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B cell chronic lymphocytic leukemia constitutes a third of grownup leukemic malignancies, with an age adjusted incidence price of 4. two per a hundred 000 guys and ladies per year in the United States. Approximately 15 000 new situations of chronic lymphocytic leukemia are diagnosed each and every yearin the United States, with similar prices in Europe.

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The primary evaluation of effi cacy was based mostly on the assessments of response and illness progression for every affected person by the independent response assessment panel, members of which had been masked to remedy assignment. Response requirements and progression had been assessed according to the Nationwide Cancer Institute Doing work Groups 1996 recommendations for CLL, requirements for illness progression had been specifi ed in the research protocol and had been in accordance with these recommendations. eight The wellness relevant top quality of life instrument was a fi vedimensional query naire about wellness status and a visual analogue scale thermometer for self rating recent wellness relevant top quality of life. The fi ve dimensions had been mobility, self care, typical activities, ache or discomfort, and anxiousness or depression, rated according to three feasible levels.

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The major examination of effi cacy was based mostly on the assessments of response and condition progression for every single affected person by the independent response evaluation panel, members of which have been masked to treatment method assignment. Response requirements and progression have been assessed according to the Nationwide Cancer Institute Working Groups 1996 recommendations for CLL, requirements for condition progression have been specifi ed in the examine protocol and have been in accordance with these recommendations. eight The wellness associated top quality of life instrument was a fi vedimensional question naire about wellness standing and a visual analogue scale thermometer for self rating existing wellness associated top quality of life.

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The quantity of CD4 CD25bright T cells infused with the graft is not identified. Cyclosporine A, which experienced been employed to treat symptoms, was continued for graft vs. host illness prophylaxis. Palifermin was administered every day for three times previous to the begin of the preparative program and three times immediately after the stem cell infusion for mucositis prevention and gastrointestinal protection.

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Probably the most generally reported AEs in any pa tients handled with asenapine integrated insomnia, seda tion, depression, headache, somnolence, elevated excess weight, dizziness, nausea, and akathisia.

The asenapine therapy group of AEs compared with Entinostat

Over 90% of sufferers who remained within the asenapine arm via three weeks maintained the beginning dosage of ten mg BID. The prices of utilization of con present medicines had been comparable in all three therapy arms. Tolerability. Asenapine and olanzapine had been asso ciated with prevalences of treatmentrelated AEs of 60. 8% and 52. 9%,

Hydrogen sulfide regulates cardiac sarcoplasmic reticulum Ca(2+) uptake via K(ATP) channel and PI3K/Akt pathway.

Hydrogen sulfide regulates cardiac sarcoplasmic reticulum Ca(2+) uptake via K(ATP) channel and PI3K/Akt pathway.

Life Sci. 2012 Aug 2;

Authors: Chen Y, Zhao J, Du J, Xu G, Tang C, Geng B

Abstract
AIMS: To investigate the effects of hydrogen sulfide (H(2)S) on calcium uptake activity of the rat cardiac sarcoplasmic reticulum (SR) and possible signaling. MAIN METHODS: Crude SR was isolated after treatment with H(2)S, then SR Ca(2+) uptake and SR Ca(2+)-ATPase (SERCA) activity was measured by the isotopic tracer method. The possible roles of the K(ATP) channel and PI3K/Akt and SR-membrane protein phospholamban (PLB) pathway were analyzed by specific blockers, and target protein activation was assayed by measuring protein phosphorylation. KEY FINDINGS: Exogenous H(2)S lowered Ca(2+) uptake into the SR time or concentration dependently, which was associated with decreased SERCA activity. Inhibiting endogenous H(2)S production by DL-propargylglycine increased SR Ca(2+) uptake and SERCA activity. H(2)S inhibition of PLB phosphorylation was through SERCA activity and was reversed by two PI3K inhibitors, wortmannin and LY294002. Glibenclamide (a K(ATP) channel blocker) blocked the inhibitory effects of H(2)S on PLB and Akt phosphorylation. Pinacidil (a K(ATP) channel opener) reduced the phosphorylation of PLB and reversed the effects of DL-propargylglycine. H(2)S preconditioning increased PLB phosphorylation but did not affect SERCA activity. SIGNIFICANCE: Endogenous H(2)S transiently and reversibly inhibits SR Ca(2+) uptake in rat heart SR because of downregulated SERCA activity associated with PLB phosphorylation by the PI3K/Akt or K(ATP) channel. The transient negative regulation of SR Ca(2+) uptake and the L-type Ca(2+) channel contributes to Ca(2+) cycle homeostasis, which might be an important molecular mechanism in ischemic diseases.

PMID: 22884808 [PubMed - as supplied by publisher]

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Biased clique shuffling reveals stabilizing mutations in cellulase Cel7A.

Biased clique shuffling reveals stabilizing mutations in cellulase Cel7A.

Biotechnol Bioeng. 2012 Aug 10;

Authors: Dana CM, Saija P, Kal SM, Bryan MB, Blanch HW, Clark DS

Abstract
Renewable fuels produced from biomass-derived sugars are receiving increasing attention. Lignocellulose-degrading enzymes derived from fungi are attractive for saccharification of biomass because they can be produced at higher titers and at significantly less cost than those produced by bacteria or archaea. However, their properties can be suboptimal; for example, they are subject to product inhibition and are sensitive to small changes in pH. Furthermore, increased thermostability would be advantageous for saccharification as increased temperature may reduce the opportunity for microbial contamination. We have developed a mutagenesis platform to improve these properties and applied it to increase the operating temperature and thermostability of the fungal glycosyl hydrolase Cel7A. Secretion of Cel7A at titers of 26 mg/L with limited hyperglycosylation was achieved using a Saccharomyces cerevisiae strain with upregulated protein disulfide isomerase, an engineered ?-factor prepro leader, and deletion of a plasma membrane ATPase. Using biased clique shuffling (BCS) of eleven Cel7A genes, we generated a small library (469) rich in activity (86% of the chimeras were active) and identified 51 chimeras with improved thermostability, many of which contained mutations in the loop networks that extend over the enzyme's active site. This BCS library was far superior as a source of active and stable chimeras compared to an equimolar library prepared from the same eleven genes. Biotechnol. Bioeng. � 2012 Wiley Periodicals, Inc.

PMID: 22887329 [PubMed - as supplied by publisher]

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Clinical utility, safety, and tolerability of ezogabine (retigabine) in the treatment of epilepsy.

Clinical utility, safety, and tolerability of ezogabine (retigabine) in the treatment of epilepsy.

Drug Healthc Patient Saf. 2012;4:81-86

Authors: Ciliberto MA, Weisenberg JL, Wong M

Abstract
One-third of patients with epilepsy continue to have seizures despite current treatments, indicating the need for better antiseizure medications with novel mechanisms of action. Ezogabine (retigabine) has recently been approved for adjunctive treatment of partial-onset seizures in adult patients with epilepsy. Ezogabine utilizes a novel mechanism of action, involving activation of specific potassium channels. The most common side effects of ezogabine are shared by most antiseizure medications and primarily consist of central nervous system (CNS) symptoms, such as somnolence, dizziness, confusion, and fatigue. In addition, a small percentage of patients on ezogabine experience a unique adverse effect affecting the bladder, which results in urinary hesitancy; thus, patients on ezogabine should be monitored carefully for potential urological symptoms. Overall, ezogabine appears to be well tolerated and represents a reasonable new option for treating patients with intractable epilepsy.

PMID: 22888276 [PubMed - as supplied by publisher]

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A Serial Sample Loading System: Interfacing Multiwell Plates with Microfluidic Devices.

A Serial Sample Loading System: Interfacing Multiwell Plates with Microfluidic Devices.

J Lab Autom. 2012 Aug 10;

Authors: Rane TD, Zec HC, Wang TH

Abstract
There is an increasing demand for novel high-throughput screening (HTS) technologies in the pharmaceutical and biotechnological industries. The robotic sample-handling techniques currently used in these industries, although fast, are still limited to operating in multiwell plates with the sample volumes per reaction in the microliter regime. Digital microfluidics offers an alternative for reduction in sample volume consumption for HTS but lacks a reliable technique for transporting a large number of samples to the microfluidic device. In this report, we develop a technique for serial delivery of sample arrays to a microfluidic device from multiwell plates, through a single sample inlet. Under this approach, a serial array of sample plugs, separated by an immiscible carrier fluid, is loaded into a capillary and delivered to a microfluidic device. Similar approaches have been attempted in the past, however, either with a slower sample loading device such as a syringe pump or vacuum-based sample loading with limited driving pressure. We demonstrated the application of our positive-pressure-based serial sample loading (SSL) system to load a series of sample plugs into a capillary. The adaptability of the SSL system to generate sample plugs with a variety of volumes in a predictable manner was also demonstrated.

