Cell Signaling Pathways

Neural crest cells (NCCs) are a multipotent, migratory cell population that generates an astonishingly diverse array of cell types during vertebrate development. The trunk neural crest has long been considered of particular significance. First, it has been held that the trunk neural crest has a morphogenetic role, acting to coordinate the development of the peripheral nervous system, secretory cells of the endocrine system and pigment cells of the skin. Second, the trunk neural crest additionally has skeletal potential. However, it has been demonstrated that a key role of the trunk neural crest streams is to organize the innervation of the intestine. Although trunk NCCs have a limited capacity for self-renewal, sometimes they become neural-crest-derived tumor cells and reveal the fact that that NCCs and tumor cells share the same molecular machinery. In this review we describe the routes taken by trunk NCCs and consider the signals and cues that pattern these trajectories. We also d...

Non-small cell lung cancer (NSCLC) is the most common and prevalent subtype of lung cancer and continues to be one of the leading causes of cancer-related deaths worldwide. Despite various treatment options, a majority of NSCLC patients continue to experience disease progression and associated side effects, which are largely attributed to drug resistance, indicating the need for alternative strategies to combat this deadly disease. Among various applicable alternative approaches, repurposed drugs such as arsenic compounds have been shown to exert anticarcinogenic properties against NSCLC and possess the ability to overcome drug resistance mechanisms. Notably, numerous studies have demonstrated that the antitumor effects of arsenic compounds such as arsenic trioxide, arsenic sulfide, and tetra arsenic hexoxide are mediated via their ability to target several oncogenic signaling pathways, including nuclear factor-kappa B (NF-kB), epidermal growth factor receptor (EGFR), and signal transducer and activator of transcription 3 (STAT3). Inhibition of such signaling cascades results in altered cellular activities, including cell cycle arrest, decreased proliferation, and increased apoptosis. Importantly, these arsenic compounds have also been shown to overcome tumor resistance mechanisms and/or exert synergy in combination with other therapeutic agents resulting in the augmentation of cancer cell cytotoxicity. This review highlights the anticarcinogenic mechanisms of arsenic compounds and their impact on the efficacy of therapeutic agents.

Long-term treatment of cancer with chemotherapeutics leads to the development of resistant forms that reduce treatment options. The main associated mechanism is the overexpression of transport proteins, particularly P-glycoprotein (P-gp, ABCB1). In this study, we have tested the anticancer and multidrug resistance (MDR) modulation activity of 15 selenocompounds. Out of the tested compounds, K3, K4, and K7 achieved the highest sensitization rate in ovarian carcinoma cells (HOC/ ADR) that are resistant to the action of the Adriamycin. These compounds induced oxidation stress, inhibited P-gp transport activity and altered ABC gene expression. To verify the effect of compounds, 3D cell models were used to better mimic in vivo conditions. K4 and K7 triggered the most significant ROS release. All selected selenoesters inhibited P-gp efflux in a dose-dependent manner while simultaneously altering the expression of the ABC genes, especially P-gp in paclitaxel-resistant breast carcinoma cells (MCF-7/PAX). K4, and K7 demonstrated sensitization potential in resistant ovarian spheroids. Additionally, all selected selenoesters achieved a high cytotoxic effect in 3D breast and ovarian models, which was comparable to that in 2D cultures. K7 was the only non-competitive P-gp inhibitor, and therefore appears to have considerable potential for the treatment of drug-resistant cancer. Cancer is the second most common global cause of death behind cardiovascular disease. In 2020, Global Cancer Observatory (GCO) reported that nearly 2.3 million women were diagnosed with breast cancer (BC) and around 314,000 with ovarian cancer (OC) 1 . During the treatment process, some tumours activate specific cellular mechanisms by which their cells acquire the ability to develop resistances to multiple drugs, what is known as multidrug resistance (MDR) 2 . The pathogenesis of MDR in cancer is highly complex and involves several factors. The main mechanism associated with MDR development appears to be overexpression of genes encoding the transport proteins (ABC) affecting the concentrations of chemotherapeutics in tumours 3 . ATP-binding cassettes (ABCs) represent a superfamily of efflux proteins that utilize the energy from ATP hydrolysis to transport specific molecules. So far, 48 human ABC transporters, grouped into 7 subfamilies (ABCA-ABCG), form the human ABC superfamily 4 . Their primary function is associated with the translocation of several substrates across the plasma membrane, including glycolipids, phospholipids, steroids, and xenobiotics.

