bluuebunny/crossref_metadata_2025 huggingface dataset:
Polyunsaturated fatty acids in various macroalgal species from north Atlantic and tropical seas
Authors: van Ginneken Vincent JT , Helsper Johannes PFG , de Visser Willem , van Keulen Herman , Brandenburg Willem A
Published: June 2011

Background

In this study the efficacy of using marine macroalgae as a source for polyunsaturated fatty acids, which are associated with the prevention of inflammation, cardiovascular diseases and mental disorders, was investigated.

Methods

The fatty acid (FA) composition in lipids from seven sea weed species from the North Sea (Ulva lactuca, Chondrus crispus, Laminaria hyperborea, Fucus serratus, Undaria pinnatifida, Palmaria palmata, Ascophyllum nodosum) and two from tropical seas (Caulerpa taxifolia, Sargassum natans) was determined using GCMS. Four independent replicates were taken from each seaweed species.

Results

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs), were in the concentration range of 2-14 mg/g dry matter (DM), while total lipid content ranged from 7-45 mg/g DM. The n-9 FAs of the selected seaweeds accounted for 3%-56% of total FAs,n-6 FAs for 3%-32% andn-3 FAs for 8%-63%. Red and brown seaweeds contain arachidonic (C20:4, n-6) and/or eicosapentaenoic acids (EPA, C20:5, n-3), the latter being an important "fish" FA, as major PUFAs while in green seaweeds these values are low and mainly C16 FAs were found. A unique observation is the presence of another typical "fish" fatty acid, docosahexaenoic acid (DHA, C22:6, n-3) at ≈ 1 mg/g DM inS. natans. The n-6: n-3 ratio is in the range of 0.05-2.75 and in most cases below 1.0. Environmental effects on lipid-bound FA composition in seaweed species are discussed.

Conclusion

Marine macroalgae form a good, durable and virtually inexhaustible source for polyunsaturated fatty acids with an (n-6) FA: (n-3) FA ratio of about 1.0. This ratio is recommended by the World Health Organization to be less than 10 in order to prevent inflammatory, cardiovascular and nervous system disorders. Some marine macroalgal species, likeP. palmata, contain high proportions of the "fish fatty acid" eicosapentaenoic acid (EPA, C20:5, n-3), while inS. natansalso docosahexaenoic acid (DHA, C22:6, n-3) was detected.
T-bet controls severity of hypersensitivity pneumonitis
Authors: Abdelsamed Hossam Aly , Desai Meena , Nance Stephanie C , Fitzpatrick Elizabeth A
Published: June 2011

Hypersensitivity Pneumonitis (HP) is an interstitial lung disease that develops following repeated exposure to inhaled environmental antigens. The disease is characterized by alveolitis, granuloma formation and in some patients' fibrosis. IFNγ plays a critical role in HP; in the absence of IFNγ granuloma formation does not occur. However, recent studies using animal models of HP have suggested that HP is a Th17 disease calling into question the role of IFNγ. In this study, we report that initially IFNγ production is dependent on IL-18 and the transcription factor T-bet, however as the disease continues IFNγ production is IL-18-independent and partially T-bet dependent. Although IFNγ production is required for granuloma formation its role is distinct from that of T-bet. Mice that are deficient in T-bet and exposed toS. rectivirguladevelop more severe disease characterized by an exacerbated Th17 cell response, decreased Th1 cell response, and increased collagen production in the lung. T-bet-mediated protection does not appear to be due to the development of a protective Th1 response; shifting the balance from a Th17 predominant response to a Th1 response by inhibition of IL-6 also results in lung pathology. The results from this study suggest that both Th1 and Th17 cells can be pathogenic in this model and that IFNγ and T-bet play divergent roles in the disease process.
Identification of a novel SEREX antigen family, ECSA, in esophageal squamous cell carcinoma
Authors: Kagaya Akiko , Shimada Hideaki , Shiratori Tooru , Kuboshima Mari , Nakashima-Fujita Kazue , Yasuraoka Mari , Nishimori Takanori , Kurei Shunsuke , Hachiya Takahisa , Murakami Akihiro , Tamura Yutaka , Nomura Fumio , Ochiai Takenori , Matsubara Hisahiro , Takiguchi Masaki , Hiwasa Takaki
Published: June 2011

Background

Diagnosis of esophageal squamous cell carcinoma (SCC) may improve with early diagnosis. Currently it is difficult to diagnose SCC in the early stage because there is a limited number of tumor markers available.

Results

Fifty-two esophageal SCC SEREX antigens were identified by SEREX (serological identification of antigens by recombinant cDNA expression cloning) using a cDNA phage library and sera of patients with esophageal SCC. Sequence analysis revealed that three of these antigens were similar in amino acid sequences, and they were designated as ECSA (e sophageal c arcinoma S EREX a ntigen)-1, -2 and -3. The ECSA family was also similar to an EST clone, hepatocellular carcinoma-associated antigen 25a (HCA25a). Serum antibody levels to ECSA-1, -2 and -3 were significantly higher in patients with esophageal SCC than in healthy donors. Based on the conserved amino acid sequences, three peptides were synthesized and used for enzyme-linked immunosorbent assays (ELISA). The serum antibody levels against one of these peptides were significantly higher in patients with esophageal SCC. This peptide sequence was also conserved in FAM119A, GOSR1 and BBS5, suggesting that these are also ECSA family members. Reverse transcription followed by quantitative PCR analysis showed that the mRNA expression levels of ECSA-1, -2 and -3 and FAM119A but not of HCA25a, GOSR1 and BBS5 were frequently elevated in esophageal SCC tissues.

