bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial genome sequence analysis: A custom bioinformatics pipeline substantially improves Affymetrix MitoChip v2.0 call rate and accuracy
Authors: Xie Hongbo M , Perin Juan C , Schurr Theodore G , Dulik Matthew C , Zhadanov Sergey I , Baur Joseph A , King Michael P , Place Emily , Clarke Colleen , Grauer Michael , Schug Jonathan , Santani Avni , Albano Anthony , Kim Cecilia , Procaccio Vincent , Hakonarson Hakon , Gai Xiaowu , Falk Marni J
Published: October 2011

Background

Mitochondrial genome sequence analysis is critical to the diagnostic evaluation of mitochondrial disease. Existing methodologies differ widely in throughput, complexity, cost efficiency, and sensitivity of heteroplasmy detection. Affymetrix MitoChip v2.0, which uses a sequencing-by-genotyping technology, allows potentially accurate and high-throughput sequencing of the entire human mitochondrial genome to be completed in a cost-effective fashion. However, the relatively low call rate achieved using existing software tools has limited the wide adoption of this platform for either clinical or research applications. Here, we report the design and development of a custom bioinformatics software pipeline that achieves a much improved call rate and accuracy for the Affymetrix MitoChip v2.0 platform. We used this custom pipeline to analyze MitoChip v2.0 data from 24 DNA samples representing a broad range of tissue types (18 whole blood, 3 skeletal muscle, 3 cell lines), mutations (a 5.8 kilobase pair deletion and 6 known heteroplasmic mutations), and haplogroup origins. All results were compared to those obtained by at least one other mitochondrial DNA sequence analysis method, including Sanger sequencing, denaturing HPLC-based heteroduplex analysis, and/or the Illumina Genome Analyzer II next generation sequencing platform.

Results

An average call rate of 99.75% was achieved across all samples with our custom pipeline. Comparison of calls for 15 samples characterized previously by Sanger sequencing revealed a total of 29 discordant calls, which translates to an estimated 0.012% for the base call error rate. We successfully identified 4 known heteroplasmic mutations and 24 other potential heteroplasmic mutations across 20 samples that passed quality control.

Conclusions

Affymetrix MitoChip v2.0 analysis using our optimized MitoChip Filtering Protocol (MFP) bioinformatics pipeline now offers the high sensitivity and accuracy needed for reliable, high-throughput and cost-efficient whole mitochondrial genome sequencing. This approach provides a viable alternative of potential utility for both clinical diagnostic and research applications to traditional Sanger and other emerging sequencing technologies for whole mitochondrial genome analysis.
Efficacy and tolerance of the topical application of potassium hydroxide (10% and 15%) in the treatment of molluscum contagiosum: Randomized clinical trial: Research protocol
Authors: Marsal Josep R , Cruz Ines , Teixido Concepcio , Diez Olga , Martinez Mireia , Galindo Gisela , Real Jordi , Schoenenberger Joan A , Pera Helena
Published: October 2011

Background

Molluscum contagiosum is a non-severe pediatric viral infection. Because it is highly contagious and current treatments have negative aesthetic and psychological effects, we want to test an alternative treatment in the primary care setting, consisting of two different concentrations of potassium hydroxide solution.

Methods/design

The study design is a double-blind, randomized clinical trial, using three types of topical treatment. The treatment consist of daily applications of potassium hydroxide (KOH) in aqueous solution at 10% and 15% concentration, and a placebo administered in the control group. Four follow-up visits (at 15, 30, 45 and 60 days) are planned to evaluate treatment effectiveness and patient tolerance.

The main outcome measure of the trial will be the healing rate, defined as lesion disappearance in the affected zones after the topic application of the experimental treatment. Secondary measures will be the principal characteristics and evolution of the affected zone (surface area, number of lesions, size and density of lesions), treatment tolerance (hyperpigmentation, itching, burning, pain), recurrence rate and the natural evolution of lesions in the control group.

Discussion

KOH can potentially be an effective and safe treatment for MC in primary care, and can also reduce referrals to dermatologists and hospital pediatric departments. In addition, KOH may be a valid and less expensive alternative to current invasive treatments (surgical excision).

Trial Registration

ClinicalTrials.gov: NCT01348386
Reactions of Nicotiana species to inoculation with monopartite and bipartite begomoviruses
Authors: Akhtar Sohail , Briddon Rob W , Mansoor Shahid
Published: October 2011

Background

Some Nicotiana species are widely used as experimental hosts for plant viruses. Nicotiana species differ in ploidy levels, chromosome numbers and have diverse geographical origins. Thus, these species are useful model systems to investigate virus-host interactions, co-evolution of pathogens and hosts and the effects of ploidy level on virus resistance/susceptibility.

Results

Here we have studied the responses of seven Nicotiana species to inoculation with Cotton leaf curl Multan virus (CLCuMV), a monopartite begomovirus, and Tomato leaf curl New Delhi virus (ToLCNDV), a bipartite begomovirus, both from the Indian subcontinent. All Nicotiana species supported the replication of both begomoviruses in inoculated leaves. However, only three Nicotiana species, namely N. benthamiana, N. tabacum and N. sylvestris showed symptoms when inoculated with ToLCNDV, while N. benthamiana was the only species that developed leaf curl symptoms when inoculated with CLCuMV. CLCuMV accumulated to detectable levels in N. tabacum, but plants remained asymptomatic. A previously identified mutation of RNA dependent RNA polymerase 1 was shown to be present only in N. benthamiana. The finding is in line with earlier results showing that the susceptibility of this species to a diverse range of plant viruses correlates with a defective RNA silencing-mediated host defense.

