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What is this summary about? This is a plain language summary of a research study called ALPINE. The study involved people who had been diagnosed with, and previously treated at least once for, relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).Lymphocytes help to find and fight off viruses and infections in the body, but when someone has CLL or SLL, the body creates abnormal lymphocytes, leaving the patient with a weakened immune system and susceptible to illness. In CLL, these lymphocytes are in the bone marrow and bloodstream, whereas for SLL, they are mostly found in the lymph nodes, such as those in the neck.How was the research done? The ALPINE study was designed to directly compare the cancer-fighting effects and side effects of zanubrutinib and ibrutinib as treatment for patients with relapsed or refractory CLL/SLL.What were the results? After 30 months, zanubrutinib was more effective than ibrutinib at reducing and keeping the cancer from coming back. Clinical Trial Registration: NCT03734016 (ClinicalTrials.gov).
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Adenina , Resistencia a Antineoplásicos , Leucemia Linfocítica Crónica de Células B , Piperidinas , Inhibidores de Proteínas Quinasas , Pirazoles , Pirimidinas , Humanos , Piperidinas/uso terapéutico , Adenina/análogos & derivados , Adenina/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Pirimidinas/uso terapéutico , Pirazoles/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Antineoplásicos/uso terapéutico , Pirazinas/uso terapéutico , Tiazoles/uso terapéutico , Resultado del TratamientoRESUMEN
Adverse birth outcomes remain challenging public health problems in China. Increasing evidence indicated that prenatal depression and anxiety are associated with adverse birth outcomes, highlighting the importance and severity of prenatal depression and anxiety in China. The COVID-19 pandemic is likely to further exacerbate prenatal mental health problems and increase the risk of adverse birth outcomes. The aim of this study is to assess and compare the impacts of prenatal mental health issues on birth outcomes before and during the COVID-19 pandemic in Ma'anshan, Anhui, China. Participants in this study were women who visited local maternal and child health hospitals in Ma'anshan, Anhui, China. Two independent sets of individual maternal data (npre-pamdemic = 1148; npandemic = 2249) were collected. Prenatal depression and anxiety were measured online using the Edinburgh Postnatal Depression Scale (EPDS) and the General Anxiety Disorder-7 (GAD-7). Adverse birth outcomes were determined using hospital-recorded infant birth weight and gestational age at delivery. In this study, we found that the pandemic cohort had lower mean EPDS and GAD-7 scores than the pre-pandemic cohort. The prevalence of prenatal depression (14.5%) and anxiety (26.7%) among the pandemic cohort were lower than the pre-pandemic cohort (18.6% and 36.3%). No significant difference was found in the prevalence of adverse birth outcomes comparing the two cohorts. Prenatal depression was associated with small gestational age only in the pandemic cohort (OR = 1.09, 95% CI 1.00-1.19, p = 0.042). Overall, this study highlighted an association between prenatal depression and small for gestational age in Anhui, China. Addressing prenatal depression may thus be key in improving birth outcomes. Future studies could focus on potential causal relationships.
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Ansiedad , COVID-19 , Depresión , Salud Mental , Complicaciones del Embarazo , Resultado del Embarazo , Humanos , Femenino , COVID-19/epidemiología , COVID-19/psicología , Embarazo , China/epidemiología , Adulto , Depresión/epidemiología , Ansiedad/epidemiología , Resultado del Embarazo/epidemiología , Complicaciones del Embarazo/epidemiología , Complicaciones del Embarazo/psicología , Recién Nacido , SARS-CoV-2 , Pandemias , Edad Gestacional , Peso al Nacer , Prevalencia , Adulto JovenRESUMEN
PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson's disease (PD) and Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction, and impairs mitophagy as evidenced by the accumulation of the PINK1 substrate pS65-Ubiquitin (pUb). We discovered MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes its active complex, resulting in increased rates of mitophagy. Treatment with MTK458 mediates clearance of accumulated pUb and α-synuclein pathology in α-synuclein pathology models in vitro and in vivo. Our findings from preclinical PD models suggest that pharmacological activation of PINK1 warrants further clinical evaluation as a therapeutic strategy for disease modification in PD.