Cellular stress responses are mediated through conserved signaling pathways that translate external and internal perturbations into adaptive molecular programs. Although the components of these pathways are well characterised, less attention has been given to the intrinsic limits of their signaling capacity. Existing models often assume a proportional relationship between stress intensity and signaling output; however, biochemical constraints suggest that stress signaling is subject to saturation. This paper proposes a conceptual framework in which cellular stress pathways exhibit finite signaling capacity, resulting in qualitative changes in cellular outcomes once saturation thresholds are exceeded. By synthesising evidence from receptor kinetics, signal transduction cascades, and transcriptional regulation, this model provides a systems-level explanation for why mild stress promotes adaptation, whereas excessive stress leads to dysregulation or cell death. This work is theoretical in nature and does not present original experimental data. The framework is intended to organise existing observations and guide future experimental investigation.

Genome instability of cancer cells translates into increased entropy and lower information processing capacity, leading to metabolic reprograming toward higher energy states, presumed to be aligned with a cancer growth imperative. Dubbed as the cell adaptive fitness, the proposition postulates that the coupling between cell signaling and metabolism constrains cancer evolutionary dynamics along trajectories privileged by the maintenance of metabolic sufficiency for survival. In particular, the conjecture postulates that clonal expansion becomes restricted when genetic alterations induce a sufficiently high level of disorder, that is, high entropy, in the regulatory signaling network, abrogating as a result the ability of cancer cells to successfully replicate, leading to a stage of clonal stagnation. The proposition is analyzed in the context of an in-silico model of tumor evolutionary dynamics to illustrate how cell-inherent adaptive fitness may predictably constrain clonal evolution of tumors, which would have significant implications for the design of adaptive cancer therapies.

Heptahelical G protein-coupled receptors (GPCR) comprise a large family of integral membrane proteins involved in a wide array of cell signaling pathways. For high resolution structural studies of these receptors, multi-milligram quantities of pure and structurally unperturbed proteins are required. Purification of recombinant GPCRs typically involves their solubilization into detergent micelles followed by chromatographic purification. Because of relatively low expression levels of these recombinant receptors, it is challenging to design an efficient strategy for selective and efficient purification with high yield. Here, we describe a recently introduced purification system employing a high affinity molecular switch based on fragment complementation, with a calcium dependent capture and EDTA mediated chelation elution. This technique was successfully applied to the purification of the recombinant cannabinoid receptor CB2, a promising target for the development of drugs for inflamm...

Aberrant activation of Wnt/β-catenin signaling, frequently caused by oncogenic mutations, plays a crucial role in the development, progression, and therapy resistance of gastric, esophageal, hepatic, pancreatic, and colorectal cancers. Concurrently, circular RNAs (cir-cRNAs), produced by back-splicing of precursor mRNAs (pre-mRNAs), have emerged as critical modulators of this pathway. Accumulating evidence indicates that specific circRNAs regulate Wnt/β-catenin signaling by sponging microRNAs, interacting with RNA-binding proteins, modulating protein function, and altering the expression of pathway components. Some circRNAs are also subject to feedback regulation by Wnt signaling itself. Clinically, tumor-associated circRNAs are present in body fluids and correlate with disease stage, metastatic burden, and patient survival, underscoring their potential as early and minimally invasive biomarkers. Moreover, targeting oncogenic circRNAs has shown promise in preclinical models of Wnt-driven gastrointestinal malignancies. In this review, we summarize the current understanding of the interplay between circRNAs and Wnt/β-catenin signaling in gastric and esophageal cancers. We also discuss the translational challenges and emerging opportunities for biomarker development and targeted therapy. CITE AS: Chmielewski, P. P., et al. (2025). Wnt Signaling and Circular RNAs in Esophageal and Gastric Cancers: Opportunities for Early Detection and Targeted Therapy. Journal of Clinical Medicine, 14(13), 4805. https://doi.org/10.3390/jcm14134805

Human offspring are weaned earlier than the offspring of other great apes but take longer to reach nutritional independence. An analysis of human disorders of imprinted genes suggests genes of paternal origin, expressed in infants, have been selected to favor more intense suckling than genes of maternal origin. The same analysis suggests that genes of maternal origin may favor slower childhood growth but earlier sexual maturation. These observations are consistent with a hypothesis in which slow maturation was an adaptation of offspring that reduced maternal fitness, whereas early weaning was an adaptation of mothers that reduced the fitness of individual offspring.

