bluuebunny/crossref_metadata_2025 huggingface dataset:
Stress inducible proteinase inhibitor diversity in Capsicum annuum
Authors: Mishra Manasi , Mahajan Neha , Tamhane Vaijayanti A , Kulkarni Mahesh J , Baldwin Ian T , Gupta Vidya S , Giri Ashok P
Published: November 2012

Background

Wound-inducible Pin-II Proteinase inhibitors (PIs) are one of the important plant serine PIs which have been studied extensively for their structural and functional diversity and relevance in plant defense against insect pests. To explore the functional specialization of an array of Capsicum annuum (L.) proteinase inhibitor (CanPIs) genes, we studied their expression, processing and tissue-specific distribution under steady-state and induced conditions. Inductions were performed by subjecting C. annuum leaves to various treatments, namely aphid infestation or mechanical wounding followed by treatment with either oral secretion (OS) of Helicoverpa armigera or water.

Results

The elicitation treatments regulated the accumulation of CanPIs corresponding to 4-, 3-, and 2-inhibitory repeat domains (IRDs). Fourty seven different CanPI genes composed of 28 unique IRDs were identified in total along with those reported earlier. The CanPI gene pool either from uninduced or induced leaves was dominated by 3-IRD PIs and trypsin inhibitory domains. Also a major contribution by 4-IRD CanPI genes possessing trypsin and chymotrypsin inhibitor domains was specifically revealed in wounded leaves treated with OS. Wounding displayed the highest number of unique CanPIs while wounding with OS treatment resulted in the high accumulation of specifically CanPI-4, -7 and −10. Characterization of the PI protein activity through two dimensional gel electrophoresis revealed tissue and induction specific patterns. Consistent with transcript abundance, wound plus OS or water treated C. annuum leaves exhibited significantly higher PI activity and isoform diversity contributed by 3- and 4-IRD CanPIs. CanPI accumulation and activity was weakly elicited by aphid infestation yet resulted in the higher expression of CanPI-26, -41 and −43.

Conclusions

Plants can differentially perceive various kinds of insect attacks and respond appropriately through activating plant defenses including regulation of PIs at transcriptional and post-translational levels. Based on the differentially elicited CanPI accumulation patterns, it is intriguing to speculate that generating sequence diversity in the form of multi-IRD PIs is a part of elaborative plant defense strategy to obtain a diverse pool of functional units to confine insect attack.
The effect of a trunk release maneuver on Peak Pressure Index, trunk displacement and perceived discomfort in older adults seated in a high Fowler’s position: a randomized controlled trial
Authors: Best Krista L , Desharnais Guylaine , Boily Jeanette , Miller William C , Camp Pat G
Published: November 2012

Background

Pressure ulcers pose significant negative individual consequences and financial burden on the healthcare system. Prolonged sitting in High Fowler’s position (HF) is common clinical practice for older adults who spend extended periods of time in bed. While HF aids in digestion and respiration, being placed in a HF may increase perceived discomfort and risk of pressure ulcers due to increased pressure magnitude at the sacral and gluteal regions. It is likely that shearing forces could also contribute to risk of pressure ulcers in HF. The purpose of this study was to evaluate the effect of a low-tech and time-efficient Trunk Release Manuever (TRM) on sacral and gluteal pressure, trunk displacement and perceived discomfort in ambulatory older adults.

Method

A randomized controlled trial was used. We recruited community-living adults who were 60 years of age and older using posters, newspaper advertisements and word-of-mouth. Participants were randomly allocated to either the intervention or control group. The intervention group (n = 59) received the TRM, while the control group (n = 58) maintained the standard HF position.

Results

The TRM group had significantly lower mean (SD) PPI values post-intervention compared to the control group, 59.6 (30.7) mmHg and 79.9 (36.5) mmHg respectively (p = 0.002). There was also a significant difference in trunk displacement between the TRM and control groups, +3.2 mm and −5.8 mm respectively (p = 0.005). There were no significant differences in perceived discomfort between the groups.

Conclusion

The TRM was effective for reducing pressure in the sacral and gluteal regions and for releasing the trunk at the point of contact between the skin and the support surface, but did not have an effect on perceived discomfort. The TRM is a simple method of repositioning which may have important clinical application for the prevention of pressure ulcers that may occur as a result of HF.
Impact of adequate empirical combination therapy on mortality from bacteremic Pseudomonas aeruginosapneumonia
Authors: Park So-Youn , Park Hyun Jung , Moon Song Mi , Park Ki-Ho , Chong Yong Pil , Kim Mi-Na , Kim Sung-Han , Lee Sang-Oh , Kim Yang Soo , Woo Jun Hee , Choi Sang-Ho
Published: November 2012

Background

Pseudomonas aeruginosa has gained an increasing amount of attention in the treatment of patients with pneumonia. However, the benefit of empirical combination therapy for pneumonia remains unclear. We evaluated the effects of adequate empirical combination therapy and multidrug-resistance in bacteremic Pseudomonas pneumonia on the mortality.

Methods

A retrospective cohort study was performed at the 2,700-bed tertiary care university hospital. We reviewed the medical records of patients with bacteremic pneumonia between January 1997 and February 2011. Patients who received either inappropriate or appropriate empirical therapy were compared by using marginal structural model. Furthermore, we investigated the direct impact of combination therapy on clinical outcomes in patients with monomicrobial bacteremic pneumonia.

Results

Among 100 consecutive patients with bacteremic Pseudomonas pneumonia, 65 patients were classified in the adequate empirical therapy group, 32 of whom received monotherapy and 33 combination therapy. In the marginal structural model, only inadequate therapy was significantly associated with 28-day mortality (p = 0.02), and multidrug-resistance was not a significant risk factor.

