bluuebunny/crossref_metadata_2025 huggingface dataset:
The novel protein kinase Vlk is essential for stromal function of mesenchymal cells
Authors: Kinoshita Masaki , Era Takumi , Jakt Lars Martin , Nishikawa Shin-Ichi
Published: May 2009

From a list of protein kinases (PKs) that are newly induced upon differentiation of mouse embryonic stem cells to mesendoderm, we identified a previously uncharacterized kinase, Vlk (vertebrate lonesome kinase),that is well conserved in vertebrates but has no homologs outside of the vertebrate lineage. Its kinase domain cannot be classified into any of the previously defined kinase groups or families. Although Vlk is first expressed in E-cadherin-positive anterior visceral endoderm and mesendoderm,its expression is later confined to E-cadherin-negative mesenchyme. Vlk is enriched in the Golgi apparatus and blocks VSVG transport from the Golgi to the plasma membrane. Targeted disruption of Vlk leads to a defect in lung development and to delayed ossification of endochondral bone. Vlk-/- mice display neonatal lethality due to respiratory failure, with a suckling defect arising from a cleft palate. Our results demonstrate that Vlk is a novel vertebrate-specific PK that is involved in the regulation of the rate of protein export from the Golgi, thereby playing an important role in the formation of functional stroma by mesenchymal cells.
Juvenile hormone counteracts the bHLH-PAS transcription factors MET and GCE to prevent caspase-dependent programmed cell death inDrosophila
Authors: Liu Ying , Sheng Zhentao , Liu Hanhan , Wen Di , He Qianyu , Wang Sheng , Shao Wei , Jiang Rong-Jing , An Shiheng , Sun Yaning , Bendena William G. , Wang Jian , Gilbert Lawrence I. , Wilson Thomas G. , Song Qisheng , Li Sheng
Published: May 2009

Juvenile hormone (JH) regulates many developmental and physiological events in insects, but its molecular mechanism remains conjectural. Here we report that genetic ablation of the corpus allatum cells of the Drosophilaring gland (the JH source) resulted in JH deficiency, pupal lethality and precocious and enhanced programmed cell death (PCD) of the larval fat body. In the fat body of the JH-deficient animals, Dronc and Drice,two caspase genes that are crucial for PCD induced by the molting hormone 20-hydroxyecdysone (20E), were significantly upregulated. These results demonstrated that JH antagonizes 20E-induced PCD by restricting the mRNA levels of Dronc and Drice. The antagonizing effect of JH on 20E-induced PCD in the fat body was further confirmed in the JH-deficient animals by 20E treatment and RNA interference of the 20E receptor EcR. Moreover, MET and GCE, the bHLH-PAS transcription factors involved in JH action, were shown to induce PCD by upregulating Droncand Drice. In the Met- and gce-deficient animals, Dronc and Drice were downregulated, whereas in the Met-overexpression fat body, Dronc and Drice were significantly upregulated leading to precocious and enhanced PCD, and this upregulation could be suppressed by application of the JH agonist methoprene. For the first time, we demonstrate that JH counteracts MET and GCE to prevent caspase-dependent PCD in controlling fat body remodeling and larval-pupal metamorphosis in Drosophila.
Dynamic, auxin-responsive plasma membrane-to-nucleus movement ofArabidopsisBRX
Authors: Scacchi Emanuele , Osmont Karen S. , Beuchat Julien , Salinas Paula , Navarrete-Gómez Marisa , Trigueros Marina , Ferrándiz Cristina , Hardtke Christian S.
Published: May 2009

In Arabidopsis, interplay between nuclear auxin perception and trans-cellular polar auxin transport determines the transcriptional auxin response. In brevis radix (brx) mutants, this response is impaired, probably indirectly because of disturbed crosstalk between the auxin and brassinosteroid pathways. Here we provide evidence that BRX protein is plasma membrane-associated, but translocates to the nucleus upon auxin treatment to modulate cellular growth, possibly in conjunction with NGATHA class B3 domain-type transcription factors. Application of the polar auxin transport inhibitor naphthalene phthalamic acid (NPA) resulted in increased BRX abundance at the plasma membrane. Thus, nuclear translocation of BRX could depend on cellular auxin concentration or on auxin flux. Supporting this idea,NPA treatment of wild-type roots phenocopied the brx root meristem phenotype. Moreover, BRX is constitutively turned over by the proteasome pathway in the nucleus. However, a stabilized C-terminal BRX fragment significantly rescued the brx root growth phenotype and triggered a hypocotyl gain-of-function phenotype, similar to strong overexpressors of full length BRX. Therefore, although BRX activity is required in the nucleus,excess activity interferes with normal development. Finally, similar to the PIN-FORMED 1 (PIN1) auxin efflux carrier, BRX is polarly localized in vascular cells and subject to endocytic recycling. Expression of BRX under control of the PIN1 promoter fully rescued the brx short root phenotype, suggesting that the two genes act in the same tissues. Collectively, our results suggest that BRX might provide a contextual readout to synchronize cellular growth with the auxin concentration gradient across the root tip.
Molecular mechanisms of clathrin-independent endocytosis
Authors: Hansen Carsten G. , Nichols Benjamin J.
Published: May 2009

