Structure of exciton condensates in imbalanced electron-hole bilayers

We investigate the possibility of excitonic superfluidity in electron-hole bilayers. We calculate the phase diagram of the system for the whole range of electron-hole density imbalance and for different degrees of electrostatic screening, using mean-field theory and a Ginzburg–Landau expansion. We are able to resolve differences on previous work in the literature which concentrated on restricted regions of the parameter space. We also give detailed descriptions of the pairing wave function in the Fulde–Ferrell–Larkin–Ovchinnikov paired state. The Ginzburg–Landau treatment allows us to investigate the energy scales involved in the pairing state and discuss the possible spontaneous breaking of two-dimensional translation symmetry in the ground state

Anaesthesia for serial whole-lung lavage in a patient with severe pulmonary alveolar proteinosis: a case report

<p>Abstract</p> <p>Introduction</p> <p>Pulmonary alveolar proteinosis is a rare condition that requires treatment by whole-lung lavage. We report a case of severe pulmonary alveolar proteinosis and discuss a safe and effective strategy for the anaesthetic management of patients undergoing this complex procedure.</p> <p>Case presentation</p> <p>A 34-year-old Caucasian man was diagnosed with severe pulmonary alveolar proteinosis. He developed severe respiratory failure and subsequently underwent serial whole-lung lavage. Our anaesthetic technique included the use of pre-oxygenation, complete lung separation with a left-sided double-lumen endotracheal tube, one-lung ventilation with positive end-expiratory pressure, appropriate ventilatory monitoring, cautious use of positional manoeuvres and single-lumen endotracheal tube exchange for short-term postoperative ventilation.</p> <p>Conclusion</p> <p>Patients with pulmonary alveolar proteinosis may present with severe respiratory failure and require urgent whole-lung lavage. We have described a safe and effective strategy for anaesthesia for whole-lung lavage. We recommend our anaesthetic technique for patients undergoing this complex and uncommon procedure.</p

Heterarchy of Transcription Factors Driving Basal and Luminal Cell Phenotypes in Human Urothelium

Cell differentiation is effected by complex networks of transcription factors that co-ordinate re-organisation of the chromatin landscape. The hierarchies of these relationships can be difficult to dissect. During in vitro differentiation of normal human uro-epithelial cells, formaldehyde-assisted isolation of regulatory elements (FAIRE-seq) and RNA-seq were used to identify alterations in chromatin accessibility and gene expression changes following activation of the nuclear receptor PPARG as a differentiation-initiating event. Regions of chromatin identified by FAIRE-seq as having altered accessibility during differentiation were found to be enriched with sequence-specific binding motifs for transcription factors predicted to be involved in driving basal and differentiated urothelial cell phenotypes, including FOXA1, P63, GRHL2, CTCF and GATA3. In addition, co-occurrence of GATA3 motifs was observed within sub-sets of differentiation-specific peaks containing P63 or FOXA1 after induction of differentiation. Changes in abundance of GRHL2, GATA3, and P63 were observed in immunoblots of chromatin-enriched extracts. Transient siRNA knockdown of P63 revealed that P63 favoured a basal-like phenotype by inhibiting differentiation and promoting expression of basal marker genes. GATA3 siRNA prevented differentiation-associated downregulation of P63 protein and transcript, and demonstrated positive feedback of GATA3 on PPARG transcript, but showed no effect on FOXA1 transcript or protein expression. This approach indicates that as a transcriptionally-regulated programme, urothelial differentiation operates as a heterarchy wherein GATA3 is able to co-operate with FOXA1 to drive expression of luminal marker genes, but that P63 has potential to transrepress expression of the same genes

From Vampire to Apollo: William Blake's Ghosts of the Flea (c. 1819-20)

Varley’s Zodiacal Physiognomy and Blake’s Visionary Heads are the two mainstays of a project which involved séance-like meetings at Varley’s house. While the lights were still on, Varley’s guests would have listened to the stories about the flea. With The Ghost of a Flea in front of them, the recitals of the flea’s pompous speeches, combined with the fact that it was just a ghost who leered after human blood, Varley’s guests may have laughed very heartily, if not in front of him then behind his back. Each evening followed the same protocol. When the lights were off, Varley would call out a name and Blake would look around, suddenly exclaiming ‘There he is!’ and start drawing. The flea is the most striking of the Visionary Heads, though it is not the only head which exists in different versions. If appearance is elemental to any kind of judgement of one human being of another, then Blake deliberately confused Varley. By working up the sketch, he played on Varley’s expectations; he presented him with an extraordinary and very puzzling painting, The Ghost of a Flea. But why, if Blake could have chosen any monster, did he settle on the ghost of a flea

