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1.  The Hunt Opinion Model—An Agent Based Approach to Recurring Fashion Cycles 
PLoS ONE  2016;11(11):e0166323.
We study a simple agent-based model of the recurring fashion cycles in the society that consists of two interacting communities: “snobs” and “followers” (or “opinion hunters”, hence the name of the model). Followers conform to all other individuals, whereas snobs conform only to their own group and anticonform to the other. The model allows to examine the role of the social structure, i.e. the influence of the number of inter-links between the two communities, as well as the role of the stability of links. The latter is accomplished by considering two versions of the same model—quenched (parameterized by fraction L of fixed inter-links) and annealed (parameterized by probability p that a given inter-link exists). Using Monte Carlo simulations and analytical treatment (the latter only for the annealed model), we show that there is a critical fraction of inter-links, above which recurring cycles occur. For p ≤ 0.5 we derive a relation between parameters L and p that allows to compare both models and show that the critical value of inter-connections, p*, is the same for both versions of the model (annealed and quenched) but the period of a fashion cycle is shorter for the quenched model. Near the critical point, the cycles are irregular and a change of fashion is difficult to predict. For the annealed model we also provide a deeper theoretical analysis. We conjecture on topological grounds that the so-called saddle node heteroclinic bifurcation appears at p*. For p ≥ 0.5 we show analytically the existence of the second critical value of p, for which the system undergoes Hopf’s bifurcation.
doi:10.1371/journal.pone.0166323
PMCID: PMC5106037  PMID: 27835679
2.  TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells 
Scientific Reports  2016;6:30904.
Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. However, there has not been an adequate system to explore the mechanisms of human ADM induction. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to analyse ADM in human cells. In this system, well-known mouse ADM inducers did not promote ADM in human cells. In contrast, TGF-β1 efficiently converted human acinar cells to duct-like cells (AD) in a SMAD-dependent manner, highlighting fundamental differences between the species. Functionally, AD cells gained transient proliferative capacity. Furthermore, oncogenic KRAS did not induce acinar cell proliferation, but did sustain the proliferation of AD cells, suggesting that oncogenic KRAS requires ADM-associated-changes to promote PDAC initiation. This ADM model provides a novel platform to explore the mechanisms involved in the development of human pancreatic diseases.
doi:10.1038/srep30904
PMCID: PMC4971483  PMID: 27485764
3.  Crystal Nucleation in Liquids: Open Questions and Future Challenges in Molecular Dynamics Simulations 
Chemical Reviews  2016;116(12):7078-7116.
The nucleation of crystals in liquids is one of nature’s most ubiquitous phenomena, playing an important role in areas such as climate change and the production of drugs. As the early stages of nucleation involve exceedingly small time and length scales, atomistic computer simulations can provide unique insights into the microscopic aspects of crystallization. In this review, we take stock of the numerous molecular dynamics simulations that, in the past few decades, have unraveled crucial aspects of crystal nucleation in liquids. We put into context the theoretical framework of classical nucleation theory and the state-of-the-art computational methods by reviewing simulations of such processes as ice nucleation and the crystallization of molecules in solutions. We shall see that molecular dynamics simulations have provided key insights into diverse nucleation scenarios, ranging from colloidal particles to natural gas hydrates, and that, as a result, the general applicability of classical nucleation theory has been repeatedly called into question. We have attempted to identify the most pressing open questions in the field. We believe that, by improving (i) existing interatomic potentials and (ii) currently available enhanced sampling methods, the community can move toward accurate investigations of realistic systems of practical interest, thus bringing simulations a step closer to experiments.
doi:10.1021/acs.chemrev.5b00744
PMCID: PMC4919765  PMID: 27228560
4.  The odor of a plant metabolite affects life history traits in dietary restricted adult olive flies 
Scientific Reports  2016;6:28540.
