bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytokines in inflammatory bowel disease
Authors: Moldoveanu Al.C. , Diculescu M. , Braticevici Carmen Fierbinţeanu
Published: October 2015

Inflammatory bowel diseases are chronic afflictions, characterized by active and remission periods. Inflammation is the most common type of response that the human body uses as a defense mechanism against aggressors from the environment. The frequency and degree of inflammation depends on the size of the affected tissues. The gastrointestinal tract is, by far, the most susceptible tissue to inflammatory responses, because of its constant exposure to various antigenic, mutagenic and toxic factors.

In inflammatory bowel diseases there is a loss of immune tolerance to intestinal flora that is mediated by various substances, including cytokines. Cytokines represent a key signal in the intestinal immune response. Activated dendritic cells and macrophages secrete cytokines that actively intervene in inflammation regulation, in both Crohn’s disease and ulcerative colitis. After their secretion by antigen presented cells, cytokines activate and differentiate T cells, stirring up the adaptive immune response.

Cytokines have an important role in the pathogenesis of inflammatory bowel diseases. The identification of new cytokines, as well as the changing of the pathogenesis paradigms in inflammatory bowel diseases has been done on animal tests and clinical studies. Thus, there is promising evidence basis for future therapy research based on cytokines, and anti-cytokine antibodies.
Serum ghrelin level is associated with cardiovascular risk score
Authors: Pop Dana , Peter P. , Dădârlat Alexandra , Sitar-Tăut Adela , Zdrenghea D.
Published: October 2015

Ghrelin, a newly discovered bioactive peptide, was originally reported to induce growth hormone release. Recent studies have shown beneficial hemodynamic effects of ghrelin in the cardiovascular system to support the wide distribution of its receptors in cardiovascular tissues. The aim of the study was to determine whether cardiovascular risk factors influence plasma ghrelin levels.

Methods. We evaluated in the Rehabilitation Hospital Cluj-Napoca, Cardiology - Department 88 consecutive subjects, 65 (73.86%) being women, with mean age 61.7±10.33 years. We assessed the presence of cardiovascular risk factors (obesity, arterial hypertension, diabetes mellitus, metabolic syndrome, smoking and lipid fractions). Plasma ghrelin levels were determined with a commercial ELISA kit (pg/ml).

Results. After the evaluation of cardiovascular risk factors, we found no statistically significant difference between ghrelin levels in the patients with vs those without cardiovascular risk factors (p>0.05). A negative correlation was found between ghrelin levels and age, r = −0.32 (p <0.05). Using the HeartScore Internet tool we calculated the cardiovascular risk for each patient according to the risk score system (SCORE) for high cardiovascular risk countries. Statistically, the risk of fatal cardiovascular events in the next 10 years was indirectly correlated with the ghrelin levels in each patient - correlation between ghrelin levels and SCORE system r=−0.25, p=0.015. In conclusion, low serum ghrelin concentrations are associated with an increased global cardiovascular risk, calculated based on the European SCORE scale. However, we could not demonstrate a direct relationship between any of the major risk factors and ghrelin.
Role of Duke treadmill score in the diagnosis of ischemic heart disease in women
Authors: Dǎdârlat Alexandra , Zdrenghea D. , Pop Dana
Published: October 2015

Ischemic heart disease is underdiagnosed in women due to atypical symptomatology as well as to the lower specificity of several paraclinical tests, such as exercise stress testing. The aim of the study was to ascertain whether the Duke treadmill score (DTS) could be an efficient parameter in the diagnosis of ischemic heart disease in women.

Material and method. 105 patients were enrolled in the study, 45.71% women with average age ranged between 20 and 70 years, investigated in the Rehabilitation Hospital, Cardiology-Departament, Cluj-Napoca, Romania. All the patients were clinically assessed as concerns the presence of cardiovascular risk factors, and they underwent electrocardiographic, echocardiographic and treadmill stress tests. DST was calculated according to the formula: exercise time – 5 x (ST deviation expressed in mm–4 x Angina Index).