Conclusions

We have identified a new gene family designated ECSA. Serum antibodies against the conserved domain of the ECSA family may be a promising tumor marker for esophageal SCC.
Antiviral drugs against hepatitis C virus
Authors: Rehman Sidra , Ashfaq Usman A , Javed Tariq
Published: June 2011

Hepatitis C virus (HCV) infection is a major worldwide problem causes acute and chronic HCV infection. Current treatment of HCV includes pegylated interferon-α (PEG IFN- α) plus ribavirin (RBV) which has significant side effects depending upon the type of genotype. Currently, there is a need to develop antiviral agents, both from synthetic chemistry and Herbal sources. In the last decade, various novel HCV replication, helicase and entry inhibitors have been synthesized and some of which have been entered in different phases of clinical trials. Successful results have been acquired by executing combinational therapy of compounds with standard regime in different HCV replicons. Even though, diverse groups of compounds have been described as antiviral targets against HCV via Specifically Targeted Antiviral Therapy for hepatitis C (STAT-C) approach (in which compounds are designed to directly block HCV or host proteins concerned in HCV replication), still there is a need to improve the properties of existing antiviral compounds. In this review, we sum up potent antiviral compounds against entry, unwinding and replication of HCV and discussed their activity in combination with standard therapy. Conclusively, further innovative research on chemical compounds will lead to consistent standard therapy with fewer side effects.
Review and application of group theory to molecular systems biology
Authors: Rietman Edward A , Karp Robert L , Tuszynski Jack A
Published: June 2011

In this paper we provide a review of selected mathematical ideas that can help us better understand the boundary between living and non-living systems. We focus on group theory and abstract algebra applied to molecular systems biology. Throughout this paper we briefly describe possible open problems. In connection with the genetic code we propose that it may be possible to use perturbation theory to explore the adjacent possibilities in the 64-dimensional space-time manifold of the evolving genome.

With regards to algebraic graph theory, there are several minor open problems we discuss. In relation to network dynamics and groupoid formalism we suggest that the network graph might not be the main focus for understanding the phenotype but rather the phase space of the network dynamics. We show a simple case of aC6network and its phase space network. We envision that the molecular network of a cell is actually a complex network of hypercycles and feedback circuits that could be better represented in a higher-dimensional space. We conjecture that targeting nodes in the molecular network that have key roles in the phase space, as revealed by analysis of the automorphism decomposition, might be a better way to drug discovery and treatment of cancer.
In vitro-generated interspecific recombinants between bovine herpesviruses 1 and 5 show attenuated replication characteristics and establish latency in the natural host
Authors: Del Medico Zajac Maria P , Romera Sonia A , Ladelfa María F , Kotsias Fiorella , Delgado Fernando , Thiry Julien , Meurens François , Keil Günther , Thiry Etienne , Muylkens Benoît
Published: June 2011

Background

Interspecific recombinant viruses R1ΔgC and R2ΔgI were isolated afterin vitroco-infection with BoHV-1 and BoHV-5, two closely related alphaherpesviruses that infect cattle. The genetic characterization of R1ΔgC and R2ΔgI showed that they are composed of different sections of the parental genomes. The aim of this study was the characterization of thein vivobehavior of these recombinants in the natural host.

Results

Four groups of four 3-month-old calves of both genders were intranasally inoculated with either the recombinant or parental viruses. A control group of two animals was also included. Viral excretion and clinical signs were monitored after infection. Histopathological examination of the central nervous system (CNS) was performed and the establishment of latency in trigeminal ganglia was analyzed by PCR. The humoral response was also evaluated using ELISA tests.

Three out of four animals from the BoHV-5 infected group excreted virus for 4-10 days. Two calves shed R1ΔgC virus for one day. In R2ΔgI and BoHV-1.2ΔgCΔgI groups, infectious virus was isolated only after two or three blind passages. None of the infected animals developed neurological signs, although those infected with BoHV-5 showed histopathological evidence of viral infection. Latent viral DNA was detected in at least one calf from each infected group. Serum and/or mucosal antibodies were detected in all groups.

Conclusion

Both BoHV-1/-5 recombinants and the BoHV-1 parental strain are attenuated in calves, although they are able to replicate in animals at low rates and to establish latent infections.
Robotic image-guided reirradiation of lateral pelvic recurrences: preliminary results
Authors: Dewas Sylvain , Bibault Jean Emmanuel , Mirabel Xavier , Nickers Philippe , Castelain Bernard , Lacornerie Thomas , Jarraya Hajer , Lartigau Eric
Published: June 2011

Background

The first-line treatment of a pelvic recurrence in a previously irradiated area is surgery. Unfortunately, few patients are deemed operable, often due to the location of the recurrence, usually too close to the iliac vessels, or the associated surgical morbidity. The objective of this study is to test the viability of robotic image-guided radiotherapy as an alternative treatment in inoperable cases.

