bluuebunny/crossref_metadata_2025 huggingface dataset:
A Phase II Study of an Herbal Decoction That Includes Astragali Radix for Cancer-Associated Anorexia in Patients With Advanced Cancer
Authors: Jae Jin Lee  , Jung Joo Lee
Published: February 2010

Hypothesis: Anorexia and cancer cachexia produce significant loss of adipose tissue and muscle mass and eventually reduce survival in cancer patients. Study design: This phase II study was conducted to assess the efficacy and the safety of an herbal decoction with Astragali Radix in patients with anorexia in advanced cancer. Methods: All patients with histologic evidence of an incurable malignancy had a weight loss of at least 5% during the preceding 6 months and a patient-estimated severe anorexia.The herbal decoction was administered 30 minutes after meals, three times a day for 3 weeks.The score of appetite, body weight, the cytokines, IL-1β, IL-6, TNF-α, and anthropometric measurements were assessed. For the assessment of anorexia, a visual analog scale (VAS: 0 mm = no anorexia, 100 mm = maximal anorexia) was used. Results: Eleven patients were recruited from January, 2007 to January, 2009. The mean age was 59.8 years old. The change in anorexia from baseline with the herbal decoction was significantly different and anorexia was improved (anorexia VAS score, 60mm vs. 40mm, p = 0.008). The mean value of the maximal body weight was 55.6 kg and differed significantly from the 54.6 kg at baseline ( p = 0.009). Changes in cytokine levels and anthropometric measurements from baseline to the 3rd week were not significant. All toxicities were manageable. Conclusion: Appetite and body weight were improved with the herbal decoction. This herbal decoction shows some potential for management of cancer-related anorexia.
Curcuma wenyujin Extract Induces Apoptosis and Inhibits Proliferation of Human Cervical Cancer Cells In Vitro and In Vivo
Authors: Lim Chuan-Bian , Ky Nung , Ng Hui-Min , Hamza Mohamed Sabry , Yan Zhao
Published: February 2010

An essential oil extract, derived from the rhizome of Curcuma wenyujin (CWE), possesses antioxidative, antimicrobial, and anti-inflammatory properties. However, it remains unknown how exactly CWE inhibits tumor growth. In this study, using human cervical cancer HeLa cells, the authors postulated that CWE has the ability to inhibit tumor growth. The study shows that CWE dose-dependently suppressed colony formation and inhibited the proliferation of HeLa cells through blockade of cell cycle progression at G1 phase and apoptosis. CWE-induced G1 arrest was associated with retinoblastoma protein dephosphorylation and reduced amounts of cyclins D1 and D3, and cyclin-dependent kinase 4 and 6 proteins. CWE treatment resulted in apoptosis in HeLa cells as evidenced by morphological changes, caspase activation and PARP cleavage, which can be reversed by a pan-caspase inhibitor. It was observed that CWE treatment activated the mitochondrial apoptotic pathway indicated by a decrease in Mcl-1 and Bcl-xL levels, resulting in mitochondrial membrane potential loss and caspases 9 activation. CWE-treated cells displayed reduced PTEN, AKT, and STAT3 phosphorylation and downregulation of NFκB signaling, providing a mechanism for the G1 arrest and apoptosis observed. Furthermore, CWE inhibited tumor growth of HeLa in a xenograft mouse tumor model, suggesting that CWE inhibited tumorigenesis by inhibiting cell proliferation and inducing apoptosis. These findings are the first to reveal the molecular basis for the anticervical cancer action of CWE. The results suggest that CWE could be developed as a drug for the management of cervical cancer.
A Mineral-Rich Red Algae Extract Inhibits Polyp Formation and Inflammation in the Gastrointestinal Tract of Mice on a High-Fat Diet
Authors: Aslam Muhammad N. , Paruchuri Tejaswi , Bhagavathula Narasimharao , Varani James
Published: February 2010

The purpose of this study was to determine whether a mineral-rich extract derived from the red marine algae Lithothamnion calcareum could be used as a dietary supplement for chemoprevention against colon polyp formation. A total of 60 C57bl/6 mice were divided into 3 groups based on diet. One group received a low-fat, rodent chow diet (AIN76A). The second group received a high-fat “Western-style” diet (HFWD). The third group was fed the same HFWD with the mineral-rich extract included as a dietary supplement. Mice were maintained on the respective diets for 15 months. Autopsies were performed at the time of death or at the completion of the study. To summarize, the cumulative mortality rate was higher in mice on the HFWD during the 15-month period (55%) than in mice from the low-fat diet or the extract-supplemented high-fat diet groups (20% and 30%, respectively; P < .05 with respect to both). Autopsies revealed colon polyps in 20% of the animals on the HFWD and none in animals of the other 2 groups ( P < .05). In addition to the grossly visible polyps, areas of hyperplasia in the colonic mucosa and inflammatory foci throughout the gastrointestinal tract were observed histologically in animals on the high-fat diet. Both were significantly reduced in animals on the low-fat diet and animals on the extract-supplemented HFWD.These data suggest that the mineral-rich algae extract may provide a novel approach to chemoprevention in the colon.
Hemocompatibility of Carotid Artery Stents: Alterations of the Electrical Parameters of Erythrocyte Cell Membrane—A Word of Caution
Authors: Basoli Antonio , Cametti Cesare , Faraglia Vittorio , Gili Tommaso , Rizzo Luigi , Taurino Maurizio
Published: February 2010