Conclusions

The results presented show that individual Nicotiana species respond differently to inoculation with begomoviruses. The inability of begomoviruses to systemically infect several Nicotiana species is likely due to inhibition of virus movement, rather than replication, and thus provides a novel model to study virus-host interactions in resistant/susceptible hosts.
17β-Estradiol Protects the Lung against Acute Injury: Possible Mediation by Vasoactive Intestinal Polypeptide
Authors: Hamidi Sayyed A. , Dickman Kathleen G. , Berisha Hasan , Said Sami I.
Published: October 2011

Beyond their classical role as a class of female sex hormones, estrogens (e.g. 17β-estradiol) exert important biological actions, both protective and undesirable. We have investigated the ability of estradiol to protect the lung in three models of acute injury induced by 1) oxidant stress due to the herbicide paraquat; 2) excitotoxicity, caused by glutamate agonist N-methyl-d-aspartate; and 3) acute alveolar anoxia. We also assessed the role of estrogen receptors (ER) ERα and ERβ and the neuropeptide vasoactive intestinal peptide (VIP) in mediating this protection. Isolated guinea pig or rat lungs were perfused in situ at constant flow and mechanically ventilated. The onset and severity of lung injury were monitored by increases in pulmonary arterial and airway pressures, wet/dry lung weight ratio, and bronchoalveolar lavage fluid protein content. Estradiol was infused into the pulmonary circulation, beginning 10 min before induction of injury and continued for 60–90 min. Lung injury was marked by significant increases in the above measurements, with paraquat producing the most severe, and excitotoxicity the least severe, injury. Estradiol significantly attenuated the injury in each model. Both ER were constitutively expressed and immunohistochemically demonstrable in normal lung, and their selective agonists reduced anoxic injury, the only model in which they were tested. As it protected against injury, estradiol rapidly and significantly stimulated VIP mRNA expression in rat lung. Estradiol attenuated acute lung injury in three experimental models while stimulating VIP gene expression, a known mechanism of lung protection. The up-regulated VIP expression could have partially mediated the protection by estrogen.
The Teacher and the Cop: The Role of ‘Private Space in Increasingly Transparent Clinical Practice
Authors: Exworthy Mark , Hockey1 Peter , Gilbert Alexandra
Published: October 2011

Education and enforcement have been two contrasting ways of managing clinical performance. Both are needed but recently health policy has placed greater emphasis on the latter, possibly to the detriment of the former. This paper examines the ways in which education and other formative aspects of clinical practice can be conducted. The boundary between education and enforcement involves a distinction between public and private space. Private space is the territory within which clinicians can review their performance and improve it from an educational perspective. The boundary between public and private space is fluid, particularly since the advent of systems to ensure clinicians' competence. The sensitive management of this boundary will determine whether the benefits of transparent clinical practice will be realized in terms of improved patient care.
Is Bladder Ultrasound Indicated as Part of the Routine Investigation of Haematuria?
Authors: Purnell V E , Desai S , Husain J , Dodgeon J
Published: October 2011

Many patients presenting with haematuria undergo intravenous urography, renal tract ultrasound and cystoscopy. Renal tract ultrasound includes imaging of the bladder, which can significantly increase scan times by necessitating bladder filling, which can impact negatively on appointment scheduling. Little published literature exists on whether ultrasound of the bladder in the presence of haematuria is of any clinical benefit. This study aims to redress this by comparing bladder ultrasound to the gold standard of cystoscopy and also by assessing temporal implications in this patient group. A prospective study was undertaken where 96 consecutive urology-referred patients had their bladder ultrasound findings compared with the findings of cystoscopy under the headings of mass, trabeculation, diverticulum, stone and fistula. Ultrasound had poor sensitivity (47.8%), but good specificity (94.5%) in detecting the predefined bladder pathologies with a poor Kappa score of 0.33 when compared with cystoscopy. In addition, there was a significant time burden placed on the list by including bladder scanning as part of the renal tract sonographic assessment. In conclusion, bladder ultrasound is not shown to be a clinically useful adjunct to cystoscopy for the detection of bladder pathology. We would recommend that, in the setting of haematuria, ultrasound be used only for upper tract assessment.
Clinical Usefulness of Recombinant Activated Factor VII in Patients with Liver Failure Undergoing Invasive Procedures
Authors: Krisl Jill C , Meadows Holly E , Greenberg Charles S , Mazur Joseph E
Published: October 2011

Objective:

To evaluate the use of recombinant activated factor VII (rFVIIa) in patients with liver failure undergoing invasive procedures.

Methods:

An OVID/MEDUNE and PubMed search (1997-June 2011) was performed to identify literature on the use of rFVIIa to reduce bleeding risk in patients with liver failure undergoing invasive procedures.

Study Selection and Data Extraction:

English-language data evaluating the efficacy of rFVIIa to reverse coagulopathies prior to invasive procedures in patients with liver disease were included.