Food quality shapes life history traits either directly or through response of individuals to additional environmental factors, such as chemical cues. Plant extracts used as food additives modulate key life history traits; however little is known regarding such effects for olfactory chemical cues. Exploiting an interesting experimental system that involves the olive fly (Bactrocera oleae) and the plant metabolite α-pinene we asked whether exposure of adults to this compound modulates adult longevity and female reproduction in similar manner in a stressful – dietary (protein) restricted (DR) and in a relaxed- full diet (FD) feeding environment. Accordingly, we exposed males and females to the aroma of α-pinene and measured lifespan and age-specific fecundity in the above two dietary contexts. Our results demonstrate that exposure to α-pinene increased longevity in males and fecundity in females only under dietary restricted conditions. In relaxed food conditions, females exposed to α-pinene shifted high egg-laying towards younger ages compared to non-exposed ones. This is the first report demonstrating that a plant compound affects key life history traits of adult olive flies through olfaction. These effects are sex-specific and more pronounced in dietary restricted adults. Possible underlying mechanisms and the ecological significance are discussed.
doi:10.1038/srep28540
PMCID: PMC4919778  PMID: 27339862
5.  Far-Infrared and Raman Spectroscopy Investigation of Phonon Modes in Amorphous and Crystalline Epitaxial GeTe-Sb2Te3 Alloys 
Scientific Reports  2016;6:28560.
A combination of far-infrared and Raman spectroscopy is employed to investigate vibrational modes and the carrier behavior in amorphous and crystalline ordered GeTe-Sb2Te3 alloys (GST) epitaxially grown on Si(111). The infrared active GST mode is not observed in the Raman spectra and vice versa, indication of the fact that inversion symmetry is preserved in the metastable cubic phase in accordance with the Fm3 space group. For the trigonal phase, instead, a partial symmetry break due to Ge/Sb mixed anion layers is observed. By studying the crystallization process upon annealing with both the techniques, we identify temperature regions corresponding to the occurrence of different phases as well as the transition from one phase to the next. Activation energies of 0.43 eV and 0.08 eV for the electron conduction are obtained for both cubic and trigonal phases, respectively. In addition a metal-insulator transition is clearly identified to occur at the onset of the transition between the disordered and the ordered cubic phase.
doi:10.1038/srep28560
PMCID: PMC4919779  PMID: 27340085
6.  The Phosphorylation and Distribution of Cortactin Downstream of Integrin α9β1 Affects Cancer Cell Behaviour 
Scientific Reports  2016;6:28529.
Integrins, a family of heterodimeric adhesion receptors are implicated in cell migration, development and cancer progression. They can adopt conformations that reflect their activation states and thereby impact adhesion strength and migration. Integrins in an intermediate activation state may be optimal for migration and we have shown previously that fully activated integrin α9β1 corresponds with less migratory behaviour in melanoma cells. Here, we aimed to identify components associated with the activation status of α9β1. Using cancer cell lines with naturally occuring high levels of this integrin, activation by α9β1-specific ligands led to upregulation of fibronectin matrix assembly and tyrosine phosphorylation of cortactin on tyrosine 470 (Y470). Specifically, cortactin phosphorylated on Y470, but not Y421, redistributed together with α9β1 to focal adhesions where active β1 integrin also localises, upon integrin activation. This was commensurate with reduced migration. The localisation and phosphorylation of cortactin Y470 was regulated by Yes kinase and PTEN phosphatase. Cortactin levels influenced fibronectin matrix assembly and active β1 integrin on the cell surface, being inversely correlated with migratory behaviour. This study underlines the complex interplay between cortactin and α9β1 integrin that regulates cell-extracellular matrix interactions.
doi:10.1038/srep28529
PMCID: PMC4919783  PMID: 27339664
7.  STARD6 on steroids: solution structure, multiple timescale backbone dynamics and ligand binding mechanism 
Scientific Reports  2016;6:28486.
START domain proteins are conserved α/β helix-grip fold that play a role in the non-vesicular and intracellular transport of lipids and sterols. The mechanism and conformational changes permitting the entry of the ligand into their buried binding sites is not well understood. Moreover, their functions and the identification of cognate ligands is still an active area of research. Here, we report the solution structure of STARD6 and the characterization of its backbone dynamics on multiple time-scales through 15N spin-relaxation and amide exchange studies. We reveal for the first time the presence of concerted fluctuations in the Ω1 loop and the C-terminal helix on the microsecond-millisecond time-scale that allows for the opening of the binding site and ligand entry. We also report that STARD6 binds specifically testosterone. Our work represents a milestone for the study of ligand binding mechanism by other START domains and the elucidation of the biological function of STARD6.
doi:10.1038/srep28486
PMCID: PMC4919784  PMID: 27340016
8.  Healthcare Programmes for Truck Drivers in Sub-Saharan Africa: A Systematic Review and Meta-Analysis 
PLoS ONE  2016;11(6):e0156975.
Background
Truck drivers have unique health needs, and by virtue of their continuous travel, experience difficulty in accessing healthcare. Currently, planning for effective care is hindered by lack of knowledge about their health needs and about the impact of on-going programmes on this population’s health outcomes. We reviewed healthcare programmes implemented for sub-Saharan African truck drivers, assessed the evaluation methods, and examined impact on health outcomes.
