Recent Stressful Life Events and Perceived Stress as Serial Mediators of the Association between Adverse Childhood Events and Insomnia.

Insomnia is common in college students and linked to poorer mental and physical health. There is growing evidence that adverse childhood experiences (ACEs) may contribute to insomnia in adulthood. However, beyond the need for additional replication of these findings, there is a need to identify underlying mechanisms that plausibly connect the two experiences. Based on a serial mediation model, the current study examined the role of two theoretically informed mediators: recent stressful life events and perceived stress. A cross-sectional survey of 2,218 college students at a large university in the southwestern United States was conducted between August 2020 and December 2021. The sample was predominantly Hispanic (96%) and female (73%), with a mean age of 20.7 years. Standardized measures of adverse childhood experiences, recent stressful life events, perceived stress, and insomnia were administered to participants online. Almost 20% of participants reported having experienced four or more adverse childhood experiences and 63% met the threshold for insomnia. Reporting four or more ACEs was associated with significantly greater insomnia severity, and this relationship was serially mediated by both recent stressful life events and perceived stress. However, recent stressful life events appeared to be the most powerful mediator. The results of the current study indicate that recent exposure to stressful life events serves as a plausible mechanism linking early adversity during childhood to adult insomnia and could therefore serve as a potential target for intervention. The findings suggest that students would benefit from university-wide efforts to reduce the number and/or intensity of common stressors.

Treatment Access for Gastrointestinal Stromal Tumor in Predominantly Low- and Middle-Income Countries.

Importance: Gastrointestinal stromal tumor (GIST) is a rare cancer treated with the tyrosine kinase inhibitors imatinib mesylate or sunitinib malate. In general, in low- and middle-income countries (LMICs), access to these treatments is limited. Objective: To describe the demographic characteristics, treatment duration, and survival of patients with GIST in LMICs treated with imatinib and sunitinib through The Max Foundation programs. Design, Setting, and Participants: This retrospective database cohort analysis included patients in 2 access programs administered by The Max Foundation: the Glivec International Patient Assistance Program (GIPAP), from January 1, 2001, to December 31, 2016, and the Max Access Solutions (MAS) program, January 1, 2017, to October 12, 2020. Sixty-six countries in which The Max Foundation facilitates access to imatinib and sunitinib were included. Participants consisted of patients with approved indications for imatinib, including adjuvant therapy in high-risk GIST by pathologic evaluation of resected tumor or biopsy-proven unresectable or metastatic GIST. All patients were reported to have tumors positive for CD117(c-kit) by treating physicians. A total of 9866 patients received treatment for metastatic and/or unresectable disease; 2100 received adjuvant imatinib; 49 received imatinib from another source and were only included in the sunitinib analysis; and 53 received both imatinib and sunitinib through The Max Foundation programs. Data were analyzed from October 13, 2020, to January 30, 2024. Main Outcomes and Measures: Demographic and clinical information was reported by treating physicians. Kaplan-Meier analysis was used to estimate time to treatment discontinuation (TTD) and overall survival (OS). An imputation-based informed censoring model estimated events for patients lost to follow-up after treatment with adjuvant imatinib. Patients who were lost to follow-up with metastatic or unresectable disease were presumed deceased. Results: A total of 12 015 unique patients were included in the analysis (6890 male [57.6%]; median age, 54 [range, 0-100] years). Of these, 2100 patients were treated with imatinib in the adjuvant setting (median age, 54 [range 8-88] years) and 9866 were treated with imatinib for metastatic or unresectable disease (median age, 55 [range, 0-100] years). Male patients comprised 5867 of 9866 patients (59.5%) with metastatic or unresectable disease and 1023 of 2100 patients (48.7%) receiving adjuvant therapy. The median OS with imatinib for unresectable or metastatic disease was 5.8 (95% CI, 5.6-6.1) years, and the median TTD was 4.2 (95% CI, 4.1-4.4) years. The median OS with sunitinib for patients with metastatic or unresectable GIST was 2.0 (95% CI, 1.5-2.5) years; the median TTD was 1.5 (95% CI, 1.0-2.1) years. The 10-year OS rate in the adjuvant setting was 73.8% (95% CI, 67.2%-81.1%). Conclusions and Relevance: In this cohort study of patients with GIST who were predominantly from LMICs and received orally administered therapy through the GIPAP or MAS programs, outcomes were similar to those observed in high-resource countries. These findings underscore the feasibility and relevance of administering oral anticancer therapy to a molecularly defined population in LMICs, addressing a critical gap in cancer care.