Data Synthesis:

Following administration of rFVIIa, prothrombin time (PT) and international normalized ratio (INR) response is within 30 minutes. Doses ranging from 20 to 120 μg/kg have been studied, with a reduction in PT seen in a dose-dependent manner. One study in patients with no bleeding administered 5, 20, and 80 μg/kg sequentially during a 24-day period. All doses provided reversal of prolonged PT within 10 minutes, and the duration was dose-dependent. In a study of 15 patients with fulminant liver failure, requiring intracranial pressure monitor placement, a rFVIIa dose of 40 μg/kg was compared to fresh frozen plasma. In patients who received rFVIIa, the PT and INR normalized, compared to none of the patients in the fresh frozen plasma group.

Conclusions:

Retrospective and prospective data demonstrate that rFVIIa effectively reverses elevated PT and INR, reducing the risk of bleeding and safely facilitating invasive procedures. Based on available data, a dose of 20-40 μg/kg 30 minutes prior to an invasive procedure should be considered in patients with acute or chronic liver failure at risk for bleeding complications. A major limitation of rFVIIa use is the high cost of therapy. A prospective, randomized trial could help determine the appropriate dose of rFVIIa, timing of dose in relationship to procedure, and usefulness of subsequent doses.
IVF-Conceiving Fathers' Experiences of Early Parenthood
Authors: Bracks-Zalloua Peggy , McMahon Catherine , Gibson Frances
Published: October 2011

This study explored the experiences of fathers during early parenthood, with a particular focus on relationships with their partners, their children and the impact of infertility treatment. Eight fathers who had a child conceived through in-vitro fertilisation (IVF) participated in in-depth interviews and responses were analysed using Modified Analytic Induction. Findings indicated that in the first year of their child's life fathers deferred primary caretaking to their partners, as they perceived them as more able to meet the needs of the child at that developmental stage. However, as the child grew older, and fathers could interact more they came to view themselves as the friend or playmate of the child, a role they experienced as highly rewarding. Reasons that may have accounted for deferring the primary caretaker role in the first year included low self-efficacy beliefs about their ability to care for a newborn infant, perceived partner criticism of their parenting abilities, and the complementary parenting roles adopted in their family. Findings also revealed that fathers experienced relationship concerns due to increased parenting responsibilities limiting the time and energy they had to engage in companionate activities with their partners. Fathers in this research explicitly reported that the difficulties associated with conception and IVF treatment had no impact on early parenthood.
Girls at Risk of Chronic Partner Abuse: Assertive Tendency, Warning Signs, Risk Sensitivity, and Self-Confidence
Authors: Murphy Kylie A.
Published: October 2011

Factors associated with chronic exposure to warning-sign behaviour (WSB) in girls' romantic relationships need to be understood in order to develop responsive prevention programs. Data was provided by 152 Australian adolescent girls (M= 14.7 years, range = 13 to 17), 66 of whom reported recent relationship experience and exposure to at least one WSB. Guided by the dyadic slippery-slope model of chronic partner abuse, relationships were tested between frequency of WSB exposure, perceived WSB risk, confidence in self-agency, and assertive tendency in romantic relationships. Girls who reported more assertive responses to WSBs reported less frequent exposure to WSBs in the past 3 months. Risk sensitivity, while weakly related to assertiveness in non-WSB-exposed girls, was unrelated to assertive tendency in WSB-exposed girls. Girls with greater WSB exposure had lower perceived self-agency, and lower perceived self-agency was associated with less assertiveness in response to Dominance and Possessiveness WSBs. These results are discussed in relation to dyadic slippery-slope theory, and point to the potential importance of strategically timed, empowerment-oriented programming in partner abuse prevention.
Die Grammatikalisierung des sein-Perfekts. – Eine korpuslinguistische Untersuchung zur Hilfsverbselektion der Bewegungsverben im Deutschen
Authors: Gillmann Melitta
Published: October 2011

In German, unlike in English or Swedish, there are two different perfect auxiliaries: the more frequently used haben and the auxiliary sein. The latter only occurs with a restricted group of verbs. Against the traditional view, it has recently been argued that both periphrases do not form a homogenous category, i. e. there was no grammaticalisation of sein + second participle at all. According to this view the periphrases do not only differ formally but also functionally.

In contrast, this article claims that the periphrasis consisting of sein + second participle has been grammaticalised in German. Although the construction had a resultative function in the Old High German period, it nowadays also refers to past situations which can be relevant to the point of speech. Therefore, its function is equivalent to the haben perfect. The reanalysis of sein + second participle is reflected by the distribution of the auxiliaries which is not strictly conditioned by aktionsart anymore. Though a corpus-based investigation of verbs of movement shows there are still restrictions for the periphrasis with sein: It is not permitted in prototypically transitive sentences. Whereas agentivity of the subject doesn't influence the auxiliary choice, sentences with prototypical objects prohibit the perfect with sein. Those objects are usually individuated or referential. Hence, they can underlie a change of state or position. Obviously, sein perfect has broken the actional restrictions, but there are still limitations concerning the argument structure. This shows that the sein periphrasis is only weakly grammaticalized.
Dichtung als Argumentationstechnik. Eine Interpretation der averroischen Bearbeitung der aristotelischen ›Poetik‹ in ihren lateinischen Übertragungen
Authors: Wels Volkhard
Published: October 2011

