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1.  Uterine Spiral Artery Remodeling Involves Endothelial Apoptosis Induced by Extravillous Trophoblasts Through Fas/FasL Interactions 
Invasion of uterine spiral arteries by extravillous trophoblasts in the first trimester of pregnancy results in loss of endothelial and musculoelastic layers. This remodeling is crucial for an adequate blood supply to the fetus with a failure to remodel implicated in the etiology of the hypertensive disorder preeclampsia. The mechanism by which trophoblasts induce this key process is unknown. This study gives the first insights into the potential mechanisms involved.
Methods and Results
Spiral arteries were dissected from nonplacental bed biopsies obtained at Caesarean section, and a novel model was used to mimic in vivo events. Arteries were cultured with trophoblasts in the lumen, and apoptotic changes in the endothelial layer were detected after 20 hours, leading to loss of endothelium by 96 hours. In vitro, coculture experiments showed that trophoblasts stimulated apoptosis of primary decidual endothelial cells and an endothelial cell line. This was blocked by caspase inhibition and NOK2, a FasL blocking antibody. NOK2 also abrogated trophoblast-induced endothelial apoptosis in the vessel model.
Extravillous trophoblast induction of endothelial apoptosis is a possible mechanism by which the endothelium is removed, and vascular remodeling may occur in uterine spiral arteries. Fas/FasL interactions have an important role in trophoblast-induced endothelial apoptosis.
PMCID: PMC4228192  PMID: 15499040
apoptosis; endothelium; trophoblast; pregnancy; arteries
2.  Crystal structure of a layered coordination polymer based on a 44 net containing Cd2+ ions and 1,5-bis­(pyridin-4-yl)pentane linkers 
[Cd(C15H18N2)2(H2O)2](ClO4)2·C15H18N2·C2H6O, is a layered coordination polymer containing highly squashed 44 nets. The polymeric sheets alternate with layers of counter ions, free ligands and solvent molecules.
The title compound, poly[[di­aqua­bis­[1,5-bis­(pyridin-4-yl)pentane-κ2 N:N′]cadmium] bis­(perchlorate) 1,5-bis­(pyridin-4-yl)pentane ethanol mono­solvate], [Cd(C15H18N2)2(H2O)2](ClO4)2·C15H18N2·C2H6O, is a layered coordination polymer built up from highly squashed 44 nets in which the octa­hedral trans-CdO2N4 nodes (Cd site symmetry -1) are linked by the bifunctional ligands, forming infinite (110) sheets. The cationic sheets are charge-balanced by inter­layer perchlorate ions. A free 1,5-bis­(pyridin-4-yl)pentane mol­ecule and an ethanol mol­ecule of crystallization are also found in the inter­sheet region. A number of O—H⋯O, O—H⋯N and C—H⋯O hydrogen bonds help to consolidate the layered structure.
PMCID: PMC4158512  PMID: 25249860
Cadmium; flexible ligand; layered coordination polymer; crystal structure
3.  Suppression of the auxin response pathway enhances susceptibility to Phytophthora cinnamomi while phosphite-mediated resistance stimulates the auxin signalling pathway 
BMC Plant Biology  2014;14:68.
Phytophthora cinnamomi is a devastating pathogen worldwide and phosphite (Phi), an analogue of phosphate (Pi) is highly effective in the control of this pathogen. Phi also interferes with Pi starvation responses (PSR), of which auxin signalling is an integral component. In the current study, the involvement of Pi and the auxin signalling pathways in host and Phi-mediated resistance to P. cinnamomi was investigated by screening the Arabidopsis thaliana ecotype Col-0 and several mutants defective in PSR and the auxin response pathway for their susceptibility to this pathogen. The response to Phi treatment was also studied by monitoring its effect on Pi- and the auxin response pathways.
Here we demonstrate that phr1-1 (phosphate starvation response 1), a mutant defective in response to Pi starvation was highly susceptible to P. cinnamomi compared to the parental background Col-0. Furthermore, the analysis of the Arabidopsis tir1-1 (transport inhibitor response 1) mutant, deficient in the auxin-stimulated SCF (Skp1 − Cullin − F-Box) ubiquitination pathway was also highly susceptible to P. cinnamomi and the susceptibility of the mutants rpn10 and pbe1 further supported a role for the 26S proteasome in resistance to P. cinnamomi. The role of auxin was also supported by a significant (P < 0.001) increase in susceptibility of blue lupin (Lupinus angustifolius) to P. cinnamomi following treatment with the inhibitor of auxin transport, TIBA (2,3,5-triiodobenzoic acid). Given the apparent involvement of auxin and PSR signalling in the resistance to P. cinnamomi, the possible involvement of these pathways in Phi mediated resistance was also investigated. Phi (especially at high concentrations) attenuates the response of some Pi starvation inducible genes such as AT4, AtACP5 and AtPT2 in Pi starved plants. However, Phi enhanced the transcript levels of PHR1 and the auxin responsive genes (AUX1, AXR1and AXR2), suppressed the primary root elongation, and increased root hair formation in plants with sufficient Pi.
