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1.  Robotic transthoracic esophagectomy 
BMC Surgery  2015;15:47.
We have initially published our experience with the robotic transthoracic esophagectomy in 32 patients from a single institute. The present paper is the extension of our experience with robotic system and to best of our knowledge this represents the largest series of robotic transthoracic esophagectomy worldwide. The objective of this study was to investigate the feasibility of the robotic transthoracic esophagectomy for esophageal cancer in a series of patients from a single institute.
A retrospective review of medical records was conducted for 83 esophageal cancer patients who underwent robotic esophagectomy at our institute from December 2009 to December 2012. All patients underwent a thorough clinical examination and pre-operative investigations. All patients underwent robotic esophageal mobilization. En-bloc dissection with lymphadenectomy was performed in all cases with preservation of Azygous vein. Relevant data were gathered from medical records.
The study population comprised of 50 men and 33 women with mean age of 59.18 years. The mean operative time was 204.94 mins (range 180 to 300). The mean blood loss was 86.75 ml (range 50 to 200). The mean number of lymph node yield was 18. 36 (range 13 to 24). None of the patient required conversion. The mean ICU stay and hospital stay was 1 day (range 1 to 3) and 10.37 days (range 10 to 13), respectively. A total of 16 (19.28%) complication were reported in these patents. Commonly reported complication included dysphagia, pleural effusion and anastomotic leak. No treatment related mortality was observed. After a median follow-up period of 10 months, 66 patients (79.52%) survived with disease free stage.
We found robot-assisted thoracoscopic esophagectomy feasible in cases of esophageal cancer. The procedure allowed precise en-bloc dissection with lymphadenectomy in mediastinum with reduced operative time, blood loss and complications.
Electronic supplementary material
The online version of this article (doi:10.1186/s12893-015-0024-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4417322  PMID: 25898903
2.  Treatment of gallbladder stone with common bile duct stones in the laparoscopic era 
BMC Surgery  2015;15:7.
Laparoscopic common bile duct exploration (LCBDE) for stone can be carried out by either laparoscopic transcystic stone extraction (LTSE) or laparoscopic choledochotomy (LC). It remains unknown as to which approach is optimal for management of gallbladder stone with common bile duct stones (CBDS) in Chinese patients.
From May 2000 to February 2009, we prospective treated 346 consecutive patients with gallbladder stones and CBDS with laparoscopic cholecystectomy and LCBDE. Intraoperative findings, postoperative complications, postoperative hospital stay and costs were analyzed.
Because of LCBDE failure,16 cases (4.6%) required open surgery. Of 330 successful LCBDE-treated patients, 237 underwent LTSE and 93 required LC. No mortality occurred in either group. The bile duct stone clearance rate was similar in both groups. Patients in the LTSE group were significantly younger and had fewer complications with smaller, fewer stones, shorter operative time and postoperative hospital stays, and lower costs, compared to those in the LC group. Compared with patients with T-tube insertion, patients in the LC group with primary closure had shorter operative time, shorter postoperative hospital stay, and lower costs.
In cases requiring LCBDE, LTSE should be the first choice, whereas LC may be restricted to large, multiple stones. LC with primary closure without external drainage of the CBDS is as effective and safe as the T-tube insertion approach.
PMCID: PMC4417333  PMID: 25623774
Cholecystectomy; Laparoscopic; Common bile duct stones (CBDS); Transcystic; Choledochotomy; Primary closure
3.  Structure determination of molecules in an alignment laser field by femtosecond photoelectron diffraction using an X-ray free-electron laser 
Scientific Reports  2016;6:38654.
We have successfully determined the internuclear distance of I2 molecules in an alignment laser field by applying our molecular structure determination methodology to an I 2p X-ray photoelectron diffraction profile observed with femtosecond X-ray free electron laser pulses. Using this methodology, we have found that the internuclear distance of the sample I2 molecules in an alignment Nd:YAG laser field of 6 × 1011 W/cm2 is elongated by from 0.18 to 0.30 Å “in average” relatively to the equilibrium internuclear distance of 2.666 Å. Thus, the present experiment constitutes a critical step towards the goal of femtosecond imaging of chemical reactions and opens a new direction for the study of ultrafast chemical reaction in the gas phase.
PMCID: PMC5146652  PMID: 27934891
4.  Microglia/macrophage Polarization after Experimental Intracerebral Hemorrhage 
Translational stroke research  2015;6(6):407-409.