A thiol-ene mediated approach for peptide bioconjugation using 'green' solvents under continuous flow.

Flow chemistry has emerged as an integral process within the chemical sector permitting energy efficient synthetic scale-up while improving safety and minimising solvent usage. Herein, we report the first applications of the photoactivated, radical-mediated thiol-ene reaction for peptide bioconjugation under continuous flow. Bioconjugation reactions employing deep eutectic solvents, bio-based solvents and fully aqueous systems are reported here for a range of biologically relevant peptide substrates. The use of a water soluble photoinitiator, Irgacure 2959, permitted synthesis of glycosylated peptides in fully aqueous conditions, obviating the need for addition of organic solvents and enhancing the green credentials of these rapid, photoactivated, bioconjugation reactions.

Combination treatment with monoclonal antibodies: Dupilumab and ustekinumab for the treatment of severe atopic dermatitis and Crohn disease.

Evidence of effectiveness and safety in combined therapies is scarce and based on case reports and small case series. We report a case of dual biologic therapy with ustekinumab and dupilumab in a patient with severe Crohn disease and atopic dermatitis. There was no interference between these drugs after a 7-month follow-up.

A Critical Assessment on Calculating Vibrational Spectra in Nanostructured Materials.

Vibrational spectroscopy is an omnipresent spectroscopic technique to characterize functional nanostructured materials such as zeolites, metal-organic frameworks (MOFs), and metal-halide perovskites (MHPs). The resulting experimental spectra are usually complex, with both low-frequency framework modes and high-frequency functional group vibrations. Therefore, theoretically calculated spectra are often an essential element to elucidate the vibrational fingerprint. In principle, there are two possible approaches to calculate vibrational spectra: (i) a static approach that approximates the potential energy surface (PES) as a set of independent harmonic oscillators and (ii) a dynamic approach that explicitly samples the PES around equilibrium by integrating Newton's equations of motions. The dynamic approach considers anharmonic and temperature effects and provides a more genuine representation of materials at true operating conditions; however, such simulations come at a substantially increased computational cost. This is certainly true when forces and energy evaluations are performed at the quantum mechanical level. Molecular dynamics (MD) techniques have become more established within the field of computational chemistry. Yet, for the prediction of infrared (IR) and Raman spectra of nanostructured materials, their usage has been less explored and remain restricted to some isolated successes. Therefore, it is currently not a priori clear which methodology should be used to accurately predict vibrational spectra for a given system. A comprehensive comparative study between various theoretical methods and experimental spectra for a broad set of nanostructured materials is so far lacking. To fill this gap, we herein present a concise overview on which methodology is suited to accurately predict vibrational spectra for a broad range of nanostructured materials and formulate a series of theoretical guidelines to this purpose. To this end, four different case studies are considered, each treating a particular material aspect, namely breathing in flexible MOFs, characterization of defects in the rigid MOF UiO-66, anharmonic vibrations in the metal-halide perovskite CsPbBr3, and guest adsorption on the pores of the zeolite H-SSZ-13. For all four materials, in their guest- and defect-free state and at sufficiently low temperatures, both the static and dynamic approach yield qualitatively similar spectra in agreement with experimental results. When the temperature is increased, the harmonic approximation starts to fail for CsPbBr3 due to the presence of anharmonic phonon modes. Also, the spectroscopic fingerprints of defects and guest species are insufficiently well predicted by a simple harmonic model. Both phenomena flatten the potential energy surface (PES), which facilitates the transitions between metastable states, necessitating dynamic sampling. On the basis of the four case studies treated in this Review, we can propose the following theoretical guidelines to simulate accurate vibrational spectra of functional solid-state materials: (i) For nanostructured crystalline framework materials at low temperature, insights into the lattice dynamics can be obtained using a static approach relying on a few points on the PES and an independent set of harmonic oscillators. (ii) When the material is evaluated at higher temperatures or when additional complexity enters the system, e.g., strong anharmonicity, defects, or guest species, the harmonic regime breaks down and dynamic sampling is required for a correct prediction of the phonon spectrum. These guidelines and their illustrations for prototype material classes can help experimental and theoretical researchers to enhance the knowledge obtained from a lattice dynamics study.