The auxin response pathway, particularly auxin sensitivity and transport, plays an important role in resistance to P. cinnamomi in Arabidopsis, and phosphite-mediated resistance may in some part be through its effect on the stimulation of the PSR and auxin response pathways.
PMCID: PMC3999932  PMID: 24649892
Abscisic acid; Indole-3-acetic acid (IAA); Phosphate starvation response (PSR); TIBA; Ubiquitin proteasome pathway (UPP)
4.  Neural precursor cells induce cell death of high-grade astrocytomas via stimulation of TRPV1 
Nature medicine  2012;18(8):10.1038/nm.2827.
Primary astrocytomas of World Health Organization grade 3 and grade 4 (HG-astrocytomas) are preponderant among adults and are almost invariably fatal despite multimodal therapy. Here, we show that the juvenile brain has an endogenous defense mechanism against HG-astrocytomas. Neural precursor cells (NPCs) migrate to HG-astrocytomas, reduce glioma expansion and prolong survival by releasing a group of fatty acid ethanolamides that have agonistic activity on the vanilloid receptor (transient receptor potential vanilloid subfamily member-1; TRPV1). TRPV1 expression is higher in HG-astrocytomas than in tumor-free brain and TRPV1 stimulation triggers tumor cell death via the activating transcription factor-3 (ATF3) controlled branch of the ER stress pathway. The anti-tumorigenic response of NPCs is lost with aging. NPC-mediated tumor suppression can be mimicked in the adult brain by systemic administration of the synthetic vanilloid Arvanil, suggesting that TRPV1 agonists hold potential as new HG-astrocytoma therapeutics.
PMCID: PMC3480991  PMID: 22820645
5.  Combining Inferential and Deductive Approaches to Estimate the Potential Geographical Range of the Invasive Plant Pathogen, Phytophthora ramorum 
PLoS ONE  2013;8(5):e63508.
Phytophthora ramorum, an invasive plant pathogen of unknown origin, causes considerable and widespread damage in plant industries and natural ecosystems of the USA and Europe. Estimating the potential geographical range of P. ramorum has been complicated by a lack of biological and geographical data with which to calibrate climatic models. Previous attempts to do so, using either invaded range data or surrogate species approaches, have delivered varying results. A simulation model was developed using CLIMEX to estimate the global climate suitability patterns for establishment of P. ramorum. Growth requirements and stress response parameters were derived from ecophysiological laboratory observations and site-level transmission and disease factors related to climate data in the field. Geographical distribution data from the USA (California and Oregon) and Norway were reserved from model-fitting and used to validate the models. The model suggests that the invasion of P. ramorum in both North America and Europe is still in its infancy and that it is presently occupying a small fraction of its potential range. Phytophthora ramorum appears to be climatically suited to large areas of Africa, Australasia and South America, where it could cause biodiversity and economic losses in plant industries and natural ecosystems with susceptible hosts if introduced.
PMCID: PMC3646738  PMID: 23667628
6.  Koi Herpesvirus Encodes and Expresses a Functional Interleukin-10 
Journal of Virology  2012;86(21):11512-11520.
Koi herpesvirus (KHV) (species Cyprinid herpesvirus 3) ORF134 was shown to transcribe a spliced transcript encoding a 179-amino-acid (aa) interleukin-10 (IL-10) homolog (khvIL-10) in koi fin (KF-1) cells. Pairwise sequence alignment indicated that the expressed product shares 25% identity with carp IL-10, 22 to 24% identity with mammalian (including primate) IL-10s, and 19.1% identity with European eel herpesvirus IL-10 (ahvIL-10). In phylogenetic analyses, khvIL-10 fell in a divergent position from all host IL-10 sequences, indicating extensive structural divergence following capture from the host. In KHV-infected fish, khvIL-10 transcripts were observed to be highly expressed during the acute and reactivation phases but to be expressed at very low levels during low-temperature-induced persistence. Similarly, KHV early (helicase [Hel] and DNA polymerase [DNAP]) and late (intercapsomeric triplex protein [ITP] and major capsid protein [MCP]) genes were also expressed at high levels during the acute and reactivation phases, but only low-level expression of the ITP gene was detected during the persistent phase. Injection of khvIL-10 mRNA into zebrafish (Danio rerio) embryos increased the number of lysozyme-positive cells to a similar degree as zebrafish IL-10. Downregulation of the IL-10 receptor long chain (IL-10R1) using a specific morpholino abrogated the response to both khvIL-10 and zebrafish IL-10 transcripts, indicating that, despite the structural divergence, khvIL-10 functions via this receptor. This is the first report describing the characteristics of a functional viral IL-10 gene in the Alloherpesviridae.