To examine further the direct impact of combination therapy, we performed a subgroup analysis of the 65 patients who received adequate therapy. Multivariate logistic regression analysis identified absence of septic shock at the time of bacteremia (OR, 0.07; 95% CI, 0.01-0.49; p = 0.008), and adequate combination therapy (OR, 0.05; 95% CI, 0.01-0.34; p = 0.002) as variables independently associated with decreased all-cause 28-day mortality.

Conclusions

Our study suggests that adequate empirical combination therapy can decrease mortality in patients with bacteremic Pseudomonas pneumonia.
Pancreatic cancer circulating tumour cells express a cell motility gene signature that predicts survival after surgery
Authors: Sergeant Gregory , van Eijsden Rudy , Roskams Tania , Van Duppen Victor , Topal Baki
Published: November 2012

Background

Most cancer deaths are caused by metastases, resulting from circulating tumor cells (CTC) that detach from the primary cancer and survive in distant organs. The aim of the present study was to develop a CTC gene signature and to assess its prognostic relevance after surgery for pancreatic ductal adenocarcinoma (PDAC).

Methods

Negative depletion fluorescence activated cell sorting (FACS) was developed and validated with spiking experiments using cancer cell lines in whole human blood samples. This FACS-based method was used to enrich for CTC from the blood of 10 patients who underwent surgery for PDAC. Total RNA was isolated from 4 subgroup samples, i.e. CTC, haematological cells (G), original tumour (T), and non-tumoural pancreatic control tissue (P). After RNA quality control, samples of 6 patients were eligible for further analysis. Whole genome microarray analysis was performed after double linear amplification of RNA. ‘Ingenuity Pathway Analysis’ software and AmiGO were used for functional data analyses. A CTC gene signature was developed and validated with the nCounter system on expression data of 78 primary PDAC using Cox regression analysis for disease-free (DFS) and overall survival (OS).

Results

Using stringent statistical analysis, we retained 8,152 genes to compare expression profiles of CTC vs. other subgroups, and found 1,059 genes to be differentially expressed. The pathway with the highest expression ratio in CTC was p38 mitogen-activated protein kinase (p38 MAPK) signaling, known to be involved in cancer cell migration. In the p38 MAPK pathway, TGF-β1, cPLA2, and MAX were significantly upregulated. In addition, 9 other genes associated with both p38 MAPK signaling and cell motility were overexpressed in CTC. High co-expression of TGF-β1 and our cell motility panel (≥ 4 out of 9 genes for DFS and ≥ 6 out of 9 genes for OS) in primary PDAC was identified as an independent predictor of DFS (p=0.041, HR (95% CI) = 1.885 (1.025 – 3.559)) and OS (p=0.047, HR (95% CI) = 1.366 (1.004 – 1.861)).

Conclusions

Pancreatic CTC isolated from blood samples using FACS-based negative depletion, express a cell motility gene signature. Expression of this newly defined cell motility gene signature in the primary tumour can predict survival of patients undergoing surgical resection for pancreatic cancer.

Trial Registration

Clinical trials.gov NCT00495924
Antioxidant defense system and family environment in adolescents with family history of psychosis
Authors: Gonzalez-Pinto Ana , Martinez-Cengotitabengoa Monica , Arango Celso , Baeza Immaculada , Otero-Cuesta Soraya , Graell-Berna Montserrat , Soutullo César , Leza Juan Carlos , Micó Juan Antonio
Published: November 2012

Background

Our objective was to determine antioxidant defence activity in healthy controls (HC) and healthy unaffected second-degree relatives of patients with early onset psychosis (HC-FHP), and to assess its relationship with familiar environment measured using the Family Environment Scale (FES).

Methods

We included 82 HC and 14 HC-FHP aged between 9 and 17 years. Total antioxidant status, lipid peroxidation, antioxidant enzyme activities and glutathione levels were determined in blood samples.

Results

There was a significant decrease in the total antioxidant level in the HC-FHP group compared with the HC group (OR = 2.94;p= 0.009), but no between-group differences in the Global Assessment of Functioning (GAF) scale scores. For the FES, the HC-FHP group had significantly higher scores in the cohesion (p= 0.007) and intellectual-cultural dimensions (p=0.025). After adjusting for these two FES dimensions, total antioxidant status remained significantly different between groups (OR = 10.86,p= 0.009).

Conclusions

Although causal relationships cannot be assumed, we can state that family environment is not playing a role in inducing oxidative stress in these healthy subjects. It could be hypothesized that families with affected relatives protect themselves from psychosis with positive environmental factors such as cohesion and intellectual-cultural activities.
3p21.3 tumor suppressor gene RBM5 inhibits growth of human prostate cancer PC-3 cells through apoptosis
Authors: Zhao Lijing , Li Ranwei , Shao Chen , Li Ping , Liu Jian , Wang Ke
Published: November 2012

Background

Recent studies have indicated that the nuclear RNA-binding protein RBM5 has the ability to modulate apoptosis and suppress tumor growth. The aim of this study is to investigate the expression of RBM5 in human prostate cancer and its mechanism of tumor suppression.

Methods

The expression of RBM5 protein in cancerous prostatic tissues and normal tissues was examined by IHC. PC-3 cell line was used to determine the apoptotic function of RBM5 in vitro. PC-3 cells were transiently transfected with pcDNA3.1-RBM5. Cell viability was determined by MTT assay. Rhodamine 123 staining and Annexin V analysis were performed to observe the apoptotic activity of PC-3 cells overexpressing RBM5. Expression of apoptosis-related genes was assessed by western blot.