Methods
We searched scientific and institutional databases, and online search engines to include all publications describing a healthcare programme in sub-Saharan Africa where the main clients were truck drivers. We consulted experts and organisations working with mobile populations to identify unpublished reports. Forest plots of impact and outcome indicators with unadjusted risk ratios and 95% confidence intervals were created to map the impact of these programmes. We performed a subgroup analysis by type of indicator using a random-effects model to assess between-study heterogeneity. We conducted a sensitivity analysis to examine both the summary effect estimate chosen (risk difference vs. risk ratio) and model to summarise results (fixed vs. random effects).
Results
Thirty-seven publications describing 22 healthcare programmes across 30 countries were included from 5,599 unique records. All programmes had an HIV-prevention focus with only three expanding their services to cover conditions other primary healthcare services. Twelve programmes were evaluated and most evaluations assessed changes in input, output, and outcome indicators. Absence of comparison groups, preventing attribution of the effect observed to the programme and lack of biologically confirmed outcomes were the main limitations. Four programmes estimated a quantitative change in HIV prevalence or reported STI incidence, with mixed results, and one provided anecdotal evidence of changes in AIDS-related mortality and social norms. Most programmes showed positive changes in risk behaviours, knowledge, and attitudes. Our conclusions were robust in sensitivity analyses.
Conclusion
Diverse healthcare programmes tailored to the needs of truck drivers implemented in 30 sub-Saharan African countries have shown potential benefits. However, information gaps about availability of services and their effects impede further planning and implementation of effective healthcare programmes for truck drivers.
doi:10.1371/journal.pone.0156975
PMCID: PMC4917167  PMID: 27333301
9.  Analyses of Sox-B and Sox-E Family Genes in the Cephalopod Sepia officinalis: Revealing the Conserved and the Unusual 
PLoS ONE  2016;11(6):e0157821.
Cephalopods provide an unprecedented opportunity for comparative studies of the developmental genetics of organ systems that are convergent with analogous vertebrate structures. The Sox-family of transcription factors is an important class of DNA-binding proteins that are known to be involved in many aspects of differentiation, but have been largely unstudied in lophotrochozoan systems. Using a degenerate primer strategy we have isolated coding sequence for three members of the Sox family of transcription factors from a cephalopod mollusk, the European cuttlefish Sepia officinalis: Sof-SoxE, Sof-SoxB1, and Sof-SoxB2. Analyses of their expression patterns during organogenesis reveals distinct spatial and temporal expression domains. Sof-SoxB1 shows early ectodermal expression throughout the developing epithelium, which is gradually restricted to presumptive sensory epithelia. Expression within the nervous system appears by mid-embryogenesis. Sof-SoxB2 expression is similar to Sof-SoxB1 within the developing epithelia in early embryogenesis, however appears in largely non-overlapping expression domains within the central nervous system and is not expressed in the maturing sensory epithelium. In contrast, Sof-SoxE is expressed throughout the presumptive mesodermal territories at the onset of organogenesis. As development proceeds, Sof-SoxE expression is elevated throughout the developing peripheral circulatory system. This expression disappears as the circulatory system matures, but expression is maintained within undifferentiated connective tissues throughout the animal, and appears within the nervous system near the end of embryogenesis. SoxB proteins are widely known for their role in neural specification in numerous phylogenetic lineages. Our data suggests that Sof-SoxB genes play similar roles in cephalopods. In contrast, Sof-SoxE appears to be involved in the early stages of vasculogenesis of the cephalopod closed circulatory system, a novel role for a member of this gene family.
doi:10.1371/journal.pone.0157821
PMCID: PMC4917168  PMID: 27331398
10.  Synergistic activation of Arg1 gene by retinoic acid and IL-4 involves chromatin remodeling for transcription initiation and elongation coupling 
Nucleic Acids Research  2016;44(16):7568-7579.
