bluuebunny/crossref_metadata_2025 huggingface dataset:
Hmga2 regulates self-renewal of retinal progenitors
Authors: Parameswaran Sowmya , Xia Xiaohuan , Hegde Ganapati , Ahmad Iqbal
Published: October 2014

In vertebrate retina, histogenesis occurs over an extended period. To sustain the temporal generation of diverse cell types, retinal progenitor cells (RPCs) must self-renew. However, self-renewal and regulation of RPCs remain poorly understood. Here, we demonstrate that cell-extrinsic factors coordinate with the epigenetic regulator high-mobility group AT-hook 2 (Hmga2) to regulate self-renewal of late retinal progenitor cells (RPCs). We observed that a small subset of RPCs was capable of clonal propagation and retained multipotentiality of parents in the presence of endothelial cells (ECs), known self-renewal regulators in various stem cell niches. The self-renewing effects, also observed in vivo, involve multiple intercellular signaling pathways, engaging Hmga2. As progenitors exhaust during retinal development, expression of Hmga2 progressively decreases. Analyses of Hmga2-expression perturbation, in vitro and in vivo, revealed that Hmga2 functionally helps to mediate cell-extrinsic influences on late-retinal progenitor self-renewal. Our results provide a framework for integrating the diverse intercellular influences elicited by epigenetic regulators for self-renewal in a dynamic stem cell niche: the developing vertebrate retina.
Quiescent neuronal progenitors are activated in the juvenile guinea pig lateral striatum and give rise to transient neurons
Authors: Luzzati Federico , Nato Giulia , Oboti Livio , Vigna Elisa , Rolando Chiara , Armentano Maria , Bonfanti Luca , Fasolo Aldo , Peretto Paolo
Published: October 2014

In the adult brain, active stem cells are a subset of astrocytes residing in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. Whether quiescent neuronal progenitors occur in other brain regions is unclear. Here, we describe a novel neurogenic system in the external capsule and lateral striatum (EC-LS) of the juvenile guinea pig that is quiescent at birth but becomes active around weaning. Activation of neurogenesis in this region was accompanied by the emergence of a neurogenic-like niche in the ventral EC characterized by chains of neuroblasts, intermediate-like progenitors and glial cells expressing markers of immature astrocytes. Like neurogenic astrocytes of the SVZ and DG, these latter cells showed a slow rate of proliferation and retained BrdU labeling for up to 65 days, suggesting that they are the primary progenitors of the EC-LS neurogenic system. Injections of GFP-tagged lentiviral vectors into the SVZ and the EC-LS of newborn animals confirmed that new LS neuroblasts originate from the activation of local progenitors and further supported their astroglial nature. Newborn EC-LS neurons existed transiently and did not contribute to neuronal addition or replacement. Nevertheless, they expressed Sp8 and showed strong tropism for white matter tracts, wherein they acquired complex morphologies. For these reasons, we propose that EC-LS neuroblasts represent a novel striatal cell type, possibly related to those populations of transient interneurons that regulate the development of fiber tracts during embryonic life.
Arid3b is essential for second heart field cell deployment and heart patterning
Authors: Uribe Verónica , Badía-Careaga Claudio , Casanova Jesús C. , Domínguez Jorge N. , de la Pompa José Luis , Sanz-Ezquerro Juan José
Published: October 2014

Arid3b, a member of the conserved ARID family of transcription factors, is essential for mouse embryonic development but its precise roles are poorly understood. Here, we show that Arid3b is expressed in the myocardium of the tubular heart and in second heart field progenitors. Arid3b-deficient embryos show cardiac abnormalities, including a notable shortening of the poles, absence of myocardial differentiation and altered patterning of the atrioventricular canal, which also lacks epithelial-to-mesenchymal transition. Proliferation and death of progenitors as well as early patterning of the heart appear normal. However, DiI labelling of second heart field progenitors revealed a defect in the addition of cells to the heart. RNA microarray analysis uncovered a set of differentially expressed genes in Arid3b-deficient tissues, including Bhlhb2, a regulator of cardiomyocyte differentiation, and Lims2, a gene involved in cell migration. Arid3b is thus required for heart development by regulating the motility and differentiation of heart progenitors. These findings identify Arid3b as a candidate gene involved in the aetiology of human congenital malformations.
Multiple endothelial cells constitute the tip of developing blood vessels and polarize to promote lumen formation
Authors: Pelton John C. , Wright Catherine E. , Leitges Michael , Bautch Victoria L.
Published: October 2014

Blood vessel polarization in the apical-basal axis is important for directed secretion of proteins and lumen formation; yet, when and how polarization occurs in the context of angiogenic sprouting is not well understood. Here, we describe a novel topology for endothelial cells at the tip of angiogenic sprouts in several mammalian vascular beds. Two cells that extend filopodia and have significant overlap in space and time were present at vessel tips, both in vitro and in vivo. The cell overlap is more extensive than predicted for tip cell switching, and it sets up a longitudinal cell-cell border that is a site of apical polarization and lumen formation, presumably via a cord-hollowing mechanism. The extent of cell overlap at the tip is reduced in mice lacking aPKCζ, and this is accompanied by reduced distal extension of both the apical border and patent lumens. Thus, at least two polarized cells occupy the distal tip of blood vessel sprouts, and topology, polarization and lumenization along the longitudinal border of these cells are influenced by aPKCζ.
The tumor suppressor Nf2 regulates corpus callosum development by inhibiting the transcriptional coactivator Yap
Authors: Lavado Alfonso , Ware Michelle , Paré Joshua , Cao Xinwei
Published: October 2014

