bluuebunny/crossref_metadata_2025 huggingface dataset:
RETRACTED: MicroRNA‐16 inhibits glioma cell growth and invasion through suppression of BCL2 and the nuclear factor‐κB1/MMP9 signaling pathway
Authors: Yang Tian‐Quan , Lu Xiao‐Jun , Wu Ting‐Feng , Ding Da‐Dong , Zhao Zhao‐Hui , Chen Gui‐Lin , Xie Xue‐Shun , Li Bin , Wei Yong‐Xin , Guo Ling‐Chuan , Zhang Yu , Huang Yu‐Lun , Zhou You‐Xin , Du Zi‐Wei
Published: January 2014

Recent studies have identified a class of small non‐coding RNA molecules, named microRNA (miRNA), that is dysregulated in malignant brain glioblastoma. Substantial data have indicated that miRNA‐16 (miR‐16) plays a significant role in tumors of various origins. This miRNA has been linked to various aspects of carcinogenesis, including cell apoptosis and migration. However, the molecular functions of miR‐16 in gliomagenesis are largely unknown. We have shown that the expression of miR‐16 in human brain glioma tissues was lower than in non‐cancerous brain tissues, and that the expression of miR‐16 decreased with increasing degrees of malignancy. Our data suggest that the expression of miR‐16 and nuclear factor (NF)‐κB1 was negatively correlated with glioma levels. MicroRNA‐16 decreased glioma malignancy by downregulating NF‐κB1 and MMP9, and led to suppressed invasiveness of human glioma cell lines SHG44, U87, and U373. Our results also indicated that upregulation of miR‐16 promoted apoptosis by suppressing BCL2 expression. Finally, the upregulation of miR‐16 in a nude mice model of human glioma resulted in significant suppression of glioma growth and invasiveness. Taken together, our experiments have validated the important role of miR‐16 as a tumor suppressor gene in glioma growth and invasiveness, and revealed a novel mechanism of miR‐16‐mediated regulation in glioma growth and invasiveness through inhibition of BCL2 and the NF‐κB1/MMP‐9 signaling pathway. Therefore, our experiments suggest the possible future use of miR‐16 as a therapeutic target in gliomas.
Genome‐wide approach to identify second gene targets for malignant rhabdoid tumors using high‐density oligonucleotide microarrays
Authors: Takita Junko , Chen Yuyan , Kato Motohiro , Ohki Kentaro , Sato Yusuke , Ohta Shigeru , Sugita Kanji , Nishimura Riki , Hoshino Noriko , Seki Masafumi , Sanada Masashi , Oka Akira , Hayashi Yasuhide , Ogawa Seishi
Published: January 2014

Malignant rhabdoid tumor (MRT) is a rare and highly lethal cancer that mainly affects infants and young children. The majority of MRT are characterized by loss of function of SMARCB1 on chromosome 22q11.2. However, little is known about genetic changes other than SMARCB1 alterations that are responsible for the development and/or progression of MRT. To explore additional gene targets in MRT, we analyzed 21 MRT specimens (12 fresh tumors and 9 MRT‐derived cell lines) using high‐density single nucleotide polymorphism genotyping microarrays. Although MRT genomes are characterized by common 22q11.2 deletions, affecting the SMARCB1 locus with a frequency of 95.2% (20/21 specimens), other genetic changes have been less frequent. Of the 20 specimens with deletions of 22q11.2, eight specimens showed uniparental disomy of the SMARCB1 locus with homozygous deletions or gene mutations. High‐resolution analysis also disclosed the recurrent hemizygous/homozygous deletions of 7q35–q36.1, involving the CNTNAP2 locus in three specimens. Mutations analysis of CNTNAP2 showed a novel R157C missense mutation in a primary case, and methylation analysis showed recurrent hypermethylation of CNTNAP2 in three of nine cell lines. These results demonstrated that CNTNAP2 is one of the additional gene targets, other than SMARCB1, in MRT.
Probing the Origin of Structural Stability of Single and Double Stapled p53 Peptide Analogs Bound to MDM2
Authors: Guo Zuojun , Streu Kristina , Krilov Goran , Mohanty Udayan
Published: January 2014

The stabilization of secondary structure is believed to play an important role in the peptide–protein binding interaction. In this study, the α‐helical conformation and structural stability of single and double stapled all‐hydrocarbon cross‐linked p53 peptides when bound and unbound to MDM2 are investigated. We determined the effects of the peptide sequence, the stereochemistry of the cross‐linker, the conformation of the double bond in the alkene bridge, and the length of the bridge, to the relative stability of the α‐helix structure. The binding affinity calculations by WaterMap provided over one hundred hydration sites in the MDM2 binding pocket where water density is greater than twice that of the bulk, and the relative value of free energy released by displacing these hydration sites. In agreement with the experimental data, potentials of mean force obtained by weighted histogram analysis methods indicated the order of peptides from lowest to highest binding affinity. Our study provides a comprehensive rationalization of the relationship between peptide stapling strategy, the secondary structural stability, and the binding affinity of p53/MDM2 complex. We hope our efforts can help to further the development of a new generation p53/MDM2 inhibitors that can reactivate the function of p53 as tumor suppressor gene.
Co-existence of clonal expanded autologous and transplacental-acquired maternal T cells in recombination activating gene-deficient severe combined immunodeficiency
Authors: Lev A , Simon A J , Ben-Ari J , Takagi D , Stauber T , Trakhtenbrot L , Rosenthal E , Rechavi G , Amariglio N , Somech R
Published: January 2014