Surface colonization allows diatoms, a dominant group of phytoplankton in oceans, to adapt to harsh marine environments while mediating biofoulings to human-made underwater facilities. The regulatory pathways underlying diatom surface colonization, which involves morphotype switching in some species, remain mostly unknown. Here, we describe the identification of 61 signaling genes, including G-protein-coupled receptors (GPCRs) and protein kinases, which are differentially regulated during surface colonization in the model diatom species, Phaeodactylum tricornutum. We show that the transformation of P. tricornutum with constructs expressing individual GPCR genes induces cells to adopt the surface colonization morphology. P. tricornutum cells transformed to express GPCR1A display 30% more resistance to UV light exposure than their nonbiofouling wild-type counterparts, consistent with increased silicification of cell walls associated with the oval biofouling morphotype. Our results provide a mechanistic definition of morphological shifts during surface colonization and identify candidate target proteins for the screening of eco-friendly, antibiofouling molecules.

Increasing numbers of reports have revealed novel catalytically active cryptic guanylate cyclases (GCs) and adenylate cyclases (ACs) operating within complex proteins in prokaryotes and eukaryotes. Here we review the structural and functional aspects of some of these cyclases and provide examples that illustrate their roles in the regulation of the intramolecular functions of complex proteins, such as the phytosulfokine receptor (PSKR), and reassess their contribution to signal generation and tuning. Another multidomain protein, Arabidopsis thaliana K+ uptake permease (AtKUP5), also harbors multiple catalytically active sites including an N-terminal AC and C-terminal phosphodiesterase (PDE) with an abscisic acid-binding site. We argue that this architecture may enable the fine-tuning and/or sensing of K+ flux and integrate hormone responses to cAMP homeostasis. We also discuss how searches with motifs based on conserved amino acids in catalytic centers led to the discovery of GCs and ACs and propose how this approach can be applied to discover hitherto masked active sites in bacterial, fungal, and animal proteomes. Finally, we show that motif searches are a promising approach to discover ancient biological functions such as hormone or gas binding.

The liver is an organ susceptible to a multitude of injuries that causes liver damage, like steatosis, non-alcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, and ischemia-reperfusion injury. Extra virgin olive oil (EVOO), presents several protective effects on the liver, reducing hepatic steatosis, hepatocyte ballooning, fibrogenesis, preventing lipid peroxidation, among other effects. Due to its high levels of monounsaturated fatty acids, mainly oleic acid and phenolic compounds, such as hydroxytyrosol and oleuropein, EVOO is able to participate in the activation of different signaling pathways in the hepatocytes involved in the prevention of inflammation, oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and insulin resistance, allowing the prevention or resolution of liver damage. The aim of this work is to offer an update of the molecular effects of EVOO in the liver and its protective properties to prevent the establishment of liver damage ...

In the developing organism, complex molecular programs orchestrate the generation of cells in adequate numbers, drive them to migrate along the correct pathways towards appropriate territories, eliminate superfluous cells, and induce terminal differentiation of survivors into the appropriate cell-types. Despite strict controls constraining developmental processes, malignancies can emerge in still immature organisms. This is the case of neuroblastoma (NB), a highly heterogeneous disease, predominantly affecting children before the age of 5 years. Highly metastatic forms represent half of the cases and are diagnosed when disseminated foci are detectable. NB arise from a transient population of embryonic cells, the neural crest (NC), and especially NC committed to the establishment of the sympatho-adrenal tissues. The NC is generated at the dorsal edge of the neural tube (NT) of the vertebrate embryo, under the action of NC specifier gene programs. NC cells (NCCs) undergo an epithelial to mesenchymal transition, and engage on a remarkable journey in the developing embryo, contributing to a plethora of cell-types and tissues. Various NCC sub-populations and derived lineages adopt specific migratory behaviors, moving individually as well as collectively, exploiting the different embryonic substrates they encounter along their path. Here we discuss how the specific features of NCC in development are reiterated during NB metastatic behaviors.

