Pygmy Chameleons of the genus Rhampholeon represent a moderately diverse, geographically circumscribed radiation, with most species (18 out of 19 extant taxa) limited to East Africa. The one ...exception is Rhampholeon spectrum, a species restricted to West-Central African rainforests. We set out to characterize the geographic basis of genetic variation in this disjunctly distributed Rhampholeon species using a combination of multilocus Sanger data and genomic sequences to explore population structure and range-wide phylogeographic patterns. We also employed demographic analyses and niche modeling to distinguish between alternate explanations to contextualize the impact of past geological and climatic events on the present-day distribution of intraspecific genetic variation. Phylogenetic analyses suggest that R. spectrum is a complex of five geographically delimited populations grouped into two major clades (montane vs. lowland). We found pronounced population structure suggesting that divergence and, potentially, speciation began between the late Miocene and the Pleistocene. Sea level changes during the Pleistocene climatic oscillations resulted in allopatric divergence associated with dispersal over an ocean channel barrier and colonization of Bioko Island. Demographic inferences and range stability mapping each support diversification models with secondary contact due to population contraction in lowland and montane refugia during the interglacial period. Allopatric divergence, congruent with isolation caused by geologic uplift of the East African rift system, the "descent into the Icehouse," and aridification of sub-Saharan Africa during the Eocene-Oligocene are identified as the key events explaining the population divergence between R. spectrum and its closely related sister clade from the Eastern Arc Mountains. Our results unveil cryptic genetic diversity in R. spectrum, suggesting the possibility of a species complex distributed across the Lower Guinean Forest and the Island of Bioko. We highlight the major element of species diversification that modelled today's diversity and distributions in most West-Central African vertebrates.
The ASPP (apoptosis-stimulating protein of p53) family of proteins can function in the nucleus to modulate the transcriptional activity of p53, with ASPP1 and ASPP2 contributing to the expression of ...apoptotic target genes. In this study, we describe a new function for cytoplasmic ASPP1 in controlling YAP (Yes-associated protein)/TAZ. ASPP1 can inhibit the interaction of YAP with LATS1 (large tumor suppressor 1), a kinase that phosphorylates YAP/TAZ and promotes cytoplasmic sequestration and protein degradation. This function of ASPP1 therefore enhances nuclear accumulation of YAP/TAZ and YAP/TAZ-dependent transcriptional regulation. The consequence of YAP/TAZ activation by ASPP1 is to inhibit apoptosis, in part through the down-regulation of Bim expression, leading to resistance to anoikis and enhanced cell migration. These results reveal a potential oncogenic role for cytoplasmic ASPP1, in contrast to the tumor-suppressive activity described previously for nuclear ASPP1.
A novel coronavirus (CoV), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 in Wuhan, China and has since spread as a global pandemic. Safe and effective vaccines ...are thus urgently needed to reduce the significant morbidity and mortality of Coronavirus Disease 2019 (COVID-19) disease and ease the major economic impact. There has been an unprecedented rapid response by vaccine developers with now over one hundred vaccine candidates in development and at least six having reached clinical trials. However, a major challenge during rapid development is to avoid safety issues both by thoughtful vaccine design and by thorough evaluation in a timely manner. A syndrome of “disease enhancement” has been reported in the past for a few viral vaccines where those immunized suffered increased severity or death when they later encountered the virus or were found to have an increased frequency of infection. Animal models allowed scientists to determine the underlying mechanism for the former in the case of Respiratory syncytial virus (RSV) vaccine and have been utilized to design and screen new RSV vaccine candidates. Because some Middle East respiratory syndrome (MERS) and SARS-CoV-1 vaccines have shown evidence of disease enhancement in some animal models, this is a particular concern for SARS-CoV-2 vaccines. To address this challenge, the Coalition for Epidemic Preparedness Innovations (CEPI) and the Brighton Collaboration (BC) Safety Platform for Emergency vACcines (SPEAC) convened a scientific working meeting on March 12 and 13, 2020 of experts in the field of vaccine immunology and coronaviruses to consider what vaccine designs could reduce safety concerns and how animal models and immunological assessments in early clinical trials can help to assess the risk. This report summarizes the evidence presented and provides considerations for safety assessment of COVID-19 vaccine candidates in accelerated vaccine development.
