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1.
FASEB J ; 24(6): 1768-79, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20103718

RESUMO

The controls of human keratin expression in situ remain to be fully elucidated. Here, we have investigated the effects of the neurohormone prolactin (PRL) on keratin expression in a physiologically and clinically relevant test system: organ-cultured normal human hair follicles (HFs). Not only do HFs express a wide range of keratins, but they are also a source and target of PRL. Microarray analysis revealed that PRL differentially regulated a defined subset of keratins and keratin-associated proteins. Quantitative immunohistomorphometry and quantitative PCR confirmed that PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes. PRL also up-regulated K15 promoter activity and K15 protein expression in situ, whereas it inhibited K6 and K31 expression. These regulatory effects were reversed by a pure competitive PRL receptor antagonist. Antagonist alone also modulated keratin expression, suggesting that "tonic stimulation" by endogenous PRL is required for normal expression levels of selected keratins. Therefore, our study identifies PRL as a major, clinically relevant, novel neuroendocrine regulator of both human keratin expression and human epithelial stem cell biology in situ.


Assuntos
Biomarcadores/metabolismo , Folículo Piloso/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Queratinas/metabolismo , Prolactina/farmacologia , Adulto , Idoso , Western Blotting , Feminino , Perfilação da Expressão Gênica , Folículo Piloso/metabolismo , Humanos , Técnicas Imunoenzimáticas , Queratinócitos/metabolismo , Queratinas/genética , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Técnicas de Cultura de Órgãos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
3.
J Invest Dermatol ; 129(5): 1071-87, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19110541

RESUMO

The polypeptide hormone prolactin (PRL) is best known as the pituitary modulator of lactation and reproduction. However, based on the almost ubiquitous distribution of PRL receptors (PRLR) and an ever-growing list of extrapituitary PRL-expressing tissues, a vast range of PRL actions "beyond the mammary horizon" has now been documented or claimed. For example, PRL modulates hair growth in domestic animals with seasonal hair growth changes ("PRL-pelage axis"). Given that the mammary gland is an epidermal derivative, it is not surprising that the pilosebaceous unit, another epidermal derivative, has also surfaced as a prominent, PRLR-expressing, nonclassical PRL target organ. Moreover, the fact that murine and human hair follicles even synthesize PRL strongly invites one to explore fully the dermatological dimensions of this multifunctional, cytokine-like neuroendocrine bioregulator, which remain insufficiently charted. After describing the relevant essentials of general PRL/PRLR biology, we summarize clinical observations that provide insights into how PRL may impact on the skin, and define important research frontiers and controversies in the quest to better characterize the complex role of PRL in human skin biology and pathology. Focusing on psoriasis, alopecia, and stress-related dermatoses, we then discuss the possible role of PRL/PRLR in cutaneous pathology, and identify potential therapeutic targets for the management of these skin disorders. We close by delineating major open questions at this emerging frontier of basic and clinical cutaneous neuroendocrinology, and argue that systematic exploration of the "PRL-skin connection" will fertilize the development of previously unreported neuroendocrinological strategies for managing selected skin disorders.


Assuntos
Hormônios Peptídicos/fisiologia , Prolactina/fisiologia , Fenômenos Fisiológicos da Pele , Animais , Regulação da Temperatura Corporal/fisiologia , Folículo Piloso/crescimento & desenvolvimento , Humanos , Imunidade/fisiologia , Dermatopatias/etiologia , Dermatopatias/fisiopatologia , Cicatrização/fisiologia
4.
Exp Dermatol ; 16(11): 936-45, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17927577

RESUMO

The trimethylated amino acid l-carnitine plays a key role in the intramitochondrial transport of fatty acids for beta-oxidation and thus serves important functions in energy metabolism. Here, we have tested the hypothesis that l-carnitine, a frequently employed dietary supplement, may also stimulate hair growth by increasing energy supply to the massively proliferating and energy-consuming anagen hair matrix. Hair follicles (HFs) in the anagen VI stage of the hair cycle were cultured in the presence of 0.5-50 microm of l-carnitine-l-tartrate (CT) for 9 days. At day 9, HFs treated with 5 microm or 0.5 microm of CT showed a moderate, but significant stimulation of hair shaft elongation compared with vehicle-treated controls (P < 0.05). Also, CT prolonged the duration of anagen VI, down regulated apoptosis (as measured by TUNEL assay) and up regulated proliferation (as measured by Ki67 immunohistology) of hair matrix keratinocytes (P < 0.5). By immunohistology, intrafollicular immunoreactivity for TGFbeta2, a key catagen-promoting growth factor, in the dermal papilla and TGF-beta II receptor protein in the outer root sheath and dermal papilla was down regulated. As shown by caspase activity assay, caspase 3 and 7, which are known to initiate apoptosis, are down regulated at day 2 and day 4 after treatment of HFs with CT compared with vehicle-treated control indicating that CT has an immediate protective effect on HFs to undergo programmed cell death. Our findings suggest that l-carnitine stimulates human scalp hair growth by up regulation of proliferation and down regulation of apoptosis in follicular keratinocytes in vitro. They further encourage one to explore topical and nutraceutical administration of l-carnitine as a well-tolerated, relatively safe adjuvant treatment in the management of androgenetic alopecia and other forms of hair loss.