PMCID: PMC3486318  PMID: 22896613
7.  Acclimation responses of Arabidopsis thaliana to sustained phosphite treatments 
Journal of Experimental Botany  2013;64(6):1731-1743.
Phosphite () induces a range of physiological and developmental responses in plants by disturbing the homeostasis of the macronutrient phosphate. Because of its close structural resemblance to phosphate, phosphite impairs the sensing, membrane transport, and subcellular compartmentation of phosphate. In addition, phosphite induces plant defence responses by an as yet unknown mode of action. In this study, the acclimation of Arabidopsis thaliana plants to a sustained phosphite supply in the growth medium was investigated and compared with plants growing under varying phosphate supplies. Unlike phosphate, phosphite did not suppress the formation of lateral roots in several Arabidopsis accessions. In addition, the expression of well-documented phosphate-starvation-induced genes, such as miRNA399d and At4, was not repressed by phosphite accumulation, whilst the induction of PHT1;1 and PAP1 was accentuated. Thus, a mimicking of phosphate by phosphite was not observed for these classical phosphate-starvation responses. Metabolomic analysis of phosphite-treated plants showed changes in several metabolite pools, most prominently those of aspartate, asparagine, glutamate, and serine. These alterations in amino acid pools provide novel insights for the understanding of phosphite-induced pathogen resistance.
PMCID: PMC3617837  PMID: 23404904
Arabidopsis; phosphate; phosphate-starvation response; phosphite
8.  Impact of gastro-oesophageal reflux on microRNA expression, location and function 
BMC Gastroenterology  2013;13:4.
Ulceration of the oesophageal squamous mucosa (ulcerative oesophagitis) is a pathological manifestation of gastro-oesophageal reflux disease, and is a major risk factor for the development of Barrett’s oesophagus. Barrett’s oesophagus is characterised by replacement of reflux-damaged oesophageal squamous epithelium with a columnar intestinal-like epithelium. We previously reported discovery of microRNAs that are differentially expressed between oesophageal squamous mucosa and Barrett’s oesophagus mucosa. Now, to better understand early steps in the initiation of Barrett’s oesophagus, we assessed the expression, location and function of these microRNAs in oesophageal squamous mucosa from individuals with ulcerative oesophagitis.
Quantitative real-time PCR was used to compare miR-21, 143, 145, 194, 203, 205 and 215 expression levels in oesophageal mucosa from individuals without pathological gastro-oesophageal reflux to individuals with ulcerative oesophagitis. Correlations between microRNA expression and messenger RNA differentiation markers BMP-4, CK8 and CK14 were analyzed. The cellular localisation of microRNAs within the oesophageal mucosa was determined using in-situ hybridisation. microRNA involvement in proliferation and apoptosis was assessed following transfection of a human squamous oesophageal mucosal cell line (Het-1A).
miR-143, miR-145 and miR-205 levels were significantly higher in gastro-oesophageal reflux compared with controls. Elevated miR-143 expression correlated with BMP-4 and CK8 expression, and elevated miR-205 expression correlated negatively with CK14 expression. Endogenous miR-143, miR-145 and miR-205 expression was localised to the basal layer of the oesophageal epithelium. Transfection of miR-143, 145 and 205 mimics into Het-1A cells resulted in increased apoptosis and decreased proliferation.
Elevated miR-143, miR-145 and miR-205 expression was observed in oesophageal squamous mucosa of individuals with ulcerative oesophagitis. These miRNAs localised to the basal layer of the oesophageal epithelium. They reduced proliferation and increased apoptosis, and may play roles in regulating epithelial restoration in response to injury caused by gastro-oesophageal reflux.
