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Sex Determina.ion in Homo sa.iens a. a.Multi-Step Process: Potentia. for Development of Va.ia.ts a.d Sex Differences in Disea.e Risk

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Journa. of Biomedica. Science a.d Engineering 2024年第1期17卷 13-34页

作者： david a. hart Depa.tment of Surgery Faculty of Kinesiology McCaig Institute for Bone & Joint Health University of Calgary Cal-gary Canada

Reproduction via.cis-bina.y mecha.isms a.pea.s to ha.e evolved fa.rly ea.ly in the evolution of complex orga.isms, a.d a.system committed to prior to evolution of huma.s. While the evolution of a.chromosoma.-specific a.proa.h ha. been a.successful stra.egy for surviva. of a.la.ge va.iety of species including huma.s, the fidelity of sex determina.ion lea.ing to 100% cis-bina.y outcomes is not a.hieved in ma.y species, with evidence for homosexua. or bisexua. beha.iour evident in more tha. 1500 species. Thus, such outcomes indica.es tha. sex determina.ion is a.multi-step process a.d not a.single event, a.d a. such, could lea. to the a.pea.a.ce of va.ia.ts during the process which developed much ea.lier tha. huma.s. Va.ia.ts could a.ise either due to intrinsic va.ia.ion in the steps of determina.ion, or a.so be influenced by environmenta. fa.tors of a.biologica. or psychologica. na.ure. In contra.t to homosexua. va.ia.ts which do not require interventions such a. hormone thera.y or surgery, expression of gender dysphoria. is more ba.ed in psychology, but a.so ha. biologica. underpinnings a.d ca. be influenced by such hormona. interventions a.d surgery. While the numbers of those with gender dysphoria.is sma.l (~0.6% - 1.0% of popula.ion), the a.tention given to this issue ra.ses the possibility of biologica. a.d psychologica. environmenta. fa.tors impa.ting the emergence of some of those expressing gender dysphoria. Furthermore, tra.sitioning from ma.e-to-fema.e or fema.e-to-ma.e ca. ha.e consequences rega.ding disea.e risks la.ter in life, including the a.pea.a.ce of a.toimmune disea.es. This review will a.tempt to review some of the evidence rega.ding sex determina.ion, discuss why the system ha. potentia.ly not been improved upon during evolution, how a.potentia. role for sex chromosome function on neurodevelopment ma. be centra. to va.ia.ion in huma.s, a.d how commitment to the current stra.egy is likely integra.ed into other sex-rela.ed events such a. puberty, pre

关键词： Sex Determina.ion Va.ia.t Development Fidelity of Sex Determina.ion Biologica. Sex Determina.ion Species Va.ia.ion

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Perspective: Is It Time to Rena.e MSC (Mesenchyma. Stem Cells/Medicina. Signa.ing Cells) with a.Na.e tha. Reflects Their Combined In Vivo Functions a.d Their In Vitro a.ilities?—Possibly “Pluripotent Mesenchyma. Regula.ory Cells (PMRC)”

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Journa. of Biomedica. Science a.d Engineering 2021年第8期14卷 317-324页

作者： david a. hart Depa.tment of Surgery a.d Fa.ulty of Kinesiology University of Calgary Calgary Alberta Canada McCa.g Institute for Bone & Joint Hea.th University of Calgary Calgary Alberta Canada Bone & Joint Hea.th Stra.egic Clinica. Network Alberta Health Services Edmonton Alberta Canada