Compositional Evolution of Individual CoNPs on Co/TiO2 during CO and Syngas Treatment Resolved through Soft XAS/X-PEEM.

The nanoparticle (NP) redox state is an important parameter in the performance of cobalt-based Fischer-Tropsch synthesis (FTS) catalysts. Here, the compositional evolution of individual CoNPs (6-24 nm) in terms of the oxide vs metallic state was investigated in situ during CO/syngas treatment using spatially resolved X-ray absorption spectroscopy (XAS)/X-ray photoemission electron microscopy (X-PEEM). It was observed that in the presence of CO, smaller CoNPs (i.e., ≤12 nm in size) remained in the metallic state, whereas NPs ≥ 15 nm became partially oxidized, suggesting that the latter were more readily able to dissociate CO. In contrast, in the presence of syngas, the oxide content of NPs ≥ 15 nm reduced, while it increased in quantity in the smaller NPs; this reoxidation that occurs primarily at the surface proved to be temporary, reforming the reduced state during subsequent UHV annealing. O K-edge measurements revealed that a key parameter mitigating the redox behavior of the CoNPs were proximate oxygen vacancies (Ovac). These results demonstrate the differences in the reducibility and the reactivity of Co NP size on a Co/TiO2 catalyst and the effect Ovac have on these properties, therefore yielding a better understanding of the physicochemical properties of this popular choice of FTS catalysts.

LGBTQ+ identity-related abuse during childhood and associations with depression and suicide behavior: Role of adulthood cisheterosexism and expressive suppression.

BACKGROUND: Exposure to minority stressors specific to LGBTQ+ individuals, such as heterosexism and cissexism (or cisheterosexism) is not covered under the traditional adverse childhood experiences framework. This is important because childhood identity-related abuse by a parent/caregiver can lead to mental health challenges in later life through the adoption of maladaptive coping mechanisms. OBJECTIVE: The present study aimed to examine the role of cisheterosexism and expressive suppression as serial mediators in the associations between identity-related abuse and depressive symptoms and suicide behavior. PARTICIPANTS AND SETTING: Participants included 563 LGBTQ+ identifying adults between 18 and 64 years (M = 30.02, SD = 9.05) from different regions of Spain and were recruited through social media (e.g., Twitter, Facebook, and Instagram). METHOD: A serial mediation model was conducted with cisheterosexism and expressive suppression as the mediators in the associations between LGBTQ+ identity-related childhood abuse and depressive symptoms and suicide behavior. RESULTS: Findings indicated a positive indirect effect of identity-related abuse on depressive symptoms through cumulative cisheterosexism (B = 0.628, p < .01), and via cumulative cisheterosexism and suppression (B = 0.146, p < .05). No significant indirect effect was found for identity-related abuse on depressive symptoms via suppression (B = 0.086). An indirect effect was found for identity-related abuse on suicide behavior via cumulative cisheterosexism (B = 0.250, p < .01). CONCLUSIONS: Findings reveal that LGBTQ+ identity-related cisheterosexist experiences perpetrated by parents or caregivers are associated with harmful, long-term impacts on symptoms of depression and suicide behavior via experiences of cisheterosexism and expressive suppression.

Two structurally defined Aß polymorphs promote different pathological changes in susceptible mice.