The corpus callosum connects cerebral hemispheres and is the largest axon tract in the mammalian brain. Callosal malformations are among the most common congenital brain anomalies and are associated with a wide range of neuropsychological deficits. Crossing of the midline by callosal axons relies on a proper midline environment that harbors guidepost cells emitting guidance cues to instruct callosal axon navigation. Little is known about what controls the formation of the midline environment. We find that two components of the Hippo pathway, the tumor suppressor Nf2 (Merlin) and the transcriptional coactivator Yap (Yap1), regulate guidepost development and expression of the guidance cue Slit2 in mouse. During normal brain development, Nf2 suppresses Yap activity in neural progenitor cells to promote guidepost cell differentiation and prevent ectopic Slit2 expression. Loss of Nf2 causes malformation of midline guideposts and Slit2 upregulation, resulting in callosal agenesis. Slit2 heterozygosity and Yap deletion both restore callosal formation in Nf2 mutants. Furthermore, selectively elevating Yap activity in midline neural progenitors is sufficient to disrupt guidepost formation, upregulate Slit2 and prevent midline crossing. The Hippo pathway is known for its role in controlling organ growth and tumorigenesis. Our study identifies a novel role of this pathway in axon guidance. Moreover, by linking axon pathfinding and neural progenitor behaviors, our results provide an example of the intricate coordination between growth and wiring during brain development.
Spatial gradients of protein-level time delays set the pace of the traveling segmentation clock waves
Authors: Ay Ahmet , Holland Jack , Sperlea Adriana , Devakanmalai Gnanapackiam Sheela , Knierer Stephan , Sangervasi Sebastian , Stevenson Angel , Özbudak Ertuğrul M.
Published: October 2014

The vertebrate segmentation clock is a gene expression oscillator controlling rhythmic segmentation of the vertebral column during embryonic development. The period of oscillations becomes longer as cells are displaced along the posterior to anterior axis, which results in traveling waves of clock gene expression sweeping in the unsegmented tissue. Although various hypotheses necessitating the inclusion of additional regulatory genes into the core clock network at different spatial locations have been proposed, the mechanism underlying traveling waves has remained elusive. Here, we combined molecular-level computational modeling and quantitative experimentation to solve this puzzle. Our model predicts the existence of an increasing gradient of gene expression time delays along the posterior to anterior direction to recapitulate spatiotemporal profiles of the traveling segmentation clock waves in different genetic backgrounds in zebrafish. We validated this prediction by measuring an increased time delay of oscillatory Her1 protein production along the unsegmented tissue. Our results refuted the need for spatial expansion of the core feedback loop to explain the occurrence of traveling waves. Spatial regulation of gene expression time delays is a novel way of creating dynamic patterns; this is the first report demonstrating such a control mechanism in any tissue and future investigations will explore the presence of analogous examples in other biological systems.
Delivery of the CSF-1R to the lumen of macropinosomes promotes its destruction in macrophages
Authors: Lou Jieqiong , Low-Nam Shalini T. , Kerkvliet Jason G. , Hoppe Adam D.
Published: October 2014

Activation of the macrophage Colony Stimulating Factor-1 Receptor (CSF-1R) by CSF-1 stimulates pronounced macropinocytosis and drives proliferation of macrophages. While the role of macropinocytosis in CSF-1R signaling remains unknown, we show that despite internalizing large quantities of plasma membrane, macropinosomes contribute little to the internalization of the CSF-1/CSF-1R complex. Rather, internalization of the CSF-1R in small, endocytic vesicles, sensitive to clathrin disruption, out-compete macropinosomes for CSF-1R endocytosis. Following internalization, small vesicles carrying the CSF-1R underwent homotypic fusion and then trafficked to newly formed macropinosomes bearing Rab5. As these macropinosomes matured, acquiring Rab7, the CSF-1R was transported into their lumen, and degraded. Inhibition of macropinocytosis delayed receptor degradation despite no disruption of CSF-1R endocytosis. These data indicate that CSF-1-stimulated macropinosomes are sites of multivesicular body formation and accelerate CSF-1R degradation. Further, we demonstrate that macropinocytosis and cell growth have a matching dose dependence on CSF-1, suggesting that macropinosomes may be a central mechanism coupling CSF-1R signaling and macrophage growth.
Numbers: give me five
Authors: Harries Judith
Published: October 2014

Tailoring your mathematical activities to a specific number can help children become more familiar with it. Judith Harries focuses on the number five and looks at relevant shapes, patterns and rhymes.
A good night's sleep
Authors: de Bruin Eleanor
Published: October 2014

As Jill Murphy's book shows, it is not always easy to fall asleep. The following activities by Eleanor de Bruin explore children's different bedtime routines and the noises that keep Mr Bear awake.
It's a jungle in there
Authors: Bruin Eleanor de
Published: October 2014

Explore the jungle without leaving your home. Eleanor de Bruin shares three activities that will stimulate your children's memory, creativity, fine motor skills and mathematic abilities.
Relational Aggression and Response Decision Biases in Social Information Processing in Australian Adolescent Females
Authors: Jenkins Joanna M. , Fletcher Janet
Published: October 2014