Assuntos
Carnitina/farmacologia , Folículo Piloso/efeitos dos fármacos , Folículo Piloso/crescimento & desenvolvimento , Adulto , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Folículo Piloso/metabolismo , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Tartaratos/farmacologia , Fator de Crescimento Transformador beta2/metabolismo
6.
FASEB J ; 20(13): 2366-8, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16966487

RESUMO

Mast cells (MCs) have recently been reported to play a pivotal role in the elicitation of inflammatory reactions that are beneficial to the host, e.g., during innate immune responses to bacteria. To explore whether MCs also contribute to wound repair, we studied experimentally induced skin wounds in MC-deficient Kit(W)/Kit(W-v) mice, normal Kit+/+ mice, and MC-reconstituted Kit(W)/Kit(W-v) mice. Wound closure was significantly impaired in the absence of MCs during the first 6 days of wound healing and histomorphometric analyses of MC degranulation at the wound edges revealed distance-dependent MC activation, i.e., MC degranulation was most prominent directly adjacent to the wound. In addition, Kit(W)/Kit(W-v) mice showed impaired extravasation and recruitment of neutrophils to the wounded areas. Notably, wound closure, extravasation, and neutrophil recruitment were found to be normal in MC-reconstituted Kit(W)/Kit(W-v) mice. Therefore, we examined whether MCs promote wound healing by releasing histamine or TNF-alpha. Interestingly, wound closure was reduced in mice treated with an H1-receptor antagonist but not after treatment with an H2-receptor antagonist or in the absence of TNF-alpha. Taken together, our findings indicate that MC activation and histamine release are required for normal cutaneous wound healing.


Assuntos
Mastócitos/fisiologia , Pele/lesões , Cicatrização , Animais , Divisão Celular , Cruzamentos Genéticos , Modelos Animais de Doenças , Antagonistas dos Receptores Histamínicos H1/farmacologia , Liberação de Histamina , Queratinócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Necrose Tumoral alfa/deficiência , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/fisiologia
7.
Semin Cutan Med Surg ; 25(1): 2-10, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16616298

RESUMO

The mammalian hair follicle represents a unique, highly regenerative neuroectodermal-mesodermal interaction system that contains numerous stem cells. It is the only organ in the mammalian organism that undergoes life-long cycles of rapid growth (anagen), regression (catagen), and resting periods (telogen). These transformations are controlled by changes in the local signaling milieu, based on changes in expression/activity of a constantly growing number of cytokines, hormones, neurotransmitters, and their cognate receptors as well as of transcription factors and enzymes that have become recognized as key mediators of hair follicle cycling. Transplantation experiments have shown that the driving force of cycling, the "hair cycle clock," is located in the hair follicle itself. However, the exact underlying molecular mechanisms that drive this oscillator system remain unclear. These controls of hair follicle cycling are of great clinical interest because hair loss or unwanted hair growth largely reflect undesired changes in hair follicle cycling. To develop therapeutic agents for the management of these hair cycle abnormalities, it is critical to decipher and pharmacologically target the key molecular controls that underlie the enigmatic "hair cycle clock."


Assuntos
Ciclo Celular/fisiologia , Hormônios Esteroides Gonadais/metabolismo , Folículo Piloso/citologia , Folículo Piloso/metabolismo , Ritmo Circadiano/fisiologia , Humanos
8.
Am J Pathol ; 168(3): 748-56, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16507890