Over 30 yea.s a.o, it wa. reported by Ca.la. tha. cells could be found in va.ious a.ult tissues a.d fluids of a.va.iety of species tha. could be induced in vitro to progress towa.ds linea.es such a. chondrogenesis, osteogenesis a.d a.ipogenesis with different “cockta.ls” of rea.ents. These cells were ca.led Mesenchyma. Stem Cells (MSC) to reflect this pluripotency. a.ter 30 yea.s of intense resea.ch effort to directly use such cells for the repa.r or regenera.ion of da.a.ed or injured tissues, the effort ha. met with limited in vivo success, but their use for in vitro tissue engineering ha. met with some success. This fa.lure to live up to expecta.ions for in vivo differentia.ion success ha. led Ca.la. to recently rena.e these cells Medicina. Signa.ing Cells (MSC) to reflect other a.ilities of these cells to secrete media.ors a.d relea.e exosomes conta.ning biologica.ly a.tive molecules tha. ca. influence their neighboring cells in a.pa.a.rine ma.ner. However, neither of these na.es completely ca.tures the combined a.pa.ent in vivo functioning of MSC a.d their in vitro a.ilities to exhibit pluripotent beha.ior. Thus, it is suggested, ba.ed on the a.tributes of these cells a.d their tissue a.d clona. heterogeneity, tha. a. a.terna.ive na.e be a.plied to these cells a.d they be described a. Pluripotent Mesenchyma. Regula.ory Cells (PMRC). This na.e reflects their regula.ory function a. pericytes in tissues, a. well a. their well-known immunoregula.ory a.tivity when injected into the intra.a.ticula. spa.e a.d their influence on a.tivities such a. wound hea.ing. It a.so reflects their a.ility to differentia.e a.ong severa. different linea.es to fa.ilita.e tissue engineering a.proa.hes for tissue repa.r.

关键词： Mesenchyma. Stem Cells Medicina. Signa.ing Cells Pluripotent Cells Pluripotent Mesenchyma. Regula.ory Cells

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Huma. Heterogeneity a.d Surviva. of the Species: How Did It a.ise a.d Being Susta.ned?—The Conundrum Fa.ing Resea.chers

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Journa. of Biomedica. Science a.d Engineering 2021年第5期14卷 212-221页

作者： david a. hart Depa.tment of Surgery a.d Fa.ulty of Kinesiology University of Calgary Calgary Canada Bone & Joint Hea.th Stra.egic Clinica. Networks Alberta Health Services Edmonton Canada McCa.g Institute for Bone & Joint Hea.th University of Calgary Calgary Canada Centre for Hip Hea.th a.d Mobility a.d Depa.tment of Fa.ily Pra.tice University of British Columbia Vancouver Canada

Current huma.s, Homo sa.iens, a.e genetica.ly a.d epigenetica.ly very heterogeneous, a.d subsequently a.so biologica.ly a.d physiologica.ly heterogeneous. Much of this heterogeneity likely a.ose during evolutiona.y pr... 详细信息

Current humans, Homo sapiens, a.e genetica.ly a.d epigenetica.ly very heterogeneous, a.d subsequently a.so biologica.ly a.d physiologica.ly heterogeneous. Much of this heterogeneity likely a.ose during evolutiona.y processes, via.va.ious itera.ions of huma.oid linea.es, a.d interbreeding. While a.va.ta.eous from a.species perspective, the heterogeneity of huma.s poses serious cha.lenges to resea.chers a.tempting to understa.d complex disea.e processes. While the use of inbred preclinica. models ma.es the resea.ch effort more effective a. some levels, the findings a.e often not tra.sla.a.le to the more heterogeneous huma. popula.ions. This conundrum lea.s to considera.le resea.ch a.tivity with inbred preclinica. models, but modest progress in understa.ding ma.y complex huma. conditions a.d disea.es. This a.ticle discusses severa. of the issues a.ound huma. heterogeneity a.d the need to cha.ge some directions in preclinica. model resea.ch. Using newer a.tificia. Intelligence a.d Ma.hine Lea.ning a.proa.hes ca. begin to deduce importa.t elements from the complexity of huma. heterogeneity.a.>

关键词： Huma. Heterogeneity Species Surviva. Genetic Va.ia.ion Evolutiona.ily Conserved Pa.demics a.d Surviva.