All-trans Retinoic acid (RA) and its derivatives are potent therapeutics for immunological functions including wound repair. However, the molecular mechanism of RA modulation in innate immunity is poorly understood, especially in macrophages. We found that topical application of RA significantly improves wound healing and that RA and IL-4 synergistically activate Arg1, a critical gene for tissue repair, in M2 polarized macrophages. This involves feed forward regulation of Raldh2, a rate-limiting enzyme for RA biosynthesis, and requires Med25 to coordinate RAR, STAT6 and chromatin remodeler, Brg1 to remodel the +1 nucleosome of Arg1 for transcription initiation. By recruiting elongation factor TFIIS, Med25 also facilitates transcriptional initiation-elongation coupling. This study uncovers synergistic activation of Arg1 by RA and IL-4 in M2 macrophages that involves feed forward regulation of RA synthesis and dual functions of Med25 in nucleosome remodeling and transcription initiation-elongation coupling that underlies robust modulatory activity of RA in innate immunity.
doi:10.1093/nar/gkw392
PMCID: PMC5027474  PMID: 27166374
11.  Musashi mediates translational repression of the Drosophila hypoxia inducible factor 
Nucleic Acids Research  2016;44(16):7555-7567.
Adaptation to hypoxia depends on a conserved α/β heterodimeric transcription factor called Hypoxia Inducible Factor (HIF), whose α-subunit is regulated by oxygen through different concurrent mechanisms. In this study, we have identified the RNA binding protein dMusashi, as a negative regulator of the fly HIF homologue Sima. Genetic interaction assays suggested that dMusashi participates of the HIF pathway, and molecular studies carried out in Drosophila cell cultures showed that dMusashi recognizes a Musashi Binding Element in the 3′ UTR of the HIFα transcript, thereby mediating its translational repression in normoxia. In hypoxic conditions dMusashi is downregulated, lifting HIFα repression and contributing to trigger HIF-dependent gene expression. Analysis performed in mouse brains revealed that murine Msi1 protein physically interacts with HIF-1α transcript, suggesting that the regulation of HIF by Msi might be conserved in mammalian systems. Thus, Musashi is a novel regulator of HIF that inhibits responses to hypoxia specifically when oxygen is available.
doi:10.1093/nar/gkw372
PMCID: PMC5027473  PMID: 27141964
12.  Squamous Cell Carcinoma of Parotid Gland Associated with Concurrent Lymphoepithelial Cysts and Lymphoepithelial Lesion: Case Report and Proposed Histogenesis 
Head and Neck Pathology  2014;9(2):305-308.
Lymphoepithelial cyst and lymphoepithelial lesion have similar histologic features and an affinity for the parotid gland. Though considered as different entities, both conditions arise from heterotopic salivary epithelial rests or inclusions in intra- or peri-parotid lymph nodes. We present a case of squamous cell carcinoma of parotid gland associated with concurrent lymphoepithelial cyst and lymphoepithelial lesion in a patient who was not infected with human immunodeficiency virus. We propose that lymphoepithelial cyst and lymphoepithelial lesion have a similar histogenesis.
doi:10.1007/s12105-014-0571-3
PMCID: PMC4424203  PMID: 25284597
Lymphoepithelial cyst; Lymphoepithelial lesion; Histogenesis
13.  Relationship of multi-biomarker disease activity score and other risk factors with radiographic progression in an observational study of patients with rheumatoid arthritis 
Rheumatology (Oxford, England)  2015;55(2):357-366.
Objectives. To evaluate the multi-biomarker disease activity (MBDA) score as a predictor of radiographic progression and compare it with other risk factors among patients with established RA receiving non-biologic DMARDs.
Methods. For 163 patients with RA, we assessed 271 visits for MBDA score (scale of 1−100), clinical data and subsequent 1-year radiographic progression (change in Sharp−van der Heijde score [SHS]). Scatter plot and non-parametric quantile regression curves evaluated the relationship between the MBDA score and change in SHS. Changes in joint space narrowing and erosions were compared among MBDA categories with Wilcoxon rank-sum tests. The ability of the MBDA score to independently predict progression was determined by multivariate models and cross-classification of MBDA score with other risk factors. Generalized estimating equation methodology was used in model estimations to adjust for same-patient visits, always ≥1 year apart.
Results. Patient characteristics included 67% female, 66%/67% RF+/anti-CCP+; mean age 55 years, MBDA score 43 (moderate = 30−44); median disease duration 4.6 years, SHS 23. Radiographic progression was infrequent for low MBDA scores. Relative risk for progression increased continuously as the MBDA score increased, reaching 17.4 for change in SHS >5 with MBDA scores ≥60. Joint space narrowing and erosion progression were associated with MBDA score. MBDA score was associated with radiographic progression after adjustments for other risk factors. MBDA score significantly differentiated risk for progression when swollen joint count, CRP or DAS28–CRP was low, and among seropositive patients.
