Senescence is a widely appreciated tumour suppressive mechanism, which acts as a barrier to cancer development by arresting cell cycle progression in response to harmful stimuli. However, senescent ...cell accumulation becomes deleterious in aging and contributes to a wide range of age-related pathologies. Furthermore, senescence has beneficial roles and is associated with a growing list of normal physiological processes including wound healing and embryonic development. Therefore, the biological role of senescent cells has become increasingly nuanced and complex. The emergence of sophisticated, next-generation profiling technologies, such as single-cell RNA sequencing, has accelerated our understanding of the heterogeneity of senescence, with distinct final cell states emerging within models as well as between cell types and tissues. In order to explore data sets of increasing size and complexity, the senescence field has begun to employ machine learning (ML) methodologies to probe these intricacies. Most notably, ML has been used to aid the classification of cells as senescent, as well as to characterise the final senescence phenotypes. Here, we provide a background to the principles of ML tasks, as well as some of the most commonly used methodologies from both traditional and deep ML. We focus on the application of these within the context of senescence research, by addressing the utility of ML for the analysis of data from different laboratory technologies (microscopy, transcriptomics, proteomics, methylomics), as well as the potential within senolytic drug discovery. Together, we aim to highlight both the progress and potential for the application of ML within senescence research.
Melanocytes reside within the basal epidermis of human skin, and function to protect the skin from ultraviolet light through the production of melanin. Prolonged exposure of the skin to UV light can ...induce irreparable DNA damage and drive cells into senescence, a sustained cell cycle arrest that prevents the propagation of this damage. Senescent cells can also be detrimental and contribute to skin ageing phenotypes through their senescence-associated secretory phenotype. Senescent cells can act in both an autocrine and paracrine manner to produce widespread tissue inflammation and skin ageing. Recently, melanocytes have been identified as the main senescent cell population within the epidermis and have been linked to a variety of skin ageing phenotypes, such as epidermal thinning and the presence of wrinkles. However, the literature surrounding melanocyte senescence is limited and tends to focus on the role of senescence in the prevention of melanoma. Therefore, this review aims to explore the current understanding of the contribution of senescent melanocytes to human skin ageing.
Yap/Taz are well-established downstream effectors of the Hippo pathway, known to regulate organ size by directing proliferation and apoptosis. Although the functions of Yap/Taz have been extensively ...studied, little is known about their role in brain development. Here, through genetic ablation, we show that Yap/Taz are required for cerebellar morphogenesis. Yap/Taz deletion in neural progenitors causes defects in secondary fissure formation, leading to abnormal folia development. Although they seemed very likely to serve an important function in the development of cerebellar granule cell precursors, Yap/Taz are dispensable for their proliferation. Furthermore, Yap/Taz loss does not rescue the medulloblastoma phenotype caused by constitutively active Smoothened. Importantly, Yap/Taz are highly expressed in radial glia and play a crucial role in establishing the radial scaffold and cellular polarity of neural progenitors during embryogenesis. We found that Yap/Taz are necessary to establish and maintain junctional integrity of cerebellar neuroepithelium as prominent junction proteins are not maintained at the apical junction in the absence of Yap/Taz. Our study identifies a novel function of Yap/Taz in cerebellar foliation and finds that they are required to establish the radial glia scaffold and junctional stability.
•Yap/Taz are required for cerebellar morphogenesis by establishing the radial glia scaffold and cellular polarity.•Yap/Taz deletion causes abnormal folia development due to defects in secondary fissure formation.•Yap/Taz are dispensable for the proliferation of CGNPs and medulloblastoma caused by constitutively active Smoothened.•Yap/Taz are necessary to establish and maintain junctional integrity of the cerebellar neuroepithelium.
Senescence, a state of stable growth arrest, plays an important role in ageing and age‐related diseases in vivo. Although the INK4/ARF locus is known to be essential for senescence programmes, the ...key regulators driving p16 and ARF transcription remain largely underexplored. Using siRNA screening for modulators of the p16/pRB and ARF/p53/p21 pathways in deeply senescent human mammary epithelial cells (DS HMECs) and fibroblasts (DS HMFs), we identified EGR2 as a novel regulator of senescence. EGR2 expression is up‐regulated during senescence, and its ablation by siRNA in DS HMECs and HMFs transiently reverses the senescent phenotype. We demonstrate that EGR2 activates the ARF and p16 promoters and directly binds to both the ARF and p16 promoters. Loss of EGR2 down‐regulates p16 levels and increases the pool of p16− p21− ‘reversed’ cells in the population. Moreover, EGR2 overexpression is sufficient to induce senescence. Our data suggest that EGR2 is a direct transcriptional activator of the p16/pRB and ARF/p53/p21 pathways in senescence and a novel marker of senescence.
