bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cortical HCN channels: function, trafficking and plasticity
Authors: Shah Mala M. 
Published: April 2014

AbstractThe hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels belong to the superfamily of voltage‐gated potassium ion channels. They are, however, activated by hyperpolarizing potentials and are permeable to cations. Four HCN subunits have been cloned, of which HCN1 and HCN2 subunits are predominantly expressed in the cortex. These subunits are principally located in pyramidal cell dendrites, although they are also found at lower concentrations in the somata of pyramidal neurons as well as other neuron subtypes. HCN channels are actively trafficked to dendrites by binding to the chaperone protein TRIP8b. Somato‐dendritic HCN channels in pyramidal neurons modulate spike firing and synaptic potential integration by influencing the membrane resistance and resting membrane potential. Intriguingly, HCN channels are present in certain cortical axons and synaptic terminals too. Here, they regulate synaptic transmission but the underlying mechanisms appear to vary considerably amongst different synaptic terminals. In conclusion, HCN channels are expressed in multiple neuronal subcellular compartments in the cortex, where they have a diverse and complex effect on neuronal excitability.
Molecular mechanisms of neuronal nitric oxide synthase in cardiac function and pathophysiology
Authors: Zhang Yin Hua , Jin Chun Zi , Jang Ji Hyun , Wang Yue 
Published: April 2014

AbstractNeuronal nitric oxide synthase (nNOS or NOS1) is the major endogenous source of myocardial nitric oxide (NO), which facilitates cardiac relaxation and modulates contraction. In the healthy heart it regulates intracellular Ca2+, signalling pathways and oxidative homeostasis and is upregulated from early phases upon pathogenic insult. nNOS plays pivotal roles in protecting the myocardium from increased oxidative stress, systolic/diastolic dysfunction, adverse structural remodelling and arrhythmias in the failing heart. Here, we show that the downstream target proteins of nNOS and underlying post‐transcriptional modifications are shifted during disease progression from Ca2+‐handling proteins [e.g. PKA‐dependent phospholamban phosphorylation (PLN‐Ser16)] in the healthy heart to cGMP/PKG‐dependent PLN‐Ser16 with acute angiotensin II (Ang II) treatment. In early hypertension, nNOS‐derived NO is involved in increases of cGMP/PKG‐dependent troponin I (TnI‐Ser23/24) and cardiac myosin binding protein C (cMBP‐C‐Ser273). However, nNOS‐derived NO is shown to increase S‐nitrosylation of various Ca2+‐handling proteins in failing myocardium. The spatial compartmentation of nNOS and its translocation for diverse binding partners in the diseased heart or various nNOS splicing variants and regulation in response to pathological stress may be responsible for varied underlying mechanisms and functions. In this review, we endeavour to outline recent advances in knowledge of the molecular mechanisms mediating the functions of nNOS in the myocardium in both normal and diseased hearts. Insights into nNOS gene regulation in various tissues are discussed. Overall, nNOS is an important cardiac protector in the diseased heart. The dynamic localization and various mediating mechanisms of nNOS ensure that it is able to regulate functions effectively in the heart under stress.
The microbiota–gut–brain axis in gastrointestinal disorders: stressed bugs, stressed brain or both?
Authors: De Palma Giada , Collins Stephen M. , Bercik Premysl , Verdu Elena F. 
Published: April 2014

AbstractThe gut–brain axis is the bidirectional communication between the gut and the brain, which occurs through multiple pathways that include hormonal, neural and immune mediators. The signals along this axis can originate in the gut, the brain or both, with the objective of maintaining normal gut function and appropriate behaviour. In recent years, the study of gut microbiota has become one of the most important areas in biomedical research. Attention has focused on the role of gut microbiota in determining normal gut physiology and immunity and, more recently, on its role as modulator of host behaviour (‘microbiota–gut–brain axis’). We therefore review the literature on the role of gut microbiota in gut homeostasis and link it with mechanisms that could influence behaviour. We discuss the association of dysbiosis with disease, with particular focus on functional bowel disorders and their relationship to psychological stress. This is of particular interest because exposure to stressors has long been known to increase susceptibility to and severity of gastrointestinal diseases.
Balance between the proximal dendritic compartment and the soma determines spontaneous firing rate in midbrain dopamine neurons
Authors: Jang Jinyoung , Um Ki Bum , Jang Miae , Kim Shin Hye , Cho Hana , Chung Sungkwon , Kim Hyun Jin , Park Myoung Kyu 
Published: April 2014