It is commonly accepted that the presence of high amounts of maternal T cells excludes Omenn syndrome (OS) in severe combined immunodeficiency (SCID). We report a SCID patient with a novel mutation in the recombination activating gene (RAG)1 gene (4-BP DEL.1406 TTGC) who presented with immunodeficiency and OS. Several assays, including representatives of specific T cell receptors (TCR), Vβ families and TCR-γ rearrangements, were performed in order to understand more clearly the nature and origin of the patient's T cells. The patient had oligoclonal T cells which, based on the patient–mother human leucocyte antigen (HLA)-B50 mismatch, were either autologous or of maternal origin. These cell populations were different in their numbers of regulatory T cells (Treg) and the diversity of TCR repertoires. This is the first description of the co-existence of large amounts of clonal expanded autologous and transplacental-acquired maternal T cells in RAG1-deficient SCID.
Blastopathies and microcephaly in a Chornobyl impacted region of Ukraine
Authors: Wertelecki Wladimir , Yevtushok Lyubov , Zymak‐Zakutnia Natalia , Wang Bin , Sosyniuk Zoriana , Lapchenko Serhiy , Hobart Holly H.
Published: January 2014

This population‐based descriptive epidemiology study demonstrates that rates of conjoined twins, teratomas, neural tube defects, microcephaly, and microphthalmia in the Rivne province of Ukraine are among the highest in Europe. The province is 200 km distant from the Chornobyl site and its northern half, a region known as Polissia, is significantly polluted by ionizing radiation. The rates of neural tube defects, microcephaly and microphthalmia in Polissia are statistically significantly higher than in the rest of the province. A survey of at‐birth head size showed that values were statistically smaller in males and females born in one Polissia county than among neonates born in the capital city. These observations provide clues for confirmatory and cause‐effect prospective investigations. The strength of this study stems from a reliance on international standards prevalent in Europe and a decade‐long population‐based surveillance of congenital malformations in two distinct large populations. The limitations of this study, as those of other descriptive epidemiology investigations, is that identified cause‐effect associations require further assessment by specific prospective investigations designed to address specific teratogenic factors.
Pilot of BRAF mutation analysis in indeterminate, suspicious and malignant thyroid FNA cytology
Authors: Johnson S. J. , Hardy S. A. , Roberts C. , Bourn D. , Mallick U. , Perros P.
Published: January 2014

Background

BRAF V600E mutation has been reported to show a high specificity for papillary thyroid carcinoma (PTC). Using this marker to upgrade ‘indeterminate’ or ‘suspicious’ thyroid fine needle aspiration (FNA) cytology to ‘malignant’ could potentially allow one‐stage therapeutic total thyroidectomy.

Methods

For a 14‐month period, FNA cytology specimens in the Thy3–5 categories, which are the UK equivalents of indeterminate (Thy3a, atypical; Thy3f, follicular), suspicious for malignancy (Thy4) and malignant (Thy5) in the Bethesda System, underwent BRAF mutation testing by melt curve analysis. The results were correlated with histology.

Results

We tested 123 cytology specimens of which 12 (9.8%) failed. The BRAF mutation rate in the remainder was 16.2% (18/111), with 93 showing the wild‐type. Seventeen mutations were V600E and one was non‐V600E. The rate of mutation increased significantly (P < 0.0001 if Thy3a and Thy3f were combined) with the cytology category: 1/42 Thy3a (2.4%), 1/36 Thy3f (2.8%), 4/15 Thy4 (26.7%), 12/18 Thy5 (66.7%). All BRAF mutations correlated with PTC on histology, except for one recurrent PTC without histology. One mutation‐positive case with Thy3a cytology showed the target lesion to be a 10‐mm follicular adenoma on histology with an immediately adjacent 4‐mm micro‐PTC, in a patient who did not require total thyroidectomy.

Conclusion

BRAF mutational analysis by melt curve analysis is feasible in routine thyroid cytology, and in our series had a 100% specificity for PTC in subsequent histology. The application of BRAF analysis could be useful for indeterminate cytology, but we suggest that it would be most appropriate and cost‐effective for Thy4/suspicious cases, for which it could enable one‐stage therapeutic surgery in the context of multidisciplinary discussion. In contrast, the sensitivity is low and there is no role for avoiding diagnostic thyroid surgery if wild‐type BRAF is found.
Mitochondrial inhibitor sodium azide inhibits the reorganization of mitochondria‐rich cytoplasm and the establishment of the anteroposterior axis in ascidian embryo
Authors: Ishii Hirokazu , Shirai Takuma , Makino Chisato , Nishikata Takahito
Published: January 2014

