CADM1 and MAL promoter methylation levels in hrHPV‐positive cervical scrapes increase proportional to degree and duration of underlying cervical disease

Combined detection of cell adhesion molecule 1 (CADM1) and T‐lymphocyte maturation‐associated protein (MAL) promoter methylation in cervical scrapes is a promising triage strategy for high‐risk human papillomavirus (hrHPV)‐positive women. Here, CADM1 and MAL DNA methylation levels were analysed in cervical scrapes of hrHPV‐positive women with no underlying high‐grade disease, high‐grade cervical intraepithelial neoplasia (CIN) and cervical cancer. CADM1 and MAL methylation levels in scrapes were first related to CIN‐grade of the corresponding biopsy and second to CIN‐grade stratified by the presence of ‘normal’ or ‘abnormal’ cytology as present in the accompanying scrape preceding the cervical biopsy. The scrapes included 167 women with ≤CIN1, 54 with CIN2/3 and 44 with carcinoma. In a separate series of hrHPV‐positive scrapes of women with CIN2/3 (n = 48), methylation levels were related to duration of preceding hrHPV infection (PHI; <5 and ≥5 years). Methylation levels were determined by quantitative methylation‐specific PCR and normal cytology scrapes of hrHPV‐positive women with histologically ≤CIN1 served as reference. CADM1 and MAL methylation levels increased proportional to severity of the underlying lesion, showing an increase of 5.3‐ and 6.2‐fold in CIN2/3, respectively, and 143.5‐ and 454.9‐fold in carcinomas, respectively, compared to the reference. Methylation levels were also elevated in CIN2/3 with a longer duration of PHI (i.e. 11.5‐ and 13.6‐fold, respectively). Moreover, per histological category, methylation levels were higher in accompanying scrapes with abnormal cytology than in scrapes with normal cytology. Concluding, CADM1 and MAL promoter methylation levels in hrHPV‐positive cervical scrapes are related to the degree and duration of underlying cervical disease and markedly increased in cervical cancer.     

Vulvar intraepithelial neoplasia: Incidence and long‐term risk of vulvar squamous cell carcinoma

The risk of vulvar squamous cell carcinoma (VSCC) in patients with high‐grade vulvar intraepithelial neoplasia (VIN) is considered lower in high‐grade squamous intraepithelial lesion (HSIL) compared to differentiated VIN (dVIN), but studies are limited. Our study investigated both the incidence of high‐grade VIN and the cumulative incidence of VSCC in patients with HSIL and dVIN separately. A database of women diagnosed with high‐grade VIN between 1991 and 2011 was constructed with data from the Dutch Pathology Registry (PALGA). The European standardized incidence rate (ESR) and VSCC risk were calculated, stratified for HSIL and dVIN. The effects of type of VIN (HSIL vs dVIN), age and lichen sclerosis (LS) were estimated by Cox regression. In total, 1148 patients were diagnosed with high‐grade VIN between 1991 and 2011. Between 1991‐1995 and 2006‐2011, the ESR of HSIL increased from 2.39 (per 100 000 woman‐years) to 3.26 and the ESR of dVIN increased from 0.02 to 0.08. The 10‐year cumulative VSCC risk was 10.3%; 9.7% for HSIL and 50.0% for dVIN (log rank P < .001). Type of VIN, age and presence of LS were independent risk factors for progression to VSCC, with hazard ratios of 3.0 (95% confidence interval [CI] 1.3‐7.1), 2.3 (95% CI 1.5‐3.4) and 3.1 (95% CI 1.8‐5.3), respectively. The incidence of high‐grade VIN is rising. Because of the high cancer risk in patients with dVIN, better identification and timely recognition are urgently needed.     

Love withdrawal is related to heightened processing of faces with emotional expressions and incongruent emotional feedback: evidence from ERPs

Parental use of love withdrawal is thought to affect children's later psychological functioning because it creates a link between children's performance and relational consequences. To investigate whether love withdrawal is also associated with the underlying level of basic information processing in the brain, we studied event-related potentials to feedback stimuli that combined performance feedback with emotional facial expressions. We focused on the VPP (face processing) and N400 (incongruence processing). More maternal use of love withdrawal was related to more positive VPP amplitudes, larger effects of the emotional facial expression on VPP amplitude, and more negative N400 responses to incongruent combinations of feedback and facial expressions. Our findings suggest a heightened processing of faces with emotional expressions and greater sensitivity to incongruence between feedback and facial expression in individuals who experienced more love withdrawal.     