There is good evidence that, in addition to the canonical clathrin-associated endocytic machinery, mammalian cells possess multiple sets of proteins that are capable of mediating the formation of endocytic vesicles. The identity, mechanistic properties and function of these clathrin-independent endocytic pathways are currently under investigation. This Commentary briefly recounts how the field of clathrin-independent endocytosis has developed to date. It then highlights recent progress in identifying key proteins that might define alternative types of endocytosis. These proteins include CtBP (also known as BARS), flotillins (also known as reggies) and GRAF1. We argue that a combination of information about pathway-specific proteins and the ultrastructure of endocytic invaginations provides a means of beginning to classify endocytic pathways.
The stimulation of dendrite growth by Sema3A requires integrin engagement and focal adhesion kinase
Authors: Schlomann Uwe , Schwamborn Jens C. , Müller Myriam , Fässler Reinhard , Püschel Andreas W.
Published: May 2009

The rate and direction of axon and dendrite growth depend on multiple guidance signals and growth factors. Semaphorin 3A (Sema3A) acts as a repellent for axons and attractant for dendrites. Here, we show that the requirement for integrin engagement distinguishes the response of axons and dendrites to Sema3A in hippocampal neurons. Sema3A promotes the extension of hippocampal dendrites by a pathway that requires focal adhesion kinase (FAK). The stimulation of dendrite growth and FAK phosphorylation by Sema3A depend on integrin engagement. Unlike their function as a target of Sema3A during the collapse of axonal growth cones, integrins facilitate the stimulation of dendrite extension. Conditional inactivation of the genes encoding β1 integrin or FAK blocks the growth-promoting effect of Sema3A but not the collapse of axonal growth cones. Our results demonstrate that different pathways mediate the stimulation of dendrite growth and the collapse of axonal growth cones by Sema3A.
Radiation-induced mitotic catastrophe in PARG-deficient cells
Authors: Amé Jean-Christophe , Fouquerel Elise , Gauthier Laurent R. , Biard Denis , Boussin François D. , Dantzer Françoise , de Murcia Gilbert , Schreiber Valérie
Published: May 2009

Poly(ADP-ribosyl)ation is a post-translational modification of proteins involved in the regulation of chromatin structure, DNA metabolism, cell division and cell death. Through the hydrolysis of poly(ADP-ribose) (PAR), Poly(ADP-ribose) glycohydrolase (PARG) has a crucial role in the control of life-and-death balance following DNA insult. Comprehension of PARG function has been hindered by the existence of many PARG isoforms encoded by a single gene and displaying various subcellular localizations. To gain insight into the function of PARG in response to irradiation, we constitutively and stably knocked down expression of PARG isoforms in HeLa cells. PARG depletion leading to PAR accumulation was not deleterious to undamaged cells and was in fact rather beneficial, because it protected cells from spontaneous single-strand breaks and telomeric abnormalities. By contrast, PARG-deficient cells showed increased radiosensitivity, caused by defects in the repair of single- and double-strand breaks and in mitotic spindle checkpoint, leading to alteration of progression of mitosis. Irradiated PARG-deficient cells displayed centrosome amplification leading to mitotic supernumerary spindle poles, and accumulated aberrant mitotic figures, which induced either polyploidy or cell death by mitotic catastrophe. Our results suggest that PARG could be a novel potential therapeutic target for radiotherapy.
Coatomer-dependent protein delivery to lipid droplets
Authors: Soni Krishnakant G. , Mardones Gonzalo A. , Sougrat Rachid , Smirnova Elena , Jackson Catherine L. , Bonifacino Juan S.
Published: May 2009

Lipid droplets (LDs) are cytoplasmic organelles that store neutral lipids for use as an energy supply in times of nutrient deprivation and for membrane assembly. Misregulation of LD function leads to many human diseases, including lipodystrophy, obesity and neutral lipid storage disorders. A number of proteins have been shown to localize to the surface of lipid droplets, including lipases such as adipose triglyceride lipase (ATGL) and the PAT-domain proteins ADRP (adipophilin) and TIP47, but the mechanism by which they are targeted to LDs is not known. Here we demonstrate that ATGL and ADRP, but not TIP47, are delivered to LDs by a pathway mediated by the COPI and COPII coatomer proteins and their corresponding regulators.
Development of a new measurement method for serum calcium with chlorophosphonazo-III
Authors: Hokazono Eisaku , Osawa Susumu , Nakano Tomota , Kawamoto Yukari , Oguchi Yuji , Hotta Taeko , Kayamori Yuzo , Kang Dongchon , Cho Yuichiro , Shiba Kiyoko , Sato Kenji
Published: May 2009

Background

Although serum calcium has been measured using the o-cresolphthalein complexone (oCPC) method in the clinical laboratory, this method still has some problems regarding linearity and reagent stability. We developed a new measurement procedure using chlorophosphonazo-III (CPZ-III: 2,7-bis (4-chloro-2-phosphonophenylazo) -1,8- dihydroxy-3, 6-naphthalenedisulphonic acid, disodium salt) as a chelator with an acid medium for serum calcium measurement. The present method showed better linearity and reagent stability compared with the oCPC method.

Methods

Characteristics were studied in optimized conditions measuring wavelength by absorption spectra analysis, and interference of protein and metals with Mg2+, Fe2+, Cu2+ and Zn2+. The method was applied to an automated analyser (7170; Hitachi High Technologies Corp). The measurement performance was evaluated for accuracy, precision, recovery rate, linearity and reagent stability with a comparison study against atomic absorption spectrophotometry (AAS).