Relational aggression is becoming increasingly recognized as a very prevalent behaviour amongst females, especially within school settings. Robust findings have supported N.R Crick and K.A. Dodge's Social Information Processing Model (1994) as being a useful model in explaining physical aggression amongst males. However, little research has examined the model with regards to relational aggression in females and research that does exist has shown inconsistent findings. The current study examined the fifth step of the model, Response Decision, in a sample of female adolescents. The four factors that have previously been identified as contributing to the response decision step were examined, including response evaluation, outcome expectancies, self-efficacy evaluation, and response selection. In view of suggestions made by W.F.Arsenio and E.A.Lemerise (2004), level of moral reasoning was also examined with regard to how relationally aggressive responses were evaluated. These factors were examined within hypothetical relationally aggressive peer situations in relationally aggressive, overtly aggressive, relationally plus overtly aggressive and non-aggressive participants. The results show that compared to non-aggressive and overtly aggressive females, relationally aggressive females show a bias in the four processes of the response decision step. Differences in levels of moral reasoning were also found between the different aggression type groups. Hence the findings provide support for Crick and Dodge's (1994) Social Information Processing model in explaining relationally aggressive behaviour. The findings are discussed with regards to their implications for educational settings.
Interaction of initial litter quality and thinning intensity on litter decomposition rate, nitrogen accumulation and release in a pine plantation
Authors: Chen Xiao , Page-Dumroese Deborah , Lv Ruiheng , Wang Weiwei , Li Guolei , Liu Yong
Published: October 2014

Thinning alters litter quality and microclimate under forests. Both of these two changes after thinning induce alterations of litter decomposition rates and nutrient cycling. However, a possible interaction between these two changes remains unclear. We placed two types of litter (LN, low N concentration litter; HN, high N concentration litter) in a Chinese pine ( CarriÃ¨re) plantation under four thinning treatments to test the impacts of litter quality, thinning or their combination on decomposition rate and N cycling. In our study, N was accumulated to approach an underlying critical acid-unhydrolyzable residue to nitrogen ratio (approximately 57â69) in litter. Moreover, an interaction between litter quality and thinning on decomposition rates, N accumulation and net release did exist. On one hand, one year decomposition rate of LN was elevated after thinning while that of HN remained the same or even lower (under light thinning); N accumulation of LN declined with light thinning and was restored with the increase of thinning intensity whereas that of HN did not decline with thinning and increased under heavy thinning; Net N release from LN was only found in light and heavy thinning while that from HN was found in all treatments, moreover net N release from LN and HN were both elevated under heavy thinning. On the other hand, HN decomposed faster, accumulated less and released more N than LN did under all treatments. Generally, high N concentration in litter and high-intensity thinning can lead to rapid litter decomposition and N cycling in coniferous plantations.Pinus tabulaeformis
The Dutch Colonial Policy on Islam: Reading the Intellectual Journey of Snouck Hurgronje
Authors: Burhanudin Jajat
Published: October 2014

This article will explore the intellectual journey of Snouck Hurgonje as a hired scholar for the colonial agenda. His life in Mecca and then the Indies, his knowledge on Islam and the Muslims as revealed in the works he produced, and the way it was transformed into the colonial policies, are the main subjects of the discussion. The way Snouck Hurgronje dealt with Muslims on his tour of duty, for example by collaborating with the penghulu, and working together with the Arab, Said Oesman, will also be explored. It should be stated that, in line with Snouck Hurgonje’s advice, the Dutch policy on Islam was directed (among other things) to draw the native elite --in this particular case the penghulu-- into the colonial orbit.

[Artikel ini membahas perjalanan intelektual Snouck Hurgonje, seorang ilmuwan yang bekerja di bawah dan untuk kepentingan colonial Belanda di Indonesia. Kehidupannya di Mekah, kemudian kembali lagi ke Indonesia, pengetahuannya tentang agama dan orang Islam yang tertuang dalam kerya-karyanya, serta proses pengetahuan itu semua dalam mempengaruhi kebijakan pemerintah kolonial menjadi tema utama diskusi dalam tulisan ini. Selain itu, akan dibahas pula cara-cara Snouck Hurgonje dalam berhubungan dengan orang-orang Islam selama menjalani tugasnya, misalnya ketika bekerjasama dengan para penghulu atau ketika bekerjasama dengan tokoh Arab, Said Oesman. Perlu ditegaskan pula bahwa sejalan dengan saran-saran Snouck Hurgonje, kebijakan pemerintah kolonial Belanda tentang Islam antara lain lebih ditujukan untuk menarik kalangan elit pribumi, dalam hal ini adalah para penghulu, ke lingkaran pemerintah kolonial.]
Being Woman in the Land of Shari‘a: Politics of the Female Body, Piety, and Resistance in Langsa, Aceh
Authors: Ansor Muhammad
Published: October 2014

This study investigates the dynamic of institutionalization of Shari’a in Aceh, which focuses on analysis of the patterns of Langsa women’s resistance against religious leaders and state interpretations of the dress standards in the public space. This matter emerged because the implementation of Shari’a has been supported by local people, but the standard of Islamic dress that should be applied is still debatable among various groups in Aceh that have varied understandings and different religious visions. The regulation of dress code has been an issue for religious leaders, intellectuals, and Moslem activists. The resistance of Langsa women against the politics of body discipline could be open and secret. To analyze the forms of women’s resistance, the researcher applied James C. Scott’s hidden transcripts theory. Inspired by this theoretical framework, the researcher found that Langsa women, intellectuals, and religious leaders expressed their resistance over how women should dress in public space. In collecting the data, the researcher used observation, in-depth interviews, and focus group discussions. Accordingly, the research shows how Langsa women express their resistance towards religious hegemony and state interpretation of Islam.