Conclusion. MBDA score enhanced the ability of conventional risk factors to predict radiographic progression in patients with established RA receiving non-biologic DMARDs.
doi:10.1093/rheumatology/kev341
PMCID: PMC4710803  PMID: 26385370
DMARD; multi-biomarker disease activity; non-biologic; prediction; radiographic progression; rheumatoid arthritis
14.  Transobturator Midurethral Slings versus Single-Incision Slings for Stress Incontinence in Overweight Patients 
ABSTRACT
Purpose:
To compare transobturator midurethral sling (TOS) and single-incision sling procedures in terms of their effects on urinary incontinence and the quality of life in overweight (BMI ≥25-29.9 kg/m2) female patients using the International Consultation on Incontinence Questionnaire scoring form (ICIQ-SF) and Quality of Life of Persons with Urinary Incontinence scoring form (I-QOL).
Materials and Methods:
In this prospective trial, the patients were divided into two groups consecutively; first 20 overweight female patients underwent the TOS (Unitape T®,Promedon, Cordoba, Argentina) procedure and the subsequent 20 consecutive overweight female patients underwent the single-incision sling [TVT-secur (Ethicon Inc., Sommerville, USA)] procedure. Age, urinary incontinence period, parity and daily pads usage were recorded. No usage of pads was defined as subjective cure rate postoperatively. Before the operation and 6. month after the surgery, the patients completed the ICIQ-SF and I-QOL.
Results:
There was no significant difference between the two groups in terms of mean age, duration of incontinence, parity, and BMI (p>0.05). ICIQ-SF and I-QOL revealed that the patients in the TOS group showed significantly better improvement (76.20% versus 64.10%, p=0.001, 81.31% versus 69.28%, p=0.001, respectively). In addition, subjective cure rates were found higher in TOS group (75% versus 55%, p=0.190).
Conclusions:
The existing data is showed that incontinence symptoms and the quality of life have higher improvement in overweight female patients who underwent the TOS procedure. It is likely that the TOS procedure may provide stronger urethral support and better contributes to continence in this group of patients.
doi:10.1590/S1677-5538.IBJU.2014.0209
PMCID: PMC4757000  PMID: 26401864
Urinary Incontinence; Stress; Overweight; Suburethral Slings
15.  Evaluation of female overactive bladder using urodynamics: relationship with female voiding dysfunction 
ABSTRACT
Purpose:
To investigate the role of urodynamic study (UDS) in female patients with overactive bladder (OAB) analyzing the relationship between OAB symptoms and female voiding dysfunction (FVD).
Materials and Methods:
We analyzed the clinical and urodynamic data of 163 women with OAB symptoms. OAB symptoms were categorized as dry and wet. FVD was described as detrusor underactivity (DUA), which was defined as a maximum flow rate (Qmax) of ≤15mL/s associated with a detrusor pressure at Qmax (PdetQmax) of ≤20cmH2O, along with bladder outlet obstruction (BOO), which was defined as a Qmax of ≤15mL/s with a PdetQmax of >20cmH2O. Clinical and urodynamic results were compared between patients with dry and wet symptoms and between those with and without FVD.
Results:
78 (47.9%) had dry, and 85 (52.1%) had wet symptoms. The entire group had a relatively low Qmax (15.1±6.6mL/s) and relatively high number of BOO (42.9%, 70/163) and DUA (8.6%, 14/163). A significantly higher number of patients with wet symptoms had detrusor overactivity compared to those with dry, as detected by the UDS (p<0.05). No significant differences were found in BOO and DUA number between dry and wet groups. Further, the international prostate symptom score did not different significantly between patients with and without FVD.
Conclusion:
A significant number of women with OAB had voiding dysfunction. However, the OAB symptoms themselves were not useful for predicting the presence of FVD. Therefore, UDS may be necessary for accurate diagnosis in women with OAB symptoms.
doi:10.1590/S1677-5538.IBJU.2014.0195
PMCID: PMC4757001  PMID: 26401865
Urinary Bladder, Overactive; Urodynamics; Urination Disorders
16.  Urodynamic outcome of parasacral transcutaneous electrical neural stimulation for overactive bladder in children 
ABSTRACT
Objective:
To evaluate the urodynamic changes immediately after the first session (acute effect) and after the last session of parasacral TENS in children with idiopathic OAB.
Materials and methods:
We performed urodynamic evaluation immediately before and after the first session of parasacral TENS and immediately after the last session (7 weeks later). Only children with idiopathic isolated OAB were included. Patients with dysfunctional voiding were not included.