In ascidian eggs, cytoplasmic and cortical reorganization, previously called ooplasmic segregation, occurs in two phases during the first cell cycle. In the second phase of reorganization, the mitochondria‐rich cytoplasm (myoplasm) moves to the future posterior side, concurrent with sperm aster migration along the egg cortex. Although this reorganization is the critical step for establishing the anteroposterior axis, its molecular mechanism is not fully understood. In this study, we showed that low concentrations of the mitochondrial inhibitor sodium azide (NaN3), which showed the low toxicity in sperm, inhibited the second phase of reorganization without the microtubule depolymerization. In the NaN3‐treated embryo, the sperm aster was not attracted to the cortex and altered its migration pathway; therefore, the myoplasm remained at the vegetal pole. Consequently, the anteroposterior axis was not established. Another mitochondrial inhibitor, oligomycin, did not affect these processes. These results suggest that NaN3 inhibits unknown molecules that are important for the second phase of reorganization. Identifying the target molecule of NaN3 will lead to a molecular understanding of cytoplasmic and cortical reorganization.
Multiple environmental controls on phytoplankton growth strategies determine adaptive responses of the N : P ratio
Authors: Daines Stuart J. , Clark James R. , Lenton Timothy M.
Published: January 2014

The controls on the ‘Redfield’ N : P stoichiometry of marine phytoplankton and hence the N : P ratio of the deep ocean remain incompletely understood. Here, we use a model for phytoplankton ecophysiology and growth, based on functional traits and resource‐allocation trade‐offs, to show how environmental filtering, biotic interactions, and element cycling in a global ecosystem model determine phytoplankton biogeography, growth strategies and macromolecular composition. Emergent growth strategies capture major observed patterns in marine biomes. Using a new synthesis of experimental RNA and protein measurements to constrain per‐ribosome translation rates, we determine a spatially variable lower limit on adaptive rRNA:protein allocation and hence on the relationship between the largest cellular P and N pools. Comparison with the lowest observed phytoplankton N : P ratios and N : P export fluxes in the Southern Ocean suggests that additional contributions from phospholipid and phosphorus storage compounds play a fundamental role in determining the marine biogeochemical cycling of these elements.
Estimating the burden of early onset dementia; systematic review of disease prevalence
Authors: Lambert M. A. , Bickel H. , Prince M. , Fratiglioni L. , Von Strauss E. , Frydecka D. , Kiejna A. , Georges J. , Reynish E. L.
Published: January 2014

Dementia is more common in older age but a number of people develop symptoms at a younger age and are said to have early onset dementia (EOD). Those with EOD face different challenges to those with onset later in life. It has been difficult to quantify this disease burden. This is a systematic review of papers reporting on the prevalence of EOD. A search of Medline and Embase was performed. This was followed by a hand search of the references of these papers. Eleven suitable studies were included. All of the data was from more economically developed countries. The studies were heterogeneous in their design hindering direct comparison. The majority of the papers looked at all types of dementia although many gave a breakdown of the prevalence of different subgroups. A variety of diagnostic criteria was employed. Figures of 38 to 260 per 100 000 are quoted by papers looking at various different types of dementia together with an onset of between 30 and 64 or up to 420 per 100 000 for those aged 55–64. Prevalence rises as age approaches 65. Epidemiological data for prevalence rates for EOD are sparse. EOD remains a rare condition with low case numbers. Assimilation and comparison of results from existing studies is difficult due to methodological heterogeneity. Cross‐national standardization of methodology should be a priority for future research in this area.
Intellectual development before and after the onset of infantile spasms: A controlled prospective longitudinal study in tuberous sclerosis
Authors: Humphrey Ayla , MacLean Cathy , Ploubidis George B. , Granader Yael , Clifford Michelle , Haslop Maisy , Neville Brian G.R. , Yates John R.W. , Bolton Patrick F. ,   the Tuberous Sclerosis 2000 Study Group
Published: January 2014

Objective

Infantile spasms (IS) have long been suspected to be a risk factor for impairment in intellectual development, but there are no controlled, prospective longitudinal data in well‐characterized conditions to confirm this suspicion. We tested the hypothesis in a longitudinal study of children with tuberous sclerosis (TS), who have a high risk of developing IS.

Methods

Eleven infants with TS were recruited and studied longitudinally using the Mullen Scales of Early Learning. Seizure histories were assessed using a structured parent interview and by review of medical notes. Intellectual development was examined in relation to the onset and length of exposure to IS and other types of seizures.

Results

Six children developed IS and five children developed other types of seizure disorders. Among those that developed IS, estimated mean IQ dropped significantly (nonparametric test for trend p = 0.002) from 92 (prior to onset of spasms) to 73 (after exposure to IS for a month or less) and 62 (after exposure to IS for more than a month). By contrast, there was no significant drop in estimated IQ among the five infants exposed to other types of seizure disorders (nonparametric test for trend p = 0.9). All six children exposed to infantile spasms developed clinically significant intellectual impairment.

Significance

These data provide the first clear evidence of clinically significant, dose dependent, impairment in intellectual development following exposure to infantile spasms. The mechanisms underlying this developmental impairment and methods for preventing it require in depth study.
Altered thalamic GABAA‐receptor subunit expression in the stargazer mouse model of absence epilepsy
Authors: Seo Steve , Leitch Beulah
Published: January 2014

Purpose

Absence seizures, also known as petit mal seizures, arise from disruptions within the cortico‐thalamocortical network. Interconnected circuits within the thalamus consisting of inhibitory neurons of the reticular thalamic nucleus (RTN) and excitatory relay neurons of the ventral posterior (VP) complex, generate normal intrathalamic oscillatory activity. The degree of synchrony in this network determines whether normal (spindle) or pathologic (spike wave) oscillations occur; however, the cellular and molecular mechanisms underlying absence seizures are complex and multifactorial and currently are not fully understood. Recent experimental evidence from rodent models suggests that regional alterations in γ‐aminobutyric acid (GABA)ergic inhibition may underlie hypersynchronous oscillations featured in absence seizures. The aim of the current study was to investigate whether region‐specific differences in GABAA receptor (GABAAR) subunit expression occur in the VP and RTN thalamic regions in the stargazer mouse model of absence epilepsy where the primary deficit is in α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) expression.