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WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a research study called ALPINE. The study involved people who had been diagnosed with, and previously treated at least once for, relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Lymphocytes help to find and fight off viruses and infections in the body, but when someone has CLL or SLL, the body creates abnormal lymphocytes, leaving the patient with a weakened immune system and susceptible to illness. In CLL, these lymphocytes are in the bone marrow and bloodstream, whereas for SLL, they are mostly found in the lymph nodes, such as those in the neck. HOW WAS THE RESEARCH DONE?: The ALPINE study was designed to directly compare the cancer-fighting effects and side effects of zanubrutinib and ibrutinib as treatment for patients with relapsed or refractory CLL/SLL. WHAT WERE THE RESULTS?: After 30 months, zanubrutinib was more effective than ibrutinib at reducing and keeping the cancer from coming back. Clinical Trial Registration: NCT03734016 (ClinicalTrials.gov).
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Adenina/análogos & derivados , Leucemia Linfocítica Crónica de Células B , Linfoma de Células B , Pirimidinas , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/patología , Piperidinas/uso terapéutico , Pirazoles/efectos adversos , Linfoma de Células B/tratamiento farmacológicoRESUMEN
The microbiota influences intestinal health and physiology, yet the contributions of commensal protists to the gut environment have been largely overlooked. Here, we discover human- and rodent-associated parabasalid protists, revealing substantial diversity and prevalence in nonindustrialized human populations. Genomic and metabolomic analyses of murine parabasalids from the genus Tritrichomonas revealed species-level differences in excretion of the metabolite succinate, which results in distinct small intestinal immune responses. Metabolic differences between Tritrichomonas species also determine their ecological niche within the microbiota. By manipulating dietary fibers and developing in vitro protist culture, we show that different Tritrichomonas species prefer dietary polysaccharides or mucus glycans. These polysaccharide preferences drive trans-kingdom competition with specific commensal bacteria, which affects intestinal immunity in a diet-dependent manner. Our findings reveal unappreciated diversity in commensal parabasalids, elucidate differences in commensal protist metabolism, and suggest how dietary interventions could regulate their impact on gut health.
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Microbioma Gastrointestinal , Parabasalidea , Polisacáridos , Animales , Humanos , Ratones , Fibras de la Dieta , Intestino Delgado/metabolismo , Polisacáridos/metabolismo , Parabasalidea/metabolismo , Carbohidratos de la Dieta/metabolismo , BiodiversidadRESUMEN
OBJECTIVES: In this study, we first assessed whether four routine activity theory (RAT) variables (Internet exposure, target suitability, proximity to offender, and guardianship) determine Tanzanian adolescents' online sexual exploitation (OSE). Second, we identified two types of guardianship that moderate the relationships between these variables and adolescents' OSE. Third, we assessed the moderating effect of locality (rural area) on the relationships among the RAT variables and OSE. METHOD: Our analysis was based on a stratified random sample of 1014 secondary school adolescents aged 12-20 years (M = 15.67; SD = 1.35) recruited from urban and rural regions of Tanzania. We used Poisson regressions to test the main effects of the RAT variables and the moderating effects of two types of guardianship and locality on OSE. RESULTS: We found that OSE increased with the suitability of the respondents and with online exposure. Social guardianship had a moderating effect on OSE by reducing the positive influence of target suitability. Living in a rural area also had a moderating effect on OSE through reinforcing the effect of proximity to potential perpetrators in cyberspace. CONCLUSION: RAT can effectively increase our understanding of the OSE of minors in Tanzania. Furthermore, social rather than physical guardianship can mitigate the risk factors of OSE.
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Instituciones Académicas , Conducta Sexual , Adolescente , Humanos , Tanzanía/epidemiología , Factores de Riesgo , EstudiantesRESUMEN
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause of ALS/FTD is expansion of the intronic hexanucleotide repeat (GGGGCC)n in C9orf72. Here, we investigate the formation of nucleic acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of ALS/FTD. We observe significant aggregation of the hexanucleotide sequence (GGGGCC)n, which we associate to the formation of multimolecular G-quadruplexes (mG4s) by using a range of biophysical techniques. Exposing the condensates to G4-unfolding conditions leads to prompt disassembly, highlighting the key role of mG4-formation in the condensation process. We further validate the biological relevance of our findings by detecting an increased prevalence of G4-structures in C9orf72 mutant human motor neurons when compared to healthy motor neurons by staining with a G4-selective fluorescent probe, revealing signal in putative condensates. Our findings strongly suggest that RNA G-rich repetitive sequences can form protein-free condensates sustained by multimolecular G-quadruplexes, highlighting their potential relevance as therapeutic targets for C9orf72 mutation-related ALS/FTD.