The hemocompatibility of standard surgical treatment of carotid artery disease through the insertion of metallic stents is investigated by means of radio wave dielectric spectroscopy technique that allows the measurements of the electrical parameters of the red blood cell membrane. Our measurements suggest that both the membrane permittivity and the membrane conductivity, which characterize the overall electrical behavior of the cell membrane, undergo an appreciable alteration of their standard values as a consequence of the stent insertion. These alterations persist over long period of time, up to 4 weeks. Even if these effects could not cause any evident damage at physiological or clinical level to the patient, the presence of a host response to the stent implant suggests that a full hemocompatibility has not yet reached, and a word of caution is necessary.
Pain Following 980-nm Endovenous Laser Ablation and Segmental Radiofrequency Ablation for Varicose Veins: A Prospective Observational Study
Authors: Shepherd Amanda C. , Gohel Manj S. , Lim Chung S. , Hamish Maher , Davies Alun H.
Published: February 2010

Objectives: The aim of this study was to evaluate postoperative pain following endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) and identify risk factors for increased pain. Methods: Patients undergoing either segmental RFA (VNUS Closure Fast TM, VNUS Medical Technologies, San Jose, California) or EVLA (980 nm) for varicose veins completed a preoperative disease-specific quality-of-life questionnaire (Aberdeen Varicose Vein Questionnaire [AVVQ]) and a diary card recording postoperative pain, return to normal activities, and return to work. Median 3- and 10-day pain scores were calculated. Results: In all, 81 patients returned diary cards (RFA = 45, EVLA = 36). Patients receiving RFA reported less postoperative pain than those receiving EVLA at 3 days (14.5 vs 25.8 mm, P = .053, Mann-Whitney U test) and 10 days (13 vs 23.3 mm, P = .014, Mann-Whitney U test) and returned to work earlier than those receiving EVLA (median 5 vs 9 days, P = .022). Conclusions: Patients treated with segmental RFA had less postoperative pain and returned to work quicker than those treated with EVLA.
A technique for arthroscopic all-inside suturing in the wrist
Authors: Piñal F. Del , García-Bernal F. J. , Cagigal L. , Studer A. , Regalado J. , Thams C.
Published: February 2010

A technique for arthroscopic all-inside suturing in the wrist is presented. The procedure allows placement of the knot inside the joint without additional incisions. We have applied it in cases of dorsal, foveal and coronal tears of the triangular fibrocartilage. No special instrument is required apart from a Tuohy needle.
Mind shift, mode shift: A lifestyle approach to reducing car ownership and use based on behavioural economics and social marketing
Authors: Young Stephen , Caisey Vivienne
Published: February 2010

This paper sets out a new approach to the Wicked Problems of obesity and climate change, and the linked and causative Wicked Problem of increasing car ownership and use. Policies to bring about modal shift from car dependence to forms of transport that cause lower emissions, and are less obesogenic, are conventionally based on framing car use as an externality to be addressed by policies such as taxation or regulation. These policies have been hampered by the reluctance of politicians and policymakers to countenance electoral risk by impinging on the individual’s perceived right to personal mobility. This paper’s approach combines insights and methods from behavioural economics and social marketing: it shifts the focus by considering car ownership and use not as an externality to be addressed in the aggregate, but as the product of individual behaviours and lifestyle choices. Behavioural economics can help to uncover the motivations, heuristicsi and cognitive biases behind such behaviours. Social marketing builds on the premise that people will only change their behaviour if they are sufficiently motivated to do so. It can be used to design interventions which help sectors of the population make transport choices that are more optimal — both for the individuals concerned and for all of us who are affected by these Wicked Problems.
Chondromyxoid Fibroma of the Distal Phalanx of the Big Toe
Authors: Kwok Bill Chang  , Tun Hing Lui
Published: February 2010

Chondromyxoid fibroma rarely arises in the distal phalanx of the toe. It shows a wide spectrum of histology, mimicking other primary bone tumors. A 40-year-old woman had persistent swelling of her big toe after a minor injury a few years ago before a consultation. A radiographic and magnetic resonance imaging study suggested a highly aggressive tumor. Amputation was performed, and pathology of the lesion showed chondromyxoid fibroma.
Phosphorylation of CLEC-2 is dependent on lipid rafts, actin polymerization, secondary mediators, and Rac
Authors: Pollitt Alice Y. , Grygielska Beata , Leblond Bertrand , Désiré Laurent , Eble Johannes A. , Watson Steve P.
Published: February 2010

The C-type lectin-like receptor 2 (CLEC-2) activates platelets through Src and Syk tyrosine kinases via a single cytoplasmic YxxL motif known as a hem immunoreceptor tyrosine-based activation motif (hemITAM). Here, we demonstrate using sucrose gradient ultracentrifugation and methyl-β-cyclodextrin treatment that CLEC-2 translocates to lipid rafts upon ligand engagement and that translocation is essential for hemITAM phosphorylation and signal initiation. HemITAM phosphorylation, but not translocation, is also critically dependent on actin polymerization, Rac1 activation, and release of ADP and thromboxane A2 (TxA2). The role of ADP and TxA2 in mediating phosphorylation is dependent on ligand engagement and rac activation but is independent of platelet aggregation. In contrast, tyrosine phosphorylation of the GPVI-FcRγ-chain ITAM, which has 2 YxxL motifs, is independent of actin polymerization and secondary mediators. These results reveal a unique series of proximal events in CLEC-2 phosphorylation involving actin polymerization, secondary mediators, and Rac activation.
Reference equations for specific airway resistance in children: the Asthma UK initiative
Authors: Kirkby J. , Stanojevic S. , Welsh L. , Lum S. , Badier M. , Beardsmore C. , Custovic A. , Nielsen K. , Paton J. , Tomalak W. , Stocks J.
Published: February 2010

Plethysmographic specific airway resistance (sRaw) is a useful research method for discriminating lung disease in young children. Its use in clinical management has, however, been limited by lack of consensus regarding equipment, methodology and reference data.