The paper argues that Averroes' paraphrase of Aristotle's ›Poetics‹ is a consistent theory of poetry, though not having much in common with Aristotle's original conception. Based on the translation of ›tragedy‹ and ›comedy‹ as ›praise‹ and ›blame‹, Averroes develops a concept of poetry as a moral-philosophical argument to praise virtue and to blame vice. The focus lies on the interpretation of Aristotelian mimesis as similitudo, that is ›parabolic quality‹. Being a parabolic argument poetry is distinguishable only gradually from other argumentative techniques such as demonstrative logic or rhetoric.
DNA methylation: dynamic and stable regulation of memory
Authors: Vaissière Thomas , Miller Courtney A.
Published: October 2011

Epigenetic mechanisms have emerged as a central process in learning and memory. Histone modifications and DNA methy­lation are epigenetic events that can mediate gene transcription. Interesting features of these epigenetic changes are their transient and long lasting potential. Recent advances in neuroscience suggest that DNA methylation is both dynamic and stable, mediating the formation and maintenance of memory. In this review, we will further illustrate the recent hypothesis that DNA methylation participates in the transcriptional regulation necessary for memory.
Multiple Adaptable Mechanisms Early in the Primate Visual Pathway
Authors: Dhruv Neel T. , Tailby Chris , Sokol Sach H. , Lennie Peter
Published: October 2011

We describe experiments that isolate and characterize multiple adaptable mechanisms that influence responses of orientation-selective neurons in primary visual cortex (V1) of anesthetized macaque (Macaca fascicularis). The results suggest that three adaptable stages of machinery shape neural responses in V1: a broadly tuned early stage and a spatio-temporally tuned later stage, both of which provide excitatory input, and a normalization pool that is also broadly tuned.

The early stage and the normalization pool are revealed by adapting gratings that themselves fail to evoke a response from the neuron: either low temporal frequency gratings at the null orientation or gratings of any orientation drifting at high temporal frequencies. When effective, adapting stimuli that altered the sensitivity of these two mechanisms caused reductions of contrast gain and often brought about a paradoxical increase in response gain due to a relatively greater desensitization of the normalization pool.

The tuned mechanism is desensitized only by stimuli well matched to a neuron's receptive field. We could thus infer desensitization of the tuned mechanism by comparing effects obtained with adapting gratings of preferred and null orientation modulated at low temporal frequencies.
Identification of Neural Feedback for Upright Stance in Humans: Stabilization rather than Sway Minimization
Authors: Kiemel Tim , Zhang Yuanfen , Jeka John J.
Published: October 2011

A fundamental issue in motor control is how to determine the task goals for a given behavior. Here, we address this question by separately identifying the musculoskeletal and feedback components of the human postural control loop. Eighteen subjects were perturbed by two mechanical perturbations (gentle pulling from behind at waist and shoulder levels) and one sensory perturbation (movement of a virtual visual scene). Body kinematics was described by the leg and trunk segment angles in the sagittal plane. Muscle activations were described by ankle and hip EMG signals, with each EMG signal computed as a weighted sum of rectified EMG signals from multiple muscles at the given joint. The mechanical perturbations were used to identify feedback, defined as the mapping from the two segment angles to the two EMG signals. The sensory perturbation was used to estimate parameters in a mechanistic model of the plant, defined as the mapping from the two EMG signals to the two segment angles. Using the plant model and optimal control theory, we compared identified feedback to optimal feedback for a range of cost functions. Identified feedback was similar to feedback that stabilizes upright stance with near-minimum muscle activation, but was not consistent with feedback that substantially increases muscle activation to reduce movements of the body's center of mass or center of pressure. The results suggest that the common assumption of reducing sway may not apply to musculoskeletal systems that are inherently unstable.
Time-Limited Consolidation and Task Interference: No Direct Link
Authors: Been Marin , Jans Bert , De Weerd Peter
Published: October 2011

Perceptual skills improve with daily practice (Fahle and Poggio, 2002; Fine and Jacobs, 2002). Practice induces plasticity in task-relevant brain regions during an “offline” consolidation period thought to last several hours, during which initially fragile memory traces become stable (Karni, 1996; Dudai, 2004). Impaired retention of a task if followed by training in another task is considered evidence for the instability of memory traces during consolidation (Dudai, 2004). However, it remains unknown when after training memory traces become stable and resistant against interference, where in the brain the neuronal mechanisms responsible for interference are localized, and how these mechanisms produce interference. Here, we show in human participants strong interference between two visual skill-learning tasks for surprisingly long time intervals between training periods (up to 24 h). Interference occurred during asymptotic learning, but only when stimuli were similar between tasks. This supports a strong contribution to interference of low-level visual cortical areas (Karni and Bertini, 1997; Ahissar and Hochstein, 2004), where similar stimuli recruit overlapping neuronal populations. Our finding of stimulus-dependent and time-independent interference reveals a fundamental limit in cortical plasticity that constrains the simultaneous representation of multiple skills in a single neuronal population, rather than a time-limited consolidation process.
Motor Adaptation Training for Faster Relearning
Authors: Malone Laura A. , Vasudevan Erin V. L. , Bastian Amy J.
Published: October 2011