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Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , G-Cuádruplex , Humanos , Demencia Frontotemporal/genética , Esclerosis Amiotrófica Lateral/genética , ARN/genética , ARN/química , Proteína C9orf72/genética , Expansión de las Repeticiones de ADN/genéticaRESUMEN
The increasing demand for novel natural compounds has prompted the exploration of innovative approaches in bioengineering. This study investigates the bioengineering potential of the marine diatom Phaeodactylum tricornutum through the introduction of cannabis genes, specifically, tetraketide synthase (TKS), and olivetolic acid cyclase (OAC), for the production of the cannabinoid precursor, olivetolic acid (OA). P. tricornutum is a promising biotechnological platform due to its fast growth rate, amenability to genetic manipulation, and ability to produce valuable compounds. Through genetic engineering techniques, we successfully integrated the cannabis genes TKS and OAC into the diatom. P. tricornutum transconjugants expressing these genes showed the production of the recombinant TKS and OAC enzymes, detected via Western blot analysis, and the production of cannabinoids precursor (OA) detected using the HPLC/UV spectrum when compared to the wild-type strain. Quantitative analysis revealed significant olivetolic acid accumulation (0.6-2.6 mg/L), demonstrating the successful integration and functionality of the heterologous genes. Furthermore, the introduction of TKS and OAC genes led to the synthesis of novel molecules, potentially expanding the repertoire of bioactive compounds accessible through diatom-based biotechnology. This study demonstrates the successful bioengineering of P. tricornutum with cannabis genes, enabling the production of OA as a precursor for cannabinoid production and the synthesis of novel molecules with potential pharmaceutical applications.
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Cannabinoides , Cannabis , Diatomeas , Alucinógenos , Cannabis/genética , Cannabinoides/genética , Diatomeas/genética , Agonistas de Receptores de Cannabinoides , BioingenieríaRESUMEN
Orbital Apex Syndrome (OAS) complicating Herpes Zoster Ophthalmicus (HZO) is associated with significant visual impairment. We present four patients with HZO OAS, to highlight clinical features and outcomes in order to promote earlier recognition and management of this potentially sight-threatening complication. CT and MRI imaging findings included expansion and enhancement of extraocular muscles and intraconal fat and involvement of the orbital apex and cavernous sinus. All patients received systemic steroid and antiviral therapy, but a standardised dosage and duration of treatment remains to be defined. Final visual acuity and extraocular motility outcomes were variable.
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OBJECTIVE: Older adults are prone to the negative effects of exposure to violence on their mental health. This study aimed to examine the impact of exposure to violence during social unrest and the role of resilience in the mental health of older people. DESIGN: A total of 1,203 people aged 65 years or older were randomly selected for a telephone survey using the random digit dialing numbering method in Hong Kong. MEASUREMENTS: A 13-item scale was developed to measure exposure to violence. The Chinese versions of the Connor-Davidson Resilience Scale and the Startle, Physiological Arousal, Anger, and Numbness scales for measuring mental health status were adopted in the survey. RESULTS: The results showed that the more frequently older people were exposed to information, the more negative mental health status they had. However, exposure to witnessing and experiencing violence was not significantly associated with mental health status. Older adults' level of resilience had a moderating effect between exposure to information and mental health, whereas the effect of exposure to information on mental health was stronger for respondents with lower resilience. CONCLUSION: This study showed that emotional problems caused by exposure to related information among older people should be properly addressed during massive social unrest and conflict. Their resilience capacity is an important moderating factor. Future interventions and support services should focus on enhancing the resilience of older people to better equip them with overcoming problems related to macro-social issues.