PMCID: PMC3553039  PMID: 23297865
microRNA; Gastro-oesophageal reflux disease; Ulcerative oesophagitis; Apoptosis; Proliferation; Barrett’s oesophagus
9.  Fungal Planet description sheets: 128–153 
Novel species of microfungi described in the present study include the following from Australia: Catenulostroma corymbiae from Corymbia, Devriesia stirlingiae from Stirlingia, Penidiella carpentariae from Carpentaria, Phaeococcomyces eucalypti from Eucalyptus, Phialophora livistonae from Livistona, Phyllosticta aristolochiicola from Aristolochia, Clitopilus austroprunulus on sclerophyll forest litter of Eucalyptus regnans and Toxicocladosporium posoqueriae from Posoqueria. Several species are also described from South Africa, namely: Ceramothyrium podocarpi from Podocarpus, Cercospora chrysanthemoides from Chrysanthemoides, Devriesia shakazului from Aloe, Penidiella drakensbergensis from Protea, Strelitziana cliviae from Clivia and Zasmidium syzygii from Syzygium. Other species include Bipolaris microstegii from Microstegium and Synchaetomella acerina from Acer (USA), Brunneiapiospora austropalmicola from Rhopalostylis (New Zealand), Calonectria pentaseptata from Eucalyptus and Macadamia (Vietnam), Ceramothyrium melastoma from Melastoma (Indonesia), Collembolispora aristata from stream foam (Czech Republic), Devriesia imbrexigena from glazed decorative tiles (Portugal), Microcyclospora rhoicola from Rhus (Canada), Seiridium phylicae from Phylica (Tristan de Cunha, Inaccessible Island), Passalora lobeliae-fistulosis from Lobelia (Brazil) and Zymoseptoria verkleyi from Poa (The Netherlands). Valsalnicola represents a new ascomycete genus from Alnus (Austria) and Parapenidiella a new hyphomycete genus from Eucalyptus (Australia). Morphological and culture characteristics along with ITS DNA barcodes are also provided.
PMCID: PMC3589791  PMID: 23606771
ITS DNA barcodes; LSU; novel fungal species; systematics
10.  A stomatin dimer modulates the activity of acid-sensing ion channels 
The EMBO Journal  2012;31(17):3635-3646.
Stomatins govern membrane trafficking and ion channel activity. The banana-shaped stomatin-domain dimmers oligomerize into a cylindrical structure. A dynamic hydrophobic pocket at the concave side of the dimer mediates repression of acid-sensing ion channel 3 (ASIC3) activity.
Stomatin proteins oligomerize at membranes and have been implicated in ion channel regulation and membrane trafficking. To obtain mechanistic insights into their function, we determined three crystal structures of the conserved stomatin domain of mouse stomatin that assembles into a banana-shaped dimer. We show that dimerization is crucial for the repression of acid-sensing ion channel 3 (ASIC3) activity. A hydrophobic pocket at the inside of the concave surface is open in the presence of an internal peptide ligand and closes in the absence of this ligand, and we demonstrate a function of this pocket in the inhibition of ASIC3 activity. In one crystal form, stomatin assembles via two conserved surfaces into a cylindrical oligomer, and these oligomerization surfaces are also essential for the inhibition of ASIC3-mediated currents. The assembly mode of stomatin uncovered in this study might serve as a model to understand oligomerization processes of related membrane-remodelling proteins, such as flotillin and prohibitin.
PMCID: PMC3433786  PMID: 22850675
ASIC; ion channel regulation; membrane trafficking; protein structure; stomatin family
11.  A world checklist of Onychophora (velvet worms), with notes on nomenclature and status of names 
ZooKeys  2012;1-70.
Currently, the number of valid species of Onychophora is uncertain. To facilitate taxonomic work on this understudied animal group, we present an updated checklist for the two extant onychophoran subgroups, Peripatidae and Peripatopsidae, along with an assessment of the status of each species. According to our study, 82 species of Peripatidae and 115 species of Peripatopsidae have been described thus far. However, among these 197 species, 20 are nomina dubia due to major taxonomic inconsistencies. Apart from nomina dubia, many of the valid species also require revision, in particular representatives of Paraperipatus within the Peripatopsidae, and nearly all species of Peripatidae. In addition to extant representatives, the record of unambiguous fossils includes three species with uncertain relationship to the extant taxa. For all species, we provide a list of synonyms, information on types and type localities, as well as remarks on taxonomic and nomenclatural problems and misspellings. According to recent evidence of high endemism and cryptic speciation among the Peripatidae and Peripatopsidae, previous synonyms are revised. Putative mutations, subspecies and variations are either raised to the species status or synonymised with corresponding taxa. In our revised checklist, we follow the rules and recommendations of the International Code of Zoological Nomenclature to clarify previous inconsistencies.
