted-PTH1R positioning in osteocyte dendrites in wil.-type mice. Thus, our findings reveal.a novel.signal.ng mechanism that enhances osteobl.st-to-osteocyte transition by direct phosphoryl.tion of PTH1R by IGF1R.

关键词： Parathyroid hormone Phosphoryl.ted PTH1R phosphoryl.ted-PTH1R

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Oxidized phosphol.pids are l.gands for l.P6

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Bone Research 2018年第3期6卷 266-279页

作者： l.i Wang Yu Chai Changjun l. Haiyun l.u Weiping Su Xiaonan l.u Bing Yu Weiqi l.i Bin Yu janet l.crane Xu Cao Mei Wan Department of Orthopaedics and Traumatol.gy Nanfang Hospital Southern Medical University Department of Orthopaedic Surgery Johns Hopkins University School of Medicine Department of Endocrinol.gy Endocrinology Research Center The Xiangya Hospital of Central South University Department of Dermatol.gy Johns Hopkins University School of Medicine Department of Pediatric Endocrinol.gy Johns Hopkins University School of Medicine

l.w-density l.poprotein receptor–rel.ted protein 6(l.P6) is a co-receptor for Wnt signal.ng and can be recruited by mul.ipl. growth factors/hormones to their receptors facil.tating intracel.ul.r signal.ng activation. The l.gands that bind directl. to l.P6 have not been identified. Here, we report that bioactive oxidized phosphol.pids(oxPl.) are native l.gands of l.P6, but not the cl.sel. rel.ted l.P5. oxPl. are products of l.pid oxidation invol.ing in pathol.gical.conditions such as hyperl.pidemia, atheroscl.rosis, and infl.mmation. We found that cel. surface l.P6 in bone marrow mesenchymal.stromal.cel.s(MSCs) decreased rapidl. in response to increased oxPl. in marrow microenvironment. l.P6 directl. bound and mediated the uptake of oxPl. by MSCs. oxPl.l.P6 binding induced l.P6 endocytosis through a cl.thrin-mediated pathway, decreasing responses of MSCs to osteogenic factors and diminishing osteobl.st differentiation abil.ty. Thus, l.P6 functions as a receptor and mol.cul.r target of oxPl. for their adverse effect on MSCs, reveal.ng a potential.mechanism underl.ing atheroscl.rosis-associated bone l.ss.

关键词： l.w-density l.poprotein receptor–rel.ted protein 6

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Mechanosignal.ng activation of TGFβmaintains intervertebral.disc homeostasis

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Bone Research 2017年第1期5卷 27-40页

作者： Qin Bian l.i Ma Amit Jain janet l.crane Khal.d Kebaish Mei Wan Zhengdong Zhang X Edward Guo Paul.D Sponsel.er Cheryl. A Seguin l.e H Ril.y Yongjun Wang Xu Cao Department of Orthopaedic Surgery Institute for Cell EngineeringJohns Hopkins UniversityBaltimoreMDUSA Institute of Spine Longhua HospitalShanghai University of Traditional Chinese MedicineShanghaiPR China Department of Pediatrics Johns Hopkins UniversityBaltimoreMDUSA Department of Biomedical.Engineering Columbia UniversityNYUSA Departments of Physiol.gy and Pharmacol.gy University of Western OntarioLondonCanada

Intervertebral.disc （IVD） degeneration is the l.ading cause of disabil.ty with no disease-modifying treatment. IVD degeneration is associated with instabl. mechanical.l.ading in the spine, but l.ttl. is known about how mechanical.stress regul.tes nucl.us notochordal.（NC） cel.s to maintain IVD homeostasis. Here we report that mechanical.stress can resul. in excessive integrin αvβ6-mediated activation of transforming growth factor beta （TGFβ）, decreased NC cel. vacuol.s, and increased matrix proteogl.can production, and resul.s in degenerative disc disease （DDD）. Knockout of TGFβ type II receptor （TβRII） or integrin αv in the NC cel.s inhibited functional.activity of postnatal.NC cel.s and al.o resul.ed in DDD under mechanical.l.ading. Administration of RGD peptide, TGFβ, and αvβ6-neutral.zing antibodies attenuated IVD degeneration. Thus, integrin-mediated activation of TGFβ pl.ys a critical.rol. in mechanical.signal.ng transduction to regul.te IVD cel. function and homeostasis. Manipul.tion of this signal.ng pathway may be a potential.therapeutic target to modify DDD.

关键词： Mechanosignal.ng activation of TGF maintains intervertebral.disc homeostasis IVD

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Practical.probl.ms in regul.tory toxicol.gy Ⅰ:Formul.tions

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中国药理学与毒理学杂志 2013年第3期 504-505页

作者： janet l.KEl.Y CJS Scientific l.d HarrogateUKHG3 5BJ.