Results:
18 children (4 boys and 14 girls, mean age of 8.7) were included in the first analysis (urodynamic study before and immediately after the first session) and 12 agreed to undergo the third urodynamic study. Urodynamic before and immediately after the first session: There was no change in the urodynamic parameters, namely low MCC, low bladder compliance, presence of IDC, the average number of IDC, or in the maximum detrusor pressure after the first exam. Urodynamic after the last session: The bladder capacity improved in most patients with low capacity (58% vs. 8%). Detrusor overactivity was observed in 11 (92%) before treatment and 8 (76%) after. There was not a significant reduction in the average number of inhibited contractions after TENS (p=0.560) or in the detrusor pressure during the inhibited contraction (p=0.205).
Conclusion:
There was no change in the urodynamic parameters immediately after the first session of stimulation. After the last session, the only urodynamic finding that showed improvement was bladder capacity.
doi:10.1590/S1677-5538.IBJU.2014.0303
PMCID: PMC4757003  PMID: 26401867
Urodynamics; Transcutaneous Electric Nerve Stimulation; Child; Bladder
17.  Cadherin juxtamembrane region derived peptides inhibit TGFβ1 induced gene expression 
Bioarchitecture  2014;4(3):103-110.
Bioactive peptides in the juxtamembrane regions of proteins are involved in many signaling events. The juxtamembrane regions of cadherins were examined for the identification of bioactive regions. Several peptides spanning the cytoplasmic juxtamembrane regions of E- and N-cadherin were synthesized and assessed for the ability to influence TGFβ responses in epithelial cells at the gene expression and protein levels. Peptides from regions closer to the membrane appeared more potent inhibitors of TGFβ signaling, blocking Smad3 phosphorylation. Thus inhibiting nuclear translocation of phosphorylated Smad complexes and subsequent transcriptional activation of TGFβ signal propagating genes. The peptides demonstrated a peptide-specific potential to inhibit other TGFβ superfamily members, such as BMP4.
doi:10.4161/bioa.32143
PMCID: PMC4201599  PMID: 25108297
BMP4; E-cadherin; Jagged; N-cadherin; Smad; TGFβ; adherens junctions; palmitic acid; peptide
18.  Protein Kinase D family kinases 
Bioarchitecture  2014;4(3):111-115.
Highly invasive pancreatic tumors are often recognized in late stages due to a lack of clear symptoms and pose major challenges for treatment and disease management. Broad-band Protein Kinase D (PKD) inhibitors have recently been proposed as additional treatment option for this disease. PKDs are implicated in the control of cancer cell motility, angiogenesis, proliferation and metastasis. In particular, PKD2 expression is elevated in pancreatic cancer, whereas PKD1 expression is comparably lower. In our recent study we report that both kinases control PDAC cell invasive properties in an isoform-specific, but opposing manner. PKD1 selectively mediates anti-migratory/anti-invasive features by preferential regulation of the actin-regulatory Cofilin-phosphatase Slingshot1L (SSH1L). PKD2, on the other hand enhances invasion and angiogenesis of PDAC cells in 3D-ECM cultures and chorioallantois tumor models by stimulating expression and secretion of matrix-metalloproteinase 7 and 9 (MMP7/9). MMP9 also enhances PKD2-mediated tumor angiogenesis releasing extracellular matrix-bound VEGF-A. We thus suggest high PKD2 expression and loss of PKD1 may be beneficial for tumor cells to enhance their matrix-invading abilities. In our recent study we demonstrate for the first time PKD1 and 2 isoform-selective effects on pancreatic cancer cell invasion, in-vitro and in-vivo, defining isoform-specific regulation of PKDs as a major future issue.
doi:10.4161/bioa.29273
PMCID: PMC4201600  PMID: 24847910
PKD1; PKD2; MMP7; MMP9; invasion; angiogenesis; isoform specificity
19.  0.1 kilopascal difference for mechanophenotyping 
Bioarchitecture  2014;4(3):116-118.