Adaptation is an error-driven motor learning process that can account for predictable changes in the environment (e.g., walking on ice) or in ourselves (e.g., injury). Our ability to recall and build upon adapted motor patterns across days is essential to this learning process. We investigated how different training paradigms affect the day-to-day memory of an adapted walking pattern. Healthy human adults walked on a split-belt treadmill, and returned the following day to assess recall, relearning rate, and performance. In the first experiment, one group adapted and de-adapted (i.e., washed-out the learning) several times on day 1 to practice the initial stage of learning where errors are large; another group adapted only one time and then practiced in the adapted (“learned”) state where errors were small. On day 2, they performed washout trials before readapting. The group that repeatedly practiced the initial portion of adaptation where errors are large showed the fastest relearning on the second day. In fact, the memory was nearly as strong as that of a third group that was left overnight in the adapted state and was not washed-out before reexposure on the second day. This demonstrates that alternating exposures to early adaptation and washout can enhance readaptation. In the second experiment, we tested whether the opposite split-belt pattern interferes with day 2 relearning. Surprisingly, it did not, and instead was similar to practicing in the adapted state. These results show that the structure of the initial phase of learning influences the ease of motor relearning.
Nonlinear Interactions between Excitatory and Inhibitory Retinal Synapses Control Visual Output
Authors: Sagdullaev Botir T. , Eggers Erika D. , Purgert Robert , Lukasiewicz Peter D.
Published: October 2011

The visual system is highly sensitive to dynamic features in the visual scene. However, it is not known how or where this enhanced sensitivity first occurs. We investigated this phenomenon by studying interactions between excitatory and inhibitory synapses in the second synaptic layer of the mouse retina. We found that these interactions showed activity-dependent changes that enhanced signaling of dynamic stimuli. Excitatory signaling from cone bipolar cells to ganglion cells exhibited strong synaptic depression, attributable to reduced glutamate release from bipolar cells. This depression was relieved by amacrine cell inhibitory feedback that activated presynaptic GABACreceptors. We found that the balance between excitation and feedback inhibition depended on stimulus frequency; at short interstimulus intervals, excitation was enhanced, attributable to reduced inhibitory feedback. This dynamic interplay may enrich visual processing by enhancing retinal responses to closely spaced temporal events, representing rapid changes in the visual environment.
Glutaminase Dysregulation in HIV-1-Infected Human Microglia Mediates Neurotoxicity: Relevant to HIV-1-Associated Neurocognitive Disorders
Authors: Huang Yunlong , Zhao Lixia , Jia Beibei , Wu Li , Li Yuju , Curthoys Norman , Zheng Jialin C.
Published: October 2011

Microglia represent the main cellular targets of HIV-1 in the brain. Infected and/or activated microglia play a pathogenic role in HIV-associated neurocognitive disorders (HAND) by instigating primary dysfunction and subsequent death of neurons. Although microglia are known to secrete neurotoxins when infected with HIV-1, the detailed mechanism of neurotoxicity remains unclear. Using a human microglia primary culture system and macrophage-tropic HIV-1 strains, we have now demonstrated that HIV-1 infection of microglia resulted in a significant increase in extracellular glutamate concentrations and elevated levels of neurotoxicity. RNA and protein analysis revealed upregulation of the glutamate-generating enzyme glutaminase isoform glutaminase C in HIV-1-infected microglia. The clinical relevance of these findings was further corroborated with investigation of postmortem brain tissues. The glutaminase C levels in the brain tissues of HIV dementia individuals were significantly higher than HIV serum-negative control and correlated with elevated concentrations of glutamate. When glutaminase was subsequently inhibited by siRNA or by a small molecular inhibitor, the HIV-induced glutamate production and the neuronal loss was diminished. In conclusion, these findings support glutaminase as a potential component of the HAND pathogenic process as well as a novel therapeutic target in their treatment.
Misalignment of PLP/DM20 Transmembrane Domains Determines Protein Misfolding in Pelizaeus–Merzbacher Disease
Authors: Dhaunchak Ajit Singh , Colman David R. , Nave Klaus-Armin
Published: October 2011

A large number of genetic diseases have been associated with truncated or misfolded membrane proteins trapped in the endoplasmic reticulum (ER). In the ER, they activate the unfolded protein response, which can trigger cell death. Hence, a better understanding of protein misfolding features might help in developing novel therapies. Here, we have studied the molecular basis of Pelizaeus–Merzbacher disease, a leukodystrophy defined by mutations of thePLP1gene and ER retention of two encoded tetraspan myelin proteins, PLP and DM20. In mouse oligodendroglial cells, mutant isoforms of PLP/DM20 with fewer than all four transmembrane (TM) domains are fully ER retained. Surprisingly, a truncated PLP with only two N-terminal TM domains shows normal cell-surface expression when coexpressed with a second truncated PLP harboring the two C-terminal TM domains. This striking ability to properly self-align the TM domains is disease relevant, as shown for the smaller splice isoform DM20. Here, the increased length of TM domain 3 allows for compensation of the effect of severalPLP1point mutations that impose a conformational constraint onto the adjacent extracellular loop region. We conclude that an important determinant in the quality control of polytopic membrane proteins is the free alignment of their TM domains.
Transforming Growth Factor α Transforms Astrocytes to a Growth-Supportive Phenotype after Spinal Cord Injury
Authors: White Robin E. , Rao Meghan , Gensel John C. , McTigue Dana M. , Kaspar Brian K. , Jakeman Lyn B.
Published: October 2011