PMID: 22885789 [PubMed - as supplied by publisher]

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Alteration of complement hemolytic activity in different trauma and sepsis models.

Alteration of complement hemolytic activity in different trauma and sepsis models.

J Inflamm Res. 2012;5:59-66

Authors: Ehrnthaller C, Amara U, Weckbach S, Kalbitz M, Huber-Lang M, Bahrami S

Abstract
Complement activation is involved in various diseases in which innate immunity plays a crucial role. However, its pathophysiological relevance is not clearly understood. Experimental models have been widely used to characterize the role of complement activation under different pathological conditions, such as hypoxemia, ischemia and reperfusion, tissue damage, and polymicrobial invasion. Screening of the complement status and function is, however, strongly dependent on the laboratory-specific techniques being used to sample and measure complement, making it difficult to compare the results found in different laboratories. Therefore, we evaluated complement function by measuring complement hemolytic activity (CH50) in various animal models of isolated ischemia reperfusion (I/R: kidney, liver, gut), hemorrhagic traumatic shock (HTS), endotoxic shock (LPS), and sepsis (CLP). Complement activation was less pronounced in isolated models of ischemia and reperfusion, whereas a strong complement response was observed early after HTS, CLP, and LPS. In summary, CH50 is a well-established, quick, and cost-effective screening method of complement function. However, because we obtained different results in clinically relevant animal models, further differentiation using specific complement factor analysis is necessary.

PMID: 22879778 [PubMed - as supplied by publisher]

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Cell surface expression of hERG channels is regulated by caveolin-3 via Nedd4-2.

Cell surface expression of hERG channels is regulated by caveolin-3 via Nedd4-2.

J Biol Chem. 2012 Aug 9;

Authors: Guo J, Wang T, Li X, Shallow H, Yang T, Li W, Xu J, Fridman MD, Yang X, Zhang S

Abstract
The human ether-a-go-go-related gene (hERG) encodes the rapidly activating delayed rectifier potassium channel (I(Kr)) which plays an important role in cardiac repolarization. A reduction or increase in hERG current can cause long or short QT syndrome, respectively, leading to fatal cardiac arrhythmias. The channel density in the plasma membrane is a key determinant of the whole cell current amplitude. To gain insight into the molecular mechanisms for the regulation of hERG density at the plasma membrane, we used whole-cell voltage clamp, Western blot, and immunocytochemistry methods to investigated the effects of an integral membrane protein, caveolin 3 (Cav3) on hERG expression levels. Our data demonstrate that Cav3, hERG and ubiquitin-ligase Nedd4-2 interact with each other and form a complex. Expression of Cav3 thus enhances hERG-Nedd4-2 interaction, leading to an increased ubiquitination and degradation of mature hERG channels expressed in the plasma membrane. Disrupting Nedd4-2 interaction with hERG by mutations eliminates Cav3 effects on hERG channels. Knockdown of endogenous Cav3 or Nedd4-2 in cultured neonatal rat ventricular myocytes via siRNA led to an increase in native I(Kr). Our data indicate that hERG expression in the plasma membrane is regulated by Cav3 via Nedd4-2. These findings extend our understanding of the regulation of hERG channels and cardiac electrophysiology.

PMID: 22879586 [PubMed - as supplied by publisher]

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Targeted Deletion of Kcne2 Impairs HCN Channel Function in Mouse Thalamocortical Circuits.

Targeted Deletion of Kcne2 Impairs HCN Channel Function in Mouse Thalamocortical Circuits.

PLoS One. 2012;7(8):e42756

Authors: Ying SW, Kanda VA, Hu Z, Purtell K, King EC, Abbott GW, Goldstein PA

Abstract
BACKGROUND: Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels generate the pacemaking current, I(h), which regulates neuronal excitability, burst firing activity, rhythmogenesis, and synaptic integration. The physiological consequence of HCN activation depends on regulation of channel gating by endogenous modulators and stabilization of the channel complex formed by principal and ancillary subunits. KCNE2 is a voltage-gated potassium channel ancillary subunit that also regulates heterologously expressed HCN channels; whether KCNE2 regulates neuronal HCN channel function is unknown.
METHODOLOGY/PRINCIPAL FINDINGS: We investigated the effects of Kcne2 gene deletion on I(h) properties and excitability in ventrobasal (VB) and cortical layer 6 pyramidal neurons using brain slices prepared from Kcne2(+/+) and Kcne2(-/-) mice. Kcne2 deletion shifted the voltage-dependence of I(h) activation to more hyperpolarized potentials, slowed gating kinetics, and decreased I(h) density. Kcne2 deletion was associated with a reduction in whole-brain expression of both HCN1 and HCN2 (but not HCN4), although co-immunoprecipitation from whole-brain lysates failed to detect interaction of KCNE2 with HCN1 or 2. Kcne2 deletion also increased input resistance and temporal summation of subthreshold voltage responses; this increased intrinsic excitability enhanced burst firing in response to 4-aminopyridine. Burst duration increased in corticothalamic, but not thalamocortical, neurons, suggesting enhanced cortical excitatory input to the thalamus; such augmented excitability did not result from changes in glutamate release machinery since miniature EPSC frequency was unaltered in Kcne2(-/-) neurons.
CONCLUSIONS/SIGNIFICANCE: Loss of KCNE2 leads to downregulation of HCN channel function associated with increased excitability in neurons in the cortico-thalamo-cortical loop. Such findings further our understanding of the normal physiology of brain circuitry critically involved in cognition and have implications for our understanding of various disorders of consciousness.

PMID: 22880098 [PubMed - in process]

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Par-1 controls myosin-II activity through myosin phosphatase to regulate border cell migration.

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Par-1 controls myosin-II activity through myosin phosphatase to regulate border cell migration.

Curr Biol. 2012 Mar 6;22(5):363-72

Authors: Majumder P, Aranjuez G, Amick J, McDonald JA

Abstract
BACKGROUND: Localized actomyosin contraction couples with actin polymerization and cell-matrix adhesion to regulate cell protrusions and retract trailing edges of migrating cells. Although many cells migrate in collective groups during tissue morphogenesis, mechanisms that coordinate actomyosin dynamics in collective cell migration are poorly understood. Migration of Drosophila border cells, a genetically tractable model for collective cell migration, requires nonmuscle myosin-II (Myo-II). How Myo-II specifically controls border cell migration and how Myo-II is itself regulated is largely unknown.
RESULTS: We show that Myo-II regulates two essential features of border cell migration: (1) initial detachment of the border cell cluster from the follicular epithelium and (2) the dynamics of cellular protrusions. We further demonstrate that the cell polarity protein Par-1 (MARK), a serine-threonine kinase, regulates the localization and activation of Myo-II in border cells. Par-1 binds to myosin phosphatase and phosphorylates it at a known inactivating site. Par-1 thus promotes phosphorylated myosin regulatory light chain, thereby increasing Myo-II activity. Furthermore, Par-1 localizes to and increases active Myo-II at the cluster rear to promote detachment; in the absence of Par-1, spatially distinct active Myo-II is lost.
CONCLUSIONS: We identify a critical new role for Par-1 kinase: spatiotemporal regulation of Myo-II activity within the border cell cluster through localized inhibition of myosin phosphatase. Polarity proteins such as Par-1, which intrinsically localize, can thus directly modulate the actomyosin dynamics required for border cell detachment and migration. Such a link between polarity proteins and cytoskeletal dynamics may also occur in other collective cell migrations.

PMID: 22326025 [PubMed - indexed for MEDLINE]

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Cell surface expression of hERG channels is regulated by caveolin-3 via Nedd4-2.

Cell surface expression of hERG channels is regulated by caveolin-3 via Nedd4-2.