Methods

Sixteen patients previously treated with radiotherapy were reirradiated with CyberKnife® for lateral pelvic lesions. Recurrences of primary rectal cancer (4 patients), anal canal (6), uterine cervix cancer (4), endometrial cancer (1), and bladder carcinoma (1) were treated. The median dose of the previous treatment was 45 Gy (EqD2 range: 20 to 96 Gy). A total dose of 36 Gy in six fractions was delivered with the CyberKnife over three weeks. The responses were evaluated according to RECIST criteria.

Results

Median follow-up was 10.6 months (1.9 to 20.5 months). The actuarial local control rate was 51.4% at one year. Median disease-free survival was 8.3 months after CyberKnife treatment. The actuarial one-year survival rate was 46%. Acute tolerance was limited to digestive grade 1 and 2 toxicities.

Conclusions

Robotic stereotactic radiotherapy can offer a short and well-tolerated treatment for lateral pelvic recurrences in previously irradiated areas in patients otherwise not treatable. Efficacy and toxicity need to be evaluated over the long term, but initial results are encouraging.
Protein kinase D1 (PKD1) activation mediates a compensatory protective response during early stages of oxidative stress-induced neuronal degeneration
Authors: Asaithambi Arunkumar , Kanthasamy Arthi , Saminathan Hariharan , Anantharam Vellareddy , Kanthasamy Anumantha G
Published: June 2011

Background

Oxidative stress is a key pathophysiological mechanism contributing to degenerative processes in many neurodegenerative diseases and therefore, unraveling molecular mechanisms underlying various stages of oxidative neuronal damage is critical to better understanding the diseases and developing new treatment modalities. We previously showed that protein kinase C delta (PKCδ) proteolytic activation during the late stages of oxidative stress is a key proapoptotic signaling mechanism that contributes to oxidative damage in Parkinson's disease (PD) models. The time course studies revealed that PKCδ activation precedes apoptotic cell death and that cells resisted early insults of oxidative damage, suggesting that some intrinsic compensatory response protects neurons from early oxidative insult. Therefore, the purpose of the present study was to characterize protective signaling pathways in dopaminergic neurons during early stages of oxidative stress.

Results

Herein, we identify that protein kinase D1 (PKD1) functions as a key anti-apoptotic kinase to protect neuronal cells against early stages of oxidative stress. Exposure of dopaminergic neuronal cells to H2O2or 6-OHDA induced PKD1 activation loop (PKD1S744/748) phosphorylation long before induction of neuronal cell death. Blockade of PKCδ cleavage, PKCδ knockdown or overexpression of a cleavage-resistant PKCδ mutant effectively attenuated PKD1 activation, indicating that PKCδ proteolytic activation regulates PKD1 phosphorylation. Furthermore, the PKCδ catalytic fragment, but not the regulatory fragment, increased PKD1 activation, confirming PKCδ activity modulates PKD1 activation. We also identified that phosphorylation of S916 at the C-terminal is a preceding event required for PKD1 activation loop phosphorylation. Importantly, negative modulation of PKD1 by the RNAi knockdown or overexpression of PKD1S916Aphospho-defective mutants augmented oxidative stress-induced apoptosis, while positive modulation of PKD1 by the overexpression of full length PKD1 or constitutively active PKD1 plasmids attenuated oxidative stress-induced apoptosis, suggesting an anti-apoptotic role for PKD1 during oxidative neuronal injury.

Conclusion

Collectively, our results demonstrate that PKCδ-dependent activation of PKD1 represents a novel intrinsic protective response in counteracting early stage oxidative damage in neuronal cells. Our results suggest that positive modulation of the PKD1-mediated compensatory protective mechanism against oxidative damage in dopaminergic neurons may provide novel neuroprotective strategies for treatment of PD.
Novel multiplex technology for diagnostic characterization of rheumatoid arthritis
Authors: Chandra Piyanka E , Sokolove Jeremy , Hipp Berthold G , Lindstrom Tamsin M , Elder James T , Reveille John D , Eberl Heike , Klause Ursula , Robinson William H
Published: June 2011

Introduction

The aim of this study was to develop a clinical-grade, automated, multiplex system for the differential diagnosis and molecular stratification of rheumatoid arthritis (RA).

Methods

We profiled autoantibodies, cytokines, and bone-turnover products in sera from 120 patients with a diagnosis of RA of < 6 months' duration, as well as in sera from 27 patients with ankylosing spondylitis, 28 patients with psoriatic arthritis, and 25 healthy individuals. We used a commercial bead assay to measure cytokine levels and developed an array assay based on novel multiplex technology (Immunological Multi-Parameter Chip Technology) to evaluate autoantibody reactivities and bone-turnover markers. Data were analyzed by Significance Analysis of Microarrays and hierarchical clustering software.

Results

We developed a highly reproducible, automated, multiplex biomarker assay that can reliably distinguish between RA patients and healthy individuals or patients with other inflammatory arthritides. Identification of distinct biomarker signatures enabled molecular stratification of early-stage RA into clinically relevant subtypes. In this initial study, multiplex measurement of a subset of the differentiating biomarkers provided high sensitivity and specificity in the diagnostic discrimination of RA: Use of 3 biomarkers yielded a sensitivity of 84.2% and a specificity of 93.8%, and use of 4 biomarkers a sensitivity of 59.2% and a specificity of 96.3%.