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Exposición a la Violencia , Resiliencia Psicológica , Humanos , Anciano , Salud Mental , Hong Kong/epidemiología , ViolenciaRESUMEN
During development, much of the enteric nervous system (ENS) arises from the vagal neural crest that emerges from the caudal hindbrain and colonizes the entire gastrointestinal tract. However, a second ENS contribution comes from the sacral neural crest that arises in the caudal neural tube and populates the post-umbilical gut. By coupling single-cell transcriptomics with axial-level-specific lineage tracing in avian embryos, we compared the contributions of embryonic vagal and sacral neural crest cells to the chick ENS and the associated peripheral ganglia (Nerve of Remak and pelvic plexuses). At embryonic day (E) 10, the two neural crest populations form overlapping subsets of neuronal and glia cell types. Surprisingly, the post-umbilical vagal neural crest much more closely resembles the sacral neural crest than the pre-umbilical vagal neural crest. However, some differences in cluster types were noted between vagal and sacral derived cells. Notably, RNA trajectory analysis suggests that the vagal neural crest maintains a neuronal/glial progenitor pool, whereas this cluster is depleted in the E10 sacral neural crest which instead has numerous enteric glia. The present findings reveal sacral neural crest contributions to the hindgut and associated peripheral ganglia and highlight the potential influence of the local environment and/or developmental timing in differentiation of neural crest-derived cells in the developing ENS.
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Sistema Nervioso Entérico , Cresta Neural , Tracto Gastrointestinal , Neuroglía/metabolismo , Neuronas/fisiología , Movimiento Celular/fisiologíaRESUMEN
Steady improvements in ambient air quality in the USA over the past several decades, in part a result of public policy1,2, have led to public health benefits1-4. However, recent trends in ambient concentrations of particulate matter with diameters less than 2.5 µm (PM2.5), a pollutant regulated under the Clean Air Act1, have stagnated or begun to reverse throughout much of the USA5. Here we use a combination of ground- and satellite-based air pollution data from 2000 to 2022 to quantify the contribution of wildfire smoke to these PM2.5 trends. We find that since at least 2016, wildfire smoke has influenced trends in average annual PM2.5 concentrations in nearly three-quarters of states in the contiguous USA, eroding about 25% of previous multi-decadal progress in reducing PM2.5 concentrations on average in those states, equivalent to 4 years of air quality progress, and more than 50% in many western states. Smoke influence on trends in the number of days with extreme PM2.5 concentrations is detectable by 2011, but the influence can be detected primarily in western and mid-western states. Wildfire-driven increases in ambient PM2.5 concentrations are unregulated under current air pollution law6 and, in the absence of further interventions, we show that the contribution of wildfire to regional and national air quality trends is likely to grow as the climate continues to warm.
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Contaminantes Atmosféricos , Contaminación del Aire , Material Particulado , Incendios Forestales , Humanos , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/química , Contaminación del Aire/análisis , Contaminación del Aire/legislación & jurisprudencia , Contaminación del Aire/estadística & datos numéricos , Calentamiento Global/estadística & datos numéricos , Material Particulado/análisis , Material Particulado/química , Humo/análisis , Estados Unidos , Incendios Forestales/estadística & datos numéricos , Política Ambiental/legislación & jurisprudencia , Política Ambiental/tendenciasAsunto(s)
Carcinoma de Células Pequeñas , Colitis Ulcerosa , Reservorios Cólicos , Proctocolectomía Restauradora , Humanos , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/cirugía , Colitis Ulcerosa/patología , Carcinoma de Células Pequeñas/patología , Carcinoma de Células Pequeñas/cirugía , Proctocolectomía Restauradora/efectos adversos , Recto/cirugía , Anastomosis Quirúrgica , Reservorios Cólicos/efectos adversos , Reservorios Cólicos/patología , Resultado del Tratamiento , Canal AnalRESUMEN
Health Canada approved pembrolizumab in the first-line setting for advanced non-small-cell lung cancer with PD-L1 ≥ 50% and no EGFR/ALK aberration. The keynote 024 trial showed 55% of such patients progress with pembrolizumab monotherapy. We propose that the combination of baseline CT and clinical factors can help identify those patients who may progress. In 138 eligible patients from our institution, we retrospectively collected their baseline variables, including baseline CT findings (primary lung tumor size and metastatic site), smoking pack years, performance status, tumor pathology, and demographics. The treatment response was assessed via RECIST 1.1 using the baseline and first follow-up CT. Associations between the baseline variables and progressive disease (PD) were tested by logistic regression analyses. The results showed 46/138 patients had PD. The baseline CT "number of involved organs" by metastasis and smoking pack years were independently associated with PD (p < 0.05), and the ROC analysis showed a good performance of the model that integrated these variables in predicting PD (AUC: 0.79). This pilot study suggests that the combination of baseline CT disease and smoking PY can identify who may progress on pembrolizumab monotherapy and can potentially facilitate decision-making for the optimal first-line treatment in the high PD-L1 cohort.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Progresión de la Enfermedad , Neoplasias Pulmonares/patología , Proyectos Piloto , Estudios Retrospectivos , Fumar , Tomografía Computarizada por Rayos XRESUMEN