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Obesity, the Obesity Epidemic, a.d Meta.olic Dysfunction: The Conundrum Presented by the Disconnect between Evolution a.d Modern Societies

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Journa. of Biomedica. Science a.d Engineering 2021年第5期14卷 203-211页

作者： david a. hart Bone & Joint Hea.th Stra.egic Clinica. Network Alberta Health Services Edmonton Canada Depa.tment of Surgery a.d Fa.ulty of Kinesiology University of Calgary Calgary Canada McCa.g Institute for Bone & Joint Hea.th University of Calgary Calgary Canada Centre for Hip Hea.th & Mobility University of British Columbia Vancouver Canada

Currently, there is a. obesity epidemic in the developed world, with both a.ults a.d children being a.fected. The consequences of this epidemic on hea.th a.d hea.th outcomes ha.e impa.t a. multiple levels, a.d it is i... 详细信息

a. style="font-fa.ily:Verda.a.">Currently, there is a. obesity epidemic in the developed world, with both a.ults a.d children being a.fected. The consequences of this epidemic on hea.th a.d hea.th outcomes ha.e impa.t a. multiple levels, a.d it is increa.ing. The ba.is for this epidemic, which a.pea.s to ha.e emerged with significa.ce ~40 - 50 yea.s a.o, is unknown but is believed by ma.y to ha.e much of its ba.is in poor diets a.d ina.tivity/sedenta.y beha.iour. a.a.ysis of the huma. genome ha. revea.ed >100 loci which exhibit risk for development of obesity. Why there a.e so ma.y loci, a.d how they benefited huma.s evolutiona.ily a.e unknown. In spite of these limita.ions, there a.e urgent needs for effective short-term interventions to a.sist those with obesity, a. well a. longer-term needs to effectively prevent development of obesity. For the former, persona.ized exercise progra.s, use of prebiotics, optima. nutrition a.d surgica. interventions ca. be effective for some individua.s but more interventions tha. a.dress ca.se a.e a.so needed. For longer term solutions more deta.led genetic a.d epigenetic understa.ding of risk will be required. a. a.tra.tive specula.ion is tha. the genomic risk fa.tors for obesity (>100 identified) ha.e been reta.ned evolutiona.ily to a.dress a.ute meta.olic needs a.d current conditions ha.e converted such risks to a.chronic sta.e, ma.ing reversa. more difficult a.d with more consequences, including possible epigenetic modifica.ions of risk genes. Other contributing fa.tors to chronic obesity could a.so rela.e to chemica. disruptors in the environment over the pa.t 50+ yea.s which ma. impa.t meta.olic regula.ion via.the esta.lished risk genomic risk fa.tors or new va.ia.ts. Therefore, to effectively control this high impa.t epidemic of obesity likely requires a.more deta.led genetic a.d epigenetic a.a.ysis of fa.ilies with obesity a.d a.a.ysis of isola.ed popula.ions, a. well a. a.more thorough investiga.ion of chemica.s ca.a.le

关键词： Obesity Obesity Epidemic Meta.olic Disturba.ces Evolution Cha.a.teristics of Obesity Ca.ses of Obesity

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Is a.ipocyte Differentia.ion the Defa.lt Linea.e for Mesenchyma. Stem/Progenitor Cells a.ter Loss of Mecha.ica. Loa.ing? a.Perspective from Spa.e Flight a.d Model Systems

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Journa. of Biomedica. Science a.d Engineering 2014年第10期7卷 799-808页

作者： david a. hart McCa.g Institute for Bone & Joint Hea.th University of Ca.ga.y Calgary Canada

Mesenchyma. stem/progenitor cells (MSC/MPC) a.e found in ma.y tissues a.d fluids including bone ma.row, a.ipose tissues, muscle, synovia. membra.es, synovia. fluid, a.d blood. Such cells from different sources ca. prolifera.e a.d differentia.e into different linea.es (e.g. osteogenic, chondrogenic a.d a.ipogenic) a.ter suita.le stimula.ion. However, deta.ls rega.ding the regula.ion of MSC/MPC prolifera.ion a.d differentia.ion sta.us a.e still unclea. a.d it is likely tha. regula.ion involves both biologica. a.d mecha.ica. influences in the different environments. It ha. been noted tha. in huma.s a.d preclinica. a.ima. models tha. exposure to microgra.ity/spa.e flight or prolonged bed rest (a.surroga.e for microgra.ity) ca. lea. to infiltra.ion of skeleta. muscle a.d bone ma.row with fa.. Simila.ly, in preclinica. models trea.ed with multiple intra.uscula. injections of Botulinum Toxin a.to induce muscle wea.ness a.d a.rophy, there is a.so a. infiltra.ion of the muscle with fa.. The origins a.d ba.is for these fa. deposits a.e la.gely unknown, but there is a.possibility tha. the a.tered mecha.ica. a.d biologica. environments lea. to dysregula.ion of MSC/MPC a.d progression to preferentia. differentia.ion towa.ds the a.ipocyte linea.e. Furthermore, loss of MSC regula.ory control by either mecha.ica. a.d/or biologica. fa.tors ma. a.so contribute to their involvement in obesity development a.d progression. Thus, the utility of using MSC/MPC from some sources for tissue engineering purposes ma. be compromised a.d further resea.ch rega.ding optima. loa.ing for tissue engineering purposes is likely wa.ra.ted.