J Biol Chem. 2012 Aug 9;

Authors: Guo J, Wang T, Li X, Shallow H, Yang T, Li W, Xu J, Fridman MD, Yang X, Zhang S

Abstract
The human ether-a-go-go-related gene (hERG) encodes the rapidly activating delayed rectifier potassium channel (I(Kr)) which plays an important role in cardiac repolarization. A reduction or increase in hERG current can cause long or short QT syndrome, respectively, leading to fatal cardiac arrhythmias. The channel density in the plasma membrane is a key determinant of the whole cell current amplitude. To gain insight into the molecular mechanisms for the regulation of hERG density at the plasma membrane, we used whole-cell voltage clamp, Western blot, and immunocytochemistry methods to investigated the effects of an integral membrane protein, caveolin 3 (Cav3) on hERG expression levels. Our data demonstrate that Cav3, hERG and ubiquitin-ligase Nedd4-2 interact with each other and form a complex. Expression of Cav3 thus enhances hERG-Nedd4-2 interaction, leading to an increased ubiquitination and degradation of mature hERG channels expressed in the plasma membrane. Disrupting Nedd4-2 interaction with hERG by mutations eliminates Cav3 effects on hERG channels. Knockdown of endogenous Cav3 or Nedd4-2 in cultured neonatal rat ventricular myocytes via siRNA led to an increase in native I(Kr). Our data indicate that hERG expression in the plasma membrane is regulated by Cav3 via Nedd4-2. These findings extend our understanding of the regulation of hERG channels and cardiac electrophysiology.

PMID: 22879586 [PubMed - as supplied by publisher]

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Oral administration of collagen tripeptide improves dryness and pruritus in the acetone-induced dry skin model.

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Oral administration of collagen tripeptide improves dryness and pruritus in the acetone-induced dry skin model.
J Dermatol Sci. 2012 May;66(2):136-43
Authors: Okawa T, Yamaguchi Y, Takada S, Sakai Y, Numata N, Nakamura F, Nagashima Y, Ikezawa Z, Aihara M
Abstract
BACKGROUND: Dry skin causes pruritus and discomfort in patients with xerosis and atopic dermatitis. General treatment for skin dryness involves the topical application of an emollient. However, more effective, simpler therapies are desired. Collagen tripeptide (CTP) is a highly purified, non-antigenic, low-allergenic collagen fraction that is known to have various biological effects.
OBJECTIVE: To clarify the therapeutic effects of CTP for dry skin using acetone-induced dry skin model mice.
METHODS: ICR mice were treated with acetone followed by oral administration of CTP (80 or 500mg/kg/day) for 3 days. Hyaluronic acid production induced by CTP was assessed using human dermal fibroblasts in vitro and in an acetone-induced dry skin model mice in vivo. Transepidermal water loss (TEWL) and scratching behavior were evaluated. Furthermore, the effects of CTP on intraepidermal nerve fibers and expression of semaphorin 3A (Sema3A) and nerve growth factor (NGF) were examined by immunohistochemistry and quantitative RT-PCR.
RESULTS: CTP enhanced hyaluronic acid production in human dermal fibroblasts in vitro and in murine skin in vivo. Oral administration of CTP in acetone-induced dry skin model mice significantly decreased TEWL and suppressed scratching behavior. Intraepidermal nerve growth was dramatically inhibited in CTP-treated mice. Quantitative PCR analysis and immunohistochemical study revealed that CTP abolished the increased NGF and decreased Sema3A levels induced by acetone treatment.
CONCLUSION: Oral administration of CTP improves dry skin and normalizes axon-guidance factors in the epidermis in addition to reducing pruritus. CTP may be used in a new therapeutic strategy against dry skin and pruritus.

PMID: 22410290 [PubMed - indexed for MEDLINE]
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Deciphering the role of the ERCC2 gene polymorphism on anticancer drug sensitivity.

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Deciphering the role of the ERCC2 gene polymorphism on anticancer drug sensitivity.

Carcinogenesis. 2012 May;33(5):962-8

Authors: Moisan F, Laroche-Clary A, Auzanneau C, Ricard N, Pourquier P, Robert J, Le Morvan V

Abstract
ERCC2 [Xeroderma pigmentosum (XP) group D] belongs to the nucleotide excision repair pathway. It is also part of the TFIIH transcription complex and is required for the association of the cyclin-dependent kinase (CDK)-activating kinase (CAK) subcomplex with TFIIH. Using the NCI-60 panel of human tumor cell lines, we had shown that the ERCC2 gene variant Gln(751) was significantly associated to increased taxanes sensitivity and decreased ERCC2 gene expression. Since TFIIH is involved in both DNA repair and cell cycle progression, we hypothesized that quantitative or qualitative ERCC2 alterations might cause CAK liberation, allowing its activation of the G(2)/M transition. Enhancing mitosis entry would lead to hypersensitivity to spindle poisons, explaining the effect of ERCC2 polymorphisms on taxane sensitivity. Starting from ERCC2-deficient XP6BE, we generated several isogenic clones differing only by the Lys751Gln variation. Wild-type and variant ERCC2-expressing clones recovered ultraviolet radiation and cisplatin resistance but presented similar sensitivity to paclitaxel, demonstrating that the amino acid change was not involved in paclitaxel differential sensitivity in the NCI-60 panel. Using small interfering RNA approach, we knocked down ERCC2 expression and observed a block in the G(2)/M phase, with a consistent increase in paclitaxel sensitivity and no change in cisplatin sensitivity. We observed in addition an increase in CDK1 activity, as evaluated by histone H1 phosphorylation. We evaluated messenger RNA (mRNA) half-life in the isogenic lines and observed a more rapid degradation in cells bearing the variant construct. We concluded that the increased paclitaxel sensitivity of ERCC2 variant cell lines is a consequence of lower gene expression, likely due to decreased stability of the variant ERCC2 mRNA.

PMID: 22345163 [PubMed - indexed for MEDLINE]

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Par-1 controls myosin-II activity through myosin phosphatase to regulate border cell migration.

Related Articles

Par-1 controls myosin-II activity through myosin phosphatase to regulate border cell migration.

Curr Biol. 2012 Mar 6;22(5):363-72

Authors: Majumder P, Aranjuez G, Amick J, McDonald JA

Abstract
BACKGROUND: Localized actomyosin contraction couples with actin polymerization and cell-matrix adhesion to regulate cell protrusions and retract trailing edges of migrating cells. Although many cells migrate in collective groups during tissue morphogenesis, mechanisms that coordinate actomyosin dynamics in collective cell migration are poorly understood. Migration of Drosophila border cells, a genetically tractable model for collective cell migration, requires nonmuscle myosin-II (Myo-II). How Myo-II specifically controls border cell migration and how Myo-II is itself regulated is largely unknown.
RESULTS: We show that Myo-II regulates two essential features of border cell migration: (1) initial detachment of the border cell cluster from the follicular epithelium and (2) the dynamics of cellular protrusions. We further demonstrate that the cell polarity protein Par-1 (MARK), a serine-threonine kinase, regulates the localization and activation of Myo-II in border cells. Par-1 binds to myosin phosphatase and phosphorylates it at a known inactivating site. Par-1 thus promotes phosphorylated myosin regulatory light chain, thereby increasing Myo-II activity. Furthermore, Par-1 localizes to and increases active Myo-II at the cluster rear to promote detachment; in the absence of Par-1, spatially distinct active Myo-II is lost.
CONCLUSIONS: We identify a critical new role for Par-1 kinase: spatiotemporal regulation of Myo-II activity within the border cell cluster through localized inhibition of myosin phosphatase. Polarity proteins such as Par-1, which intrinsically localize, can thus directly modulate the actomyosin dynamics required for border cell detachment and migration. Such a link between polarity proteins and cytoskeletal dynamics may also occur in other collective cell migrations.

PMID: 22326025 [PubMed - indexed for MEDLINE]

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Fetal and neonatal presentation of long QT syndrome.

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Fetal and neonatal presentation of long QT syndrome.

Pacing Clin Electrophysiol. 2012 Apr;35(4):e87-90

Authors: Komarlu R, Beerman L, Freeman D, Arora G

Abstract
This report describes a fetus presenting with intrauterine tachycardia and hydrops fetalis. Soon after birth the neonate was noted to be in torsades de pointes that responded dramatically to medical management. Long QT syndrome (LQTS) was diagnosed on electrocardiogram obtained soon after birth. The prognosis is poor when LQTS presents in utero or during the first week of life. However, our infant did well with medical management and has remained free of arrhythmias at follow-up.

PMID: 21401653 [PubMed - indexed for MEDLINE]

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185 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

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These pubmed results were generated on 2012/07/25

PubMed, a service of the National Library of Medicine, includes over 15 million citations for biomedical articles back to the 1950's. These citations are from MEDLINE and additional life science journals. PubMed includes links to many sites providing full text articles and other related resources.

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Oral administration of collagen tripeptide improves dryness and pruritus in the acetone-induced dry skin model.