Results

The within-run and between-run variations (coefficient of variation [CV]) were 0.92–1.01% and 0.75–1.43%, respectively. The linearity was 0–7.0 mmol/L. The comparison study obtained y = 1.002 x (AAS) – 0.10, S y/x = 0.18 mmol/L, n = 50. Reagent stability was at least 20 d at 4°C without daily calibration.

Conclusion

The new calcium measurement method in serum was demonstrated to have reliable and acceptable performances as a routine test in clinical laboratory.
Delayed appearance of markers of intravascular haemolysis in a case of paroxysmal cold haemoglobinuria
Authors: Slack Sally D , Laboi Paul , Howard Martin R , Waise Ahmed A
Published: May 2009

The aetiology of haemolytic disease is diverse and the diagnosis often relies on laboratory testing. We describe a case of intravascular haemolysis, which illustrates that significant intravascular haemolysis can occur in the absence of any abnormal haematological findings. Despite gross haemoglobinuria at presentation, the haemoglobin and reticulocyte counts were both within reference limits and a normal blood film was observed. Subsequently, acute tubular necrosis occurred secondary to haemolysis, and acute renal failure was evident by day 2. However, the haemoglobin decreased slowly reaching a nadir of 75 g/L on day 6 (reference interval 130–180 g/L). A diagnosis of paroxysmal cold haemoglobinuria secondary to mycoplasma infection was subsequently made. Biochemical analysis was useful in this case to confirm that the gross pigmentation in the samples received could be attributable to intravascular haemolysis.
A double-blind placebo-controlled study to evaluate the effect of progestelle progesterone cream on postmenopausal women
Authors: Benster Beverly , Carey Adam , Wadsworth Fred , Vashisht Arvind , Domoney Claudine , Studd John
Published: May 2009

Objective

To evaluate the effect on climacteric symptoms and quality of life, and the safety of four doses of progestelle progesterone cream administered for 24 weeks to postmenopausal women complaining of moderate to severe menopausal symptoms.

Design

Single-centre, double-blind, randomized, placebo-controlled study.

Population

Two hundred and twenty-three healthy postmenopausal women, aged between 40 and 60 years and complaining of severe menopausal symptoms were recruited through newspaper advertisements.

Methods

Women were randomly allocated to progestelle progesterone cream 60, 40, 20, 5 mg or placebo, to be applied daily for six months.

Main outcome measures

The primary efficacy variable was the psychological, somatic and vasomotor components of the Greene Climacteric Scale after six months. Secondary endpoints were incidence of hot flushes and night sweats, the nine subscales of the Medical Outcome Survey Short Form-36 (SF-36), serum progesterone, endometrial thickness and histology after six months. Adverse events were sought and recorded and followed up to resolution.

Results

There were no statistically significant differences between any of the treatment groups and placebo for any of the components of the Greene Score. A statistically significant difference between the 20 mg group and placebo was found for the physical functioning (95% confidence interval [CI] 1.7–12.3; P = 0.01) and social functioning (95% CI 1.9–16.7; P = 0.01) scales of SF-36 after six months. No other statistically significant differences were found between any treatment group and placebo for any of the other secondary efficacy variables. There appeared to be a higher incidence of headache in the groups treated with progesterone cream.

Conclusions

Progesterone cream was no more effective than placebo for relief of menopausal symptoms.
Ovarian sickling as a proposed mechanism for premature ovarian failure necessitating ovum donation
Authors: Chase A R , Howard J , Oteng-Ntim E
Published: May 2009

Iron overload in female patients with sickle cell disease (SCD) has been reported to result in gonadal dysfunction. To date there has been no report in the literature of ovarian sickling being a reason for gonadodysgenesis (premature ovarian failure [POF]) in women. This case report describes POF in a woman with SCD and suggests ovarian sickling as its cause. We propose that frequent episodes of intravascular sickling, vessel occlusion and infarction as well as tissue hypoxia associated with chronic anaemia could account for the ovarian dysgenesis and hence POF.
Depression and the menopause: why antidepressants are not enough?
Authors: Graziottin Alessandra , Serafini Audrey
Published: May 2009

Background

Gender differences, related to varying sexual hormone levels and hormone secretion patterns across the lifespan, contribute to women's vulnerability to mood disorders and major depression. Women are more prone than men to depression, from puberty onwards, with a specific exposure across the menopausal transition. However, controversy still exists in considering fluctuation/loss of estrogen as a specific aetiologic factor contributing to depression in perimenopause and beyond.

Aims

To briefly review the interaction between changes in menopausal hormone levels, mood disorders, associated neuropsychological co-morbidities and ageing, and to evaluate the currently available therapeutic options for perimenopausal mood disorders: (a) treatment of light to moderate mood disorders with hormonal therapy (HT); (b) treatment of major depression with antidepressants; (c) the synergistic effect between HT and antidepressants in treating menopausal depression.

Results

Depression across the menopause has a multifactorial aetiology. Predictive factors include: previous depressive episodes such as premenstrual syndrome and/or postpartum depression; co-morbidity with major menopausal symptoms, especially hot flashes, nocturnal sweating, insomnia; menopause not treated with HT; major existential stress; elevated body mass index; low socioeconomic level and ethnicity. Postmenopausal depression is more severe, has a more insidious course, is more resistant to conventional antidepressants in comparison with premenopausal women and has better outcomes when antidepressants are combined with HT.