Astrocytes are both detrimental and beneficial for repair and recovery after spinal cord injury (SCI). These dynamic cells are primary contributors to the growth-inhibitory glial scar, yet they are also neuroprotective and can form growth-supportive bridges on which axons traverse. We have shown that intrathecal administration of transforming growth factor α (TGFα) to the contused mouse spinal cord can enhance astrocyte infiltration and axonal growth within the injury site, but the mechanisms of these effects are not well understood. The present studies demonstrate that the epidermal growth factor receptor (EGFR) is upregulated primarily by astrocytes and glial progenitors early after SCI. TGFα directly activates the EGFR on these cellsin vitro, inducing their proliferation, migration, and transformation to a phenotype that supports robust neurite outgrowth. Overexpression of TGFαin vivoby intraparenchymal adeno-associated virus injection adjacent to the injury site enhances cell proliferation, alters astrocyte distribution, and facilitates increased axonal penetration at the rostral lesion border. To determine whether endogenous EGFR activation is required after injury, SCI was also performed onVelvet(C57BL/6J-EgfrVel/J) mice, a mutant strain with defective EGFR activity. The affected mice exhibited malformed glial borders, larger lesions, and impaired recovery of function, indicating that intrinsic EGFR activation is necessary for neuroprotection and normal glial scar formation after SCI. By further stimulating precursor proliferation and modifying glial activation to promote a growth-permissive environment, controlled stimulation of EGFR at the lesion border may be considered in the context of future strategies to enhance endogenous cellular repair after injury.
Effects of Elevation of Brain Magnesium on Fear Conditioning, Fear Extinction, and Synaptic Plasticity in the Infralimbic Prefrontal Cortex and Lateral Amygdala
Authors: Abumaria Nashat , Yin Bin , Zhang Ling , Li Xiang-Yao , Chen Tao , Descalzi Giannina , Zhao Liangfang , Ahn Matae , Luo Lin , Ran Chen , Zhuo Min , Liu Guosong
Published: October 2011

Anxiety disorders, such as phobias and posttraumatic stress disorder, are among the most common mental disorders. Cognitive therapy helps in treating these disorders; however, many cases relapse or resist the therapy, which justifies the search for cognitive enhancers that might augment the efficacy of cognitive therapy. Studies suggest that enhancement of plasticity in certain brain regions such as the prefrontal cortex (PFC) and/or hippocampus might enhance the efficacy of cognitive therapy. We found that elevation of brain magnesium, by a novel magnesium compound [magnesium-l-threonate (MgT)], enhances synaptic plasticity in the hippocampus and learning and memory in rats. Here, we show that MgT treatment enhances retention of the extinction of fear memory, without enhancing, impairing, or erasing the original fear memory. We then explored the molecular basis of the effects of MgT treatment on fear memory and extinction. In intact animals, elevation of brain magnesium increased NMDA receptors (NMDARs) signaling, BDNF expression, density of presynaptic puncta, and synaptic plasticity in the PFC but, interestingly, not in the basolateral amygdala.In vitro, elevation of extracellular magnesium concentration increased synaptic NMDAR current and plasticity in the infralimbic PFC, but not in the lateral amygdala, suggesting a difference in their sensitivity to elevation of brain magnesium. The current study suggests that elevation of brain magnesium might be a novel approach for enhancing synaptic plasticity in a regional-specific manner leading to enhancing the efficacy of extinction without enhancing or impairing fear memory formation.
Biasing Perception by Spatial Long-Term Memory
Authors: Summerfield Jennifer J. , Rao Anling , Garside Nicola , Nobre Anna C.
Published: October 2011

Human perception is highly flexible and adaptive. Selective processing is tuned dynamically according to current task goals and expectations to optimize behavior. Arguably, the major source of our expectations about events yet to unfold is our past experience; however, the ability of long-term memories to bias early perceptual analysis has remained untested. We used a noninvasive method with high temporal resolution to record neural activity while human participants detected visual targets that appeared at remembered versus novel locations within naturalistic visual scenes. Upon viewing a familiar scene, spatial memories changed oscillatory brain activity in anticipation of the target location. Memory also enhanced neural activity during early stages of visual analysis of the target and improved behavioral performance. Both measures correlated with subsequent target-detection performance. We therefore demonstrated that memory can directly enhance perceptual functions in the human brain.
Beyond the morphology of the glucose curve following an oral glucose tolerance test in obese youth
Authors: Nolfe Giuseppe , Spreghini Maria Rita , Wietrzycowska Sforza Rita , Morino Giuseppe , Manco Melania
Published: October 2011

Background

To describe the morphology of glucose curve during the oral glucose tolerance test (OGTT) and any association with glucose tolerance, insulin action and secretion in obese youth.

Study design

Cross-sectional.

Methods

OGTT data of 553 patients were analysed. Subjects were divided in groups based on the morphology (i.e. monophasic, biphasic, triphasic and upward monotonous) of glucose curve. Insulin action was estimated by the homeostasis model assessment of insulin resistance, the insulin sensitivity, the muscle insulin sensitivity and the hepatic insulin resistance indexes (HIRI), and the oral glucose insulin sensitivity (OGIS). Insulin secretion was estimated by the insulinogenic index (IGI). Disposition index, including the insulin secretion–sensitivity index-2, and areas under glucose (AUCG) and insulin (AUCI) curves were computed.