Conclusions

The multiplex biomarker assay described herein has the potential to diagnose RA with greater sensitivity and specificity than do current clinical tests. Its ability to stratify RA patients in an automated and reproducible manner paves the way for the development of assays that can guide RA therapy.
In vivo-transmigrated human neutrophils are resistant to antiapoptotic stimulation
Authors: Christenson Karin , Björkman Lena , Karlsson Jennie , Sundqvist Martina , Movitz Charlotta , Speert David P , Dahlgren Claes , Bylund Johan
Published: June 2011

Neutrophils respond to microbial invasion or injury by transmigration from blood to tissue. Transmigration involves cellular activation and degranulation, resulting in altered levels of surface receptors and changed responsiveness to certain stimuli. Thus, fundamental functional changes are associated with neutrophil transmigration from blood to tissue. Neutrophils isolated from peripheral blood spontaneously enter apoptosis, a process that can be accelerated or delayed by different pro- or antiapoptotic factors. How tissue neutrophils that have transmigrated in vivo regulate cell death is poorly understood. In this study, in vivo-transmigrated neutrophils (tissue neutrophils) were collected using a skin chamber technique and compared with blood neutrophils from the same donors with respect to regulation of cell death. Skin chamber fluid contained a variety of cytokines known to activate neutrophils and regulate their lifespan. Freshly prepared tissue neutrophils had elevated activity of caspase 3/7 but were fully viable; spontaneous cell death after in vitro culture was also similar between blood and tissue neutrophils. Whereas apoptosis of cultured blood neutrophils was delayed by soluble antiapoptotic factors (e.g., TLR ligands), tissue neutrophils were completely resistant to antiapoptotic stimulation, even though receptors were present and functional. In vitro transmigration of blood neutrophils into skin chamber fluid did not fully confer resistance to antiapoptotic stimulation, indicating that a block of antiapoptotic signaling occurs specifically during in vivo transmigration. We describe a novel, functional alteration that takes place during in vivo transmigration and highlights the fact that life and death of neutrophils may be regulated differently in blood and tissue.
Telomerase-Driven Expression of the Sodium Iodide Symporter (NIS) for in Vivo Radioiodide Treatment of Cancer: A New Broad-Spectrum NIS-Mediated Antitumor Approach
Authors: Riesco-Eizaguirre Garcilaso , De la Vieja Antonio , Rodríguez Irene , Miranda Soledad , Martín-Duque Pilar , Vassaux Georges , Santisteban Pilar
Published: June 2011

Context:

Telomerase promoters (hTERT and hTR) are useful for transcriptional targeting in gene therapy models of cancer. Telomerase-driven expression of the sodium iodide symporter (NIS) in tumor cells has been successfully used as a reporter gene in vivo using positron emission tomography (PET) imaging.

Objective:

The aim of this study was to investigate the NIS-mediated therapeutic effect of telomerase promoters in a wide variety of human cancer cell lines.

Design and Methods:

Promoter fragments from either hTERT or hTR were used to drive the expression of NIS in cell lines derived from melanoma (M14), breast (MDA-MB-231), colon (HT-29), lung (H460), ovarian (OVCAR-3), and thyroid (TPC-1) carcinomas. Iodide uptake assays, protein immunodetection, and clonigenic assays were used to confirm NIS functional expression and the 131I-mediated cytopathic effect. Tumor xenografts in mice were infected with hTERT and hTR and then treated using radioiodide.

Results:

Both promoters were selectively active in cancer cells that were effectively killed by exposure to 131I. One single dose of 1 mCi 131I markedly suppressed tumor growth of melanoma-derived tumor xenografts compared with controls. This effect was more modest in colon cancer-derived xenografts in part due to the reduced infectivity and the tumor cystic nature. The therapeutic effect of hTR promoter was found to be stronger than that of hTERT promoter.

Conclusions:

These results demonstrate that telomerase-driven expression of NIS could potentially have applications for 131I therapy of a wide variety of cancers. Additionally, this is the first study to report NIS-mediated 131I therapy of melanoma tumors in vivo.
Treatment of Congenital Hyperinsulinism with Lanreotide Acetate (Somatuline Autogel)
Authors: Modan-Moses Dalit , Koren Ilana , Mazor-Aronovitch Kineret , Pinhas-Hamiel Orit , Landau Heddy
Published: June 2011

Context:

Congenital hyperinsulinism (CH) may be treated conservatively in many children with octreotide given by multiple sc injections or via an insulin pump.

Objective:

We describe two children treated with a once-monthly injection of a long-acting somatostatin analog.

Patients and Methods:

Both patients presented with hypoglycemia 30 min after birth and were subsequently diagnosed with CH. Patients were initially treated with diazoxide, hydrochlorothiazide, frequent feedings, and octreotide via an insulin pump. With this therapy, they were normoglycemic with a good growth rate, normal weight gain, and excellent neurodevelopment. Treatment with the long-acting somatostatin analog lanreotide acetate (Somatuline Autogel), administered by deep sc injection of 30 mg once a month, was started at the ages of 4½ and 4 yr, respectively. Octreotide infusion was gradually weaned over 1 month. Continuous glucose monitoring after discontinuation of pump therapy showed normoglycemia. The first patient has now been treated with the lanreotide acetate for over 5 yr, and the second for 3 yr. Treatment is well-tolerated, and both the patients and their parents are satisfied with the transition from pump therapy to once-a-month injection and prefer it to pump therapy.

