bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adapting principles of developmental biology and agent-based modelling for automated urban residential layout design
Authors: Sun Yuchao , Taplin John 
Published: January 2017

The objective is to automate the design of residential layouts as an aid for planners dealing with complex situations. The algorithm COmputational Urban Layout Design, applied to sites with various shapes, is guided by the goal of many mutually accessible residences and can be set to generate orthogonal or irregular road layouts. Using biological principles of genomic equivalence, conditional differentiation and induction, it grows from an embryonic ‘adaptive cell’ into a plan. Cells are ‘genetically identical’ with full development potential and can simultaneously lay roads and residential lots, using the gene set to change cell expression and adapt to local contexts. Cells can be seen as self-propagating agents that sort out their dependencies through local interactions. When COmputational Urban Layout Design is set to grow a non-orthogonal layout, the plan has winding roads and irregular residential lots. Such a plan achieves the objective of relatively high residential density and accessibility, leading to walkable and coherent communities.
RETRACTED ARTICLE: Progranulin causes adipose insulin resistance via increased autophagy resulting from activated oxidative stress and endoplasmic reticulum stress
Authors: Guo Qinyue , Xu Lin , Li Huixia , Sun Hongzhi , Liu Jiali , Wu Shufang , Zhou Bo 
Published: January 2017

Abstract
Background
Progranulin (PGRN) has recently emerged as an important regulator for insulin resistance. However, the direct effect of progranulin in adipose insulin resistance associated with the autophagy mechanism is not fully understood.

Methods
In the present study, progranulin was administered to 3T3-L1 adipocytes and C57BL/6 J mice with/without specific inhibitors of oxidative stress and endoplasmic reticulum stress, and metabolic parameters, oxidative stress, endoplasmic reticulum stress and autophagy markers were assessed.

Results
Progranulin treatment increased iNOS expression, NO synthesis and ROS generation, and elevated protein expressions of CHOP, GRP78 and the phosphorylation of PERK, and caused a significant increase in Atg7 and LC3-II protein expression and a decreased p62 expression, and decreased insulin-stimulated tyrosine phosphorylation of IRS-1 and glucose uptake, demonstrating that progranulin activated oxidative stress and ER stress, elevated autophagy and induced insulin insensitivity in adipocytes and adipose tissue of mice. Interestingly, inhibition of iNOS and ER stress both reversed progranulin-induced stress response and increased autophagy, protecting against insulin resistance in adipocytes. Furthermore, the administration of the ER stress inhibitor 4-phenyl butyric acid reversed the negative effect of progranulin in vivo.

Conclusion
Our findings showed the clinical potential of the novel adipokine progranulin in the regulation of insulin resistance, suggesting that progranulin might mediate adipose insulin resistance, at least in part, by inducing autophagy via activated oxidative stress and ER stress.
A phase II trial of stereotactic body radiotherapy with concurrent anti-PD1 treatment in metastatic melanoma: evaluation of clinical and immunologic response
Authors: De Wolf Katrien , Kruse Vibeke , Sundahl Nora , van Gele Mireille , Chevolet Ines , Speeckaert Reinhart , Brochez Lieve , Ost Piet 
Published: January 2017

Abstract
Background
Antibodies blocking programmed cell death 1 (PD-1) have encouraging responses in patients with metastatic melanoma. Response to anti-PD-1 treatment requires pre-existing CD8+ T cells that are negatively regulated by PD-1-mediated adaptive immune resistance. Unfortunately, less than half of melanoma tumours have these characteristics. Combining anti-PD-1 treatment with other immunomodulating treatments to activate CD8+ T cells is therefore of vital importance to increase response rates and long-term survival benefit in melanoma patients. Both preclinical and retrospective clinical data support the hypothesis that radiotherapy increases the response rates to anti-PD-1 treatment by stimulating the accumulation and activation of CD8+ T cells in the tumour microenvironment. Combining radiotherapy with a PD-1 blocking antibody might therefore increase response rates and even induce long-term survival. The current phase II study will be testing these hypotheses and aims to improve local and distant tumour responses by exploiting the pro-immunogenic effects of radiotherapy in addition to anti-PD-1 treatment.