Results

In patients with normal glucose tolerance (n=522), prevalent morphology of the glucose curve was monophasic (n=285, 54%). Monophasic morphology was associated with the highest concentration of 1 h plasma glucose (P<0.0001) and AUCG (P<0.0001); biphasic morphology with better insulin sensitivity as estimated by OGIS (P<0.03) and lower AUCI (P<0.0001); triphasic morphology with the highest values of HIRI (P<0.02) and IGI (P<0.007).

By combining morphologies of glucose and insulin curves or time of the glucose peak, a deeper characterisation of different phenotypes of glucose metabolism emerged.

Conclusions

Morphologies of the glucose curve seem reflecting different metabolic phenotypes of insulin action and secretion, particularly when combined with morphologies of insulin curve or time of glucose peak. Such findings may deserve validation in cohort study, in which glucose metabolism would be estimated by using gold standard techniques.
RSUME is implicated in HIF-1-induced VEGF-A production in pituitary tumour cells
Authors: Shan B , Gerez J , Haedo M , Fuertes M , Theodoropoulou M , Buchfelder M , Losa M , Stalla G K , Arzt E , Renner U
Published: October 2011

The recently cloned small RWD-domain containing protein RSUME was shown to increase protein levels of hypoxia-inducible factor-1α (HIF-1α). The latter is the oxygen-regulated subunit of HIF-1, the most important transcription factor of the cellular adaptive processes to hypoxic conditions. It is also a major regulator of vascular endothelial growth factor-A (VEGF-A), which is critically involved in the complex process of tumour neovascularisation. In this study, the expression and role of RSUME in pituitary tumours was studied. We found that RSUME mRNA was up-regulated in pituitary adenomas and significantly correlated with HIF-1α mRNA levels. Hypoxia (1% O2) or treatment with hypoxia-mimicking CoCl2enhanced RSUME and HIF-1α expression, induced translocation of HIF-1α to the nuclei and stimulated VEGF-A production both in pituitary tumour cell lines and primary human pituitary adenoma cell cultures. When RSUME expression was specifically down-regulated by siRNA, the CoCl2-induced increase VEGF-A secretion was strongly reduced which was shown to be a consequence of the RSUME knockdown-associated reduction of HIF-1α synthesis. Thus, RSUME plays an important role in initiating pituitary tumour neovascularisation through regulating HIF-1α levels and subsequent VEGF-A production and may therefore be critically involved in pituitary adenoma progression.
Testosterone protects from metabolic syndrome-associated prostate inflammation: an experimental study in rabbit
Authors: Vignozzi Linda , Morelli Annamaria , Sarchielli Erica , Comeglio Paolo , Filippi Sandra , Cellai Ilaria , Maneschi Elena , Serni Sergio , Gacci Mauro , Carini Marco , Piccinni Marie-Pierre , Saad Farid , Adorini Luciano , Vannelli Gabriella B , Maggi Mario
Published: October 2011

Metabolic syndrome (MetS) and benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) are often associated. One of their common denominators is hypogonadism. However, testosterone supplementation is limited by concerns for potential prostatic side effects. The objective was to determine whether MetS-associated prostate alterations are prevented by testosterone supplementation. We used a previously described animal model of MetS, obtained by feeding male rabbits a high-fat diet (HFD) for 12 weeks. Subsets of HFD rabbits were treated with testosterone or with the farnesoid X receptor agonist INT-747. Rabbits fed a standard diet were used as controls. HFD-animals develop hypogonadism and all the MetS features: hyperglycemia, glucose intolerance, dyslipidemia, hypertension, and visceral obesity. In addition, HFD-animals show a prostate inflammation. Immunohistochemical analysis demonstrated that HFD-induced prostate fibrosis, hypoxia, and inflammation. The mRNA expression of several proinflammatory (IL8, IL6, IL1β, and TNFα), T lymphocyte (CD4, CD8, Tbet, Gata3, and ROR γt), macrophage (TLR2, TLR4, and STAMP2), neutrophil (lactoferrin), inflammation (COX2 and RAGE), and fibrosis/myofibroblast activation (TGFβ, SM22α, αSMA, RhoA, and ROCK1/ROCK2) markers was significantly increased in HFD prostate. Testosterone, as well as INT-747, treatment prevented some MetS features, although only testosterone normalized all the HFD-induced prostate alterations. Interestingly, the ratio between testosterone and estradiol plasma level retains a significant, negative, association with all the fibrosis and the majority of inflammatory markers analyzed. These data highlight that testosterone protects rabbit prostate from MetS-induced prostatic hypoxia, fibrosis, and inflammation, which can play a role toward the development/progression of BPH/LUTS.
Modeling the Distribution of Acidity within Nuclear Fuel (UO2) Corrosion Product Deposits and Porous Sites
Authors: Cheong W-J. , Keech P. G. , Wren J. C. , Shoesmith D. W. , Qin Z.
Published: October 2011