Conclusion:

Lanreotide acetate may be a safe and effective alternative to octreotide pump therapy in patients with CH, offering an improved quality of life. Longer follow-up of a larger patient group is needed.
Analytical evaluation of a high-sensitivity troponin T assay and its clinical assessment in acute coronary syndrome
Authors: Chenevier-Gobeaux Camille , Meune Christophe , Blanc Marie-Céline , Cynober Luc , Jaffray Patrick , Lefevre Guillaume
Published: June 2011

Background

The recently developed, highly sensitive cardiac troponin T (hs-cTnT) immunoassay improves the detection of acute myocardial infarction (AMI). However, this assay requires further analytical and clinical evaluation.

Methods

Imprecision, linearity, limits of quantification and interferences were evaluated; hs-cTnT was compared with a conventional cardiac troponin I assay (cTnI), performed on an X-pand®HM, in a population of patients with suspected AMI. Finally, the 99th percentile cut-off point for a reference population was explored in 213 healthy control subjects.

Results

Imprecision analysis demonstrated coefficients of variation (CVs) below 4%, linearity showed a 0.999 coefficient of correlation, with excellent recovery (99.9%) and a limit of quantification (10%CV) was found at 9.2 ng/L. A negative interference (>20%) with haemolysis was observed when supplemental haemoglobin was above 0.25 g/dL. Patients with suspected AMI more frequently displayed an increased hs-cTnT (83%) than an increased cTnI (55%, P < 0.01). Unstable angina was present in 63% of patients with an increased hs-cTnT associated with no increase in cTnI. The 99th percentile value for our reference population was 16.9 ng/L. In 213 healthy blood donors, hs-cTnT levels were significantly correlated with age ( P < 0.0001), and were higher in men than in women ( P < 0.0001).

Conclusions

The analytical performance of hs-cTnT complied with the international guidelines for AMI detection. Determining the degree of haemolysis in a sample is of paramount importance to the interpretation of hs-cTnT results. The 99th percentile value of our reference population was established.
Computational analysis of the structural mechanism of inhibition of chemokine receptor CXCR4 by small molecule antagonists
Authors: Kawatkar Sameer P , Yan Maocai , Gevariya Harsukh , Lim Mi Youn , Eisold Steven , Zhu Xuejun , Huang Ziwei , An Jing
Published: June 2011

Understanding the structural mechanism of receptor–ligand interactions for the chemokine receptor CXCR4 is essential for determining its physiological and pathological functions and for developing new therapies targeted to CXCR4. We have recently reported a structural mechanism for CXCR4 antagonism by a novel synthetic CXCR4 antagonist RCP168 and compared its effectiveness against the natural agonist SDF-1 α. In the present study, using molecular docking, we further investigate the binding modes of another seven small molecules known to act as CXCR4 antagonists. The predicted binding modes were compared with previously published mutagenesis data for two of these (AMD3100 and AMD11070). Four antagonists, including AMD3100, AMD11070, FC131 and KRH-1636, bound in a similar fashion to CXCR4. Two important acidic amino acid residues (Asp262 and Glu288) on CXCR4, previously found essential for AMD3100 binding, were also involved in binding of the other ligands. These four antagonists use a binding site in common with that used by RCP168, which is a novel synthetic derivative of vMIP-II in which the first 10 residues are replaced by D-amino acids. Comparison of binding modes suggested that this binding site is different from the binding region occupied by the N-terminus of SDF-1 α, the only known natural ligand of CXCR4. These observations suggest the presence of a ligand-binding site (site A) that co-exists with the agonist (SDF-1 α) binding site (site B). The other three antagonists, including MSX123, MSX202 and WZ811, are smaller in size and had very similar binding poses, but binding was quite different from that of AMD3100. These three antagonists bound at both sites A and B, thereby blocking both binding and signaling by SDF-1 α.
Coeliac disease and pregnancy outcomes
Authors: Butler M M , Kenny L C , McCarthy F P
Published: June 2011

Coeliac disease is a gluten-sensitive enteropathy affecting up to 1% of the population. An accumulating body of evidence supports the association of coeliac disease with adverse pregnancy outcomes, including increased risk of miscarriage and intrauterine growth restriction. Reports differ regarding the extent and severity of these associations, in addition to the exact pathophysiology underlying these associations. Overall, coeliac disease is believed to be a significant condition in pregnancy and reproductive medicine with some advocating the screening of coeliac disease in all pregnant women or some specific high-risk groups.
Diverse environmental stresses elicit distinct responses at the level of pre-mRNA processing in yeast
Authors: Bergkessel Megan , Whitworth Gregg B. , Guthrie Christine
Published: June 2011