The aim of our study was to collate reference data from healthy children (3–10 yrs), document methodological differences, explore the impact of these differences and construct reference equations from the collated dataset.

Centres were approached to contribute sRawdata as part of the Asthma UK initiative. A random selection of pressure–flow plots were assessed for quality and site visits elucidated data collection and analysis protocols.

Five centres contributed 2,872 measurements. Marked variation in methodology and analysis excluded two centres. sRawover-read sheets were developed for quality control. Reference equations and recommendations for recording and reporting both specific effective and total airway resistance (sReffand sRtot, respectively) were developed for White European children from 1,908 measurements made under similar conditions.

Reference sRawdata collected from a single centre may be misleading, as methodological differences exist between centres. These preliminary reference equations can only be applied under similar measurement conditions. Given the potential clinical usefulness of sRaw, particularly with respect to sReff, methodological guidelines need to be established and used in prospective data collection.
Serotype-specific pneumococcal disease may be influenced by mannose-binding lectin deficiency
Authors: Vallès X. , Roca A. , Lozano F. , Morais L. , Suárez B. , Casals F. , Mandomando I. , Sigaúque B. , Nhalungo D. , Esquinas C. , Quintó L. , Alonso P.L. , Torres A.
Published: February 2010

Previous studies of the association between the mannose-binding lectin pathway deficiencies and invasive pneumococcal disease are inconclusive. Invasiveness ofStreptococcus pneumoniaeis dependent on serotype. We aimed to determine the association between invasive pneumococcal disease andMBL2andMASP2genetic variants, regarding serotype distribution.

A hospital-based case–control study was conducted in children admitted to hospital in rural Mozambique in June 2002–November 2003. The study included children admitted to hospital with invasive pneumococcal disease, in whomS. pneumoniaewas isolated from blood and subsequently serotyped. Sequence-based typing analysis of amplicons covering the polymorphic regions ofMASP2(exon 3) andMBL2(promoter and exon 1) was performed.

An overall high frequency ofMBL2genotypes associated with low serum levels of MBL (43%) was found. Carriers of MBL-deficient genotypes were associated with invasive pneumococcal disease produced by low-invasive serotypes (OR 5.55, 95% CI 1.4–21.9; p = 0.01).

Our data suggest that susceptibility to pneumococcal disease among MBL-deficient patients may be influenced by serotype invasiveness. Type-specific capsular serotype ofS. pneumoniaewould need to be taken into account in further genetic association studies of invasive pneumococcal disease.
Influence of pneumococcal serotype group on outcome in adults with bacteraemic pneumonia
Authors: Luján M. , Gallego M. , Belmonte Y. , Fontanals D. , Vallès J. , Lisboa T. , Rello J.
Published: February 2010

The influence of infecting serotype group on outcome in bacteraemic pneumococcal pneumonia remains unclear.

We performed a prospective, 10-yr observational study in an 800-bed teaching hospital. 299 adults diagnosed with pneumonia whose blood cultures showed growth ofStreptococcus pneumoniaewere included in the study. High invasive disease potential (H) serotypes included serotypes 1, 5 and 7F, which served as a reference category, were compared with low invasive disease potential (L) serotypes (3, 6A, 6B, 8, 19F, and 23F) and other (O) serotypes (non-H, non-L). The influence on outcome was determined for each group of serotypes after adjusting for underlying conditions and severity of illness at admission.

Overall, 30-day mortality was 11%. H serotypes (n = 93) infected primarily younger people and presented a higher risk of complicated parapneumonic effusion or empyema (17.2versus5.1%; p = 0.01), with lower mortality (3.2%). The isolation of L serotypes (n = 78) was an independent risk factor for 30-day mortality (OR 7.02, 95% CI 1.72–28.61), as were Charlson score (OR 1.30, 95% CI 1.08–1.58), alcohol abuse (OR 3.99, 95% CI 1.39–11.39) and severity of illness measured by American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) criteria (OR 4.80, 95% CI 1.89–12.13).

A vaccination strategy including serotypes 3, 6A, 6B, 8, 19F and 23F may improve survival in adults.
Factors influencing duration of exposure with symptoms and costs of occupational asthma
Authors: Miedinger D. , Malo J-L. , Ghezzo H. , L'Archevêque J. , Zunzunegui M-V.
Published: February 2010

The most important factor for the prognosis of occupational asthma is the length of exposure with symptoms prior to removal from exposure. We wanted to identify factors, including socioeconomic status, that can influence the delay in submitting a claim to a medicolegal agency after the onset of asthmatic symptoms, and to confirm that this delay is associated with worse respiratory prognosis and higher direct costs.

This is a cross-sectional study of subjects who claimed compensation for occupational asthma at the Workers' Compensation Board of Quebec, Canada. Data were collected at re-evaluation ∼2.5 yrs after diagnosis. Information on the number of years with symptoms and removal from exposure was obtained from the medicolegal file.