PMCID: PMC3426840  PMID: 22930648
Peripatidae; Peripatopsidae; species list; catalogue; taxonomy
12.  Regulation of ASIC channels by a stomatin/STOML3 complex located in a mobile vesicle pool in sensory neurons 
Open Biology  2012;2(6):120096.
A complex of stomatin-family proteins and acid-sensing (proton-gated) ion channel (ASIC) family members participate in sensory transduction in invertebrates and vertebrates. Here, we have examined the role of the stomatin-family protein stomatin-like protein-3 (STOML3) in this process. We demonstrate that STOML3 interacts with stomatin and ASIC subunits and that this occurs in a highly mobile vesicle pool in dorsal root ganglia (DRG) neurons and Chinese hamster ovary cells. We identify a hydrophobic region in the N-terminus of STOML3 that is required for vesicular localization of STOML3 and regulates physical and functional interaction with ASICs. We further characterize STOML3-containing vesicles in DRG neurons and show that they are Rab11-positive, but not part of the early-endosomal, lysosomal or Rab14-dependent biosynthetic compartment. Moreover, uncoupling of vesicles from microtubules leads to incorporation of STOML3 into the plasma membrane and increased acid-gated currents. Thus, STOML3 defines a vesicle pool in which it associates with molecules that have critical roles in sensory transduction. We suggest that the molecular features of this vesicular pool may be characteristic of a ‘transducosome’ in sensory neurons.
PMCID: PMC3390797  PMID: 22773952
ion channel; mechanotransduction; peripheral sensory neurons; stomatin-like proteins
13.  Fungal Planet description sheets: 107–127 
Novel species of microfungi described in the present study include the following from Australia: Phytophthora amnicola from still water, Gnomoniopsis smithogilvyi from Castanea sp., Pseudoplagiostoma corymbiae from Corymbia sp., Diaporthe eucalyptorum from Eucalyptus sp., Sporisorium andrewmitchellii from Enneapogon aff. lindleyanus, Myrmecridium banksiae from Banksia, and Pilidiella wangiensis from Eucalyptus sp. Several species are also described from South Africa, namely: Gondwanamyces wingfieldii from Protea caffra, Montagnula aloes from Aloe sp., Diaporthe canthii from Canthium inerne, Phyllosticta ericarum from Erica gracilis, Coleophoma proteae from Protea caffra, Toxicocladosporium strelitziae from Strelitzia reginae, and Devriesia agapanthi from Agapanthus africanus. Other species include Phytophthora asparagi from Asparagus officinalis (USA), and Diaporthe passiflorae from Passiflora edulis (South America). Furthermore, novel genera of coelomycetes include Chrysocrypta corymbiae from Corymbia sp. (Australia), Trinosporium guianense, isolated as a contaminant (French Guiana), and Xenosonderhenia syzygii, from Syzygium cordatum (South Africa). Pseudopenidiella piceae from Picea abies (Czech Republic), and Phaeocercospora colophospermi from Colophospermum mopane (South Africa) represent novel genera of hyphomycetes. Morphological and culture characteristics along with ITS DNA barcodes are provided for all taxa.
PMCID: PMC3409410  PMID: 23105159
ITS DNA barcodes; LSU; novel fungal species; systematics
14.  Multiple new Phytophthora species from ITS Clade 6 associated with natural ecosystems in Australia: evolutionary and ecological implications 
During surveys of dying vegetation in natural ecosystems and associated waterways in Australia many new taxa have been identified from Phytophthora ITS Clade 6. For representative isolates, the region spanning the internal transcribed spacer region of the ribosomal DNA, the nuclear gene encoding heat shock protein 90 and the mitochondrial cox1 gene were PCR amplified and sequenced. Based on phylogenetic analysis and morphological and physiological comparison, four species and one informally designated taxon have been described; Phytophthora gibbosa, P. gregata, P. litoralis, P. thermophila and P. taxon paludosa. Phytophthora gibbosa, P. gregata and P. taxon paludosa form a new cluster and share a common ancestor; they are homothallic and generally associated with dying vegetation in swampy or water-logged areas. Phytophthora thermophila and P. litoralis are sister species to each other and more distantly to P. gonapodyides. Both new species are common in waterways and cause scattered mortality within native vegetation. They are self-sterile and appear well adapted for survival in an aquatic environment and inundated soils, filling the niche occupied by P. gonapodyides and P. taxon salixsoil in the northern hemisphere. Currently the origin of these new taxa, their pathogenicity and their role in natural ecosystems are unknown. Following the precautionary principle, they should be regarded as a potential threat to native ecosystems and managed to minimise their further spread.
