bluuebunny/crossref_metadata_2025_split huggingface dataset:
Substrate Availability of Mutant SPT Alters Neuronal Branching and Growth Cone Dynamics in Dorsal Root Ganglia
Authors: Jun Byung Kyu , Chandra Ankush , Kuljis Dika , Schmidt Brian P. , Eichler Florian S. 
Published: October 2015

Serine palmitoyltransferase (SPT) is a key enzyme in the first step of sphingolipid biosynthesis. Mutations in theSPTLC1gene that encodes for SPT subunits cause hereditary sensory neuropathy type 1. However, little is understood about how mutant SPT regulates mechanisms of sensory neuron and axonal growth. Using transgenic mice overexpressing the C133W SPT mutant, we found that mutant dorsal root ganglia (DRG) during growthin vitroexhibit increased neurite length and branching, coinciding with elevated expression of actin-cross-linking proteins at the neuronal growth cone, namely phosphorylated Ezrin/Radixin/Moesin. In addition, inhibition of SPT was able to reverse the mutant phenotype. Because mutant SPT preferentially usesl-alanine over its canonical substratel-serine, we also investigated the effects of substrate availability on DRG neurons. Supplementation withl-serine or removal ofl-alanine independently restored normal growth patterns in mutant SPTLC1C133WDRG. Therefore, we report that substrate availability and selectivity of SPT influence the regulation of neurite growth in DRG neurons.SIGNIFICANCE STATEMENTHereditary sensory neuropathy type 1 is an autosomal-dominant disorder that leads to a sensory neuropathy due to mutations in the serine palmitoyltransferase (SPT) enzyme. We investigated how mutant SPT and substrate levels regulate neurite growth. Because SPT is an important enzyme in the synthesis of sphingolipids, our data are of broader significance to other peripheral and metabolic disorders.
Encoding of Vicarious Reward Prediction in Anterior Cingulate Cortex and Relationship with Trait Empathy
Authors: Lockwood Patricia. L. , Apps Matthew A.J. , Roiser Jonathan P. , Viding Essi 
Published: October 2015

Empathy—the capacity to understand and resonate with the experiences of others—can depend on the ability to predict when others are likely to receive rewards. However, although a plethora of research has examined the neural basis of predictions about the likelihood of receiving rewards ourselves, very little is known about the mechanisms that underpin variability in vicarious reward prediction. Human neuroimaging and nonhuman primate studies suggest that a subregion of the anterior cingulate cortex in the gyrus (ACCg) is engaged when others receive rewards. Does the ACCg show specialization for processing predictions about others' rewards and not one's own and does this specialization vary with empathic abilities? We examined hemodynamic responses in the human brain time-locked to cues that were predictive of a high or low probability of a reward either for the subject themselves or another person. We found that the ACCg robustly signaled the likelihood of a reward being delivered to another. In addition, ACCg response significantly covaried with trait emotion contagion, a necessary foundation for empathizing with other individuals. In individuals high in emotion contagion, the ACCg was specialized for processing others' rewards exclusively, but for those low in emotion contagion, this region also responded to information about the subject's own rewards. Our results are the first to show that the ACCg signals probabilistic predictions about rewards for other people and that the substantial individual variability in the degree to which the ACCg is specialized for processing others' rewards is related to trait empathy.SIGNIFICANCE STATEMENTSuccessfully cooperating, competing, or empathizing with others can depend on our ability to predict when others are going to get something rewarding. Although many studies have examined how the brain processes rewards we will get ourselves, very little is known about vicarious reward processing. Here, we show that a subregion of the anterior cingulate cortex in the gyrus (ACCg) shows a degree of specialization for processing others' versus one's own rewards. However, the degree to which the ACCg is specialized varies with people's ability to empathize with others. This new insight into how vicarious rewards are processed in the brain and vary with empathy may be key for understanding disorders of social behavior, including psychopathy and autism.
Experience-Dependent Induction of Hippocampal ΔFosB Controls Learning
Authors: Eagle Andrew L. , Gajewski Paula A. , Yang Miyoung , Kechner Megan E. , Al Masraf Basma S. , Kennedy Pamela J. , Wang Hongbing , Mazei-Robison Michelle S. , Robison Alfred J. 
Published: October 2015