PMCID: PMC4628553  PMID: 26446073
5.  Association of dietary protein consumption with incident silent cerebral infarcts and stroke: the ARIC Study 
Background and Purpose
The effect of dietary protein on the risk of stroke has shown inconsistent results. We aimed to evaluate the relationship of dietary protein sources with the risk of stroke and silent cerebral infarcts in a large community based cohort.
We studied 11,601 adults (age 45–64 at baseline in 1987–1989) enrolled in the Atherosclerosis Risk in Communities (ARIC) Study, free of diabetes mellitus and cardiovascular disease. Dietary protein intake was assessed with validated food frequency questionnaires at baseline and after 6 years of follow-up. Incident stroke events were identified through hospital discharge codes and stroke deaths and physician-adjudicated through December 31, 2011. A subset of participants (n = 653) underwent brain MRI imaging in 1993–1995 and in 2004–2006. Cox proportional hazard models and logistic regression were used for statistical analyses.
During a median follow-up of 22.7 years, there were 699 stroke events. In multivariable analyses, total, animal and vegetable protein consumption was not associated with risk for stroke. Red meat consumption was associated with increased stroke risk, particularly ischemic events. The hazard ratios [95% confidence intervals] for risk of ischemic stroke across ascending quintiles of red meat consumption were 1 [ref], 1.13 [0.85–1.49], 1.44 [1.09–1.90], 1.33 [0.99–1.79], 1.47 [1.06–2.05], ptrend = 0.01. No association of major dietary protein sources with silent cerebral infarcts was detected.
This study supports the notion that consumption of red meat may increase the risk for ischemic stroke. No association between dietary protein intake and silent cerebral infarcts was found.
PMCID: PMC4659717  PMID: 26514185
dietary protein; stroke; silent cerebral infarct; community study
6.  Direct evidence for microbial-derived soil organic matter formation and its ecophysiological controls 
Nature Communications  2016;7:13630.
Soil organic matter (SOM) and the carbon and nutrients therein drive fundamental submicron- to global-scale biogeochemical processes and influence carbon-climate feedbacks. Consensus is emerging that microbial materials are an important constituent of stable SOM, and new conceptual and quantitative SOM models are rapidly incorporating this view. However, direct evidence demonstrating that microbial residues account for the chemistry, stability and abundance of SOM is still lacking. Further, emerging models emphasize the stabilization of microbial-derived SOM by abiotic mechanisms, while the effects of microbial physiology on microbial residue production remain unclear. Here we provide the first direct evidence that soil microbes produce chemically diverse, stable SOM. We show that SOM accumulation is driven by distinct microbial communities more so than clay mineralogy, where microbial-derived SOM accumulation is greatest in soils with higher fungal abundances and more efficient microbial biomass production.
Soil microbes process plant remnants and are hypothesized to synthesize soil organic matter (SOM). Here, Kallenbach and colleagues directly measure chemically diverse and stable SOM derived from microbial communities in the absence of plant compounds.
PMCID: PMC5133697  PMID: 27892466
7.  Disruption of Higher Order DNA Structures in Friedreich’s Ataxia (GAA)n Repeats by PNA or LNA Targeting 
PLoS ONE  2016;11(11):e0165788.
Expansion of (GAA)n repeats in the first intron of the Frataxin gene is associated with reduced mRNA and protein levels and the development of Friedreich’s ataxia. (GAA)n expansions form non-canonical structures, including intramolecular triplex (H-DNA), and R-loops and are associated with epigenetic modifications. With the aim of interfering with higher order H-DNA (like) DNA structures within pathological (GAA)n expansions, we examined sequence-specific interaction of peptide nucleic acid (PNA) with (GAA)n repeats of different lengths (short: n=9, medium: n=75 or long: n=115) by chemical probing of triple helical and single stranded regions. We found that a triplex structure (H-DNA) forms at GAA repeats of different lengths; however, single stranded regions were not detected within the medium size pathological repeat, suggesting the presence of a more complex structure. Furthermore, (GAA)4-PNA binding of the repeat abolished all detectable triplex DNA structures, whereas (CTT)5-PNA did not. We present evidence that (GAA)4-PNA can invade the DNA at the repeat region by binding the DNA CTT strand, thereby preventing non-canonical-DNA formation, and that triplex invasion complexes by (CTT)5-PNA form at the GAA repeats. Locked nucleic acid (LNA) oligonucleotides also inhibited triplex formation at GAA repeat expansions, and atomic force microscopy analysis showed significant relaxation of plasmid morphology in the presence of GAA-LNA. Thus, by inhibiting disease related higher order DNA structures in the Frataxin gene, such PNA and LNA oligomers may have potential for discovery of drugs aiming at recovering Frataxin expression.