Foetal bovine serum (FBS) is often the serum supplement of choice for in vitro human cell culture. This study compares the effect of FBS and autologous human serum (AuHS) supplement in human peripheral blood mononuclear cell (PBMC) culture to prepare secretome. The PBMC (n = 7) were cultured either in RPMI-1640 containing L-glutamine and 50 units/ml Penicillin-Streptomycin (BM) or in BM with either AuHS or FBS. Viability, proliferation and differentiation of PBMC were evaluated. Paracrine factors present in the secretomes (n = 6) were analysed using ProcartaPlex Human Cytokine panel (17 plex). Ingenuity Pathway Analysis (IPA) was performed to predict activation or inhibition of biological functions related to tissue regeneration. The viability of PBMC that were cultured with FBS supplement was significantly reduced at 96 h compared to those at 0 and 24 h (P < .05). While the reduction of the viability of PBMC that were cultured with AuHS supplement was not significantly different...

The liver is an organ susceptible to a multitude of injuries that causes liver damage, like steatosis, non-alcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, and ischemia-reperfusion injury. Extra virgin olive oil (EVOO), presents several protective effects on the liver, reducing hepatic steatosis, hepatocyte ballooning, fibrogenesis, preventing lipid peroxidation, among other effects. Due to its high levels of monounsaturated fatty acids, mainly oleic acid and phenolic compounds, such as hydroxytyrosol and oleuropein, EVOO is able to participate in the activation of different signaling pathways in the hepatocytes involved in the prevention of inflammation, oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and insulin resistance, allowing the prevention or resolution of liver damage. The aim of this work is to offer an update of the molecular effects of EVOO in the liver and its protective properties to prevent the establishment of liver damage ...

Background: H. sapiens-M. tuberculosis H37Rv protein-protein interaction (PPI) data are essential for understanding the infection mechanism of the formidable pathogen M. tuberculosis H37Rv. Computational prediction is an important strategy to fill the gap in experimental H. sapiens-M. tuberculosis H37Rv PPI data. Homology-based prediction is frequently used in predicting both intra-species and inter-species PPIs. However, some limitations are not properly resolved in several published works that predict eukaryote-prokaryote inter-species PPIs using intra-species template PPIs. Results: We develop a stringent homology-based prediction approach by taking into account (i) differences between eukaryotic and prokaryotic proteins and (ii) differences between inter-species and intra-species PPI interfaces. We compare our stringent homology-based approach to a conventional homology-based approach for predicting host-pathogen PPIs, based on cellular compartment distribution analysis, disease gene list enrichment analysis, pathway enrichment analysis and functional category enrichment analysis. These analyses support the validity of our prediction result, and clearly show that our approach has better performance in predicting H. sapiens-M. tuberculosis H37Rv PPIs. Using our stringent homology-based approach, we have predicted a set of highly plausible H. sapiens-M. tuberculosis H37Rv PPIs which might be useful for many of related studies. Based on our analysis of the H. sapiens-M. tuberculosis H37Rv PPI network predicted by our stringent homology-based approach, we have discovered several interesting properties which are reported here for the first time. We find that both host proteins and pathogen proteins involved in the host-pathogen PPIs tend to be hubs in their own intra-species PPI network. Also, both host and pathogen proteins involved in host-pathogen PPIs tend to have longer primary sequence, tend to have more domains, tend to be more hydrophilic, etc. And the protein domains from both host and pathogen proteins involved in host-pathogen PPIs tend to have lower charge, and tend to be more hydrophilic. Conclusions: Our stringent homology-based prediction approach provides a better strategy in predicting PPIs between eukaryotic hosts and prokaryotic pathogens than a conventional homology-based approach. The properties we have observed from the predicted H. sapiens-M. tuberculosis H37Rv PPI network are useful for understanding inter-species host-pathogen PPI networks and provide novel insights for host-pathogen interaction studies. Reviewers: This article was reviewed by Michael Gromiha, Narayanaswamy Srinivasan and Thomas Dandekar.