关键词： Mesenchyma. Stem Cells a.ipose-Linea.e Microgra.ity Bed Rest Muscle Wea.ness MSC Regula.ion a.ipose Tissue

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Why Mesenchyma. Stem/Progenitor Cell Heterogeneity in Specific Environments? —Implica.ions for Tissue Engineering a.plica.ions Following Injury or Degenera.ion of Connective Tissues

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Journa. of Biomedica. Science a.d Engineering 2014年第8期7卷 526-532页

作者： david a. hart McCa.g Institute for Bone & Joint Hea.th University of Ca.ga.y Calgary Canada

Mesenchyma. stem/progenitor cells (MSC/MPC) from a.va.iety of tissue sources (bone ma.row, a.ipose tissue, fa. pa.s, synovia. membra.es, synovia. fluid, skin, muscle a.d periostea. tissue) ha.e been widely a.plied for tissue engineering a.plica.ions to genera.e repla.ements for injured or degenera.ed tissues. a.terna.ively, they ha.e a.so been injected a. free cells in a. a.tempt to fa.ilita.e in vivo repa.r. Nea.ly a.l studies reported ha.e used mixed cell popula.ions of MSC/MPC, usua.ly defined by cell surfa.e phenotypes a.d/or functiona. a.ility to differentia.e towa.ds multiple cell linea.es. Using more deta.led cell surfa.e phenotyping a.d limiting dilution a.proa.hes to isola.e individua. MSC/MPC clones ha.e indica.ed tha. such mixed cell popula.ions a.e very heterogeneous. In a.dition subsets of cells from different sources ma. ha.e epigenetic modifica.ions. While it is clea. tha. MSC/MPC cells exhibit heterogeneity, the question of why this is the ca.e ha. not been well a.dressed. This review will a.dress some of these issues, a. well a. provide some insights into the implica.ions when using such diverse cells for tissue engineering a.plica.ions.

关键词： Mesenchyma. Stem/Progenitor Cells Cell Heterogeneity Tissue-Specific Heterogeneity Tissue Engineering

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a.e We Lea.ning a. Much a. Possible from Spa.eflight to Better Understa.d Hea.th a.d Risks to Hea.th on Ea.th, a. Well a. in Spa.e?

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Journa. of Biomedica. Science a.d Engineering 2018年第6期11卷 109-118页

作者： david a. hart Huma. Performa.ce La.ora.ory University of Calgary Calgary Canada Fa.ulty of Kinesiology University of Calgary Calgary Canada Depa.tment of Surgery University of Calgary Calgary Canada McCa.g Institute for Bone & Joint Hea.th University of Calgary Calgary Canada a.berta.Hea.th Services Bone & Joint Hea.th Stra.egic Clinica. Network Edmonton Canada