Current knowledge understands the mesenchymal cell invasion in a 3D matrix as a combined process of cell-to-matrix adhesion based cell migration and matrix remodeling. Excluding cell invasion stimulated by cytokines and chemokines, the basal cell invasion itself is a complicated process that can be regulated by matrix ligand type, density, geometry, and stiffness, etc. Understanding such a complicated biological process requires delicate dissections into simplified model studies by altering only one or two elements at a time. Past cell motility studies focusing on matrix stiffness have revealed that a stiffer matrix promotes 2D X-Y axis lateral cell motility. Here, we comment on two recent studies that report, instead of stiffer matrix, a softer matrix promotes matrix proteolysis and the formation of invadosome-like protrusions (ILPs) along the 3D Z axis. These studies also reveal that soft matrix precisely regulates such ILPs formation in the stiffness scale range of 0.1 kilopascal in normal cells. In contrast, malignant cells such as cancer cells can form ILPs in response to a much wider range of matrix stiffness. Further, different cancer cells respond to their own favorable range of matrix stiffness to spontaneously form ILPs. Thus, we hereby propose the idea of utilizing the matrix stiffness to precisely regulate ILP formation as a mechanophenotyping tool for cancer metastasis prediction and pathological diagnosis.
doi:10.4161/bioa.29175
PMCID: PMC4201601  PMID: 25029598
cell migration; cell invasion; cancer metastasis; invadosomes; invadopodia; podosomes; matrix stiffness; mechanophenotyping; cellular architecture; soft matrix
20.  Therapies for sarcopenia and regeneration of old skeletal muscles 
Bioarchitecture  2014;4(3):81-87.
Age related loss of skeletal muscle mass and function (sarcopenia) reduces independence and the quality of life for individuals, and leads to falls and fractures with escalating health costs for the rapidly aging human population. Thus there is much interest in developing interventions to reduce sarcopenia. One area that has attracted recent attention is the proposed use of myogenic stem cells to improve regeneration of old muscles. This mini-review challenges the fundamental need for myogenic stem cell therapy for sarcopenia. It presents evidence that demonstrates the excellent capacity of myogenic stem cells from very old rodent and human muscles to form new muscles after experimental myofiber necrosis. The many factors required for successful muscle regeneration are considered with a strong focus on integration of components of old muscle bioarchitecture. The fundamental role of satellite cells in homeostasis of normal aging muscles and the incidence of endogenous regeneration in old muscles is questioned. These issues, combined with problems for clinical myogenic stem cell therapies for severe muscle diseases, raise fundamental concerns about the justification for myogenic stem cell therapy for sarcopenia.
doi:10.4161/bioa.29668
PMCID: PMC4201602  PMID: 25101758
sarcopenia; aging skeletal muscle; cell therapy; myogenic stem cells; regeneration
21.  The role of vertebrate nonmuscle Myosin II in development and human disease 
Bioarchitecture  2014;4(3):88-102.
Three different genes each located on a different chromosome encode the heavy chains of nonmuscle myosin II in humans and mice. This review explores the functional consequences of the presence of three isoforms during embryonic development and beyond. The roles of the various isoforms in cell division, cell-cell adhesion, blood vessel formation and neuronal cell migration are addressed in animal models and at the cellular level. Particular emphasis is placed on the role of nonmuscle myosin II during cardiac and brain development, and during closure of the neural tube and body wall. Questions addressed include the consequences on organ development, of lowering or ablating a particular isoform as well as the effect of substituting one isoform for another, all in vivo. Finally the roles of the three isoforms in human diseases such as cancer as well as in syndromes affecting a variety of organs in humans are reviewed.
doi:10.4161/bioa.29766
PMCID: PMC4201603  PMID: 25098841
Cancer; MYH9-RD; Pentalogy of Cantrell; Congenital Diaphragmatic Hernia; Double Outlet of Right Ventricle; Neuronal Migration; Cell Adhesion; Body Wall Closure; Cytokinesis; Karyokinesis; Placental Vascular Formation
22.  The Effects of Desflurane and Propofol on the Release of Thyroid Hormones in Euthyroid Patients Undergoing Elective Lumbar Discectomy 
Objective
In this study, we aimed to compare the effects of desflurane and propofol on the release of thyroid hormones in euthyroid patients undergoing single-level lumbar discectomy.
Methods
The study group included 21–65-year-old American Society of Anesthesiology (ASA) I–II euthyroid 40 patients undergoing elective single-level lumbar discectomy. They were randomly divided into 2 groups (n=20). In the maintenance of anaesthesia, Group D received desflurane inhalational anaesthesia and remifentanil infusion, and Group P received propofol and remifentanil IV infusions. Four blood samples for the determination of plasma levels of free triiodothyronine (FT3), free thyroxine (FT4) and thyrotropin (TSH) were collected 5 min before and 60 min after the induction of anaesthesia and 60 min and 24 h after the surgery.
