842 research outputs found
Modeling Amyloid Beta Peptide Insertion into Lipid Bilayers
Inspired by recent suggestions that the Alzheimer's amyloid beta peptide (A
beta) can insert into cell membranes and form harmful ion channels, we model
insertion of the 40 and 42 residue forms of the peptide into cell membranes
using a Monte Carlo code which is specific at the amino acid level. We examine
insertion of the regular A-beta peptide as well as mutants causing familial
Alzheimer's disease, and find that all but one of the mutants change the
insertion behavior by causing the peptide to spend more simulation steps in
only one leaflet of the bilayer. We also find that A-beta 42, because of the
extra hydrophobic residues relative to A-beta 40, is more likely to adopt this
conformation than A-beta 40 in both wild-type and mutant forms. We argue
qualitatively why these effects happen. Here, we present our results and
develop the hypothesis that this partial insertion increases the probability of
harmful channel formation. This hypothesis can partly explain why these
mutations are neurotoxic simply due to peptide insertion behavior. We further
apply this model to various artificial A-beta mutants which have been examined
experimentally, and offer testable experimental predictions contrasting the
roles of aggregation and insertion with regard to toxicity of A-beta mutants.
These can be used through further experiments to test our hypothesis.Comment: 14 pages; 8 figures; 2nd revisio
Editorial: The translational and therapeutic potential of the tumor microenvironment in oral cancer
The role of icIL-1RA in keratinocyte senescence and development of the senescence-associated secretory phenotype
There is compelling evidence that senescent cells, through the
senescence-associated secretory phenotype (SASP), can promote
malignant transformation and invasion. Interleukin-1 (IL-1) is a key
mediator of this cytokine network, but the control of its activity in the
senescence programme has not been elucidated. IL-1 signalling is
regulated by IL-1RA, which has four variants. Here, we show that
expression of intracellular IL-1RA type 1 (icIL-1RA1), which
competitively inhibits binding of IL-1 to its receptor, is progressively
lost during oral carcinogenesis ex vivo and that the pattern of
expression is associated with keratinocyte replicative fate in vitro. We
demonstrate that icIL-1RA1 is an important regulator of the SASP in
mortal cells, as CRISPR/Cas9-mediated icIL-1RA1 knockdown in
normal and mortal dysplastic oral keratinocytes is followed by
increased IL-6 and IL-8 secretion, and rapid senescence following
release from RhoA-activated kinase inhibition. Thus, we suggest that
downregulation of icIL-1RA1 in early stages of the carcinogenesis
process can enable the development of a premature and deregulated
SASP, creating a pro-inflammatory state in which cancer is more likely
to arise.A scholarship from Becas Chile, Comisión Nacional de Investigación Cientı́fica y Tecnológicahttps://journals.biologists.com/jcsam2022Oral Pathology and Oral Biolog
Calmodulin interacts with angiotensin-converting enzyme-2 (ACE2) and inhibits shedding of its ectodomain
AbstractAngiotensin-converting enzyme-2 (ACE2) is a regulatory protein of the renin–angiotensin system (RAS) and a receptor for the causative agent of severe-acute respiratory syndrome (SARS), the SARS-coronavirus. We have previously shown that ACE2 can be shed from the cell surface in response to phorbol esters by a process involving TNF-α converting enzyme (TACE; ADAM17). In this study, we demonstrate that inhibitors of calmodulin also stimulate shedding of the ACE2 ectodomain, a process at least partially mediated by a metalloproteinase. We also show that calmodulin associates with ACE2 and that this interaction is decreased by calmodulin inhibitors
The role of HOX genes in head and neck squamous cell carcinoma
Recent decades have witnessed the publication of numerous studies reporting alterations in the
genome and transcriptome of head and neck squamous cell carcinoma (HNSCC). Currently, the
utilisation of these alterations as biomarkers and targets for therapy are limited and new, useful
molecular characteristics are being sought. Many of the published HNSCC gene expression profiles
demonstrate alterations in the expression of HOX genes. These are a family of Homeobox
containing genes which are involved in developmental patterning and morphogenesis in the embryo,
and which are often aberrantly expressed in cancer. The 39 HOX genes found in the human genome
are arranged in 4 paralogous groups at different chromosomal loci. These control a wide range of
cellular processes, including proliferation and migration, which are relevant in the context of cancer
development. In this review article we will outline the biology of HOX genes in relation to cancer
and summarise the accumulating evidence for their role in the development of HNSCC and the
possibility that they could be a therapeutic target in this malignancy. We will also identify areas
where our current understanding is weak in order to focus future work and appraise the ongoing