Gene expression in eukaryotic cells is profoundly influenced by the post-transcriptional processing of mRNAs, including the splicing of introns in the nucleus and both nuclear and cytoplasmic degradation pathways. These processes have the potential to affect both the steady-state levels and the kinetics of changes to levels of intron-containing transcripts. Here we report the use of a splicing isoform-specific microarray platform to investigate the effects of diverse stress conditions on pre-mRNA processing. Interestingly, we find that diverse stresses cause distinct patterns of changes at this level. The responses we observed are most dramatic for the RPGs and can be categorized into three major classes. The first is characterized by accumulation of RPG pre-mRNA and is seen in multiple types of amino acid starvation regimes; the magnitude of splicing inhibition correlates with the severity of the stress. The second class is characterized by a rapid decrease in both pre- and mature RPG mRNA and is seen in many stresses that inactivate the TORC1 kinase complex. These decreases depend on nuclear turnover of the intron-containing pre-RNAs. The third class is characterized by a decrease in RPG pre-mRNA, with only a modest reduction in the mature species; this response is observed in hyperosmotic and cation-toxic stresses. We show that casein kinase 2 (CK2) makes important contributions to the changes in pre-mRNA processing, particularly for the first two classes of stress responses. In total, our data suggest that complex post-transcriptional programs cooperate to fine-tune expression of intron-containing transcripts in budding yeast.
Tumor-targeting drug delivery of chemotherapeutic agents
Authors: Ojima Iwao
Published: June 2011

Despite the significant progress in the development of cancer detection, prevention, surgery, and therapy, there is still no common cure for this disease. In addition, the long-standing problem of chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Therefore, various “molecularly targeted cancer therapies” have been developed for use in specific cancers, including tumor-targeting drug delivery systems (TTDDS). In general, a TTDDS consists of a tumor recognition moiety and a cytotoxic “warhead” connected through a “smart” linker to form a conjugate. When a multi-functionalized nanomaterial is used as the vehicle, a “Trojan horse” approach becomes possible for mass delivery of cytotoxic warheads to maximize the efficacy. This account presents the progress in the molecular approaches to the design and development of novel drug delivery systems for tumor-targeting chemotherapy in our laboratory.
HOPE-BAL
Authors: Marwitz Sebastian , Abdullah Mahdi , Vock Christina , Fine Jay S. , Visvanathan Sudha , Gaede Karoline I. , Hauber Hans-Peter , Zabel Peter , Goldmann Torsten
Published: June 2011

The bronchoalveolar lavage (BAL) and its cells have been widely used as a support for clinical diagnosis and as a versatile tool for research questions since many years. Because there are no sufficient possibilities of long-term storage, the authors explore in this study the utility of a new fixative for fixation and paraffin embedding of human lavage cells with the possibility of implementing standard molecular biology techniques. HOPE-fixed, paraffin-embedded BAL cells of patients with different lung diseases (asthma, chronic obstructive pulmonary diseases, tuberculosis, sarcoidosis, emphysema, and fibrosis) were subjected to immunohistochemistry, in situ hybridization, quantitative polymerase chain reaction, and transcription microarray analysis. Furthermore, two-dimensional gel electrophoresis was conducted to evaluate the range of possible applications for research, diagnostics, and further implementing in biobanks. The authors show, by targeting some exemplary molecules, the power of screening and validating HOPE-BAL for new biomarkers. The transforming growth factor β signaling pathway may play a central role in immunomodulation upon infection as well as asthma. Furthermore, haptoglobin was overexpressed in asthma and sarcoidosis. Because of the excellent preservation of nucleic acids, protein, and morphologic structures, HOPE-BAL is a step forward into enhanced molecular diagnostics and biobanking in pulmonary medicine.
Effect of Immunohistochemistry on Molecular Analysis of Tissue Samples
Authors: Tangrea Michael A. , Mukherjee Sumana , Gao Bing , Markey Sanford P. , Du Qiang , Armani Michael , Kreitman Matthew S. , Rosenberg Alex M. , Wallis Benjamin S. , Eberle Franziska C. , Duncan Francesca C. , Hanson Jeffrey C. , Chuaqui Rodrigo F. , Rodriguez-Canales Jaime , Emmert-Buck Michael R.
Published: June 2011

Laser-based tissue microdissection is an important tool for the molecular evaluation of histological sections. The technology has continued to advance since its initial commercialization in the 1990s, with improvements in many aspects of the process. More recent developments are tailored toward an automated, operator-independent mode that relies on antibodies as targeting probes, such as immuno–laser capture microdissection or expression microdissection (xMD). Central to the utility of expression-based dissection techniques is the effect of the staining process on the biomolecules in histological sections. To investigate this issue, the authors analyzed DNA, RNA, and protein in immunostained, microdissected samples. DNA was the most robust molecule, exhibiting no significant change in quality after immunostaining but a variable 50% to 75% decrease in the total yield. In contrast, RNA in frozen and ethanol-fixed, paraffin-embedded samples was susceptible to hydrolysis and digestion by endogenous RNases during the initial steps of staining. Proteins from immunostained tissues were successfully analyzed by one-dimensional electrophoresis and mass spectrometry but were less amenable to solution phase assays. Overall, the results suggest investigators can use immunoguided microdissection methods for important analytic techniques; however, continued improvements in staining protocols and molecular extraction methods are key to further advancing the capability of these methods.
Walter Gropius: Letters to an Angel, 1927–35
Authors: Reidel James
Published: June 2011

A previously unpublished selection of letters by Walter Gropius to his daughter, Manon, reveals a personal side of the architect and Bauhaus founder. In Walter Gropius: Letters to an Angel, 1927–35, James Reidel chronicles a decisive period in Gropius's life, from his last months at the Bauhaus until his move to England. At the center of the letters is the architect's quest for a closer relationship with his daughter, whom he rarely saw following his 1920 divorce from her mother, Alma Mahler-Werfel. However, the correspondence also offers rare insights into Gropius's political, social, and religious views, and it highlights those professional activities that he deemed worthy of his daughter's attention—housing, C.I.A.M., theater, and automobile design. Gropius's last letter was written shortly before Manon died from the complications of polio.
Terrorism and Criminal Law: The Dream of Prevention, the Nightmare of the Rule of Law
Authors: Meliá Manuel Cancio
Published: June 2011