Related Articles

Oral administration of collagen tripeptide improves dryness and pruritus in the acetone-induced dry skin model.

J Dermatol Sci. 2012 May;66(2):136-43

Authors: Okawa T, Yamaguchi Y, Takada S, Sakai Y, Numata N, Nakamura F, Nagashima Y, Ikezawa Z, Aihara M

Abstract
BACKGROUND: Dry skin causes pruritus and discomfort in patients with xerosis and atopic dermatitis. General treatment for skin dryness involves the topical application of an emollient. However, more effective, simpler therapies are desired. Collagen tripeptide (CTP) is a highly purified, non-antigenic, low-allergenic collagen fraction that is known to have various biological effects.
OBJECTIVE: To clarify the therapeutic effects of CTP for dry skin using acetone-induced dry skin model mice.
METHODS: ICR mice were treated with acetone followed by oral administration of CTP (80 or 500mg/kg/day) for 3 days. Hyaluronic acid production induced by CTP was assessed using human dermal fibroblasts in vitro and in an acetone-induced dry skin model mice in vivo. Transepidermal water loss (TEWL) and scratching behavior were evaluated. Furthermore, the effects of CTP on intraepidermal nerve fibers and expression of semaphorin 3A (Sema3A) and nerve growth factor (NGF) were examined by immunohistochemistry and quantitative RT-PCR.
RESULTS: CTP enhanced hyaluronic acid production in human dermal fibroblasts in vitro and in murine skin in vivo. Oral administration of CTP in acetone-induced dry skin model mice significantly decreased TEWL and suppressed scratching behavior. Intraepidermal nerve growth was dramatically inhibited in CTP-treated mice. Quantitative PCR analysis and immunohistochemical study revealed that CTP abolished the increased NGF and decreased Sema3A levels induced by acetone treatment.
CONCLUSION: Oral administration of CTP improves dry skin and normalizes axon-guidance factors in the epidermis in addition to reducing pruritus. CTP may be used in a new therapeutic strategy against dry skin and pruritus.

PMID: 22410290 [PubMed - indexed for MEDLINE]

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Loss of Perivascular Kir4.1 Potassium Channels in the Sclerotic Hippocampus of Patients With Mesial Temporal Lobe Epilepsy.

Loss of Perivascular Kir4.1 Potassium Channels in the Sclerotic Hippocampus of Patients With Mesial Temporal Lobe Epilepsy.

J Neuropathol Exp Neurol. 2012 Aug 8;

Authors: Heuser K, Eid T, Lauritzen F, Thoren AE, Vindedal GF, Taub�ll E, Gjerstad L, Spencer DD, Ottersen OP, Nagelhus EA, de Lanerolle NC

Abstract
ABSTRACT: Recent experimental data in mice have shown that the inwardly rectifying K channel Kir4.1 mediates K spatial buffering in the hippocampus. Here we used immunohistochemistry to examine the distribution of Kir4.1 in hippocampi from patients with medication-refractory temporal lobe epilepsy. The selectivity of the antibody was confirmed in mice with a glial conditional deletion of the gene encoding Kir4.1. These mice showed a complete loss of labeled cells, indicating that Kir4.1 is restricted to glia. In human cases, Kir4.1 immunoreactivity observed in cells morphologically consistent with astrocytes was significantly reduced in 12 patients with hippocampal sclerosis versus 11 patients without sclerosis and 4 normal autopsy controls. Loss of astrocytic Kir4.1 immunoreactivity was most pronounced around vessels and was restricted to gliotic areas. Loss of Kir4.1 expression was associated with loss of dystrophin and ?-syntrophin, but not with loss of ?-dystroglycan, suggesting partial disruption of the dystrophin-associated protein complex. The changes identified in patients with hippocampal sclerosis likely interfere with K homeostasis and may contribute to the epileptogenicity of the sclerotic hippocampus.

PMID: 22878665 [PubMed - as supplied by publisher]

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custom peptide price; +185 new citations

185 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

custom peptide price

These pubmed results were generated on 2012/07/25

PubMed, a service of the National Library of Medicine, includes over 15 million citations for biomedical articles back to the 1950's. These citations are from MEDLINE and additional life science journals. PubMed includes links to many sites providing full text articles and other related resources.

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[Effect of the Ca2+ -activated K+ channel in veratridine-induced cortex neurons damage].

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[Effect of the Ca2+ -activated K+ channel in veratridine-induced cortex neurons damage].

Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2005 May;21(2):140-4

Authors: Lai XH, Xu G, Zhu WM, Yuan GG

Abstract
AIM: To observe the effects of Ca2+ -activated K+ channel of primary cultured fetal SD rat cortex neurons in the veratridine triggered neuronal damage.
METHODS: The patch clamp technique of cell-attach and inside-out mode for these two kinds of single channel recordings were used.
RESULTS: Extracellular veratridine activated the Kca. In Ca2+ bath solution of cell-attach mode, Vp + 30 mV, when the concentration (micromol/L) of veratridine were 15,25,50 and 75, the open probabilities of the channel were 0.014 +/- 0.003, 0.085 +/- 0.010, 0.132 +/- 0.016 and 0.059 +/- 0.006 (P < 0.01) respectively. It appeared concentration-dependent within 50 micromol/L veratridine. In Ca2+ free bath solution of cell-attach mode, Vp = +50 mV, when the concentration (micromol/L) of veratridine were 15, 40,60 and 100, the open probabilities of the channel were 0.014 +/- 0.010, 0.113 +/- 0.006, 0.141 +/- 0.004 and 0.295 +/- 0.009 (P < 0.05) respectively. In the 6 cases of inside-out mode patch clamp, Vp = +40 mV, when the concentration of veratridine were 0, 25 micromol/L and 50 micromol/L, the open probabilities of the channel were 0.011 +/- 0.008, 0.010 +/- 0.010 and 0.012 +/- 0.007 (P > 0.05) respectively. There were no significant difference on open probabilities, average open/close times and amplitudes at different intracellular veratridine concentration.
CONCLUSION: Veratridine can affect the activation of the Kca channel through regulating the concentration of cytoplasmic free Ca2+. The opening of Kca activated by increase of intracellular Ca2+ during the early stage of anoxia may be a protection reaction of ischemic neurons.

PMID: 21171324 [PubMed - indexed for MEDLINE]

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Deciphering the potential efficacy of acetyl-L-carnitine (ALCAR) in maintaining connexin-mediated lenticular homeostasis.

Deciphering the potential efficacy of acetyl-L-carnitine (ALCAR) in maintaining connexin-mediated lenticular homeostasis.

Mol Vis. 2012;18:2076-86

Authors: Muralidharan AR, Leema G, Annadurai T, Anitha TS, Thomas PA, Geraldine P

Abstract
PURPOSE: To determine the putative role of acetyl-L-carnitine (ALCAR) in maintaining normal intercellular communication in the lens through connexin.
METHODS: In the present study, Wistar rat pups were divided into 3 groups of eight each. On postpartum day ten, Group I rat pups received an intraperitoneal injection (50 �l) of 0.89% saline. Rats in Groups II and III received a subcutaneous injection (50 �l) of sodium selenite (19 �mol/kg bodyweight); Group III rat pups also received an intraperitoneal injection of ALCAR (200 mg/kg bodyweight) once daily on postpartum days 9-14. Both eyes of each pup were examined from day 16 up to postpartum day 30. Alterations in the mean activity of the channel pumps, calcium-ATPase and sodium/potassium-ATPase, were determined. The expression of genes encoding key lenticular gap junctions (connexin 46 and connexin 50) and a channel pump (plasma membrane Ca(2+)-ATPase [PMCA1]) was evaluated by reverse transcription-PCR. Immunoblot analysis was also performed to confirm the differential expression of key lenticular connexin proteins. In addition, bioinformatics analysis was performed to determine the interacting residues of the connexin proteins with ALCAR.
RESULTS: Significantly lower mean activities of Ca(2+)-ATPase and Na(+)/K(+) -ATPase were observed in the lenses of Group II rats than those in Group I rat lenses. However, the observed mean activities of Ca(2+)-ATPase and Na(+)/K(+)-ATPase in Group III rat lenses were significantly higher than those in Group II rat lenses. The mean mRNA transcript levels of the connexin 46 and connexin 50 genes were significantly lower, while the mean levels of PMCA1 gene transcripts were significantly higher, in Group II rat lenses than in Group I rat lenses. Immunoblot analysis also confirmed the altered expression of connexin proteins in lysates of whole lenses of Group II rats. However, the expression of connexin 46 and connexin 50 proteins in lenses from group III rats was essentially similar to that noted in lenses from normal (Group I) rats. Hydrogen bond-interaction between ALCAR and amino acid residues at the functional domain regions of connexin 46 and connexin 50 proteins was also demonstrated through bioinformatics tools.
CONCLUSIONS: The results suggest that ALCAR plays a key role in maintaining lenticular homeostasis by promoting gap junctional intercellular communication.