PMCID: PMC5112992  PMID: 27846236
8.  Synaptic generation of an intracellular retrograde signal requires activation of the tyrosine kinase and mitogen-activated protein kinase signaling cascades in Aplysia 
Cellular changes underlying memory formation can be generated in an activity-dependent manner at specific synapses. Thus an important question concerns the mechanisms by which synaptic signals communicate with the cell body to mediate these cellular changes. A monosynaptic circuit that is enhanced by sensitization in Aplysia is well-suited to study this question because three different subcellular compartments: (i) the sensorimotor SN-MN synapses, (ii) the SN projections to MNs via axonal connections, (iii) the SN cell bodies, can all be manipulated and studied independently. Here, we report that activity-dependent (AD) training in either the entire SN-MN circuit or in only the synaptic compartment, activates MAPK in a temporally and spatially specific pattern. Specifically, we find (i) MAPK activation is first transiently generated at SN-MN synapses during training, (ii) immediately after training MAPK is transiently activated in SN-MN axonal connections and persistently activated in SN cell bodies, and finally, (iii) MAPK is activated in SN cell bodies and SN-MN synapses 1hr after training. These data suggest that there is an intracellularly transported retrograde signal generated at the synapse which is later responsible for delayed MAPK activation at SN somata. Finally, we find that this retrograde signal requires activation of tyrosine kinase (TK) and MEK signaling cascades specifically at the synapses.
PMCID: PMC4648669  PMID: 26238564
retrograde signal; MAPK; tyrosine kinase; intracellular communication; long-term memory
9.  Health-related Quality of Life in Accordance with Fracture History and Comorbidities in Korean Patients with Osteoporosis 
Journal of Bone Metabolism  2016;23(4):199-206.
The purpose of this study was to explore health-related quality of life (HRQOL) among Korean patients with osteoporosis and to measure the impact of fractures and comorbidity on their quality of life (QOL) using the Korean National Health and Nutrition Examination Survey (KNHANES) data with a nationwide representativeness.
This study was based on 4-year-data obtained from the KNHANES 2008 to 2011. Osteoporosis was diagnosed in 2,078 survey participants according to their bone mineral density measurements using dual energy X-ray absorptiometry. According to the World Health Organization study group, T-scores at or above -1.0 are considered normal, those between -1.0 and -2.5 as osteopenia, and those at or below -2.5 as osteoporosis The EuroQol five-dimensional questionnaire (EQ-5D) index score was used to assess the QOL.
Of 2,078 patients diagnosed with osteoporosis, fractures were found to occur at 11.02%. Wrist fracture was the most frequent, affecting 4.52% of the patients, with a significantly different prevalence among men and women (P<0.001). The overall EQ-5D index score was 0.84±0.01 among patients with osteoporosis. With the exception of cancer, the EQ-5D index score were significantly lower for those having osteoarthritis, rheumatoid arthritis, hypertension, diabetes, chronic obstructive pulmonary disease and cardiovascular events compared to those without the related diseases.
We found that low health utility was associated with previous spine fracture and comorbidities in patients with osteoporosis. In particular, the number of fracture experiences greatly deteriorated the HRQOL in patients with osteoporosis. Thus, prevention of secondary fractures and chronic care model for comorbidities should be a priority for osteoporosis management in order to improve HRQOL.
PMCID: PMC5153376  PMID: 27965941
Comorbidity; Fractures bone; Osteoporosis; Quality of life
10.  Exchange protein directly activated by cAMP encoded by the mammalian rapgef3 gene: Structure, function and therapeutics 
Gene  2015;570(2):157-167.
Mammalian exchange protein directly activated by cAMP isoform 1 (EPAC1), encoded by the RAPGEF3 gene, is one of the two-membered family of cAMP sensors that mediate the intracellular functions of cAMP by acting as guanine nucleotide exchange factors for the Ras-like Rap small GTPases. Extensive studies have revealed that EPAC1-mediated cAMP signaling is highly coordinated spatiotemporally through the formation of dynamic signalosomes by interacting with a diverse array of cellular partners. Recent functional analyses of genetically engineered mouse models further suggest that EPAC1 functions as an important stress response switch and is involved in pathophysiological conditions of cardiac stresses, chronic pain, cancer and infectious diseases. These findings, coupled with the development of EPAC specific small molecule modulators, validate EPAC1 as a promising target for therapeutic interventions.