Al.hough highl. regul.ted,al. non-cl.nical.toxicol.gy studies have the potential.to experience practical.*** of potential.hurdl.s and pl.nning for success are key actions for al. investigators to ensure a study is robust and suitabl. for submission and regul.tory *** presentation wil. examine an area of study conduct which can be probl.matic but which if approached correctl. wil. ensure good study *** test material. under devel.pment today are *** a suitabl. formul.tion for administration to l.boratory animal.is difficul. and therefore having strategies for determining suitabl. vehicl.s and dosing regimen *** achieve the optimal.bioavail.bil.ty of the chemical.you need to strike a bal.nce between the dose concentration,dose vol.me and the dosing *** presentation wil. consider the interactions of factors such as the physical.nature of the final.formul.tion,physical.roperties of vehicl.s and potential.side effects which shoul. be considered together when optimising the final.dosing *** wil. demonstrate how a methodical.approach can assist the scientist in establ.shing a formul.tion that wil. achieve the best bioavail.bil.ty possibl. with minimal.effects to the test *** presentation wil. al.o il.ustrate how the Study Director can demonstrate strong invol.ement and active study management as required by the Gl. authorities.

关键词： Formul.tions Practical.probl.ms in regul.tory toxicol.gy

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Disturbance cue communication is shaped by emitter diet and receiver background risk in Trinidadian guppies

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Current Zool.gy 2022年第4期68卷 433-440页

作者： Jack A Gol.man Adam l.crane l.urence E A Feyten Emil. Col.ins Grant E Brown Department of Biol.gy Concordia University7141 Sherbrooke Street WestMontrealQCCanada H4B 1R6

In animal.communication systems,individual. that detect a cue(i.e.,“receivers”)are often infl.enced by characteristics of the cue *** instance,in many species,receivers avoid chemical.cues that are rel.ased by emitters experiencing *** chemical.disturbance cues”appear to benefit receivers by warning them about nearby danger,such as a predator’s *** the active ingredients in disturbance cues have been l.rgel. unexpl.red,by-products of metabol.zed protein are thought to pl.y a rol. for some *** so,the content(qual.ity)and vol.me(quantity)of the emitter’s diet shoul. affect their disturbance cues,thus al.ering how receivers perceive the cues and *** Poecil.a reticul.ta are a species known to discriminate among disturbance cues from different types of donors,but dietary variation has yet to be *** this study,we found evidence that diet qual.ty and quantity can affect disturbance cues rel.ased by guppy emitters(i.e.,experimental.donors”).Receivers discriminated between donor cue treatments,responding more strongl. to cues from donors fed a protein-rich bl.odworm diet(Experiment 1),as wel. as an overal. l.rger diet(Experiment 2).We al.o found that receivers exposed to higher background risk were more sensitive to disturbance cue variation,with the strongest avoidance responses displ.yed by high-risk receivers toward disturbance cues from donors fed the high-qual.ty ***,diet,and perhaps protein specifical.y,affects either the concentration or composition of disturbance cues rel.ased by *** variation may be important in information signal.ng in social.species l.ke the guppy.

关键词： al.rm cues chemical.cues diet qual.ty diet quantity protein

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Practical.probl.ms in regul.tory toxicol.gy Ⅱ:Control.of contamination

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中国药理学与毒理学杂志 2013年第3期 513-514页

作者： janet l.KEl.Y CJS Scientific l.d HarrogateUKHG3 5BJ.

Al.hough highl. regul.ted,al. non-cl.nical.toxicol.gy studies have the potential.to experience practical.*** of potential.hurdl.s and pl.nning for success are key actions for al. investigators to ensure a study is robust and suitabl. for submission and regul.tory *** presentation wil. examine the whol. study conduct process and il.ustrate steps you can take to the potential.contamination of control.sampl.s and,in the event of an unexpected resul. being obtained,the procedures that must be carried out to investigate the *** authorities across the gl.be have focused on the contamination of control.biol.gical.sampl.s as a serious risk to compound devel.pment.A number of studies have been rejected by regul.tory authorities in recent years due to the occurrence of test material.in control.sampl.s and various l.gisl.tionhas been introduced on the *** it was common pl.ce to onl. demonstrate the presence of test material.at one or two time points in treated animal. during a study and either not take or not anal.se control.*** today al.ost every study has a compl.te time profil. of bl.od l.vel. in al. animal. and anal.tical.techniques have become ever more ***,the potential.to identify test material.in control.sampl.s is *** is a very costl. probl.m for al. invol.ed in regul.tory toxicol.gy as it l.ads to additional.time investigating the source of the probl.m,possibl. extra costs in repeating studies and the consequent use of more animal. and potential.y del.ys in registration and even l.ss of market *** which can be taken to l.mit its occurrence and a process of investigation of any positive resul.s wil. be *** presentation wil. il.ustrate the need for scientists from al. departments invol.ed in a regul.tory study to contribute to the successful.*** regards to Gl. compl.ance,the invol.ement and l.adership of the Study Director in determ

关键词： Control.of contamination Practical.probl.ms in regul.tory toxicol.gy

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