Succinate produced by the commensal protist Tritrichomonas musculis (T. mu) stimulates chemosensory tuft cells, resulting in intestinal type 2 immunity. Tuft cells express the succinate receptor SUCNR1, yet this receptor does not mediate antihelminth immunity nor alter protist colonization. Here, we report that microbial-derived succinate increases Paneth cell numbers and profoundly alters the antimicrobial peptide (AMP) landscape in the small intestine. Succinate was sufficient to drive this epithelial remodeling, but not in mice lacking tuft cell chemosensory components required to detect this metabolite. Tuft cells respond to succinate by stimulating type 2 immunity, leading to interleukin-13-mediated epithelial and AMP expression changes. Moreover, type 2 immunity decreases the total number of mucosa-associated bacteria and alters the small intestinal microbiota composition. Finally, tuft cells can detect short-term bacterial dysbiosis that leads to a spike in luminal succinate levels and modulate AMP production in response. These findings demonstrate that a single metabolite produced by commensals can markedly shift the intestinal AMP profile and suggest that tuft cells utilize SUCNR1 and succinate sensing to modulate bacterial homeostasis.
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Antiinfecciosos , Mucosa Intestinal , Ratones , Animales , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Intestinos , Ácido Succínico/metabolismo , Antiinfecciosos/metabolismoRESUMEN
Anti-dsDNA antibodies are pathogenically heterogeneous, implying distinct origins and antigenic properties. Unexpectedly, during the clinical and molecular characterization of autoantibodies to the endonuclease DNase1L3 in patients with systemic lupus erythematosus (SLE), we identified a subset of neutralizing anti-DNase1L3 antibodies previously catalogued as anti-dsDNA. Based on their variable heavy-chain (VH) gene usage, these antibodies can be divided in two groups. One group is encoded by the inherently autoreactive VH4-34 gene segment, derives from anti-DNase1L3 germline-encoded precursors, and gains cross-reactivity to dsDNA - and some additionally to cardiolipin - following somatic hypermutation. The second group, originally defined as nephritogenic anti-dsDNA antibodies, is encoded by diverse VH gene segments. Although affinity maturation results in dual reactivity to DNase1L3 and dsDNA, their binding efficiencies favor DNase1L3 as the primary antigen. Clinical, transcriptional and monoclonal antibody data support that cross-reactive anti-DNase1L3/dsDNA antibodies are more pathogenic than single reactive anti-dsDNA antibodies. These findings point to DNase1L3 as the primary target of a subset of antibodies classified as anti-dsDNA, shedding light on the origin and pathogenic heterogeneity of antibodies reactive to dsDNA in SLE.
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Lupus Eritematoso Sistémico , Humanos , Lupus Eritematoso Sistémico/genética , Autoanticuerpos , Anticuerpos Antinucleares/genética , ADN/metabolismo , Anticuerpos Monoclonales , Endodesoxirribonucleasas/genéticaRESUMEN
Using tissue whole exome sequencing (WES) and circulating tumor cell-free DNA (ctDNA), this Australasian Leukaemia & Lymphoma Group translational study sought to characterize primary and acquired molecular determinants of response and resistance of marginal zone lymphoma (MZL) to zanubrutinib for patients treated in the MAGNOLIA clinical trial. WES was performed on baseline tumor samples obtained from 18 patients. For 7 patients, ctDNA sequence was interrogated using a bespoke hybrid-capture next-generation sequencing assay for 48 targeted genes. Somatic mutations were correlated with objective response data and survival analysis using Fisher exact test and Kaplan-Meier (log-rank) method, respectively. Baseline WES identified mutations in 33 of 48 (69%) prioritized genes. NF-κB, NOTCH, or B-cell receptor (BCR) pathway genes were implicated in samples from 16 of 18 patients (89%). KMT2D mutations (n = 11) were most common, followed by FAT1 (n = 9), NOTCH1, NOTCH2, TNFAIP3 (n = 5), and MYD88 (n = 4) mutations. MYD88 or TNFAIP3 mutations correlated with improved progression-free survival (PFS). KMT2D mutations trended to worse PFS. Acquired resistance mutations PLCG2 (R665W/R742P) and BTK (C481Y/C481F) were detected in 2 patients whose disease progressed. A BTK E41K noncatalytic activating mutation was identified before treatment in 1 patient who was zanubrutinib-refractory. MYD88, TNFAIP3, and KMT2D mutations correlate with PFS in patients with relapsed/refractory MZL treated with zanubrutinib. Detection of acquired BTK and PLCG2 mutations in ctDNA while on therapy is feasible and may herald clinical disease progression. This trial was registered at https://anzctr.org.au/ as #ACTRN12619000024145.