Methods

Immunofluorescence confocal microscopy and semiquantitative Western blot analysis were used to investigate region‐specific changes in GABAAR subunits in the thalamus of the stargazer mouse model of absence epilepsy to determine whether changes in GABAergic inhibition could contribute to the mechanisms underlying seizures in this model of absence epilepsy.

Key Findings

Immunofluorescence confocal microscopy revealed that GABAAR α1 and β2 subunits are predominantly expressed in the VP, whereas α3 and β3 subunits are localized primarily in the RTN. Semiquantitative Western blot analysis of VP and RTN samples from epileptic stargazers and their nonepileptic littermates showed that GABAAR α1 and β2 subunit expression levels in the VP were significantly increased (α1: 33%, β2: 96%) in epileptic stargazers, whereas α3 and β3 subunits in the RTN were unchanged in the epileptic mice compared to nonepileptic control littermates.

Significance

These findings suggest that region‐specific differences in GABAAR subunits in the thalamus of epileptic mice, specifically up‐regulation of GABAARs in the thalamic relay neurons of the VP, may contribute to generation of hypersynchronous thalamocortical activity in absence seizures. Understanding region‐specific differences in GABAAR subunit expression could help elucidate some of the cellular and molecular mechanisms underlying absence seizures and thereby identify targets by which drugs can modulate the frequency and severity of epileptic seizures. Ultimately, this information could be crucial for the development of more specific and effective therapeutic drugs for treatment of this form of epilepsy.
PIGO mutations in intractable epilepsy and severe developmental delay with mild elevation of alkaline phosphatase levels
Authors: Nakamura Kazuyuki , Osaka Hitoshi , Murakami Yoshiko , Anzai Rie , Nishiyama Kiyomi , Kodera Hirofumi , Nakashima Mitsuko , Tsurusaki Yoshinori , Miyake Noriko , Kinoshita Taroh , Matsumoto Naomichi , Saitsu Hirotomo
Published: January 2014

Aberrations in the glycosylphosphatidylinositol (GPI)–anchor biosynthesis pathway constitute a subclass of congenital disorders of glycosylation, and mutations in seven genes involved in this pathway have been identified. Among them, mutations in PIGV and PIGO, which are involved in the late stages of GPI‐anchor synthesis, and PGAP2, which is involved in fatty‐acid GPI‐anchor remodeling, are all causative for hyperphosphatasia with mental retardation syndrome (HPMRS). Using whole exome sequencing, we identified novel compound heterozygous PIGO mutations (c.389C>A [p.Thr130Asn] and c.1288C>T [p.Gln430*]) in two siblings, one of them having epileptic encephalopathy. GPI‐anchored proteins (CD16 and CD24) on blood granulocytes were slightly decreased compared with a control and his mother. Our patients lacked the characteristic features of HPMRS, such as facial dysmorphology (showing only a tented mouth) and hypoplasia of distal phalanges, and had only a mild elevation of serum alkaline phosphatase (ALP). Our findings therefore expand the clinical spectrum of GPI‐anchor deficiencies involving PIGO mutations to include epileptic encephalopathy with mild elevation of ALP.
Changing name of epilepsy in Korea; cerebroelectric disorder (noi‐jeon‐jeung,뇌전증,腦電症)
Authors: Kim Heung Dong , Kang Hoon‐Chul , Lee Sang Ahm , Huh Kyun , Lee Byung‐In
Published: January 2014

Public misconception of epilepsy may lead to significant stigma to the disease itself, thereby causing impaired quality of life in people with epilepsy. Traditionally, epilepsy has been considered to be the consequence of evanescent spiritual forces, and even demonic possession (in many countries). The names of epilepsy in some East Asian countries originated from China, and include madness in their meaning. We recently changed the Korean name of epilepsy, gan‐jil (간질, 癎疾: a crazy, convulsive disease having meaning similar to 癲癎), to a neutral and scientifically explainable name: noi‐jeon‐jeung (뇌전증; 腦電症; cerebroelectric disorder). We expect that changing the stigmatized name of epilepsy to a neutral and scientific term with the meaning of cerebroelectric disorder will reduce the social stigma by understanding of epilepsy as one of the neurologic disorders.
Direct association of the unique C‐terminal tail of transmembrane AMPA receptor regulatory protein γ‐8 with calcineurin
Authors: Itakura Makoto , Watanabe Izumi , Sugaya Tsukiko , Takahashi Masami
Published: January 2014