Deregulation of Rab and Rab Effector Genes in Bladder Cancer

Growing evidence indicates that Rab GTPases, key regulators of intracellular transport in eukaryotic cells, play an important role in cancer. We analysed the deregulation at the transcriptional level of the genes encoding Rab proteins and Rab-interacting proteins in bladder cancer pathogenesis, distinguishing between the two main progression pathways so far identified in bladder cancer: the Ta pathway characterized by a high frequency of FGFR3 mutation and the carcinoma in situ pathway where no or infrequent FGFR3 mutations have been identified. A systematic literature search identified 61 genes encoding Rab proteins and 223 genes encoding Rab-interacting proteins. Transcriptomic data were obtained for normal urothelium samples and for two independent bladder cancer data sets corresponding to 152 and 75 tumors. Gene deregulation was analysed with the SAM (significant analysis of microarray) test or the binomial test. Overall, 30 genes were down-regulated, and 13 were up-regulated in the tumor samples. Five of these deregulated genes (LEPRE1, MICAL2, RAB23, STXBP1, SYTL1) were specifically deregulated in FGFR3-non-mutated muscle-invasive tumors. No gene encoding a Rab or Rab-interacting protein was found to be specifically deregulated in FGFR3-mutated tumors. Cluster analysis showed that the RAB27 gene cluster (comprising the genes encoding RAB27 and its interacting partners) was deregulated and that this deregulation was associated with both pathways of bladder cancer pathogenesis. Finally, we found that the expression of KIF20A and ZWINT was associated with that of proliferation markers and that the expression of MLPH, MYO5B, RAB11A, RAB11FIP1, RAB20 and SYTL2 was associated with that of urothelial cell differentiation markers. This systematic analysis of Rab and Rab effector gene deregulation in bladder cancer, taking relevant tumor subgroups into account, provides insight into the possible roles of Rab proteins and their effectors in bladder cancer pathogenesis. This approach is applicable to other group of genes and types of cancer

Loss of the Urothelial Differentiation Marker FOXA1 Is Associated with High Grade, Late Stage Bladder Cancer and Increased Tumor Proliferation

Approximately 50% of patients with muscle-invasive bladder cancer (MIBC) develop metastatic disease, which is almost invariably lethal. However, our understanding of pathways that drive aggressive behavior of MIBC is incomplete. Members of the FOXA subfamily of transcription factors are implicated in normal urogenital development and urologic malignancies. FOXA proteins are implicated in normal urothelial differentiation, but their role in bladder cancer is unknown. We examined FOXA expression in commonly used in vitro models of bladder cancer and in human bladder cancer specimens, and used a novel in vivo tissue recombination system to determine the functional significance of FOXA1 expression in bladder cancer. Logistic regression analysis showed decreased FOXA1 expression is associated with increasing tumor stage (p<0.001), and loss of FOXA1 is associated with high histologic grade (p<0.001). Also, we found that bladder urothelium that has undergone keratinizing squamous metaplasia, a precursor to the development of squamous cell carcinoma (SCC) exhibited loss of FOXA1 expression. Furthermore, 81% of cases of SCC of the bladder were negative for FOXA1 staining compared to only 40% of urothelial cell carcinomas. In addition, we showed that a subpopulation of FOXA1 negative urothelial tumor cells are highly proliferative. Knockdown of FOXA1 in RT4 bladder cancer cells resulted in increased expression of UPK1B, UPK2, UPK3A, and UPK3B, decreased E-cadherin expression and significantly increased cell proliferation, while overexpression of FOXA1 in T24 cells increased E-cadherin expression and significantly decreased cell growth and invasion. In vivo recombination of bladder cancer cells engineered to exhibit reduced FOXA1 expression with embryonic rat bladder mesenchyme and subsequent renal capsule engraftment resulted in enhanced tumor proliferation. These findings provide the first evidence linking loss of FOXA1 expression with histological subtypes of MIBC and urothelial cell proliferation, and suggest an important role for FOXA1 in the malignant phenotype of MIBC

Polar Flagellar Biosynthesis and a Regulator of Flagellar Number Influence Spatial Parameters of Cell Division in Campylobacter jejuni

Spatial and numerical regulation of flagellar biosynthesis results in different flagellation patterns specific for each bacterial species. Campylobacter jejuni produces amphitrichous (bipolar) flagella to result in a single flagellum at both poles. These flagella confer swimming motility and a distinctive darting motility necessary for infection of humans to cause diarrheal disease and animals to promote commensalism. In addition to flagellation, symmetrical cell division is spatially regulated so that the divisome forms near the cellular midpoint. We have identified an unprecedented system for spatially regulating cell division in C. jejuni composed by FlhG, a regulator of flagellar number in polar flagellates, and components of amphitrichous flagella. Similar to its role in other polarly-flagellated bacteria, we found that FlhG regulates flagellar biosynthesis to limit poles of C. jejuni to one flagellum. Furthermore, we discovered that FlhG negatively influences the ability of FtsZ to initiate cell division. Through analysis of specific flagellar mutants, we discovered that components of the motor and switch complex of amphitrichous flagella are required with FlhG to specifically inhibit division at poles. Without FlhG or specific motor and switch complex proteins, cell division occurs more often at polar regions to form minicells. Our findings suggest a new understanding for the biological requirement of the amphitrichous flagellation pattern in bacteria that extend beyond motility, virulence, and colonization. We propose that amphitrichous bacteria such as Campylobacter species advantageously exploit placement of flagella at both poles to spatially regulate an FlhG-dependent mechanism to inhibit polar cell division, thereby encouraging symmetrical cell division to generate the greatest number of viable offspring. Furthermore, we found that other polarly-flagellated bacteria produce FlhG proteins that influence cell division, suggesting that FlhG and polar flagella may function together in a broad range of bacteria to spatially regulate division