Results

The expression of RBM5 protein was significantly decreased in cancerous prostatic tissues compared to the normal tissues. PC-3 cells overexpressing RBM5 showed not only significant growth inhibition compared with the vector controls, but also dysfunction of mitochondrial membrane potential and increased apoptotic activity. To further define RBM5 function in apoptotic pathways, we investigated differential expression profiles of various BH3-only proteins including Bid, Bad, and Bim, and apoptosis regulatory proteins include P53, cleaved caspase9, and cleaved caspase3. We found that the expression of both BH3-only proteins and apoptosis regulatory proteins was increased in RBM5 transfected cells.

Conclusion

The expression of RBM5 protein was significantly decreased in cancerous prostatic tissues, which suggests that RBM5 plays an important role in the pathogenesis of prostate cancer. RBM5 may induce the apoptosis of prostate cancer PC-3 cells by modulating the mitochondrial apoptotic pathway, and thus RBM5 might be a promising target for gene therapy on prostate cancer.
Laparoscopy-assisted versus open D2 radical gastrectomy for advanced gastric cancer without serosal invasion: a case control study
Authors: Chen Qi-Yue , Huang Chang-Ming , Lin Jian-Xian , Zheng Chao-Hui , Li Ping , Xie Jian-Wei , Wang Jia-Bin , Lu Jun
Published: November 2012

Background

The application of laparoscopic surgery for advanced gastric cancer (AGC) remains questionable on account of technical difficulty of D2 lymphadenectomy, and there has been few large-scale follow-up results regarding the oncological adequacy of laparoscopic surgery compared with that of open surgeries for AGC. The aim of this study is to evaluate technical feasibility and oncological efficacy of laparoscopy-assisted gastrectomy (LAG) for advanced gastric cancer without serosal invasion.

Methods

From January 2008 to December 2012, 1114 patients with gastric cancer underwent D2 gastrectomy, including 336 T2 and T3 patients in term of depth of invasion. Of all 336 patients, 224 underwent LAG, while open gastrectomy (OG) performed on the other 112 patients. The comparison was based on the clinicopathologic characteristics, surgical outcome, and follow-up results.

Results

There are not significant differences in clinicopathological characteristics between the two groups (P > 0.05). The operation time and first ambulation time was similar in the two groups. However, estimated blood loss, bowel function recovery time and duration of hospital stay were significantly less in the LAG group. No significant difference in morbidity and mortality was found between the LAG group and OG group (11.1% vs. 15.3%, P = 0.266; 0.9% vs. 1.8%, P = 0.859). The mean number of resected lymph nodes (LNS) between the LAG group and OG group was similar (30.6 ± 10.1 vs. 30.3 ± 8.6, P = 0.786). Furthermore, the mean number of removed LNS in each station was not significantly different in the distal gastrectomy and total gastrectomy (P > 0.05). No statistical difference was seen in 1 year survival rate (91.5% vs. 89.8% P > 0.05) and the survival curve after surgery between the LAG group and OG group.

Conclusion

Laparoscopy-assisted D2 radical gastrectomy is feasible, effective and has comparative oncological efficacy compared with open gastrectomy for advanced gastric cancer without serosal invasion.
Effect of antiviral therapy on the survival and incidence of major complications in HBV-associated cirrhotic patients after splenectomy for hypersplenism and portal hypertension
Authors: Tian Ningqiang , Liu Zhengwen , Yang Mingbo , Li Zhu , Zhang Guoyu , Han Qunying , Li Na , Zhu Qianqian , Lv Yi , Wang Yawen , Xing Fanfan
Published: November 2012

Background

Splenectomy remains a common approach for the management of hypersplenism and portal hypertension in hepatitis B virus (HBV)-associated cirrhotic patients in China and some other Asian countries. The effects of antiviral therapy on the survival and occurrence of complications in asplenic HBV-associated cirrhotic patients are unknown. This study analyzed the effect of antiviral therapy on survival and occurrence of major complications in HBV-associated cirrhotic patients after splenectomy for hypersplenism and portal hypertension.

Results

Of the 57 eligible patients for analysis, 28 patients received nucleos(t)ide analogs (treatment group) for antiviral treatment after splenectomy, while 29 patients received no antiviral treatment (control group). After a median of 3 years and 9 months, the overall survival and complication-free survival in the treatment group were higher though not statistically significant than those in the control group. Multivariate analysis showed that antiviral treatment was associated with increased but not statistically significant overall survival (hazard ratio (HR): 2.272, 95% confidence interval (CI): 0.952–5.424,P = 0.064) and the antiviral treatment was significantly associated with increased complication-free survival of the patients (HR: 7.229, 95% CI: 1.271–41.117,P = 0.026). The complication-free survival in patients aged ≤ 40 years was higher than that in patients aged > 40 years in the antiviral treatment patients (P = 0.020).

Conclusions

Antiviral therapy initiating after splenectomy may reduce the incidence of complications and tend to improve the survival in asplenic HBV-associated cirrhotic patients, especially in younger patients, supporting the use of antiviral therapy in these patients after splenectomy.
Mini-implants in the palatal slope – a retrospective analysis of implant survival and tissue reaction
Authors: Ziebura Thomas , Flieger Stefanie , Wiechmann Dirk
Published: November 2012

Background

To identify insertion procedure and force application related complications in Jet Screw (JS) type mini-implants when inserted in the palatal slope.