60 subjects were included in the study. Being older, having a revenue of >30,000 Canadian dollars and having occupational asthma due to high molecular weight agents were all positively associated with the number of years of exposure with symptoms before removal from exposure. Subjects with persistent airway hyperresponsiveness at follow-up had a higher number of years with symptoms. Experiencing symptoms in the workplace for <1 yr generated lower direct costs.

These findings might help in surveillance programmes that could be preferentially targeted for these subgroups of workers.
Comparative analyses reveal distinct sets of lineage-specific genes within Arabidopsis thaliana
Authors: Lin Haining , Moghe Gaurav , Ouyang Shu , Iezzoni Amy , Shiu Shin-Han , Gu Xun , Buell C Robin
Published: February 2010

Background

The availability of genome and transcriptome sequences for a number of species permits the identification and characterization of conserved as well as divergent genes such as lineage-specific genes which have no detectable sequence similarity to genes from other lineages. While genes conserved among taxa provide insight into the core processes among species, lineage-specific genes provide insights into evolutionary processes and biological functions that are likely clade or species specific.

Results

Comparative analyses using the Arabidopsis thaliana genome and sequences from 178 other species within the Plant Kingdom enabled the identification of 24,624 A. thaliana genes (91.7%) that were termed Evolutionary Conserved (EC) as defined by sequence similarity to a database entry as well as two sets of lineage-specific genes within A. thaliana. One of the A. thaliana lineage-specific gene sets share sequence similarity only to sequences from species within the Brassicaceae family and are termed Conserved Brassicaceae-Specific Genes (914, 3.4%, CBSG). The other set of A. thaliana lineage-specific genes, the Arabidopsis Lineage-Specific Genes (1,324, 4.9%, ALSG), lack sequence similarity to any sequence outside A. thaliana. While many CBSGs (76.7%) and ALSGs (52.9%) are transcribed, the majority of the CBSGs (76.1%) and ALSGs (94.4%) have no annotated function. Co-expression analysis indicated significant enrichment of the CBSGs and ALSGs in multiple functional categories suggesting their involvement in a wide range of biological functions. Subcellular localization prediction revealed that the CBSGs were significantly enriched in proteins targeted to the secretory pathway (412, 45.1%). Among the 107 putatively secreted CBSGs with known functions, 67 encode a putative pollen coat protein or cysteine-rich protein with sequence similarity to the S-locus cysteine-rich protein that is the pollen determinant controlling allele specific pollen rejection in self-incompatible Brassicaceae species. Overall, the ALSGs and CBSGs were more highly methylated in floral tissue compared to the ECs. Single Nucleotide Polymorphism (SNP) analysis showed an elevated ratio of non-synonymous to synonymous SNPs within the ALSGs (1.99) and CBSGs (1.65) relative to the EC set (0.92), mainly caused by an elevated number of non-synonymous SNPs, indicating that they are fast-evolving at the protein sequence level.

Conclusions

Our analyses suggest that while a significant fraction of the A. thaliana proteome is conserved within the Plant Kingdom, evolutionarily distinct sets of genes that may function in defining biological processes unique to these lineages have arisen within the Brassicaceae and A. thaliana.
Genomics based analysis of interactions between developing B-lymphocytes and stromal cells reveal complex interactions and two-way communication
Authors: Zetterblad Jenny , Qian Hong , Zandi Sasan , Månsson Robert , Lagergren Anna , Hansson Frida , Bryder David , Paulsson Nils , Sigvardsson Mikael
Published: February 2010

Background

The use of functional genomics has largely increased our understanding of cell biology and promises to help the development of systems biology needed to understand the complex order of events that regulates cellular differentiation in vivo. One model system clearly dependent on the integration of extra and intra cellular signals is the development of B-lymphocytes from hematopoietic stem cells in the bone marrow. This developmental pathway involves several defined differentiation stages associated with specific expression of genes including surface markers that can be used for the prospective isolation of the progenitor cells directly from the bone marrow to allow for ex vivo gene expression analysis. The developmental process can be simulated in vitro making it possible to dissect information about cell/cell communication as well as to address the relevance of communication pathways in a rather direct manner. Thus we believe that B-lymphocyte development represents a useful model system to take the first steps towards systems biology investigations in the bone marrow.

Results

In order to identify extra cellular signals that promote B lymphocyte development we created a database with approximately 400 receptor ligand pairs and software matching gene expression data from two cell populations to obtain information about possible communication pathways. Using this database and gene expression data from NIH3T3 cells (unable to support B cell development), OP-9 cells (strongly supportive of B cell development), pro-B and pre-B cells as well as mature peripheral B-lineage cells, we were able to identify a set of potential stage and stromal cell restricted communication pathways. Functional analysis of some of these potential ways of communication allowed us to identify BMP-4 as a potent stimulator of B-cell development in vitro. Further, the analysis suggested that there existed possibilities for progenitor B cells to send signals to the stroma. The functional consequences of this were investigated by co-culture experiments revealing that the co-incubation of stromal cells with B cell progenitors altered both the morphology and the gene expression pattern in the stromal cells.

Conclusions

We believe that this gene expression data analysis method allows for the identification of functionally relevant interactions and therefore could be applied to other data sets to unravel novel communication pathways.
Air pollution and mortality in the Canary Islands: a time-series analysis
Authors: López-Villarrubia Elena , Ballester Ferran , Iñiguez Carmen , Peral Nieves
Published: February 2010

Background

The island factor of the cities of Las Palmas de Gran Canaria and Santa Cruz de Tenerife, along with their proximity to Africa and their meteorology, create a particular setting that influences the air quality of these cities and provides researchers an opportunity to analyze the acute effects of air-pollutants on daily mortality.