Misfolded Aß is involved in the progression of Alzheimer's disease (AD). However, the role of its polymorphic variants or conformational strains in AD pathogenesis is not fully understood. Here, we study the seeding properties of two structurally defined synthetic misfolded Aß strains (termed 2F and 3F) using in vitro and in vivo assays. We show that 2F and 3F strains differ in their biochemical properties, including resistance to proteolysis, binding to strain-specific dyes, and in vitro seeding. Injection of these strains into a transgenic mouse model produces different pathological features, namely different rates of aggregation, formation of different plaque types, tropism to specific brain regions, differential recruitment of Aß40 /Aß42 peptides, and induction of microglial and astroglial responses. Importantly, the aggregates induced by 2F and 3F are structurally different as determined by ssNMR. Our study analyzes the biological properties of purified Aß polymorphs that have been characterized at the atomic resolution level and provides relevant information on the pathological significance of misfolded Aß strains.

Daily Heterosexist Experiences in LGBTQ+ Adults from Spain: Measurement, Prevalence, and Clinical Implications.

Lesbian, gay, bisexual, transgender, and queer (LGBTQ+) individuals face unique stressors related to their sexual and gender identities that have a detrimental impact on their mental health. Nonetheless, studies have not yet investigated these minority stressors among LGBTQ+ individuals from Spain. The limited availability of standardized tools/instruments to measure minority stressors in Spanish makes it challenging to explore these experiences among Spanish speaking individuals. The present study aimed to examine the factor structure of the Daily Heterosexist Experiences Questionnaire (DHEQ) among LGBTQ+ adults from Spain, compare rates of minority stressors across diverse gender and sexual orientations, and examine the impact of daily heterosexist experiences (henceforth referred to as heterosexist experiences) on symptoms of depression and suicidal behavior. The sample was composed of 509 LGBTQ+ identifying adults in the age range of 18 to 60 years old. Confirmatory factor analysis indicated a good fit for the six dimensions of the DHEQ scale. Individuals identified as transgender or reporting a minority sexual orientation (i.e., asexual, pansexual) indicated higher levels of exposure to heterosexist experiences. Moreover, those with higher levels of heterosexist experiences had higher symptoms of depression and suicide behavior. The present study provides a tool for examining minority stressors in Spanish speaking LGBTQ+ adults. Assessing for minority stressors may aid in the identification of risk and protective factors when working with LGBTQ+ treatment seeking adults.

Las personas lesbianas, gais, bisexuales, transexuales y queer (LGBTQ+) enfrentan en su día a día estresores únicos relacionados con sus identidades sexuales y de género que pueden perjudicar a su salud mental. Sin embargo, no hay investigación que explore estos estresores minoritarios en población LGBTQ+ de España. La limitada disponibilidad de instrumentos estandarizados para medir los estresores minoritarios/experiencias heterosexistas en español dificulta hoy en día explorar estas experiencias en las personas de habla hispana. El presente estudio tiene como objetivo examinar la estructura factorial del Cuestionario de Experiencias Heterosexistas Diarias (DHEQ, según sus siglas en inglés) en adultos LGBTQ+ de España, comparar las tasas de experiencias heterosexistas en diversas identidades de género y orientaciones sexuales y examinar el impacto de las experiencias heterosexistas en los síntomas de depresión y comportamiento suicida. La muestra constaba de 509 adultos LGBTQ+ en el rango de edad de 18 a 60 años. El análisis factorial confirmatorio indica un buen ajuste para las seis dimensiones de la escala DHEQ. Las personas que se identificaron como trans o con una orientación sexual minoritaria (por ejemplo, asexual, pansexual) indicaban mayores niveles de exposición a experiencias heterosexistas. Además, niveles más altos de experiencias heterosexistas se asocian a mayores síntomas de depresión y comportamiento suicida. El presente estudio proporciona una herramienta para examinar experiencias heterosexistas en población adulta LGBTQ+ de habla hispana. La evaluación de experiencias heterosexistas puede ayudar en la identificación de factores de riesgo y de protección cuando se trabaja con adultos LGBTQ+ en el ámbito clínico.

