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1.  Inhibition of HMGCoA reductase by simvastatin protects mice from injurious mechanical ventilation 
Respiratory Research  2015;16(1):24.
Background
Mortality from severe acute respiratory distress syndrome exceeds 40% and there is no available pharmacologic treatment. Mechanical ventilation contributes to lung dysfunction and mortality by causing ventilator-induced lung injury. We explored the utility of simvastatin in a mouse model of severe ventilator-induced lung injury.
Methods
Male C57BL6 mice (n = 7/group) were pretreated with simvastatin or saline and received protective (8 mL/kg) or injurious (25 mL/kg) ventilation for four hours. Three doses of simvastatin (20 mg/kg) or saline were injected intraperitoneally on days −2, −1 and 0 of the experiment. Lung mechanics, (respiratory system elastance, tissue damping and airway resistance), were evaluated by forced oscillation technique, while respiratory system compliance was measured with quasi-static pressure-volume curves. A pathologist blinded to treatment allocation scored hematoxylin-eosin-stained lung sections for the presence of lung injury. Pulmonary endothelial dysfunction was ascertained by bronchoalveolar lavage protein content and lung tissue expression of endothelial junctional protein Vascular Endothelial cadherin by immunoblotting. To assess the inflammatory response in the lung, we determined bronchoalveolar lavage fluid total cell content and neutrophil fraction by microscopy and staining in addition to Matrix-Metalloprotease-9 by ELISA. For the systemic response, we obtained plasma levels of Tumor Necrosis Factor-α, Interleukin-6 and Matrix-Metalloprotease-9 by ELISA. Statistical hypothesis testing was undertaken using one-way analysis of variance and Tukey’s post hoc tests.
Results
Ventilation with high tidal volume (HVt) resulted in significantly increased lung elastance by 3-fold and decreased lung compliance by 45% compared to low tidal volume (LVt) but simvastatin abrogated lung mechanical alterations of HVt. Histologic lung injury score increased four-fold by HVt but not in simvastatin-pretreated mice. Lavage pleocytosis and neutrophilia were induced by HVt but were significantly attenuated by simvastatin. Microvascular protein permeability increase 20-fold by injurious ventilation but only 4-fold with simvastatin. There was a 3-fold increase in plasma Tumor Necrosis Factor-α, a 7-fold increase in plasma Interleukin-6 and a 20-fold increase in lavage fluid Matrix-Metalloprotease-9 by HVt but simvastatin reduced these levels to control. Lung tissue vascular endothelial cadherin expression was significantly reduced by injurious ventilation but remained preserved by simvastatin.
Conclusion
High-dose simvastatin prevents experimental hyperinflation lung injury by angioprotective and anti-inflammatory effects.
doi:10.1186/s12931-015-0173-y
PMCID: PMC4336762
Ventilator lung injury; Acute respiratory distress syndrome; Acute lung injury; Pulmonary edema; Statin; Lung function; Lung compliance; Endothelial permeability
2.  Axonal transport of TDP-43 mRNA granules in neurons is impaired by ALS-causing mutations 
Neuron  2014;81(3):536-543.
Summary
The RNA binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. Thus, TDP43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43.
doi:10.1016/j.neuron.2013.12.018
PMCID: PMC3939050  PMID: 24507191
3.  A Prion-like Trigger of Antiviral Signaling 
Cell  2011;146(3):348-350.
The MAVS protein plays a critical role in the assembly of an antiviral signaling complex on mitochondrial membranes. Hou et al. (2011) now report that virus infection induces a conformational change in MAVS, leading to the prion-like formation of functional self-aggregates that provide a sensitive trigger for antiviral signaling.
doi:10.1016/j.cell.2011.07.018
PMCID: PMC4272580  PMID: 21816270
4.  A neurodegeneration-specific gene expression signature and immune profile of acutely isolated microglia from an ALS mouse model 
Cell reports  2013;4(2):385-401.