The "integrated diagnosis" for infiltrating gliomas in the 2016 revised World Health Organization (WHO) classification of tumors of the central nervous system requires assessment of the tumor for IDH mutations and 1p/19q codeletion. Since TERT promoter mutations and ATRX alterations have been shown to be associated with prognosis, we analyzed whether these tumor markers provide additional prognostic information within each of the five WHO 2016 categories. We used data for 1206 patients from the UCSF Adult Glioma Study, the Mayo Clinic and The Cancer Genome Atlas (TCGA) with infiltrative glioma, grades II-IV for whom tumor status for IDH, 1p/19q codeletion, ATRX, and TERT had been determined. All cases were assigned to one of 5 groups following the WHO 2016 diagnostic criteria based on their morphologic features, and IDH and 1p/19q codeletion status. These groups are: (1) Oligodendroglioma, IDH-mutant and 1p/19q-codeleted; (2) Astrocytoma, IDH-mutant; (3) Glioblastoma, IDH-...

Objectives: Glioma susceptibility is inversely related to a history of allergies and atopy. Lung allergies are associated with 30% lower glioma susceptibility, compared to no lung allergies. Asthma and eczema also reduce the chance of glioma. However, the effect of allergy on glioma survival is not well characterized. Because of the allergy-glioma inverse relationship we examined the association of allergy with glioma survival in The Cancer Genome Atlas (TCGA). Patients and methods: We evaluated the association between allergy and overall survival in TCGA Glioma (LGG) dataset. In order to have a sample of sufficient size to analyze, we classified as allergic any patient who answered yes to any of the manifestations of allergy that were queried. Results: We analyzed data from 526 patients with glioma. History of allergy conferred a survival advantage on glioma patients, when stratified by tumor histologic grade (p = 0.049). Because allergy confers a favorable prognosis, we performed Cox regression. The effect of allergy on survival was significant (p = 0.025, HR 0.525, 95% CI 0.299-0.924), independent of the effect of chromosome 1p (p < 0.001, HR 93.4, 95% CI 16-546) and 19q (p = 0.801, HR 1.2, 95% CI 0.23-6.9) codeletion or TP53 mutation (p = 0.015, HR 2.7, 95% CI 1.2-5.9), unrelated to TERT expression (p = 0.365, HR 1.1, 95% CI 0.89-1.4) or ATRX mutation (p = 0.904, HR 1.04, 95% CI 0.51-2.14), independent of tumor grade (grade 2 versus grade 3, p = 0.004, HR 2.2, 95% CI 1.3-3.8), not independent of histology (oligodendroglioma and oligoastrocytoma, NOS versus astrocytoma, p = 0.08, HR 0.62, 95% CI 0.36-1.1). Diminished RNA expression of three loci, having reproducible genetic associations with allergic disease risk, are significantly associated with increased survival in glioma: FOSL2, APOBR, and NCF4. Diminished NCF4 copy number is significantly associated with reduced survival (D). Conclusion: Our finding of the improved prognosis that allergy confers on glioma increases the potential importance of understanding the allergy-glioma inverse association. If the mechanism could be more clearly elucidated, new, more effective treatments and preventive measures may be developed. Further studies are warranted.

Downstream signalling involving adenylyl cyclases (ACs) and kinases is a key component of several processes in plants including cell division, growth, and response to stress. ACs are enzymes that generate the second messenger molecule, 3′,5′-cyclic adenosine monophosphate (cAMP) from 5′-adenosine triphosphate (ATP) while kinases are enzymes that catalyze the addition of a phosphate group to other molecules (trans-phosphorylation) or themselves (auto-phosphorylation). Apparently, while there has been an expanded record of various ACs and kinases identified in plants, no plant molecule to date has been shown to possess both the AC and kinase activities/functions and with such activities/functions having the characteristic of cross-talking interactions. Therefore, in an endeavor to find such a molecule, we searched the amino acid sequence of a known Arabidopsis AC, pentatricopeptide repeat (AtPPR) protein, and found a kinase-specific sequence signature (KSSS), which we speculated to be...

Plants are constantly exposed to environmental stresses and in part due to their sessile nature, they have evolved signal perception and adaptive strategies that are distinct from those of other eukaryotes. This is reflected at the cellular level where receptors and signalling molecules cannot be identified using standard homology-based searches querying with proteins from prokaryotes and other eukaryotes. One of the reasons for this is the complex domain architecture of receptor molecules. In order to discover hidden plant signalling molecules, we have developed a motif-based approach designed specifically for the identification of functional centers in plant molecules. This has made possible the discovery of novel components involved in signalling and stimulus-response pathways; the molecules include cyclic nucleotide cyclases, a nitric oxide sensor and a novel target for the hormone abscisic acid. Here, we describe the major steps of the method and illustrate it with recent and e...