PMID: 22876134 [PubMed - in process]

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Prolactin regulates tuberoinfundibular dopamine neuron discharge pattern: novel feedback control mechanisms in the lactotrophic axis.

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Prolactin regulates tuberoinfundibular dopamine neuron discharge pattern: novel feedback control mechanisms in the lactotrophic axis.

J Neurosci. 2012 Jun 6;32(23):8074-83

Authors: Lyons DJ, Hellysaz A, Broberger C

Abstract
Balance in the body's hormonal axes depends on feedback onto neuroendocrine hypothalamic neurons. This phenomenon involves transcriptional and biosynthetic effects, yet less is known about the potential rapid modulation of electrical properties. Here, we investigated this issue in the lactotrophic axis, in which the pituitary hormone prolactin is tonically inhibited by tuberoinfundibular dopamine (TIDA) neurons located in the hypothalamic arcuate nucleus. Whole-cell recordings were performed on slices of the rat hypothalamus. In the presence of prolactin, spontaneously oscillating TIDA cells depolarized, switched from phasic to tonic discharge, and exhibited broadened action potentials. The underlying prolactin-induced current is composed of separate low- and high-voltage components that include the activation of a transient receptor potential-like current and the inhibition of a Ca(2+)-dependent BK-type K(+) current, respectively, as revealed by ion substitution experiments and pharmacological manipulation. The two components of the prolactin-induced current appear to be mediated through distinct signaling pathways as the high-voltage component is abolished by the phosphoinositide 3-kinase blocker wortmannin, whereas the low-voltage component is not. This first description of the central electrophysiological actions of prolactin suggests a novel feedback mechanism. By simultaneously enhancing the discharge and spike duration of TIDA cells, increased serum prolactin can promote dopamine release to limit its own secretion with implications for the control of lactation, sexual libido, fertility, and body weight.

PMID: 22674282 [PubMed - indexed for MEDLINE]

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Prolactin regulates tuberoinfundibular dopamine neuron discharge pattern: novel feedback control mechanisms in the lactotrophic axis.

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Prolactin regulates tuberoinfundibular dopamine neuron discharge pattern: novel feedback control mechanisms in the lactotrophic axis.

J Neurosci. 2012 Jun 6;32(23):8074-83

Authors: Lyons DJ, Hellysaz A, Broberger C

Abstract
Balance in the body's hormonal axes depends on feedback onto neuroendocrine hypothalamic neurons. This phenomenon involves transcriptional and biosynthetic effects, yet less is known about the potential rapid modulation of electrical properties. Here, we investigated this issue in the lactotrophic axis, in which the pituitary hormone prolactin is tonically inhibited by tuberoinfundibular dopamine (TIDA) neurons located in the hypothalamic arcuate nucleus. Whole-cell recordings were performed on slices of the rat hypothalamus. In the presence of prolactin, spontaneously oscillating TIDA cells depolarized, switched from phasic to tonic discharge, and exhibited broadened action potentials. The underlying prolactin-induced current is composed of separate low- and high-voltage components that include the activation of a transient receptor potential-like current and the inhibition of a Ca(2+)-dependent BK-type K(+) current, respectively, as revealed by ion substitution experiments and pharmacological manipulation. The two components of the prolactin-induced current appear to be mediated through distinct signaling pathways as the high-voltage component is abolished by the phosphoinositide 3-kinase blocker wortmannin, whereas the low-voltage component is not. This first description of the central electrophysiological actions of prolactin suggests a novel feedback mechanism. By simultaneously enhancing the discharge and spike duration of TIDA cells, increased serum prolactin can promote dopamine release to limit its own secretion with implications for the control of lactation, sexual libido, fertility, and body weight.

PMID: 22674282 [PubMed - indexed for MEDLINE]

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Strategy of lipid recognition by invariant natural killer T cells: 'one for all and all for one'.

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Strategy of lipid recognition by invariant natural killer T cells: 'one for all and all for one'.

Immunology. 2012 Jul;136(3):273-82

Authors: Mallevaey T, Selvanantham T

Abstract
Invariant natural killer T (iNKT) cells are evolutionarily conserved lipid-reactive T cells that bridge innate and adaptive immune responses. Despite a relatively restricted T-cell receptor (TCR) diversity, these cells respond to a variety of structurally distinct foreign (i.e. microbial or synthetic) as well as host-derived (self-) lipid antigens presented by the CD1d molecule. These multi-tasking lymphocytes are among the first responders in immunity, and produce an impressive array of cytokines and chemokines that can tailor the ensuing immune response. Accordingly, iNKT cells play important functions in autoimmune diseases, cancer, infection and inflammation. These properties make iNKT cells appealing targets in immune-based therapies. Yet, much has to be learned on the mechanisms that allow iNKT cells to produce polarized responses. Responses of iNKT cells are influenced by the direct signals perceived by the cells through their TCRs, as well as by indirect co-stimulatory (and potentially co-inhibitory) cues that they receive from antigen-presenting cells or the local milieu. A decade ago, biochemists and immunologists have started to describe synthetic lipid agonists with cytokine skewing potential, paving a new research avenue in the iNKT cell field. Yet how iNKT cells translate various antigenic signals into distinct functional responses has remained obscure. Recent findings have revealed a unique and innate mode of lipid recognition by iNKT cells, and suggest that both the lipid antigen presented and the diversity of the TCR modulate the strength of CD1d-iNKT TCR interactions. In this review, we focus on novel discoveries on lipid recognition by iNKT cells, and how these findings may help us to design effective strategies to steer iNKT cell responses for immune intervention.

PMID: 22671023 [PubMed - indexed for MEDLINE]

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Biochemical characteristics of the Ca(2+) pumping ATPase in the peribacteroid membrane from broad bean root nodules.

Biochemical characteristics of the Ca(2+) pumping ATPase in the peribacteroid membrane from broad bean root nodules.

Protoplasma. 2012 Aug 8;

Authors: Krylova V, Andreev IM, Zartdinova R, Izmailov SF

Abstract
Ca(2+)-ATPase in the peribacteroid membrane (PBM) of symbiosomes isolated from Vicia faba root nodules was characterized in terms of its hydrolytic and transport activities. Both activities were found to be pH-dependent and exhibit pH optimum at pH�7.0. Translocation of Ca(2+) through the PBM by the Ca(2+)-ATPase was shown to be fueled by ATP and other nucleotide triphosphates in the following order: ATP?>?ITP???GTP???UTP???CTP, the K ( m ) of the enzyme for MgATP being about 100�?M. Ca-dependent ITP-hydrolytic activity of symbiosomes was investigated in the presence of the Ca-EGTA buffer system and showed the affinity of PBM Ca(2+)-ATPase for Ca(2+) of about 0.1�?M. The transport activity of Ca(2+)-ATPase was inhibited by erythrosin B as well as orthovanadate, but markedly stimulated by calmodulin from bovine brain. These results allowed us to conclude that this enzyme belongs to IIB-type Ca(2+)-ATPases which are present in other plant membranes.

PMID: 22872095 [PubMed - as supplied by publisher]

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Individual patient-specific immunity against high-grade glioma after vaccination with autologous tumor derived peptides bound to the 96 KD chaperone protein.

Individual patient-specific immunity against high-grade glioma after vaccination with autologous tumor derived peptides bound to the 96 KD chaperone protein.