RESUMO

The prototypic pituitary hormone prolactin (PRL) exerts a wide variety of bioregulatory effects in mammals and is also found in extrapituitary sites, including murine skin. Here, we show by reverse transcriptase-polymerase chain reaction and immunohistology that, contrary to a previous report, human skin and normal human scalp hair follicles (HFs), in particular, express both PRL and PRL receptors (PRL-R) at the mRNA and protein level. PRL and PRL-R immunoreactivity can be detected in the epithelium of human anagen VI HFs, while the HF mesenchyme is negative. During the HF transformation from growth (anagen) to apoptosis-driven regression (catagen), PRL and PRL-R immunoreactivity appear up-regulated. Treatment of organ-cultured human scalp HFs with high-dose PRL (400 ng/ml) results in a significant inhibition of hair shaft elongation and premature catagen development, along with reduced proliferation and increased apoptosis of hair bulb keratinocytes (Ki-67/terminal dUTP nick-end labeling immunohistomorphometry). This shows that PRL receptors, expressed in HFs, are functional and that human skin and human scalp HFs are both direct targets and sources of PRL. Our data suggest that PRL acts as an autocrine hair growth modulator with catagen-promoting functions and that the hair growth-inhibitory effects of PRL demonstrated here may underlie the as yet ill-understood hair loss in patients with hyper-prolactinemia.


Assuntos
Comunicação Autócrina , Folículo Piloso/crescimento & desenvolvimento , Prolactina/metabolismo , Receptores da Prolactina/metabolismo , Couro Cabeludo/metabolismo , Apoptose , Proliferação de Células/efeitos dos fármacos , Folículo Piloso/efeitos dos fármacos , Folículo Piloso/metabolismo , Humanos , Hiperprolactinemia/genética , Hiperprolactinemia/metabolismo , Queratinócitos/química , Queratinócitos/citologia , Queratinócitos/metabolismo , Antígeno Ki-67/análise , Técnicas de Cultura de Órgãos , Comunicação Parácrina , Prolactina/genética , Prolactina/farmacologia , Receptores da Prolactina/efeitos dos fármacos , Couro Cabeludo/efeitos dos fármacos , Transcrição Genética
10.
J Invest Dermatol ; 124(6): 1119-26, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15955085

RESUMO

Diffuse hair loss ranks among the most frequent and psychologically most distressing adverse effects of systemic therapy with retinoids, which severely limits their therapeutic use even where clinically desired. Since the underlying mechanisms of retinoid-induced effluvium are as yet unknown, we have investigated the influence of the prototypic retinoid all-trans retinoic acid (ATRA, tretinoin) on the growth of human scalp hair follicles (HF) in culture. HF in the anagen VI stage of the hair cycle were cultured in the presence of 10(-8) or 10(-10) M ATRA. Compared with controls, hair shaft elongation declined significantly already after 2 d in the ATRA-treated group, and approximately 80% of the ATRA-treated HF had prematurely entered catagen-like stage at day 6, compared with 30% in the control group. This corresponded to an upregulation of apoptotic and a downregulation of Ki67-positive cells in ATRA-treated HF. Since transforming growth factor (TGF)-beta has been implicated as a key inducer of catagen, we next studied whether ATRA treatment had any effect on follicular expression. TGF-beta2 immunoreactivity was detected in the outer root sheath of anagen VI scalp HF. In catagen follicles, TGF-beta2 was also expressed in the regressing epithelial strand. After 4 d of ATRA treatment, TGF-beta2 was significantly upregulated in anagen HF in the dermal papilla (DP) and the dermal sheath, 7, and TGF-beta neutralizing antibody partially abrogated at RA induced hair growth inhibition. Real-time PCR confirmed a significant upregulation of TGF-beta2 transcripts in ATRA-treated hair bulbs. This study is the first to provide direct evidence that ATRA can indeed induce a catagen-like stage in human HF and suggests that this occurs, at least in part, via upregulation of TGF-beta2 in the DP. Therefore, topical TGF-beta2/TGF-beta receptor II antagonists deserve to be explored for the prevention and management of retinoid-induced hair loss.


Assuntos
Derme/metabolismo , Folículo Piloso/efeitos dos fármacos , Hipotricose/induzido quimicamente , Retinoides/efeitos adversos , Fator de Crescimento Transformador beta/metabolismo , Tretinoína/farmacologia , Anticorpos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Derme/efeitos dos fármacos , Cabelo/efeitos dos fármacos , Cabelo/crescimento & desenvolvimento , Humanos , Queratinócitos/citologia , Queratinócitos/fisiologia , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta2 , Regulação para Cima
11.
Differentiation ; 72(9-10): 489-511, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15617561

