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Abstract Background Merkel cell carcinoma (MCC), a rare cutaneous neuroendocrine endocrine tumour is increasing in incidence, and continues to carry a poor prognosis. Objectives The objectives of this study were to examine all Irish cases of MCC from 1 January 1994 over 2 decades, focusing on gender and organ transplantation recipients (OTRs). Cases were identified from the National Cancer Registry of Ireland. Covariates of interest included age, body site, period of diagnosis, deprivation‐status and history of non‐melanoma skin cancer (NMSC). Results In total 314 MCC cases were identified. A female predominance was noted (53.8%). Comparison between age‐standardised rates between the earliest period (1994–1996) with the latest period (2012–2014) showed an increase of 105% in total. The trend in age‐standardised incidence rates were noted to be increasing significantly (p = 0.0004). Average age at diagnosis was 77.6 years (male 75.1 years, female 79.7 years). Overall, the majority of MCC cases presented on the head and neck (n = 170, 54.1%). Differences in anatomical location of MCCs were noted between genders. Males were found to be more likely to have a history of previous NMSCs (males n = 73 [57.9%], females n = 53 [42.1%]). Thirty‐one percentage of patients died from MCC, average survival was 3.5 years in those who died of this malignancy. Ten organ transplant recipients developed MCC. OTR who developed MCC were diagnosed at a younger average age of 65.1 years. Standardized incidence ratio for MCC in OTR was 59.96. A higher proportion of OTR died from MCC (70%), with a shorter median survival of 0.14 years. In competing risks regression, gender was not significantly associated with risk of dying, females having a non‐significantly higher hazard of dying. Organ transplant recipients and patients from less deprived areas were at greater risk of dying from MCC. Conclusions This population based study provides epidemiological, clinical and outcome data for MCC over a 20‐year period.

Abstract Background Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5 −/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5 −/y rats. Methods To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. Results Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5 −/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5 −/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. Conclusions Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. Limitations This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.

Abstract The parasite Toxoplasma gondii persists in its hosts by converting from replicating tachyzoites to latent bradyzoites housed in tissue cysts. The molecular mechanisms that mediate T. gondii differentiation remain poorly understood. Through a mutagenesis screen, we identified translation initiation factor eIF1.2 as a critical factor for T. gondii differentiation. A F97L mutation in eIF1.2 or the genetic ablation of eIF1.2 (∆eif1.2) markedly impeded bradyzoite cyst formation in vitro and in vivo. We demonstrated, at single-molecule level, that the eIF1.2 F97L mutation impacts the scanning process of the ribosome preinitiation complex on a model mRNA. RNA sequencing and ribosome profiling experiments unveiled that ∆eif1.2 parasites are defective in upregulating bradyzoite induction factors BFD1 and BFD2 during stress-induced differentiation. Forced expression of BFD1 or BFD2 significantly restored differentiation in ∆eif1.2 parasites. Together, our findings suggest that eIF1.2 functions by regulating the translation of key differentiation factors necessary to establish chronic toxoplasmosis.

ObjectiveCollege students showed a high prevalence of stress, anxiety, and depression, with medical and nursing students experiencing particularly elevated levels of mental health challenges.Optimism significantly influences overall well-being by promoting a healthy lifestyle and cognitive responses. However, the association of optimism with sleep quality, stress, and mental health in college students remains unexplored. This study aimed to (1) explore the associations of optimism with sleep quality, stress, and mental health and (2) ascertain whether sleep quality and stress mediate the association between optimism and mental health among college students.MethodsA cross-sectional study was conducted using online surveys with students from health science majors at a public university in the northeast United States from September to December 2022. A total of 222 students participated in the study, providing data on sociodemographics, optimism, sleep quality, stress, anxiety, and depression. Parallel and serial mediation models were utilized to examine the potential mediating roles of sleep quality and stress in the association between optimism and mental health.ResultsThe study found that optimism influences anxiety and depression through both direct and indirect pathways. In line with predictions, the parallel mediation analysis revealed that the impact of optimism on anxiety (βtotal = −0.598, 95% confident interval [CI]: −0.778 to −0.392) and depression (βtotal = −0.724, 95% CI: −0.919 to −0.519) was mediated by stress and sleep quality. Furthermore, the serial mediation models revealed that stress and sleep quality co-mediated the relationship betweenoptimism and anxiety (indirect effect [IE] = −0.074, 95% CI: −0.135 to −0.029) or depression (IE = −0.084, 95% CI: −0.142 to −0.036) in a sequential manner.ConclusionOptimism was negatively correlated with poor sleep quality, stress, anxiety, and depression. Enhanced optimism was linked to high sleep quality and less stress, anxiety, and depression. These insights emphasize the potential for school-based optimism interventions to improve sleep quality, ameliorate stress-related concerns, and alleviate mental health challenges in college students.

How histone modifications crosstalk with DNA methylation to regulate epigenomic patterning and genome stability in mammals remains elusive. Here, the authors show that DNA methyltransferase DNMT1 is a reader for histone H4K20 trimethylation via its BAH1 domain, which leads to optimal maintenance of DNA methylation at repetitive LINE-1 elements.

T regulatory (Treg) cells are essential for maintaining immune homeostasis, but how the stability of their lineage and function is regulated is unclear. Here the authors show that Ndfip1 is essential for suppressing Tregcell IL-4 production and metabolic alteration to preserve Treg lineage and function.

Ndfip1 is an activator of Itch E3 ubiquitin ligase that limits T cell activation. Here the authors identify Jak1 in a proteomic screen for Ndfip dependent substrates, and show that Ndfip1/2 double-deficient T cells have reduced degradation of Jak1 and as a result are hyper-responsive to cytokine stimulation.