Clin Cancer Res. 2012 Aug 7;

Authors: Crane CA, Han SJ, Ahn BJ, Oehlke J, Kivett V, Fedoroff A, Butowski N, Chang SM, Clarke J, Berger MS, McDermott MW, Prados MD, Parsa AT

Abstract
Background: Cancer immunotherapy offers hope of a highly specific non-toxic adjuvant treatment. Heat shock protein peptide complexes (HSPPCs) found in cancer cells carry tumor-specific antigenic proteins and can facilitate adaptive and innate immune response. Here we show that peptides bound to a 96 kD chaperone protein (HSP-96) from brain tissue containing glioblastoma multiforme (GBM) can be used to safely immunize patients with recurrent GBM. Methods: Multimodality immunomonitoring was completed on 12 patients with recurrent GBM before and after immunization with an autologous HSPPC vaccine derived from surgically resected tumor. Clinical endpoints included safety assessments and overall survival. RESULTS: No adverse events attributable to the vaccine were found. Testing of peripheral blood leukocytes (PBLs) before and after vaccination revealed a significant peripheral immune response specific for the peptides bound to HSP-96, in 11 of the 12 patients treated. Brain biopsies of immune responders after vaccination revealed focal CD4, CD8 and CD56 IFNgamma positive cell infiltrates, consistent with tumor site specific immune responses. Immune responders had a median survival of 47 weeks after surgery and vaccination, compared to 16 weeks for the single non-responder. CONCLUSIONS: These data provide the first evidence in humans of individual patient-specific immune responses against autologous tumor derived peptides bound to HSP-96.

PMID: 22872572 [PubMed - as supplied by publisher]

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Individual patient-specific immunity against high-grade glioma after vaccination with autologous tumor derived peptides bound to the 96 KD chaperone protein.

Individual patient-specific immunity against high-grade glioma after vaccination with autologous tumor derived peptides bound to the 96 KD chaperone protein.

Clin Cancer Res. 2012 Aug 7;

Authors: Crane CA, Han SJ, Ahn BJ, Oehlke J, Kivett V, Fedoroff A, Butowski N, Chang SM, Clarke J, Berger MS, McDermott MW, Prados MD, Parsa AT

Abstract
Background: Cancer immunotherapy offers hope of a highly specific non-toxic adjuvant treatment. Heat shock protein peptide complexes (HSPPCs) found in cancer cells carry tumor-specific antigenic proteins and can facilitate adaptive and innate immune response. Here we show that peptides bound to a 96 kD chaperone protein (HSP-96) from brain tissue containing glioblastoma multiforme (GBM) can be used to safely immunize patients with recurrent GBM. Methods: Multimodality immunomonitoring was completed on 12 patients with recurrent GBM before and after immunization with an autologous HSPPC vaccine derived from surgically resected tumor. Clinical endpoints included safety assessments and overall survival. RESULTS: No adverse events attributable to the vaccine were found. Testing of peripheral blood leukocytes (PBLs) before and after vaccination revealed a significant peripheral immune response specific for the peptides bound to HSP-96, in 11 of the 12 patients treated. Brain biopsies of immune responders after vaccination revealed focal CD4, CD8 and CD56 IFNgamma positive cell infiltrates, consistent with tumor site specific immune responses. Immune responders had a median survival of 47 weeks after surgery and vaccination, compared to 16 weeks for the single non-responder. CONCLUSIONS: These data provide the first evidence in humans of individual patient-specific immune responses against autologous tumor derived peptides bound to HSP-96.

PMID: 22872572 [PubMed - as supplied by publisher]

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Expression and function of K(V)2-containing channels in human urinary bladder smooth muscle.

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Expression and function of K(V)2-containing channels in human urinary bladder smooth muscle.

Am J Physiol Cell Physiol. 2012 Jun;302(11):C1599-608

Authors: Hristov KL, Chen M, Afeli SA, Cheng Q, Rovner ES, Petkov GV

Abstract
The functional role of the voltage-gated K(+) (K(V)) channels in human detrusor smooth muscle (DSM) is largely unexplored. Here, we provide molecular, electrophysiological, and functional evidence for the expression of K(V)2.1, K(V)2.2, and the electrically silent K(V)9.3 subunits in human DSM. Stromatoxin-1 (ScTx1), a selective inhibitor of K(V)2.1, K(V)2.2, and K(V)4.2 homotetrameric channels and of K(V)2.1/9.3 heterotetrameric channels, was used to examine the role of these channels in human DSM function. Human DSM tissues were obtained during open bladder surgeries from patients without a history of overactive bladder. Freshly isolated human DSM cells were studied using RT-PCR, immunocytochemistry, live-cell Ca(2+) imaging, and the perforated whole cell patch-clamp technique. Isometric DSM tension recordings of human DSM isolated strips were conducted using tissue baths. RT-PCR experiments showed mRNA expression of K(V)2.1, K(V)2.2, and K(V)9.3 (but not K(V)4.2) channel subunits in human isolated DSM cells. K(V)2.1 and K(V)2.2 protein expression was confirmed by Western blot analysis and immunocytochemistry. Perforated whole cell patch-clamp experiments revealed that ScTx1 (100 nM) inhibited the amplitude of the voltage step-induced K(V) current in freshly isolated human DSM cells. ScTx1 (100 nM) significantly increased the intracellular Ca(2+) level in DSM cells. In human DSM isolated strips, ScTx1 (100 nM) increased the spontaneous phasic contraction amplitude and muscle force, and enhanced the amplitude of the electrical field stimulation-induced contractions within the range of 3.5-30 Hz stimulation frequencies. These findings reveal that ScTx1-sensitive K(V)2-containing channels are key regulators of human DSM excitability and contractility and may represent new targets for pharmacological or genetic intervention for bladder dysfunction.

PMID: 22422395 [PubMed - indexed for MEDLINE]

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Probing protein phosphatase substrate binding: affinity pull-down of ILKAP phosphatase 2C with phosphopeptides.

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Probing protein phosphatase substrate binding: affinity pull-down of ILKAP phosphatase 2C with phosphopeptides.

Mol Biosyst. 2012 Apr;8(5):1452-60

Authors: H�jlys-Larsen KB, S�rensen KK, Jensen KJ, Gammeltoft S

Abstract
Proteomics and high throughput analysis for systems biology can benefit significantly from solid-phase chemical tools for affinity pull-down of proteins from complex mixtures. Here we report the application of solid-phase synthesis of phosphopeptides for pull-down and analysis of the affinity profile of the integrin-linked kinase associated phosphatase (ILKAP), a member of the protein phosphatase 2C (PP2C) family. Phosphatases can potentially dephosphorylate these phosphopeptide substrates but, interestingly, performing the binding studies at 4 �C allowed efficient binding to phosphopeptides, without the need for phosphopeptide mimics or phosphatase inhibitors. As no proven ILKAP substrates were available, we selected phosphopeptide substrates among known PP2C? substrates including the protein kinases: p38, ATM, Chk1, Chk2 and RSK2 and synthesized directly on PEGA solid supports through a BAL type handle. The results show that phosphopeptides tethered to a flexible solid support bind with high affinity and specificity to ILKAP, which is pulled down from lysates of cells transfected with ILKAP cDNA. Phosphorylation on Ser or Thr residues is important for binding of ILKAP, but sequences around the phosphorylated residue are important for the binding affinity of ILKAP. We conclude that solid-phase affinity pull-down of proteins from complex mixtures can be applied in phosphoproteomics and systems biology.

PMID: 22348942 [PubMed - indexed for MEDLINE]

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Myosin heavy chain composition of the human genioglossus muscle.

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Myosin heavy chain composition of the human genioglossus muscle.

J Speech Lang Hear Res. 2012 Apr;55(2):609-25

Authors: Daugherty M, Luo Q, Sokoloff AJ

Abstract
BACKGROUND: The human tongue muscle genioglossus (GG) is active in speech, swallowing, respiration, and oral transport, behaviors encompassing a wide range of tongue shapes and movement speeds. Studies demonstrate substantial diversity in patterns of human GG motor unit activation, but whether this is accompanied by complex expression of muscle contractile proteins is not known.
PURPOSE: The authors tested for conventional myosin heavy chain (MHC) MHCI, MHCIIA, MHCIIX, developmental MHCembryonic and MHCneonatal and unconventional MHC?cardiac, MHCextraocular, and MHCslow tonic in antero-superior (GG-A) and posterior (GG-P) adult human GG.
METHOD: SDS-PAGE, Western blot, and immunohistochemistry were used to describe MHC composition of GG-A and GG-P and the prevalence of muscle fiber MHC phenotypes in GG-A.
RESULTS: By SDS-PAGE, only conventional MHC are present with ranking from most to least prevalent MHCIIA > MHCI > MHCIIX in GG-A and MHCI > MHCIIA > MHCIIX in GG-P. By immunohistochemistry, many muscle fibers contain MHCI, MHCIIA, and MHCIIX, but few contain developmental or unconventional MHC. GG-A is composed of 5 phenotypes (MHCIIA > MHCI-IIX > MHCI > MHCI-IIA > MHCIIX). Phenotypes MHCI, MHCIIA, and MHCI-IIX account for 96% of muscle fibers.
CONCLUSIONS: Despite activation of GG during kinematically diverse behaviors and complex patterns of GG motor unit activity, the human GG is composed of conventional MHC isoforms and 3 primary MHC phenotypes.