The objective of this review is to discuss the cha.ges in huma. biology a.d physiology tha. occur when huma.s, who evolved on Ea.th for millions of yea.s, now a.e subjected to spa.e flight for extended periods of time, a.d how deta.ling such cha.ges a.socia.ed with spa.e flight could help better understa.d risks for loss of hea.th on Ea.th. Spa.e progra.s invest hea.ily in the selection a.d tra.ning of a.trona.ts. They a.so a.e investing in ma.nta.ning the hea.th of a.trona.ts, both for extensive sta.s in low ea.th orbit on ISS, a.d in prepa.a.ion for deep spa.e missions in the future. This effort is critica. for the success of such missions a. the N is sma.l a.d the ta.ks needed to be performed in a.hostile environment a.e complex a.d dema.ding. However, spa.e is a.unique environment, devoid of ma.y of the “bounda.y conditions” tha. sha.ed huma. evolution (e.g. 1 g environment, ma.netic fields, ba.kground ra.ia.ion, oxygen, wa.er, etc). Therefore, for huma.s to be successful in spa.e, we need to lea.n to a.a.t a.d minimize the impa.t of a. a.tered environment on huma. hea.th. Conversely, we ca. a.so lea.n considera.ly from this a.tered environment for life on ea.th. The question is, a.e we getting the ma.ima. informa.ion from life in spa.e to lea.n a.out like on ea.th? The a.swer is likely No, a.d a. such, our “Return on Investment” is not a. grea. a. it could be. Even though the number of a.trona.ts is not la.ge, wha. we ca. lea.n from them could help sha.e new questions for resea.ch focused on hea.th for those on ea.th, a. well is contribute to “precision hea.th” from the study of a.trona.t diversity. This la.ter effort would contribute to both the hea.th of a.trona.ts identifying risks, a. well a. contribute to hea.th on ea.th via.better understa.ding of the huma. genome a.d epigenome, a. well a. fa.tors contributing to risk for disea.es on ea.th, pa.ticula.ly a. individua.s a.e a.d regula.ory systems become a.tered. Better use of the Interna.iona. Spa.e Sta.ion

关键词： Physiology Genome Epigenome Spa.e Flight Precision Medicine Precision Hea.th Silent Muta.ions a.celera.ed a.ing

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Evidence for a.Potentia. “Knee-Eye-Bra.n a.is” Involved in Mobility a.d Na.iga.ion Control: Knee Injury a.d Obesity Ma. Disrupt a.is Integrity

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Journa. of Biomedica. Science a.d Engineering 2018年第3期11卷 37-44页

作者： david a. hart Fa.ulty of Kinesiology University of Calgary Calgary Alberta Canada Depa.tment of Surgery University of Calgary Calgary Alberta Canada McCa.g Institute for Bone & Joint Hea.th University of Calgary Calgary Alberta Canada Bone & Joint Hea.th Stra.egic Clinica. Network Alberta Health Services Alberta Canada

Huma.s depend on the coordina.ed a.tivity of their lower extremities for mobility, a. essentia. fea.ure of Homo sa.iens. In a.dition, they use vision to use this mobility to successfully na.iga.e through their environment. During development, mobility a.pea.s to ma.ure first, a.d then it is coordina.ed with na.iga.ion. Thus, the two, mobility a.d na.iga.ion a.e likely interdependent in function. Recent studies ha.e indica.ed tha. compromising the integrity of the knee, a.centra. element of the lower extremity motion segment, ca. lea. to molecula. a.tera.ions in both the cornea.including the centra. cornea.where light pa.ses, a. well a. the interior of the eye (the vitreous humor). Not a.l insults to the knee lea. to reproducible a.tera.ions in the eye, indica.ing some specificity in the response. In a.dition, it wa. recently reported tha. a.tera.ions to the cells in the vitreous humor occur following dieta.y induction of obesity in a.ra. model. a. huma.s with obesity, a. well a. a.thritis of the knee a.e a. risk for ocula. involvement a.d exhibit a.tered ga.t cha.a.teristics, the clinica. a.d preclinica. da.a.ra.se the possibility of a.“knee-eye-bra.n a.is” to control or regula.e mobility a.d na.iga.ion. Better delinea.ion of such a. a.is could ha.e implica.ions for va.ia.ions in control during ma.ura.ion, a.d well a. during a.ing when vision a.d mobility ca. be compromised, with increa.ed risk for serious fa.ls a.d fa.lure to successfully na.iga.e the environment.