Methods
The trial will be conducted in patients with metastatic melanoma. Nivolumab or pembrolizumab, both antibodies that target PD-1, will be administrated according to the recommended dosing schedule. Prior to the 2nd cycle, radiotherapy will be delivered in three fractions of 8 Gy to the largest FDG-avid metastatic lesion. The primary endpoint is the proportion of patients with a partial or complete response in non-irradiated metastases according to RECIST v1.1. Secondary endpoints include response rate according to immune related response criteria, metabolic response, local control and survival. To identify peripheral blood biomarkers, peripheral blood mononuclear cells and serum samples will be collected prospectively before, during and after treatment and subjected to flow cytometry and cytokine measurement.

Discussion
The current phase II trial aims at exploring the suggested benefits of combining anti-PD-1 treatment and radiotherapy. The translational focus on immunologic markers might be suitable for predicting efficacy and monitoring the effect so to improve patient selection for future clinical applications.
ClinicalTrials.gov Identifier NCT02821182
Endocytic turnover of Rab8 controls cell polarization
Authors: Vidal-Quadras Maite , Holst Mikkel R. , Francis Monika K. , Larsson Elin , Hachimi Mariam , Yau Wai-Lok , Peränen Johan , Martín-Belmonte Fernando , Lundmark Richard 
Published: January 2017

ABSTRACT
Adaptation of cell shape and polarization through the formation and retraction of cellular protrusions requires balancing of endocytosis and exocytosis combined with fine-tuning of the local activity of small GTPases like Rab8. Here, we show that endocytic turnover of the plasma membrane at protrusions is directly coupled to surface removal and inactivation of Rab8. Removal is induced by reduced membrane tension and mediated by the GTPase regulator associated with focal adhesion kinase-1 (GRAF1, also known as ARHGAP26), a regulator of clathrin-independent endocytosis. GRAF1-depleted cells were deficient in multi-directional spreading and displayed elevated levels of GTP-loaded Rab8, which was accumulated at the tips of static protrusions. Furthermore, GRAF1 depletion impaired lumen formation and spindle orientation in a 3D cell culture system, indicating that GRAF1 activity regulates polarity establishment. Our data suggest that GRAF1-mediated removal of Rab8 from the cell surface restricts its activity during protrusion formation, thereby facilitating dynamic adjustment of the polarity axis.
The Arabidopsis homolog of Scc4/MAU2 is essential for embryogenesis
Authors: Minina Elena A. , Reza Salim Hossain , Gutierrez-Beltran Emilio , Elander Pernilla H. , Bozhkov Peter V. , Moschou Panagiotis N. 
Published: January 2017

ABSTRACT
Factors regulating dynamics of chromatin structure have direct impact on expression of genetic information. Cohesin is a multi-subunit protein complex that is crucial for pairing sister chromatids during cell division, DNA repair and regulation of gene transcription and silencing. In non-plant species, cohesin is loaded on chromatin by the Scc2–Scc4 complex (also known as the NIBPL–MAU2 complex). Here, we identify the Arabidopsis homolog of Scc4, which we denote Arabidopsis thaliana (At)SCC4, and show that it forms a functional complex with AtSCC2, the homolog of Scc2. We demonstrate that AtSCC2 and AtSCC4 act in the same pathway, and that both proteins are indispensable for cell fate determination during early stages of embryo development. Mutant embryos lacking either of these proteins develop only up to the globular stage, and show the suspensor overproliferation phenotype preceded by ectopic auxin maxima distribution. We further establish a new assay to reveal the AtSCC4-dependent dynamics of cohesin loading on chromatin in vivo. Our findings define the Scc2–Scc4 complex as an evolutionary conserved machinery controlling cohesin loading and chromatin structure maintenance, and provide new insight into the plant-specific role of this complex in controlling cell fate during embryogenesis.
Derlin-1 promotes ubiquitylation and degradation of the epithelial Na+ channel, ENaC
Authors: You Hui , Ge Yamei , Zhang Jian , Cao Yizhi , Xing Jing , Su Dongming , Huang Yujie , Li Min , Qu Shen , Sun Fei , Liang Xiubin 
Published: January 2017