Monocyte-derived cells invade brain parenchyma and amyloid plaques in human Alzheimer's disease hippocampus.

Microglia are brain-resident myeloid cells and play a major role in the innate immune responses of the CNS and the pathogenesis of Alzheimer's disease (AD). However, the contribution of nonparenchymal or brain-infiltrated myeloid cells to disease progression remains to be demonstrated. Here, we show that monocyte-derived cells (MDC) invade brain parenchyma in advanced stages of AD continuum using transcriptional analysis and immunohistochemical characterization in post-mortem human hippocampus. Our findings demonstrated that a high proportion (60%) of demented Braak V-VI individuals was associated with up-regulation of genes rarely expressed by microglial cells and abundant in monocytes, among which stands the membrane-bound scavenger receptor for haptoglobin/hemoglobin complexes or Cd163. These Cd163-positive MDC invaded the hippocampal parenchyma, acquired a microglial-like morphology, and were located in close proximity to blood vessels. Moreover, and most interesting, these invading monocytes infiltrated the nearby amyloid plaques contributing to plaque-associated myeloid cell heterogeneity. However, in aged-matched control individuals with hippocampal amyloid pathology, no signs of MDC brain infiltration or plaque invasion were found. The previously reported microglial degeneration/dysfunction in AD hippocampus could be a key pathological factor inducing MDC recruitment. Our data suggest a clear association between MDC infiltration and endothelial activation which in turn may contribute to damage of the blood brain barrier integrity. The recruitment of monocytes could be a consequence rather than the cause of the severity of the disease. Whether monocyte infiltration is beneficial or detrimental to AD pathology remains to be fully elucidated. These findings open the opportunity to design targeted therapies, not only for microglia but also for the peripheral immune cell population to modulate amyloid pathology and provide a better understanding of the immunological mechanisms underlying the progression of AD.

Treatment of multiple sclerosis with rituximab: A Spanish multicenter experience.

Introduction: Rituximab (RTX) is considered a potential therapeutic option for relapsing-remitting (RRMS) and progressive forms (PMS) of multiple sclerosis (MS). The main objective of this work was to investigate the effectiveness and safety of rituximab in MS. Patients and methods: Observational multicenter study of clinical and radiological effectiveness and safety of rituximab in RRMS and PMS. Results: A total of 479 rituximab-treated patients were included in 12 Spanish centers, 188 RRMS (39.3%) and 291 (60.7%) PMS. Despite standard treatment, the annualized relapse rate (ARR) the year before RTX was 0.63 (SD: 0.8) and 156 patients (41%) had at least one gadolinium-enhanced lesion (GEL) on baseline MRI. Mean EDSS had increased from 4.3 (SD: 1.9) to 4.8 (SD: 1.7) and almost half of the patients (41%) had worsened at least one point. After a median follow-up of 14.2 months (IQR: 6.5-27.2), ARR decreased by 85.7% (p < 0.001) and GEL by 82.9%, from 0.41 to 0.07 (p < 0.001). A significant decrease in EDSS to 4.7 (p = 0.046) was observed after 1 year of treatment and this variable remained stable during the second year of therapy. There was no evidence of disease activity in 68% of patients. Infusion-related symptoms were the most frequent side effect (19.6%) and most were mild. Relevant infections were reported only in 18 patients (including one case of probable progressive multifocal leukoencephalopathy). Conclusion: Rituximab could be an effective and safe treatment in RRMS, including aggressive forms of the disease. Some selected PMS patients could also benefit from this treatment.

Factor structure of the international trauma questionnaire in trauma exposed LGBTQ+ adults: Role of cumulative traumatic events and minority stress heterosexist experiences.