关键词： Knee Injury Eye Cornea Vitreous Humor Vitreous Humor Cells Obesity

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Trea.ments for fibrosis development a.d progression: Lessons lea.ned from preclinica. models a.d potentia. impa.t on huma. conditions such a. scleroderma. pulmona.y fibrosis, hypertrophic sca.ring a.d tendinopa.hies

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Journa. of Biomedica. Science a.d Engineering 2013年第8期6卷 1-9页

作者： david a. hart McCa.g Institute for Bone & Joint Health University of Calgary Calgary Canada

Progressive fibrosis of a.tissue or orga. in response to a.da.a.ing insult ma. result in loss of orga. function if the a.ute response is excessive, or a.chronic fibrotic response is initia.ed due to the persistence of the insult. In the a.thor’s la.ora.ory over the pa.t severa. yea.s, a.number of preclinica. models of fibrosis or fibrogenic responses ha.e been cha.a.terized for the effectiveness of va.ious trea.ment a.proa.hes to either prevent or impede fibrosis development a.d progression to identify commona.ities a.d tra.sla.a.le resea.ch directions tha. could provide insights into huma. disea.es. These ha.e ma.nly included either chemica.ly induced pulmona.y fibrosis models or overt physica. injury models in ra.s, pigs a.d ra.bits. Some prelimina.y studies in huma. popula.ions ha.e a.so been underta.en. The interventions eva.ua.ed ha.e included fibrinolytic a.ents a.d drugs ta.geting specific cell popula.ions. The results indica.e tha. some a.proa.hes lend themselves to modifying fibrotic rea.tions in some models a.d not others, while others ma. ha.e a.more genera.ized impa.t on fibrogenic responses due to interference with a.norma. cell functions in the injury environment.

关键词： Fibrosis Chronic Fibrotic Response Fibrinolytic a.ents Cell Function

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Influence of Spa.e Environments in System Physiologic a.d Molecula. Integrity: Redefining the Concept of Huma. Hea.th beyond the Bounda.y Conditions of Ea.th

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Journa. of Biomedica. Science a.d Engineering 2019年第8期12卷 400-408页

作者： david a. hart Huma. Performa.ce La.ora.ory Faculty of Kinesiology Calgary Canada McCa.g Institute for Bone & Joint Hea.th Calgary Canada Depa.tment of Surgery University of Calgary Calgary Canada Bone & Joint Hea.th Stra.egic Clinica. Network Alberta Health Services Edmonton Canada

Spa.e tra.el since the 1960s ha. led to a.number of physiologica. a.tera.ions to homeosta.is in a.trona.ts. Extensive va.ia.ion in the pa.tern of responses observed ha. led a.concerted effort to develop countermea.ures to overcome such cha.ges a.d restore homeosta.is, a.d thus “hea.th” is defined a. more “Ea.th-like”. These a.a.ta.ions to a.spa.e environment by a.species which evolved a.d norma.ly exists in the 1 g environment, the geoma.netic field, a.d ba.kground ra.ia.ion of Ea.th a.e viewed a. threa.s to hea.th a. defined by the conditions of Ea.th. Exposure to spa.e ca. lea. to a.tera.ions in genomic sta.ility a.d epigenetic signa.ures, a.tera.ions which could redefine “hea.th” a.d responses to risks for loss of hea.th for those who will return to Ea.th. In contra.t, in the future individua.s born in non-Ea.th spa.e environments will likely develop a. integra.ed meta.olic set point defined by those conditions. They will thus be sha.ed by both the loca. environments, a.d spa.e-a.socia.ed genomic/epigenomic a.tera.ions to their pa.ents. Therefore, such a. a.tered set point for those born a.d ra.sed in non-Ea.th spa.e environments will potentia.ly ha.e physiologica. a.d molecula. consequences which ma. lea. to either new evolutiona.y a.a.ta.ion, or to compromise of long term hea.th due to dra.tica.ly a.tered set points for integra.ed physiologic function which is a. odds with the evolutiona.y history of huma.s. The implica.ions of the two options will be critica. for defining “hea.th” in a.tered environments encountered during spa.e ventures, a. well a. providing insights into the regula.ion of huma. integrity a. the physiologica. level. Therefore, the definition of “hea.th” is dependent on the bounda.y conditions surrounding development a.d ma.ura.ion, a.d is a.dyna.ic concept.

关键词： Spa.e Explora.ion a.trona.t Hea.th Meta.olic Set Points Epigenetics Huma. Genome New Definitions

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