Conclusion

The current evidence contributes to a re-reading of the relationship between menopause and depression. The combination of the antidepressant with HT seems to offer the best therapeutic potential in terms of efficacy, rapidity of improvement and consistency of remission in the follow-up.
Hormonal management of migraine at menopause
Authors: Nappi Rossella E , Sances Grazia , Detaddei Silvia , Ornati Alessandra , Chiovato Luca , Polatti Franco
Published: May 2009

In this review, we underline the importance of linking migraine to reproductive stages for optimal management of such a common disease across the lifespan of women. Menopause has a variable effect on migraine depending on individual vulnerability to neuroendocrine changes induced by estrogen fluctuations and on the length of menopausal transition. Indeed, an association between estrogen ‘milieu’ and attacks of migraine is strongly supported by several lines of evidence. During the perimenopause, it is likely to observe a worsening of migraine, and a tailored hormonal replacement therapy (HRT) to minimize estrogen/progesterone imbalance may be effective. In the natural menopause, women experience a more favourable course of migraine in comparison with those who have surgical menopause. When severe climacteric symptoms are present, postmenopausal women may be treated with continuous HRT. Even tibolone may be useful when analgesic overuse is documented. However, the transdermal route of oestradiol administration in the lowest effective dose should be preferred to avoid potential vascular risk.
Testosterone therapy in men
Authors: Theodoraki Aikaterini , Bouloux Pierre-Marc
Published: May 2009

Androgens exert effects on virtually all bodily tissues, and have a multitude of physiological roles in health. Testosterone, the predominant androgen in men, when deficient (hypogonadism), leads to a multiplicity of symptoms and signs that are corrected with physiological substitution. The impact of hypogonadism depends on the age at which it occurs. In any case, when testosterone replacement is initiated close monitoring for efficacy and safety is advised. The relation of ageing, the metabolic syndrome, type 2 diabetes, obesity and survival with plasma testosterone has been closely examined in recent studies. However, the effect of testosterone replacement therapy on the above clinical states needs to be clarified in large long-term duration/outcome studies. Recent research has shed light on possible molecular testosterone targets. Based on those research outcomes, drugs targeting the androgen receptor, which spare androgenic effects and preserve anabolic tissue effects, called selective androgen receptor modulators (SARMS), are under clinical trials. The role of testosterone in regulating erectile function has been studied in animal models and critical tissue testosterone targets have been elucidated.
Evidence-based medicine in obstetrics: can levels B and C recommendations be elevated to level A recommendations?
Authors:   For the Evidenced-Based Medicine Obstetric Group:, Chauhan Suneet P , Chang Eugene , Brost Brian , Assel Barbara , Baxter Jason , Smith James A , Grobman Robert , Berghella Vincenzo , Scardo James A , Magann Everett F , Morrison John C
Published: May 2009

In this study, 65% (132/195) of level B/C obstetric recommendations are amenable to randomized clinical trials (RCTs) and seven were identified as most needed. The purpose of the survey was to evaluate levels B and C recommendations in obstetric practice bulletins (PBs) regarding the feasibility of performing RCT to elevate each subject to level A evidence. Eleven geographically dispersed physicians with experience in research reviewed levels B and C recommendations for the ethical and logistical feasibility of performing an RCT. In the 35 obstetric PBs, 195 level B/C recommendations were reviewed. The majority considered 47 (24%) topics unethical for an RCT and thought 16 (11%) did not need an RCT, thus leaving 132 (67%) levels B and C recommendations available for an RCT. Two-thirds of levels B and C recommendations in obstetric PB are amenable to RCTs and potentially becoming level A evidence.
Dicer independent small RNAs associate with telomeric heterochromatin
Authors: Cao Fang , Li Xiangzhi , Hiew Samantha , Brady Hugh , Liu Yifan , Dou Yali
Published: May 2009

Small RNAs play important roles in the establishment and maintenance of heterochromatin structures. We show the presence of telomere specific small RNAs (tel-sRNAs) in mouse embryonic stem cells that are ∼24 nucleotides in length, Dicer-independent, and 2′-O-methylated at the 3′ terminus. The tel-sRNAs are asymmetric with specificity toward telomere G-rich strand, and evolutionarily conserved from protozoan to mammalian cells. Furthermore, tel-sRNAs are up-regulated in cells that carry null mutation of H3K4 methyltransferase MLL (Mll(−/−)) and down-regulated in cells that carry null mutations of histone H3K9 methyltransferase SUV39H (Suv39h1/h2(−/−)), suggesting that they are subject to epigenetic regulation. These results support that tel-sRNAs are heterochromatin associated pi-like small RNAs.
Characterization of the Schizosaccharomyces pombe Spt5-Spt4 complex
Authors: Schwer Beate , Schneider Susanne , Pei Yi , Aronova Anna , Shuman Stewart
Published: May 2009

