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1.
LGBT Health ; 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38563664

RESUMO

Purpose: This study investigated the prevalence rates of various types of intimate partner violence (IPV) among lesbian, gay, and bisexual (LGB) adults in Hong Kong and examined the associations between IPV and different addictive behavior and mental health problems. Methods: A total of 759 LGB adults completed an online cross-sectional survey between November 2021 and February 2022. Data on past-year IPV and LGB-specific tactics (whether perpetrated or experienced by participants), addictive behavior, anxiety, depression, and demographics were collected and analyzed with descriptive statistics and logistic regressions. Results: Psychological aggression was the most common type of IPV within an LGB relationship (22.1%), followed by physical assault (10.8%) and IPV-related injury (4.1%). LGB-specific tactics were experienced by 39.0% of the LGB adults. Depression, anxiety, and frequent gambling were significantly associated with specific types of IPV and LGB-specific tactics. Conclusion: IPV was prevalent in the LGB population. Findings on correlates provided insights for future development of IPV detection and intervention.

2.
Sociol Health Illn ; 2023 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-38078806

RESUMO

This article examines how lesbians and gay men imagine and build their 'intimate networks of care' and negotiate moral expectations towards intergenerational family care as they age. To date, little is known about the strength and complexities of different intimate ties or the role of intergenerational dynamics in shaping ageing sexual minority people's care needs and choices. Based on narrative interviews with ageing Chinese lesbians and gay men, the findings reveal their experiences of constantly juggling their ties with families of origin, moral values around intergenerational care and the urge to receive support from and offer support to chosen networks of people. Participants exercised agency in expanding their networks of care by building friendship and (online and offline) community networks for mutual care and support in later life. Nevertheless, as evidenced by the centrality of ageing with(out) children, and the moral obligation of caring for parents in participants' narratives, participants experienced tensions between enacting what was considered morally right/wrong and developing networks of care that were perceived as emotionally intimate. Linking relational sociology with the sociology of morality, we discuss the conceptual utility of 'intimate networks of care' for sociological theorising of the linkages between sexuality, care and relational lives.

3.
Int Soc Work ; 66(2): 534-546, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37042018

RESUMO

This article examines older women's experiences of searching for face masks and handling mask-related issues during COVID-19. Set within the context of the Hong Kong government's policy reaction to the shortage of masks in early 2020, the article draws on interviews with 40 older women in Hong Kong to identify their various forms of vulnerability to welfare threats and their active and diverse responses in times of crisis. The findings reveal the implications of the government's residual policy response for people's vulnerability to welfare threats. They also carry practical implications for the support that social workers can provide.

4.
Midwifery ; 121: 103656, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37019000

RESUMO

OBJECTIVE: This study aimed to explore how Chinese lesbian couples perceived having children through assisted reproductive technology (ART) and its impact on their experiences of family formation. DESIGN: This study adopted netnography to investigate online forum data created by self-identified lesbian couples in relation to assisted reproduction. Summative content analysis was used to analyse data. FINDINGS: Based on data analysis, A luan B huai, in which a lesbian conceives a child using her partner's egg, was seen as the best way to establish a family because it created a sense of symbolic connectedness with the child for both of them. Moreover, lesbian couples also indicated the crucial role that having children plays in maintaining family harmony, despite their opposition to heterosexual family traditions. With the stratification of reproductive tourism, certain groups of lesbians - for instance, those with limited social and cultural capital - might be at a disadvantage in the global setting of reproductive tourism. CONCLUSIONS AND IMPLICATIONS: Lesbian couples valued the benefits of ART in assisting them to achieve their childbearing goals and build a family. Healthcare providers should take the initiative to enhance fertility care by addressing the concerns and unique challenges faced by lesbian populations.


Assuntos
Homossexualidade Feminina , Minorias Sexuais e de Gênero , Feminino , Criança , Humanos , Reprodução , Heterossexualidade , Técnicas de Reprodução Assistida
5.
Cell Rep ; 42(4): 112335, 2023 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-37027294

RESUMO

Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism. Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function.