Methods

From 2000 to 2004, the relationship between daily changes in PM10, PM2.5, SO2, NO2, CO, and ozone levels and daily total mortality and mortality due to respiratory and heart diseases were assessed using Generalized Additive Poisson models controlled for potential confounders. The lag effect (up to five days) as well as the concurrent and previous day averages and distributed lag models were all estimated. Single and two pollutant models were also constructed.

Results

Daily levels of PM10, PM2.5, NO2, and SO2 were found to be associated with an increase in respiratory mortality in Santa Cruz de Tenerife and with increased heart disease mortality in Las Palmas de Gran Canaria, thus indicating an association between daily ozone levels and mortality from heart diseases. The effects spread over five successive days. SO2 was the only air pollutant significantly related with total mortality (lag 0).

Conclusions

There is a short-term association between current exposure levels to air pollution and mortality (total as well as that due specifically to heart and respiratory diseases) in both cities. Risk coefficients were higher for respiratory and cardiovascular mortality, showing a delayed effect over several days.
NSC114792, a novel small molecule identified through structure-based computational database screening, selectively inhibits JAK3
Authors: Kim Byung-Hak , Jee Jun-Goo , Yin Chang-Hong , Sandoval Claudio , Jayabose Somasundaram , Kitamura Daisuke , Bach Erika A , Baeg Gyeong-Hun
Published: February 2010

Background

Human or animals lacking either JAK3 or the common gamma chain (γc) expression display severe combined immunodeficiency disease, indicating the crucial role of JAK3 in T-cell development and the homeostasis of the immune system. JAK3 has also been suggested to contribute to the pathogenesis of tumorigenesis. Recent studies identified activatingJAK3mutations in patients with various hematopoietic malignancies, including acute megakaryoblastic leukemia. Importantly, functional analyses of some of thoseJAK3mutations have been shown to cause lethal hematopoietic malignancies in animal models. These observations make JAK3 an ideal therapeutic target for the treatment of various human diseases. To identify novel small molecule inhibitors of JAK3, we performed structure-based virtual screen using the 3D structure of JAK3 kinase domain and the NCI diversity set of compounds.

Results

We identified NSC114792 as a lead compound. This compound directly blocked the catalytic activity of JAK3 but not that of other JAK family membersin vitro. In addition, treatment of 32D/IL-2Rβ cells with the compound led to a block in IL-2-dependent activation of JAK3/STAT5 but not IL-3-dependent activation of JAK2/STAT5. Consistent with the specificity of NSC114792 for JAK3, it selectively inhibited persistently-activated JAK3, but failed to affect the activity of other JAK family members and other oncogenic kinases in various cancer cell lines. Finally, we showed that NSC114792 decreases cell viability by inducing apoptosis through down-regulating anti-apoptotic gene expression only in cancer cells harboring persistently-active JAK3.

Conclusions

NSC114792 is a lead compound that selectively inhibits JAK3 activity. Therefore, our study suggests that this small molecule inhibitor of JAK3 can be used as a starting point to develop a new class of drugs targeting JAK3 activity, and may have therapeutic potential in various diseases that are caused by aberrant JAK3 activity.
Impaired antiviral activity of interferon alpha against hepatitis C virus 2a in Huh-7 cells with a defective Jak-Stat pathway
Authors: Hazari Sidhartha , Chandra Partha K , Poat Bret , Datta Sibnarayan , Garry Robert F , Foster Timothy P , Kousoulas Gus , Wakita Takaji , Dash Srikanta
Published: February 2010

Background

The sustained virological response to interferon-alpha (IFN-α) in individuals infected with hepatitis C virus (HCV) genotype 1 is only 50%, but is about 80% in patients infected with genotype 2-6 viruses. The molecular mechanisms explaining the differences in IFN-α responsiveness between HCV 1 and other genotypes have not been elucidated.

Results

Virus and host cellular factors contributing to IFN responsiveness were analyzed using a green fluorescence protein (GFP) based replication system of HCV 2a and Huh-7 cell clones that either possesses or lack a functional Jak-Stat pathway. The GFP gene was inserted into the C-terminal non-structural protein 5A of HCV 2a full-length and sub-genomic clones. Both HCV clones replicated to a high level in Huh-7 cells and could be visualized by either fluorescence microscopy or flow cytometric analysis. Huh-7 cells transfected with the GFP tagged HCV 2a genome produced infectious virus particles and the replication of fluorescence virus particles was demonstrated in naïve Huh-7.5 cells after infection. IFN-α effectively inhibited the replication of full-length as well as sub-genomic HCV 2a clones in Huh-7 cells with a functional Jak-Stat pathway. However, the antiviral effect of IFN-α against HCV 2a virus was not observed in Huh-7 cell clones with a defect in Jak-Stat signaling. HCV infection or replication did not alter IFN-α induced Stat phosphorylation or ISRE promoter-luciferase activity in both the sensitive and resistant Huh-7 cell clones.