Transmembrane α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA) receptor regulatory proteins (TARPs) are auxiliary subunits that regulate AMPA receptor trafficking to the plasma membrane and localization to postsynaptic sites. The classical TARP family consists of four members: stargazin/γ‐2, γ‐3, γ‐4 and γ‐8. The TARP γ‐8 isoform, which is highly expressed in the hippocampus, has a unique, long C‐terminal domain with five distinct regions: two glycine‐rich regions, a serine/arginine‐rich region, a proline/alanine (P/A) rich region, and a PSD‐95/Dlg/ZO‐1 (PDZ) binding motif. We performed mass spectrometry and immunoprecipitation assays to identify specific binding partners for the γ‐8 C‐terminal tail and found that γ‐8, but not stargazin/γ‐2, co‐immunoprecipitated with calcineurin/PP2B, a Ca2+/calmodulin‐dependent Ser/Thr phosphatase. Co‐immunoprecipitation and immunoblot analyses of lysates from COS‐7 cells co‐transfected with calcineurin and either wild type or chimeric γ‐8 revealed that a section of the C‐terminal tail (residues 356–421) can bind calcineurin. Futhermore, γ‐8 lacking the P/A‐rich region (residues 383–399) did not bind to calcineurin. In addition, the GST‐γ‐8 C‐terminal tail (residues 353–414) fusion protein containing the P/A‐rich region bound to purified calcineurin in a Ca2+/calmodulin‐dependent manner, whereas GST‐γ‐8 with a deletion of the P/A‐rich region did not. Peptide competition assays demonstrated that γ‐8 may interact with the hydrophobic pocket defined by β‐sheet 14 and/or adjacent regions of the catalytic A subunit of calcineurin. These results indicate that the γ‐8 P/A‐rich region is essential for binding calcineurin, suggesting that the γ‐8/calcineurin complex may regulate AMPA receptor phosphorylation and trafficking.

Structured digital abstract

gamma-8 physically interacts with Cn A by anti bait coimmunoprecipitation (View interaction)

gamma-8 binds to Cn A by pull down (View interaction)

gamma-2 physically interacts with PSD-95 by anti bait coimmunoprecipitation (View interaction)

gamma-2 physically interacts with GluA1 and GluA2 by anti bait coimmunoprecipitation (View interaction)

gamma-8 physically interacts with beta -tubulin, Cn A and alpha-tubulin by anti bait coimmunoprecipitation (View interaction)

gamma-8 physically interacts with GluA1 and GluA2 by anti bait coimmunoprecipitation (View interaction)

Cn A physically interacts with Cn B and gamma-8 by anti bait coimmunoprecipitation (1, 2, 3)

gamma-8 physically interacts with PSD-95 by anti bait coimmunoprecipitation (View interaction)

gamma-8 physically interacts with GluA1, GluA2, Cn B and Cn A by anti bait coimmunoprecipitation (View interaction)

gamma-8 physically interacts with Cn A by anti bait coimmunoprecipitation (View interaction)

PSD-95, gamma-8 and Cn A colocalize by fluorescence microscopy (View interaction)
Transient state microscopy probes patterns of altered oxygen consumption in cancer cells
Authors: Spielmann Thiemo , Xu Lei , Gad Annica K. B. , Johansson Sofia , Widengren Jerker
Published: January 2014

Altered cellular metabolism plays an important role in many diseases, not least in many forms of cancer, where cellular metabolic pathways requiring lower oxygen consumption are often favored (the so‐called Warburg effect). In this work, we have applied fluorescence‐based transient state imaging and have exploited the environment sensitivity of long‐lived dark states of fluorophores, in particular triplet state decay rates, to image the oxygen consumption of living cells. Our measurements can resolve differences in oxygen concentrations between different regions of individual cells, between different cell types, and also based on what metabolic pathways the cells use. In MCF‐7 breast cancer cells, higher oxygen consumption can be detected when they rely on glutamine instead of glucose as their main metabolite, predominantly undergoing oxidative phosphorylation rather than glycolysis. By use of the high triplet yield dye Eosin Y the irradiance requirements during the measurements can be kept low. This reduces the instrumentation requirements, and harmful biological effects from high excitation doses can be avoided. Taken together, our imaging approach is widely applicable and capable of detecting subtle changes in oxygen consumption in live cells, stemming from the Warburg effect or reflecting other differences in the cellular metabolism. This may lead to new diagnostic means as well as advance our understanding of the interplay between cellular metabolism and major disease categories, such as cancer.
Transcriptional regulation of chicken cytochrome P450 2D49 basal expression by CCAAT/enhancer‐binding protein α and hepatocyte nuclear factor 4α
Authors: Yang Qi , Tang Shulin , Dong Linfeng , Chen Qingmei , Liu Xin , Jiang Jun , Deng Yiqun
Published: January 2014

Chicken cytochrome P450 (CYP)2D49 is structurally and functionally related to human CYP2D6, which is an important drug‐metabolizing enzyme. To date, little is known about the transcriptional regulation of this cytochrome. Through deletion analysis of the CYP2D49 promoter, we identified two putative degenerate CCAAT/enhancer‐binding protein (C/EBP)‐binding sites and an imperfect DR1 element (the site contains direct repeats of the hexamer AGGTCA separated by a one‐nucleotide spacer motif) within regions –296/–274, –274/–226, and –226/–183, respectively, which may play critical roles in the transcriptional activation of the CYP2D49 gene. Electrophoretic mobility shift assays and chromatin immunoprecipitation assays showed that the putative C/EBP boxes and DR1 element in the CYP2D49 promoter are functional motifs that bind to C/EBPα and hepatocyte nuclear factor 4α (HNF4α), respectively. Furthermore, we studied the functional importance and relationships of these transcription factor‐binding sites by examining the effects of mutation and deletion of these regions on promoter activity. These studies revealed that the two C/EBP‐binding sites show a compensatory relationship and work cooperatively with the DR1 element to modulate the transcription of CYP2D49. The results of overexpressing C/EBPα and HNF4α in culture cells further confirmed that both C/EBPα and HNF4α contribute significantly to sustaining a high level of CYP2D49 transcription. In conclusion, the data indicate that the constitutive hepatic expression of CYP2D49 is governed by both C/EBPα and HNF4α. Further studies will be required to fully characterize the molecular mechanisms that modulate CYP2D49 expression.
Different affinity of nuclear factor‐kappa B proteins to DNA modified by antitumor cisplatin and its clinically ineffective trans isomer
Authors: Kasparkova Jana , Thibault Thomas , Kostrhunova Hana , Stepankova Jana , Vojtiskova Marie , Muchova Tereza , Midoux Patrick , Malinge Jean‐Marc , Brabec Viktor
Published: January 2014