Assuntos
Metabolismo Energético , Glicólise , Humanos , Feminino , Camundongos , Animais , Glicólise/fisiologia , Imageamento por Ressonância Magnética , Neurônios/metabolismo , Glucose/metabolismo
6.
Nat Neurosci ; 26(5): 737-750, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37095396

RESUMO

Pathological hallmarks of Alzheimer's disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. Here, we report that activation of cyclic GMP-AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of Cgas in mice with tauopathy diminished the microglial IFN-I response, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation increased, while activation of IFN-I decreased, the neuronal MEF2C expression network linked to cognitive resilience in AD. Pharmacological inhibition of cGAS in mice with tauopathy enhanced the neuronal MEF2C transcriptional network and restored synaptic integrity, plasticity and memory, supporting the therapeutic potential of targeting the cGAS-IFN-MEF2C axis to improve resilience against AD-related pathological insults.


Assuntos
Microglia , Nucleotidiltransferases , Proteínas tau , Animais , Camundongos , Cognição , Imunidade Inata , Interferons , Fatores de Transcrição MEF2/genética , Microglia/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo
7.
JAMA Netw Open ; 6(3): e231706, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36877523

RESUMO

This cross-sectional study compares race and ethnicity reporting in 3 medical journals before and after implementation of updated guidance on the reporting of race and ethnicity in August 2021.


Assuntos
Etnicidade , Publicações Periódicas como Assunto , Humanos
8.
J Lesbian Stud ; 27(1): 137-145, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35757991

RESUMO

Intimate partner violence (IPV) has been identified as a public health issue among both heterosexual and lesbian, gay, bisexual, trans, and queer (LGBTQ) populations. While attention has often been paid to IPV among heterosexual couples, there is limited research on the causes of and interventions for IPV confronting same-sex couples, especially those in non-Euro-American contexts. This article highlights the "double closet" nature of same-sex IPV, and, in particular, the triply marginalized position of lesbian victims of IPV due to their gender, sexuality, and experiences of violence in China. Extending ongoing discussions about minority stress faced by sexual minority people, it reveals how the daily stressors associated with identity concealment, coupled with relational selfhood and heteronormative institutional constraints, complicate lesbian relationships and violence in China. Focusing on the family-centered context provides an important window into the ways in which the perceived need to stay in the closet (hide one's sexual identity) and rejection from the family of origin and the state influence lesbians' experiences of IPV and inhibit many of them from disclosing violence. This article builds a dialogue between discussions of the closet and existing literature on IPV. It concludes by drawing attention to the need to break the silence around IPV and build alliances for developing culturally sensitive interventions aimed at addressing IPV.


Assuntos
Homossexualidade Feminina , Violência por Parceiro Íntimo , Minorias Sexuais e de Gênero , Humanos , Feminino , Heterossexualidade , China
9.
J Homosex ; 70(14): 3470-3492, 2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-35849423

RESUMO

This study examines how Chinese lesbians and gay men make sense of the prospect of growing old and plan for later life in Hong Kong, where same-sex relationships are yet to be legally recognized. Drawing on in-depth narrative interviews, the results show that lesbians and gay men in midlife reported a range of previous, current, and anticipated challenges associated with the stigma attached to homosexuality. These, in turn, shaped their ways of perceiving and planning for later life. Three forms of reflexivity in response to minority stress and the prospect of aging were identified: coping with fears of aging alone, striving for self-mastery, and planning ahead with feelings of wariness. Participants' concerns and plans around aging demonstrated differing degrees of reflexivity, through which they attempted to navigate family norms and structural constraints and find ways to accumulate resources for later life. Meanwhile, their heightened sense of uncertainty and insecurity showed that their perceptions and experiences of aging were influenced by minority stress and material, familial, and socio-political circumstances. This article builds a constructive dialogue between sexuality and aging studies by unraveling both the aging insecurity and capacities for reflexive planning among an oft-neglected group of sexual minority people in midlife.