Methods

Setting and Sample Population: The Department of Orthodontics, the University Hospital Münster. Forty-one consecutively started patients treated using mini-implants in the palatal slope. In this retrospective study, 66 JS were evaluated. Patient records were used to obtain data on the mode of utilization and complications. Standardized photographs overlayed with a virtual grid served to test the hypothesis that deviations from the recommended insertion site or the type of mechanics applied might be related to complications regarding bleeding, gingival overgrowth or implant failure.

Results

Two implants (3%) were lost, and two implants (3%), both loaded with a laterally directed force, exhibited loosening while still serving for anchorage. Complications that required treatment did not occur, the most severe problem observed being gingival proliferation which was attributable neither to patients’ age nor to applied mechanics or deviations from the ideal implant position.

Conclusions

The JS mini-implant is reliable for sagittal and vertical movements or anchorage purposes. Laterally directed forces might be unfavorable. The selection of implant length as well as the insertion procedure should account for the possibility of gingival overgrowth.
Genomic profiling of rectal adenoma and carcinoma by array-based comparative genomic hybridization
Authors: Shi Zhi-Zhou , Zhang Yue-Ming , Shang Li , Hao Jia-Jie , Zhang Tong-Tong , Wang Bo-Shi , Liang Jian-Wei , Chen Xi , Zhang Ying , Wang Gui-Qi , Wang Ming-Rong , Zhang Yu
Published: November 2012

Background

Rectal cancer is one of the most common cancers in the world. Early detection and early therapy are important for the control of death caused by rectal cancer. The present study aims to investigate the genomic alterations in rectal adenoma and carcinoma.

Methods

We detected the genomic changes of 8 rectal adenomas and 8 carcinomas using array CGH. Then 14 genes were selected for analyzing the expression between rectal tumor and paracancerous normal tissues as well as from adenoma to carcinoma by real-time PCR. The expression of GPNMB and DIS3 were further investigated in rectal adenoma and carcinoma tissues by immunohistochemistry.

Results

We indentified ten gains and 22 losses in rectal adenoma, and found 25 gains and 14 losses in carcinoma. Gains of 7p21.3-p15.3, 7q22.3-q32.1, 13q13.1-q14.11, 13q21.1-q32.1, 13q32.2-q34, 20p11.21 and 20q11.23-q12 and losses of 17p13.1-p11.2, 18p11.32-p11.21 and 18q11.1-q11.2 were shared by both rectal adenoma and carcinoma. Gains of 1q, 6p21.33-p21.31 and losses of 10p14-p11.21, 14q12-q21.1, 14q22.1-q24.3, 14q31.3-q32.1, 14q32.2-q32.32, 15q15.1-q21.1, 15q22.31 and 15q25.1-q25.2 were only detected in carcinoma but not in adenoma. Copy number and mRNA expression of EFNA1 increased from rectal adenoma to carcinoma. C13orf27 and PMEPA1 with increased copy number in both adenoma and carcinoma were over expressed in rectal cancer tissues. Protein and mRNA expression of GPNMB was significantly higher in cancer tissues than rectal adenoma tissues.

Conclusion

Our data may help to identify the driving genes involved in the adenoma-carcinoma progression.
Predictors of use of pain medications for persistent knee pain after primary Total Knee Arthroplasty: a cohort study using an institutional joint registry
Authors: Singh Jasvinder A , Lewallen David G
Published: November 2012

Introduction

To study the use of pain medications for persistent index knee pain and their predictors after primary Total Knee Arthroplasty (TKA).

Methods

The Mayo Total Joint Registry collects patient-reported data including pain medication use on all patients who undergo TKA. We used data from patients who underwent primary TKA from 1993-2005. We examined whether gender, age (reference, ≤60 yrs), body mass index (BMI; reference, <25 kg/m2), comorbidities measured by Deyo-Charlson index (5-point increase), anxiety and depression predicted use of pain medications (non-steroidal anti-inflammatory drugs (NSAIDs) and opioids) 2- and 5-years after primary TKA. Multivariable logistic regression additionally adjusted for operative diagnosis, American Society of Anesthesiologists (ASA) score, implant fixation and distance from the medical center.

Results

7,139 of the 10,957 eligible (65%) at 2-years and 4,234 of 7,404 eligible (57%) completed questionnaires. Significant predictors of NSAIDs use were (Odds ratio (95% confidence interval)): male gender at 2- and 5-years, 0.5 (0.4, 0.6) and 0.6 (0.5, 0.8); age >70-80 years, 0.7 (0.5, 0.9), 0.6 (0.4, 0.8); and depression, 1.4 (1.0, 1.8) and 1.7 (1.1, 2.5). BMI ≥40 was associated with NSAIDs use only at 2-years, 1.6 (1.1, 2.5). Significant predictors of opioid pain medication use at 2- and 5-years were: male gender, 0.5 (0.3, 0.9) and 0.4 (0.2, 0.8); age >70-80 years, 0.3 (0.1, 0.6), 0.3 (0.1, 0.8); and anxiety, 3.0 (1.6, 5.7) and 4.0 (1.7, 9.4).