The hippocampus (HPC) is known to play an important role in learning, a process dependent on synaptic plasticity; however, the molecular mechanisms underlying this are poorly understood. ΔFosB is a transcription factor that is induced throughout the brain by chronic exposure to drugs, stress, and variety of other stimuli and regulates synaptic plasticity and behavior in other brain regions, including the nucleus accumbens. We show here that ΔFosB is also induced in HPC CA1 and DG subfields by spatial learning and novel environmental exposure. The goal of the current study was to examine the role of ΔFosB in hippocampal-dependent learning and memory and the structural plasticity of HPC synapses. Using viral-mediated gene transfer to silence ΔFosB transcriptional activity by expressing ΔJunD (a negative modulator of ΔFosB transcriptional function) or to overexpress ΔFosB, we demonstrate that HPC ΔFosB regulates learning and memory. Specifically, ΔJunD expression in HPC impaired learning and memory on a battery of hippocampal-dependent tasks in mice. Similarly, general ΔFosB overexpression also impaired learning. ΔJunD expression in HPC did not affect anxiety or natural reward, but ΔFosB overexpression induced anxiogenic behaviors, suggesting that ΔFosB may mediate attentional gating in addition to learning. Finally, we found that overexpression of ΔFosB increases immature dendritic spines on CA1 pyramidal cells, whereas ΔJunD reduced the number of immature and mature spine types, indicating that ΔFosB may exert its behavioral effects through modulation of HPC synaptic function. Together, these results suggest collectively that ΔFosB plays a significant role in HPC cellular morphology and HPC-dependent learning and memory.SIGNIFICANCE STATEMENTConsolidation of our explicit memories occurs within the hippocampus, and it is in this brain region that the molecular and cellular processes of learning have been most closely studied. We know that connections between hippocampal neurons are formed, eliminated, enhanced, and weakened during learning, and we know that some stages of this process involve alterations in the transcription of specific genes. However, the specific transcription factors involved in this process are not fully understood. Here, we demonstrate that the transcription factor ΔFosB is induced in the hippocampus by learning, regulates the shape of hippocampal synapses, and is required for memory formation, opening up a host of new possibilities for hippocampal transcriptional regulation.
Multisensory Integration of Visual and Vestibular Signals Improves Heading Discrimination in the Presence of a Moving Object
Authors: Dokka Kalpana , DeAngelis Gregory C. , Angelaki Dora E. 
Published: October 2015

Humans and animals are fairly accurate in judging their direction of self-motion (i.e., heading) from optic flow when moving through a stationary environment. However, an object moving independently in the world alters the optic flow field and may bias heading perception if the visual system cannot dissociate object motion from self-motion. We investigated whether adding vestibular self-motion signals to optic flow enhances the accuracy of heading judgments in the presence of a moving object. Macaque monkeys were trained to report their heading (leftward or rightward relative to straight-forward) when self-motion was specified by vestibular, visual, or combined visual-vestibular signals, while viewing a display in which an object moved independently in the (virtual) world. The moving object induced significant biases in perceived heading when self-motion was signaled by either visual or vestibular cues alone. However, this bias was greatly reduced when visual and vestibular cues together signaled self-motion. In addition, multisensory heading discrimination thresholds measured in the presence of a moving object were largely consistent with the predictions of an optimal cue integration strategy. These findings demonstrate that multisensory cues facilitate the perceptual dissociation of self-motion and object motion, consistent with computational work that suggests that an appropriate decoding of multisensory visual-vestibular neurons can estimate heading while discounting the effects of object motion.SIGNIFICANCE STATEMENTObjects that move independently in the world alter the optic flow field and can induce errors in perceiving the direction of self-motion (heading). We show that adding vestibular (inertial) self-motion signals to optic flow almost completely eliminates the errors in perceived heading induced by an independently moving object. Furthermore, this increased accuracy occurs without a substantial loss in the precision. Our results thus demonstrate that vestibular signals play a critical role in dissociating self-motion from object motion.
APOE Isoforms Control Pathogenic Subretinal Inflammation in Age-Related Macular Degeneration
Authors: Levy Olivier , Lavalette Sophie , Hu Shulong J. , Housset Michael , Raoul William , Eandi Chiara , Sahel José-Alain , Sullivan Patrick M. , Guillonneau Xavier , Sennlaub Florian 
Published: October 2015