ABSTRACT
Ubiquitylation of the epithelial Na+ channel (ENaC) plays a critical role in cellular functions, including transmembrane transport of Na+, Na+ and water balance, and blood pressure stabilization. Published studies have suggested that ENaC subunits are targets of ER-related degradation (ERAD) in yeast systems. However, the molecular mechanism underlying proteasome-mediated degradation of ENaC subunits remains to be established. Derlin-1, an E3 ligase mediator, links recognized target proteins to ubiquitin-mediated proteasomal degradation in the cytosol. In the present study, we found that derlin-1 suppressed the expression of ENaC at the protein level and that the subunit α-ENaC (also known as SCNN1A) physically interacted with derlin-1 at the membrane-anchored domains or the loop regions, and that derlin-1 initiated α-ENaC retrotranslocation. In addition, HUWE1, an endoplasmic reticulum (ER)-resident E3 ubiquitin ligase, was recruited and promoted K11-linked polyubiquitylation of α-ENaC and, hence, formation of an α-ENaC ubiquitin-mediated degradation complex. These findings suggest that derlin-1 promotes ENaC ubiquitylation and enhances ENaC ubiquitin- mediated proteasome degradation. The derlin-1 pathway therefore may represent a significant early checkpoint in the recognition and degradation of ENaC in mammalian cells.
Chronological changes of radiofrequency ablation zone in rabbit liver: an in vivo correlation between gross pathology and histopathology
Authors: Song Kyoung D , Lee Min Woo , Rhim Hyunchul , Kang Tae Wook , Cha Dong Ik , Yang Jehoon 
Published: January 2017

Objective:
To examine the gross pathology and histopathology of ablation zones created from radiofrequency (RF) ablation and to correlate their chronological changes.

Methods:
A total of 48 in vivo ablation zones (16 rabbit livers) were obtained immediately after and also 30 min, 1 h and 2 h after RF ablation and were subjected to haematoxylin and eosin (H&E) staining, nicotinamide adenine dinucleotide (NADH) diaphorase staining, terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining. Chronological changes in gross pathology and histopathology were evaluated and correlated with each other.

Results:
Peripheral red zones on gross pathology correlated with peripheral zones on H&E staining, lightly stained peripheral zones on NADH staining and peripheral positive zones on TUNEL staining. Central white zones on gross pathology correlated with combined central and border zones on H&E staining, central negative zones on NADH staining and combined central-positive and middle-negative zones on TUNEL staining. Boundary visibility between central white and peripheral red zones on gross pathology was significantly higher at 1 and 2 h than immediately after RF ablation. As time increased after RF ablation, visibility of the border zone on H&E staining and the grade of positively stained hepatocytes in the peripheral zone on TUNEL staining increased.

Conclusion:
Chronological changes in gross pathology of RF ablation zones correlated well with histopathology. The boundary between the central white and peripheral red zones tended to become clear at 1 h after RF ablation.

Advances in knowledge:
(1) RF ablation zones show chronological changes on gross pathology and histopathology. (2) Gross pathology and histopathology correlate well with each other.
Geological study for a wetland restoration: the case of the drained Mouria Lake (W. Peloponnese).
Authors: Chatziapostolou A. , Siavalas G. , Kalaitzidis S. , Christanis K. 
Published: January 2017

The Μouria Lake was drained for cultivation during late 1960’s. A 0.5-ha large pilot-scale wetland is now constructed in order to study the sedimentological lakerestoration aspects. The uppermost horizons (up to 3 m thick) consist of fine sediments (mud, silt, clay) of fluvial origin, deposited in a lacustrine environment and constituting the lagoonal bottom material, which extents all over the area ever covered by the original Mouria Lake. A sand layer (3 m beneath the current surface) constitutes the substrate of the lagoonal bottom revealing a higher energy deposition environment in comparison to the overlying fine sediments. High pH and electric conductivity values reveal strong alkaline environment and high content of dissolved solids, respectively. The sediments reveal high CEC, as a result of high clay minerals content. Other main mineral phases that occur include quartz, feldspars and calcite. The weathering of marginal rocks is the major factor controlling the mineralogical-geochemical composition of the sediments. The strong alkaline features of the sediments inhibit trace element mobilization. Continuous monitoring of the chemical composition is necessary in order to predict and prevent a possible mobilization of hazardous trace elements and the subsequent release to the environment.
Simulation of ERT surface-to-tunnel measurements.
Authors: Simyrdanis K. , Tsourlos P. , Soupios P. , Tsokas G. 
Published: January 2017