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Linfoma de Células B de la Zona Marginal , Factor 88 de Diferenciación Mieloide , Humanos , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Mutación , FN-kappa B/metabolismo , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Linfoma de Células B de la Zona Marginal/genética , Linfoma de Células B de la Zona Marginal/patología , Inhibidores de Proteínas QuinasasRESUMEN
ABSTRACT: The experience of pain is determined by many factors and has a significant impact on quality of life. This study aimed to determine sex differences in pain prevalence and intensity reported by participants with diverse disease states in several large international clinical trials. Individual participant data meta-analysis was conducted using EuroQol-5 Dimension (EQ-5D) questionnaire pain data from randomised controlled trials published between January 2000 and January 2020 and undertaken by investigators at the George Institute for Global Health. Proportional odds logistic regression models, comparing pain scores between females and males and fitted with adjustments for age and randomized treatment, were pooled in a random-effects meta-analysis. In 10 trials involving 33,957 participants (38% females) with EQ-5D pain score data, the mean age ranged between 50 and 74. Pain was reported more frequently by females than males (47% vs 37%; P < 0.001). Females also reported greater levels of pain than males (adjusted odds ratio 1.41, 95% CI 1.24-1.61; P < 0.001). In stratified analyses, there were differences in pain by disease group ( P for heterogeneity <0.001), but not by age group or region of recruitment. Females were more likely to report pain, and at a higher level, compared with males across diverse diseases, all ages, and geographical regions. This study reinforces the importance of reporting sex-disaggregated analysis to identify similarities and differences between females and males that reflect variable biology and may affect disease profiles and have implications for management.
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Calidad de Vida , Caracteres Sexuales , Humanos , Masculino , Femenino , Ensayos Clínicos Controlados Aleatorios como Asunto , Dolor/epidemiología , Encuestas y CuestionariosRESUMEN
PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson's disease (PD) and Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction and impairs mitophagy, driving accumulation of the PINK1 substrate pS65-Ubiquitin (pUb) in primary neurons and in vivo. We synthesized MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes an active heterocomplex, thereby increasing mitophagy. MTK458 mediates clearance of α-synuclein pathology in PFF seeding models in vitro and in vivo and reduces pUb. We developed an ultrasensitive assay to quantify pUb levels in plasma and observed an increase in pUb in PD subjects that correlates with disease progression, paralleling our observations in PD models. Our combined findings from preclinical PD models and patient biofluids suggest that pharmacological activation of PINK1 is worthy of further study as a therapeutic strategy for disease modification in PD. Highlights: Discovery of a plasma Parkinson's Disease biomarker candidate, pS65-Ubiquitin (pUb)Plasma pUb levels correlate with disease status and progression in PD patients.Identification of a potent, brain penetrant PINK1 activator, MTK458MTK458 selectively activates PINK1 by stimulating dimerization and stabilization of the PINK1/TOM complexMTK458 drives clearance of α-synuclein pathology and normalizes pUb in in vivo Parkinson's models.
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Owing to the complication in organisation, the dangerous job nature and the rise of demonstrations and protests across the world in the past decade, police work-related stress has become a topic of global concern. This review aimed to provide an understanding of predictors, mediators and moderators of police work-related stress from a multi-level perspective. Using a scoping review approach underpinned by the six-stage methodological framework, studies were found from six electronic databases (MEDLINE, Web of Science, Sociological Abstracts, Scopus, PsycINFO and PsychiatryOnline) and grey literature sources. Thirty studies were yielded across 35,446 participants from 12 locations. This review contributes to a systematic understanding of the factors affecting police work-related stress by identifying six predictors, four mediators and three moderators. It then discusses limitations and future research.