Assuntos
Envelhecimento , Minorias Sexuais e de Gênero , Feminino , Humanos , Masculino , População do Leste Asiático , Homossexualidade Feminina , Homossexualidade Masculina
10.
Artigo em Inglês | MEDLINE | ID: mdl-36429352

RESUMO

This article aims to advance the discussion of government policies for improving women's work and family life. It focuses on exploring whether it is reasonable to expect that the supported adult worker model will play an important role in guiding governments to reduce the gender employment gap and, at the same time, increase women's resources for strengthening their control over family and work life. This model posits that governments should take a proactive approach to encouraging women to take part in formal employment, such as providing care support measures. To examine the impact of the model, this article develops an 'input adult worker model typology' and an 'output adult worker model typology' using cluster analysis of comparative data covering 15 countries. The findings show that it is important not to overestimate the impact of the supported adult worker model on reducing the gender employment gap or increasing women's control over their lives in most of the 15 countries. The evidence generated from these typologies highlights the difficulties involved in promoting women's welfare despite the use of the adult worker model as a substitute for the male-breadwinner model.


Assuntos
Política de Planejamento Familiar , Adulto , Masculino , Humanos , Feminino , Emprego , Governo , Europa (Continente) , Seguridade Social
11.
Am J Mens Health ; 16(5): 15579883221120985, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36082415

RESUMO

Older adults' mental health and suicidal tendencies have garnered much attention because of their vulnerability. Few studies have examined the impact of psychological well-being and suicide attempts among older men who have sex with men (OMSM). This study examines the levels of depression and suicidal tendencies among OMSM, factors impacting their mental health, and their likelihood of committing suicide. Descriptive statistics are used to analyze the correlation between depression and suicidal tendencies among OMSM in the United States. We constructed a regression model using relevant data, and scales were selected based on a literature review. The validity and relevance of the control variables were considered. Depression and suicidal tendencies were dependent variables. Data were obtained from the U.S. General Social Survey and analyzed with an ordinary least squares model. There were significant differences between MSM and general groups in depression and suicidal tendency scores (t = 67.084, 58.193, p < .01). Compared with general groups, MSM scored significantly higher on depression and suicidal tendencies. The regression analysis revealed that sex with men was associated with depression and suicidal tendencies (p < .01) among older men. This indicates that OMSM generally have higher levels of depression and suicidal tendencies than the general population. Finally, in the intermediary test, the level of depression had a significant mediating effect on the relationship between homosexuality and suicidal tendencies (p < .01). This suggests that depression intervention can help reduce suicidal tendencies among OMSM.


Assuntos
Minorias Sexuais e de Gênero , Tentativa de Suicídio , Idoso , Depressão/epidemiologia , Depressão/psicologia , Homossexualidade Masculina/psicologia , Humanos , Masculino , Saúde Mental , Ideação Suicida , Tentativa de Suicídio/psicologia , Estados Unidos
12.
Artigo em Inglês | MEDLINE | ID: mdl-35681974

RESUMO

This article examines the ways in which lesbians explore opportunities and navigate constraints in their family and work lives in urban China. It not only reveals Chinese lesbians' difficulties in gaining equal access to the labour market and developing their desired family lives, but also discusses possible ways of enhancing the applicability of the adult worker model for sexual minority women. Previous research has indicated a shift from the male breadwinner model to the adult worker model, suggesting that both men and women are expected to join the labour market, and that women should not carry all the care responsibilities within the family. However, the model largely overlooks the interplay of gender and sexuality factors in shaping work and family lives. This article adopts a qualitative mixed-methods approach, including interviews with 20 Chinese lesbians and social media analysis, to examine lesbians' experiences of taking part in the family as adults and in the wider economy as workers. It shows how gender norms, heteronormativity, and policy intersect in generating obstacles for Chinese lesbians to thrive as respectable adult workers. This has important implications for attempts to improve the adult worker model to fit better with people's diverse work/family needs.


Assuntos
Homossexualidade Feminina , Minorias Sexuais e de Gênero , Adulto , China , Relações Familiares , Feminino , Humanos , Masculino
13.
Front Psychol ; 13: 726343, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35572280