The Spt5-Spt4 complex regulates early transcription elongation by RNA polymerase II and has an imputed role in pre-mRNA processing via its physical association with mRNA capping enzymes. Here we characterize the Schizosaccharomyces pombe core Spt5-Spt4 complex as a heterodimer and map a trypsin-resistant Spt4-binding domain within the Spt5 subunit. A genetic analysis of Spt4 in S. pombe revealed it to be inessential for growth at 25°C–30°C but critical at 37°C. These results echo the conditional spt4Δ growth phenotype in budding yeast, where we find that Saccharomyces cerevisiae and S. pombe Spt4 are functionally interchangeable. Complementation of S. cerevisiae spt4Δ and a two-hybrid assay for Spt4-Spt5 interaction provided a readout of the effects of 33 missense and truncation mutations on S. pombe Spt4 function in vivo, which were interpreted in light of the recent crystal structure of S. cerevisiae Spt4 fused to a fragment of Spt5. Our results highlight the importance of the Spt4 Zn2+-binding residues—Cys12, Cys15, Cys29, and Asp32—and of Ser57, a conserved constituent of the Spt4-Spt5 interface. The 990-amino acid S. pombe Spt5 protein has an exceptionally regular carboxyl-terminal domain (CTD) composed of 18 nonapeptide repeats. We find that as few as three nonamer repeats sufficed for S. pombe growth, but only when Spt4 was present. Synthetic lethality of the spt51-835spt4Δ double mutant at 34°C suggests that interaction of Spt4 with the central domain of Spt5 overlaps functionally with the Spt5 CTD.
Uncertainty, Risk Aversion, and WTA vs. WTP
Authors: Okada Erica Mina
Published: May 2009

We examine a previously unstudied category of exchange items in which the true value is unknown to both the buyer and seller at the time of exchange but becomes known to both at a future time after the exchange. Real-world examples of such exchange items as in our study include forward contracts and fixed-fee turnkey contracts. We demonstrate that the discrepancy between the seller's willingness to accept (WTA) and buyer's willingness to pay (WTP) increases with (1) the level of uncertainty about the exchange item's value and (2) the exchange parties' level of risk aversion. In a series of studies, we manipulate and measure the level of uncertainty of the exchange item, measure the level of risk aversion of the exchange parties, and study the respective effects on decreasing the WTP while increasing the WTA.
Practice Prize Winner—Pricing Digital Content Product Lines: A Model and Application for the National Academies Press
Authors: Kannan P. K. , Pope Barbara Kline , Jain Sanjay
Published: May 2009

We examine the problem of how a content provider, specifically the National Academies Press (NAP), can optimally price the different forms of its product—print and PDF—that it sells online. Whereas products in the traditional product line generally tend to be substitutes, the different content product forms could range from being substitutes to being complements across customers. Thus the content provider can possibly sell bundles of the product forms, leading to additional revenue. We first discuss NAP's decision context and describe the model we proposed for developing NAP's optimal pricing policies for its different forms. We describe the choice experiment we conducted on the publisher's website that maximally uses the online interface to collect relevant data needed to estimate our model. We show how NAP embraced the results from the model for developing a new business model and how it used the insights derived from the study to set pricing policies and monitor sales performance as a function of pricing. Finally, we perform validation of the model and the implemented policies using dynamic modeling of sales data from NAP's website. The paper illustrates how e-commerce technologies can lead to the development of optimal policies using marketing models.
Anticoagulation: Low-Molecular-Weight Heparins in Renal Impairment and Obesity: Available Evidence and Clinical Practice Recommendations Across Medical and Surgical Settings
Authors: Nutescu Edith A , Spinier Sarah A , Wittkowsky Ann , Dager William E
Published: May 2009

Objective

To develop practical recommendations for the use of low-molecular-weight heparins (LMWHs) as prophylaxis and treatment of venous thromboembolism and acute coronary syndromes in patients with impaired renal function or obesity.

Data Sources

Multiple MEDLINE searches were performed (November 2008) to identify studies for inclusion, using a comprehensive list of search terms including, but not limited to, LMWH, enoxaparin, dalteparin, tinzaparin, obesity, weight, renal, kidney, elderly, monitoring, and anti-Xa.

Study Selection And Data Extraction

Only articles published in English that were relevant for this review were included.

Data Synthesis

In the majority of patients, standardized prophylaxis or treatment doses of LMWHs can be used without the need for monitoring and adjusting regimens. For patients with severe renal impairment (estimated creatinine clearance [CrCl] <30 mL/min), doses of some LMWHs should be adjusted or unfractionated heparin should be used instead. CrCl should be estimated using the Cockcroft-Gault method. Differences are noted in the degree of accumulation of various LMWHs in patients with moderate-to-severe renal impairment, and thus, the degree of dose adjustment may differ among the various LMWHs. Increasing the prophylactic doses of LMWH may be appropriate in morbidly obese patients (body mass index ≥40 kg/m2). The use of total body weight is appropriate for therapeutic doses of LMWH in obese patients. Laboratory monitoring of the anticoagulation effect of LMWHs is generally not necessary, but should be considered in patients with morbid obesity (weight >190 kg), those with severe renal impairment, and those with moderate renal impairment with prolonged (>10 days) LMWH use. When anti-Xa activity is monitored, it should be determined using a chromogenic method and a calibration curve based on the LMWH used.