Colorectal cancer is a major global health problem resulting in over 600,000 deaths worldwide every year with the majority of these due to metastatic disease. Wnt signalling, and more specifically β-catenin-related transcription, has been shown to drive both tumorigenesis and the metastatic process in colorectal neoplasia, yet its complex interactions with other key signalling pathways, such as hedgehog, remain to be elucidated. We have previously shown that the Hedgehog (HH) signalling pathway is active in cells from colorectal tumours, and that inhibition of the pathway with cyclopamine induces apoptosis. We now show that cyclopamine treatment reduces β-catenin related transcription in colorectal cancer cell lines, and that this effect can be reversed by addition of Sonic Hedgehog protein. We also show that cyclopamine concomitantly induces expression of the tumour suppressor and prognostic indicator E-cadherin. Consistent with a role for HH in regulating the invasive potential we show that cyclopamine reduces the expression of transcription factors (Slug, Snail and Twist) associated with the epithelial-mesenchymal transition and reduces the invasiveness of colorectal cancer cells in vitro. Taken together, Cancers 2015, 7 1886 these data show that pharmacological inhibition of the hedgehog pathway has therapeutic potential in the treatment of colorectal cancer.

Background: H. sapiens-M. tuberculosis H37Rv protein-protein interaction (PPI) data are essential for understanding the infection mechanism of the formidable pathogen M. tuberculosis H37Rv. Computational prediction is an important strategy to fill the gap in experimental H. sapiens-M. tuberculosis H37Rv PPI data. Homology-based prediction is frequently used in predicting both intra-species and inter-species PPIs. However, some limitations are not properly resolved in several published works that predict eukaryote-prokaryote inter-species PPIs using intra-species template PPIs. Results: We develop a stringent homology-based prediction approach by taking into account (i) differences between eukaryotic and prokaryotic proteins and (ii) differences between inter-species and intra-species PPI interfaces. We compare our stringent homology-based approach to a conventional homology-based approach for predicting host-pathogen PPIs, based on cellular compartment distribution analysis, disease gene list enrichment analysis, pathway enrichment analysis and functional category enrichment analysis. These analyses support the validity of our prediction result, and clearly show that our approach has better performance in predicting H. sapiens-M. tuberculosis H37Rv PPIs. Using our stringent homology-based approach, we have predicted a set of highly plausible H. sapiens-M. tuberculosis H37Rv PPIs which might be useful for many of related studies. Based on our analysis of the H. sapiens-M. tuberculosis H37Rv PPI network predicted by our stringent homology-based approach, we have discovered several interesting properties which are reported here for the first time. We find that both host proteins and pathogen proteins involved in the host-pathogen PPIs tend to be hubs in their own intra-species PPI network. Also, both host and pathogen proteins involved in host-pathogen PPIs tend to have longer primary sequence, tend to have more domains, tend to be more hydrophilic, etc. And the protein domains from both host and pathogen proteins involved in host-pathogen PPIs tend to have lower charge, and tend to be more hydrophilic. Conclusions: Our stringent homology-based prediction approach provides a better strategy in predicting PPIs between eukaryotic hosts and prokaryotic pathogens than a conventional homology-based approach. The properties we have observed from the predicted H. sapiens-M. tuberculosis H37Rv PPI network are useful for understanding inter-species host-pathogen PPI networks and provide novel insights for host-pathogen interaction studies. Reviewers: This article was reviewed by Michael Gromiha, Narayanaswamy Srinivasan and Thomas Dandekar.

