Effect of psoralens and ultraviolet radiation on murine dendritic epidermal cells

AbstractMonofunctional psoralens produce less phototoxicity than bifunctional psoralens after ultraviolet A (UVA) irradiation. We investigated the effect of repetitive treatments with angelicin (isopsoralen), a monofunctional psoralen, plus UVA radiation (IPUVA) on the number and morphology of dendritic epidermal cells (dEC). This effect was compared with that of 8-methoxypsoralen plus UVA radiation (PUVA), UVA alone, and UVB radiation. C3H/HeN mice were treated topically with the drugs three times/wk for 4 consecutive wk; followed each time by 1 or 2.5 J/cm2 of UVA radiation. Other groups of mice were treated with the drugs alone, UVA alone, or 0.81 J/cm2 of UVB. Epidermal sheets were stained for ATPase, Ia, and Thy-1 markers. Mice treated with PUVA and UVB exhibited severe phototoxicity, whereas no overt phototoxicity was observed in mice treated with IPUVA, UVA alone, or the drugs alone. Early during the PUVA and UVA treatments the ATPase marker was lost from dEC, followed by loss of the Ia marker; the Ia marker was lost before the ATPase marker from dEC in animals treated with IPUVA. At the end of the treatment, however, nearly total depletion of ATPase+, Ia+, and Thy-1+ dEC was observed in mice treated with PUVA and IPUVA. UVB radiation caused rapid depletion of Thy-1+ dEC as well as ATPase+ and Ia+ cells. During treatments with IPUVA, PUVA, UVA, and UVB, the Langerhans cells became rounded and lost their dendrites. These changes were quantitated by image analysis. We conclude that alterations of cutaneous immune cells can occur in the absence of overt phototoxicity, and that monofunctional and bifunctional psoralens plus low dose of UVA radiation may have different effects on dEC markers

Universal sex differences in the desire for sexual variety: tests from 52 nations, 6 Continents, and 13 Islands

Evolutionary psychologists have hypothesized that men and women possess both long-term and short-term mating strategies, with men's short-term strategy differentially rooted in the desire for sexual variety. In this article, findings from a cross-cultural survey of 16,288 people across 10 major world regions (including North America, South America, Western Europe, Eastern Europe, Southern Europe, Middle East, Africa, Oceania, South/Southeast Asia, and East Asia) demonstrate that sex differences in the desire for sexual variety are culturally universal throughout these world regions. Sex differences were evident regardless of whether mean, median, distributional, or categorical indexes of sexual differentiation were evaluated. Sex differences were evident regardless of the measures used to evaluate them. Among contemporary theories of human mating, pluralistic approaches that hypothesize sex differences in the evolved design of short-term mating provide the most compelling account of these robust empirical findings

Delocalization and destabilization of the ARF tumor suppressor by the leukemia-associated NPM mutant

One-third of acute myeloid leukemias (AML) are characterized by the aberrant cytoplasmic localization of Nucleophosmin (NPM), due to mutations within its putative nucleolar localization signal. NPM mutations are mutually exclusive with major AML-associated chromosome rearrangements, and are frequently associated with a normal karyotype, suggesting that they are critical during leukemogenesis. The underlying molecular mechanisms are, however, unknown. NPM is a nucleo-cytoplasmic shuttling protein that has been implicated in several cellular processes, including ribosome biogenesis, centrosome duplication, cell cycle progression and stress response. It has been recently shown that NPM is required for the stabilization and proper nucleolar localization of the tumor suppressor p19Arf. We report here that the AML-associated NPM mutant localizes mainly in the cytoplasm, due to an alteration of its nucleus-cytoplasmic shuttling equilibrium, forms a direct complex with p19Arf, but is unable to protect it from degradation. As a consequence, cells or leukemic blasts expressing the NPM mutant have low levels of cytoplasmic Arf. Inactivation of p19Arf, a key regulator of the p53-dependent cellular response to oncogene expression, might therefore contribute to leukemogenesis in AMLs with mutated NPM