Nuclear factor‐kappa B (NF‐кB) comprises a family of protein transcription factors that have a regulatory function in numerous cellular processes and are implicated in the cancer cell response to antineoplastic drugs, including cisplatin. We characterized the effects of DNA adducts of cisplatin and ineffective transplatin on the affinity of NF‐кB proteins to their consensus DNA sequence (кB site). Although the кB site–NF‐κB protein interaction was significantly perturbed by DNA adducts of cisplatin, transplatin adducts were markedly less effective both in cell‐free media and in cellulo using a decoy strategy derivatized‐approach. Moreover, NF‐κB inhibitor JSH‐23 [4‐methyl‐N¹‐(3‐phenylpropyl)benzene‐1,2‐diamine] augmented cisplatin cytotoxicity in ovarian cancer cells and the data showed strong synergy with JSH‐23 for cisplatin. The distinctive structural features of DNA adducts of the two platinum complexes suggest a unique role for conformational distortions induced in DNA by the adducts of cisplatin with respect to inhibition of the binding of NF‐кB to the platinated кB sites. Because thousands of κB sites are present in the DNA, the mechanisms underlying the antitumor efficiency of cisplatin in some tumor cells may involve downstream processes after inhibition of the binding of NF‐κB to κB site(s) by DNA adducts of cisplatin, including enhanced programmed cell death in response to drug treatment.
Removing bacteria from rough surface titanium discs with chlorhexidine and additional brushing with dentifrice
Authors: Park Jun‐Beom , Koh Minchul , Jang Yun‐Ji , Choi Bong‐Kyu , Kim Kack‐Kyun , Ko Youngkyung
Published: January 2014

Objectives

This in vitro study was conducted: (i) to evaluate the effect of using cotton pellets soaked with chlorhexidine (CHX) on titanium surface roughness; (ii) to assess the removal of Porphyromonas gingivalis (P. gingivalis) from resorbable blast material (RBM) titanium surfaces using CHX pellets; and (iii) to evaluate the effects of additional brushing on bacterial removal efficiency.

Materials and methods

RBM titanium discs were treated with CHX‐soaked cotton pellets, and change in surface roughness was measured using confocal microscopy. After the titanium discs were incubated with P. gingivalis for 2 days, the discs were cleaned with CHX pellets for 40 s. The quantity of remaining adherent bacteria was measured using crystal violet assay. Additional brushing was performed with dentifrice for a total of 40 s, and bacterial removal efficiency with brushing and dentifrice was evaluated using crystal violet assay and scanning electron microscopy.

Results

The changes in surface roughness after treatment were observed by confocal microscopy. Statistically significant decrease in surface roughness was seen in CHX 40‐s group (p < 0.05). Cleaning with CHX‐soaked pellets resulted in significant decrease in remaining adherent bacteria. Brushing the bacteria‐incubated discs with dentifrice reduced adhering bacteria. There were fewer bacteria left on the CHX‐pre‐treated discs compared with the brushing‐only group, but there were no significant differences when compared with the brushing‐only group (p > 0.05).

Conclusions

This study clearly showed that burnishing with CHX influenced the RBM titanium surface, and burnishing with CHX pellets and brushing with dentifrice were efficient in removing bacteria from the contaminated titanium surface.
Self‐monitoring has potential for home exercise programmes in patients with haemophilia
Authors: Goto M. , Takedani H. , Haga N. , Kubota M. , Ishiyama M. , Ito S. , Nitta O.
Published: January 2014

Haemophiliacs who have had to keep a physically inactive lifestyle due to bleeding during childhood are likely to have little motivation for exercise. The purpose of this study is to clarify the effectiveness of the self‐monitoring of home exercise for haemophiliacs. A randomized controlled trial was conducted with intervention over 8 weeks at four hospitals in Japan. Subjects included 32 male outpatients aged 26–64 years without an inhibitor who were randomly allocated to a self‐monitoring group and a control group. Individual exercise guidance with physical activity for improvement of their knee functions was given to both groups. The self‐monitoring materials included an activity monitor and a feedback system so that the self‐monitoring group could send feedback via the Internet and cellular phone. The self‐monitoring was performed by checking exercise adherence and physical activity levels, bleeding history and injection of a coagulation factor. Both groups showed significant improvements in exercise adherence (P < 0.001) and physical function such as the strength of knee extension (P < 0.001), range of knee extension (P < 0.001), range of ankle dorsiflexion (P < 0.01), a modified Functional Reach (P < 0.05) and 10 metre gait time (P < 0.01). In particular, improvements in exercise adherence (P < 0.05), self‐efficacy (P < 0.05), and strength of knee extension (P < 0.05) were significant in the self‐monitoring group compared with those in the control group. No increase in bleeding frequency and pain scale was noted. The self‐monitoring of home exercise for haemophilic patients is useful for the improvement of exercise adherence, self‐efficacy and knee extension strength.
Early lipid changes with atazanavir/ritonavir or darunavir/ritonavir
Authors: Martinez E , Gonzalez‐Cordon A , Ferrer E , Domingo P , Negredo E , Gutierrez F , Portilla J , Curran A , Podzamczer D , Murillas J , Bernardino JI , Santos I , Carton JA , Peraire J , Pich J , Perez I , Gatell JM ,   ATADAR Study Group
Published: January 2014