RESUMO

The hair follicle, a unique characteristic of mammals, represents a stem cell-rich, prototypic neuroectodermal-mesodermal interaction system. This factory for pigmented epithelial fibers is unique in that it is the only organ in the mammalian body which, for its entire lifetime, undergoes cyclic transformations from stages of rapid growth (anagen) to apoptosis-driven regression (catagen) and back to anagen, via an interspersed period of relative quiescence (telogen). While it is undisputed that the biological "clock" that drives hair follicle cycling resides in the hair follicle itself, the molecular nature of the underlying oscillator system remains to be clarified. To meet this challenge is of profound general interest, since numerous key problems of modern biology can be studied exemplarily in this versatile model system. It is also clinically important, since the vast majority of patients with hair growth disorders suffers from an undesired alteration of hair follicle cycling. Here, we sketch basic background information and key concepts that one needs to keep in mind when exploring the enigmatic "hair cycle clock"(HCC), and summarize competing models of the HCC. We invite the reader on a very subjective guided tour, which focuses on our own trials, errors, and findings toward the distant goal of unravelling one of the most fascinating mysteries of biology: Why does the hair follicle cycle at all? How does it do it? What are the key players in the underlying molecular controls? Attempting to offer at least some meaningful answers, we share our prejudices and perspectives, and define crucial open questions.


Assuntos
Relógios Biológicos , Folículo Piloso/fisiologia , Animais , Previsões , Folículo Piloso/crescimento & desenvolvimento , Humanos , Modelos Biológicos
12.
Exp Dermatol ; 13(10): 635-42, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15447724

RESUMO

Minoxidil induces new hair growth in approximately one-third of patients with androgenetic alopecia after 1 year of treatment. With several conflicting reports in the literature based on small-scale studies, the current study aimed to clarify whether organ culture of human scalp anagen VI hair follicles is a suitable in vitro test system for reproducing, and experimentally dissecting, the recognized in vivo hair-growth-promoting capacity of minoxidil. Hair shaft elongation was studied in terminal anagen VI hair follicles microdissected from the occipital scalp of 36 healthy adults. A total of 2300 hair follicles, approximately 65 per individual, were tested using modifications of a basic organ culture protocol. It is shown here that minoxidil does not significantly increase hair shaft elongation or the duration of anagen VI in ex vivo culture despite several enhancements on the conventional methodology. This disparity to what is seen clinically in minoxidil responders may be explained by the following: (i) use of occipital (rather than frontotemporal or vertex) hair follicles; (ii) use of, already maximally growing, anagen VI hair follicles; (iii) a predominance of hair follicles from minoxidil unresponsive-donors; (iv) use of minoxidil rather than its sulfate metabolite; and/or (v) use of a suboptimal minoxidil dosage. This disparity questions the usefulness of standard human hair follicle organ culture in minoxidil research. Unexpectedly, minoxidil even inhibited hair shaft elongation in the absence of insulin, which may indicate that the actual hair-growth-modulatory effects of minoxidil depend on the concomitant local presence/absence of other growth modulators.


Assuntos
Fármacos Dermatológicos/farmacologia , Folículo Piloso/efeitos dos fármacos , Folículo Piloso/crescimento & desenvolvimento , Minoxidil/farmacologia , Adulto , Idoso , Feminino , Humanos , Insulina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Técnicas de Cultura de Órgãos
13.
J Invest Dermatol ; 123(3): 455-7, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15304082

RESUMO

Hair loss, as it occurs with telogen effluvium and androgenetic alopecia, provokes anxieties and distress more profound than its objective severity would appear to justify. This reflects the profound symbolic and psychosocial importance of hair. Stress has long been implicated as one of the causal factors involved in hair loss. Recently, in vivo studies in mice have substantiated the long-held popular belief that stress can exert profound hair growth-inhibitory catagen-inducing and hair-damaging pro-inflammatory effects. Insights into the negative impact of stress on hair growth and the integration of stress-coping strategies into the management of hair loss disorders as well as the development of new pharmacotherapeutic strategies might lead to enhanced therapeutic modalities with the alleviation of clinical symptoms as well as the concomitant psychological implications.


Assuntos
Alopecia/etiologia , Alopecia/psicologia , Estresse Psicológico/complicações , Adaptação Psicológica , Alopecia/tratamento farmacológico , Animais , Substâncias de Crescimento/uso terapêutico , Humanos
14.
Am J Pathol ; 162(5): 1611-21, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12707045