Ubiquitin-specific peptidase 42 (USP42) is a deubiquitylating enzyme that can target p53 and contribute to the stabilization of p53 in response to stress. We now show that USP42 can also regulate ...transcription independently of p53. USP42 co-localized with RNA polymerase II (RNA Pol II) in nuclear foci, bound to histone H2B, and deubiquitylated H2B. Depletion of USP42 increased H2B ubiquitylation at a model promoter and decreased both basal and induced transcription from a number of promoters. These results are consistent with a role for USP42 in regulating transcription by deubiquitylating histones.
Background: Ubiquitin modification of histones regulates gene expression.
Results: USP42 targets histone H2B at promoters, leading to decreased ubiquitylation. This correlates with the regulation of transcription driven by a number of transcription factors.
Conclusion: USP42 contributes to the modulation of transcription.
Significance: The identification of histone H2B as a target for USP42 extends our understanding of the factors that can regulate gene expression.
The p53 tumour suppressor protein is a transcription factor that prevents oncogenic progression by activating the expression of apoptosis and cell‐cycle arrest genes in stressed cells. The stability ...of p53 is tightly regulated by ubiquitin‐dependent degradation, driven mainly by the ubiquitin ligase MDM2. In this study, we have identified USP42 as a DUB that interacts with and deubiquitinates p53. USP42 forms a direct complex with p53 and controls level of ubiquitination during the early phase of the response to a range of stress signals. Although we do not find a clear role for USP42 in controlling either the basal or fully activated levels of p53, the function of USP42 is required to allow the rapid activation of p53‐dependent transcription and a p53‐dependent cell‐cycle arrest in response to stress. These functions of USP42 are likely to contribute to the repair and recovery of cells from mild or transient damage.
An RNAi screen identifies USP42 as a ubiquitin‐specific isopeptidase that stabilizes p53 under transient stress conditions, and selectively enhances p53 function in the induction of cell‐cycle arrest.
The study aims to combine the delivery of two anticancer drugs to target both proliferating cancer cells and dormant cancer stem cells (CSCs) present in colorectal cancer. Two drugs were selected and ...encapsulated in lipid nanocapsules: SN38, the active form of irinotecan, which is unstable in the plasma but active against replicating cells, and salinomycin, a highly toxic ionophore active against cancer stem cells that is not suitable for clinical use. Using an engineered medium that enhanced the ratio of CSCs in HCT116 cell cultures, we demonstrated by clonogenicity tests and in sphere assays that Salinomycin acts mainly on CSCs, while SN38 acts mainly on proliferating cancer cells. In a preclinical murine CRC model, encapsulation of both drugs in lipid nanocapsules reduced their toxicity, including hemolysis, and led to a higher survival than what was observed following treatment with single drugs or non-encapsulated drugs. Nanoparticles loaded with an anticancer drug and salinomycin were effective against the therapy-resistant dormant CSCs and cancer cells.
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Chromosomal instability (CIN), a feature of most adult neoplasms from their early stages onward, is a driver of tumorigenesis. However, several malignancy subtypes, including some triple-negative ...breast cancers, display a paucity of genomic aberrations, thus suggesting that tumor development may occur in the absence of CIN. Here we show that the differentiation status of normal human mammary epithelial cells dictates cell behavior after an oncogenic event and predetermines the genetic routes toward malignancy. Whereas oncogene induction in differentiated cells induces massive DNA damage, mammary stem cells are resistant, owing to a preemptive program driven by the transcription factor ZEB1 and the methionine sulfoxide reductase MSRB3. The prevention of oncogene-induced DNA damage precludes induction of the oncosuppressive p53-dependent DNA-damage response, thereby increasing stem cells' intrinsic susceptibility to malignant transformation. In accord with this model, a subclass of breast neoplasms exhibit unique pathological features, including high ZEB1 expression, a low frequency of TP53 mutations and low CIN.