[Tulisan ini membahas dinamika pelembagaan syariat Islam di Aceh dengan fokus resistensi tersembunyi perempuan Langsa terhadap penafsiran elite agama dan pemerintah perihal pembakuan standar pakaian di ruang publik. Meskipun implementasi syariat Islam Aceh mendapat dukungan masyarakat setempat, tetapi ketika sebuah tafsir tertentu tentang pakaian Islami dibakukan dalam regulasi (Qanun), muncul perdebatan dari sebagian muslim yang berpola pemikiran dan visi keagamaan berbeda. Bukan hanya perdebatan di kalangan elite agama, intelektual, maupun aktivis, perempuan di berbagai daerah di Aceh pun mengekspresikan resistensi, baik secara terbuka maupun tersembunyi. Peneliti menggunakan teori hidden transcripts sebagaimana dikemukakan James C. Scott untuk menganalisa resistensi tersebut. Data dikumpulkan melalui observasi, wawancara mendalam, serta diskusi kelompok terfokus (FGD). Penelitian ini memperlihatkan bagaimana perempuan Langsa mengekspresikan resistensi tersembunyi atas hegemoni elite agama dan pemerintah dalam menafsirkan Islam].
Political connectedness and business performance: evidence from Turkish industry rankings
Authors: Özcan Gül Berna , Gündüz Umut
Published: October 2014

This paper examines the degree to which political connections affect business rankings through a statistical analysis of Turkey's industry rankings between 2003 and 2011. The analysis demonstrates that business performance is associated with connectedness through industry and firm level data. We show that political connectedness varies according to the firm's channel of access to obtain favouritism either through direct personal ties or institutional networks. Ideological motivations emerge to be significant in mobilizing, shaping and tying firm behaviour to broader political agendas. In the conclusion we discuss the impact of deepening connectedness on long-term business fortunes and political institutions.
Wolfe-type second-order fractional symmetric duality
Authors: Jayswal Anurag , Stancu-Minasian Ioan M. , Prasad Ashish K.
Published: October 2014

In the present paper, we examine duality results for Wolfe-type second-order fractional symmetric dual programs. These duality results are then used to investigate minimax mixed integer symmetric dual fractional programs. We also discuss self-duality results at the end.
H. B. Reitlinger and the origins of the efficiency at maximum power
formula for heat engines
Authors: Vaudrey Alexandre , Lanzetta François , Feidt Michel
Published: October 2014

Even if not so ancient, the history of the heat engine efficiency at
maximum power expression has been yet turbulent. More than a decade
after the publication of the seminal article by Curzon and
Ahlborn in 1975, two older works by Chambadal and Novikov
were rediscovered, both dating from 1957. Then,
some years ago, the name of Yvon arose from a textual reference
to this famous relation in a conference article published in 1955.
Thanks to a historical study of French-written books not published for a long time,
and since never translated into other languages,
we bring to light in this paper that this relation was actually first
proposed by Henri B. Reitlinger in 1929.
Microwave-assisted alcoholysis of dialkyl phosphites by ethylene glycol and ethanolamine
Authors: Keglevich György , Bálint Erika , Tajti Ádám , Mátravölgyi Béla , Balogh György Tibor , Bálint Mária , Ilia Gheorghe
Published: October 2014

A study on the microwave-assisted alcoholysis of diethyl phosphite with ethylene glycol revealed that after optimization of the conditions (molar ratio, temperature and time), the target “monomer,” (HOCH2CH2O)2P(O)H was formed in a proportion of 59 %, but with an incomplete conversion. The formation of the (HOCH2CH2O)(EtO)P(O)H and H(EtO)(O)POCH2CH2OP(O)(OEt)H by-products was, in most cases, inevitable. The alcoholysis with ethanolamine was more efficient and took place in a conversion of 100 % to afford H2NCH2CH2O)2P(O)H in a proportion of 85 %. An alkyl substituent on theN-atom prevented the alcoholysis.
Amygdala Inputs to the Prefrontal Cortex Elicit Heterosynaptic Suppression of Hippocampal Inputs
Authors: Tejeda Hugo A. , O'Donnell Patricio
Published: October 2014

Whereas cooperative communication between the hippocampus (HP) and prefrontal cortex (PFC) is critical for cognitive functions, an antagonistic relationship may exist between the basolateral amygdala (BLA) and PFC during emotional processing. As PFC neurons integrate information from converging excitatory BLA and HP inputs, we explored whether the ability of BLA inputs to evoke feedforward inhibition in the PFC affects converging HP synaptic inputs usingin vivointracellular recordings in anesthetized rats. BLA train stimulation decreased HP synaptic responses in the PFCin vivo. This effect was dependent on the timing of HP-evoked responses and the strength of BLA activation. BLA train stimulation also produced heterosynaptic suppression of responses from the amygdalo-piriform cortex, an associative temporal cortical structure. Heterosynaptic suppression was unidirectional as HP trains failed to modify BLA synaptic responses. These findings provide a mechanism by which BLA activation could decrease PFC neural activity and transiently attenuate the HP influence on PFC function.
Loss of Mitochondrial Fission Depletes Axonal Mitochondria in Midbrain Dopamine Neurons
Authors: Berthet Amandine , Margolis Elyssa B. , Zhang Jue , Hsieh Ivy , Zhang Jiasheng , Hnasko Thomas S. , Ahmad Jawad , Edwards Robert H. , Sesaki Hiromi , Huang Eric J. , Nakamura Ken
Published: October 2014