Conclusions

Additional data are needed for specific dose guiding in obese and renally impaired patients, who are often excluded from larger clinical trials. Practice recommendations are made based on available evidence and authors' clinical opinions.
The transformation of synthetic hectorite in the presence of Cu(II)
Authors: Fischer Håkon , Weidler Peter G. , Grobéty Bernard , Luster Jörg , Gehring Andreas U.
Published: May 2009

The influence of Cu(II) on the hydrothermal and thermal transformations of a synthetic hectorite was investigated by a combined approach using mainly X-ray diffraction, thermal analyses, and electron paramagnetic resonance spectroscopy. The presence of Cu(II) during hydrothermal treatment increased the crystallite size. Copper (II) was both structure-bound and associated with the inner surfaces of the particles. Upon heating, structural destabilization of the hectorite began at ∼400°C as indicated by the formation of free radicals. Between 600 and 700°C, the hectorite converted to enstatite, and in the presence of Cu(II), to enstatite and richterite. The formation of richterite as an additional conversion product is explained by the creation of structural weakness due to structure-bound Cu(II) in F-containing hectorite. Our results suggest that traces of Cu(II), typical of natural environments, may influence the conversion products in high-temperature geochemical systems.
Mineralogical and physicochemical investigation of Mg-smectite from Jbel Ghassoul, Morocco
Authors: Benhammou Abdelaziz , Tanouti Boumediene , Nibou Lahbib , Yaacoubi Abdelrani , Bonnet Jean-Pierre
Published: May 2009

‘Ghassoul’ clay is a Mg-rich clay from Morocco which is of great industrial use and interest, but its characterization is still incomplete. The purpose of this study was to provide further details regarding the structure and characteristics of this important commercial clay mineral. Mineralogical and physicochemical characterizations of the raw form of ‘Ghassoul’ clay from Jbel Ghassoul in Morocco, and of its <2 µm size fraction, purified and Na+-saturated, were carried out using X-ray diffraction (XRD), X-ray fluorescence (XRF), infrared spectroscopy (IR), and differential and thermogravimetric analysis (DTA/TG). The XRD data revealed that the raw Ghassoul clay consists mainly of a Mg-rich trioctahedral smectite, stevensite, together with quartz and dolomite. The IR spectra consisted of vibrations typical of trioctahedral smectites. The DTA/TG curves were also similar to those of trioctahedral smectites. Chemical analysis confirms that this Mg-rich trioctahedral smectite is a stevensite characterized by a limited isomorphic substitution of Si4+ by Al3+. The thermal transformations examined by in situ XRD as a function of the firing temperature from 100 to 1200°C indicated that stevensite was transformed to enstatite (MgSiO3) at temperatures >800°C and that quartz was transformed to cristobalite when the temperature exceeded 1100°C. These transformations were irreversible. The specific surface area and cation exchange capacity (CEC) of the ‘Ghassoul’ clay are 133 m2/g and 75 meq/100 g, respectively. The main exchangeable cation is Mg2+ (53 meq/100 g).
Associations between psychopathic traits and mental disorders among adolescents with substance use problems
Authors: Hemphälä Malin , Tengström Anders
Published: May 2009

Objectives. The aim of this study was to examine the association between psychopathic traits and mental disorders and to study associations between psychopathic traits and familial problems across gender.

Design. This is a cross‐sectional study.

Methods. One hundred and Eighty adolescents seeking help at a substance abuse treatment clinic (99 girls, 81 boys) and their parents (165 mothers, 90 fathers) were studied. The assessment included Psychopathy checklist: Youth version (PCL‐YV) and SCID I/II or Kiddie‐Sads‐Present and Lifetime Version (K‐SADS‐PL).

Results. Across gender, there was a positive correlation between externalizing symptoms and PCL‐YV score. Among boys, there was a positive correlation between internalizing symptoms and PCL‐YV score. Further, the behavioural dimension of psychopathy was predictive of externalizing symptoms across gender. The interpersonal and affective dimension of psychopathy predicted oppositional defiant disorder (ODD)‐symptoms among girls. Parent problem behaviour predicted PCL‐YV score amongst girls only.

Conclusions. Psychopathic traits do not only exist among adolescents who are identified because of their criminal behaviour. There were gender differences in the association between symptoms and psychopathic traits. It is suggested that different dimensions of psychopathy predisposed substance use for girls and for boys, and that ODD is particularly important in the expression of psychopathic traits among girls. This study showed transmission of antisocial behaviour between two generations among girls.
Early Research on Human Genetics Using the Twin Method: Who Really Invented the Method?
Authors: Mayo Oliver
Published: May 2009

The twin method consists of a formal comparison between the resemblance between identical (monozygotic, MZ) twins and the resemblance between fraternal (dizygotic, DZ) twins for some trait of interest. It was developed between 1900 and about 1940, as more accurate tools for diagnosis of zygosity and for statistically analyzing the resemblance between relatives were built. Its early use was in the demonstration that a trait was inherited or that part of the causation of a trait was genetical, but it has now evolved to the point that twin registries constitute an important resource for the identification of specific genes and their interactions both with other genes and with the internal and external environment. Who really invented the method is still an unsettled question, which this article explores.
Genetic Dominance Influences Blood Biomarker Levels in a Sample of 12,000 Swedish Elderly Twins
Authors: Rahman Iffat , Bennet Anna M. , Pedersen Nancy L. , de Faire Ulf , Svensson Per , Magnusson Patrik K. E.
Published: May 2009