Key points
The electrical coupling between the soma and dendritic compartments has been regarded as a key determinant for the spontaneous firing rate (SFR) in midbrain dopamine neurons.
Isolated nigral dopamine neurons showed a wide range of soma size and a variable number of primary dendrites but preserved a quite consistent SFR.
The SFR was not correlated with soma size or with the number of primary dendrites, but it was strongly correlated with the area ratios of the proximal dendritic compartments to the somatic compartment.
Tetrodotoxin puff and local Ca2+ perturbation experiments, computer simulation, and local glutamate uncaging experiments suggest the importance of the proximal dendritic compartments in pacemaker activity.
These results lead us to a novel conclusion that the proximal dendritic compartments, not the whole dendritic compartments, play a key role in the somatodendritic balance that determines the SFR in dopamine neurons.
AbstractMidbrain dopamine (DA) neurons are slow intrinsic pacemakers that require the elaborate composition of many ion channels in the somatodendritic compartments. Understanding the major determinants of the spontaneous firing rate (SFR) of midbrain DA neurons is important because they determine the basal DA levels in target areas, including the striatum. As spontaneous firing occurs synchronously at the soma and dendrites, the electrical coupling between the soma and dendritic compartments has been regarded as a key determinant for the SFR. However, it is not known whether this somatodendritic coupling is served by the whole dendritic compartments or only parts of them. In the rat substantia nigra pars compacta (SNc) DA neurons, we demonstrate that the balance between the proximal dendritic compartment and the soma determines the SFR. Isolated SNc DA neurons showed a wide range of soma size and a variable number of primary dendrites but preserved a quite consistent SFR. The SFR was not correlated with soma size or with the number of primary dendrites, but it was strongly correlated with the area ratios of the proximal dendritic compartments to the somatic compartment. Tetrodotoxin puff and local Ca2+ perturbation experiments, computer simulation, and local glutamate uncaging experiments suggest the importance of the proximal dendritic compartments in pacemaker activity. These data indicate that the proximal dendritic compartments, not the whole dendritic compartments, play a key role in the somatodendritic balance that determines the SFR in DA neurons.
MexY-Promoted Aminoglycoside Resistance in Pseudomonas aeruginosa: Involvement of a Putative Proximal Binding Pocket in Aminoglycoside Recognition
Authors: Lau Calvin Ho-Fung , Hughes Daniel , Poole Keith 
Published: April 2014

ABSTRACT

The resistance-nodulation-division (RND) family multidrug efflux system MexXY-OprM is a major determinant of aminoglycoside resistance in
Pseudomonas aeruginosa
, although the details of aminoglycoside recognition and export by MexY, the substrate-binding RND component of this efflux system, have not been elucidated. To identify regions/residues of MexY important for aminoglycoside resistance, plasmid-borne
mexY
was mutagenized and mutations that impaired MexY-promoted aminoglycoside (streptomycin) resistance were identified in a Δ
mexY
strain of
P. aeruginosa
. Sixty-one streptomycin-sensitive
mexY
mutants were recovered; among these, 7 unique mutations that yielded wild-type levels of MexY expression were identified. These mutations compromised resistance to additional aminoglycosides and to other antimicrobials and occurred in both the transmembrane and periplasmic regions of the protein. Mapping of the mutated residues onto a 3-dimensional structure of MexY modeled on
Escherichia coli
AcrB revealed that these tended to occur in regions implicated in general pump operation (transmembrane domain) and MexY trimer assembly (docking domain) and, thus, did not provide insights into aminoglycoside recognition. A region corresponding to a proximal binding pocket connected to a periplasm-linked cleft, part of a drug export pathway of AcrB, was identified in MexY and proposed to play a role in aminoglycoside recognition. To test this, selected residues (K79, D133, and Y613) within this pocket were mutagenized and the impact on aminoglycoside resistance was assessed. Mutations of D133 and Y613 compromised aminoglycoside resistance, while, surprisingly, the K79 mutation enhanced aminoglycoside resistance, confirming a role for this putative proximal binding pocket in aminoglycoside recognition and export.