Disruptions in mitochondrial dynamics may contribute to the selective degeneration of dopamine (DA) neurons in Parkinson's disease (PD). However, little is known about the normal functions of mitochondrial dynamics in these neurons, especially in axons where degeneration begins, and this makes it difficult to understand the disease process. To study one aspect of mitochondrial dynamics—mitochondrial fission—in mouse DA neurons, we deleted the central fission protein dynamin-related protein 1 (Drp1). Drp1 loss rapidly eliminates the DA terminals in the caudate–putamen and causes cell bodies in the midbrain to degenerate and lose α-synuclein. Without Drp1, mitochondrial mass dramatically decreases, especially in axons, where the mitochondrial movement becomes uncoordinated. However, in the ventral tegmental area (VTA), a subset of midbrain DA neurons characterized by small hyperpolarization-activated cation currents (Ih) is spared, despite near complete loss of their axonal mitochondria. Drp1 is thus critical for targeting mitochondria to the nerve terminal, and a disruption in mitochondrial fission can contribute to the preferential death of nigrostriatal DA neurons.
Cognitive Deterioration and Functional Compensation in ALS Measured with fMRI Using an Inhibitory Task
Authors: Witiuk Kelsey , Fernandez-Ruiz Juan , McKee Ryan , Alahyane Nadia , Coe Brian C. , Melanson Michel , Munoz Douglas P.
Published: October 2014

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons, resulting in progressive weakness and muscle atrophy. Recent studies suggest that nondemented ALS patients can show selective cognitive impairments, predominantly executive dysfunction, but little is known about the neural basis of these impairments. Oculomotor studies in ALS have described deficits in antisaccade execution, which requires the implementation of a task set that includes inhibition of automatic responses followed by generation of a voluntary action. It has been suggested that the dorsolateral prefrontal cortex (DLPFC) contributes in this process. Thus, we investigated whether deterioration of executive functions in ALS patients, such as the ability to implement flexible behavior during the antisaccade task, is related to DLPFC dysfunction. While undergoing an fMRI scan, 12 ALS patients and 12 age-matched controls performed an antisaccade task with concurrent eye tracking. We hypothesized that DLPFC deficits would appear during the antisaccade preparation stage, when the task set is being established. ALS patients made more antisaccade direction errors and showed significant reductions in DLPFC activation. In contrast, regions, such as supplementary eye fields and frontal eye fields, showed increased activation that was anticorrelated with the number of errors. The ALS group also showed reduced saccadic latencies that correlated with increased activation across the oculomotor saccade system. These findings suggest that ALS results in deficits in the inhibition of automatic responses that are related to impaired DLPFC activation. However, they also suggest that ALS patients undergo functional changes that partially compensate the neurological impairment.
Effects of HIV-1 Tat on Enteric Neuropathogenesis
Authors: Ngwainmbi Joy , De Dipanjana D. , Smith Tricia H. , El-Hage Nazira , Fitting Sylvia , Kang Minho , Dewey William L. , Hauser Kurt F. , Akbarali Hamid I.
Published: October 2014

The gastrointestinal (GI) tract presents a major site of immune modulation by HIV, resulting in significant morbidity. Most GI processes affected during HIV infection are regulated by the enteric nervous system. HIV has been identified in GI histologic specimens in up to 40% of patients, and the presence of viral proteins, including thetrans-activator of transcription (Tat), has been reported in the gut indicating that HIV itself may be an indirect gut pathogen. Little is known of how Tat affects the enteric nervous system. Here we investigated the effects of the Tat protein on enteric neuronal excitability, proinflammatory cytokine release, and its overall effect on GI motility. Direct application of Tat (100 nm) increased the number of action potentials and reduced the threshold for action potential initiation in isolated myenteric neurons. This effect persisted in neurons pretreated with Tat for 3 d (19 of 20) and in neurons isolated from Tat+(Tat-expressing) transgenic mice. Tat increased sodium channel isoforms Nav1.7 and Nav1.8 levels. This increase was accompanied by an increase in sodium current density and a leftward shift in the sodium channel activation voltage. RANTES, IL-6, and IL-1β, but not TNF-α, were enhanced by Tat. Intestinal transit and cecal water content were also significantly higher in Tat+transgenic mice than Tat−littermates (controls). Together, these findings show that Tat has a direct and persistent effect on enteric neuronal excitability, and together with its effect on proinflammatory cytokines, regulates gut motility, thereby contributing to GI dysmotilities reported in HIV patients.
Dopamine Invigorates Reward Seeking by Promoting Cue-Evoked Excitation in the Nucleus Accumbens
Authors: du Hoffmann Johann , Nicola Saleem M.
Published: October 2014

Approach to reward is a fundamental adaptive behavior, disruption of which is a core symptom of addiction and depression. Nucleus accumbens (NAc) dopamine is required for reward-predictive cues to activate vigorous reward seeking, but the underlying neural mechanism is unknown. Reward-predictive cues elicit both dopamine release in the NAc and excitations and inhibitions in NAc neurons. However, a direct link has not been established between dopamine receptor activation, NAc cue-evoked neuronal activity, and reward-seeking behavior. Here, we use a novel microelectrode array that enables simultaneous recording of neuronal firing and local dopamine receptor antagonist injection. We demonstrate that, in the NAc of rats performing a discriminative stimulus task for sucrose reward, blockade of either D1 or D2 receptors selectively attenuates excitation, but not inhibition, evoked by reward-predictive cues. Furthermore, we establish that this dopamine-dependent signal is necessary for reward-seeking behavior. These results demonstrate a neural mechanism by which NAc dopamine invigorates environmentally cued reward-seeking behavior.
Urokinase-Type Plasminogen Activator Promotes Dendritic Spine Recovery and Improves Neurological Outcome Following Ischemic Stroke
Authors: Wu Fang , Catano Marcela , Echeverry Ramiro , Torre Enrique , Haile Woldeab B. , An Jie , Chen Changhua , Cheng Lihong , Nicholson Andrew , Tong Frank C. , Park Jaekeun , Yepes Manuel
Published: October 2014