PMCID: PMC3160797  PMID: 22025801
aquatic habitat; breeding systems; evolution; phylogeny; radiation; sterility; survival
15.  Fungal Planet description sheets: 69–91 
Novel species of microfungi described in the present study include the following from Australia: Bagadiella victoriae and Bagadiella koalae on Eucalyptus spp., Catenulostroma eucalyptorum on Eucalyptus laevopinea, Cercospora eremochloae on Eremochloa bimaculata, Devriesia queenslandica on Scaevola taccada, Diaporthe musigena on Musa sp., Diaporthe acaciigena on Acacia retinodes, Leptoxyphium kurandae on Eucalyptus sp., Neofusicoccum grevilleae on Grevillea aurea, Phytophthora fluvialis from water in native bushland, Pseudocercospora cyathicola on Cyathea australis, and Teratosphaeria mareebensis on Eucalyptus sp. Other species include Passalora leptophlebiae on Eucalyptus leptophlebia (Brazil), Exophiala tremulae on Populus tremuloides and Dictyosporium stellatum from submerged wood (Canada), Mycosphaerella valgourgensis on Yucca sp. (France), Sclerostagonospora cycadis on Cycas revoluta (Japan), Rachicladosporium pini on Pinus monophylla (Netherlands), Mycosphaerella wachendorfiae on Wachendorfia thyrsifolia and Diaporthe rhusicola on Rhus pendulina (South Africa). Novel genera of hyphomycetes include Noosia banksiae on Banksia aemula (Australia), Utrechtiana cibiessia on Phragmites australis (Netherlands), and Funbolia dimorpha on blackened stem bark of an unidentified tree (USA). Morphological and culture characteristics along with ITS DNA barcodes are provided for all taxa.
PMCID: PMC3160798  PMID: 22025808
ITS DNA barcodes; LSU; novel fungal species; systematics
16.  Ureterocolic fistula in the presence of a solitary kidney 
BMJ Case Reports  2009;2009:bcr06.2008.0301.
Among the entero-urinary fistulae, those between the ureter and colon are rare. Most spontaneous ureterocolic fistulae are caused by urinary calculi. We report a case of a spontaneous ureterocolic fistula which occurred as a consequence of diverticular disease. This rare presentation was further complicated as it occurred in the presence of a solitary kidney. The patient underwent a laparoscopic defunctioning loop ileostomy and after 6 weeks underwent definitive surgical treatment of the ureterocolic fistula. We describe the presentation and management of this fistula and review the current literature.
PMCID: PMC3030306  PMID: 21686866
17.  Functional Neurokinin and NMDA Receptor Activity in an Animal Naturally Lacking Substance P: The Naked Mole-Rat 
PLoS ONE  2010;5(12):e15162.
Naked mole-rats are extremely unusual among mammals in that their cutaneous C-fibers lack the neuropeptide Substance P (SP). In other mammals, SP plays an important role in nociception: it is released from C-fibers onto spinal neurons where it facilitates NMDA receptor activity and causes sensitization that can last for minutes, hours or days. In the present study, we tested the effects of intrathecal application of: 1) SP, 2) an SP antagonist (GR-82334), and 3) an NMDA antagonist (APV) on heat-evoked foot withdrawal. In the naked mole-rat, at a high enough concentration, application of SP caused a large, immediate, and long-lasting sensitization of foot withdrawal latency that was transiently reversed by application of either antagonist. However, neither SP nor NMDA antagonists had an effect when administered alone to naïve animals. In contrast, both antagonists induced an increase in basal withdrawal latency in mice. These results indicate that spinal neurons in naked mole-rats have functional SP and NMDA receptors, but that these receptors do not participate in heat-evoked foot withdrawal unless SP is experimentally introduced. We propose that the natural lack of SP in naked mole-rat C-fibers may have resulted during adaptation to living in a chronically high carbon dioxide, high ammonia environment that, in other mammals, would stimulate C-fibers and evoke nocifensive behavior.
PMCID: PMC3006196  PMID: 21200438
18.  Unilateral spontaneous rupture of a testicular implant thirteen years after bilateral insertion: a case report 
We describe a case of spontaneous, non traumatic rupture of a single artificial testis in a patient who had undergone bilateral, staged radical orchidectomy followed by prosthesis insertion. The consequences and radiological appearances of implant rupture are discussed. We believe it is the longest time interval recorded between prosthesis insertion and rupture.