strategies for pharmacological intervention.http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1600-07142017-04-30hb2016Oral Pathology and Oral Biolog
Challenges and directions in studying cell-cell communication by extracellular vesicles
Extracellular vesicles (EVs) are increasingly recognized as important mediators of intercellular communication. They have important roles in numerous physiological and pathological processes, and show considerable promise as novel biomarkers of disease, as therapeutic agents and as drug delivery vehicles. Intriguingly, however, understanding of the cellular and molecular mechanisms that govern the many observed functions of EVs remains far from comprehensive, at least partly due to technical challenges in working with these small messengers. Here, we highlight areas of consensus as well as contentious issues in our understanding of the intracellular and intercellular journey of EVs: from biogenesis, release and dynamics in the extracellular space, to interaction with and uptake by recipient cells. We define knowledge gaps, identify key questions and challenges, and make recommendations on how to address these
Boundary Conditions for Interacting Membranes
We investigate supersymmetric boundary conditions in both the Bagger-Lambert
and the ABJM theories of interacting membranes. We find boundary conditions
associated to the fivebrane, the ninebrane and the M-theory wave. For the ABJM
theory we are able to understand the enhancement of supersymmetry to produce
the (4,4) supersymmetry of the self-dual string. We also include supersymmetric
boundary conditions on the gauge fields that cancel the classical gauge anomaly
of the Chern-Simons terms.Comment: 36 pages, latex, v2 minor typos correcte
Impact of socioeconomic deprivation on rate and cause of death in severe mental illness
Background:
Socioeconomic status has important associations with disease-specific mortality in the general population. Although individuals with Severe Mental Illnesses (SMI) experience significant premature mortality, the relationship between socioeconomic status and mortality in this group remains under investigated.<p></p>
Aims:
To assess the impact of socioeconomic status on rate and cause of death in individuals with SMI (schizophrenia and bipolar disorder) relative to the local (Glasgow) and wider (Scottish) populations.<p></p>
Methods:
Cause and age of death during 2006-2010 inclusive for individuals with schizophrenia or bipolar disorder registered on the Glasgow Psychosis Clinical Information System (PsyCIS) were obtained by linkage to the Scottish General Register Office (GRO). Rate and cause of death by socioeconomic status, measured by Scottish Index of Multiple Deprivation (SIMD), were compared to the Glasgow and Scottish populations.<p></p>
Results:
Death rates were higher in people with SMI across all socioeconomic quintiles compared to the Glasgow and Scottish populations, and persisted when suicide was excluded. Differences were largest in the most deprived quintile (794.6 per 10,000 population vs. 274.7 and 252.4 for Glasgow and Scotland respectively). Cause of death varied by socioeconomic status. For those living in the most deprived quintile, higher drug-related deaths occurred in those with SMI compared to local Glasgow and wider Scottish population rates (12.3% vs. 5.9%, p = <0.001 and 5.1% p = 0.002 respectively). A lower proportion of deaths due to cancer in those with SMI living in the most deprived quintile were also observed, relative to the local Glasgow and wider Scottish populations (12.3% vs. 25.1% p = 0.013 and 26.3% p = <0.001). The proportion of suicides was significantly higher in those with SMI living in the more affluent quintiles relative to Glasgow and Scotland (54.6% vs. 5.8%, p = <0.001 and 5.5%, p = <0.001).
Discussion and conclusions:
Excess mortality in those with SMI occurred across all socioeconomic quintiles compared to the Glasgow and Scottish populations but was most marked in the most deprived quintiles when suicide was excluded as a cause of death. Further work assessing the impact of socioeconomic status on specific causes of premature mortality in SMI is needed
Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis
Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two. Analysis of CAF cultured ex vivo, showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. In vitro, we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-? signaling. Similar to TGF-?1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which differentially promote tumor cell invasion. Notably, second harmonic generation imaging and bioinformatic analysis of SMA-positive human HNSCC and EAC showed that collagen fiber organization correlates with poor prognosis, indicating that heterogeneity within the SMA-positive CAF population differentially impacts on survival. These results show that non-fibrogenic, SMA-positive myofibroblasts can be directly generated through induction of fibroblast senescence and suggest that senescence and myofibroblast differentiation are closely linked processes
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