Exposure to prolonged and/or multiple types of psychological trauma and stressors has been shown to be more strongly associated with ICD-11 complex posttraumatic stress disorder (CPTSD) than posttraumatic stress disorder (PTSD). Lesbian, gay, bisexual, trans- and queer adults (LGBTQ+) are at a heightened risk of exposure to traumatic events, and minority stressors including harassment, discrimination, rejection by family, and isolation. OBJECTIVE: To examine the factor structure of the international trauma questionnaire (ITQ), a self-report measure of PTSD and CPTSD, and the associations of cumulative lifetime trauma exposure assessed via the life events checklist and minority stress assessed via the daily heterosexist experiences scale, with CPTSD (three PTSD symptom clusters, three clusters reflecting disturbances in self-organization [DSO]) among LGBTQ + adults. METHOD: Participants comprised 225 LGBTQ + adults (including 74 transgender and gender diverse individuals; age range: 18-60 years; M/SD = 31.35/9.48) residing in Spain. RESULTS: Confirmatory factor analyses indicated that both a first-order six-factor model and a hierarchical two-factor model, comprising PTSD and DSO as second-order factors, fit the data best. Cumulative traumatic events score was associated with PTSD, and cumulative minority stress was associated with PTSD and DSO. Among the minority stress subscales, harassment based on gender expression was positively associated with all symptom clusters of PTSD and DSO. CONCLUSION: This is the first study to examine the role of minority stressors alongside exposure to psychological traumas in ICD-11 PTSD and CPTSD and emphasizes the inclusion of minority stressors in trauma-related assessments. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Transportin 1 is a major nuclear import receptor of the nitric oxide synthase interacting protein.

The nitric oxide synthase interacting protein (NOSIP), an E3-ubiquitin ligase, is involved in various processes like neuronal development, craniofacial development, granulopoiesis, mitogenic signaling, apoptosis, and cell proliferation. The best-characterized function of NOSIP is the regulation of endothelial nitric oxide synthase activity by translocating the membrane-bound enzyme to the cytoskeleton, specifically in the G2 phase of the cell cycle. For this, NOSIP itself has to be translocated from its prominent localization, the nucleus, to the cytoplasm. Nuclear import of NOSIP was suggested to be mediated by the canonical transport receptors importin α/ß. Recently, we found NOSIP in a proteomic screen as a potential importin 13 cargo. Here, we describe the nuclear shuttling characteristics of NOSIP in living cells and in vitro and show that it does not interact directly with importin α. Instead, it formed stable complexes with several importins (-ß, -7, -ß/7, -13, and transportin 1) and was also imported into the nucleus in digitonin-permeabilized cells by these factors. In living HeLa cells, transportin 1 seems to be the major nuclear import receptor for NOSIP. A detailed analysis of the NOSIP-transportin 1 interaction revealed a high affinity and an unusual binding mode, involving the N-terminal half of transportin 1. In contrast to nuclear import, nuclear export of NOSIP seems to occur mostly by passive diffusion. Thus, our results uncover additional layers in the larger process of endothelial nitric oxide synthase regulation.

Daily Heterosexist Experiences in LGBTQ+ Adults from Spain: Measurement, Prevalence, and Clinical Implications / Las experiencias diarias heterosexistas en adultos LGBTQ+ de España: medición, prevalencia e implicaciones clínicas

Lesbian, gay, bisexual, transgender, and queer (LGBTQ+) individuals face unique stressors related to their sexual and gender identities that have a detrimental impact on their mental health. Nonetheless, studies have not yet investigated these minority stressors among LGBTQ+ individuals from Spain. The limited availability of standardized tools/instruments to measure minority stressors in Spanish makes it challenging to explore these experiences among Spanish speaking individuals. The present study aimed to examine the factor structure of the Daily Heterosexist Experiences Questionnaire (DHEQ) among LGBTQ+ adults from Spain, compare rates of minority stressors across diverse gender and sexual orientations, and examine the impact of daily heterosexist experiences (henceforth referred to as heterosexist experiences) on symptoms of depression and suicidal behavior. The sample was composed of 509 LGBTQ+ identifying adults in the age range of 18 to 60 years old. Confirmatory factor analysis indicated a good fit for the six dimensions of the DHEQ scale. Individuals identified as transgender or reporting a minority sexual orientation (i.e., asexual, pansexual) indicated higher levels of exposure to heterosexist experiences. Moreover, those with higher levels of heterosexist experiences had higher symptoms of depression and suicide behavior. The present study provides a tool for examining minority stressors in Spanish speaking LGBTQ+ adults. Assessing for minority stressors may aid in the identification of risk and protective factors when working with LGBTQ+ treatment seeking adults. (AU)