Results
Plasma TSH levels in both groups reached the highest levels at the first postoperative hour and returned to the preoperative levels 24 hours after the surgery. Regarding plasma FT3 levels, there were no significant differences within and between groups. There were no significant differences in plasma FT4 levels within the patients of Group P, but in Group D, FT4 levels reached its peak in the first hour of anaesthesia induction and returned back to preoperative levels 24 hours postoperatively (p<0.05).
Conclusion
Further studies are needed to confirm our findings and evaluate patients with thyroid gland pathologies.
doi:10.5152/TJAR.2014.66934
PMCID: PMC4917160  PMID: 27366470
Thyroid gland; desflurane; propofol
23.  A New Threat in Anaesthesia-Bonzai 
doi:10.5152/TJAR.2014.37531
PMCID: PMC4917159  PMID: 27366485
24.  The Comparison of the Effects of Epidural Bupivacaine and Levobupivacaine on the Autonomic Nervous System and Cardiac Arrhythmia Parameters in Inguinal Hernia Surgeries 
Objective
The aim of this study is to investigate the effects of bupivacaine and levobupivacaine, used to create epidural anaesthesia in inguinal hernia operations, on heart rate variability and cardiac arrhythmia parameters.
Methods
Sixty male patients of the American Society of Anesthesiology (ASA) I–II group, scheduled to be operated on for inguinal hernia surgery with epidural anaesthesia, were randomly divided into two groups. The patients, with a 12-channel Holter recorder (Rozinn RZ153+12-USA) attached 1 hour before the operation to record until the end of the surgery, were taken into the preparation room and anaesthetised. In group L (n=30), 17 mL of 0.5% levobupivacaine (Chirocain 0.5%-Abbot, El-verum, Norway) was given into the epidural space within 10 minutes, versus 17 mL of 0.5% bupivacaine in (Marcain 0.5%, Astra Zeneca, İstanbul, Turkey) group B (n=30). After 30 minutes, when there was enough block, the operation had been started. Holter recordings, starting 1 hour before the anaesthetic procedure and completed by the end of the operations, were transferred to the computer. The records were evaluated by the cardiologists.
Results
When analysing the frequency effect measurement results of the heart rate variability, it was seen that neither of the medications created any statistically significant change in or among the groups in total, very-low-frequency (VLF), low-frequency (LF), high-frequency (HF) and LF/HF ratio levels. Only normalised low-frequency band was significantly lower in Group L (p=0.013).
Conclusion
In the volumes and concentrations that were used in our study, levobupivacaine and bupivacaine created sensory blockade at the same level on average and did not reduce heart rate variability at the levels of these blockages.
doi:10.5152/TJAR.2014.34635
PMCID: PMC4917162  PMID: 27366472
Anaesthesia; epidural; levobupivacaine; bupivacaine; arrhythmia
25.  Cardiac and Liver Marker Alterations After Laparoscopic Gynaecologic Operations 
Objective
In our study, we aimed to investigate the effect of laparoscopic procedures in which the abdominal cavity at a Trendelenburg position of 15 degrees was insufflated with CO2 on cardiac and liver markers.
Methods
Forty patients scheduled for laparoscopic gynaecological surgery were included in the study. Venous blood samples were taken the day before operation and 6 hours after surgery, and later, lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase-MB (CK-MB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), myoglobin (MY) and d-dimer (d-D) were measured.
Results
There was no statistically significant difference in the values of preoperative and postoperative ALT (16.8±9.4 and 17.8±9.3; p=0.579), AST (19.4±7 and 20.9±7.6; p=0.361) and ALP (65.2±16.2 and 63.3±16.9; p=0.609), but LDH (385.1±117.3 and 460.6±156.3; p=0.003), CK (113.8±138.5 and 247.9±283.5; p=0.0001), CK-MB (22.8±13.3 and 28.7±16; p=0.011), MY (28.1±12.9 and 138.8±129; p=0.0001) and d-D (509.5±815: 1026±1054; p=0.0001) increased significantly.
Conclusion
After laparoscopic operations in the Trendelenburg position, postoperative serum ALT, AST and ALP levels, remained unchanged, when compared to preoperative values, but LDH, CK, CK-MB, myoglobin and d-dimer values increased significantly.
doi:10.5152/TJAR.2014.83604
PMCID: PMC4917161  PMID: 27366471
Gynaecological laparoscopic surgery; Trendelenburg; cardiac enzymes; liver enzymes

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