RESUMO

For scholars, practitioners, and legislators concerned about sexual minority adolescents, one of the main goals is to create more positive and inclusive learning environments for this minority group. Numerous factors, such as repeated patterns of homophobic bullying by classmates and others in school, have been a significant barrier to achieving this goal. In addition, lesbian, gay, bisexual, transgender, and queer (LGBTQ) adolescents encounter substantial inequality across a broad spectrum of wellbeing and education consequences. Compared with their heterosexual counterparts, LGBTQ adolescents experience more anxiety, depression, suicidal thoughts, antisocial behavior, poorer academic performance, less school attachment and protection, and a weaker desire to finish their studies. Such discrepancies based on gender and sexuality were linked to more maltreatment encountered by LGBTQ adolescents. It is crucial to recognize the backgrounds and expectations of LGBTQ adolescents to offer them the best resources. To overcome the inequality and obstacles faced by these LGBTQ adolescents, it is essential to examine tools and techniques that can be utilized. This study examined the literature that explains why society fails to provide enough support to LGBTQ students. Specifically, mechanisms explaining how LGBTQ adolescents interact with others in the learning environment and how such discrepancies arise will be examined. Following that, violence and prejudice, which are fundamental causes of psychological problems among LGBTQ adolescents, will be explored. This review paper thus provides supportive strategies for schools to develop more inclusive learning environments for LGBTQ adolescents.

14.
Sci Transl Med ; 14(642): eabm5527, 2022 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-35476595

RESUMO

Intracellular accumulation of TAU aggregates is a hallmark of several neurodegenerative diseases. However, global genetic reduction of TAU is beneficial also in models of other brain disorders that lack such TAU pathology, suggesting a pathogenic role of nonaggregated TAU. Here, conditional ablation of TAU in excitatory, but not inhibitory, neurons reduced epilepsy, sudden unexpected death in epilepsy, overactivation of the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin pathway, brain overgrowth (megalencephaly), and autism-like behaviors in a mouse model of Dravet syndrome, a severe epileptic encephalopathy of early childhood. Furthermore, treatment with a TAU-lowering antisense oligonucleotide, initiated on postnatal day 10, had similar therapeutic effects in this mouse model. Our findings suggest that excitatory neurons are the critical cell type in which TAU has to be reduced to counteract brain dysfunctions associated with Dravet syndrome and that overall cerebral TAU reduction could have similar benefits, even when initiated postnatally.


Assuntos
Transtorno Autístico , Epilepsias Mioclônicas , Epilepsia , Morte Súbita Inesperada na Epilepsia , Proteínas tau , Animais , Transtorno Autístico/complicações , Transtorno Autístico/genética , Modelos Animais de Doenças , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/genética , Epilepsia/complicações , Epilepsia/genética , Epilepsia/metabolismo , Síndromes Epilépticas , Humanos , Lactente , Camundongos , Neurônios/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Espasmos Infantis , Proteínas tau/metabolismo
15.
Psychiatr Rehabil J ; 45(1): 71-78, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33734779

RESUMO

Background: Recovery-oriented, strengths-based intervention engages service users' strengths and resources to support their recovery process. This model was developed in an American context and has been applied in Hong Kong. It is important to formulate an understanding of strengths better fit to Hong Kong Chinese. Aims: This exploratory qualitative study examined Hong Kong Chinese service users' views on strengths and preferred translation for the word strengths, along with its cultural nuances. Method: Twenty-six people with serious mental illnesses were individually interviewed at a mental health center in Hong Kong, based on a photo-elicitation technique and reflection on Chinese terms related to strengths. Analysis of data employed the constant comparative method. Results: Participants reported that social factors, such as support by helping professionals and engagement in family roles, as well as spiritual beliefs and practices, are important for recovery. These insights and their preferred translations of strengths generate a culturally nuanced understanding of strengths. Conclusions & Implications for Practice: The strengths model applied in Hong Kong can be enhanced by a more culturally nuanced perspective, for example, including the importance of family-based identity and filial piety, beliefs related to harmony and fate, and practices such as a temple or church attendance. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Assuntos
Serviços de Saúde Mental , Saúde Mental , Cultura , Hong Kong , Humanos , Pesquisa Qualitativa
16.
Hum Mol Genet ; 31(9): 1500-1518, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34791217