PMCID: PMC4556420  PMID: 26119090
RAPGEF3; EPAC1; cAMP signaling; Signalosomes; Therapeutic target
11.  PARP1 Differentially Interacts with Promoter region of DUX4 Gene in FSHD Myoblasts 
The goal of the study is to identity proteins, which interact with the promoter region of double homeobox protein 4 (DUX4) gene known to be causative for the autosomal dominant disorder Facioscapulohumeral Muscular Dystrophy (FSHD).
We performed a DNA pull down assay coupled with mass spectrometry analysis to identify proteins that interact with a DUX4 promoter probe in Rhabdomyosarcomca (RD) cells. We selected the top ranked protein poly (ADP-ribose) polymerase 1 (PARP1) from our mass spectrometry data for further ChIP-qPCR validation using patients' myoblasts. We then treated FSHD myoblasts with PARP1 inhibitors to investigate the role of PARP1 in the FSHD myoblasts.
In our mass spectrometry analysis, PARP1 was found to be the top ranked protein interacting preferentially with the DUX4 promoter probe in RD cells. We further validated this interaction by immunoblotting in RD cells (2-fold enrichment compared to proteins pulled down by a control probe, p<0.05) and ChIP-qPCR in patients' myoblasts (65-fold enrichment, p<0.01). Interestingly, the interaction was only observed in FSHD myoblasts but not in the control myoblasts. Upon further treatment of FSHD myoblasts with PARP1 inhibitors, we showed that treatment with a PARP1 inhibitor, 3-aminobenzamide (0.5 mM), for 24 h had a suppression of DUX4 (2.6 fold, p<0.05) and ZSCAN4, a gene previously shown to be upregulated by DUX4, (1.6 fold, p<0.01) in FSHD myoblasts. Treatment with fisetin (0.5 mM), a polyphenol compound with PARP1 inhibitory property, for 24 h also suppressed the expression of DUX4 (44.8 fold, p<0.01) and ZSCAN4 (2.2 fold, p<0.05) in the FSHD myoblasts. We further showed that DNA methyltransferase 1 (DNMT1), a gene regulated by PARP1 was also enriched at the DUX4 promoter in RD cells through immunoblotting (2-fold, p<0.01) and immortalized FSHD myoblasts (42-fold, p<0.01) but not control myoblasts through ChIP qPCR.
Our results showed that PARP1 and DNMT1 interacted with DUX4 promoter and may be involved in modulating DUX4 expression in FSHD.
PMCID: PMC5051271  PMID: 27722032
Facioscapulohumeral muscular dystrophy; Myoblast; Immunoblotting; DUX4 Gene
12.  On Ghosts and Other Unwelcome Guests 
Journal of General Internal Medicine  2015;30(10):1389-1391.
PMCID: PMC4579201  PMID: 25986141
13.  DISC1 Causes Associative Memory and Neurodevelopmental Defects in Fruit Flies 
Molecular psychiatry  2016;21(9):1232-1243.
Originally found in a Scottish family with diverse mental disorders, the DISC1 protein has been characterized as an intracellular scaffold protein that associates with diverse binding partners in neural development. To explore its functions in a genetically tractable system, we expressed the human DISC1 in fruit flies (Drosophila melanogaster). As in mammalian neurons, DISC1 is localized to diverse subcellular domains of developing fly neurons including the nuclei, axons and dendrites. Overexpression of DISC1 impairs associative memory. Experiments with deletion/mutation constructs have revealed the importance of amino terminal domain (46–290) for memory suppression whereas carboxyl domain (598–854) and the amino terminal residues (1–45) including the nuclear localization signal (NLS1) are dispensable. DISC1 overexpression also causes suppression of axonal and dendritic branching of mushroom body neurons, which mediate a variety of cognitive functions in the fly brain. Analyses with deletion constructs reveal that protein domains 598–854 and 349–402 are both required for the suppression of axonal branching while amino-terminal domains including NLS1 are dispensable. In contrast, NLS1 was required for the suppression of dendritic branching, suggesting a mechanism involving gene expression. Moreover, domain 403–596 is also required for the suppression of dendritic branching. We also show that overexpression of DISC1 suppresses glutamatergic synaptogenesis in developing neuromuscular junctions. Deletion/mutation experiments have revealed the importance of protein domains 403–596 and 349–402 for synaptic suppression, while amino terminal domains including NLS1 are dispensable. Finally, we show that DISC1 functionally interacts with the fly homolog of Dysbindin (DTNBP1) via direct protein-protein interaction in developing synapses.