Contrary to Alzheimer's disease (AD), theAPOE2allele increases and theAPOE4allele reduces the risk to develop age-related macular degeneration (AMD) compared with the most commonAPOE3allele. The underlying mechanism for this association with AMD and the reason for the puzzling difference with AD are unknown. We previously demonstrated that pathogenic subretinal mononuclear phagocytes (MPs) accumulate inCx3cr1-deficient mice due to the overexpression of APOE, interleukin-6, and CC chemokine ligand 2 (CCL2). We here show using targeted replacement mice expressing the human APOE isoforms (TRE2,TRE3, andTRE4) that MPs ofTRE2mice express increased levels of APOE, interleukin-6, and CCL2 and develop subretinal MP accumulation, photoreceptor degeneration, and exaggerated choroidal neovascularization similar to AMD. Pharmacological inhibition of the cytokine induction inhibited the pathogenic subretinal inflammation. In the context of APOE-dependent subretinal inflammation inCx3cr1GFP/GFPmice, theAPOE4allele led to diminished APOE and CCL2 levels and protectedCx3cr1GFP/GFPmice against harmful subretinal MP accumulation observed inCx3cr1GFP/GFPTRE3mice. Our study shows that pathogenic subretinal inflammation is APOE isoform-dependent and provides the rationale for the previously unexplained implication of the APOE2 isoform as a risk factor and the APOE4 isoform as a protective factor in AMD pathogenesis.SIGNIFICANCE STATEMENTThe understanding of how genetic predisposing factors, which play a major role in age-related macular degeneration (AMD), participate in its pathogenesis is an important clue to decipher the pathomechanism and develop efficient therapies. In this study, we used transgenic, targeted replacement mice that carry the three human APOE isoform-defining sequences at the mouse APOE chromosomal location and express the human APOE isoforms. Our study is the first to show howAPOE2provokes andAPOE4inhibits the cardinal AMD features, inflammation, degeneration, and exaggerated neovascularization. Our findings reflect the clinical association of the genetic predisposition that was recently confirmed in a major pooled analysis. They emphasize the role of APOE in inflammation and inflammation in AMD.
Regulated Dynamic Trafficking of Neurexins Inside and Outside of Synaptic Terminals
Authors: Neupert Christian , Schneider Romy , Klatt Oliver , Reissner Carsten , Repetto Daniele , Biermann Barbara , Niesmann Katharina , Missler Markus , Heine Martin 
Published: October 2015