Conclusions

Female gender and younger age were associated with higher risk of use of NSAIDs and opioids after primary TKA. Depression was associated with higher NSAID use and anxiety with higher opioid pain medication use after primary TKA.
The multidrug-resistant PMEN1 pneumococcus is a paradigm for genetic success
Authors: Wyres Kelly L , Lambertsen Lotte M , Croucher Nicholas J , McGee Lesley , von Gottberg Anne , Liñares Josefina , Jacobs Michael R , Kristinsson Karl G , Beall Bernard W , Klugman Keith P , Parkhill Julian , Hakenbeck Regine , Bentley Stephen D , Brueggemann Angela B
Published: November 2012

Background

Streptococcus pneumoniae, also called the pneumococcus, is a major bacterial pathogen. Since its introduction in the 1940s, penicillin has been the primary treatment for pneumococcal diseases. Penicillin resistance rapidly increased among pneumococci over the past 30 years, and one particular multidrug-resistant clone, PMEN1, became highly prevalent globally. We studied a collection of 426 pneumococci isolated between 1937 and 2007 to better understand the evolution of penicillin resistance within this species.

Results

We discovered that one of the earliest known penicillin-nonsusceptible pneumococci, recovered in 1967 from Australia, was the likely ancestor of PMEN1, since approximately 95% of coding sequences identified within its genome were highly similar to those of PMEN1. The regions of the PMEN1 genome that differed from the ancestor contained genes associated with antibiotic resistance, transmission and virulence. We also revealed that PMEN1 was uniquely promiscuous with its DNA, donating penicillin-resistance genes and sometimes many other genes associated with antibiotic resistance, virulence and cell adherence to many genotypically diverse pneumococci. In particular, we describe two strains in which up to 10% of the PMEN1 genome was acquired in multiple fragments, some as long as 32 kb, distributed around the recipient genomes. This type of directional genetic promiscuity from a single clone to numerous unrelated clones has, to our knowledge, never before been described.

Conclusions

These findings suggest that PMEN1 is a paradigm of genetic success both through its epidemiology and promiscuity. These findings also challenge the existing views about horizontal gene transfer among pneumococci.
Hepatitis B Screening Before Chemotherapy: A Survey of Practitioners' Knowledge, Beliefs, and Screening Practices
Authors: Lee Ronita S.M. , Bell Chaim M. , Singh Jeffrey M. , Hicks Lisa K.
Published: November 2012

Canadian oncologists'/hematologists' knowledge regarding risk factors for hepatitis B carriage seems to be low, potentially undermining the success of a selective screening strategy.
Attitudes of Patients With Cancer About Personalized Medicine and Somatic Genetic Testing
Authors: Gray Stacy W. , Hicks-Courant Katherine , Lathan Christopher S. , Garraway Levi , Park Elyse R. , Weeks Jane C.
Published: November 2012

Patients have relayed misunderstandings about somatic testing and a reluctance to have full sequencing; oncologists must consider how they present testing to patients so concerns over discrimination and psychological harm do not hinder test uptake.
Practice Benchmarking in the Age of Targeted Auditing
Authors: Langdale Ryan P. , Holland Ben F.
Published: November 2012

The authors' analysis of this data set produced benchmarks from which medical oncologists can monitor, measure, and improve on common areas of billing fraud, waste, or abuse in their practices.
Effort Required in Eligibility Screening for Clinical Trials
Authors: Penberthy Lynne T. , Dahman Bassam A. , Petkov Valentina I. , DeShazo Jonathan P.
Published: November 2012

This study provides results based on prospectively captured effort to estimate the largely nonreimbursed costs of eligibility screening and suggests that screening can be a significant financial burden to an institution.
TheDrosophilaWIF1 homolog Shifted maintains glypican-independent Hedgehog signaling and interacts with the Hedgehog co-receptors Ihog and Boi
Authors: Avanesov Andrei , Blair Seth S.
Published: November 2012

Hedgehog (Hh) family proteins are secreted signaling ligands whose short- and long-range activities transform cellular fates in multiple contexts in organisms ranging from metazoans to humans. In the developing Drosophila wing, extracellular Hh binds to cell-bound glypican heparan sulfate proteoglycans (HSPGs) and the secreted protein Shifted (Shf), a member of Wnt inhibitory factor 1 (WIF1) family. The glypicans and Shf are required for long-range Hh movement and signaling; it has been proposed that Shf promotes long-range Hh signaling by reinforcing binding between Hh and the glypicans, and that much or all of glypican function in Hh signaling requires Shf. However, we will show here that Shf maintains short-range Hh signaling in the wing via a mechanism that does not require the presence of or binding to the Drosophila glypicans Dally and Dally-like protein. Conversely, we demonstrate interactions between Hh and the glypicans that are maintained, and even strengthened, in the absence of Shf. We present evidence that Shf binds to the CDO/BOC family Hh co-receptors Interference hedgehog (Ihog) and Brother of Ihog, suggesting that Shf regulates short-range Hh signaling through interactions with the receptor complex. In support of a functional interaction between Ihog and members of the Shf/WIF1 family, we show that Ihog can increase the Wnt-inhibitory activity of vertebrate WIF1; this result raises the possibility of interactions between WIF1 and vertebrate CDO/BOC family members.
MEF2A regulates the Gtl2-Dio3 microRNA mega-cluster to modulate WNT signaling in skeletal muscle regeneration
Authors: Snyder Christine M. , Rice Amanda L. , Estrella Nelsa L. , Held Aaron , Kandarian Susan C. , Naya Francisco J.
Published: November 2012