Las personas lesbianas, gais, bisexuales, transexuales y queer (LGBTQ+) enfrentan en su día a día estresores únicos relacionados con sus identidades sexuales y de género que pueden perjudicar a su salud mental. Sin embargo, no hay investigación que explore estos estresores minoritarios en población LGBTQ+ de España. La limitada disponibilidad de instrumentos estandarizados para medir los estresores minoritarios/experiencias heterosexistas en español dificulta hoy en día explorar estas experiencias en las personas de habla hispana. El presente estudio tiene como objetivo examinar la estructura factorial del Cuestionario de Experiencias Heterosexistas Diarias (DHEQ, según sus siglas en inglés) en adultos LGBTQ+ de España, comparar las tasas de experiencias heterosexistas en diversas identidades de género y orientaciones sexuales y examinar el impacto de las experiencias heterosexistas en los síntomas de depresión y comportamiento suicida. La muestra constaba de 509 adultos LGBTQ+ en el rango de edad de 18 a 60 años. El análisis factorial confirmatorio indica un buen ajuste para las seis dimensiones de la escala DHEQ. Las personas que se identificaron como trans o con una orientación sexual minoritaria (por ejemplo, asexual, pansexual) indicaban mayores niveles de exposición a experiencias heterosexistas. Además, niveles más altos de experiencias heterosexistas se asocian a mayores síntomas de depresión y comportamiento suicida. El presente estudio proporciona una herramienta para examinar experiencias heterosexistas en población adulta LGBTQ+ de habla hispana. La evaluación de experiencias heterosexistas puede ayudar en la identificación de factores de riesgo y de protección cuando se trabaja con adultos LGBTQ+ en el ámbito clínico. (AU)

Relapsing-remitting and primary progressive multiple sclerosis treated with ocrelizumab: A comparative study.

OBJECTIVES: To compare the clinical and radiological effectiveness of ocrelizumab in primary progressive multiple sclerosis (PPMS) and relapsing-remitting multiple sclerosis (RRMS) in a clinical practice setting and describe its tolerability and adverse events. METHODS: A retrospective observational cohort study was conducted comparing clinical and magnetic resonance imaging (MRI) data of all patients with (pw)PPMS and RRMS who had received treatment with ocrelizumab at least one cycle and have been followed up for one year at minimum. RESULTS: 42 patients (27 women) treated with ocrelizumab: 29 had RRMS and 13 PPMS. The follow-up period was 26.4 ± 8.4 months. The proportion of pwRRMS with no evidence of disease activity (NEDA) in the first year was 69.2% and in the second was 80%. In the first year, radiological activity was reduced by 80.0% in pwRRMS and 91.7% in pwPPMS. In the second year, radiological activity was completely reduced in both groups. A statistically significant difference (p<0.05) was observed between the pre-ocrelizumab rate of disability progression vs. the first year rate of progression for pwRRMS and pwPPMS. However, an increase in the disability progression rate in the second year of treatment was found in pwPPMS. Ocrelizumab was mostly well tolerated and some adverse effects were reported: infusion-related reactions (IRRs) were the most frequent adverse event, followed by infections and hematological side effects. Discontinuations were due to infections, hematological complications, and perception of ineffectiveness. CONCLUSIONS: Ocrelizumab was very effective in reducing relapses and MRI activity. The rate of progression was slowed down; however, the effect was more evident for pwRRMS than for pwPPMS over time.

A near-infrared probe for detecting and interposing amyloid beta oligomerization in early Alzheimer's disease.