Spines are dendritic protrusions that receive most of the excitatory input in the brain. Early after the onset of cerebral ischemia dendritic spines in the peri-infarct cortex are replaced by areas of focal swelling, and their re-emergence from these varicosities is associated with neurological recovery after acute ischemic stroke (AIS). Urokinase-type plasminogen activator (uPA) is a serine proteinase that plays a central role in tissue remodeling via binding to the urokinase plasminogen activator receptor (uPAR). We report that cerebral cortical neurons release uPA during the recovery phase from ischemic strokein vivoor hypoxiain vitro. Although uPA does not have an effect on ischemia- or hypoxia-induced neuronal death, genetic deficiency of uPA (uPA−/−) or uPAR (uPAR−/−) abrogates functional recovery after AIS. Treatment with recombinant uPA after ischemic stroke induces neurological recovery in wild-type and uPA−/−but not in uPAR−/−mice. Diffusion tensor imaging studies indicate that uPA−/−mice have increased water diffusivity and decreased anisotropy associated with impaired dendritic spine recovery and decreased length of distal neurites in the peri-infarct cortex. We found that the excitotoxic injury induces the clustering of uPAR in dendritic varicosities, and that the binding of uPA to uPAR promotes the reorganization of the actin cytoskeleton and re-emergence of dendritic filopodia from uPAR-enriched varicosities. This effect is independent of uPA's proteolytic properties and instead is mediated by Rac-regulated profilin expression and cofilin phosphorylation. Our data indicate that binding of uPA to uPAR promotes dendritic spine recovery and improves functional outcome following AIS.
Germline deletion and a somatic mutation of the PRKAR1A gene in a Carney complex-related pituitary adenoma
Authors: Iwata T , Tamanaha T , Koezuka R , Tochiya M , Makino H , Kishimoto I , Mizusawa N , Ono S , Inoshita N , Yamada S , Shimatsu A , Yoshimoto K
Published: October 2014

Objective

The objective was to assess involvement of loss of the PRKAR1A gene encoding a type 1α regulatory subunit of cAMP-dependent protein kinase A located on 17q24 in a Carney complex (CNC)-related pituitary adenoma.

Design

We investigated aberrations of the PRKAR1A gene in a CNC patient with a GH-producing pituitary adenoma, whose family has three other members with probable CNC.

Methods

A gene mutation was identified by a standard DNA sequencing method based on PCR. DNA copy number was measured to evaluate allelic loss on 17q24 by quantitative PCR. The breakpoints of deletion were determined by cloning a rearranged region in the deleted allele.

Results

A PRKAR1A mutation of c.751_758del8 (p.S251LfsX16) was found in genomic DNA obtained from a pituitary adenoma, but not leukocytes from the patient. Reduced DNA copy number at loci including the PRKAR1A gene on 17q24 was detected in both the tumor and leukocytes, suggesting a deletion at the loci at the germline level. The deletion size was determined to be ∼0.5 Mb and this large deletion was also found in two other family members.

Conclusion

This is the first case showing a CNC-related pituitary adenoma with the combination of somatic mutation and a large inherited deletion of the PRKAR1A gene. Biallelic inactivation of PRKAR1A appears to be necessary for the development of CNC-related pituitary adenoma.
Somatostatin receptor expression in hepatocellular carcinoma: prognostic and therapeutic considerations
Authors: Abdel-Rahman Omar , Lamarca Angela , Valle Juan W , Hubner Richard A
Published: October 2014

Sorafenib is the only systemic therapy to demonstrate a significant survival benefit over supportive care in robust randomised controlled trials for advanced hepatocellular carcinoma (HCC). In the context of an intense search for prognostic and predictive factors for response and efficacy of different systemic therapies (including sorafenib), a number of molecular targets have been identified, paving new avenues for potential therapeutic opportunities. Such molecular targets include somatostatin receptor (SSTR)-related alterations. In this review, we provide an overview of the various considerations relating to SSTRs as potentially novel prognostic and predictive biomarkers for HCC with special emphasis on the therapeutic potential of somatostatin analogues in HCC management.
Mechanisms of translational repression of the Smcp mRNA in round spermatids
Authors: Cullinane Danielle L , Chowdhury Tamjid A , Kleene Kenneth C
Published: October 2014