Deep senescence is reversible in normal adult human fibroblasts. Loss of early growth response 2 (EGR2) reverses epithelial and fibroblast senescence. EGR2 levels are up‐regulated in multiple models of senescence and prolonged expression of EGR2 induces fibroblast senescence. Early growth response 2 (EGR2) is a novel master transcriptional regulator of the INK/ARF locus and the senescence programme.
Land‐ocean dissolved organic matter (DOM) transport is a significant and changing term in global biogeochemical cycles which is increasing as a result of human perturbation, including land‐use ...change. Knowledge of the behavior and fate of transported DOM is lacking, particularly in the tropics and subtropics where land‐use change is occurring rapidly. We used Parallel Factor (PARAFAC) Analysis to investigate how land‐use influenced the composition of the DOM pool along a subtropical land‐use gradient (from near‐pristine broadleaf forest to agri‐urban settings) in Belize, Central America. Three humic‐like and two protein‐like components were identified, each of which was present across land uses and environments. Land‐use mapping identified a strong (R2 = 0.81) negative correlation between broadleaf forest and agri‐urban land. All PARAFAC components were positively associated with agri‐urban land‐use classes (cropland, grassland, and/or urban land), indicating that land‐use change from forested to agri‐urban exerts influence on the composition of the DOM pool. Humic‐like DOM exhibited linear accumulation with distance downstream and behaved conservatively in the coastal zone whilst protein‐like DOM exhibited nonlinear accumulation within the main river and nonconservative mixing in coastal waters, indicative of differences in reactivity. We used a hydrodynamic model to explore the potential of conservative humics to reach the region's environmentally and economically valuable coral reefs. We find that offshore corals experience short exposures (10 ± 11 days yr−1) to large (∼120%) terrigenous DOM increases, whilst nearshore corals experience prolonged exposure (113 ± 24 days yr−1) to relatively small (∼30%) terrigenous DOM increases.
Plain Language Summary
The transport of land‐derived dissolved organic matter into the oceans plays a substantial and important role in the global carbon and nutrient cycles. Land‐use change can alter the type and amount of material being transported, with widespread implications for downstream ecosystems. This is particularly true in the tropics and subtropics where land‐use change is occurring most rapidly, and where research into its effects is often lacking. We investigated whether land‐use had an effect on the type and amount of land‐derived material found in a subtropical river system that is experiencing a rapid conversion from forest to agricultural and urban land‐use. We found that streams draining agricultural and urban land contained more land‐derived material than those draining forested land, and that a substantial fraction of this material reached the coastal environment. We estimated the frequency with which this land‐derived material reached the region's environmentally and economically valuable coral reefs, and suggest that land‐use‐derived material reaches nearshore corals often and offshore corals rarely.
Key Points
A shift from broadleaf forest to agri‐urban land increased colored dissolved organic matter in the Belize River watershed
Humic‐like material increased in transit downstream and behaved conservatively in coastal waters, indicative of its recalcitrance
Land‐use change has increased terrigenous dissolved organic matter concentrations overlying Belize's coral reefs
Previous research examining the relationship between gender-role presentation and minority stress has largely focused on the negative effects of gender nonconformity. Some research suggests, however, ...that gender-role nonconformity may be protective against minority stress via participation in sexual minority in-group norms, which may include rejecting traditional gender-role norms and gender presentation. Historically, the meaning and value of masculinity and femininity within sexual minority communities has varied by race/ethnicity. As such, race/ethnicity may moderate the links between gender and minority stressors. This study used a diverse sample of sexual minority women (SMW) (
N
= 612) and separate indicators of masculinity and femininity to examine the effects of gender role on distal (victimization and discrimination) and proximal (internalized homophobia and stigma consciousness) measures of minority stress. We used multivariate generalized linear models to determine whether the effects of masculinity and femininity on the minority stress outcomes were moderated by race/ethnicity. We found that in many cases the relationships between masculinity and femininity and minority stress varied across racial/ethnic groups, and in fact, worked in opposite directions for White SMW compared to Black and Latina SMW. For example, our results showed that masculinity was associated with lower levels of victimization, discrimination, and stigma consciousness among Black and Latina SMW, but higher levels among White SMW. Results from this study suggest that these differences have important implications for exposure to minority stress.
According to the established model of murine innate lymphoid cell (ILC) development, helper ILCs develop separately from natural killer (NK) cells. However, it is unclear how helper ILCs and NK cells ...develop in humans. Here we elucidated key steps of NK cell, ILC2, and ILC3 development within human tonsils using ex vivo molecular and functional profiling and lineage differentiation assays. We demonstrated that while tonsillar NK cells, ILC2s, and ILC3s originated from a common CD34−CD117+ ILC precursor pool, final steps of ILC2 development deviated independently and became mutually exclusive from those of NK cells and ILC3s, whose developmental pathways overlapped. Moreover, we identified a CD34−CD117+ ILC precursor population that expressed CD56 and gave rise to NK cells and ILC3s but not to ILC2s. These data support a model of human ILC development distinct from the mouse, whereby human NK cells and ILC3s share a common developmental pathway separate from ILC2s.