Conclusions

The cellular Jak-Stat pathway is critical for a successful IFN-α antiviral response against HCV 2a. HCV infection or replication did not alter signaling by the Jak-Stat pathway. GFP labeled JFH1 2a replicon based stable cell lines with IFN sensitive and IFN resistant phenotypes can be used to develop new strategies to overcome IFN-resistance against hepatitis C.
Efficacy of IP6 + inositol in the treatment of breast cancer patients receiving chemotherapy: prospective, randomized, pilot clinical study
Authors: Bačić Ivan , Družijanić Nikica , Karlo Robert , Škifić Ivan , Jagić Stjepan
Published: February 2010

Background

Prospective, randomized, pilot clinical study was conducted to evaluate the beneficial effects of inositol hexaphosphate (IP6) + Inositol in breast cancer patients treated with adjuvant therapy.

Patients and methods

Patients with invasive ductal breast cancer where polychemotherapy was indicated were monitored in the period from 2005-2007. Fourteen patients in the same stage of ductal invasive breast cancer were involved in the study, divided in two randomized groups. One group was subjected to take IP6 + Inositol while the other group was taking placebo. In both groups of patients the same laboratory parameters were monitored. When the treatment was finished, all patients have filled questionnaires QLQ C30 and QLQ-BR23 to determine the quality of life.

Results

Patients receiving chemotherapy, along with IP6 + Inositol did not have cytopenia, drop in leukocyte and platelet counts. Red blood cell counts and tumor markers were unaltered in both groups. However, patients who took IP6 + Inositol had significantly better quality of life (p = 0.05) and functional status (p = 0.0003) and were able to perform their daily activities.

Conclusion

IP6 + Inositol as an adjunctive therapy is valuable help in ameliorating the side effects and preserving quality of life among the patients treated with chemotherapy.
The bHLH/PAS transcription factor singleminded 2s promotes mammary gland lactogenic differentiation
Authors: Wellberg Elizabeth , Metz Richard P. , Parker Caitlin , Porter Weston W.
Published: February 2010

We have previously demonstrated that the bHLH/PAS transcription factor, singleminded 2s (Sim2s), is required for proper mammary ductal morphogenesis and luminal epithelial differentiation. Furthermore, loss of Sim2s in breast cancer cells resulted in downregulation of epithelial markers and acquisition of a basal-like phenotype. The objective of this study was to further define the role of Sim2s in mammary differentiation. We found that Sim2s is developmentally regulated throughout mammary gland development with highest expression during lactation. Mammary glands from nulliparous mice expressing Sim2s driven by the mouse mammary tumor virus (MMTV) long terminal repeat (LTR) promoter were morphologically indistinguishable from wild-type mice but displayed hallmarks of precocious lactogenic differentiation. These included elevated expression of the milk protein genes Wap and Csn2, and apical localization of the lactation marker Npt2b. Consistent with the in vivo results, Sim2s enhanced prolactin-mediated Csn2 expression in HC11 and CIT3 mouse mammary epithelial cells, and downregulation of Sim2s by shRNA in HC11 cells inhibited Csn2 expression. Chromatin immunoprecipitation (ChIP) analyses of the Csn2 gene found that Sim2s associates with the Csn2 promoter and re-ChIP experiments showed that Sim2s interacted with the RNA II polymerase (RNAPII) complex. Together, these data demonstrate, for the first time, that Sim2s is required for establishing and maintaining mammary gland differentiation.
Alterations in phosphorus, calcium and PTHrP contribute to defects in dental and dental alveolar bone formation in calcium-sensing receptor-deficient mice
Authors: Sun Wen , Sun Weiwei , Liu Jingning , Zhou Xichao , Xiao Yongjun , Karaplis Andrew , Pollak Martin R. , Brown Edward , Goltzman David , Miao Dengshun
Published: February 2010

To determine whether the calcium-sensing receptor (CaR) participates in tooth formation and dental alveolar bone development in mandibles in vivo, we examined these processes, as well as mineralization, in 2-week-old CaR-knockout (CaR−/−) mice. We also attempted to rescue the phenotype of CaR−/− mice by genetic means, in mice doubly homozygous for CaR and 25-hydroxyvitamin D 1α-hydroxylase [1α(OH)ase] or parathyroid hormone (Pth). In CaR−/− mice, which exhibited hypercalcemia, hypophosphatemia and increased serum PTH, the volumes of teeth and of dental alveolar bone were decreased dramatically, whereas the ratio of the area of predentin to total dentin and the number and surface of osteoblasts in dental alveolar bone were increased significantly, as compared with wild-type littermates. The normocalcemia present in CaR−/−;1α(OH)ase−/− mice only slightly improved the defects in dental and alveolar bone formation observed in the hypercalcemic CaR−/− mice. However, these defects were completely rescued by the additional elimination of hypophosphatemia and by an increase in parathyroid hormone-related protein (PTHrP) expression in the apical pulp, Hertwig's epithelial root sheath and mandibular tissue in CaR−/−; Pth−/− mice. Therefore, alterations in calcium, phosphorus and PTHrP contribute to defects in the formation of teeth and alveolar bone in CaR-deficient mice. This study indicates that CaR participates in the formation of teeth and in the development of dental alveolar bone in mandibles in vivo, although it appears to do so largely indirectly.
Syntabulin, a motor protein linker, controls dorsal determination
Authors: Nojima Hideaki , Rothhämel Sophie , Shimizu Takashi , Kim Cheol-Hee , Yonemura Shigenobu , Marlow Florence L. , Hibi Masahiko
Published: February 2010