In twin studies of cardiovascular disease biomarkers the dizygotic correlations are often estimated to be less than half of monozygotic correlations indicating a potential influence of nonadditive genetic factors. Using a large and homogenous sample, we estimated the additive and dominance genetic influences on levels of high density lipoprotein, low density lipoprotein, apolipoprotein A-I, apolipoprotein B, total cholesterol, triglycerides, glucose, hemoglobin Alc and c-reactive protein, all of which are biomarkers associated with cardiovascular disease. The blood biomarkers were measured on 12,000 Swedish twins born between 1911 and 1958. The large sample allowed us to obtain heritability estimates with considerable precision and provided adequate statistical power for estimation of dominance genetic components. Our study showed complete absence of the shared environment component for the investigated traits. Dominant genetic component was shown to be significant for low density lipoprotein (0.18), glucose (0.31), Hemoglobin Alc (0.55), and c-reactive protein (0.27). To our knowledge, this is the first statistically significant evidence for dominance genetic variance found for low density lipoprotein, glucose, hemoglobin Alc, and c-reactive protein in a population based twin sample. The study highlights the importance of acknowledging nonadditive genes underlying the risk of developing cardiovascular diseases.
ZMPSTE24, an integral membrane zinc metalloprotease with a connection to progeroid disorders
Authors: Barrowman Jemima , Michaelis Susan
Published: May 2009

ZMPSTE24 is an integral membrane zinc metalloprotease originally discovered in yeast as an enzyme (called Ste24p) required for maturation of the mating pheromone a-factor. Surprisingly, ZMPSTE24 has recently emerged as a key protease involved in human progeroid disorders. ZMPSTE24 has only one identified mammalian substrate, the precursor of the nuclear scaffold protein lamin A. ZMPSTE24 performs a critical endoproteolytic cleavage step that removes the hydrophobic farnesyl-modified tail of prelamin A. Failure to do so has drastic consequences for human health and longevity. Here, we discuss the discovery of the yeast and mammalian ZMPSTE24 orthologs and review the unexpected connection between ZMPSTE24 and premature aging.
Cross talk between kinin and angiotensin II receptors in mouse abdominal aorta
Authors: Rodrigues Eliete S. , Martin Renan P. , Felipe Sandra A. , Bader Michael , Oliveira Suzana M. , Shimuta Suma I.
Published: May 2009

Bradykinin (BK) is a vasorelaxant, algesic and inflammatory agent. Angiotensin II (AngII) is known to control vascular tone and promote growth, inflammation and artherogenesis. There is evidence for cross talking between BK and AngII receptors. Therefore, the effect of lack of kinin receptors was assessed in mice with genetic disruption of B1or B2and both receptors. Responsiveness of abdominal aortic rings to BK and AngII as well as the receptor gene expression of both peptides were analysed. Although no specific phenotype was displayed in the normotensive and healthy mice lacking the kinin receptors, a decreased expression level of the remaining kinin receptor mRNA was observed. AT1receptor mRNA level was also reduced, indicating that kinin receptors regulate AngII receptors. Downregulation of the receptors was well correlated with reduction in the reactivity of both agonists to induce contraction of aortic rings, but other signal regulations must be sought in these transgenic mice. We conclude that cross talk between kinin and AngII receptors occurs in mouse abdominal aorta and that both peptides may regulate the initiation and progression of important pathophysiological processes, such as hypertension and inflammation.
NMR and EPR studies of membrane transporters
Authors: Hellmich Ute A. , Glaubitz Clemens
Published: May 2009

In order to fulfill their function, membrane transport proteins have to cycle through a number of conformational and/or energetic states. Thus, understanding the role of conformational dynamics seems to be the key for elucidation of the functional mechanism of these proteins. However, membrane proteins in general are often difficult to express heterologously and in sufficient amounts for structural studies. It is especially challenging to trap a stable energy minimum, e.g., for crystallographic analysis. Furthermore, crystallization is often only possible by subjecting the protein to conditions that do not resemble its native environment and crystals can only be snapshots of selected conformational states. Nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopy are complementary methods that offer unique possibilities for studying membrane proteins in their natural membrane environment and for investigating functional conformational changes, lipid interactions, substrate-lipid and substrate-protein interactions, oligomerization states and overall dynamics of membrane transporters. Here, we review recent progress in the field including studies from primary and secondary active transporters.
Structural and functional aspects of the multidrug efflux pump AcrB
Authors: Eicher Thomas , Brandstätter Lorenz , Pos Klaas M.
Published: May 2009

The tripartite efflux system AcrA/AcrB/TolC is the main pump in Escherichia coli for the efflux of multiple antibiotics, dyes, bile salts and detergents. The inner membrane component AcrB is central to substrate recognition and energy transduction and acts as a proton/drug antiporter. Recent structural studies show that homotrimeric AcrB can adopt different monomer conformations representing consecutive states in an allosteric functional rotation transport cycle. The conformational changes create an alternate access drug transport tunnel including a hydrophobic substrate binding pocket in one of the cycle intermediates.
Pharmacological inhibitors to identify roles of cathepsin K in cell-based studies: a comparison of available tools
Authors: Desmarais Sylvie , Massé Frédéric , Percival M. David
Published: May 2009