IMPORTANCE
Bacterial RND pumps do not typically accommodate highly hydrophilic agents such as aminoglycosides, and it is unclear how those, such as MexY, which accommodate these unique substrates, do so. The results presented here indicate that aminoglycosides are likely not captured and exported by this RND pump component in a unique manner but rather utilize a previously defined export pathway that involves a proximal drug-binding pocket that is also implicated in the export of nonaminoglycosides. The observation, too, that a mutation in this pocket enhances MexY-mediated aminoglycoside resistance (K79A), an indication that it is not optimally designed to accommodate these agents, lends further support to earlier proposals that antimicrobials are not the intended pump substrates.
Global Population Structure and Evolution of Bordetella pertussis and Their Relationship with Vaccination
Authors: Bart Marieke J. , Harris Simon R. , Advani Abdolreza , Arakawa Yoshichika , Bottero Daniela , Bouchez Valérie , Cassiday Pamela K. , Chiang Chuen-Sheue , Dalby Tine , Fry Norman K. , Gaillard María Emilia , van Gent Marjolein , Guiso Nicole , Hallander Hans O. , Harvill Eric T. , He Qiushui , van der Heide Han G. J. , Heuvelman Kees , Hozbor Daniela F. , Kamachi Kazunari , Karataev Gennady I. , Lan Ruiting , Lutyńska Anna , Maharjan Ram P. , Mertsola Jussi , Miyamura Tatsuo , Octavia Sophie , Preston Andrew , Quail Michael A. , Sintchenko Vitali , Stefanelli Paola , Tondella M. Lucia , Tsang Raymond S. W. , Xu Yinghua , Yao Shu-Man , Zhang Shumin , Parkhill Julian , Mooi Frits R. 
Published: April 2014

ABSTRACTBordetella pertussiscauses pertussis, a respiratory disease that is most severe for infants. Vaccination was introduced in the 1950s, and in recent years, a resurgence of disease was observed worldwide, with significant mortality in infants. Possible causes for this include the switch from whole-cell vaccines (WCVs) to less effective acellular vaccines (ACVs), waning immunity, and pathogen adaptation. Pathogen adaptation is suggested by antigenic divergence between vaccine strains and circulating strains and by the emergence of strains with increased pertussis toxin production. We applied comparative genomics to a worldwide collection of 343B. pertussisstrains isolated between 1920 and 2010. The global phylogeny showed two deep branches; the largest of these contained 98% of all strains, and its expansion correlated temporally with the first descriptions of pertussis outbreaks in Europe in the 16th century. We found little evidence of recent geographical clustering of the strains within this lineage, suggesting rapid strain flow between countries. We observed that changes in genes encoding proteins implicated in protective immunity that are included in ACVs occurred after the introduction of WCVs but before the switch to ACVs. Furthermore, our analyses consistently suggested that virulence-associated genes and genes coding for surface-exposed proteins were involved in adaptation. However, many of the putative adaptive loci identified have a physiological role, and further studies of these loci may reveal less obvious ways in whichB. pertussisand the host interact. This work provides insight into ways in which pathogens may adapt to vaccination and suggests ways to improve pertussis vaccines.IMPORTANCEWhooping cough is mainly caused byBordetella pertussis, and current vaccines are targeted against this organism. Recently, there have been increasing outbreaks of whooping cough, even where vaccine coverage is high. Analysis of the genomes of 343B. pertussisisolates from around the world over the last 100 years suggests that the organism has emerged within the last 500 years, consistent with historical records. We show that global transmission of new strains is very rapid and that the worldwide population ofB. pertussisis evolving in response to vaccine introduction, potentially enabling vaccine escape.
Correlations of skin fold thickness and validation of prediction equations using DEXA as the gold standard for estimation of body fat composition in Pakistani children
Authors: Hussain Zainab , Jafar Tazeen , Zaman Maseeh uz , Parveen Riffat , Saeed Farzan 
Published: April 2014