Synapses depend on trafficking of key membrane proteins by lateral diffusion from surface populations and by exocytosis from intracellular pools. The cell adhesion molecule neurexin (Nrxn) plays essential roles in synapses, but the dynamics and regulation of its trafficking are unknown. Here, we performed single-particle tracking and live imaging of transfected, epitope-tagged Nrxn variants in cultured rat and mouse wild-type or knock-out neurons. We observed that structurally larger αNrxn molecules are more mobile in the plasma membrane than smaller βNrxns because αNrxns displayed higher diffusion coefficients in extrasynaptic regions and excitatory or inhibitory terminals. We found that well characterized interactions with extracellular binding partners regulate the surface mobility of Nrxns. Binding to neurexophilin-1 (Nxph1) reduced the surface diffusion of αNrxns when both molecules were coexpressed. Conversely, impeding other interactions by insertion of splice sequence #4 or removal of extracellular Ca2+augmented the mobility of αNrxns and βNrxns. We also determined that fast axonal transport delivers Nrxns to the neuronal surface because Nrxns comigrate as cargo on synaptic vesicle protein transport vesicles (STVs). Unlike surface mobility, intracellular transport of βNrxn+STVs was faster than that of αNrxns, but both depended on the microtubule motor protein KIF1A and neuronal activity regulated the velocity. Large spontaneous fusion of Nrxn+STVs occurred simultaneously with synaptophysin on axonal membranes mostly outside of active presynaptic terminals. Surface Nrxns enriched at synaptic terminals where αNrxns and Nxph1/αNrxns recruited GABAAR subunits. Therefore, our results identify regulated dynamic trafficking as an important property of Nrxns that corroborates their function at synapses.SIGNIFICANCE STATEMENTSynapses mediate most functions in our brains and depend on the precise and timely delivery of key molecules throughout life. Neurexins (Nrxns) are essential synaptic cell adhesion molecules that are involved in synaptic transmission and differentiation of synaptic contacts. In addition, Nrxns have been linked to neuropsychiatric diseases such as autism. Because little is known about the dynamic aspects of trafficking of neurexins to synapses, we investigated this important question using single-molecule tracking and time-lapse imaging. We identify distinct differences between major Nrxn variants both in surface mobility and during intracellular transport. Because their dynamic behavior is highly regulated, for example, by different binding activities, these processes have immediate consequences for the function of Nrxns at synapses.
Resistant hypertension with adrenal nodule: are we removing the right gland?
Authors: Das Gautam , Taylor Peter N , Tabasum Arshiya , Rao Bondugulapati L N , Parker Danny , Baglioni Piero , Okosieme Onyebuchi E , Scott Coombes David 
Published: October 2015

SummaryResistant hypertension is often difficult to treat and may be associated with underlying primary aldosteronism (PA). We describe the case of an elderly gentleman who presented with severe and resistant hypertension and was found to have a left adrenal incidentaloma during evaluation but had aldosterone excess secondary to unilateral adrenal hyperplasia (UAH) of the contralateral gland, which needed surgical intervention. A 65-year-old gentleman was evaluated for uncontrolled high blood pressure (BP) in spite of taking four antihypertensive medications. The high BP was confirmed on a 24-h ambulatory reading, and further biochemical evaluation showed an elevated serum aldosterone renin ratio (ARR) (1577 pmol/l per ng per ml per h). Radiological evaluation showed an adrenal nodule (15 mm) in the left adrenal gland but an adrenal vein sampling demonstrated a lateralization towards the opposite site favouring the right adrenal to be the source of excess aldosterone. A laparoscopic right adrenalectomy was performed and the histology of the gland confirmed nodular hyperplasia. Following surgery, the patient's BP improved remarkably although he remained on antihypertensives and under regular endocrine follow-up. PA remains the most common form of secondary and difficult-to-treat hypertension. Investigations may reveal incidental adrenal lesions, which may not be the actual source of excess aldosterone, but UAH may be a contributor and may coexist and amenable to surgical treatment. An adrenal vein sampling should be undertaken for correct lateralization of the source, otherwise a correctable diagnosis may be missed and the incorrect adrenal gland may be removed.Learning pointsSevere and resistant hypertension can often be associated with underlying PA.ARR is an excellent screening tool in patients with suspected PA.Lateralization with adrenal venous sampling is essential to isolate the source and differentiate between unilateral and bilateral causes of hyperaldosteronism.Adrenal incidentalomas and UAH may coexist and the latter may often be the sole cause of excess aldosterone secretion.Decisions about adrenalectomy should be made only after integrating and interpreting radiological and biochemical test findings properly.
Drosophila as an In Vivo Model for Human Neurodegenerative Disease
Authors: McGurk Leeanne , Berson Amit , Bonini Nancy M 
Published: October 2015