District heating networks are commonly addressed in the literature as one of the most effective solutions for decreasing the greenhouse gas emissions from the building sector. These systems require high investments which are returned through the heat sales. Due to the changed climate conditions and building renovation policies, heat demand in the future could decrease, prolonging the investment return period. The main scope of this paper is to assess the feasibility of using the heat demand-outdoor temperature function for heat demand forecast. The district of Alvalade, located in Lisbon (Portugal), was used as a case study. The district is consisted of 665 buildings that vary in both construction period and typology. Three weather scenarios (low, medium, high) and three district renovation scenarios were developed (shallow, intermediate, deep). To estimate the error, obtained heat demand values were compared with results from a dynamic heat demand model, previously developed and validated by the authors. The results showed that when only weather change is considered, the margin of error could be acceptable for some applications (the error in annual demand was lower than 20% for all weather scenarios considered). However, after introducing renovation scenarios, the error value increased up to 59.5% (depending on the weather and renovation scenarios combination considered). The value of slope coefficient increased on average within the range of 3.8% up to 8% per decade, that corresponds to the decrease in the number of heating hours of 22-139h during the heating season (depending on the combination of weather and renovation scenarios considered). On the other hand, function intercept increased for 7.8-12.7% per decade (depending on the coupled scenarios). The values suggested could be used to modify the function parameters for the scenarios considered, and improve the accuracy of heat demand estimations.

Over the past decades, natural products have emerged as promising agents with multiple biological activities. Many studies suggest the antioxidant, antiangiogenic, antiproliferative and anticancer effects of chalcones and their derivatives. Based on these findings, we decided to evaluate the effects of the newly synthetized chalcone L1 in a human cervical carcinoma cell (HeLa) model. Presented results were obtained by western blot and flow cytometric analyses, live cell imaging and antimigratory potential of L1 in HeLa cells was demonstrated by scratch assay. In the present study, we proved the role of L1 as an effective agent with antiproliferative activity supported by G2/M cell cycle arrest and apoptosis. Moreover, we proved that L1 is involved in modulating Transforming Growth Factor-β1 (TGF-β) signal transduction through Smad proteins and it also modulates other signalling pathways including Akt, JNK, p38 MAPK, and Erk1/2. The involvement of L1 in epithelial-to-mesenchymal tran...

Context.— The diagnosis and clinical management of patients with diffuse gliomas (DGs) have evolved rapidly over the past decade with the emergence of molecular biomarkers that are used to classify, stratify risk, and predict treatment response for optimal clinical care. Objective.— To develop evidence-based recommendations for informing molecular biomarker testing for pediatric and adult patients with DGs and provide guidance for appropriate laboratory test and biomarker selection for optimal diagnosis, risk stratification, and prediction. Design.— The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. A systematic review of literature was conducted to address the overarching question, “What ancillary tests are needed to classify DGs and sufficiently inform the clinical management of patients?” Recommendations were derived from quality of evidence, open comment feedback, and expert panel consensus....

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

The carmustine (BCNU) wafer, a biodegradable polymer, currently is the only drug that is able to be placed at the surgical site to treat malignant tumors. Biomaterials to treat cancers hold therapeutic potential; however, how they behave inside the tumor microenvironment requires further study. We previously investigated the tumor microenvironment after BCNU wafer implantation, and found that CD68-positive macrophage was significantly introduced around the wafer (Shibahara et al. J Neurooncol 2018). Recent studies demonstrated the importance of tumor-associated macrophage (TAM). However, we could not clarify whether the increased macrophage around the wafer was pro-tumor or anti-tumor phenotype. In the present study, we immunohistochemically examined expressions of CD68, IBA1, CD163, TMEM119, BIN1, CD31, and VEGF to investigate TAM after the wafer implantation. Quantitative evaluation revealed that CD68+ cells were significantly increased (P = 0.0009), whereas TMEM119+ cells were si...

The Hippo/YAP pathway serves as a major integrator of cell surface-mediated signals and regulates key processes during development and tumorigenesis. The neural crest is an embryonic tissue known to respond to multiple environmental cues in order to acquire appropriate cell fate and migration properties. Using multiple in vitro models of human neural development (pluripotent stem cell-derived neural stem cells; LUHMES, NTERA2 and SH-SY5Y cell lines), we investigated the role of Hippo/YAP signaling in neural differentiation and neural crest development. We report that the activity of YAP promotes an early neural crest phenotype and migration, and provide the first evidence for an interaction between Hippo/YAP and retinoic acid signaling in this system.

The natural communication ability of cells is explored in this paper by providing preliminary results in the estimation of the Mutual Information (MI) of signaling pathway communication channels. These results, based on an application of Molecular Communication (MC) and information theory concepts to multi-scale integrated Flux-Balance Analysis (iFBA) models are a first step to evaluate the potential of cells and their biochemical processes as a substrate for enabling engineered MC channels for the future internet of Bio-Nano Things.