Microglia are resident immune cells of the CNS that are activated by infection, neuronal injury and inflammation. Here we utilize flow cytometry and deep RNA sequencing of acutely isolated spinal cord microglia to define their activation in vivo. Analysis of resting microglia identified 29 genes that distinguish microglia from other CNS cells and peripheral macrophages/monocytes. We then analyzed molecular changes in microglia during neurodegenerative disease activation using the SOD1G93A mouse model of ALS. We find that SOD1G93A microglia are not derived from infiltrating monocytes, and that both potentially neuroprotective and toxic factors are concurrently up-regulated, including Alzheimer’s disease genes. Mutant microglia differed from SOD1WT, LPS activated microglia, and M1/M2 macrophages, that define an ALS-specific phenotype. Concurrent mRNA/FACS analysis revealed post-transcriptional regulation of microglia surface receptors, and T cell-associated changes in the transcriptome. These results provide insights into microglia biology and establish a resource for future studies of neuroinflammation.
doi:10.1016/j.celrep.2013.06.018
PMCID: PMC4272581  PMID: 23850290
Microglia; transcriptome; FACS; ALS; neuroimmunology; neurodegeneration
5.  Scheduling in the context of resident duty hour reform 
BMC Medical Education  2014;14(Suppl 1):S18.
Fuelled by concerns about resident health and patient safety, there is a general trend in many jurisdictions toward limiting the maximum duration of consecutive work to between 14 and 16 hours. The goal of this article is to assist institutions and residency programs to make a smooth transition from the previous 24- to 36-hour call system to this new model. We will first give an overview of the main types of coverage systems and their relative merits when considering various aspects of patient care and resident pedagogy. We will then suggest a practical step-by-step approach to designing, implementing, and monitoring a scheduling system centred on clinical and educational needs in the context of resident duty hour reform. The importance of understanding the impetus for change and of assessing the need for overall workflow restructuring will be explored throughout this process. Finally, as a practical example, we will describe a large, university-based teaching hospital network’s transition from a traditional call-based system to a novel schedule that incorporates the new 16-hour duty limit.
doi:10.1186/1472-6920-14-S1-S18
PMCID: PMC4304277  PMID: 25561221
6.  Generation of single cell identity by homophilic interactions between combinations of α, β and γ protocadherins 
Cell  2014;158(5):1045-1059.
Summary
Individual mammalian neurons express distinct repertoires of protocadherin (Pcdh) -α, -β and -γ proteins that function in neural circuit assembly. Here we show that all three types of Pcdhs can engage in specific homophilic interactions, that cell surface delivery of alternate Pcdhα isoforms requires cis interactions with other Pcdh isoforms, and that the extracellular cadherin domain EC6 plays a critical role in this process. Analysis of specific combinations of up to five Pcdh isoforms showed that Pcdh homophilic recognition specificities strictly depend on the identity of all of the expressed isoforms, such that mismatched isoforms interfere with cell-cell interactions. We present a theoretical analysis showing that the assembly of Pcdh-α, –β and –γ isoforms into multimeric recognition units, and the observed tolerance for mismatched isoforms can generate the cell surface diversity necessary for single-cell identity. However, competing demands of non-self discrimination and self-recognition place limitations on the mechanisms by which recognition units can function.
doi:10.1016/j.cell.2014.07.012
PMCID: PMC4183217  PMID: 25171406
7.  Allele-Specific Knockdown of ALS-Associated Mutant TDP-43 in Neural Stem Cells Derived from Induced Pluripotent Stem Cells 
PLoS ONE  2014;9(3):e91269.
