PALMD (palmdelphin) belongs to the family of paralemmin proteins implicated in cytoskeletal regulation. Single nucleotide polymorphisms in the
locus that result in reduced expression are strong risk ...factors for development of calcific aortic valve stenosis and predict severity of the disease.
Immunodetection and public database screening showed dominant expression of PALMD in endothelial cells (ECs) in brain and cardiovascular tissues including aortic valves. Mass spectrometry, coimmunoprecipitation, and immunofluorescent staining allowed identification of PALMD partners. The consequence of loss of PALMD expression was assessed in small interferring RNA-treated EC cultures, knockout mice, and human valve samples. RNA sequencing of ECs and transcript arrays on valve samples from an aortic valve study cohort including patients with the single nucleotide polymorphism rs7543130 informed about gene regulatory changes.
ECs express the cytosolic
splice variant, which associated with RANGAP1 (RAN GTP hydrolyase activating protein 1). RANGAP1 regulates the activity of the GTPase RAN and thereby nucleocytoplasmic shuttling via XPO1 (Exportin1). Reduced PALMD expression resulted in subcellular relocalization of RANGAP1 and XPO1, and nuclear arrest of the XPO1 cargoes p53 and p21. This indicates an important role for PALMD in nucleocytoplasmic transport and consequently in gene regulation because of the effect on localization of transcriptional regulators. Changes in EC responsiveness on loss of
expression included failure to form a perinuclear actin cap when exposed to flow, indicating lack of protection against mechanical stress. Loss of the actin cap correlated with misalignment of the nuclear long axis relative to the cell body, observed in
-deficient ECs,
mouse aorta, and human aortic valve samples derived from patients with calcific aortic valve stenosis. In agreement with these changes in EC behavior, gene ontology analysis showed enrichment of nuclear- and cytoskeleton-related terms in
-silenced ECs.
We identify RANGAP1 as a PALMD partner in ECs. Disrupting the PALMD/RANGAP1 complex alters the subcellular localization of RANGAP1 and XPO1, and leads to nuclear arrest of the XPO1 cargoes p53 and p21, accompanied by gene regulatory changes and loss of actin-dependent nuclear resilience. Combined, these consequences of reduced
expression provide a mechanistic underpinning for PALMD's contribution to calcific aortic valve stenosis pathology.
Tumours depend on nutrients supplied by the host for their growth and survival. Modifications to the host's diet can change nutrient availability in the tumour microenvironment, which might represent ...a promising strategy for inhibiting tumour growth. Dietary modifications can limit tumour-specific nutritional requirements, alter certain nutrients that target the metabolic vulnerabilities of the tumour, or enhance the cytotoxicity of anti-cancer drugs. Recent reports have suggested that modification of several nutrients in the diet can alter the efficacy of cancer therapies, and some of the newest developments in this quickly expanding field are reviewed here. The results discussed indicate that the dietary habits and nutritional state of a patient must be taken into account during cancer research and therapy.
Roles for E-cadherin cell surface regulation in cancer Petrova, Yuliya I; Schecterson, Leslayann; Gumbiner, Barry M
Molecular biology of the cell,
2016-Nov-01, 2016-11-00, 20161101, Letnik:
27, Številka:
21
Journal Article
Recenzirano
Odprti dostop
The loss of E-cadherin expression in association with the epithelial-mesenchymal transition (EMT) occurs frequently during tumor metastasis. However, metastases often retain E-cadherin expression, an ...EMT is not required for metastasis, and metastases can arise from clusters of tumor cells. We demonstrate that the regulation of the adhesive activity of E-cadherin present at the cell surface by an inside-out signaling mechanism is important in cancer. First, we find that the metastasis of an E-cadherin-expressing mammary cell line from the mammary gland to the lung depends on reduced E-cadherin adhesive function. An activating monoclonal antibody to E-cadherin that induces a high adhesive state significantly reduced the number of cells metastasized to the lung without affecting the growth in size of the primary tumor in the mammary gland. Second, we find that many cancer-associated germline missense mutations in the E-cadherin gene in patients with hereditary diffuse gastric cancer selectively affect the mechanism of inside-out cell surface regulation without inhibiting basic E-cadherin adhesion function. This suggests that genetic deficits in E-cadherin cell surface regulation contribute to cancer progression. Analysis of these mutations also provides insights into the molecular mechanisms underlying cadherin regulation at the cell surface.
Abstract
In this work, novel two-dimensional BC
$$_2$$
2
X (X = N, P, As) monolayers with X atoms out of the B–C plane, are predicted by means of the density functional theory. The structural, ...electronic, optical, photocatalytic and thermoelectric properties of the BC
$$_2$$
2
X monolayers have been investigated. Stability evaluation of the BC
$$_2$$
2
X single-layers is carried out by phonon dispersion, ab-initio molecular dynamics (AIMD) simulation, elastic stability, and cohesive energies study. The mechanical properties reveal all monolayers considered are stable and have brittle nature. The band structure calculations using the HSE06 functional reveal that the BC
$$_2$$
2
N, BC
$$_2$$
2
P and BC
$$_2$$
2
As are semiconducting monolayers with indirect bandgaps of 2.68 eV, 1.77 eV and 1.21 eV, respectively. The absorption spectra demonstrate large absorption coefficients of the BC
$$_2$$
2
X monolayers in the ultraviolet range of electromagnetic spectrum. Furthermore, we disclose the BC
$$_2$$
2
N and BC
$$_2$$
2
P monolayers are potentially good candidates for photocatalytic water splitting. The electrical conductivity of BC
$$_2$$
2
X is very small and slightly increases by raising the temperature. Electron doping may yield greater electric productivity of the studied monolayers than hole doping, as indicated by the larger power factor in the n-doped region compared to the p-type region. These results suggest that BC
$$_2$$
2
X (X = N, P, As) monolayers represent a new promising class of 2DMs for electronic, optical and energy conversion systems.