Defining the Riddle in Order to Solve It: There Is More Than One “Parkinson's Disease”

Background: More than 200 years after James Parkinsondescribed a clinical syndrome based on his astute observations, Parkinson's disease (PD) has evolved into a complex entity, akin to the heterogeneity of other complex human syndromes of the central nervous system such as dementia, motor neuron disease, multiple sclerosis, and epilepsy. Clinicians, pathologists, and basic science researchers evolved arrange of concepts andcriteria for the clinical, genetic, mechanistic, and neuropathological characterization of what, in their best judgment, constitutes PD. However, these specialists have generated and used criteria that are not necessarily aligned between their different operational definitions, which may hinder progress in solving the riddle of the distinct forms of PD and ultimately how to treat them. Objective: This task force has identified current in consistencies between the definitions of PD and its diverse variants in different domains: clinical criteria, neuropathological classification, genetic subtyping, biomarker signatures, and mechanisms of disease. This initial effort for “defining the riddle” will lay the foundation for future attempts to better define the range of PD and its variants, as has been done and implemented for other heterogeneous neurological syndromes, such as stroke and peripheral neuropathy. We strongly advocate for a more systematic and evidence-based integration of our diverse disciplines by looking at well-defined variants of the syndrome of PD. Conclusion: Accuracy in defining endophenotypes of “typical PD” across these different but interrelated disciplines will enable better definition of variants and their stratification in therapeutic trials, a prerequisite for breakthroughs in the era of precision medicine. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Narcissism and the Strategic Pursuit of Short-Term Mating: Universal Links across 11 World Regions of the International Sexuality Description Project-2

Previous studies have documented links between sub-clinical narcissism and the active pursuit of short-term mating strategies (e.g., unrestricted sociosexuality, marital infidelity, mate poaching). Nearly all of these investigations have relied solely on samples from Western cultures. In the current study, responses from a cross-cultural survey of 30,470 people across 53 nations spanning 11 world regions (North America, Central/South America, Northern Europe, Western Europe, Eastern Europe, Southern Europe, Middle East, Africa, Oceania, Southeast Asia, and East Asia) were used to evaluate whether narcissism (as measured by the Narcissistic Personality Inventory; NPI) was universally associated with short-term mating. Results revealed narcissism scores (including two broad factors and seven traditional facets as measured by the NPI) were functionally equivalent across cultures, reliably associating with key sexual outcomes (e.g., more active pursuit of short-term mating, intimate partner violence, and sexual aggression) and sex-related personality traits (e.g., higher extraversion and openness to experience). Whereas some features of personality (e.g., subjective well-being) were universally associated with socially adaptive facets of Narcissism (e.g., self-sufficiency), most indicators of short-term mating (e.g., unrestricted sociosexuality and marital infidelity) were universally associated with the socially maladaptive facets of narcissism (e.g., exploitativeness). Discussion addresses limitations of these cross-culturally universal findings and presents suggestions for future research into revealing the precise psychological features of narcissism that facilitate the strategic pursuit of short-term mating

Long-term dementia prevalence in Parkinson Disease: Glass half-full?