PMID: 22337492 [PubMed - indexed for MEDLINE]

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The voltage dependence of I(h) in human myelinated axons.

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The voltage dependence of I(h) in human myelinated axons.

J Physiol. 2012 Apr 1;590(Pt 7):1625-40

Authors: Howells J, Trevillion L, Bostock H, Burke D

Abstract
HCN channels are responsible for I(h), a voltage-gated inwardly rectifying current activated by hyperpolarization. This current appears to be more active in human sensory axons than motor and may play a role in the determination of threshold. Differences in I(h) are likely to be responsible for the high variability in accommodation to hyperpolarization seen in different subjects. The aim of this study was to characterise this current in human axons, both motor and sensory. Recordings of multiple axonal excitability properties were performed in 10 subjects, with a focus on the changes in threshold evoked by longer and stronger hyperpolarizing currents than normally studied. The findings confirm that accommodation to hyperpolarization is greater in sensory than motor axons in all subjects, but the variability between subjects was greater than the modality difference. An existing model of motor axons was modified to take into account the behaviour seen with longer and stronger hyperpolarization, and a mathematical model of human sensory axons was developed based on the data collected. The differences in behaviour of sensory and motor axons and the differences between different subjects are best explained by modulation of the voltage dependence, along with a modest increase of expression of the underlying conductance of I(h). Accommodation to hyperpolarization for the mean sensory data is fitted well with a value of -94.2 mV for the mid-point of activation (V(0.5)) of I(h) as compared to -107.3 mV for the mean motor data. The variation in response to hyperpolarization between subjects is accounted for by varying this parameter for each modality (sensory: -89.2 to -104.2 mV; motor -87.3 to -127.3 mV). These voltage differences are within the range that has been described for physiological modulation of I(h) function. The presence of slowly activated I(h) isoforms on both motor and sensory axons was suggested by modelling a large internodal leak current and a masking of the Na(+)/K(+)-ATPase pump activity by a tonic depolarization. In addition to an increased activation of I(h), the modelling suggests that in sensory axons the nodal slow K(+) conductance is reduced, with consequent depolarization of resting membrane potential, and action potential of shorter duration.

PMID: 22310314 [PubMed - indexed for MEDLINE]

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Probing protein phosphatase substrate binding: affinity pull-down of ILKAP phosphatase 2C with phosphopeptides.

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Probing protein phosphatase substrate binding: affinity pull-down of ILKAP phosphatase 2C with phosphopeptides.

Mol Biosyst. 2012 Apr;8(5):1452-60

Authors: H�jlys-Larsen KB, S�rensen KK, Jensen KJ, Gammeltoft S

Abstract
Proteomics and high throughput analysis for systems biology can benefit significantly from solid-phase chemical tools for affinity pull-down of proteins from complex mixtures. Here we report the application of solid-phase synthesis of phosphopeptides for pull-down and analysis of the affinity profile of the integrin-linked kinase associated phosphatase (ILKAP), a member of the protein phosphatase 2C (PP2C) family. Phosphatases can potentially dephosphorylate these phosphopeptide substrates but, interestingly, performing the binding studies at 4 �C allowed efficient binding to phosphopeptides, without the need for phosphopeptide mimics or phosphatase inhibitors. As no proven ILKAP substrates were available, we selected phosphopeptide substrates among known PP2C? substrates including the protein kinases: p38, ATM, Chk1, Chk2 and RSK2 and synthesized directly on PEGA solid supports through a BAL type handle. The results show that phosphopeptides tethered to a flexible solid support bind with high affinity and specificity to ILKAP, which is pulled down from lysates of cells transfected with ILKAP cDNA. Phosphorylation on Ser or Thr residues is important for binding of ILKAP, but sequences around the phosphorylated residue are important for the binding affinity of ILKAP. We conclude that solid-phase affinity pull-down of proteins from complex mixtures can be applied in phosphoproteomics and systems biology.

PMID: 22348942 [PubMed - indexed for MEDLINE]

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Discovery of potent and selective rhodanine type IKK? inhibitors by hit-to-lead strategy.

Discovery of potent and selective rhodanine type IKK? inhibitors by hit-to-lead strategy.

Bioorg Med Chem Lett. 2012 Jul 15;

Authors: Song H, Lee YS, Roh EJ, Seo JH, Oh KS, Lee BH, Han H, Shin KJ

Abstract
Regulation of NF-?B activation through the inhibition of IKK? has been identified as a promising target for the treatment of inflammatory and autoimmune disease such as rheumatoid arthritis. In order to develop novel IKK? inhibitors, we performed high throughput screening toward around 8000 library compounds, and identified a hit compound containing rhodanine moiety. We modified the structure of hit compound to obtain potent and selective IKK? inhibitors. Throughout hit-to-lead studies, we have discovered optimized compounds which possess blocking effect toward NF-?B activation and TNF? production in cell as well as inhibition activity against IKK?. Among them, compound 3q showed the potent inhibitory activity against IKK?, and excellent selectivity over other kinases such as p38?, p38?, JNK1, JNK2, and JNK3 as well as IKK?.

PMID: 22858099 [PubMed - as supplied by publisher]

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Improving membrane binding as a design strategy for amphipathic peptide hormones: 2-helix variants of PYY3-36.

Improving membrane binding as a design strategy for amphipathic peptide hormones: 2-helix variants of PYY3-36.

J Pept Sci. 2012 Aug 1;

Authors: Pedersen SL, Bhatia VK, Jurt S, Paulsson JF, Pedersen MH, Jorgensen R, Holst B, Stamou D, Vrang N, Zerbe O, Jensen KJ

Abstract
It has been hypothesized that amphipathic peptides might bind to membranes prior to activating their cognate receptors, but this has proven difficult to test. The peptide hormone PYY3-36 is believed to perform its appetite-suppressing actions through binding to hypothalamic Y2 receptors. It has been proposed that PYY3-36 via its amphipathic ?-helix binds to the plasma membrane prior to receptor docking. Here, our aim was to study the implication of this hypothesis using new analogs of PYY3-36. We first studied membrane binding of PYY3-36. Next, we designed a series of PYY3-36 analogs to increase membrane-binding affinity by substituting the N-terminal segment with a de novo designed ?-helical, amphipathic sequence. These 2-helix variants of PYY3-36 were assembled by solid-phase peptide synthesis. Pharmacological studies demonstrated that even though the native peptide sequence was radically changed, highly active Y2 receptor agonists were generated. A potent analog, with a Kd of 4?nM for membranes, was structurally characterized by NMR in the membrane-bound state, which clearly showed that it formed the expected 2-helix. The topology of the peptide-micelle association was studied by paramagnetic relaxation enhancement using a spin label, which confirmed that the hydrophobic residues bound to the membrane. Our studies further support the hypothesis that PYY3-36 associates with the membrane and indicate that this can be used in the design of novel molecules with high receptor binding potency. These observations are likely to be generally important for peptide hormones and biopharmaceutical drugs derived from them. This new 2-helix variant of PYY3-36 will be useful as a tool compound for studying peptide-membrane interactions. Copyright � 2012 European Peptide Society and John Wiley & Sons, Ltd.

PMID: 22865741 [PubMed - as supplied by publisher]

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Design, Synthesis and Functional Analysis of Dansylated Polytheonamide Mimic: An Artificial Peptide Ion Channel.

Design, Synthesis and Functional Analysis of Dansylated Polytheonamide Mimic: An Artificial Peptide Ion Channel.

J Am Chem Soc. 2012 Aug 4;

Authors: Itoh H, Matsuoka S, Kreir M, Inoue M

Abstract
We report herein the design, total synthesis and functional analysis of a novel artificial ion channel molecule, designated as dansylated polytheonamide mimic (3). The channel 3 was designed based on an exceptionally potent cytotoxin, polytheonamide B (1). Our strategy for the development of synthetic ion channels, which could be easily derivatized for various functions, involved two key features. First, the structure of 1 was simplified by replacing many of non-proteinogenic amino acid residues which required multi-step synthesis by commercially available amino acids while retaining those residues necessary for folding. It significantly reduced the number of synthetic steps and facilitated a practical chemical construction of 3. Secondly, the introduction of propargyl glycine at residue 44 enabled facile installation of dansyl group as a reporter of the membrane localization of 3. Application of a newly designed protective group strategy provided efficient construction of the 37 amino acid sequence of residues 12-48 through one automatic solid-phase peptide synthesis. After peptide cleavage from the resin, 3 was synthesized via dansyl group introduction and one fragment-coupling reaction with residues 1-11, followed by the global deprotection. The simplified mimic 3 exhibited potent cytotoxicity toward p388 mouse leukemia cells (IC50 = 12 nM), effectively induced ion transport across the lipid bilayers of liposomes, and displayed H+ and Na+ ion channel activities. Because of its simplified yet functional scaffold structure with a potential for diversification, our rationally designed ion channel molecule should be useful as a novel platform for developing various cytotoxic channel molecules with additional desired functions.