TDP-43 is found in cytoplasmic inclusions in 95% of amyotrophic lateral sclerosis (ALS) and 60% of frontotemporal lobar degeneration (FTLD). Approximately 4% of familial ALS is caused by mutations in TDP-43. The majority of these mutations are found in the glycine-rich domain, including the variant M337V, which is one of the most common mutations in TDP-43. In order to investigate the use of allele-specific RNA interference (RNAi) as a potential therapeutic tool, we designed and screened a set of siRNAs that specifically target TDP-43M337V mutation. Two siRNA specifically silenced the M337V mutation in HEK293T cells transfected with GFP-TDP-43wt or GFP-TDP-43M337V or TDP-43 C-terminal fragments counterparts. C-terminal TDP-43 transfected cells show an increase of cytosolic inclusions, which are decreased after allele-specific siRNA in M337V cells. We then investigated the effects of one of these allele-specific siRNAs in induced pluripotent stem cells (iPSCs) derived from an ALS patient carrying the M337V mutation. These lines showed a two-fold increase in cytosolic TDP-43 compared to the control. Following transfection with the allele-specific siRNA, cytosolic TDP-43 was reduced by 30% compared to cells transfected with a scrambled siRNA. We conclude that RNA interference can be used to selectively target the TDP-43M337V allele in mammalian and patient cells, thus demonstrating the potential for using RNA interference as a therapeutic tool for ALS.
doi:10.1371/journal.pone.0091269
PMCID: PMC3961241  PMID: 24651281
8.  Comment on “Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells” 
Science translational medicine  2013;5(188):188le2.
Egawa et al. recently showed the value of patient-specific induced pluripotent stem cells (iPSCs) for modeling amyotrophic lateral sclerosis in vitro. Their study and our work highlight the need for complementary assays to detect small, but potentially important, phenotypic differences between control iPSC lines and those carrying disease mutations.
doi:10.1126/scitranslmed.3005065
PMCID: PMC3936961  PMID: 23740897
9.  Single Molecule Imaging of Transcription Factor Binding to DNA in Live Mammalian Cells 
Nature methods  2013;10(5):421-426.
Imaging single fluorescent proteins in living mammalian cells is challenging due to out-of-focus fluorescence excitation by common microscopy schemes. We report the development of a novel fluorescence microscopy method, reflected light sheet microscopy (RLSM), which allows selective plane illumination throughout the nucleus of living mammalian cells, for reducing out-of-focus fluorescence signal. Generation of a thin light sheet parallel to the imaging plane and close to the sample surface is achieved by reflecting an elliptical laser beam incident from the top by 45° with a small mirror. The thin light sheet allows for an increased signal-to-background ratio superior to previous illumination schemes and enables imaging of single fluorescent proteins with up to 100 Hz time resolution. We demonstrate the sensitivity of RLSM by measuring the DNA-bound fraction of glucocorticoid receptor (GR) and determine the residence times on DNA of various oligomerization states and mutants of GR and estrogen receptor (ER), enabling us to resolve different modes of DNA binding of GR. Finally, we demonstrate two-color single molecule imaging by observing the spatio-temporal co-localization of two different protein pairs. The combination of our single molecule measurements and statistical analysis reveals dynamic properties of transcription factors in live mammalian cells.
doi:10.1038/nmeth.2411
PMCID: PMC3664538  PMID: 23524394
11.  Computed tomography-guided radiofrequency ablation for palliation of a painful supraclavicular soft-tissue metastasis invading the brachial plexus 
Oncology Letters  2013;6(5):1521-1523.
The present study describes a case of a painful supraclavicular soft-tissue metastasis of a skin melanoma invading the brachial plexus in a 38-year-old male. The patient was treated twice with radiofrequency ablation (RFA) under computed tomography (CT) guidance, which caused tumoral necrosis. The patient was originally referred with a 7-cm metastasis in the right supraclavicular fossa, which caused intractable pain and a degree of numbness. These symptoms were unresponsive to chemotherapy and radiotherapy and the pain was not controlled using narcotic analgesics. The lesion was treated with CT-guided RFA causing necrosis, relieving the pain and sparing the patient from using analgesics. The pain recurred 19 months thereafter and a CT scan revealed an 8-cm mass in the right supraclavicular space. The patient underwent repeat CT-guided RFA, which reduced the pain to a level that was controlled with minor oral analgesics. In conclusion, in this case of a painful supraclavicular soft-tissue metastasis invading the brachial plexus, which was intractable to chemotherapy and radiotherapy, RFA was feasible and offered substantial palliation of the symptoms, freedom from the use of narcotic analgesics and improvements to the quality of life.
doi:10.3892/ol.2013.1577
PMCID: PMC3813792  PMID: 24179552
soft tissue metastasis; supraclavicular; radiofrequency ablation; palliation; computed tomography-guided
12.  Induced expression and functional effects of aquaporin-1 in human leukocytes in sepsis 
Critical Care  2013;17(5):R199.