In amphibian and teleost embryos, the dorsal determinants (DDs) are believed to be initially localized to the vegetal pole and then transported to the prospective dorsal side of the embryo along a microtubule array. The DDs are known to activate the canonical Wnt pathway and thereby promote the expression of genes that induce the dorsal organizer. Here, by identifying the locus of the maternal-effect ventralized mutant tokkaebi, we show that Syntabulin, a linker of the kinesin I motor protein, is essential for dorsal determination in zebrafish. We found that syntabulin mRNA is transported to the vegetal pole during oogenesis through the Bucky ball (Buc)-mediated Balbiani body-dependent pathway, which is necessary for establishment of animal-vegetal (AV) oocyte polarity. We demonstrate that Syntabulin is translocated from the vegetal pole in a microtubule-dependent manner. Our findings suggest that Syntabulin regulates the microtubule-dependent transport of the DDs, and provide evidence for the link between AV and dorsoventral axis formation.
Muscle activity and hydrodynamic function of pelvic fins in trout (Oncorhynchus mykiss)
Authors: Standen E. M.
Published: February 2010

Contrary to the previous premise that pelvic fins lacked obvious function, recent work on three-dimensional fin motions suggests that pelvic fins actively control stability and speed in slowly swimming trout. This study used electromyography to measure pelvic fin muscle activity and particle imaging velocimetry to quantify flow along the ventral body region to test this hypothesis. Fish swam at slow speeds (0.13-1.36 BL s−1) while being filmed with three high speed cameras. Three-dimensional kinematics were captured for all trials. During EMG trials pelvic fin muscle activity was synchronized to kinematic motion, during particle imaging velocimetry trials, a laser light-sheet was used to visualize the flow surrounding the ventral aspect of the fish. Four main conclusions are reached: first, pelvic fins are actively oscillated during slow-speed swimming; antagonistic abductor and adductor muscles contracted simultaneously, their collective action producing a unique contralateral oscillating behaviour in the fins. Second, pelvic fins slow the flow along the ventral side affecting pitch and yaw instabilities; flow upstream of the pelvic fins is slowed by 0.02 m s−1 and flow downstream of the pelvic fins is slowed by 0.034 m s−1 compared with free stream flow. Third, pelvic fin wake influences anal fin angle of attack; flow angle in the wake of the pelvic fin was 33.84±2.4 deg. (max) and −11.83±11.2 deg. (min) compared with the free stream flow angle of 1.27±0.1 deg. Fourth, pelvic fins appear to actively damp body oscillation during slow-speed swimming, providing drag to help control speed and stabilize the body position during slow-speed swimming.
Biomechanics of locomotion in Asian elephants
Authors: Genin J. J. , Willems P. A. , Cavagna G. A. , Lair R. , Heglund N. C.
Published: February 2010

Elephants are the biggest living terrestrial animal, weighing up to five tons and measuring up to three metres at the withers. These exceptional dimensions provide certain advantages (e.g. the mass-specific energetic cost of locomotion is decreased) but also disadvantages (e.g. forces are proportional to body volume while supportive tissue strength depends on their cross-sectional area, which makes elephants relatively more fragile than smaller animals). In order to understand better how body size affects gait mechanics the movement of the centre of mass (COM) of 34 Asian elephants (Elephas maximus) was studied over their entire speed range of 0.4-5.0 m s−1 with force platforms. The mass-specific mechanical work required to maintain the movements of the COM per unit distance is ~0.2 J kg−1 m−1 (about 1/3 of the average of other animals ranging in size from a 35 g kangaroo rat to a 70 kg human). At low speeds this work is reduced by a pendulum-like exchange between the kinetic and potential energies of the COM, with a maximum energy exchange of ~60% at 1.4 m s−1. At high speeds, elephants use a bouncing mechanism with little exchange between kinetic and potential energies of the COM, although without an aerial phase. Elephants increase speed while reducing the vertical oscillation of the COM from about 3 cm to 1 cm.
Allometry of hummingbird lifting performance
Authors: Altshuler D. L. , Dudley R. , Heredia S. M. , McGuire J. A.
Published: February 2010

Vertical lifting performance in 67 hummingbird species was studied across a 4000 m elevational gradient. We used the technique of asymptotic load-lifting to elicit maximum sustained muscle power output during loaded hovering flight. Our analysis incorporated direct measurements of maximum sustained load and simultaneous wingbeat kinematics, together with aerodynamic estimates of mass-specific mechanical power output, all within a robust phylogenetic framework for the Trochilidae. We evaluated key statistical factors relevant to estimating slopes for allometric relationships by performing analyses with and without phylogenetic information, and incorporating species-specific measurement error. We further examined allometric relationships at different elevations because this gradient represents a natural experiment for studying physical challenges to animal flight mechanics. Maximum lifting capacity (i.e. vertical force production) declined with elevation, but was either isometric or negatively allometric with respect to both body and muscle mass, depending on elevational occurrence of the corresponding taxa. Maximum relative muscle power output exhibited a negative allometry with respect to muscle mass, supporting theoretical predictions from muscle mechanics.
Gene expression profiling of genetically determined growth variation in bivalve larvae (Crassostrea gigas)
Authors: Meyer E. , Manahan D. T.
Published: February 2010

