Wnt-C59 arrests stemness and suppresses growth of nasopharyngeal carcinoma in mice by inhibiting the Wnt pathway in the tumor microenvironment

Wnt/β-catenin signaling is responsible for the generation of cancer stem cells (CSCs) in many human tumors, including nasopharyngeal carcinoma (NPC). Recent studies demonstrate that Wnt or PORCN inhibitor, Wnt-C59, inhibits tumor growth in MMTV-WNT1 transgenic mice. The effect of Wnt-C59 in human tumors is not clear. In this study, the NPC cell lines investigated manifest heterogeneous responses to Wnt-C59 treatment. Wnt-C59 decreased tumor growth of SUNE1 cells in mice immediately following the administration of Wnt-C59. Mice injected with HNE1 cells did not develop visible tumors after the treatment of Wnt-C59, while control mice developed 100% tumors. Wnt-C59 inhibited stemness properties of NPC cells in a dosage-dependent manner by arresting sphere formation in both HNE1 and SUNE1 cells. Thus, Wnt-C59 has the potential to eradicate CSCs in human tumors. Active β-catenin and Axin2 proteins were strongly expressed in stromal cells surrounding growing tumors, confirming the importance of Wnt signaling activities in the microenvironment being driving forces for cell growth. These novel findings confirm the ability of Wnt-C59 to suppress Wnt-driven undifferentiated cell growth in NPC. Both anti-Wnt signaling and anti-CSC approaches are feasible strategies in cancer therapy.published_or_final_versio

Endemic, endangered and evolutionarily significant: cryptic lineages in Seychelles' frogs (Anura: Sooglossidae)

Cryptic diversity corresponding with island of origin has been previously reported in the endemic, geographically restricted sooglossid frogs of the Seychelles archipelago. The evolutionary pattern behind this has not been fully explored, and given current amphibian declines and the increased extinction risk faced by island species, we sought to identify evolutionarily significant units (ESUs) to address conservation concerns for these highly threatened anurans. We obtained genetic data for two mitochondrial (mtDNA) and four nuclear (nuDNA) genes from all known populations of sooglossid frog (on the islands of Mahé, Praslin and Silhouette) for phylogenetic analyses and to construct nuDNA haplotype networks. Bayesian and maximum likelihood analyses of mtDNA support the monophyly and molecular differentiation of populations in all species that occur on multiple islands. Haplotype networks using statistical parsimony revealed multiple high-frequency haplotypes shared between islands and taxa, in addition to numerous geographically distinct (island-specific) haplotypes for each species. We consider each island-specific population of sooglossid frog as an ESU and advise conservation managers to do likewise. Furthermore, our results identify each island lineage as a candidate species, evidence for which is supported by analyses of mtDNA based on Bayesian Poisson tree processes, and independent analyses of mtDNA and nuDNA using the multispecies coalescent. Our findings add to the growing understanding of the biogeography and hidden diversity within this globally important region

High-latitude marginal reefs support fewer but bigger corals than their tropical counterparts

Anthropogenic impacts are typically detrimental to tropical coral reefs, but the effect of increasing environmental stress and variability on the size structure of coral communities remains poorly understood. This limits our ability to effectively conserve coral reef ecosystems because size specific dynamics are rarely incorporated. Our aim is to quantify variation in the size structure of coral populations across 20 sites along a tropical-to-subtropical environmental gradient on the east coast of Australia (~ 23 to 30°S), to determine how size structure changes with a gradient of sea surface temperature, turbidity, productivity and light levels. We use two approaches: 1) linear regression with summary statistics (such as median size) as response variables, a method frequently favoured by ecologists and 2) compositional functional regression, a novel method using entire size–frequency distributions as response variables. We then predict coral population size structure with increasing environmental stress and variability. Together, we find fewer but larger coral colonies in marginal reefs, where conditions are typically more variable and stressful, than in tropical reefs. Our model predicts that coral populations may become gradually dominated by larger colonies (> 148 cm2) with increasing environmental stress. Fewer but bigger corals suggest low survival of smaller corals, slow growth, and/or poor recruitment. This finding is concerning for the future of coral reefs, as it implies that current marginal populations, or future reefs in increasingly stressful environmental conditions may have low recovery potential. We highlight the importance of continuously monitoring changes to population structure over biogeographic scales

Chlorpromazine for schizophrenia: a Cochrane systematic review of 50 years of randomised controlled trials