PMCID: PMC4993648  PMID: 26976042
DISC1; memory; axons; dendrites; synapse; dysbindin
14.  Relation of dietary inorganic arsenic to serum matrix metalloproteinase-9 (MMP-9) at different threshold concentrations of tap water arsenic 
Arsenic (As) exposure is associated with cancer, lung and cardiovascular disease, yet the mechanisms involved are not clearly understood. Elevated matrix metalloproteinase-9 (MMP-9) levels are also associated with these diseases, as well as with exposure to water As. Our objective was to evaluate the effects of dietary components of inorganic As (iAs) intake on serum MMP-9 concentration at differing levels of tap water As. In a cross-sectional study of 214 adults, dietary iAs intake was estimated from 24-h dietary recall interviews using published iAs residue data; drinking and cooking water As intake from water samples and consumption data. Aggregate iAs intake (food plus water) was associated with elevated serum MMP-9 in mixed model regression, with and without adjustment for covariates. In models stratified by tap water As, aggregate intake was a significant positive predictor of serum MMP-9 in subjects exposed to water As ≤10 μg/l. Inorganic As from food alone was associated with serum MMP-9 in subjects exposed to tap water As ≤3 μg/l. Exposure to iAs from food and water combined, in areas where tap water As concentration is ≤10 μg/l, may contribute to As-induced changes in a biomarker associated with toxicity.
PMCID: PMC4698357  PMID: 25605447
MMP-9; arsenic; dietary exposure; aggregate exposure; biomarker of toxicity
15.  The Efficacy of Low Molecular Weight Heparin for the Prevention of Venous Thromboembolism after Hip Fracture Surgery in Korean Patients 
Yonsei Medical Journal  2016;57(5):1209-1213.
The aim of this study was to investigate the efficacy of low-molecular-weight heparin (LMWH) for the prevention of venous thromboembolism in Korean patients who underwent hip fracture surgery (HFS).
Materials and Methods
Prospectively, a total 181 cases were classified into the LMWH user group (116 cases) and LMWH non-user group (65 cases). Each group was sub-classified according to fracture types as follows: 81 cases of intertrochanteric fracture (group A: 49, group B: 32) and 100 cases of neck fracture (group C: 67, group D: 33). We compared the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) according to LMWH use.
Of the 181 cases, four DVTs were found in the LMWH user groups (1 in group A, and 3 in group C). One case of PE was found in LMWH non-user group D. The incidences of DVT and PE showed no statistically significant differences between the LMWH user and non-user groups (p=0.298 and 0.359, respectively). In subgroup analysis, no statistically significant differences were found between groups A and B and between groups C and D.
The administration of LMWH was not effective in the prevention of venous thromboembolism and PE in the Korean patients who underwent HFS.
PMCID: PMC4960388  PMID: 27401653
Low molecular weight heparin; deep vein thrombosis; pulmonary embolism; hip fracture
16.  Polyphenols contribute to the antioxidant and antiproliferative activity of Phyllanthus debilis plant in-vitro 
Phyllanthus debilis (Elapitawakka) is a medicinal plant used in traditional systems of medicine in Sri Lanka. Present study was carried out to evaluate in-vitro anti-oxidant and anti-proliferative activity of the water extracts of aerial parts (AP) and roots (RP) of P.debilis plant and the role of polyphenolic compounds in view of its medicinal use.
Total polyphenols, flavonoids and proanthocyanidin content of the extracts were quantified. DPPH, hydroxyl radical, nitric oxide and hydrogen peroxide scavenging potentials and the total antioxidant capacity, ferric ion reducing power were determined to evaluate antioxidant capacity. Anti-proliferative activity was assessed with MTT assay for Human Rhabdomyosarcoma (RD) and normal rat liver cells (CC1) after 24 h exposure to the plant extracts. DPPH and MTT assays were carried out for AP and RP extracts after removal of polyphenols to assess the contribution of polyphenols on antioxidant and anti-proliferative activity of Phyllanthus debilis.