PMID: 22861006 [PubMed - as supplied by publisher]

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Aurora-A inactivation causes mitotic spindle pole fragmentation by unbalancing microtubule-generated forces.

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Aurora-A inactivation causes mitotic spindle pole fragmentation by unbalancing microtubule-generated forces.

Mol Cancer. 2011;10:131

Authors: Asteriti IA, Giubettini M, Lavia P, Guarguaglini G

Abstract
BACKGROUND: Aurora-A is an oncogenic kinase playing well-documented roles in mitotic spindle organisation. We previously found that Aurora-A inactivation yields the formation of spindles with fragmented poles that can drive chromosome mis-segregation. Here we have addressed the mechanism through which Aurora-A activity regulates the structure and cohesion of spindle poles.
RESULTS: We inactivated Aurora-A in human U2OS osteosarcoma cells either by RNA-interference-mediated silencing or treating cultures with the specific inhibitor MLN8237. We show that mitotic spindle pole fragmentation induced by Aurora-A inactivation is associated with microtubule hyperstabilisation. Silencing of the microtubule-stabilising factor ch-TOG prevents spindle pole fragmentation caused by inactivation of Aurora-A alone and concomitantly reduces the hyperstabilisation of microtubules. Furthermore, decreasing pole-directed spindle forces by inhibition of the Eg5 kinesin, or by destabilisation of microtubule-kinetochore attachments, also prevents pole fragmentation in Aurora-A-inactivated mitoses.
CONCLUSIONS: Our findings indicate that microtubule-generated forces are imbalanced in Aurora-A-defective cells and exert abnormal pressure at the level of spindle poles, ultimately causing their fragmentation. This study therefore highlights a novel role of the Aurora-A kinase in regulating the balance between microtubule forces during bipolar spindle assembly.

PMID: 22011530 [PubMed - indexed for MEDLINE]

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Acute alteration of cardiac ECG, action potential, I(Kr) and the human ether-a-go-go-related gene (hERG) K+ channel by PCB 126 and PCB 77.

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Acute alteration of cardiac ECG, action potential, I(Kr) and the human ether-a-go-go-related gene (hERG) K+ channel by PCB 126 and PCB 77.

Toxicol Appl Pharmacol. 2012 Jul 1;262(1):60-9

Authors: Park MH, Park WS, Jo SH

Abstract
Polychlorinated biphenyls (PCBs) have been known as serious persistent organic pollutants (POPs), causing developmental delays and motor dysfunction. We have investigated the effects of two PCB congeners, 3,3',4,4'-tetrachlorobiphenyl (PCB 77) and 3,3',4,4',5-pentachlorobiphenyl (PCB 126) on ECG, action potential, and the rapidly activating delayed rectifier K+ current (I(Kr)) of guinea pigs' hearts, and hERG K+ current expressed in Xenopus oocytes. PCB 126 shortened the corrected QT interval (QTc) of ECG and decreased the action potential duration at 90% (APD(90)), and 50% of repolarization (APD??) (P<0.05) without changing the action potential duration at 20% (APD??). PCB 77 decreased APD?? (P<0.05) without affecting QTc, APD??, and APD??. The PCB 126 increased the I(Kr) in guinea-pig ventricular myocytes held at 36�C and hERG K+ current amplitude at the end of the voltage steps in voltage-dependent mode (P<0.05); however, PCB 77 did not change the hERG K+ current amplitude. The PCB 77 increased the diastolic Ca�? and decreased Ca�? transient amplitude (P<0.05), however PCB 126 did not change. The results suggest that PCB 126 shortened the QTc and decreased the APD?? possibly by increasing I(Kr), while PCB 77 decreased the APD?? possibly by other modulation related with intracellular Ca�?. The present data indicate that the environmental toxicants, PCBs, can acutely affect cardiac electrophysiology including ECG, action potential, intracellular Ca�?, and channel activity, resulting in toxic effects on the cardiac function in view of the possible accumulation of the PCBs in human body.

PMID: 22676973 [PubMed - indexed for MEDLINE]

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Synthesis, characterization and in-vitro antitubercular activity of isoniazid-gelatin conjugate.

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Synthesis, characterization and in-vitro antitubercular activity of isoniazid-gelatin conjugate.

J Pharm Pharmacol. 2012 May;64(5):712-8

Authors: Cassano R, Trombino S, Ferrarelli T, Cavalcanti P, Giraldi C, Lai F, Loy G, Picci N

Abstract
OBJECTIVES: A novel and simple method to synthesize antitubercular-protein conjugate by solid phase synthesis was developed employing a carboxypolystyrene resin. The aim was to covalently bind a drug with antitubercular activity, isoniazid, to a biomacromolecule, gelatin, widely used in the pharmaceutical, cosmetic and food industry.
METHODS: Calorimetric and (1) H NMR analyses were performed to verify the bond formation between the antitubercular drug and gelatin. After absorption isoniazid delivers toxic metabolites and so an oxidation test with tert-butyl hydroperoxide was performed to assess the amount of toxic metabolites released from the prodrug (gelatin linked to isoniazid), compared with isoniazid itself.
KEY FINDINGS: ? Spectrophotometric analysis revealed that the protein derivative was an excellent isoniazid prodrug since there was a 40% reduction in release of toxic metabolites (isonicotinic acid) by the prodrug. The results clearly showed that antitubercular moieties, covalently linked to a natural polymer, allowed the introduction of peculiar features for specific pharmaceutical applications into the macromolecule. In addition, antitubercular activity of the new polymer was determined by Middlebrook 7H11 medium against Mycobacterium tuberculosis complex.
CONCLUSIONS: The new isoniazid-gelatin conjugate showed significant antitubercular activity and for this reason should be useful as an efficacious tool in the treatment of tuberculosis.

PMID: 22471367 [PubMed - indexed for MEDLINE]

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Adaptive immunity to Anaplasma pathogens and immune dysregulation: implications for bacterial persistence.

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Adaptive immunity to Anaplasma pathogens and immune dysregulation: implications for bacterial persistence.

Comp Immunol Microbiol Infect Dis. 2012 May;35(3):241-52

Authors: Brown WC

Abstract
Anaplasma marginale is an obligate intraerythrocytic bacterium that infects ruminants, and notably causes severe economic losses in cattle worldwide. Anaplasma phagocytophilum infects neutrophils and causes disease in many mammals, including ruminants, dogs, cats, horses, and humans. Both bacteria cause persistent infection - infected cattle never clear A. marginale and A. phagocytophilum can also cause persistent infection in ruminants and other animals for several years. This review describes correlates of the protective immune response to these two pathogens as well as subversion and dysregulation of the immune response following infection that likely contribute to long-term persistence. I also compare the immune dysfunction observed with intraerythrocytic A. marginale to that observed in other models of chronic infection resulting in high antigen loads, including malaria, a disease caused by another intraerythrocytic pathogen.

PMID: 22226382 [PubMed - indexed for MEDLINE]

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Lead optimization of 2-(piperidin-3-yl)-1H-benzimidazoles: identification of 2-morpholin- and 2-thiomorpholin-2-yl-1H-benzimidazoles as selective and CNS penetrating H?-antihistamines for insomnia.

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Lead optimization of 2-(piperidin-3-yl)-1H-benzimidazoles: identification of 2-morpholin- and 2-thiomorpholin-2-yl-1H-benzimidazoles as selective and CNS penetrating H?-antihistamines for insomnia.

Bioorg Med Chem Lett. 2012 Jan 1;22(1):421-6

Authors: Ravula SB, Yu J, Tran JA, Arellano M, Tucci FC, Moree WJ, Li BF, Petroski RE, Wen J, Malany S, Hoare SR, Madan A, Crowe PD, Beaton G

Abstract
The structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pK(a) and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics.

PMID: 22153347 [PubMed - indexed for MEDLINE]

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