RESUMO

Mutations in the mitochondrial protein CHCHD2 cause autosomal dominant Parkinson's disease characterized by the preferential loss of substantia nigra dopamine (DA) neurons. Therefore, understanding the function of CHCHD2 in neurons may provide vital insights into how mitochondrial dysfunction contributes to neurodegeneration in PD. To investigate the normal requirement and function of CHCHD2 in neurons, we first examined CHCHD2 levels and showed that DA neurons have higher CHCHD2 levels than other neuron types, both in vivo and in co-culture. We then generated mice with either a targeted deletion of CHCHD2 in DA neurons or a deletion in the brain or total body. All three models were viable, and loss of CHCHD2 in the brain did not cause degeneration of DA neurons. Mice lacking CHCHD2 in DA neurons did display sex-specific changes to locomotor activity, but we did not observe differences in assays of muscle strength, exercise endurance or motor coordination. Furthermore, mitochondria derived from mice lacking CHCHD2 did not display abnormalities in OXPHOS function. Lastly, resilience to CHCHD2 deletion could not be explained by functional complementation by its paralog CHCHD10, as deletion of both CHCHD10 and CHCHD2 did not cause degeneration of DA neurons in the midbrain. These findings support the hypothesis that pathogenic CHCHD2 mutations cause PD through a toxic gain-of-function, rather than loss-of-function mechanism.


Assuntos
Neurônios Dopaminérgicos , Proteínas Mitocondriais , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Neurônios Dopaminérgicos/metabolismo , Feminino , Masculino , Camundongos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Substância Negra/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
17.
Br J Sociol ; 73(1): 139-153, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34951480

RESUMO

There have been ongoing discussions about the ways in which the Internet has created new spaces for sexual minority individuals to meet, communicate, and build their communities in recent decades. Nevertheless, previous studies have paid disproportionate attention to identity politics, civil society, and rights-based movements. They have largely overlooked other possible forms of, and orientations toward, engagement with cyberspace, particularly those that have emerged and been restricted in non-Western contexts. This article examines Chinese lesbians' experiences of using cyberspace and the extent to which these experiences help them develop their intimate and family lives. Drawing on interview data and developing a framework that combines queer counterpublics scholarship with insights drawn from the notion of relational selfhood, this study reveals a wide range of personal, familial, and socio-political motivations for (not) engaging in cyberspace and the mixed feelings of connection and distance experienced by participants. By identifying three forms of (dis)engagement with cyberspace: those demonstrated by 'pioneers', 'skeptics', and 'conflicted pragmatists', this study expands the notion of queer counterpublics beyond its focus on civic and political participation and illustrates the contested and contingent nature of Chinese queer counterpublics. It shows that Chinese lesbians' interactions in cyberspace enable them to explore non-traditional paths to family formation and motherhood. Meanwhile, these interactions expose them to tensions between the new possibilities revealed by online spaces and established socio-political and familial norms. I argue that prevailing heterosexual norms, coupled with material concerns and the regulatory power of the family and the state, continue to restrict the transformative potential of cyberspace and push some lesbians to withdraw from cyberspace into themselves and refrain from taking part in collective action. The article concludes with some reflections on queer counterpublics and the complex interplay between online and offline lives in the digital age.


Assuntos
Homossexualidade Feminina , Minorias Sexuais e de Gênero , China , Feminino , Humanos , Comportamento Sexual , Parceiros Sexuais
18.
BMC Psychiatry ; 21(1): 534, 2021 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-34711212

RESUMO

BACKGROUND: The strengths model of case management (SMCM), which was developed by Rapp and Goscha through collaborative efforts at the University of Kansas, assists individuals with mental illness in their recovery by mobilizing individual and environmental resources. Increasing evidence has shown that the utilization of the SMCM improves outcomes, including increased employment/educational attainment, reduced hospitalization rates, higher self-efficacy, and hope. However, little is known about the processes through which the SMCM improves outcomes for mental health service users. This study explores the views of case workers and service users on their experience of providing or receiving the SMCM intervention. METHODS: A qualitative design was employed using individual interviews with service users and case workers drawn from two study conditions: the SMCM group and the control group (treatment as usual). For both study conditions, service users were recruited by either centres-in-charge or case workers from integrated community centres for mental wellness (ICCMWs) operated by three non-governmental organizations (NGOs) in different districts of Hong Kong. Through purposeful sampling, 24 service users and 14 case workers from the SMCM and control groups joined the study. We used an inductive approach to analyse the qualitative data. RESULTS: We identified two overarching themes: service users' and case workers' (1) perceptions of the impacts of the interventions (SMCM and control group) and (2) experiences of the interventions, such as features of the interventions and the factors that facilitated the outcomes. The results showed that there were improvements in the functional recovery of the SMCM group in areas such as employment and family relationships, how self-identified goals were achieved, and how service users gained a better understanding of their own strengths and weaknesses. Regarding their experience of the interventions, participants in both the SMCM group and the control group reported that a good relationship between service users and case workers was vital. However, some concerns were raised about the use of SMCM tools, including the strengths assessment and the personal recovery plan (PRP) and the risk of case workers being subjective in the presentation of cases in group supervision sessions. CONCLUSION: The results were promising in terms of supporting the use of the SMCM, with some refinements, in mental health services for Chinese clients. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617001435370 , registered on 10/10/2017.