A chemical-kinetic mechanism is presented that is designed to be used for autoignition, deflagrations, detonations, and diffusion flames of a number of different fuels. To keep the mechanism small, ...attention is restricted to pressures below about 100 atm, temperatures above about 1000 K, and equivalence ratios less than about 3 for the premixed systems, thereby excluding soot formation and low-temperature fuel–peroxide chemistry. Under these restrictions, hydrogen combustion is included with 21 steps among 8 chemical species, combustion of carbon monoxide with 30 steps among 11 species, methane, methanol, ethane, ethylene, and acetylene combustion with 134 steps among 30 species, and propane, propene, allene, and propyne combustion with 177 steps among 37 species. The mechanism has been extensively tested previously for all of these fuels except propane, propene, allene, and propyne. Tests are reported here for these last four fuels through comparisons with experiments and with predictions of other mechanisms for deflagration velocities and shock-tube ignition.
TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase I study (NCT02663518) evaluated the ...safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies.
Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR).
Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination,
= 35 and nivolumab combination,
= 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing.
TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.
Muc5b is required for airway defence Roy, Michelle G; Livraghi-Butrico, Alessandra; Fletcher, Ashley A ...
Nature (London),
01/2014, Letnik:
505, Številka:
7483
Journal Article
Recenzirano
Odprti dostop
Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus ...contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Adult mammalian central nervous system axons have intrinsically poor regenerative capacity, so axonal injury has permanent consequences. One approach to enhancing regeneration is to increase ...the axonal supply of growth molecules and organelles. We achieved this by expressing the adaptor molecule Protrudin which is normally found at low levels in non-regenerative neurons. Elevated Protrudin expression enabled robust central nervous system regeneration both in vitro in primary cortical neurons and in vivo in the injured adult optic nerve. Protrudin overexpression facilitated the accumulation of endoplasmic reticulum, integrins and Rab11 endosomes in the distal axon, whilst removing Protrudin’s endoplasmic reticulum localization, kinesin-binding or phosphoinositide-binding properties abrogated the regenerative effects. These results demonstrate that Protrudin promotes regeneration by functioning as a scaffold to link axonal organelles, motors and membranes, establishing important roles for these cellular components in mediating regeneration in the adult central nervous system.
Burnout in health care professionals could have serious negative consequences on quality of patient care, professional satisfaction and personal life. Our aim was to investigate the burnout ...prevalence, work and lifestyle factors potentially affecting burnout amongst European oncologists≤40 (YOs).
A survey was conducted using the validated Maslach Burnout Inventory (MBI) and additional questions exploring work/lifestyle factors. Statistical analyses were carried out to identify factors associated with burnout.
Total of 737 surveys (all ages) were collected from 41 European countries. Countries were divided into six regions. Results from 595 (81%) YOs were included (81% medical oncologists; 52% trainees, 62% women). Seventy-one percent of YOs showed evidence of burnout (burnout subdomains: depersonalization 50%; emotional exhaustion 45; low accomplishment 35%). Twenty-two percent requested support for burnout during training and 74% reported no hospital access to support services. Burnout rates were significantly different across Europe (P<0.0001). Burnout was highest in central European (84%) and lowest in Northern Europe (52%). Depersonalization scores were higher in men compared with women (60% versus 45% P=0.0001) and low accomplishment was highest in the 26–30 age group (P<0.01). In multivariable linear regression analyses, European region, work/life balance, access to support services, living alone and inadequate vacation time remained independent burnout factors (P<0.05).
This is the largest burnout survey in European Young Oncologists. Burnout is common amongst YOs and rates vary across Europe. Achieving a good work/life balance, access to support services and adequate vacation time may reduce burnout levels. Raising awareness, support and interventional research are needed.
Shaping the Future of Probiotics and Prebiotics Cunningham, Marla; Azcarate-Peril, M. Andrea; Barnard, Alan ...
Trends in microbiology (Regular ed.),
08/2021, Letnik:
29, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Recent and ongoing developments in microbiome science are enabling new frontiers of research for probiotics and prebiotics. Novel types, mechanisms, and applications currently under study have the ...potential to change scientific understanding as well as nutritional and healthcare applications of these interventions. The expansion of related fields of microbiome-targeted interventions, and an evolving landscape for implementation across regulatory, policy, prescriber, and consumer spheres, portends an era of significant change. In this review we examine recent, emerging, and anticipated trends in probiotic and prebiotic science, and create a vision for broad areas of developing influence in the field.
An expanding range of candidate probiotic species and prebiotic substrates is emerging to address newly elucidated data-driven microbial niches and host targets.Overlapping with, and adjacent to, the probiotic and prebiotic fields, new variants of microbiome-modulating interventions are developing, including synbiotics, postbiotics, microbial consortia, live biotherapeutic products, and genetically modified organisms, with renewed interest in polyphenols, fibres, and fermented foods.Personalised nutrition and precision medicine are beginning to influence the application of probiotics and prebiotics, with growing interest in modulation of microbial signatures of health and disease.Demand for probiotics and prebiotics across divergent product formats is driving innovation in quality assurance techniques to measure dose, viability, and structural and functional integrity.
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