Understanding the molecular mechanisms of skeletal muscle regeneration is crucial to exploiting this pathway for use in tissue repair. Our data demonstrate that the MEF2A transcription factor plays an essential role in skeletal muscle regeneration in adult mice. Injured Mef2a knockout mice display widespread necrosis and impaired myofiber formation. MEF2A controls this process through its direct regulation of the largest known mammalian microRNA (miRNA) cluster, the Gtl2-Dio3 locus. A subset of the Gtl2-Dio3 miRNAs represses secreted Frizzled-related proteins (sFRPs), inhibitors of WNT signaling. Consistent with these data, Gtl2-Dio3-encoded miRNAs are downregulated in regenerating Mef2a knockout muscle, resulting in upregulated sFRP expression and attenuated WNT activity. Furthermore, myogenic differentiation in Mef2a-deficient myoblasts is rescued by overexpression of miR-410 and miR-433, two miRNAs in the Gtl2-Dio3 locus that repress sFRP2, or by treatment with recombinant WNT3A and WNT5A. Thus, miRNA-mediated modulation of WNT signaling by MEF2A is a requisite step for proper muscle regeneration, and represents an attractive pathway for enhancing regeneration of diseased muscle.
A Hh-driven gene network controls specification, pattern and size of the Drosophila simple eyes
Authors: Aguilar-Hidalgo Daniel , Domínguez-Cejudo María A. , Amore Gabriele , Brockmann Anette , Lemos María C. , Córdoba Antonio , Casares Fernando
Published: November 2012

During development, extracellular signaling molecules interact with intracellular gene networks to control the specification, pattern and size of organs. One such signaling molecule is Hedgehog (Hh). Hh is known to act as a morphogen, instructing different fates depending on the distance to its source. However, how Hh, when signaling across a cell field, impacts organ-specific transcriptional networks is still poorly understood. Here, we investigate this issue during the development of the Drosophila ocellar complex. The development of this sensory structure, which is composed of three simple eyes (or ocelli) located at the vertices of a triangular patch of cuticle on the dorsal head, depends on Hh signaling and on the definition of three domains: two areas of eya and so expression – the prospective anterior and posterior ocelli – and the intervening interocellar domain. Our results highlight the role of the homeodomain transcription factor engrailed (en) both as a target and as a transcriptional repressor of hh signaling in the prospective interocellar region. Furthermore, we identify a requirement for the Notch pathway in the establishment of en maintenance in a Hh-independent manner. Therefore, hh signals transiently during the specification of the interocellar domain, with en being required here for hh signaling attenuation. Computational analysis further suggests that this network design confers robustness to signaling noise and constrains phenotypic variation. In summary, using genetics and modeling we have expanded the ocellar gene network to explain how the interaction between the Hh gradient and this gene network results in the generation of stable mutually exclusive gene expression domains. In addition, we discuss some general implications our model may have in some Hh-driven gene networks.
Protein tyrosine phosphatase 1B restrains mammary alveologenesis and secretory differentiation
Authors: Milani Emanuela S. , Brinkhaus Heike , Dueggeli Regula , Klebba Ina , Mueller Urs , Stadler Michael , Kohler Hubertus , Smalley Matthew J. , Bentires-Alj Mohamed
Published: November 2012

Tyrosine phosphorylation plays a fundamental role in mammary gland development. However, the role of specific tyrosine phosphatases in controlling mammary cell fate remains ill defined. We have identified protein tyrosine phosphatase 1B (PTP1B) as an essential regulator of alveologenesis and lactogenesis. PTP1B depletion increased the number of luminal mammary progenitors in nulliparous mice, leading to enhanced alveoli formation upon pregnancy. Mechanistically, Ptp1b deletion enhanced the expression of progesterone receptor and phosphorylation of Stat5, two key regulators of alveologenesis. Furthermore, glands from Ptp1b knockout mice exhibited increased expression of milk proteins during pregnancy due to enhanced Stat5 activation. These findings reveal that PTP1B constrains the number of mammary progenitors and thus prevents inappropriate onset of alveologenesis in early pregnancy. Moreover, PTP1B restrains the expression of milk proteins during pregnancy and thus prevents premature lactogenesis. Our work has implications for breast tumorigenesis because Ptp1b deletion has been shown to prevent or delay the onset of mammary tumors.
Otx2 is an intrinsic determinant of the embryonic stem cell state and is required for transition to a stable epiblast stem cell condition
Authors: Acampora Dario , Di Giovannantonio Luca G. , Simeone Antonio
Published: November 2012

Mouse embryonic stem cells (ESCs) represent the naïve ground state of the preimplantation epiblast and epiblast stem cells (EpiSCs) represent the primed state of the postimplantation epiblast. Studies have revealed that the ESC state is maintained by a dynamic mechanism characterized by cell-to-cell spontaneous and reversible differences in sensitivity to self-renewal and susceptibility to differentiation. This metastable condition ensures indefinite self-renewal and, at the same time, predisposes ESCs for differentiation to EpiSCs. Despite considerable advances, the molecular mechanism controlling the ESC state and pluripotency transition from ESCs to EpiSCs have not been fully elucidated. Here we show that Otx2, a transcription factor essential for brain development, plays a crucial role in ESCs and EpiSCs. Otx2 is required to maintain the ESC metastable state by antagonizing ground state pluripotency and promoting commitment to differentiation. Furthermore, Otx2 is required for ESC transition into EpiSCs and, subsequently, to stabilize the EpiSC state by suppressing, in pluripotent cells, the mesendoderm-to-neural fate switch in cooperation with BMP4 and Fgf2. However, according to its central role in neural development and differentiation, Otx2 is crucially required for the specification of ESC-derived neural precursors fated to generate telencephalic and mesencephalic neurons. We propose that Otx2 is a novel intrinsic determinant controlling the functional integrity of ESCs and EpiSCs.
MicroRNAs downregulate Bag of marbles to ensure proper terminal differentiation in the Drosophila male germline
Authors: Eun Suk Ho , Stoiber Patrick M. , Wright Heather J. , McMurdie Karen E. , Choi Caitlin H. , Gan Qiang , Lim Cindy , Chen Xin
Published: November 2012