Introduction
Gene expression profiling was performed via DNA microarrays in leukocytes from critically ill trauma patients nonseptic upon admission to the ICU, who subsequently developed either sepsis (n = 2) or severe sepsis and acute respiratory distress syndrome (n = 3). By comparing our results with published expression profiling studies in animal models of sepsis and lung injury, we found aquaporin-1 to be differentially expressed across all studies. Our aim was to determine how the water channel aquaporin-1 is involved in regulating the immune response in critically ill patients during infection acquired in the ICU.
Methods
Following the results of the initial genetic screening study, we prospectively followed aquaporin-1 leukocyte expression patterns in patients with ICU-acquired sepsis who subsequently developed septic shock (n = 16) versus critically ill patients who were discharged without developing sepsis (n = 13). We additionally determined aquaporin-1 expression upon lipopolysaccharide (LPS) exposure and explored functional effects of aquaporin-1 induction in polymorphonuclear granulocytes (PMNs).
Results
Leukocyte aquaporin-1 expression was induced at the onset of sepsis (median 1.71-fold increase; interquartile range: 0.99 to 2.42, P = 0.012 from baseline) and was further increased upon septic shock (median 3.00-fold increase; interquartile range: 1.20 to 5.40, P = 0.023 from sepsis, Wilcoxon signed-rank test); no difference was observed between baseline and discharge in patients who did not develop sepsis. Stimulation of PMNs by LPS led to increased expression of aquaporin-1 in vitro, which could be abrogated by the NF-κB inhibitor EF-24. PMN hypotonic challenge resulted in a transient increase of the relative cell volume, which returned to baseline after 600 seconds, while incubation in the presence of LPS resulted in persistently increased cell volume. The latter could be abolished by blocking aquaporin-1 with mercury and restored by incubation in β-mercaptoethanol, which abrogated the action of mercury inhibition.
Conclusions
Aquaporin-1 is induced in leukocytes of patients with ICU-acquired sepsis and exhibits higher expression in septic shock. This phenomenon may be due to LPS-triggered NF-κB activation that can also lead to alterations in plasma membrane permeability.
doi:10.1186/cc12893
PMCID: PMC4056620  PMID: 24028651
13.  Financing and current capacity for REDD+ readiness and monitoring, measurement, reporting and verification in the Congo Basin 
This paper provides the first critical analysis of the financing and current capacity for REDD+ readiness in the Congo Basin, with a particular focus on the REDD+ component of national forest monitoring and measurement, reporting and verification (M&MRV). We focus on three areas of analysis: (i) general financing for REDD+ readiness especially M&MRV; (ii) capacity and information for REDD+ implementation and M&MRV; (iii) prospects and challenges for REDD+ and M&MRV readiness in terms of financing and capacity. For the first area of analysis, a REDD+ and M&MRV readiness financing database was created based on the information from the REDD+ voluntary database and Internet searches. For the second area of analysis, a qualitative approach to data collection was adopted (semi-structured interviews with key stakeholders, surveys and observations). All 10 countries were visited between 2010 and 2012. We find that: (i) a significant amount of REDD+ financing flows into the Congo Basin (±US$550 million or almost half of the REDD+ financing for the African continent); (ii) across countries, there is an important disequilibrium in terms of REDD+ and M&MRV readiness financing, political engagement, comprehension and capacity, which also appears to be a key barrier to countries receiving equal resources; (iii) most financing appears to go to smaller scale (subnational) REDD+ projects; (iv) four distinct country groups in terms of REDD+ readiness and M&MRV status are identified; and (v) the Congo Basin has a distinct opportunity to have a specific REDD+ financing window for large-scale and more targeted national REDD+ programmes through a specific fund for the region.
doi:10.1098/rstb.2012.0310
PMCID: PMC3720028  PMID: 23878337
REDD+ readiness; national forest monitoring systems; measurement, reporting and verification; Central African Commission; financing
14.  FUNCTIONAL SIGNIFICANCE OF ISOFORM DIVERSIFICATION IN THE PROTOCADHERIN GAMMA GENE CLUSTER 
Neuron  2012;75(3):402-409.