Terrorism stands at the evolutionary peek of the expansion of Western criminal law systems. This evolution contradicts many of the constitutional foundations of Western criminal law, to the extent that a real "criminal law" for enemies appears on the near horizon of penal legislation. The basic argument here is the idea that criminal law is an effective instrument to fight against terrorism. Yet a thorough analysis reveals that this overstates the preventive capacity of the penal system. To the contrary, given the communication strategy embodied in terrorism, a penal overreaction could be quite dysfunctional for the objective of fighting terrorism: in particular, and notwithstanding the fact that it does not provide a real solution in preventive terms, it may cause a contamination effect that could modify the constitutional foundations of the overall penal law system.
Corporate Culpability as a Limit to the Overcriminalization of Corporate Criminal Liability: The Interplay Between Self-Regulation, Corporate Compliance, and Corporate Citizenship
Authors: Gómez-Jara Díez Carlos
Published: June 2011

This paper argues that there is clear sign of the overcriminalization of corporate conduct in America's criminal law and procedure: regardless of the evidence of a law-abiding behavior by a good corporate citizen, the corporation will be considered guilty if a member of its organization commits a crime within the scope of authority and with the intent to benefit the corporation. The paper explains that corporate culpability may function as a limit to this current overcriminalization as it demands in corporate criminal law what is requested in individual criminal law: that despite the agent's action and intent, the principal has not exercised some kind of due diligence. In turn, if evidence of that corporate due diligence is provided, no court should declare that a corporation is guilty. Such an approach is not only consistent with the basic tenets of criminal law, but it also reflects the different rationale for holding corporations criminally liable in modern society (as opposed to the times in which corporate criminal liability was enacted). A recent example of this overcriminalization tendency was provided by the 2nd Circuit's ruling in the case United States v. Ionia Management S.A., which is briefly discussed at the end of the paper.
“The Secret at the Root”: Performing African American Religious Modernity in Hall Johnson'sRun, Little Chillun
Authors: Weisenfeld Judith
Published: June 2011

Francis Hall Johnson's (1888–1970) work to preserve and promote Negro spirituals places him among the twentieth century's most influential interpreters of African American religious music. Johnson was most closely associated with Marc Connelly's 1930 Pulitzer Prize-winning play,The Green Pastures, for which he served as musical arranger and choral conductor. His participation in this production, which became a lightning rod for discussions about the nature of black religious thought, made him sharply aware of the complex terrain of popular culture representations of African American religious life for the consumption of white audiences. This article examines Johnson's 1933 “music-drama,”Run, Little Chillun, through which he hoped to counter the commonly deployed tropes of African Americans as a simple, naturally religious people. Moderately successful on Broadway, the production did particularly well when revived in California in 1938 and 1939 as part of the Federal Theatre and Federal Music projects.

Most critics found Johnson's presentation of black Baptist music and worship to be thrillingly authentic but were confused by the theology of the drama's other religious community, the Pilgrims of the New Day. Examining Johnson's Pilgrims of the New Day in light of his interest in Christian Science and New Thought reveals a broader objective than providing a dramatic foil for the Baptists and a platform for endorsing Christianity. With his commitment to and expertise with vernacular forms of African American religious culture unassailable, Johnson presented a critique of the conservative tendencies and restrictive parochialism of some black church members and leaders and insisted on the ability of the individual religious self to range freely across a variety of spiritual possibilities. In doing so, he presented “the secret at the root” of black culture as not only revealing the spiritual genius of people of African descent but also as offering eternal and universal truths not bound by race.
Regulation of prolactin secretion during the estrus in rats: possible role of glucocorticoids
Authors: López-Fontana Constanza M , Maselli María E , G de Di Nasso Florencia E , Telleria Carlos M , Carón Rubén W
Published: June 2011

Mifepristone (MIF) administration to cycling rats at proestrus induces hypersecretion of prolactin (PRL) at the following estrus. We aimed to assess whether this effect is due to the antiprogesterone or antiglucocorticoid action of MIF and to help underscore the nature of the circulating hormone(s) regulating PRL secretion at estrus. Female cycling rats in proestrus were treated with vehicle; the progesterone (Pg) and glucocorticoid receptor antagonists, MIF (5 mg/kg) or ORG-33628 (5 mg/kg); the glucocorticoid agonist dexamethasone (DEX; 27 mg/kg)±MIF; or the inhibitor of steroid synthesis aminoglutethimide (AG; 150 mg/kg)±MIF. The animals' blood was sampled the same day at 1800 h and at 1800 h of the following day to assess for circulating PRL and Pg levels. To distinguish antiglucocorticoid from antiprogesterone effects of MIF, we administered a highly specific neutralizing antibody against Pg. None of the antagonists modified serum PRL values at proestrus but increased PRL levels at estrus. DEX decreased the secretion of PRL at proestrus, yet the effect was entirely blocked by MIF. Furthermore, DEX decreased PRL at estrus in a MIF-reversible manner, suggesting that adrenal corticoids during proestrous may regulate PRL secretion at estrus. AG increased PRL secretion at estrus, whereas its association with MIF produced an even higher response. PRL concentration at estrus was not modified by the antiprogesterone antibody, suggesting that the effect of MIF is a consequence of its antiglucocorticoid effect and not due to its antiprogesterone properties. In conclusion, PRL secretion in the afternoon of the estrus is most likely regulated by glucocorticoids through an inhibitory action.
Effects of Stubble Height and Cutting Frequency on Regrowth of Berseem Clover in a Mediterranean Semiarid Environment
Authors: Giambalvo Dario , Amato Gaetano , Stringi Luigi
Published: June 2011