In many adult stem cell lineages, the continuous production of functional differentiated cells depends on the maintenance of progenitor cells in an undifferentiated and proliferative state, as well as the subsequent commitment to proper terminal differentiation. In the Drosophila male germline stem cell (GSC) lineage, a key differentiation factor, Bag of marbles (Bam), is required for the transition from proliferative spermatogonia to differentiating spermatocytes. We show that bam mRNA, but not Bam, is present in spermatocytes, suggesting that bam is regulated post-transcriptionally. Consistent with this, repression of Bam accumulation is achieved by microRNAs via the bam 3′UTR. When the bam 3′UTR was substituted with the 3′UTR of a constitutively expressed α-Tubulin, Bam became stabilized in spermatocytes. Moreover, such a persistent expression of Bam in spermatocytes was recapitulated by specifically mutating the putative miR-275/miR-306 recognition site at the bam 3′UTR. In addition, overexpression of miR-275 or miR-306 in spermatogonial cells resulted in a delay of the proliferation-to-differentiation transition and resembled the bam loss-of-function phenotype, suggesting that these microRNAs are sufficient to downregulate Bam. Finally, the failure of Bam downregulation in spermatocytes affected spermatid terminal differentiation and resulted in increased male sterility. Our results demonstrate that microRNAs control the stem cell differentiation pathway through regulating Bam, the downregulation of which is crucial for proper spermatid terminal differentiation.
Temperature-dependent behaviours are genetically variable in the nematode Caenorhabditis briggsae
Authors: Stegeman Gregory W. , Bueno de Mesquita Matthew , Ryu William S. , Cutter Asher D.
Published: November 2012

Temperature-dependent behaviours in C. elegans, such as thermotaxis and isothermal tracking, are complex behavioral responses that integrate sensation, foraging and learning, and have driven investigations to discover many essential genetic and neural pathways. The ease of manipulation of the Caenorhabditis model system also has encouraged its application to comparative analyses of phenotypic evolution, particularly contrasts of the classic model C. elegans with C. briggsae. And yet, few studies have investigated natural genetic variation in behavior in any nematode. Here we measure thermotaxis and isothermal tracking behavior in genetically distinct strains of C. briggsae, further motivated by the latitudinal differentiation in C. briggsae that is associated with temperature-dependent fitness differences in this species. We demonstrate that C. briggsae performs thermotaxis and isothermal tracking largely similar to C. elegans, with a tendency to prefer its rearing temperature. Comparisons of these behaviors among strains reveal substantial heritable natural variation within each species that corresponds to three general patterns of behavioral response. However, intra-species genetic differences in thermal behavior often exceed inter-species differences. These patterns of temperature-dependent behaviour motivate further development of C. briggsae as a model system for dissecting the genetic underpinnings of complex behavioural traits.
Serotonergic and cholinergic elements of the hypoxic ventilatory response in developing zebrafish
Authors: Shakarchi Kamila , Zachar Peter C. , Jonz Michael G.
Published: November 2012

The chemosensory roles of gill neuroepithelial cells (NECs) in mediating the hyperventilatory response to hypoxia are not clearly defined in fish. While serotonin (5-HT) is the predominant neurotransmitter in O2-sensitive gill NECs, acetylcholine (ACh) plays a more prominent role in O2 sensing in terrestrial vertebrates. The present study characterized the developmental chronology of potential serotonergic and cholinergic chemosensory pathways of the gill in the model vertebrate, the zebrafish (Danio rerio). In immunolabelled whole gills from larvae, serotonergic NECs were observed in epithelia of the gill filaments and gill arches, while non-serotonergic NECs were found primarily in the gill arches. Acclimation of developing zebrafish to hypoxia (PO2=75 mmHg) reduced the number of serotonergic NECs observed at 7 days post-fertilization (d.p.f.), and this effect was absent at 10 d.p.f. In vivo administration of 5-HT mimicked hypoxia by increasing ventilation frequency (Vf) in early stage (7-10 d.p.f.) and late stage larvae (14-21 d.p.f.), while ACh increased Vf only in late stage larvae. In time-course experiments, application of ketanserin inhibited the hyperventilatory response to acute hypoxia (PO2=25 mmHg) at 10 d.p.f., while hexamethonium did not have this effect until 12 d.p.f. Cells immunoreactive for the vesicular acetylcholine transporter (VAChT) began to appear in the gill filaments by 14 d.p.f. Characterization in adult gills revealed that VAChT-positive cells were a separate population of neurosecretory cells of the gill filaments. These studies suggest that serotonergic and cholinergic pathways in the zebrafish gill develop at different times and contribute to the hyperventilatory response to hypoxia.
Novel 4-Trifluoromethylthiazole-5-carboxylic Acid as Acceptor in Photosensitized Dyes
Authors: Iwata Satoru , Aoyama Misa , Uchida Satoshi , Tanaka Kiyoshi
Published: November 2012

Novel photosensitized dyes containing 4-trifluoromethylthiazole-5-carboxylic acid as an acceptor are synthesized. Stilbene-type dyes with this acceptor show high performance as dye-sensitized solar cells. The trifluoromethyl group is assumed to act as a suppressor of electron back-donation from the TiO2 conduction band to the electrolyte and as an accelerator of charge separation in the photoexcited state.
Endovenous laser ablation of varicose perforating veins with the 1470-nm diode laser using the radial fibre slim
Authors: Zerweck Christof , von Hodenberg Eva , Knittel Matthias , Zeller Thomas , Schwarz Thomas
Published: November 2012

Background

Endovenous Laser Ablation (EVLA) is one of the most accepted treatment options for varicose veins. The aim of this study was to investigate the efficacy and safety of the new radial fiber slim (ELVeS-radial-slim kit™) for the 1470 nm diode laser in perforator veins with a 1 month follow-up.