Increased autophagy in CD4+ T cells of rheumatoid arthritis patients results in T‐cell hyperactivation and apoptosis resistance

Rheumatoid arthritis (RA) is an autoimmune disease hallmarked by aberrant cellular homeostasis, resulting in hyperactive CD4⁺ T cells that are more resistant to apoptosis. Both hyperactivation and resistance to apoptosis may contribute to the pathogenicity of CD4⁺ T cells in the autoimmune process. A better knowledge of the mechanisms determining such impaired homeostasis could contribute significantly to both the understanding and the treatment of the disease. Here we investigated whether autophagy, is dysregulated in CD4⁺ T cells of RA patients, resulting in disturbed T‐cell homeostasis. We demonstrate that the rate of autophagy is significantly increased in CD4⁺ T cells from RA patients, and that increased autophagy is also a feature of in vitro activated CD4⁺ T cells. The increased apoptosis resistance observed in CD4⁺ T cells from RA patients was significantly reversed upon autophagy inhibition. These mechanisms may contribute to RA pathogenesis, as autophagy inhibition reduced both arthritis incidence and disease severity in a mouse collagen induced arthritis mouse model. Conversely, in Atg5^flox/flox‐CD4‐Cre⁺ mice, in which all T cells are autophagy deficient, T cells showed impaired activation and proliferation. These data provide novel insight into the pathogenesis of RA and underscore the relevance of autophagy as a promising therapeutic target.     

Earth history events shaped the evolution of uneven biodiversity across tropical moist forests

Far from a uniform band, the biodiversity found across Earth’s tropical moist forests varies widely between the high diversity of the Neotropics and Indomalaya and the relatively lower diversity of the Afrotropics. Explanations for this variation across different regions, the “pantropical diversity disparity” (PDD), remain contentious, due to difficulty teasing apart the effects of contemporary climate and paleoenvironmental history. Here, we assess the ubiquity of the PDD in over 150,000 species of terrestrial plants and vertebrates and investigate the relationship between the present-day climate and patterns of species richness. We then investigate the consequences of paleoenvironmental dynamics on the emergence of biodiversity gradients using a spatially explicit model of diversification coupled with paleoenvironmental and plate tectonic reconstructions. Contemporary climate is insufficient in explaining the PDD; instead, a simple model of diversification and temperature niche evolution coupled with paleoaridity constraints is successful in reproducing the variation in species richness and phylogenetic diversity seen repeatedly among plant and animal taxa, suggesting a prevalent role of paleoenvironmental dynamics in combination with niche conservatism. The model indicates that high biodiversity in Neotropical and Indomalayan moist forests is driven by complex macroevolutionary dynamics associated with mountain uplift. In contrast, lower diversity in Afrotropical forests is associated with lower speciation rates and higher extinction rates driven by sustained aridification over the Cenozoic. Our analyses provide a mechanistic understanding of the emergence of uneven diversity in tropical moist forests across 110 Ma of Earth’s history, highlighting the importance of deep-time paleoenvironmental legacies in determining biodiversity patterns.