Objectives

Ritonavir‐boosted atazanavir and darunavir are protease inhibitors that are recommended for initial treatment of HIV infection because each has shown better lipid effects and overall tolerability than ritonavir‐boosted lopinavir. The extent to which lipid effects and overall tolerability differ between treatments with atazanavir and darunavir and whether atazanavir‐induced hyperbilirubinaemia may result in more favourable metabolic effects are issues that remain to be resolved.

Methods

A 96‐week randomized clinical trial was carried out. The primary endpoint was change in total cholesterol at 24 weeks. Secondary endpoints were changes in lipids other than total cholesterol, insulin sensitivity, total bilirubin, estimated glomerular filtration rate, and CD4 and CD8 cell counts, and the proportion of patients with plasma HIV RNA < 50 HIV‐1 RNA copies/mL and study drug discontinuation because of adverse effects at 24 weeks. Analyses were intent‐to‐treat.

Results

One hundred and seventy‐eight patients received once‐daily treatment with either atazanavir/ritonavir (n = 90) or darunavir/ritonavir (n = 88) plus tenofovir/emtricitabine. At 24 weeks, mean total cholesterol had increased by 7.26 and 11.47 mg/dL in the atazanavir/ritonavir and darunavir/ritonavir arms, respectively [estimated difference −4.21 mg/dL; 95% confidence interval (CI) −12.11 to +3.69 mg/dL; P = 0.75]. However, the ratio of total to high‐density lipoprotein (HDL) cholesterol tended to show a greater decrease with atazanavir/ritonavir compared with darunavir/ritonavir (estimated difference −1.02; 95% CI −2.35 to +0.13; P = 0.07). Total bilirubin significantly increased with atazanavir/ritonavir (estimated difference +1.87 mg/dL; 95% CI +1.58 to +2.16 mg/dL; P < 0.01), but bilirubin changes were not associated with lipid changes. Secondary endpoints other than total bilirubin were not significantly different between arms.

Conclusions

Atazanavir/ritonavir and darunavir/ritonavir plus tenofovir/emtricitabine did not show significant differences in total cholesterol change or overall tolerability at 24 weeks. However, there was a trend towards a lower total to HDL cholesterol ratio with atazanavir/ritonavir and this effect was unrelated to bilirubin.
“Thinking Familiar with the Interstitial”: An Introduction
Authors: Dotson Kristie
Published: January 2014

It's not that we haven't always been here, since there was a here. It is that the letters of our names have been scrambled when they were not totally erased, and our fingertips upon the handles of history have been called the random brushings of birds. (Lorde 1990, ix)

Because… [racialized peoples'] dehumanization has not been successful, conceiving of self and others and their exercise of themselves both against dehumanization and toward liberatory possibilities has meant living double lives backed up by peopled ways of living, acting, perceiving, thinking familiar with the interstitial, liminal, and with breaking up with, delinking from, colonial modernity. (Lugones, this issue, 20; my emphasis)

We are not born women of color. We become women of color. To become women of color, we would need to become fluent in each other's histories, to resist and unlearn an impulse allowing mythologies to replace knowing about one another…. We cannot afford to cease yearning for each other's company. (Alexander 2002, 91; italics in original)
The Business Model Paradox: A Systematic Review and Exploration of Antecedents
Authors: Klang David , Wallnöfer Maria , Hacklin Fredrik
Published: January 2014

The business model has become a popular concept in business and management fields. Yet, it is suffering from a paradox between outstanding popularity and severe criticism, which appears to impede the positive development of the scholarly discourse on the business model concept. Against this background, the purpose of this study is to provide insight into the antecedents of this paradox and to understand their implications for the future development of the concept. The following contributions are made. First, the authors apply a narrative approach to recognizing and interpreting the paradox, and introduce the analysis of syntactics of scholarly discourse as a novel method of investigating management concepts. Second, as a result of elaborating on recurrent themes and tensions in scholarly discourse, the authors extend the literature on business models through theorizing on the core of the concept along the dimensions of classification, constitution and configuration. In particular, they identify the simultaneity of separation and attachment as the main antecedent of the business model paradox. Third, the authors offer implications for further advancing the development of this management concept, and highlight the need for spurring integrative research while at the same time maintaining a plurality of perspectives.
LANDIS PRO: a landscape model that predicts forest composition and structure changes at regional scales
Authors: Wang Wen J. , He Hong S. , Fraser Jacob S. , Thompson Frank R. , Shifley Stephen R. , Spetich Martin A.
Published: January 2014