Methods

Our prospective observational cohort study comprised 69 perforating veins in 55 patients. Ninety percent of all patients were in the CEAP-stage C3-C6. The radial fiber slim was used to occlude the perforating vein and the great or small saphenous vein in the same procedure. The primary efficacy endpoint of the study was ultrasonographically proven elimination of venous reflux in the perforating vein after at least one month. Secondary efficacy and further safety end points after one month were as follows: (1) sonographic exclusion of recanalization of the treated vein segments, (2) deep vein thrombosis (DVT), clinical pulmonary embolism (PE), or superficial vein thrombosis (SVT) as defined by objective testing, (3) death from any cause, (4) persistent clinical complaints such as pain and paresthesia.

Results

Follow-up could be completed in all patients. In all treated perforating varicose veins, occlusion with elimination of reflux could be demonstrated immediately after the procedure. After one month 95.6% of the treated veins were still occluded (67/69). During follow-up, we did not diagnose any DVT, PE or SVT in the area related to the treated perforating vein. No patient died. One patient reported paresthesia distally of the puncture site.

Conclusion

Endovenous laser treatment of varicose perforating veins with 1470 nm diode laser using the radial fiber slim is effective and safe with low recanalization rates during 1-month follow-up.
Revisiting Cervical Ectopic Pregnancy
Authors: Bolaji Ibrahim , Bika Olanike
Published: November 2012

The diagnosis and treatment of non-tubal or unusual pregnancy implantation presents diagnostic and therapeutic dilemmas. Cervical pregnancies (CPs) are especially dangerous due to associated life-threatening haemorrhage and associated massive blood transfusions and emergency hysterectomy. Haemostasis is the main aim of the therapy to prevent hysterectomy. Overall conservative management of an asymptomatic CP using systemic or local medical treatment seems superior to the surgical intervention. Exclusive operative methods tend to lead to a high failure rate due to severe haemorrhage. The optimum therapeutic option for symptomatic CP is still unclear. We report a case of delayed diagnosis of advanced CP, where a combination of medical, surgical and mechanical treatment was adopted and hysterectomy was avoided thereby preserving fertility. This article presents updates on the aetiology, diagnosis and management of patients with cervical ectopic pregnancy.
Multicore Enablement for Automotive Cyber Physical Systems
Authors: Herkersdorf Andreas , Michel Hans-Ulrich , Rauchfuss Holm , Wild Thomas
Published: November 2012

Smart mobility addresses ecological, safe and flexible transportation needs of individuals and the general public. Smart mobility draws synergies from integrating traditionally disjoint domains like automotive, railway, avionics and geography-/business-specific location based services. Cyber physical systems (CPS), built around multicore processor technology, provision powerful platforms to realize smart mobility applications. However, multicore processors require adequate enablement in order to tackle their inherent complexities related to efficient exploitation of parallel resources under safety, security and real-time constraints. This paper addresses two topics: First, we discuss the different notions CPS may adopt in the automotive domain and outline their potentials. Second, we propose a holistic virtualization approach consisting of Hypervisor/VMM middleware for processor virtualization in combination with hardware-assisted communication virtualization. This will allow providing high-bitrate, dependable and QoS conform interconnect services among compute, memory and I/O resources of automotive ECU systems.
The prognostic value of the metastatic lymph node ratio and maximal metastatic tumor size in pathological N1a papillary thyroid carcinoma
Authors: Jeon Min Ji , Yoon Jong Ho , Han Ji Min , Yim Ji Hye , Hong Suck Joon , Song Dong Eun , Ryu Jin-Sook , Kim Tae Yong , Shong Young Kee , Kim Won Bae
Published: November 2012

Objective

The presence of central neck lymph node (LN) metastases (defined as pN1a according to Tumor Node Metastasis classification) in papillary thyroid cancer (PTC) is known as an independent risk factor for recurrence. Extent of LN metastasis and the completeness of removal of metastatic LN must have an impact on prognosis but they are not easy to measure. Moreover, the significance of the size of metastatic tumors in LNs has not been clarified. This study was to evaluate the impact of the extent of LN metastasis and size of metastatic tumors on the recurrence in pathological N1a PTC.

Design

This retrospective observational cohort study enrolled 292 PTC patients who underwent total thyroidectomy with central neck dissection from 1999 to 2005. LN ratio was defined as the number of metastatic LNs divided by the number of removed LNs, which was regarded as variable reflecting both extent of LN metastasis and completeness of resection, and LN size as the maximal diameter of tumor in metastatic LN.

Results

The significant risk factors for recurrence in univariate analysis were large primary tumor size (defined as larger than 2 cm), high LN ratio (defined as higher than 0.4), and presence of macrometastasis (defined as larger than 0.2 cm). Age, sex, clinical node status, and microscopic perithyroidal extension had no effect on recurrence. In multivariate analysis, high LN ratio and presence of macrometastasis were independent risk factors for recurrence.

Conclusion

LN ratio and size of metastatic nodes had a significant prognostic value in pathological N1a PTC. We suggest that risk stratification of pathological N1a PTC according to the pattern of LN metastasis such as LN ratio and size would give valuable information to clinicians.