Assuntos
Transtornos Mentais , Serviços de Saúde Mental , Austrália , Administração de Caso , Humanos , Transtornos Mentais/terapia , Saúde Mental
19.
JCI Insight ; 6(19)2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34622797

RESUMO

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficiency of the iduronate-2-sulfatase (IDS) enzyme, resulting in cellular accumulation of glycosaminoglycans (GAGs) throughout the body. Treatment of MPS II remains a considerable challenge as current enzyme replacement therapies do not adequately control many aspects of the disease, including skeletal and neurological manifestations. We developed an IDS transport vehicle (ETV:IDS) that is engineered to bind to the transferrin receptor; this design facilitates receptor-mediated transcytosis of IDS across the blood-brain barrier and improves its distribution into the brain while maintaining distribution to peripheral tissues. Here we show that chronic systemic administration of ETV:IDS in a mouse model of MPS II reduced levels of peripheral and central nervous system GAGs, microgliosis, and neurofilament light chain, a biomarker of neuronal injury. Additionally, ETV:IDS rescued auricular and skeletal abnormalities when introduced in adult MPS II mice. These effects were accompanied by improvements in several neurobehavioral domains, including motor skills, sensorimotor gating, and learning and memory. Together, these results highlight the therapeutic potential of ETV:IDS for treating peripheral and central abnormalities in MPS II. DNL310, an investigational ETV:IDS molecule, is currently in clinical trials as a potential treatment for patients with MPS II.


Assuntos
Barreira Hematoencefálica/metabolismo , Terapia de Reposição de Enzimas/métodos , Iduronato Sulfatase/administração & dosagem , Mucopolissacaridose II/tratamento farmacológico , Receptores da Transferrina/metabolismo , Vesículas Transportadoras/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Glicosaminoglicanos/metabolismo , Iduronato Sulfatase/genética , Memória/efeitos dos fármacos , Camundongos , Camundongos Knockout , Destreza Motora/efeitos dos fármacos , Mucopolissacaridose II/genética , Mucopolissacaridose II/metabolismo , Mucopolissacaridose II/fisiopatologia , Fenótipo , Filtro Sensorial/efeitos dos fármacos , Esqueleto/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Transcitose
20.
Cell Rep ; 36(12): 109727, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34551293

RESUMO

In traumatic brain injury (TBI), a diversity of brain resident and peripherally derived myeloid cells have the potential to worsen damage and/or to assist in healing. We define the heterogeneity of microglia and macrophage phenotypes during TBI in wild-type (WT) mice and Ccr2-/- mice, which lack macrophage influx following TBI and are resistant to brain damage. We use unbiased single-cell RNA sequencing methods to uncover 25 microglia, monocyte/macrophage, and dendritic cell subsets in acute TBI and normal brains. We find alterations in transcriptional profiles of microglia subsets in Ccr2-/- TBI mice compared to WT TBI mice indicating that infiltrating monocytes/macrophages influence microglia activation to promote a type I IFN response. Preclinical pharmacological blockade of hCCR2 after injury reduces expression of IFN-responsive gene, Irf7, and improves outcomes. These data extend our understanding of myeloid cell diversity and crosstalk in brain trauma and identify therapeutic targets in myeloid subsets.


Assuntos
Lesões Encefálicas Traumáticas/patologia , Microglia/metabolismo , Receptores CCR2/genética , Animais , Antígenos Ly/genética , Antígenos Ly/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas Traumáticas/metabolismo , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Fator Regulador 7 de Interferon/genética , Fator Regulador 7 de Interferon/metabolismo , Interferon Tipo I/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/citologia , Monócitos/citologia , Monócitos/metabolismo , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/deficiência , Receptores CCR2/metabolismo
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