ObjectiveTo determine the correlation between dual energy X-ray absorptiometry (DEXA) and skin fold thickness (SKF) equations for estimation of body fat (BF) composition in secondary school children and validation of prediction equations by Slaughter, Goran and Dezenberg.DesignCross sectional analytical study.SettingJoint Commission for International Accredited (JCIA) tertiary care hospital of Karachi, Pakistan from January 2010 to May 2010.ParticipantsThe study was approved by the Hospital's ethical review committee. Written and verbal consents were obtained from principals of two schools and parents of 99 children (mean age of 14±1.89 years; min–max 9–19 years; 54 men and 45 women) accrued in study. DEXA scan was acquired and SKF was measured at angle of the scapula, iliac crest and mid-arm for bicep and tricep skin folds using Holtain Callipers. Correlations were established between estimated fat mass (FM) and per cent BF (%BF) calculated by DEXA and those predicted by prediction equations. On obtaining significant correlation of >0.5, overall accuracy,precisionand bias was calculated.ResultsThere was an overall increased adiposity in females with FM of 3.57 kg and %BF 6.2% higher than male counterparts (p<0.05). Slaughter equation predicted %BF accurately with overall high accuracy, minimal bias and with goodprecisionwith DEXA. Dezenberg and Goran equations had significant bias in prediction of FM which was statistically significant with low level of accuracy of the Goran equation.ConclusionsWe conclude that Slaughter equation for estimating %BF showed reasonable validation with DEXA. Nevertheless further studies with consideration for maturity and ethnicity are warranted for better results. However, for estimation of FM, previously formulated equations by Goran and Dezenberg showed significant difference in our population. We do recommend further studies for developing and validation of skin fold equations specific to Pakistani paediatric population.
Is density of neighbourhood restaurants associated with BMI in rural Chinese adults? A longitudinal study from the China Health and Nutrition Survey
Authors: Du Wenwen , Su Chang , Wang Huijun , Wang Zhihong , Wang Youfa , Zhang Bing 
Published: April 2014

ObjectivesThe neighbourhood availability of restaurants has been linked to the weight status. However, little is known regarding the relation between access to restaurant and obesity among the Chinese population. This study aims to explore the relationship between neighbourhood restaurant density and body mass index (BMI) in rural China.DesignA longitudinal study using data from the China Health and Nutrition Survey (CHNS) was conducted. Participants aged 18 and older from the 2004, 2006, 2009 and 2011 CHNS were recruited Separate sex-stratified random intercept-slope growth models of repeated BMI observations were estimated in the study.SettingThe data were derived from rural communities in nine provinces in China.ParticipantsThere were 11 835 male and 12 561 female person-years assessed in this study.OutcomesThe primary outcome of this study was weight status. It is defined as a BMI value, a continuous variable which is calculated by dividing weight (kg) by the square of height (m2).ResultsThe study indicated that among men an increase of one indoor restaurant in the neighbourhood was associated with a 0.01 kg/m2increase in BMI, and an increase of one fixed outdoor food stall was associated with a 0.01 kg/m2decrease in BMI, whereas among women, an increase of one indoor restaurant in the neighbourhood was associated with a 0.005 kg/m2increase in BMI, and an increase of one fast-food restaurant and one fixed outdoor food stall was associated with a 0.02 and 0.004 kg/m2decline in BMI, respectively.ConclusionsThe density of neighbourhood restaurants was found to be significantly related to BMI in rural China. The results indicated that providing healthy food choices and developing related public health policies are necessary to tackle obesity among rural Chinese adults.
Effect of Pumpkin Seed Oil on Hair Growth in Men with Androgenetic Alopecia: A Randomized, Double‐Blind, Placebo‐Controlled Trial
Authors: Cho Young Hye , Lee Sang Yeoup , Jeong Dong Wook , Choi Eun Jung , Kim Yun Jin , Lee Jeong Gyu , Yi Yu Hyeon , Cha Hyeong Soo 
Published: April 2014

Pumpkin seed oil (PSO) has been shown to block the action of 5‐alpha reductase and to have antiandrogenic effects on rats. This randomized, placebo‐controlled, double‐blind study was designed to investigate the efficacy and tolerability of PSO for treatment of hair growth in male patients with mild to moderate androgenetic alopecia (AGA). 76 male patients with AGA received 400 mg of PSO per day or a placebo for 24 weeks. Change over time in scalp hair growth was evaluated by four outcomes: assessment of standardized clinical photographs by a blinded investigator; patient self‐assessment scores; scalp hair thickness; and scalp hair counts. Reports of adverse events were collected throughout the study. After 24 weeks of treatment, self‐rated improvement score and self‐rated satisfaction scores in the PSO‐treated group were higher than in the placebo group (P = 0.013, 0.003). The PSO‐treated group had more hair after treatment than at baseline, compared to the placebo group (P < 0.001). Mean hair count increases of 40% were observed in PSO‐treated men at 24 weeks, whereas increases of 10% were observed in placebo‐treated men (P < 0.001). Adverse effects were not different in the two groups.
Insulin, Estrogen, Inflammatory Markers, and Risk of Benign Proliferative Breast Disease
Authors: Catsburg Chelsea , Gunter Marc J. , Chen Chu , Cote Michele L. , Kabat Geoffrey C. , Nassir Rami , Tinker Lesley , Wactawski-Wende Jean , Page David L. , Rohan Thomas E. 
Published: April 2014