Flavonoid content of the AP extract was significantly lower than that of RP (P < 0.001) while no significant difference was observed in polyphenolic as well as in proanthocyanidin contents. All the assays except for phosphomolybdate assay demonstrated that the RP extract had higher antioxidant capacity (p < 0.001) compared to AP. Further, antioxidant capacity and anti-proliferative activity were lower (p < 0.001) in AP and RP in the absence of polyphenols compared to the crude extract.
Root contains higher levels of flavonoids than the aerial part. Moreover, the presence of polyphenols is required for antioxidant and anti-proliferative activities of both AP and RP.
PMCID: PMC5009680  PMID: 27586856
Phyllanthus debilis; Polyphenols; Antioxidant activity; Anti-proliferative activity; RD; CC1
17.  The Foraging Brain: Evidence of Lévy Dynamics in Brain Networks 
PLoS ONE  2016;11(9):e0161702.
In this research we have analyzed functional magnetic resonance imaging (fMRI) signals of different networks in the brain under resting state condition. To such end, the dynamics of signal variation, have been conceived as a stochastic motion, namely it has been modelled through a generalized Langevin stochastic differential equation, which combines a deterministic drift component with a stochastic component where the Gaussian noise source has been replaced with α-stable noise. The parameters of the deterministic and stochastic parts of the model have been fitted from fluctuating data. Results show that the deterministic part is characterized by a simple, linear decreasing trend, and, most important, the α-stable noise, at varying characteristic index α, is the source of a spectrum of activity modes across the networks, from those originated by classic Gaussian noise (α = 2), to longer tailed behaviors generated by the more general Lévy noise (1 ≤ α < 2). Lévy motion is a specific instance of scale-free behavior, it is a source of anomalous diffusion and it has been related to many aspects of human cognition, such as information foraging through memory retrieval or visual exploration. Finally, some conclusions have been drawn on the functional significance of the dynamics corresponding to different α values.
PMCID: PMC5008767  PMID: 27583679
18.  Cue Reactivity in Nicotine and Alcohol Addiction: A Cross-Cultural View 
Frontiers in Psychology  2016;7:1335.
A wealth of research indicates that cue reactivity is critical to understanding the neurobiology of nicotine and alcohol addiction and developing treatments. Functional magnetic resonance imaging (fMRI) and electroencephalograph (EEG) studies have shown abnormal cue reactivity in various conditions between nicotine or alcohol addicts and the healthy. Although the causes of these abnormalities are still unclear, cultural effect can not be ignored. We conduct an review of fMRI and EEG studies about the cue reactivity in nicotine and alcohol addiction and highlight the cultural perspective. We suggest that cultural cue reactivity is a field worth of exploring which may has an effect on addictive behavior through emotion and attention. The cultural role of nicotine and alcohol addiction would provide new insight into understanding the mechanisms of nicotine and alcohol addiction and developing culture-specific therapies. We consider that culture as a context may be a factor that causes confusing outcomes in exploring nicotine and alcohol addiction which makes it possible to control the cultural influences and further contribute to the more consistent results.
PMCID: PMC5007723  PMID: 27635123
nicotine; alcohol; addiction; cross-culture; cue reactivity; context; emotion; attention
19.  aPKC Inhibition by Par3 CR3 Flanking Regions Controls Substrate Access and Underpins Apical-Junctional Polarization 
Developmental Cell  2016;38(4):384-398.
Atypical protein kinase C (aPKC) is a key apical-basal polarity determinant and Par complex component. It is recruited by Par3/Baz (Bazooka in Drosophila) into epithelial apical domains through high-affinity interaction. Paradoxically, aPKC also phosphorylates Par3/Baz, provoking its relocalization to adherens junctions (AJs). We show that Par3 conserved region 3 (CR3) forms a tight inhibitory complex with a primed aPKC kinase domain, blocking substrate access. A CR3 motif flanking its PKC consensus site disrupts the aPKC kinase N lobe, separating P-loop/αB/αC contacts. A second CR3 motif provides a high-affinity anchor. Mutation of either motif switches CR3 to an efficient in vitro substrate by exposing its phospho-acceptor site. In vivo, mutation of either CR3 motif alters Par3/Baz localization from apical to AJs. Our results reveal how Par3/Baz CR3 can antagonize aPKC in stable apical Par complexes and suggests that modulation of CR3 inhibitory arms or opposing aPKC pockets would perturb the interaction, promoting Par3/Baz phosphorylation.