Cathepsin K (Cat K) degrades bone type I collagen and is a target for the pharmacological treatment of osteoporosis. Further roles for Cat K have been recently described, some of which are supported by the use of purportedly selective Cat K inhibitors in human and rodent cell-based assays. Twelve commercial and non-commercial Cat K inhibitors were profiled against a panel of purified human, rat, and mouse cysteine cathepsins and in two cell-based enzyme occupancy assays for activity against Cat K, B, and L. Ten inhibitors, including the carbohydrazide Cat K inhibitor II (Boc-Phe-Leu-NHNH-CO-NHNH-Leu-Z), the non-covalent K4b, and the epoxide NC-2300, have either little Cat K selectivity, or appear poorly cell penetrant. The amino-acetonitrile-containing inhibitors L-873724 and odanacatib show greater than 100-fold human Cat K enzyme selectivity and have similar IC50 values against each cathepsin in cell-based and enzyme assays. The basic inhibitor balicatib has greater cellular potencies than expected on the basis of purified enzyme assays. The accumulation of [14C]-balicatib in fibroblasts is blocked by prior treatment of the cells with NH4Cl, consistent with balicatib having lysosomotropic properties. These results support the use of L-873724 and odanacatib as tools to identify novel roles for Cat K using human cell-based systems, but suggest using caution in the interpretation of studies employing the other compounds.
Renshaw Cell Recurrent Inhibition Improves Physiological Tremor by Reducing Corticomuscular Coupling at 10 Hz
Authors: Williams Elizabeth R. , Baker Stuart N.
Published: May 2009

Corticomuscular coherence between the primary motor cortex (M1) and hand muscle electromyograms (EMG) occurs at ∼20 Hz but is rarely seen at ∼10 Hz. This is unexpected, because M1 has oscillations at both frequencies, which are effectively transmitted to the spinal cord via the corticospinal tract. We have previously speculated that a specific “neural filter” may selectively reduce coherence at ∼10 Hz. This would have functional utility in minimizing physiological tremor, which often has a dominant component around this frequency. Recurrent inhibition via Renshaw cells in the spinal cord is a putative neural substrate for such a filter. Here we investigate this system in more detail with a biophysically based computational model. Renshaw cell recurrent inhibition reduced EMG oscillations at ∼10 Hz, and also reduced corticomuscular coherence at this frequency (from 0.038 to 0.014). Renshaw cell inhibitory feedback also generated synchronous oscillations in the motoneuron pool at ∼30 Hz. We show that the effects at 10 Hz and 30 Hz can both be understood from the dynamics of the inhibitory feedback loop. We conclude that recurrent inhibition certainly plays an important role in reducing 10 Hz oscillations in muscle, thereby decreasing tremor amplitude. However, our quantitative results suggest it is unlikely to be the only system for tremor reduction, and probably acts in concert with other neural circuits which remain to be elucidated.
The Role of Neurotrophins in the Seasonal-Like Growth of the Avian Song Control System
Authors: Wissman Anne Marie , Brenowitz Eliot A.
Published: May 2009

The avian song control system undergoes pronounced seasonal plasticity in response to photoperiod and hormonal cues. The action of testosterone (T) and its metabolites in the song nucleus HVC is both necessary and sufficient to promote breeding season-like growth of its efferent nuclei RA (robust nucleus of the arcopallium) and Area X, suggesting that HVC may release a trophic factor such as brain-derived neurotrophic factor (BDNF) into RA and X. BDNF is involved in many forms of adult neural plasticity in other systems and is present in the avian song system. We used a combination ofin situhybridization and intracerebral infusions to test whether BDNF plays a role in the seasonal-like growth of the song system in adult male white-crowned sparrows. BDNF mRNA levels increased in HVC in response to breeding conditions, and BDNF infusion into RA was sufficient to promote breeding-like changes in somatic area and neuronal density. Expression of the mRNA for the Trk B receptor of BDNF, however, did not vary with seasonal conditions in either HVC or RA. Local blockade of BDNF activity in RA via infusion of Trk-Fc fusion proteins inhibited the response to breeding conditions. Our results indicate that BDNF is sufficient to promote the seasonal plasticity in somatic area and cell density in RA, although NT-3 may also contribute to this process, and suggest that HVC may be a presynaptic source of increased levels of BDNF in RA of breeding-condition birds.
PHR Regulates Growth Cone Pausing at Intermediate Targets through Microtubule Disassembly
Authors: Hendricks Michael , Jesuthasan Suresh
Published: May 2009

Axonal growth cones use intermediate targets to navigate in the developing nervous system. Encountering these sites is correlated with growth cone pausing. PHR (Phr1, Esrom, Highwire, RPM-1) is a large neuronal ubiquitin ligase that interacts with multiple signaling pathways. Mouse and zebrafishphrmutants have highly penetrant axon pathfinding defects at intermediate targets. Mousephrmutants contain excessive microtubules in the growth cone, which has been attributed to upregulation of DLK/p38 signaling. Here, we ask whether this pathway and microtubule misregulation are indeed linked to guidance errors in the vertebrate brain, using the zebrafish. By live imaging, we show that loops form when microtubules retract without depolymerizing. JNK, but not p38, phosphorylation is increased in mutant growth cones. However microtubule looping cannot be suppressed by inhibiting JNK. Thephrmicrotubule defect can be phenocopied by taxol, while microtubule destabilizationin vitrousing nocodazole prevents loop formation. Acute disruptionin vivowith nocodazole suppresses the intermediate target guidance defect. Given that microtubule looping is associated with growth cone pausing, we propose that microtubule disassembly, mediated by PHR, is essential for exiting the paused state at intermediate targets.