Abstract
Women with benign proliferative breast disease (BPBD) are at increased risk for developing breast cancer. Evidence suggests that accumulation of adipose tissue can influence breast cancer development via hyperinsulinemia, increased estrogen, and/or inflammation. However, there are limited data investigating these pathways with respect to risk of BPBD. We evaluated serologic markers from these pathways in a case–control study of postmenopausal women nested within the Women's Health Initiative Clinical Trial. Cases were the 667 women who developed BPBD during follow-up, and they were matched to 1,321 controls. Levels of insulin, estradiol, C-reactive protein (CRP), and adiponectin were measured in fasting serum collected at baseline. Conditional logistic regression models were used to estimate ORs for the association of each factor with BPBD risk. Among nonusers of hormone therapy, fasting serum insulin was associated with a statistically significant increase in risk of BPBD (OR for highest vs. lowest quartile = 1.80; 95% confidence interval, CI, 1.16–2.79; Ptrend = 0.003) as were levels of estradiol (OR for highest vs. lowest tertile = 1.89; 95% CI, 1.26–2.83; Ptrend = 0.02) and CRP (OR for highest vs. lowest quartile = 2.46; 95% CI, 1.59–3.80; Ptrend &lt; 0.001). Baseline adiponectin level was inversely associated with BPBD risk (OR for highest vs. lowest quartile = 0.47; 95% CI, 0.31–0.71; Ptrend &lt; 0.001). These associations persisted after mutual adjustment, but were not observed among users of either estrogen alone or of estrogen plus progestin hormone therapy. Our results indicate that serum levels of estrogen, insulin, CRP, and adiponectin are independent risk factors for BPBD and suggest that the estrogen, insulin, and inflammation pathways are associated with the early stages of breast cancer development. Cancer Res; 74(12); 3248–58. ©2014 AACR.
IDH1 Mutations Alter Citric Acid Cycle Metabolism and Increase Dependence on Oxidative Mitochondrial Metabolism
Authors: Grassian Alexandra R. , Parker Seth J. , Davidson Shawn M. , Divakaruni Ajit S. , Green Courtney R. , Zhang Xiamei , Slocum Kelly L. , Pu Minying , Lin Fallon , Vickers Chad , Joud-Caldwell Carol , Chung Franklin , Yin Hong , Handly Erika D. , Straub Christopher , Growney Joseph D. , Vander Heiden Matthew G. , Murphy Anne N. , Pagliarini Raymond , Metallo Christian M. 
Published: April 2014

Abstract
Oncogenic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in several types of cancer, but the metabolic consequences of these genetic changes are not fully understood. In this study, we performed 13C metabolic flux analysis on a panel of isogenic cell lines containing heterozygous IDH1/2 mutations. We observed that under hypoxic conditions, IDH1-mutant cells exhibited increased oxidative tricarboxylic acid metabolism along with decreased reductive glutamine metabolism, but not IDH2-mutant cells. However, selective inhibition of mutant IDH1 enzyme function could not reverse the defect in reductive carboxylation activity. Furthermore, this metabolic reprogramming increased the sensitivity of IDH1-mutant cells to hypoxia or electron transport chain inhibition in vitro. Lastly, IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation. Cancer Res; 74(12); 3317–31. ©2014 AACR.
Molecular Pathways: Turning Proteasomal Protein Degradation into a Unique Treatment Approach
Authors: Stintzing Sebastian , Lenz Heinz-Josef 
Published: April 2014

Abstract
Cancer treatment regimens have evolved from single cytotoxic substances affecting all proliferative tissues toward antibodies and kinase inhibitors targeting tumor-specific pathways. Treatment efficacy and cancer survival have improved overall, and side effects have become less frequent. The ubiquitin-proteasome system–mediated proteasomal protein degradation is the most critical pathway to regulate the quantity of signal proteins involved in carcinogenesis and tumor progression. These processes are, as well as protein recycling, highly regulated and offer targets for biomarker and drug development. Unspecific proteasome inhibitors such as bortezomib and carfilzomib have shown clinical efficacy and are approved for clinical use. Inhibitors of more substrate-specific enzymes of degradation processes are being developed and are now in early clinical trials. The novel compounds focus on the degradation of key regulatory proteins such as p53, p27Kip1, and ß-catenin, and inhibitors specific for growth factor receptor kinase turnover are in preclinical testing. Clin Cancer Res; 20(12); 3064–70. ©2014 AACR.