The applicability of surface-to-tunnel electrical resistance tomography (ERT) measurements using a simulation tank for imaging subsurface targets is studied in this work. The tank was filled with water and inside of it was placed firmly a plastic construction where all targets were placed. Some of the targets that used were: a void plastic cylinder (resistive target) and metal plates (conductive target). Data were collected with a multichannel resistivity meter. The initial scope for these tests was to verify the reliability of developed inversionsoftware which was modified to cope with the specific measurements (surface-totunnel). Furthermore, during several experiments different electrode arrays (standard as well as new optimized) were validated. In our attempt to show the advantages of surface-to-tunnel measurements we analyzed the resolution for each configurationof traditional (surface) and surface-to-tunnel arrays. Studies also included testing the electrode displacement effect and also the effect of the tunnel size into the measurements.
Computational design of molecular motors as nanocircuits in Leishmaniasis
Authors: Kosey Dipali , Singh Shailza 
Published: January 2017

Cutaneous leishmaniasis is the most common form of lesihmaniasis, caused by Leishmania major and is spread by the bite of a sandfly.This species infects the macrophages and dendritic cells Due to multi-drug resistance, there is a need for a new therapeutic technique. Recently, a novel molecular motor of Leishmania, Myosin XXI, was classified and characterized. In addition, the drug resistance in this organism has been linked with the overexpression of ABC transporters. Systems biology aims to study the simulation and modeling of natural biological systems whereas synthetic biology deals with building novel and artificial biological parts and devices Together they have contributed enormously to drug discovery, vaccine design and development, infectious disease detection and diagnostics. Synthetic genetic regulatory networks with desired properties, like toggling and oscillation have been proposed to be useful for gene therapy. In this work, a nanocircuit with coupled bistable switch – repressilator has been designed, simulated in the presence and absence of inducer, in silico, using Tinker Cell. When inducer is added, the circuit has been shown to produce reporter at high levels, which will impair the activity of Myosin XXI and ABC transporters. Validation of the circuit was also performed using GRENITS and BoolNet. The influence of inducer on the working of the circuit, i.e., the type of gene expression, response time delay, the steady states formed by the circuit and the quasipotential landscape of the circuit were performed. It was found that the addition of inducer reduced the response time delay in the graded type of gene expression and removed the multiple intermediate attractors of the circuit. Thus, the inducer increased the probability of the circuit to be present in the dominant stable state with high reporter concentration and hence the designed nanocircuit may be used for the treatment of leishmaniasis.
The BLOC-1 Subunit Pallidin Facilitates Activity-Dependent Synaptic Vesicle Recycling
Authors: Chen Xun , Ma Wenpei , Zhang Shixing , Paluch Jeremy , Guo Wanlin , Dickman Dion K. 
Published: January 2017

AbstractMembrane trafficking pathways must be exquisitely coordinated at synaptic terminals to maintain functionality, particularly during conditions of high activity. We have generated null mutations in theDrosophilahomolog of pallidin, a central subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), to determine its role in synaptic development and physiology. We find that Pallidin localizes to presynaptic microtubules and cytoskeletal structures, and that the stability of Pallidin protein is highly dependent on the BLOC-1 components Dysbindin and Blos1. We demonstrate that the rapidly recycling vesicle pool is not sustained during high synaptic activity in pallidin mutants, leading to accelerated rundown and slowed recovery. Following intense activity, we observe a loss of early endosomes and a concomitant increase in tubular endosomal structures in synapses without Pallidin. Together, our data reveal that Pallidin subserves a key role in promoting efficient synaptic vesicle recycling and re-formation through early endosomes during sustained activity.
A Critical Role for Astrocytes in Hypercapnic Vasodilation in Brain
Authors: Howarth Clare , Sutherland Brad A. , Choi Hyun B. , Martin Chris , Lind Barbara Lykke , Khennouf Lila , LeDue Jeffrey M. , Pakan Janelle M.P. , Ko Rebecca W.Y. , Ellis-Davies Graham , Lauritzen Martin , Sibson Nicola R. , Buchan Alastair M. , MacVicar Brian A. 
Published: January 2017