SUMMARY
The mammalian Protocadherin (Pcdh) alpha, beta, and gamma gene clusters encode a large family of cadherin-like transmembrane proteins that are differentially expressed in individual neurons. The 22 isoforms of the Pcdhg gene cluster are diversified into A-, B- and C-types, and the C-type isoforms differ from all other clustered Pcdhs in sequence and expression. Here we show that mice lacking the 3 C-type isoforms are phenotypically indistinguishable from the Pcdhg null mutants, displaying virtually identical cellular and synaptic alterations resulting from neuronal apoptosis. By contrast, mice lacking 3 A-type isoforms exhibit no detectable phenotypes. Remarkably, however, genetically blocking apoptosis rescues the neonatal lethality of the C-type isoform knockouts, but not that of the Pcdhg null mutants. We conclude that the role of the Pcdhg gene cluster in neuronal survival is primarily, if not specifically mediated by its C-type isoforms, whereas a separate role essential for postnatal development, likely in neuronal wiring, requires isoform diversity.
doi:10.1016/j.neuron.2012.06.039
PMCID: PMC3426296  PMID: 22884324
15.  Accelerated high-yield generation of limb-innervating motor neurons from human stem cells 
Human pluripotent stem cells are a promising source of differentiated cells for developmental studies, cell transplantation, disease modeling, and drug testing. However, their widespread use even for intensely studied cell types like spinal motor neurons is hindered by the long duration and low yields of existing protocols for in vitro differentiation and by the molecular heterogeneity of the populations generated. We report a combination of small molecules that within 3 weeks induce motor neurons at up to 50% abundance and with defined subtype identities of relevance to neurodegenerative disease. Despite their accelerated differentiation, motor neurons expressed combinations of HB9, ISL1 and column-specific markers that mirror those observed in vivo in human fetal spinal cord. They also exhibited spontaneous and induced activity, and projected axons towards muscles when grafted into developing chick spinal cord. Strikingly, this novel protocol preferentially generates motor neurons expressing markers of limb-innervating lateral motor column motor neurons (FOXP1+/LHX3−). Access to high-yield cultures of human limb-innervating motor neuron subtypes will facilitate in-depth study of motor neuron subtype-specific properties, disease modeling, and development of large-scale cell-based screening assays.
doi:10.1523/JNEUROSCI.0906-12.2013
PMCID: PMC3711539  PMID: 23303937
16.  Unpicking neurodegeneration in a dish with human pluripotent stem cells 
Cell Cycle  2013;12(15):2339-2340.
doi:10.4161/cc.25705
PMCID: PMC3841307  PMID: 23856579
ALS; astrocytes; stem cell; reactive gliosis; glia; TDP-43; SOD1; disease modeling
17.  A Socio-Ecological Assessment Aiming at Improved Forest Resource Management and Sustainable Ecotourism Development in the Mangroves of Tanbi Wetland National Park, The Gambia, West Africa 
Ambio  2012;41(5):513-526.
Although mangroves dominated by Avicennia germinans and Rhizophora mangle are extending over 6000 ha in the Tanbi Wetland National Park (TWNP) (The Gambia), their importance for local populations (both peri-urban and urban) is not well documented. For the first time, this study evaluates the different mangrove resources in and around Banjul (i.e., timber, non-timber, edible, and ethnomedicinal products) and their utilization patterns, including the possibility of ecotourism development. The questionnaire-based results have indicated that more than 80% of peri-urban population rely on mangroves for timber and non-timber products and consider them as very important for their livelihoods. However, at the same time, urban households demonstrate limited knowledge on mangrove species and their ecological/economic benefits. Among others, fishing (including the oyster—Crassostrea cf. gasar collection) and tourism are the major income-generating activities found in the TWNP. The age-old practices of agriculture in some parts of the TWNP are due to scarcity of land available for agriculture, increased family size, and alternative sources of income. The recent focus on ecotourism (i.e., boardwalk construction inside the mangroves near Banjul city) received a positive response from the local stakeholders (i.e., users, government, and non-government organizations), with their appropriate roles in sharing the revenue, rights, and responsibilities of this project. Though the guidelines for conservation and management of the TWNP seem to be compatible, the harmony between local people and sustainable resource utilization should be ascertained.