Abstract Objectives The aim of this work was to evaluate the in vitro effect of chitosan (concentration and time of action) treatment on enamel de-remineralization behavior upon a pH cycling assay. ...Methods Different group of human tooth samples were exposed to de-remineralizing solutions of controlled pH using a random experimental design. Microhardness and phosphorus chemical analysis were employed to evaluate the loss of phosphorus from the samples. Optical coherence tomography (OCT) images were obtained for selected specimens in order to evaluate the degree of penetration of chitosan into enamel. Results Vickers microhardness results were higher for samples treated with chitosan for concentration between 2.5 mg/mL and 5.0 mg/mL and time of action between 60 s and 90 s. A maximum inhibition of mineral loss of 81% was obtained. Chemical analysis indicated lower net pohosphorus loss (net P loss) for samples treated with chitosan. Best results were obtained in the same conditions found out with microhardness measurements. Chitosan had little effect on the remineralization process. OCT results indicated a correlation of chitosan penetration with chitosan concentration. For chitosan concentrations of 2.5 g/mL and 5.0 g/mL the penetration was up to the dentin–enamel junction. Conclusions Chitosan interferes with the process of demineralization of the tooth enamel inhibiting the release of phosphorus in this laboratory study. Demineralization is influenced by the concentration and exposure time of the biopolymer to the enamel. Microhardness measurements may be used as an indication of mineral loss from tooth enamel. Additionally, OCT images support the idea that chitosan may act as a barrier against acid penetration, contributing to its demineralization inhibition.
To estimate the risk of sudden cardiac death (SCD) or sudden unexpected death (SUD) related to individual antipsychotics, a meta‐analysis of observational studies was performed. Adjusted odds ratio ...(OR) of SCD/SUD with 95% confidence intervals (CI) were extracted and pooled; heterogeneity was studied using Q statistic and I2 index, and its potential causes (e.g., hERG blockade potency) explored using meta‐regression. Two cohort (740,306 person‐years) and four case–control (2,557 cases; 17,670 controls) studies, investigating nine antipsychotics, were included. Compared with nonusers, the risk was increased for quetiapine (OR = 1.72, 95% CI: 1.33–2.23), olanzapine (OR = 2.04, 1.52–2.74), risperidone (OR = 3.04, 2.39–3.86), haloperidol (OR = 2.97, 1.59–5.54), clozapine (OR = 3.67, 1.94–6.94), and thioridazine (OR = 4.58, 2.09–10.05). Heterogeneity was found (Q = 20.0, P = 0.01; I2 = 60.0%), and the increasing mean hERG blockade potency (P = 0.01) accounted for 43% of this. The SCD/SUD risk differed between individual antipsychotics, and mean hERG blockade potency could be an explanatory factor. This should be considered when initiating antipsychotic treatment.
Plasma cytokines are useful indicators of the inflammatory response to vaccination, and can serve as potential biomarkers of the systemic reactogenicity and immunogenicity of vaccines. Measurement of ...cytokines in urine may represent a non-invasive alternative to the blood-based markers. To evaluate whether urinary cytokine levels can help predict vaccine responses to an AS01B-adjuvanted vaccine, we measured concentrations of 24 cytokines in the urine from 30 hepatitis B virus (HBV)-naïve adults following administration of AS01B-adjuvanted HBV surface antigen vaccine (NCT01777295). Levels post-dose 2 were compared with the levels measured following a single placebo (saline) injection, which was administered 1 month before the first vaccination in the same participants. Urine was collected at eight timepoints before or up to 1 week following each treatment. Urinary concentrations were normalized to creatinine levels, and paired with previously reported, participant-matched plasma levels, local and systemic reactogenicity scores, and antibody response magnitudes. Of the urine cytokine panel, only few analytes were detectable: IL-8, IL-18 and IL-6 receptor, each showing no clear changes after vaccination as compared to placebo administration, and MCP-1 (CCL2) and IP-10 (CXCL10), which displayed in most participants transient surges post-vaccination. Urine levels did not correlate with the matched plasma levels. Interestingly, urinary IP-10 levels at 1 day post-second vaccination were significantly correlated (P = 0.023) with the concurrent intensity scores of systemic reactogenicity, though not with the local reactogenicity scores or peak antibody responses. No significant correlations were detected for MCP-1. Altogether, most urinary cytokines have limited utility as a proxy for plasma cytokines to help predict the inflammatory response, the immunogenicity or the reactogenicity of AS01B-adjuvanted vaccine, with the possible exception of IP-10. The utility of urinary IP-10 as a potential complementary biomarker of systemic vaccine reactogenicity needs substantiation in larger studies.
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