Growth rates in animals are governed by a wide range of biological factors, many of which remain poorly understood. To identify the genes that establish growth differences in bivalve larvae, we compared expression patterns in contrasting phenotypes (slow- and fast-growth) that were experimentally produced by genetic crosses of the Pacific oyster Crassostrea gigas. Based on transcriptomic profiling of 4.5 million cDNA sequence tags, we sequenced and annotated 181 cDNA clones identified by statistical analysis as candidates for differential growth. Significant matches were found in GenBank for 43% of clones (N=78), including 34 known genes. These sequences included genes involved in protein metabolism, energy metabolism and regulation of feeding activity. Ribosomal protein genes were predominant, comprising half of the 34 genes identified. Expression of ribosomal protein genes showed non-additive inheritance — i.e. expression in fast-growing hybrid larvae was different from average levels in inbred larvae from these parental families. The expression profiles of four ribosomal protein genes (RPL18, RPL31, RPL352 and RPS3) were validated by RNA blots using additional, independent crosses from the same families. Expression of RPL35 was monitored throughout early larval development, revealing that these expression patterns were established early in development (in 2-day-old larvae). Our findings (i) provide new insights into the mechanistic bases of growth and highlight genes not previously considered in growth regulation, (ii) support the general conclusion that genes involved in protein metabolism and feeding regulation are key regulators of growth, and (iii) provide a set of candidate biomarkers for predicting differential growth rates during animal development.
Low plasticity in digestive physiology constrains feeding ecology in diet specialist, zebra finch (Taeniopygia guttata)
Authors: Brzęk Paweł , Lessner Krista M. , Caviedes-Vidal Enrique , Karasov William H.
Published: February 2010

It can be hypothesized that species with a wide or variable food niche are able to adjust their digestive physiology to current food type. In diet specialists, however, the capacity for such presumably costly plasticity is not necessary and flexibility of digestive physiology should be lower. Recently, we found that ontogenetic changes in the activity of digestive enzymes in house sparrow, a species that gradually consumes more carbohydrates during ontogeny, are strongly modified by diet composition. In the present study we examined digestive flexibility of nestling and adult zebra finches, typical diet specialists that consume only seeds after hatching. Both adult and nestling zebra finches could not thrive on a protein-rich and carbohydrate-free diet that supported normal development of young house sparrows. Mass-specific activity of intestinal carbohydrases (maltase and sucrase) was not elevated by higher diet carbohydrate content in both nestling and adult birds. Mass-specific activity of maltase changed less during ontogenetic development in zebra finch than in house sparrow. We conclude that the digestive physiology of zebra finch is adapted to process carbohydrate-rich food after hatching and is much less flexible than in house sparrow. We hypothesize that this difference might reflect the lack of a diet switch during ontogeny or result from high specialization to a narrow diet niche.
Development of aerobic and anaerobic metabolism in cardiac and skeletal muscles from harp and hooded seals
Authors: Burns J. M. , Skomp N. , Bishop N. , Lestyk K. , Hammill M.
Published: February 2010

In diving animals, skeletal muscle adaptations to extend underwater time despite selective vasoconstriction include elevated myoglobin (Mb) concentrations, high acid buffering ability (β) and high aerobic and anaerobic enzyme activities. However, because cardiac muscle is perfused during dives, it may rely less heavily on Mb, β and anaerobic pathways to support contractile activity. In addition, because cardiac tissue must sustain contractile activity even before birth, it may be more physiologically mature at birth and/or develop faster than skeletal muscles. To test these hypotheses, we measured Mb levels, β and the activities of citrate synthase (CS), β-hydroxyacyl-CoA dehydrogenase (HOAD) and lactate dehydrogenase (LDH) in cardiac and skeletal muscle samples from 72 harp and hooded seals, ranging in age from fetuses to adults. Results indicate that in adults cardiac muscle had lower Mb levels (14.7%), β (55.5%) and LDH activity (36.2%) but higher CS (459.6%) and HOAD (371.3%) activities (all P<0.05) than skeletal muscle. In addition, while the cardiac muscle of young seals had significantly lower [Mb] (44.7%) β (80.7%) and LDH activity (89.5%) than adults (all P<0.05), it was relatively more mature at birth and weaning than skeletal muscle. These patterns are similar to those in terrestrial species, suggesting that seal hearts do not exhibit unique adaptations to the challenges of an aquatic existence.
The influence of foot posture on the cost of transport in humans
Authors: Cunningham C. B. , Schilling N. , Anders C. , Carrier D. R.
Published: February 2010

Although humans appear to be specialized for endurance running, the plantigrade posture of our feet, in which the heel contacts the substrate at the beginning of a step, seems incompatible with economical running. In this study, we tested the hypothesis that plantigrade foot posture reduces the energetic cost of transport (COT) during walking in humans. When human subjects walked with their heels slightly elevated in a ‘low-digitigrade’ posture, COT increased by 53% above that of normal plantigrade walking. By contrast, there was no difference in COT when subjects ran with digitigrade versus plantigrade foot posture. Stride frequency increased and stride length decreased when subjects switched to digitigrade walking; however, this change did not influence the COT. Additionally, we found that possible reductions in postural stability appear not to have caused the elevated cost of digitigrade walking. Digitigrade walking, however, did (1) increase the external mechanical work performed by the limbs; (2) reduce the pendular exchange of kinetic and potential energy of the center of mass; (3) increase the average ground reaction force moment at the ankle joint; and (4) increase the recruitment of major extensor muscles of the ankle, knee, hip and back. These observations suggest that plantigrade foot posture improves the economy of walking. Relative to other mammals, humans are economical walkers, but not economical runners. Given the great distances hunter-gatherers travel, it is not surprising that humans retained a foot posture, inherited from our more arboreal great ape ancestors, that facilitates economical walking.