Graphical Abstract
•Sequences flanking the Par3 CR3 consensus PKC site cooperate to inhibit aPKC•A Par3 CR3 inhibitory arm disrupts aPKC P-loop/αB/αC contacts and αC-helix position•Mutating either CR3 arm switches Par3 into an efficient aPKC substrate in vitro•Equivalent Bazooka substitutions alter its apical localization to AJs in vivo
Par3 is required for aPKC membrane recruitment, yet it polarizes to adherens junctions upon phosphorylation. Soriano et al. show that Par3 antagonizes active aPKC kinase by separating crucial N-lobe contacts. Disrupting high-affinity Par3 contacts switches it to an efficient aPKC substrate and polarizes Par3/Bazooka from apical domains to adherens junctions.
PMCID: PMC4998004  PMID: 27554858
20.  Identification of the mitochondrially encoded subunit 6 of F1FO ATPase in Trypanosoma brucei 
Kinetoplast maxicircle DNA of trypanosomatids encodes eighteen proteins. RNA editing is required to confer translatability to mRNA for twelve of these. Sequence conservation of the predicted hydrophobic polypeptides indicates that they represent functional components of the respiratory chain. Yet, so far only two of those, cytochrome c oxidase subunit I and apocytochrome b of cytochrome c reductase, have been identified with biochemical methods. Here we report on identification of A6 subunit of F1FO ATPase encoded by a pan-edited mRNA in Trypanosoma brucei. The polypeptide was present among the 35S-labeled mitochondrial translation products characterized by anomalous migration in denaturing 2D gels. It was identified as an ATPase subunit by co-migration with this complex in Blue Native 2D gels. A partial N-terminal sequence of the corresponding polypeptide present in the gel-purified ATPase complex from Leishmania tarentolae was consistent with the predicted A6 sequence.
PMCID: PMC4570845  PMID: 26276057
mitochondrial translation; RNA editing; subunit 6; F1FO ATPase; Trypanosoma brucei
21.  New England Cod Collapse and the Climate 
PLoS ONE  2016;11(7):e0158487.
To improve fishery management, there is an increasing need to understand the long-term consequences of natural and anthropogenic climate variability for ecological systems. New England’s iconic cod populations have been in decline for several decades and have recently reached unprecedented lows. We find that 17% of the overall decline in Gulf of Maine cod biomass since 1980 can be attributed to positive phases of the North Atlantic Oscillation (NAO). This is a consequence of three results: i) a 1-unit increase in the NAO winter index is associated with a 17% decrease in the spring biomass of age-1 cod the following year; ii) this NAO-driven decrease persists as the affected cohort matures; iii) fishing practices appear to exacerbate NAO’s direct biological effect such that, since 1913, a 1-unit increase in the NAO index lowers subsequent cod catch for up to 19 years. The Georges Bank cod stock displays similar patterns. Because we statistically detect a delay between the NAO and subsequent declines in adult biomass, our findings imply that observed current NAO conditions can be used in stock forecasts, providing lead time for adaptive policy. More broadly, our approach can inform forecasting efforts for other fish populations strongly affected by natural and anthropogenic climatic variation.
PMCID: PMC4963117  PMID: 27463967
22.  Determinants of health care seeking behaviour during pregnancy in Ogun State, Nigeria 
Reproductive Health  2016;13(Suppl 1):32.
In Nigeria, women too often suffer the consequences of serious obstetric complications that may lead to death. Delay in seeking care (phase I delay) is a recognized contributor to adverse pregnancy outcomes. This qualitative study aimed to describe the health care seeking practices in pregnancy, as well as the socio-cultural factors that influence these actions.
The study was conducted in Ogun State, in south-western Nigeria. Data were collected through focus group discussions with pregnant women, recently pregnant mothers, male decision-makers, opinion leaders, traditional birth attendants, health workers, and health administrators. A thematic analysis approach was used with QSR NVivo version 10.
Findings show that women utilized multiple care givers during pregnancy, with a preference for traditional providers. There was a strong sense of trust in traditional medicine, particularly that provided by traditional birth attendants who are long-term residents in the community. The patriarchal c influenced health-seeking behaviour in pregnancy. Economic factors contributed to the delay in access to appropriate services. There was a consistent concern regarding the cost barrier in accessing health services. The challenges of accessing services were well recognised and these were greater when referral was to a higher level of care which in most cases attracted unaffordable costs.