Abstract
With the increase in the ageing population, neurodegenerative disease is devastating to families and poses a huge burden on society. The brain and spinal cord are extraordinarily complex: they consist of a highly organized network of neuronal and support cells that communicate in a highly specialized manner. One approach to tackling problems of such complexity is to address the scientific questions in simpler, yet analogous, systems. The fruit fly, Drosophila melanogaster, has been proven tremendously valuable as a model organism, enabling many major discoveries in neuroscientific disease research. The plethora of genetic tools available in Drosophila allows for exquisite targeted manipulation of the genome. Due to its relatively short lifespan, complex questions of brain function can be addressed more rapidly than in other model organisms, such as the mouse. Here we discuss features of the fly as a model for human neurodegenerative disease. There are many distinct fly models for a range of neurodegenerative diseases; we focus on select studies from models of polyglutamine disease and amyotrophic lateral sclerosis that illustrate the type and range of insights that can be gleaned. In discussion of these models, we underscore strengths of the fly in providing understanding into mechanisms and pathways, as a foundation for translational and therapeutic research.
An Amino-Terminal Polo Kinase Interaction Motif Acts in the Regulation of Centrosome Formation and Reveals a Novel Function for centrosomin (cnn) in Drosophila
Authors: Eisman Robert C , Phelps Melissa A S , Kaufman Thomas 
Published: October 2015

Abstract
The formation of the pericentriolar matrix (PCM) and a fully functional centrosome in syncytial Drosophila melanogaster embryos requires the rapid transport of Cnn during initiation of the centrosome replication cycle. We show a Cnn and Polo kinase interaction is apparently required during embryogenesis and involves the exon 1A-initiating coding exon, suggesting a subset of Cnn splice variants is regulated by Polo kinase. During PCM formation exon 1A Cnn-Long Form proteins likely bind Polo kinase before phosphorylation by Polo for Cnn transport to the centrosome. Loss of either of these interactions in a portion of the total Cnn protein pool is sufficient to remove native Cnn from the pool, thereby altering the normal localization dynamics of Cnn to the PCM. Additionally, Cnn-Short Form proteins are required for polar body formation, a process known to require Polo kinase after the completion of meiosis. Exon 1A Cnn-LF and Cnn-SF proteins, in conjunction with Polo kinase, are required at the completion of meiosis and for the formation of functional centrosomes during early embryogenesis.
La Encíclica Sollicitudo rei socialis y la preocupación de Juan Pablo II por el desarrollo de los pueblos. Reflexión en el 25 aniversario de la encíclica Sollicitudo rei socialis
Authors: Kantor Robert 
Published: October 2015

The Catholic Church’s teaching on the development of the nations is generally included in two documents: Populorum Progressio by Pope Paul VI and Sollicitudo rei socialis by John Paul II. This year marks the 25th anniversary of publishing the Encyclical Sollicitudo rei socialis, hence the motive for writing this article. A characteristic feature of the teaching of John Paul II, which we fi nd in this Encyclical, is the ethical dimension of development. The Pope repeatedly drew attention to the inequitable distribution of material goods in the world. He stressed that “True development, in keeping with the speci fi c needs of the human being – man or woman, child, adult or old person implies, especially for those who actively share in this process and are responsible for it, a lively awareness of the value of the rights of all and of each person. It likewise implies a lively awareness of the need to respect the right of every individual to the full use of the benefits offered by science and technology” Sollicitudo rei socialis 33. This article consists of the four following issues: 1. Populorum Progressio and a new analysis on the development of the nations; 2. The main motive for the publication of Sollicitudo rei socialis; 3. The concept of development in the teaching of John Paul II; 4. Topicality of the papal document – 25 years later.
Hospice Counsellor Facing the Grief of the Terminally Ill Child and Its Family
Authors: Godawa Grzegorz 
Published: October 2015

The child’s illness, suffering and death provoke many emotions in the family. The ill child and its family both experience grief which is an emotional reaction to the danger of losing health or life. Support offered by home hospices for children aims at overcoming the destructive influence of illness. A hospice counsellor’s task is to improve the ill child and its family’s quality of life. He is helping the family overcome grief and prepare for the child’s death. The hospice team supports the family members who experience anticipatory and later, actual mourning. Preventing pathological effects of grief is a basic challenge for people who offer help.