BACKGROUND: Chlorpromazine (CPZ) remains one of the most common drugs used for people with schizophrenia worldwide, and a benchmark against which other treatments can be evaluated. Quantitative reviews are rare; this one evaluates the effects of chlorpromazine in the treatment of schizophrenia in comparison with placebo. METHODS: We sought all relevant randomised controlled trials (RCT) comparing chlorpromazine to placebo by electronic and reference searching, and by contacting trial authors and the pharmaceutical industry. Data were extracted from selected trials and, where possible, synthesised and random effects relative risk (RR), the number needed to treat (NNT) and their 95% confidence intervals (CI) calculated. RESULTS: Fifty RCTs from 1955–2000 were included with 5276 people randomised to CPZ or placebo. They constitute 2008 person-years spent in trials. Meta-analysis of these trials showed that chlorpromazine promotes a global improvement (n = 1121, 13 RCTs, RR 0.76 CI 0.7 to 0.9, NNT 7 CI 5 to 10), although a considerable placebo response is also seen. People allocated to chlorpromazine tended not to leave trials early in both the short (n = 945, 16 RCTs, RR 0.74 CI 0.5 to 1.1) and medium term (n = 1861, 25 RCTs, RR 0.79 CI 0.6 to 1.1). There were, however, many adverse effects. Chlorpromazine is sedating (n = 1242, 18 RCTs, RR 2.3 CI 1.7 to 3.1, NNH 6 CI 5 to 8), increases a person's chances of experiencing acute movement disorders, Parkinsonism and causes low blood pressure with dizziness and dry mouth. CONCLUSION: It is understandable why the World Health Organization (WHO) have endorsed and included chlorpromazine in their list of essential drugs for use in schizophrenia. Low- and middle-income countries may have more complete evidence upon which to base their practice compared with richer nations using recent innovations

Delayed diagnosis of intermittent mesenteroaxial volvulus of the stomach by computed tomography: a case report

10.1186/1752-1947-2-343Journal of Medical Case Reports234

Low oxygen tension primes aortic endothelial cells to the reparative effect of tissue-protective cytokines

Erythropoietin (EPO) has both erythropoietic and tissue-protective properties. The EPO analogues carbamylated EPO (CEPO) and pyroglutamate helix B surface peptide (pHBSP) lack the erythropoietic activity of EPO but retain the tissue-protective properties that are mediated by a heterocomplex of EPO receptor (EPOR) and the β common receptor (βCR). We studied the action of EPO and its analogues in a model of wound healing where a bovine aortic endothelial cells (BAECs) monolayer was scratched and the scratch closure was assessed over 24 h under different oxygen concentrations. We related the effects of EPO and its analogues on repair to their effect on BAECs proliferation and migration (evaluated using a micro-Boyden chamber). EPO, CEPO and pHBSP enhanced scratch closure only at lower oxygen (5%), while their effect at atmospheric oxygen (21%) was not significant. The mRNA expression of EPOR was doubled in 5% compared to 21% oxygen, and this was associated with increased EPOR assessed by immunofluorescence and Western blot. By contrast βCR mRNA levels were similar in 5% and 21% oxygen. EPO and its analogues increased both BAECs proliferation and migration, suggesting that both may be involved in the reparative process. The priming effect of low oxygen tension on the action of tissue-protective cytokines may be of relevance to vascular disease, including atherogenesis and restenosis

Observation of unidirectional backscattering-immune topological electromagnetic states

One of the most striking phenomena in condensed-matter physics is the quantum Hall effect, which arises in two-dimensional electron systems subject to a large magnetic field applied perpendicular to the plane in which the electrons reside. In such circumstances, current is carried by electrons along the edges of the system, in so-called chiral edge states (CESs). These are states that, as a consequence of nontrivial topological properties of the bulk electronic band structure, have a unique directionality and are robust against scattering from disorder. Recently, it was theoretically predicted that electromagnetic analogues of such electronic edge states could be observed in photonic crystals, which are materials having refractive-index variations with a periodicity comparable to the wavelength of the light passing through them. Here we report the experimental realization and observation of such electromagnetic CESs in a magneto-optical photonic crystal fabricated in the microwave regime. We demonstrate that, like their electronic counterparts, electromagnetic CESs can travel in only one direction and are very robust against scattering from disorder; we find that even large metallic scatterers placed in the path of the propagating edge modes do not induce reflections. These modes may enable the production of new classes of electromagnetic device and experiments that would be impossible using conventional reciprocal photonic states alone. Furthermore, our experimental demonstration and study of photonic CESs provides strong support for the generalization and application of topological band theories to classical and bosonic systems, and may lead to the realization and observation of topological phenomena in a generally much more controlled and customizable fashion than is typically possible with electronic systems

FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation

FUsed in Sarcoma (FUS) is a multifunctional RNA binding protein (RBP). FUS mutations lead to its cytoplasmic mislocalization and cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Here, we use mouse and human models with endogenous ALS-associated mutations to study the early consequences of increased cytoplasmic FUS. We show that in axons, mutant FUS condensates sequester and promote the phase separation of fragile X mental retardation protein (FMRP), another RBP associated with neurodegeneration. This leads to repression of translation in mouse and human FUS-ALS motor neurons and is corroborated in vitro, where FUS and FMRP copartition and repress translation. Last, we show that translation of FMRP-bound RNAs is reduced in vivo in FUS-ALS motor neurons. Our results unravel new pathomechanisms of FUS-ALS and identify a novel paradigm by which mutations in one RBP favor the formation of condensates sequestering other RBPs, affecting crucial biological functions, such as protein translation

The inner centromere is a biomolecular condensate scaffolded by the chromosomal passenger complex.

The inner centromere is a region on every mitotic chromosome that enables specific biochemical reactions that underlie properties, such as the maintenance of cohesion, the regulation of kinetochores and the assembly of specialized chromatin, that can resist microtubule pulling forces. The chromosomal passenger complex (CPC) is abundantly localized to the inner centromeres and it is unclear whether it is involved in non-kinase activities that contribute to the generation of these unique chromatin properties. We find that the borealin subunit of the CPC drives phase separation of the CPC in vitro at concentrations that are below those found on the inner centromere. We also provide strong evidence that the CPC exists in a phase-separated state at the inner centromere. CPC phase separation is required for its inner-centromere localization and function during mitosis. We suggest that the CPC combines phase separation, kinase and histone code-reading activities to enable the formation of a chromatin body with unique biochemical activities at the inner centromere

Association of dual decline in cognition and gait speed with risk of dementia in older adults

Importance Dual decline in gait speed and cognition has been found to be associated with increased dementia risk in previous studies. However, it is unclear if risks are conferred by a decline in domain-specific cognition and gait.Objective To examine associations between dual decline in gait speed and cognition (ie, global, memory, processing speed, and verbal fluency) with risk of dementia.Design, Setting, and Participants This cohort study used data from older adults in Australia and the US who participated in a randomized clinical trial testing low-dose aspirin between 2010 and 2017. Eligible participants in the original trial were aged 70 years or older, or 65 years or older for US participants identifying as African American or Hispanic. Data analysis was performed between October 2020 and November 2021Exposures Gait speed, measured at 0, 2, 4, and 6 years and trial close-out in 2017. Cognitive measures included Modified Mini-Mental State examination (3MS) for global cognition, Hopkins Verbal Learning Test-Revised (HVLT-R) for memory, Symbol Digit Modalities (SDMT) for processing speed, and Controlled Oral Word Association Test (COWAT-F) for verbal fluency, assessed at years 0, 1, 3, 5, and close-out. Participants were classified into 4 groups: dual decline in gait and cognition, gait decline only, cognitive decline only, and nondecliners. Cognitive decline was defined as membership of the lowest tertile of annual change. Gait decline was defined as a decline in gait speed of 0.05 m/s or greater per year across the study.Main Outcomes and Measures Dementia (using Diagnostic and Statistical Manual of Mental Disorders [Fourth Edition] criteria) was adjudicated by an expert panel using cognitive tests, functional status, and clinical records. Cox proportional hazard models were used to estimate risk of dementia adjusting for covariates, with death as competing risk.Results Of 19 114 randomized participants, 16 855 (88.2%) had longitudinal gait and cognitive data for inclusion in this study (mean [SD] age, 75.0 [4.4] years; 9435 women [56.0%], 7558 participants [44.8%] with 12 or more years of education). Compared with nondecliners, risk of dementia was highest in the gait plus HVLT-R decliners (hazard ratio [HR], 24.7; 95% CI, 16.3-37.3), followed by the gait plus 3MS (HR, 22.2; 95% CI, 15.0-32.9), gait plus COWAT-F (HR, 4.7; 95% CI, 3.5-6.3), and gait plus SDMT (HR, 4.3; 95% CI, 3.2-5.8) groups. Dual decliners had a higher risk of dementia than those with either gait or cognitive decline alone for 3MS and HVLT-R.Conclusions and Relevance Of domains examined, the combination of decline in gait speed with memory had the strongest association with dementia risk. These findings support the inclusion of gait speed in dementia risk screening assessments