Tropical and subtropical moist broadleaf forests, including evergreen tropical rain forests and wet seasonal forests (hereafter tropical moist forests), are the most species-rich terrestrial biome on the planet (1–3) and are most broadly distributed throughout the Amazon basin and Atlantic forest in the Neotropics, the Congo basin and Rift Mountains in the Afrotropics, and both mainland and archipelagic South and Southeast Asia in Indomalaya (4). While all three major tropical moist forest regions (hereafter Neotropics, Afrotropics, and Indomalaya) have an exceptionally high species diversity of plants and animals in comparison with other biomes, the total regional diversity (γ-diversity) and number of species that coexist locally (α-diversity) vary dramatically across continents (2). Specifically, moist forests in the Afrotropics typically harbor lower species diversity than the Neotropics and Indomalaya (5–9), leading the Afrotropics to be labeled as the “odd man out” (9). We refer to this phenomenon as pantropical diversity disparity (PDD). This pattern has been highlighted in several keystone taxa, such as palms (family Arecaceae), which—of roughly 2,500 species globally—have ∼1,200 species in Indomalaya and 800 species in the Neotropics but only 66 species in the Afrotropics (excluding Madagascar) (10, 11). Investigating the drivers of variation in species diversity in moist forests across continents could provide an alternative perspective for understanding the processes that have shaped extraordinary tropical diversity.Explanations for the PDD have been expressed in terms of both contemporary differences in carrying capacities between regions based on the distribution of key environmental variables (9, 12, 13) and historical differences in paleoenvironmental dynamics shaping the past distribution of tropical biomes (14–19) and patterns of diversification (20–22). Species diversity in tropical moist forests may be driven by contemporary climate conditions if energy and resource availability from high precipitation, temperature, and solar radiation facilitates a greater number of coexisting species (2, 23). These environmental features have been shown to explain significant variation in species diversity along a terrestrial latitudinal gradient (24), yet they also vary longitudinally between tropical regions (2) with, for example, the Afrotropics lacking analogous sites of aseasonal high precipitation found in the Neotropics and Indomalaya, which are among the most biodiverse in these regions (12). Tropical biomes in different regions also have had dramatically different paleoenvironmental histories, associated with distinct geological and climatic dynamics (2, 9, 14, 25), which may have driven variation in speciation, extinction, and dispersal rates between regions owing to dynamic patterns of fragmentation, connectivity, and habitat heterogeneity (25, 26). For example, previous paleoenvironmental reconstructions indicate that while moist forests in the Neotropics and Indomalaya have remained relatively constant in size since the Eocene, moist forests in the Afrotropics suffered a drastic reduction in area from the Miocene onward (14, 20), which is believed to have driven widespread extinction from range contractions (25, 27). Additionally, Afrotropical moist forests lay at the center of the African tectonic plate and therefore, lack the intersection of active orogeny at plate boundaries with terrestrial mesic equatorial habitat as seen in the Neotropical and Indomalayan regions, leading to the formation of the Andes in the Neotropics and the Himalayan and southwest Chinese mountain chains, as well as the Southeast Asian archipelago in Indomalaya (2, 15). Active orogeny has presented dynamic opportunities for ecological and allopatric speciation (19, 28, 29) and may explain the disparity in biodiversity among tropical regions.Drawing inferences about historical processes that have shaped the PDD has been challenging and restricted by the limited mechanistic understanding of ecological and evolutionary processes from correlative or comparative methods (30). Instead, by combining paleoenvironmental reconstructions with spatially explicit models of ecoevolutionary processes, simulation models offer a unique but largely underused resource (but see, for example, refs. 31–34) to directly explore the evolutionary mechanisms behind the origins of biodiversity patterns in silico (30, 34). In this study, we explored the origins of the PDD in three steps. First, we quantified the ubiquity of the PDD across a wide range of plant and animal taxa. We then tested whether contemporary climate conditions can explain variation in species diversity among continents using a correlative approach. Finally and most innovatively, we assessed the role of paleoenvironmental dynamics in driving pantropical biodiversity patterns using a spatially explicit simulation model of diversification coupled with a paleoenvironmental reconstruction of temperature, aridity, and plate tectonics over the past 110 Ma. Specifically, we explored how major changes in the paleoclimate and plate tectonics have shaped speciation and extinction rates throughout the Mesozoic and Cenozoic and the spatial distribution of phylogenetic diversity. We asked the following questions. 1) Are present-day climatic differences between continents sufficient to explain differences in species diversity? 2) Could deep-time environmental dynamics have driven the emergence of present-day diversity differences between regions? 3) How has spatial and temporal variation in speciation and extinction rates shaped spatial diversity patterns, and how have mountain building, island formation, global cooling, and aridification influenced these rates? 4) What is the deep-time signature of diversification and dispersal in spatial patterns of phylogenetic diversity?