The protamine 1 (Prm1) and sperm mitochondria-associated, cysteine-rich protein (Smcp) mRNAs exemplify a widespread pattern of mRNA-specific regulation of mRNA translation in post-meiotic spermatogenic cells, spermatids. Both mRNAs are transcribed and initially stored in free-mRNPs in early spermatids, and translated on polysomes in late spermatids. In this study, we demonstrate that the 5′ and 3′-UTRs and the 3′ terminus of theSmcp3′-UTR are required for normal repression of theSmcpmRNA in transgenic mice. RNA affinity chromatography and mass spectrometry sequencing identified Y-box protein 2 (YBX2/MSY2) as the major protein that interacts with the 3′ terminus of theSmcp3′-UTR and a Y-box recognition sequence, GCCACCU, in the translation control element that is necessary forPrm1mRNA repression. Depletion of YBX2 inYbx2-null mice prematurely activatesPrm1andSmcpmRNA translation in early spermatids. Fluorescentin situhybridization reveals that theSmcpintron, theSmcpmRNA, and bothSmcp–Gfptransgenic mRNAs are strongly concentrated in the chromatoid body, and that theYbx2-null mutation does not eliminate theSmcpmRNA from the chromatoid body. This and previous findings suggest that theSmcppre-mRNA is spliced and associates with YBX2 in the chromatoid body, and that repressed free-mRNPs are stored in the general cytoplasm. As YBX2 is the predominant protein in testis free-mRNPs, it likely represses many mRNAs in early spermatids. The mechanisms by which YBX2 represses theSmcpandPrm1mRNAs are relevant to reproductive medicine because mutations in the humanYBX2gene correlate with abnormal protamine expression and male infertility.
The role of BH3-only proteins in apoptosis within the ovary
Authors: Hutt Karla J
Published: October 2014

BH3-only proteins are pro-apoptotic members of the BCL2 family that play pivotal roles in embryonic development, tissue homeostasis and immunity by triggering cell death through the intrinsic apoptosis pathway. Recentin vitroandin vivostudies have demonstrated that BH3-only proteins are also essential mediators of apoptosis within the ovary and are responsible for the initiation of the cell death signalling cascade in a cell type and stimulus-specific fashion. This review gives a brief overview of the intrinsic apoptosis pathway and summarise the roles of individual BH3-only proteins in the promotion of apoptosis in embryonic germ cells, oocytes, follicular granulosa cells and luteal cells. The role of these proteins in activating apoptosis in response to developmental cues and cell stressors, such as exposure to chemotherapy, radiation and environmental toxicants, is described. Studies on the function of BH3-only proteins in the ovary are providing valuable insights into the regulation of oocyte number and quality, as well as ovarian endocrine function, which collectively influence the female reproductive lifespan and health.
Evaluation of the use of Leptodactylus ocellatus (Anura: Leptodactylidae) frog tissues as bioindicator of metal contamination in Contas River, Northeastern Brazil
Authors: CORREIA LÍVIA O. , SIQUEIRA JÚNIOR SÉRGIO , CARNEIRO PAULO L.S. , BEZERRA MARCOS A.
Published: October 2014

This paper presents a study on the viability of the use of tissues of the Leptodactylus ocellatus species (Anura Leptodactylidae) as a bioindicator of metal pollution. The study is based on the determination and correlation of the concentrations of manganese, chromium, zinc, nickel, copper and iron in sediments and tissues (skin, muscles and viscera) of the frog Leptodactylus ocellatus collected in the middle region of the Contas River in Bahia, Brazil. The highest levels of the metals studied were found in the viscera of this animal. In this tissue, a higher correlation of the concentration of these metals with those found in sediments was also observed. The concentrations of elements found in the skin and muscles of these amphibians have revealed no correlation with the sediment where they were collected. According to the results obtained, the viscera of the L. ocellatus species presents itself as a good bioindicator of contamination by the metals studied.
Impacto econômico da doença de Alzheimer no Brasil: é possível melhorar a assistência e reduzir custos?
Authors: Gutierrez Beatriz Aparecida Ozello , Silva Henrique Salmazo da , Guimarães Cristina , Campino Antonio Carlos
Published: October 2014

O objetivo deste estudo foi discutir dados relativos aos custos da Doença de Alzheimer (DA) e as iniciativas assistenciais para reduzir custos e auxiliar a família e os cuidadores no manejo com a doença. O fator de maior custo para as pessoas com DA leve foi o do tempo do cuidador não remunerado, enquanto que para aqueles com a doença em estágio avançado foi o dos cuidados relativos à institucionalização. Frente a esse panorama a literatura propõe a adoção de modelos de atenção que maximizem a independência funcional do idoso e a manutenção de suas habilidades, como a implantação do Centro Dia para Idosos e de programas de reabilitação e amparo ao idoso e família. Esses modelos de atenção precisam ser discutidos, estruturados e implantados na realidade brasileira.
A Política Nacional de alimentação e Nutrição e seu diálogo com a Política Nacional de Segurança alimentar e Nutricional
Authors: Alves Kelly Poliany de Souza , Jaime Patricia Constante
Published: October 2014

A alimentação é um dos determinantes e condicionantes da saúde e um direito inerente a todas as pessoas. As consequências da insegurança alimentar e nutricional da população, a exemplo da obesidade, desnutrição e carências nutricionais específicas, recaem sobre o setor saúde e têm feito com que, historicamente, este tenha incorporado a responsabilidade de políticas e programas de alimentação e nutrição no Brasil. Porém, a garantia da Segurança Alimentar e Nutricional exige uma conjunção de políticas públicas, dentre as quais a Política Nacional de Alimentação e Nutrição do SUS tem papel fundamental. O artigo objetiva contribuir com o debate sobre intersetorialidade e promoção da saúde a partir da apresentação da Política Nacional de Alimentação e Nutrição e discussão do seu papel enquanto interlocutora entre o Sistema Único de Saúde e a Política e Sistema Nacional de Segurança Alimentar e Nutricional. Essa perspectiva sugere fortemente a conjunção de esforços para a promoção da saúde e de SAN, com vistas a potencializar agendas desenvolvidas em diferentes setores e acompanhadas por diferentes conselhos de políticas públicas, que não se articulam, permitindo uma melhor atuação do governo e da sociedade civil sobre os determinantes da saúde e da alimentação.
Intersetorialidade? IntersetorialidadeS!
Authors: Akerman Marco , Franco de Sá Ronice , Moyses Simone , Rezende Regiane , Rocha Dais
Published: October 2014