RESUMO

Here, we provide the first study of prolactin (PRL) and prolactin receptor (PRLR) expression during the nonseasonal murine hair cycle, which is, in contrast to sheep, comparable with the human scalp and report that both PRL and PRLR are stringently restricted to the hair follicle epithelium and are strongly hair cycle-dependent. In addition we show that PRL exerts functional effects on anagen hair follicles in murine skin organ culture by down-regulation of proliferation in follicular keratinocytes. In telogen follicles, PRL-like immunoreactivity was detected in outer root sheath (ORS) keratinocytes. During early anagen (III to IV), the developing inner root sheath (IRS) and the surrounding ORS were positive for PRL. In later anagen stages, PRL could be detected in the proximal IRS and the inner layer of the ORS. The regressing (catagen) follicle showed a strong expression of PRL in the proximal ORS. In early anagen, PRLR immunoreactivity occurred in the distal part of the ORS around the developing IRS, and subsequently to a restricted area of the more distal ORS during later anagen stages and during early catagen. The dermal papilla (DP) stayed negative for both PRL and PRLR throughout the cycle. Telogen follicles showed only a very weak PRLR staining of ORS keratinocytes. The long-form PRLR transcript was shown by real-time polymerase chain reaction to be transiently down-regulated during early anagen, whereas PRL transcripts were up-regulated during mid anagen. Addition of PRL (400 ng/ml) to anagen hair follicles in murine skin organ culture for 72 hours induced premature catagen development in vitro along with a decline in the number of proliferating hair bulb keratinocytes. These data support the intriguing concept that PRL is generated locally in the hair follicle epithelium and acts directly in an autocrine or paracrine manner to modulate the hair cycle.


Assuntos
Ciclo Celular/fisiologia , Folículo Piloso/fisiologia , Cabelo/crescimento & desenvolvimento , Prolactina/genética , Receptores da Prolactina/genética , Animais , Sequência de Bases , Primers do DNA , Células Epiteliais/citologia , Células Epiteliais/fisiologia , Feminino , Regulação da Expressão Gênica , Cabelo/citologia , Folículo Piloso/citologia , Humanos , Queratinócitos/citologia , Queratinócitos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Lactogênio Placentário/genética , Reação em Cadeia da Polimerase , Pele/citologia , Fenômenos Fisiológicos da Pele
15.
Am J Pathol ; 160(5): 1807-21, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12000732

RESUMO

We have previously shown that the ubiquitously expressed lysosomal cysteine protease, cathepsin L (CTSL), is essential for skin and hair follicle homeostasis. Here we examine the effect of CTSL deficiency on hair follicle development and cycling in ctsl(-/-) mice by light and electron microscopy, Ki67/terminal dUTP nick-end labeling, and trichohyalin immunofluorescence. Hair follicle morphogenesis in ctsl(-/-) mice was associated with several abnormalities. Defective terminal differentiation of keratinocytes occurred during the formation of the hair canal, resulting in disruption of hair shaft outgrowth. Both proliferation and apoptosis levels in keratinocytes and melanocytes were higher in ctsl(-/-) than in ctsl(+/+) hair follicles. The development of the hair follicle pigmentary unit was disrupted by vacuolation of differentiating melanocytes. Hair cycling was also abnormal in ctsl(-/-) mice. Final stages of hair follicle morphogenesis and the induction of hair follicle cycling were retarded. Thereafter, these follicles exhibited a truncated resting phase (telogen) and a premature entry into the first growth phase. Further abnormalities of telogen development included the defective anchoring of club hairs in the skin, which resulted in their abnormal shedding. Melanocyte vacuolation was again apparent during the hair cycle-associated reconstruction of the hair pigmentary unit. A hallmark of these ctsl(-/-) mice was the severe disruption in the exiting of hair shafts to the skin surface. This was mostly because of a failure of the inner root sheath (keratinocyte layer next to the hair shaft) to fully desquamate. These changes resulted in a massive dilation of the hair canal and the abnormal routing of sebaceous gland products to the skin surface. In summary, this study suggests novel roles for cathepsin proteases in skin, hair, and pigment biology. Principal target tissues that may contain protein substrate(s) for this cysteine protease include the developing hair cone, inner root sheath, anchoring apparatus of the telogen club, and organelles of lysosomal origin (eg, melanosomes).


Assuntos
Catepsinas/metabolismo , Folículo Piloso/enzimologia , Queratinócitos/enzimologia , Lisossomos/enzimologia , Melanócitos/enzimologia , Animais , Apoptose , Catepsina L , Catepsinas/deficiência , Catepsinas/genética , Diferenciação Celular , Cisteína Endopeptidases , Genótipo , Folículo Piloso/crescimento & desenvolvimento , Folículo Piloso/ultraestrutura , Imuno-Histoquímica , Proteínas de Filamentos Intermediários , Queratinócitos/citologia , Melanócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Microscopia Eletrônica , Mutação , Precursores de Proteínas/análise , Glândulas Sebáceas/crescimento & desenvolvimento , Glândulas Sebáceas/ultraestrutura , Pele/química , Pele/metabolismo , Pele/patologia
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