Introduction: Dementia occurs in up to 80% of Parkinson’s disease (PD) patients long-term, but studies reporting such high rates were published years ago and had relatively small sample sizes and other limitations. Objective: To determine long-term, cumulative dementia prevalence rates in PD using data from two large, ongoing, prospective observational studies. Design: Analyses of data from the Parkinson’s Progression Markers Initiative (PPMI) and a longstanding PD research clinical core at the University of Pennsylvania (Penn). Setting: PPMI is a multi-site international study, and Penn is a single site study at a tertiary movement disorders center. Participants: PPMI enrolls de novo, untreated PD participants at baseline, and Penn enrolls a convenience cohort from a large clinical center. Methods: For PPMI a cognitive battery and MDS-UPDRS Part I are administered annually, and the site investigator assigns a cognitive diagnosis annually. At Penn a comprehensive cognitive battery is administered either annually or biennially, and a cognitive diagnosis is made by expert consensus. Main Outcomes: Kaplan-Meier (KM) survival curves were fit for time from PD diagnosis to stable dementia diagnosis for each cohort, using assigned cognitive diagnosis of dementia as the primary endpoint (for both PPMI and Penn), and MoCA score <21 and MDS-UPDRS Part I cognition score ≥3 as secondary endpoints (for PPMI). In addition, cumulative dementia prevalence by PD disease duration was tabulated for each study and endpoint. Results: For the PPMI cohort, 417 PD participants were seen at baseline; estimated cumulative probability of dementia at year 10 disease duration were: 7% (site investigator diagnosis), 9% (MoCA) or 7.4% (MDS-UPDRS Part I cognition). For the Penn cohort, 389 PD participants were followed over time, with 184 participants (47% of cohort) eventually diagnosed with dementia. The KM curve for the Penn cohort had median time to dementia diagnosis =15 years (95% CI: 13-15) disease duration; the estimated cumulative probability of dementia was 27% at year 10, 50% at year 15, and 74% at year 20. Conclusions and Relevance: Results from two large, prospective studies suggest that dementia in Parkinson disease occurs less frequently, or later in the disease course, than often-cited previous research studies have reported

Dual targeting of the DNA damage response pathway and BCL-2 in diffuse large B-cell lymphoma

Standard chemotherapies for diffuse large B-cell lymphoma (DLBCL), based on the induction of exogenous DNA damage and oxidative stress, are often less effective in the presence of increased MYC and BCL-2 levels, especially in the case of double hit (DH) lymphomas harboring rearrangements of the MYC and BCL-2 oncogenes, which enrich for a patient’s population characterized by refractoriness to anthracycline-based chemotherapy. Here we hypothesized that adaptive mechanisms to MYC-induced replicative and oxidative stress, consisting in DNA damage response (DDR) activation and BCL-2 overexpression, could represent the biologic basis of the poor prognosis and chemoresistance observed in MYC/BCL-2-positive lymphoma. We first integrated targeted gene expression profiling (T-GEP), fluorescence in situ hybridization (FISH) analysis, and characterization of replicative and oxidative stress biomarkers in two independent DLBCL cohorts. The presence of oxidative DNA damage biomarkers identified a poor prognosis double expresser (DE)-DLBCL subset, characterized by relatively higher BCL-2 gene expression levels and enrichment for DH lymphomas. Based on these findings, we tested therapeutic strategies based on combined DDR and BCL-2 inhibition, confirming efficacy and synergistic interactions in in vitro and in vivo DH-DLBCL models. These data provide the rationale for precision-therapy strategies based on combined DDR and BCL-2 inhibition in DH or DE-DLBCL

AML1/ETO Oncoprotein Is Directed to AML1 Binding Regions and Co-Localizes with AML1 and HEB on Its Targets

A reciprocal translocation involving chromosomes 8 and 21 generates the AML1/ETO oncogenic transcription factor that initiates acute myeloid leukemia by recruiting co-repressor complexes to DNA. AML1/ETO interferes with the function of its wild-type counterpart, AML1, by directly targeting AML1 binding sites. However, transcriptional regulation determined by AML1/ETO probably relies on a more complex network, since the fusion protein has been shown to interact with a number of other transcription factors, in particular E-proteins, and may therefore target other sites on DNA. Genome-wide chromatin immunoprecipitation and expression profiling were exploited to identify AML1/ETO-dependent transcriptional regulation. AML1/ETO was found to co-localize with AML1, demonstrating that the fusion protein follows the binding pattern of the wild-type protein but does not function primarily by displacing it. The DNA binding profile of the E-protein HEB was grossly rearranged upon expression of AML1/ETO, and the fusion protein was found to co-localize with both AML1 and HEB on many of its regulated targets. Furthermore, the level of HEB protein was increased in both primary cells and cell lines expressing AML1/ETO. Our results suggest a major role for the functional interaction of AML1/ETO with AML1 and HEB in transcriptional regulation determined by the fusion protein