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•Human NK cells, ILC2s, and ILC3s develop from tonsil CD34−CD117+ ILC precursors•A CD56+ subset of CD34−CD117+ precursors generates NK cells and ILC3s but not ILC2s•Human ILC development is distinct from the established murine model
Human innate lymphoid cells (ILCs) develop from tissue-resident ILC precursors (ILCPs) in secondary lymphoid tissues. Here, Chen et al. describe a model of human ILC development in tonsils in which NK cells and group 3 ILCs derive from a CD56+ subset of ILCPs that cannot differentiate into group 2 ILCs.
Background.In contrast to the wealth of data on human papillomavirus (HPV) infections in women, much less is known about HPV in men. Methods.Between June 2003 and March 2006, a total of 240 ...heterosexually active male university students 18–20 years of age were recruited for participation in a cohort study of HPV infection. Genital cell samples were collected, at 4-month intervals, for HPV-DNA analysis by polymerase chain reaction. The subjects maintained a Web-based journal of sexual activity. Results.At 24 months, the cumulative incidence of new infection of any genital HPV type was 62.4% (95% confidence interval CI, 52.6%–72.2%). Acquisition rates did not differ by genital site (i.e., glans, penile shaft, or scrotum) of initial detection (P = .86). The most commonly detected types were HPV-84 and HPV-16. In multivariate analysis, a report of a new sex partner during the prior 0–4 (hazards ratio HR, 2.0 95% CI, 1.3–3.0) and 5–8 (HR, 1.8 95% CI, 1.2–2.7) months and a history of smoking (HR, 1.6 95% CI, 1.1–2.4) were associated with an elevated risk of HPV acquisition. Conclusion.Genital HPV infection is common and multifocal in young men, and its incidence is higher than that reported for similar cohorts of young women. The high rates of HPV infection in men should be considered when strategies for the prevention of HPV infection in female adolescents and young women are being developed.
In recent decades, the ways in which sexual minorities identify have changed dramatically. In response, social and health surveys have begun offering a greater range of response options within sexual ...orientation questions—for example, intermediate categories for “mainly heterosexual” and “mainly lesbian/gay” alongside the more common response options of “heterosexual,” “bisexual,” and “lesbian/gay.” Recent studies indicate that women who identify as “mainly heterosexual” report poorer health, greater health-risk behaviors, and higher rates of victimization than women identifying as “exclusively heterosexual.” However, we know very little about the demographic profile of women who choose the “mainly heterosexual” identity label compared to the adjacent “exclusively heterosexual” or “bisexual” labels or about changes over time in the prevalence and correlates of “mainly heterosexual” identification. This study addressed these knowledge gaps by modeling unique, high-quality survey data from three national cohorts of Australian women (Australian Longitudinal Study on Women’s Health, 2000–2017,
n
= 76,930 observations). Consistent with the facilitative environments model, we document stark cross-cohort increases in the percentage of Australian women identifying as “mainly heterosexual”—from ∼1% of those born in 1946–1951 to ∼26% of those born in 1989–1995, coinciding with comparable declines in the percentage of women identifying as “exclusively heterosexual.” We also found evidence of cohort differences in the associations between key sociodemographic factors—such as age, education, and socioeconomic status—and the likelihood of women identifying as “mainly heterosexual.” Finally, our results indicate that same-sex sexual attractions were more strongly associated with “mainly heterosexual” identification than was same-sex sexual behavior.
Non-typeable
(NTHi) is a frequent cause of lower respiratory tract infection in people with chronic obstructive pulmonary disease (COPD). Pellino proteins are a family of E3 ubiquitin ligases that ...are critical regulators of TLR signaling and inflammation. The aim of this study was to identify a role for Pellino-1 in airway defense against NTHi in the context of COPD. Pellino-1 is rapidly upregulated by LPS and NTHi in monocyte-derived macrophages (MDMs) isolated from individuals with COPD and healthy control subjects, in a TLR4 dependent manner. C57BL/6
and wild-type (WT) mice were subjected to acute (single LPS challenge) or chronic (repeated LPS and elastase challenge) airway inflammation followed by NTHi infection. Both WT and
mice develop airway inflammation in acute and chronic airway inflammation models.
animals recruit significantly more neutrophils to the airway following NTHi infection which is associated with an increase in the neutrophil chemokine, KC, in bronchoalveolar lavage fluid as well as enhanced clearance of NTHi from the lung. These data suggest that therapeutic inhibition of Pellino-1 may augment immune responses in the airway and enhance bacterial clearance in individuals with COPD.
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