Case presentation
A 50 year old Caucasian man presented to our outpatient department with an altered consistency in his right testicular prosthesis without any systemic symptoms or local inflammation. His left testicular prosthesis had retained its consistency since insertion.
The majority of cases reported to date have required exploration due to symptoms but we describe a case that was managed conservatively.
PMCID: PMC2987956  PMID: 20977707
19.  ‘‘Two-Week Waits”—Are They Leading to Earlier Diagnosis of Soft-Tissue Sarcomas? 
Sarcoma  2010;2010:312648.
Introduction. The ‘‘two-week wait” was established as a potential means of diagnosing malignant tumours earlier. This paper investigated whether these clinics are leading to earlier diagnosis of malignant soft-tissue lumps. Method. We identified all referrals to our centre from a database over a 4-year period. Results. 2225 patients were referred to our unit for investigation of a soft-tissue mass. 576 (26%) were referred under the ‘‘two-week wait” criteria. 153 (27%) of which were found to have a malignant or borderline malignant diagnosis. 1649 patients were referred nonurgently. 855 (52%) of which were diagnosed with a malignant or borderline lesion. The average size at diagnosis was 9.4 cm with no difference in size between the different referral routes. Conclusion. There is little evidence that the two-week wait clinic is leading to earlier diagnosis of soft-tissue sarcomas with the majority still being referred nonurgently.
PMCID: PMC2948916  PMID: 20936113
20.  Changes in chromatin structure during processing of wax-embedded tissue sections 
Chromosome Research  2010;18(6):677-688.
The use of immunofluorescence (IF) and fluorescence in situ hybridisation (FISH) underpins much of our understanding of how chromatin is organised in the nucleus. However, there has only recently been an appreciation that these types of study need to move away from cells grown in culture and towards an investigation of nuclear organisation in cells in situ in their normal tissue architecture. Such analyses, however, especially of archival clinical samples, often requires use of formalin-fixed paraffin wax-embedded tissue sections which need addition steps of processing prior to IF or FISH. Here we quantify the changes in nuclear and chromatin structure that may be caused by these additional processing steps. Treatments, especially the microwaving to reverse fixation, do significantly alter nuclear architecture and chromatin texture, and these must be considered when inferring the original organisation of the nucleus from data collected from wax-embedded tissue sections.
PMCID: PMC2941078  PMID: 20661639
chromatin; fluorescence in situ hybridization; heterochromatin; nuclear organisation; tissue sections
21.  Cellular and Molecular Regulation of Spiral Artery Remodelling: Lessons from the Cardiovascular Field 
Placenta  2010;31(6):465-474.
A number of important changes take place in the maternal uterine vasculature during the first few weeks of pregnancy resulting in increased blood flow to the intervillous space. Vascular endothelial and smooth muscle cells are lost from the spiral arteries and are replaced by fetal trophoblast cells. Failure of the vessels to remodel sufficiently is a common feature of pregnancy pathologies such as early pregnancy loss, intrauterine growth restriction and pre-eclampsia. There is evidence to suggest that some vascular changes occur prior to trophoblast invasion, however, in the absence of trophoblasts remodelling of the spiral arteries is reduced. Until recently our knowledge of these events has been obtained from immunohistochemical studies which, although extremely useful, can give little insight into the mechanisms involved. With the development of more complex in vitro models a picture of events at a cellular and molecular level is beginning to emerge, although some caution is required in extrapolating to the in vivo situation. Trophoblasts synthesise and release a plethora of cytokines and growth factors including members of the tumour necrosis factor family. Studies suggest that these factors may be important in regulating the remodelling process by inducing both endothelial and vascular smooth muscle cell apoptosis. In addition, it is evident from studies in other vascular beds that the structure of the vessel is influenced by factors such as flow, changes in the composition of the extracellular matrix, the phenotype of the vascular cells and the local immune cell environment. It is the aim of this review to present our current knowledge of the mechanisms involved in spiral artery remodelling and explore other possible pathways and cellular interactions that may be involved, informed by studies in the cardiovascular field.
PMCID: PMC2882556  PMID: 20359743
Spiral artery; Trophoblast; Remodelling; Endothelial; vascular smooth muscle; Apoptosis; Extracellular matrix; pregnancy
22.  Epidermal growth factor-stimulated extravillous cytotrophoblast motility is mediated by the activation of PI3-K, Akt and both p38 and p42/44 mitogen-activated protein kinases 
Human Reproduction (Oxford, England)  2008;23(8):1733-1741.