Defoliation management of forage crops affects endogenous reserves (in the root and in the stubble), the residual leaf area, and, consequently, the regrowth and biomass yield. The aim of this study was to evaluate the effect of cutting frequency (28‐d vs. 35‐d intervals) and stubble height (3 vs. 6 cm) on forage yield, regrowth, and persistence of berseem clover (Trifolium alexandrinum L.). Neither cutting interval nor cutting height affected plant survival during the crop cycle. Frequent clipping reduced crop yield. Residual biomass and leaf area were less when plants were cut at a height of 3 cm compared with 6 cm, but stubble height did not affect the total amount of dry matter (DM) removed. However, with a cutting interval of 28 d, DM yield was greater with a stubble height of 6 cm compared with 3 cm, whereas stubble height generally had no effect with a cutting interval of 35 d. This study shows that severe defoliation, which substantially reduces residual photosynthetic area, forces berseem clover plants to mobilize reserves from the taproot. With frequent clipping, taproot reserves are depleted and regrowth is impaired, whereas less frequent clipping enables taproot reserves to be restored. In contrast, less severe defoliation, which results in a considerable residual leaf area, promotes rapid regrowth regardless of the frequency of defoliation.
Exploring and Exploiting Genetic Variation from Unadapted Sorghum Germplasm in a Breeding Program
Authors: Jordan D. R. , Mace E. S. , Cruickshank A. W. , Hunt C. H. , Henzell R. G.
Published: June 2011

Loss of genetic diversity in elite breeding populations is often identified as a potential impediment to future genetic gain. The use of diverse unadapted germplasm in breeding has been suggested as one way of combating this problem but often proves impractical, due to the poor performance of progeny produced by crosses between adapted and unadapted parent lines. This study evaluates the effectiveness of a breeding method aimed at utilizing unadapted sorghum [Sorghum bicolor (L.) Moench] germplasm. The method involves producing large BC1F1 populations, using a single elite line as the recurrent parent, and then selecting the resulting progeny for key adaptive traits (e.g., height and flowering time). Populations of 30 to 90 BC1F4 lines derived from 56 unadapted parents were then evaluated in hybrid combination in 21 trials over a 4‐yr period. The unadapted sources included lines with geographic or racial diversity, phenotypic diversity for key traits, elite lines from breeding programs in other countries, and cross‐compatible wild species. Despite strong selection for acceptable height and maturity, considerable genetic variation for grain yield was retained in the populations, with molecular marker analysis indicating an average of 22% of the genome being retained in each line as compared with a theoretical 25% in the absence of selection. In all cases progeny were identified in each population that performed significantly better than the recurrent parent hybrid for grain yield, and in some cases specific adaptation of particular populations was observed. The method we used proved to be an effective way to introduce new alleles from unadapted sorghum germplasm into elite breeding material. The potential of the populations as a resource for nested association mapping to elucidate the architecture of complex traits is discussed.
General Resistance in Maize to Southern Rust (Puccinia polysora Underw.)
Authors: Brewbaker James L. , Kim Soon Kwon , So Yoon Sup , Logroño Manuel , Moon Hyeon Gui , Ming Reiguang , Lu Xiao Wu , Josue Aleksander D.
Published: June 2011

Southern corn rust (Puccinia polysora Underw.) is a major tropical disease that can lead to severe yield losses in the tropics. Occasionally it becomes of concern in temperate regions, as in 2010. We summarize 45 yr of research on the occurrence, genetic basis, and breeding of general resistance. Trials were conducted in Colombia, Hawaii, Nigeria, the Philippines, Texas, and Thailand. Temperate maize proved uniformly susceptible. No racially specific monogenes were effective. Resistance varied continuously among tropical inbreds and many of these showed stable intermediate tolerance. Two diallel populations revealed high correlations of inbred values with hybrid array means and slight heterosis for resistance. Narrow‐sense heritabilities were 51% and 66%, and mean square ratios for general to specific combining ability (GCA:SCA) were 7.8 and 10.7 to 1. Generation mean analyses were performed on six sets of families. Mean and additive effects were significant across families, while significant nonadditive effects were rare. Heritability values ranged from 19% to 49%. A set of recombinant lines segregated a primary susceptibility locus on chromosome 6. Studies of 137 near‐isogenic inbred lines (NILs) of resistant tropical inbred Hi27 revealed a dominant susceptibility quantitative trait locus (QTL) in the NIL for dwarf‐1 locus, but linkage could not be confirmed. Premature senescence was associated with rust infections in many NILs, emphasizing the ubiquity of modifying genes. No correlation existed between resistance to southern and common rusts. Resistant tropical inbreds and populations were bred to serve as sources for future improvement.