While the high cost of care is a deterrent to health seeking behaviour, the cost of death of a woman or a child to the family and community is immeasurable. The use of innovative mechanisms for health care financing may be beneficial for women in these communities to reduce the barrier of high cost services. To reduce maternal deaths all stakeholders must be engaged in the process including policy makers, opinion leaders, health care consumers and providers. Underlying socio-cultural factors, such as structure of patriarchy, must also be addressed to sustainably improve maternal health.
Trial registration
Electronic supplementary material
The online version of this article (doi:10.1186/s12978-016-0139-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4943510  PMID: 27356754
Health care; Pregnancy complications
23.  Efficacy and Safety of Panobinostat in Relapsed or/and Refractory Multiple Myeloma: Meta Analyses of Clinical Trials and Systematic Review 
Scientific Reports  2016;6:27361.
During the past decades, many novel agents have improved response and survival of patients with multiple myeloma. Nevertheless, it remains challenging when they suffer relapsing. Thus, novel therapeutic agents are needed. We aimed to assess the efficacy and safety of a novel agent panobinostat for patients with relapsed or/and refractory MM. A systematic literature review identified studies for clinical trials about panobinostat in patients with relapsed or/and refractory MM. We searched studies published between January 2000 and December 2015 in Pubmed, Ovid, EBSCO and the Cochrane library. Random-effect pooled estimates were calculated for overall response rate and rates of common adverse effects. The results showed 11 clinical trials including 700 patients with relapsed or/and refractory MM treated with panobinostat were identified. The ORR varied between 0.08 and 0.67. Pooled analyses showed the results that the ORR was 0.45 (95% CI: 0.31–0.59, I2 = 90.5%, P = 0.000) for panobinostat combined with any other kind of drugs. The most common Grade3/4 adverse effects were thrombocytopenia, neutropenia, lymphopenia, anemia, diarrhea, fatigue, nausea and so on. In conclusion, based on our analyses, the regimen of panobinostat combining with other agents seems to be well tolerated and efficacious in patients with relapsed or/and refractory MM.
PMCID: PMC4895230  PMID: 27270478
24.  The Posterosuperiorly Based Platysmal Myocutaneous Flap: The Underutilized Reconstructive Option 
The platysmal myocutaneous flap has shown promising results for the reconstruction of defects in the head and neck region. It has been successfully used for the reconstruction of the defects over the cheek, floor of the mouth, buccal mucosa, tongue, lower lip, mandibular alveolus, hypopharnx and supraglotic larynx. The posteriorly and the superiorly based platysmal flaps have a wide range of applicability in the reconstruction of intraoral defects. In the present series we have used a posterosuperiorly based platysmal flap which has shown encouraging results. It was also found that leaving the base of the mandible intact helps in maintaining the periosteal blood supply which further contributes to the survival of the flap. The thinness, arc of rotation, pliability and ease of availability of the platysmal myocutaneous flap gives the reconstructive surgeon an additional option, especially when a microvascular flap is not feasible.
PMCID: PMC4444680  PMID: 26028879
Platysmal myocutaneous flap; Superiorly based; Survival rate; Reconstruction
25.  EPAS1/HIF-2α is a driver of mammalian pexophagy 
Autophagy  2015;11(6):967-969.
Oxygen (O2) is an essential substrate in cellular metabolism and signaling and as such is linked to the survival and normal function of metazoans. Central to the molecular mechanisms underlying O2 homeostasis are hypoxia-inducible factors (HIFs), heterodimeric transcription factors composed of O2-regulated α subunits (HIF1A/HIF-1α or EPAS1/HIF-2α), and a constitutively expressed ARNT/HIF-1β subunit, that serve as master regulators of the adaptive response to hypoxia. HIF1A and EPAS1 have both unique and overlapping functions in the regulation of diverse cellular processes, but so far there has been no evidence linking HIF signaling to peroxisomes. In a recent study we identified a unique function of EPAS1 as promoter of pexophagy in hepatocytes. Here we summarize our findings and discuss potential mechanisms by which EPAS1 might trigger pexophagy.
PMCID: PMC4502715  PMID: 25997392
EPAS1; HIF-2; hypoxia; NBR1; p62; peroxisomes; pexophagy; SQSTM1; VHL; ccRCC, clear cell renal cell carcinomas; PMP, peroxisomal membrane protein; VLC, very long-chain.

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