Inter-relationship between microsatellite instability, thymidylate synthase expression, and p53 status in colorectal cancer: implications for chemoresistance

BACKGROUND: Studies indicate that thymidylate synthase (TS) expression, p53 and mismatch repair status have potential to influence colorectal cancer (CRC) outcome. There is, however, little data on the inter-relationship between these three markers. We sought to investigate whether relationships exist between these markers that might contribute to CRC phenotypes. METHODS: Four hundred and forty-one stage I-III CRCs were investigated. p53 status and TS expression were assessed by standard immunohistochemistry methods. Mismatch repair status was determined by assessment of microsatellite instability (MSI) using radiolabelled microsatellite genotyping. RESULTS: 244 tumours (55%) over-expressed p53, and 259 (58%) expressed high TS levels. 65 tumours (15%) had MSI. A significant relationship between p53 over-expression and high TS expression was observed (p = 0.01). This was independent of MSI status. A highly significant inverse relationship between MSI and p53 status was observed (p = 0.001). No relationship was seen between MSI status and TS expression (p = 0.59). CONCLUSION: Relationships exist between p53 status and TS expression, and MSI and p53 status. These inter-relationships may contribute to the clinical phenotype of CRCs associated with each of the molecular markers. High TS expression is unlikely to account for the clinical behaviour of CRCs with MSI

Skeletal muscle and performance adaptations to high-intensity training in elite male soccer players: speed endurance runs versus small-sided game training.

PURPOSE: To examine the skeletal muscle and performance responses across two different exercise training modalities which are highly applied in soccer training. METHODS: Using an RCT design, 39 well-trained male soccer players were randomized into either a speed endurance training (SET; n = 21) or a small-sided game group (SSG; n = 18). Over 4 weeks, thrice weekly, SET performed 6-10 × 30-s all-out runs with 3-min recovery, while SSG completed 2 × 7-9-min small-sided games with 2-min recovery. Muscle biopsies were obtained from m. vastus lateralis pre and post intervention and were subsequently analysed for metabolic enzyme activity and muscle protein expression. Moreover, the Yo-Yo Intermittent Recovery level 2 test (Yo-Yo IR2) was performed. RESULTS: Muscle CS maximal activity increased (P < 0.05) by 18% in SET only, demonstrating larger (P < 0.05) improvement than SSG, while HAD activity increased (P < 0.05) by 24% in both groups. Na(+)-K(+) ATPase α1 subunit protein expression increased (P < 0.05) in SET and SSG (19 and 37%, respectively), while MCT4 protein expression rose (P < 0.05) by 30 and 61% in SET and SSG, respectively. SOD2 protein expression increased (P < 0.05) by 28 and 37% in SET and SSG, respectively, while GLUT-4 protein expression increased (P < 0.05) by 40% in SSG only. Finally, SET displayed 39% greater improvement (P < 0.05) in Yo-Yo IR2 performance than SSG. CONCLUSION: Speed endurance training improved muscle oxidative capacity and exercise performance more pronouncedly than small-sided game training, but comparable responses were in muscle ion transporters and antioxidative capacity in well-trained male soccer players

Cancer risk in close relatives of women with early-onset breast cancer – a population-based incidence study

Inherited susceptibility to breast cancer is associated with an early onset and bilateral disease. The extent of familial risks has not, however, been fully assessed in population-based incidence studies. The purpose of the study was to quantify the risks for cancers of the breast, ovary and other sites of close relatives of women in whom breast cancer was diagnosed at an early age. Records collected between 1943 and 1990 at the Danish Cancer Registry were searched, and 2860 women were found in whom breast cancer was diagnosed before age 40. Population registers and parish records were used to identify 14 973 parents, siblings and offspring of these women. Cancer occurrence through to 31 December 1993 was determined within the Cancer Registry's files and compared with national incidence rates. Women with early-onset breast cancer were at a nearly fourfold increased risk of developing a new cancer later in life (268 observed vs 68.9 expected). The excess risk was most evident for second cancer of the breast (181 vs 24.5) and for ovarian cancer (20 vs 3.3). For mothers and sisters, risks for cancers of the breast and ovary were significantly increased by two- to threefold. Bilateral breast cancer and breast–ovarian cancer were very strong predictors of familial risks, with one in four female relatives predicted to develop breast and/or ovarian cancer by age 75. Mothers had a slightly increased risk of colon cancer, but not endometrial cancer. The risk for breast cancer was also increased among fathers (standardized incidence ratio 2.5; 95% CI 0.5–7.4) and especially brothers (29; 7.7–74), although based on small numbers. The risk for prostatic cancer was unremarkable. In this large population-based survey, the first-degree relatives of women who developed breast cancer before age 40 were prone to ovarian cancer as well as male and female breast cancer, but not other tumours that may share susceptibility genes with breast cancer. © 1999 Cancer Research Campaig