Electronic supplementary material
The online version of this article (doi:10.1007/s13280-012-0248-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s13280-012-0248-7
PMCID: PMC3390577  PMID: 22351596
Mangroves; Socio-ecology; Tanbi Wetland National Park; Resource utilization; Participatory methods; The Gambia
18.  Structure-based prediction of protein-protein interactions on a genome-wide scale 
Nature  2012;490(7421):556-560.
The genome-wide identification of pairs of interacting proteins is an important step in the elucidation of cell regulatory mechanisms1,2. Much of our current knowledge derives from high-throughput techniques such as yeast two hybrid and affinity purification3, as well as from manual curation of experiments on individual systems4. A variety of computational approaches based, for example, on sequence homology, gene co-expression, and phylogenetic profiles have also been developed for the genome-wide inference of protein-protein interactions (PPIs)5,6. Yet, comparative studies suggest that the development of accurate and complete repertoires of PPIs is still in its early stages7–9. Here we show that three-dimensional structural information can be used to predict PPIs with an accuracy and coverage that are superior to predictions based on non-structural evidence. Moreover, an algorithm, PrePPI, that combines structural information with other functional clues is comparable in accuracy to high-throughput experiments, yielding over 30,000 high confidence interactions for yeast and over 300,000 for human. Experimental tests of a number of predictions demonstrate the ability of the PrePPI algorithm to identify unexpected PPIs of significant biological interest. The surprising effectiveness of three-dimensional structural information can be attributed to the use of homology models combined with the exploitation of both close and remote geometric relationships between proteins.
doi:10.1038/nature11503
PMCID: PMC3482288  PMID: 23023127
19.  Gastroduodenal artery aneurysm, diagnosis, clinical presentation and management: a concise review 
Gastroduodenal artery (GDA) aneurysms are rare but a potentially fatal condition if rupture occurs. They represent about 1.5% of all visceral artery (VAA) aneurysms and are divided into true and pseudoaneurysms depending on the etiologic factors underlying their development. Atherosclerosis and pancreatitis are the two most common risk factors. Making the diagnosis can be complex and often requires the use of Computed Tomography and angiography. The later adds the advantage of being a therapeutic option to prevent or stop bleeding. If this fails, surgery is still regarded as the standard for accomplishing a definite treatment.
doi:10.1186/1750-1164-7-4
PMCID: PMC3637616  PMID: 23587203
20.  Preclinical pulmonary capillary endothelial dysfunction is present in brain dead subjects 
Pulmonary Circulation  2013;3(2):419-425.
Pulmonary endothelium is a major metabolic organ affecting pulmonary and systemic vascular homeostasis. Brain death (BD)-induced physiologic and metabolic derangements in donors’ lungs, in the absence of overt lung pathology, may cause pulmonary dysfunction and compromise post-transplant graft function. To explore the impact of BD on pulmonary endothelium, we estimated pulmonary capillary endothelium-bound (PCEB)-angiotensin converting enzyme (ACE) activity, a direct and quantifiable index of pulmonary endothelial function, in eight brain-dead patients and ten brain-injured mechanically ventilated controls. No subject suffered from acute lung injury or any other overt lung pathology. Applying indicator-dilution type techniques, we measured single-pass transpulmonary percent metabolism (%M) and hydrolysis (v) of the synthetic, biologically inactive, and highly specific for ACE substrate 3H-benzoyl-Phe-Ala-Pro, under first order reaction conditions, and calculated lung functional capillary surface area (FCSA). Substrate %M (35 ± 6.8%) and v (0.49 ± 0.13) in BD patients were decreased as compared to controls (55.9 ± 4.9, P = 0.033 and 0.9 ± 0.15, P = 0.033, respectively), denoting decreased pulmonary endothelial enzyme activity at the capillary level; FCSA, a reflection of endothelial enzyme activity per vascular bed, was also decreased (BD patients: 1,563 ± 562 mL/min vs 4,235 ± 559 in controls; P = 0.003). We conclude that BD is associated with subtle pulmonary endothelial injury, expressed by decreased PCEB-ACE activity. The applied indicator-dilution type technique provides direct and quantifiable indices of pulmonary endothelial function at the bedside that may reveal the existence of preclinical lung pathology in potential lung donors.