Trophoblast invasion is a temporally and spatially regulated scheme of events that can dictate pregnancy outcome. Evidence suggests that the potent mitogen epidermal growth factor (EGF) regulates cytotrophoblast (CTB) differentiation and invasion during early pregnancy.
In the present study, the first trimester extravillous CTB cell line SGHPL-4 was used to investigate the signalling pathways involved in the motile component of EGF-mediated CTB migration/invasion. EGF induced the phosphorylation of the phosphatidylinositol 3-kinase (PI3-K)-dependent proteins, Akt and GSK-3β as well as both p42/44 MAPK and p38 mitogen-activated protein kinases (MAPK). EGF-stimulated motility was significantly reduced following the inhibition of PI3-K (P < 0.001), Akt (P < 0.01) and both p42/44 MAPK (P < 0.001) and p38 MAPKs (P < 0.001) but not the inhibition of GSK-3β. Further analysis indicated that the p38 MAPK inhibitor SB 203580 inhibited EGF-stimulated phosphorylation of Akt on serine 473, which may be responsible for the effect SB 203580 has on CTB motility. Although Akt activation leads to GSK-3β phosphorylation and the subsequent expression of β-catenin, activation of this pathway by 1-azakenpaullone was insufficient to stimulate the motile phenotype.
We demonstrate a role for PI3-K, p42/44 MAPK and p38 MAPK in the stimulation of CTB cell motility by EGF, however activation of β-catenin alone was insufficient to stimulate cell motility.
PMCID: PMC2733823  PMID: 18487214
epidermal growth factor; extravillous cytotrophoblast; motility; PI3-K; p38 mitogen-activated protein kinases
23.  Phytophthora multivora sp. nov., a new species recovered from declining Eucalyptus, Banksia, Agonis and other plant species in Western Australia 
Persoonia  2009;22:1-13.
A new Phytophthora species, isolated from rhizosphere soil of declining or dead trees of Eucalyptus gomphocephala, E. marginata, Agonis flexuosa, and another 13 plant species, and from fine roots of E. marginata and collar lesions of Banksia attenuata in Western Australia, is described as Phytophthora multivora sp. nov. It is homothallic and produces semipapillate sporangia, smooth-walled oogonia containing thick-walled oospores, and paragynous antheridia. Although morphologically similar to P. citricola, phylogenetic analyses of the ITS and cox1 gene regions demonstrate that P. multivora is unique. Phytophthora multivora is pathogenic to bark and cambium of E. gomphocephala and E. marginata and is believed to be involved in the decline syndrome of both eucalypt species within the tuart woodland in south-west Western Australia.
PMCID: PMC2789538  PMID: 20198133
decline; dieback; forest; jarrah; phylogeny; Phytophthora citricola; tuart
24.  Plasma C reactive protein concentration indicates a direct relation between systemic inflammation and social deprivation 
Heart  2006;92(4):533-535.
PMCID: PMC1860885  PMID: 16537770
C reactive protein; coronary heart disease; deprivation; inflammation; place of residence
25.  Native TRPC7 Channel Activation by an Inositol Trisphosphate Receptor-Dependent Mechanism1 
The Journal of biological chemistry  2006;281(35):25250-25258.
In DT40 B lymphocytes, Canonical Transient Receptor Potential 7 (TRPC7) functions as a diacylglycerol-activated non-selective cation channel. However, previous work indicated that the non-store-operated Ca2+ entry in this cell type depends upon inositol trisphosphate receptors (IP3R). With the cell-attached configuration oleyl-acetyl-glycerol (OAG) induced single channel activity (75 pS) that was not observed in TRPC7−/− cells, but was rescued by expression of TRPC7 under conditions expected to produce relatively low levels of expression (LowT7TRPC7−/−). A DT40 cell line lacking IP3R (IP3R−/− cells) showed no OAG-induced single-channel activity, but this activity was rescued by transient expression of an IP3R (IP3RIP3R−/−). Single channel properties inLowT7TRPC7−/− orIP3RIP3R−/− DT40 cells were indistinguishable from one another and from wild-type cells. Thus, TRPC7 forms, or is part of, the channel underlying endogenous diacylglycerol-activated currents in DT40 B lymphocytes, and this activity of native TRPC7 requires IP3R. However, with conditions expected to produce greater expression levels, TRPC7 functioned independently of the presence of IP3R. This finding may serve to resolve previously conflicting reports from expression studies of TRPC channels.
PMCID: PMC1847618  PMID: 16822861

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