A model for acidity within pores within corrosion products on anodically-dissolving UO2 was developed using Comsol Multiphysics 3.2 to complement ongoing electrochemical measurements. It was determined that a depression of pH within pores can be maintained if: electrochemically measured dissolution currents used in the calculations are attenuated to reflect very localized pores; corrosion potentials exceed -250 mV (vs. SCE); and pore depths are > 1 μm for 300 mV or >100 μm for -50 mV (vs. SCE). Mixed diffusional-chemical equilibria control is suggested through deviations in the shapes between pH-potential and pH-pore depth plots.
A Probabilistic-Micromechanical Methodology for Assessing Zirconium Alloy Cladding Failure
Authors: Pan Yi-Ming , Chan K. S. , Riha D. S.
Published: October 2011

Cladding failure of fuel rods caused by hydride-induced embrittlement is a reliability concern for spent nuclear fuel after extended burnup. Uncertainties in the cladding temperature, cladding stress, oxide layer thickness, and the critical stress value for hydride reorientation preclude an assessment of the cladding failure risk. A set of micromechanical models for treating oxide cracking, blister cracking, delayed hydride cracking, and cladding fracture was developed and incorporated in a computer model. Results obtained from the model calculations indicate that at temperatures below a critical temperature of 318.5 °C [605.3 °F], the time to failure by delayed hydride cracking in Zr-2.5%Nb decreased with increasing cladding temperature. The overall goal of this project is to develop a probabilistic-micromechanical methodology for assessing the probability of hydride-induced failure in Zircaloy cladding and thereby establish performance criteria.
Repassivation Potential of Alloy 22 in Chloride plus Nitrate Solutions using the Potentiodynamic-Galvanostatic-Potentiostatic Method
Authors: Evans Kenneth J. , Rebak Raul B.
Published: October 2011

In general, the susceptibility of Alloy 22 to suffer crevice corrosion is measured using the Cyclic Potentiodynamic Polarization (CPP) technique. This is a fast technique that gives rather accurate and reproducible values of repassivation potential (ER1) in most cases. In the fringes of susceptibility, when the environment is not highly aggressive, the values of repassivation potential using the CPP technique may not be highly reproducible, especially because the technique is fast and because transpassive corrosion may influence or mask the nucleation and propagation of crevice corrosion. To circumvent this, the repassivation potential of Alloy 22 was measured using a slower method that combines Potentiodynamic-Galvanostatic-Potentiostatic steps (called here the Tsujikawa-Hisamatsu Electrochemical or THE method). The THE method applies the charge to the specimen in a more controlled way, which may give more reproducible repassivation potential values, especially when the environment is not aggressive. The values of repassivation potential of Alloy 22 in sodium chloride plus potassium nitrate solutions were measured using the THE and CPP methods. Results show that both methods yield similar values of repassivation potential, especially under aggressive conditions.
Characterization of Solids in Residual Wastes from Underground Storage Tanks at the Hanford Site, Washington, U.S.A.
Authors: Krupka Kenneth Michael , Deutsch William J. , Schaef H. Todd , Arey Bruce W. , Heald Steve M. , Lindberg Michael J. , Cantrell Kirk J.
Published: October 2011

Solid phase physical and chemical characterization methods have been used in an ongoing study of residual wastes from several single-shell underground waste tanks at the U.S. Department of Energy's Hanford Site in southeastern Washington State. Because these wastes are highly-radioactive dispersible powders and are chemically-complex assemblages of crystalline and amorphous solids that contain contaminants as discrete phases and/or co-precipitated within oxide phases, their detailed characterization offers an extraordinary technical challenge. X-ray diffraction (XRD) and scanning electron microscopy/energy dispersive x-ray spectroscopy (SEM/EDS) are the two principal methods used, along with a limited series of analyses by synchrotron-based methods, to characterize solid phases and their contaminant associations in these wastes. Depending on the specific tank, numerous solids (e.g., èejkaite; Na2U2O7; clarkeite; gibbsite; böhmite; dawsonite; cancrinite; Fe oxides such as hematite, goethite, and maghemite; rhodochrosite; lindbergite; whewellite; nitratine; and several amorphous phases) have been identified in residual wastes studied to date. Because many contaminants of concern are heavy elements, SEM analysis using the backscattered electron (BSE) signal has proved invaluable in distinguishing phases containing elements, such as U and Hg, within the complex assemblage of particles that make up each waste. XRD, SEM/EDS, and synchrotron-based methods provide different, but complimentary characterization data about the morphologies, crystallinity, particle sizes, surface coatings, and compositions of phases in these wastes. The impact of these techniques is magnified when each is used in an iterative fashion to help interpret the results from the other analysis methods and identify additional, more focused analyses.
An Evaluation of Single Phase Ceramic Formulations for Plutonium Disposition
Authors: Stennett Martin Christopher , Maddrell Ewan R , Scales Charlie R , Livens Francis R , Gilbert Matthew , Hyatt Neil C
Published: October 2011

Tailored ceramics are promising potential hosts for the immobilization of actinides [1]. In this study the potential of a range of different ceramic systems were investigated for the incorporation of waste plutonium, using Ce as a Pu surrogate. Durable actinide containing minerals exist in nature and provided excellent target phases for the titanate, zirconate, silicate and phosphate based formulations examined here [2]. The Ce single phase solid solution limits for each system were established and the processing parameters required to produce high quality ceramic specimens were optimised. Importantly, this was achieved within the constraints of a generic processing route suitable for fabrication of Pu bearing samples.