doi:10.4103/2045-8932.113189
PMCID: PMC3757838  PMID: 24015344
angiotensin converting enzyme; brain death; pulmonary endothelium
21.  PROTOCADHERINS MEDIATE DENDRITIC SELF-AVOIDANCE IN THE MAMMALIAN NERVOUS SYSTEM 
Nature  2012;488(7412):517-521.
Dendritic arbors of many neurons are patterned by a process called self-avoidance, in which branches arising from a single neuron repel each other1-7. By minimizing gaps and overlaps within the arbor, self-avoidance facilitates complete coverage of a neuron’s territory by its neurites1-3. Remarkably, some neurons that display self-avoidance interact freely with other neurons of the same subtype, implying that they discriminate self from non-self. Here, we demonstrate roles for the clustered protocadherins (Pcdhs) in dendritic self-avoidance and self/non-self discrimination. The Pcdh locus encodes ~60 related cadherin-like transmembrane proteins, at least some of which exhibit isoform-specific homophilic adhesion in heterologous cells and are expressed stochastically and combinatorially in single neurons7-11. Deletion of all 22 Pcdhs in the mouse gamma subcluster (Pcdhgs) disrupts self-avoidance of dendrites in retinal starburst amacrine cells (SACs) and cerebellar Purkinje cells. Further genetic analysis of SACs showed that Pcdhgs act cell-autonomously during development, and that replacement of the 22 Pcdhgs with a single isoform restores self-avoidance. Moreover, expression of the same single isoform in all SACs decreases interactions among dendrites of neighboring SACs (heteroneuronal interactions). These results suggest that homophilic Pcdhg interactions between sibling neurites (isoneuronal interactions) generate a repulsive signal that leads to self-avoidance. In this model, heteroneuronal interactions are normally permitted because dendrites seldom encounter a matched set of Pcdhgs unless they emanate from the same soma. In many respects, our results mirror those reported for Dscam1 in Drosophila: this complex gene encodes thousands of recognition molecules that exhibit stochastic expression and isoform-specific interactions, and mediate both self-avoidance and self/non-self discrimination4-7,12-15. Thus, although insect Dscams and vertebrate Pcdhs share no sequence homology, they appear to underlie similar strategies for endowing neurons with distinct molecular identities and patterning their arbors.
doi:10.1038/nature11305
PMCID: PMC3427422  PMID: 22842903
22.  Molecular and functional interaction between Protocadherin γ-C5 and GABAA receptors 
We have found that the γ2 subunit of the GABAA receptor (γ2-GABAAR) specifically interacts with protocadherin γ-C5 (Pcdh-γC5) in the rat brain. The interaction occurs between the large intracellular loop of the γ2-GABAAR and the cytoplasmic domain of Pcdh-γC5. In brain extracts, Pcdh-γC5 co-immunoprecipitates with GABAARs. In co-transfected HEK293 cells, Pcdh-γC5 promotes the transfer of γ2-GABAAR to the cell surface. We have previously shown that in cultured hippocampal neurons, endogenous Pcdh-γC5 forms clusters, some of which associate with GABAergic synapses. Overexpression of Pcdh-γC5 in hippocampal neurons increases the density ofγ2-GABAAR clusters but has no significant effect on the number of GABAergic contacts that these neurons receive, indicating that Pcdh-γC5 is not synaptogenic. Deletion of the cytoplasmic domain of Pcdh-γC5 enhanced its surface expression but decreased the association with both γ2-GABAAR clusters and presynaptic GABAergic contacts. Cultured hippocampal neurons from the Pcdh-γ triple C-type isoform knockout (TCKO) mouse (Pcdhgtcko/tcko) showed plenty of GABAergic synaptic contacts, although their density was reduced compared with sister cultures from wild type and heterozygous mice. Knocking down Pcdh-γC5 expression with shRNA decreased γ2-GABAAR cluster density and GABAergic innervation. The results indicate that although Pcdh-γC5 is not essential for GABAergic synapse formation or GABAAR clustering, i) Pcdh-γC5 regulates the surface expression of GABAARs via cis-cytoplasmic interaction with γ2-GABAAR; and ii) Pcdh-γC5 plays a role in the stabilization and maintenance of some GABAergic synapses.