LANDIS PRO predicts forest composition and structure changes incorporating species‐, stand‐, and landscape‐scales processes at regional scales. Species‐scale processes include tree growth, establishment, and mortality. Stand‐scale processes contain density‐ and size‐related resource competition that regulates self‐thinning and seedling establishment. Landscape‐scale processes include seed dispersal and disturbances. LANDIS PRO is designed to be compatible with forest inventory data, thus extensive inventory data can be directly utilized to initialize and calibrate model parameters before predicting future forest changes. LANDIS PRO allows for exploring the effects of disturbances, management, climate change, and modeling the spread of invasive species. We demonstrate that LANDIS PRO successfully predicts forest successional trajectories and stand development patterns in the Central Hardwood Forest region in U.S.
Moral Hazard, Dividends, and Risk in Banks
Authors: Onali Enrico
Published: January 2014

In non‐financial firms, higher risk taking results in lower dividend payout ratios. In banking, public guarantees may result in a positive relationship between dividend payout ratios and risk taking. I investigate the interplay between dividend payout ratios and bank risk‐taking allowing for the effect of charter values and capital adequacy regulation. I find a positive relationship between bank risk‐taking and dividend payout ratios. Proximity to the required capital ratio and a high charter value reduce the impact of bank risk‐taking on the dividend payout ratio. My results are robust to different proxies for the dividend payout ratio and bank risk‐taking.
Evolutionary changes in plant tolerance against herbivory through a resurrection experiment
Authors: Bustos‐Segura C. , Fornoni J. , Núñez‐Farfán J.
Published: January 2014

Both theoretical and empirical works have highlighted the difference in the evolutionary implications of host resistance and tolerance against their enemies. However, it has been difficult to show evolutionary changes in host defences in natural populations; thus, evaluating theoretical predictions of simultaneous evolution of defences remains a challenge. We studied the evolutionary changes in traits related to resistance and tolerance against herbivory in a natural plant population using seeds from two collections made in a period of 20 years. In a common garden experiment, we compared defensive traits of ancestral (1987) and descendant (2007) subpopulations of the annual plant Datura stramonium that shows genetic variation for tolerance and to which the specialist herbivore Lema daturaphila is locally adapted. We also examined the effects of different plant genotypes on the herbivore for testing the plant genetic variation in resistance. Based on the response to the contemporary herbivore populations, results revealed a nonsignificant response in plant resistance traits (herbivore consumption, foliar trichomes and tropane alkaloids), but a significant one in tolerance. The survival of herbivores in laboratory experiments depended on the plant genotype, which suggests genetic variation in plant resistance. Although we cannot identify the selective agent for the change nor exclude genetic drift, the results are consistent with the expectation that when resistance fails to control herbivory, tolerance should play a more important role in the evolution of the interaction.
The effects of sexual selection on life‐history traits: an experimental study on guppies
Authors: Pélabon C. , Larsen L.‐K. , Bolstad G. H. , Viken Å. , Fleming I. A. , Rosenqvist G.
Published: January 2014

Sexual selection is often prevented during captive breeding in order to maximize effective population size and retain genetic diversity. However, enforcing monogamy and thereby preventing sexual selection may affect population fitness either negatively by preventing the purging of deleterious mutations or positively by reducing sexual conflicts. To better understand the effect of sexual selection on the fitness of small populations, we compared components of female fitness and the expression of male secondary sexual characters in 19 experimental populations of guppies (Poecilia reticulata) maintained under polygamous or monogamous mating regimes over nine generations. In order to generate treatments that solely differed by their level of sexual selection, the middle‐class neighbourhood breeding design was enforced in the monogamous populations, while in the polygamous populations, all females contributed similarly to the next generation with one male and one female offspring. This experimental design allowed potential sexual conflicts to increase in the polygamous populations because selection could not operate on adult‐female traits. Clutch size and offspring survival showed a weak decline from generation to generation but did not differ among treatments. Offspring size, however, declined across generations, but more in monogamous than polygamous populations. By generation eight, orange‐ and black‐spot areas were larger in males from the polygamous treatment, but these differences were not statistically significant. Overall, these results suggest that neither sexual conflict nor the purging of deleterious mutation had important effects on the fitness of our experimental populations. However, only few generations of enforced monogamy in a benign environment were sufficient to negatively affect offspring size, a trait potentially crucial for survival in the wild. Sexual selection may therefore, under certain circumstances, be beneficial over enforced monogamy during captive breeding.
Sublethal pesticide exposure disrupts courtship in the striped lynx spider, Oxyopes salticus (Araneae: Oxyopidae)
Authors: Hanna C. , Hanna C.
Published: January 2014

The striped lynx spider, Oxyopes salticus, is a dominant predator of pests in agricultural crops where pesticides are readily applied. While past research shows pesticides directly affect the mortality of agricultural pest predators, recent research has found that pesticide exposure may cause sublethal effects in these organisms. This study examined how residues of three common pesticides (active ingredients: bifenthrin, carbaryl, malathion) impact courtship behaviour of O. salticus. Males provided with cues left by females readily performed courting behaviours. However, when females left cues on a substrate containing bifenthrin and carbaryl, males were less likely to perform courtship behaviours and did so for less time. While males on the malathion treatment showed a trend for reduced courting, this was not significantly different from the treatment without pesticides. The cue produced by females is unknown in this species. However, our study found males reduced their courting over time, suggesting that the cue is ephemeral and not long lived. This study adds important insight into the growing evidence that pesticides greatly impact the ecology of agricultural pest predators and other non‐target organisms by altering their behaviour.