SUMMARY Huntington disease (HD) is caused by a CAG·CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic strategies targeting both sense and antisense genes may be required for efficacy in HD patients. This is the first demonstration that RAN proteins are expressed across an expansion located in an open reading frame and suggests RAN translation may also contribute to other poly-glutamine diseases.

Recently, adeno-associated virus (AAV)-mediated gene therapies have attracted clinical interest for treating neurodegenerative diseases including spinal muscular atrophy (SMA), Canavan disease (CD), Parkinson’s disease (PD), and Friedreich’s ataxia (FA). The influx of clinical findings led to the first approved gene therapy for neurodegenerative disorders in 2019 and highlighted new safety concerns for patients. Large doses of systemically administered AAV stimulate host immune responses, resulting in anti-capsid and anti-transgene immunity with implications for transgene expression, treatment longevity, and patient safety. Delivering lower doses directly to the central nervous system (CNS) is a promising alternative, resulting in higher transgene expression with decreased immune responses. However, neuroinflammatory responses after CNS-targeted delivery of AAV are a critical concern. Reported signs of AAV-associated neuroinflammation in preclinical studies include dorsal root ganglion (DRG) and spinal cord pathology with mononuclear cell infiltration. In this review, we discuss ways to manage neuroinflammation, including choice of AAV capsid serotypes, CNS-targeting routes of delivery, genetic modifications to the vector and/or transgene, and adding immunosuppressive strategies to clinical protocols. As additional gene therapies for neurodegenerative diseases enter clinics, tracking biomarkers of neuroinflammation will be important for understanding the impact immune reactions can have on treatment safety and efficacy.

Spinocerebellar ataxia type 8 (SCA8) is caused by a bidirectionally transcribed CTG·CAG expansion that results in the accumulation of CUG RNA foci, an ATG-initiated polyGln and a polyAla protein expressed by repeat-associated non-ATG (RAN) translation. Although RAN proteins have been reported in a growing number of diseases, the mechanisms and role of RAN translation in disease are poorly understood. We report a novel toxic SCA8 polySer protein which accumulates in white matter (WM) regions as aggregates that increase with age and disease severity. WM regions with polySer aggregates show demyelination and axonal degeneration in SCA8 human and mouse brains. Additionally, knockdown of the eukaryotic translation initiation factor eIF3F in cells reduces steady-state levels of SCA8 polySer and other RAN proteins. Taken together, these data show polySer and WM abnormalities contribute to SCA8 and identify eIF3F as a novel modulator of RAN protein accumulation.

The structural similarities between the C-terminal domain of human pancreatic lipase (C-HPL) and C2 domains suggested a similar function, the interaction with lipids. The catalytic N-terminal domain (N-HPL) and C-HPL were produced as individual proteins, and their partitioning between the water phase and the triglyceride-water interface was assessed using trioctanoin emulsions (TC8). N-HPL did not bind efficiently to TC8 and was inactive. C-HPL did bind to TC8 and to a phospholipid monolayer with a critical surface pressure of penetration similar to that of HPL (15 mN m(-1)). These experiments, performed in the absence of colipase and bile salts, support an absolute requirement of C-HPL for interfacial binding of HPL. To refine our analysis, we determined the contribution to lipid interactions of a hydrophobic loop (beta 5') in C-HPL by investigating a HPL mutant in which beta 5' loop hydrophobicity was increased by introducing the homologous lipoprotein lipase (LPL) beta 5' loop. This mutant (HPL-beta 5'LPL) penetrated into phospholipid monolayers at higher surface pressures than HPL, and its level of binding to TC8 was higher than that of HPL in the presence of serum albumin (BSA), an inhibitory protein that competes with HPL for interfacial adsorption. The beta 5' loop of LPL is therefore tailored for an optimal interaction with the surface of triglyceride-rich lipoproteins (VLDL and chylomicrons) containing phospholipids and apoproteins. These observations support a major contribution of the beta 5' loop in the interaction of LPL and HPL with their respective substrates.

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ReSUmOEstudo quantitativo, com o objetivo de estudar a violência doméstica em mulheres em situação de aborto provocado. Foram entrevistas 147 mulheres internadas por aborto provocado numa maternidade pública, na cidade de Salvador-BA. Os sujeitos foram, na maioria, mulheres jovens, negras, com baixa escolaridade, dependentes economicamente dos cônjuges, que vivenciam violência psicológica, física e sexual cometida pelos cônjuges. Quase metade das mulheres vivenciou violência doméstica durante a gravidez atual, sendo este o motivo do aborto para 67% delas. Conclui-se que existe uma associação entre a vivência de violência doméstica e o aborto provocado. Isso repercute na saúde mental das mulheres, que desenvolvem sintomas do transtorno de estresse pós-traumático. Necessitase, portanto, de um olhar por parte dos profissionais de saúde de modo a identificar a violência doméstica enquanto agravo e associá-la ao aborto provocado, o que requer transformação no modelo de formação, incorporando a violência doméstica como objeto da saúde. descritores: Enfermagem; Enfermagem obstétrica; Saúde da mulher; Violência doméstica; Aborto induzido. aBStRaCt Quantitative study in order to study domestic violence in women with induced abortion. Interviews were conducted with 147 women hospitalized for induced abortion in a public maternity hospital in Salvador, Bahia. The subjects are characterized by mostly women, black, poorly educated, economically dependent on spouses, experienced psychological abuse, physical and sexual abuse committed by their spouses. Almost half of the women were victims of domestic violence during the current pregnancy, and that was the reason for inducing abortion for 67% of them. The study reveals an association between experience of domestic violence and induced abortion. As mental health consequences, they developed symptoms of post trauma stress disorder. It is necessary that the health professionals consider the cues to identify domestic violence as a health problem associated with induced abortion, which requires a transformation on the training model, including domestic violence as a health issue. Key words: Nursing; Obstetrical nursing; Women's health; Domestic violence; Induced abortion. ReSUmeNEstudio cuantitativo, que tuvo como objetivo estudiar la violencia doméstica en mujeres con aborto inducido. Se realizaron entrevistas con 147 mujeres internadas por aborto inducido en una maternidad pública de Salvador-BA. Los sujetos se caracterizaran por ser, en su mayoría mujeres jóvenes, negras, con un bajo nivel educativo, dependientes económicamente de los conyugues, con experiencia de abusos psicológicos, físicos y sexuales cometidos por los cónyuges. Casi la mitad de las mujeres fueron víctimas de violencia doméstica durante el embarazo actual, siendo este el motivo de aborto para 67% de ellas. El estudio reveló una asociación entre la experiencia de violencia doméstica y el aborto inducido, con consecuencias para la salud mental de las mujeres, que desarrollan síntomas de trastorno de estrese pos...

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