BACKGROUND: The misfolding and deposition of amyloid beta (Aß) in human brain is the main hallmark of Alzheimer's disease (AD) pathology. One of the drivers of Alzheimer´s pathogenesis is the production of soluble oligomeric Aß, which could potentially serve as a biomarker of AD. METHODS: Given that the diphenylalanine (FF) at the C-terminus of Aß fragments plays a key role in inducing the AD pathology, based on the hydrophobic structure of FF, we synthesized a near-infrared BF2-dipyrrolmethane fluorescent imaging probe (NB) to detect both soluble and insoluble Aß. RESULTS: We found that NB not only binds Aß, particularly oligomeric Aß, but also interposes self-assembly of Aß through π-π interaction between NB and FF. CONCLUSION: This work holds great promise in the early detection of AD and may also provide an innovative approach to decelerate and even halt AD onset and progression.

Resolving the Effect of Oxygen Vacancies on Co Nanostructures Using Soft XAS/X-PEEM.

Improving both the extent of metallic Co nanoparticle (Co NP) formation and their stability is necessary to ensure good catalytic performance, particularly for Fischer-Tropsch synthesis (FTS). Here, we observe how the presence of surface oxygen vacancies (Ovac) on TiO2 can readily reduce individual Co3O4 NPs directly into CoO/Co0 in the freshly prepared sample by using a combination of X-ray photoemission electron microscopy (X-PEEM) coupled with soft X-ray absorption spectroscopy. The Ovac are particularly good at reducing the edge of the NPs as opposed to their center, leading to smaller particles being more reduced than larger ones. We then show how further reduction (and Ovac consumption) is achieved during heating in H2/syngas (H2 + CO) and reveal that Ovac also prevents total reoxidation of Co NPs in syngas, particularly the smallest (∼8 nm) particles, thus maintaining the presence of metallic Co, potentially improving catalyst performance.

Preventive and therapeutic reduction of amyloid deposition and behavioral impairments in a model of Alzheimer's disease by whole blood exchange.

Alzheimer's disease (AD) is the major form of dementia in the elderly population. The main neuropathological changes in AD patients are neuronal death, synaptic alterations, brain inflammation, and the presence of cerebral protein aggregates in the form of amyloid plaques and neurofibrillary tangles. Compelling evidence suggests that the misfolding, aggregation, and cerebral deposition of amyloid-beta (Aß) plays a central role in the disease. Thus, prevention and removal of misfolded protein aggregates is considered a promising strategy to treat AD. In the present study, we describe that the development of cerebral amyloid plaques in a transgenic mice model of AD (Tg2576) was significantly reduced by 40-80% through exchanging whole blood with normal blood from wild type mice having the same genetic background. Importantly, such reduction resulted in improvement in spatial memory performance in aged Tg2576 mice. The exact mechanism by which blood exchange reduces amyloid pathology and improves memory is presently unknown, but measurements of Aß in plasma soon after blood exchange suggest that mobilization of Aß from the brain to blood may be implicated. Our results suggest that a target for AD therapy may exist in the peripheral circulation, which could open a novel disease-modifying intervention for AD.

Transgenic Mouse Models of Alzheimer's Disease: An Integrative Analysis.

Alzheimer's disease (AD) constitutes the most prominent form of dementia among elderly individuals worldwide. Disease modeling using murine transgenic mice was first initiated thanks to the discovery of heritable mutations in amyloid precursor protein (APP) and presenilins (PS) genes. However, due to the repeated failure of translational applications from animal models to human patients, along with the recent advances in genetic susceptibility and our current understanding on disease biology, these models have evolved over time in an attempt to better reproduce the complexity of this devastating disease and improve their applicability. In this review, we provide a comprehensive overview about the major pathological elements of human AD (plaques, tauopathy, synaptic damage, neuronal death, neuroinflammation and glial dysfunction), discussing the knowledge that available mouse models have provided about the mechanisms underlying human disease. Moreover, we highlight the pros and cons of current models, and the revolution offered by the concomitant use of transgenic mice and omics technologies that may lead to a more rapid improvement of the present modeling battery.