doi:10.1523/JNEUROSCI.0969-12.2012
PMCID: PMC3445339  PMID: 22915120
GABAA receptors; synapses; GABAergic synapse; protocadherin; PCDHGC5; interaction
23.  Smoke trails of a dying gut: portal and mesenteric vein gas 
BMJ Case Reports  2010;2010:bcr0120102660.
doi:10.1136/bcr.01.2010.2660
PMCID: PMC3030284  PMID: 22791777
24.  FUS-SMN protein interactions link the motor neuron diseases ALS and SMA 
Cell reports  2012;2(4):799-806.
Summary
Mutations in the RNA binding protein FUS cause ALS, a fatal adult motor neuron disease. Decreased expression of SMN causes the fatal childhood motor neuron disorder SMA. The SMN complex localizes in both the cytoplasm and nuclear Gems, and loss of Gems is a cellular hallmark of SMA patient fibroblasts. Here, we report that FUS associates with the SMN complex, an interaction mediated by U1 snRNP and by direct interactions between FUS and SMN. Functionally, we show that FUS is required for Gem formation in HeLa cells, and expression of FUS containing a severe ALS-causing mutation (R495X) also results in Gem loss. Strikingly, a reduction in Gems is observed in ALS patient fibroblasts expressing either mutant FUS or TDP-43, another ALS-causing protein that interacts with FUS. The physical and functional interactions between SMN, FUS, TDP-43, and Gems indicate that ALS and SMA share a biochemical pathway, adding strong new support to the view that these motor neuron diseases are related.
doi:10.1016/j.celrep.2012.08.025
PMCID: PMC3483417  PMID: 23022481
25.  Post-traumatic pulmonary pseudocyst with hemopneumothorax following blunt chest trauma: a case report 
Introduction
Post-traumatic pulmonary pseudocyst is an uncommon cavitary lesion of the lung and develops after blunt chest trauma and even more rarely following penetrating injuries. It is generally seen in young adults presenting with cough, chest pain, hemoptysis, and dyspnea. Post-traumatic pulmonary pseudocyst should be included in the differential diagnosis of cavitary pulmonary lesions. We describe the case of a 60-year-old Caucasian Greek woman who sustained traumatic pulmonary pseudocyst with hemopneumothorax due to a blunt chest trauma after a traffic accident.
Case presentation
After a traffic accident, a 60-year-old Caucasian Greek woman sustained a hemopneumothorax due to a blunt chest trauma. There was evidence of an extensive contusion in the posterior and lateral segments of the right lower lobe, a finding that was attributed to an early sign of a cavitation, and the presence of a thin-walled air cavity was detected on the anterior segment of the right lower lobe in the control computed tomography taken 24 hours after admission. Our patient was treated by catheter aspiration, and the findings of computed tomography evaluation about one month later showed complete resolution of one of the two air-filled cavitary lesions. The second pseudocyst also disappeared completely, as shown by the control computed tomography scan performed six months later.
Conclusions
Traumatic pulmonary pseudocyst is a rare complication of blunt chest trauma, and computed tomography is a more valuable imaging technique than chest radiograph for early diagnosis.
doi:10.1186/1752-1947-6-356
PMCID: PMC3485102  PMID: 23083130
Traumatic pulmonary pseudocyst; lung cyst; blunt chest trauma; pulmonary contusion

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