Este artigo problematiza a intersetorialidade e mostra a polissemia do tema. Indica que ainda há falta de teorias que o consagrem como categoria de pesquisa e avaliação. Sugere que cada uma destas possíveis direções de abordagem intersetorial estará respondendo a questões distintas favorecendo a criação de um "banco de perguntas" para a pesquisa apresentada neste artigo. O artigo contextualiza o debate intersetorial; faz aproximações ao tema; indica que aspectos ainda estão em aberto; e, inspirado pela pluralidade do vocábulo "intersetorialidadeS", aponta a necessidade de se construir uma agenda de pesquisa que favoreça aportes teóricos para que a ação intersetorial não seja um experimento na gestão pública e possa se constituir em uma práxis de governo. São sugeridas 23 questões que abrem a possibilidade de se delinear uma agenda de pesquisa sobre intersetorialidade e de se expandir a suas bases teórica e avaliativa ainda por desenvolver-se.
Processo de revisão da Política Nacional de Promoção da Saúde: múltiplos movimentos simultâneos
Authors: Rocha Dais Gonçalves , Alexandre Veruska Prado , Marcelo Vânia Cristina , Rezende Regiane , Nogueira Júlia Devidé , Franco de Sá Ronice
Published: October 2014

A política pública pode ser compreendida como a tradução de propósitos de governos e de anseios da sociedade. Impulsionados pelos avanços e desafios das transformações sociais, pela necessidade de articulação de agendas e a pequena participação social na elaboração da Política Nacional de Promoção da Saúde (PNPS), de 2006, o Ministério da Saúde e o Grupo Temático de Promoção da Saúde/Abrasco propuseram a revisão desta. Este artigo descreve os movimentos deste processo. Trata-se de uma análise de política, realizada por revisão de literatura e análise documental na perspectiva da "triangulação interna". O processo de revisão adotou: múltiplas abordagens na coleta de informações (Oficinas Regionais e com Conselhos de Saúde, Delphi Intra/Intersetorial e Questionário Eletrônico); fontes de informação heterogêneas; contextos locais diferentes (cinco regiões do Brasil) e validação por pares. Os resultados foram sistematizados com auxílio de uma matriz de análise organizada em torno de objetivos, princípios, diretrizes, temas e ações, resultando em uma minuta da nova PNPS. Por fim, foi realizado um seminário nacional para apresentar os resultados do processo e a síntese do texto revisado, possibilitando identificar ganhos do processo e próximos passos dos atores envolvidos com a nova PNPS.
O apoio institucional como pilar na cogestão da atenção primária à saúde: a experiência do Programa TEIAS - Escola Manguinhos no Rio de Janeiro, Brasil
Authors: Casanova Angela Oliveira , Teixeira Mirna Barros , Montenegro Elyne
Published: October 2014

Este artigo apresenta reflexões acerca de conceitos e práxis de um novo dispositivo para a gestão e o cuidado em saúde: o apoio institucional. Considerado como uma função gerencial e de qualidade da atenção, que tem potência para reformular as práticas hierarquizadas e autoritárias de planejamento e coordenação em saúde, o apoio institucional é disparador de mudanças que fortalecem a autonomia, a responsabilização, as práticas coletivas e as novas relações entre gestores, profissionais e usuários do sistema de saúde. Esses pressupostos estão alinhados aos conceitos da Atenção Primária à Saúde (APS) integral e participativa, o que leva à conclusão que apoio institucional e matricial são processos que provocam novos modelos de gestão e atenção à saúde. Para apreensão do modo operacional desse dispositivo, se apresenta como estudo de caso a experiência do TEIAS-Escola Manguinhos da ENSP/Fiocruz que tem como um de seus pilares a adoção do apoio institucional como estratégia de corresponsabilização e gestão participativa na APS de uma comunidade da cidade do Rio de Janeiro.
Fronteiras da autonomia da gestão local de saúde: inovação, criatividade e tomada de decisão informada por evidências
Authors: Silva Silvio Fernandes da , Souza Nathan Mendes , Barreto Jorge Otávio Maia
Published: October 2014

O propósito deste artigo foi identificar as fronteiras da autonomia da gestão municipal no contexto do pacto federativo do Sistema Único de Saúde brasileiro e a importância e possibilidade de fomentar inovação, criatividade e tomada de decisão, informada pelas melhores evidências pelos governos locais. Metodologicamente partimos de questões que propiciaram diálogo com a literatura específica, visando identificar a influência das políticas com formulação centralizada nos espaços de autonomia local para, em seguida, identificar estratégias de incentivo à inovação, criatividade e uso sistemático da evidência de pesquisas na implementação de políticas em saúde. Constatamos uma redução gradativa da autonomia decisória pelo maior comprometimento financeiro dos municípios, decorrente das novas responsabilidades assumidas, bem como a possibilidade de reversão dessa tendência no contexto mais recente. Analisamos também determinantes e desafios para a difusão de práticas inovadoras e apresentamos experiências nacionais e internacionais com essa finalidade. Concluímos ser possível tornar mais efetivo o processo decisório local, desde que se consolidem iniciativas que estimulem essa cultura e a formulação e implementação de políticas informadas por evidências.