Cerebral blood flow (CBF) is controlled by arterial blood pressure, arterial CO2, arterial O2, and brain activity and is largely constant in the awake state. Although small changes in arterial CO2are particularly potent to change CBF (1 mmHg variation in arterial CO2changes CBF by 3%–4%), the coupling mechanism is incompletely understood. We tested the hypothesis that astrocytic prostaglandin E2(PgE2) plays a key role for cerebrovascular CO2reactivity, and that preserved synthesis of glutathione is essential for the full development of this response. We combined two-photon imaging microscopy in brain slices within vivowork in rats and C57BL/6J mice to examine the hemodynamic responses to CO2and somatosensory stimulation before and after inhibition of astrocytic glutathione and PgE2synthesis. We demonstrate that hypercapnia (increased CO2) evokes an increase in astrocyte [Ca2+]iand stimulates COX-1 activity. The enzyme downstream of COX-1 that synthesizes PgE2(microsomal prostaglandin E synthase-1) depends critically for its vasodilator activity on the level of glutathione in the brain. We show that, when glutathione levels are reduced, astrocyte calcium-evoked release of PgE2is decreased and vasodilation triggered by increased astrocyte [Ca2+]iin vitroand by hypercapniain vivois inhibited. Astrocyte synthetic pathways, dependent on glutathione, are involved in cerebrovascular reactivity to CO2. Reductions in glutathione levels in aging, stroke, or schizophrenia could lead to dysfunctional regulation of CBF and subsequent neuronal damage.SIGNIFICANCE STATEMENTNeuronal activity leads to the generation of CO2, which has previously been shown to evoke cerebral blood flow (CBF) increases via the release of the vasodilator PgE2. We demonstrate that hypercapnia (increased CO2) evokes increases in astrocyte calcium signaling, which in turn stimulates COX-1 activity and generates downstream PgE2production. We demonstrate that astrocyte calcium-evoked production of the vasodilator PgE2is critically dependent on brain levels of the antioxidant glutathione. These data suggest a novel role for astrocytes in the regulation of CO2-evoked CBF responses. Furthermore, these results suggest that depleted glutathione levels, which occur in aging and stroke, will give rise to dysfunctional CBF regulation and may result in subsequent neuronal damage.
Loss of M1 Receptor Dependent Cholinergic Excitation Contributes to mPFC Deactivation in Neuropathic Pain
Authors: Radzicki Daniel , Pollema-Mays Sarah L. , Sanz-Clemente Antonio , Martina Marco 
Published: January 2017

In chronic pain, the medial prefrontal cortex (mPFC) is deactivated and mPFC-dependent tasks such as attention and working memory are impaired. We investigated the mechanisms of mPFC deactivation in the rat spared nerve injury (SNI) model of neuropathic pain. Patch-clamp recordings in acute slices showed that, 1 week after the nerve injury, cholinergic modulation of layer 5 (L5) pyramidal neurons was severely impaired. In cells from sham-operated animals, focal application of acetylcholine induced a left shift of the input/output curve and persistent firing. Both of these effects were almost completely abolished in cells from SNI-operated rats. The cause of this impairment was an ∼60% reduction of an M1-coupled, pirenzepine-sensitive depolarizing current, which appeared to be, at least in part, the consequence of M1 receptor internalization. Although no changes were detected in total M1 protein or transcript, both the fraction of the M1 receptor in the synaptic plasma membrane and the biotinylated M1 protein associated with the total plasma membrane were decreased in L5 mPFC of SNI rats. The loss of excitatory cholinergic modulation may play a critical role in mPFC deactivation in neuropathic pain and underlie the mPFC-specific cognitive deficits that are comorbid with neuropathic pain.SIGNIFICANCE STATEMENTThe medial prefrontal cortex (mPFC) undergoes major reorganization in chronic pain. Deactivation of mPFC output is causally correlated with both the cognitive and the sensory component of neuropathic pain. Here, we show that cholinergic excitation of commissural layer 5 mPFC pyramidal neurons is abolished in neuropathic pain rats due to a severe reduction of a muscarinic depolarizing current and M1 receptor internalization. Therefore, in neuropathic pain rats, the acetylcholine (ACh)-dependent increase in neuronal excitability is reduced dramatically and the ACh-induced persisting firing, which is critical for working memory, is abolished. We propose that the blunted cholinergic excitability contributes to the functional mPFC deactivation that is causal for the pain phenotype and represents a cellular mechanism for the attention and memory impairments comorbid with chronic pain.