Results. DTS was lower in women as compared to men: 2.54±5.36 vs. 6±4.69, p=0.0006. 54.28% of the patients were ranged with a low DTS risk category, whereas 45.71% belonged to a moderate and high risk category. DTS was significantly lower in women than in men with high blood pressure (2.03±4.8 vs. 5.8±4.28), hypercholesterolemia (1.14±4.51 vs. 6.24±4.13), diabetes mellitus (1.83 ± 3.73 vs. 6.13±4.8), and obesity (2.42±5.35 vs. 5.81±4.64). By analyzing the presence of cardiovascular risk factors only in women, we noticed that only those with high blood pressure (2.03±4.89 vs. 8.13 ±7.85) and hypercholesterolemia (2.31±4.76 vs. 3.89±5.95) had a statistically significant low DTS (p<0.05). In conclusion, our research, which showed differences in DTS between women and men, raises concerns about the early diagnosis of ischemic heart disease in women.
Single-centre epidemiological study on the incidence of hepatic hydatid cyst
Authors: Mihăilă Daniela Elena , Potecă T. D. , Potecă Anca , Piţuru S.
Published: October 2015

Echinococcosis is a parasitic disease caused by Echinococcus granulosus tapeworm through its larva infestation. Hydatid cyst has become a health problem interesting by the demographic changes in recent years. If until recently it was a disease of the pastors or breeders and animal lovers in rural areas, the increase in number of the stray animals in the streets of big cities has moved the curve incidence and prevalence of this disease onto the city. Worldwide pathology is prevalent in the Mediterranean, South America and Turkey. The present study examines patients admitted with the diagnosis of hydatid cyst in the surgery department of Colentina Clinical Hospital, Bucharest, across a period of six years. The results demonstrate that the incidence is higher among women (58%) than in men (41.3%). Also, statistical data processing shows that the prevalence/incidence is higher in urban areas compared to rural areas. We want the results of this research to lead to hypotheses that can be demonstrated by analytical studies, because, without fundamental knowledge provided by descriptive studies, it is almost impossible to ask about the aetiology and effects of treatments that can be used in the management of hydatid cyst.
Intravascular lymphomatosis presenting as skin lesions and subacute encephalopathy
Authors: Cojocaru Inimioara Mihaela , Mitru Adina , Nica Dana , Ardeleanu Carmen Maria
Published: October 2015

Intravascular lymphomatosis is a neoplastic multisystemic disease; it is a rare subtype of diffuse large cell lymphoma characterized by the presence of lymphoma cells in the lumina of small vessels. A 49-year-old Caucasian woman was admitted to the Department of Internal Medicine for fatigue, night sweats, loss of weight, and multiple nodules in the forearms. Three months ago the patient’s family noticed problems with her cognitive function, she displayed difficulties with common daily tasks. The neurological examination revealed bradypsychia. Laboratory data showed modestly high levels of lactate dehydrogenase, and C-reactive protein. The day after admission, the patient had headache which raised in intensity; his mental status deteriorated, she was disoriented to time and place. She presented nucal rigidity. The CSF examination revealed a hemorrhagic aspect, elements 30/mm3, cytology: lymphocytes 90%, numerous erythrocytes, proteinorachia 96 mg/dL, glycorrachia 60 mg/dL. Intravenous Methylprednisolone (0.5 g two times a day) and Mannitol 20% 1g/kgw/day were administered for five days without response. She became comatose and she died six days after hospitalization. The post-mortem macroscopical brain examination showed a swallen brain, with diffuse hemorrhagic areas in the supratentorial subcortical regions. Microscopical examination showed capillaries, venules, and many arterioles distended by large malignant cells suggesting malignant lymphocytes which were intraluminal. Every organ was involved, except for bone marrow and lymph nodes. Immunohistochemical studies showed intensive staining for B cells and negative staining for factor VIII related antigen, a specific endothelial cell marker. Intravascular lymphomatosis was the post-mortem diagnostic. It represents a difficult diagnostic challenge which involves laboratory, imagistic and immunohistochemical investigations.
Maxwell Equations for Slow-Moving Media
Authors: Rozov Andrey
Published: October 2015

In the present work, the Minkowski equations obtained on the basis of theory of relativity are used to describe electromagnetic fields in moving media. But important electromagnetic processes run under non-relativistic conditions of slow-moving media. Therefore, one should carry out its description in terms of classical mechanics. Hertz derived electrodynamic equations for moving media within the frame of classical mechanics on the basis of the Maxwell theory. His equations disagree with the experimental data concerned with the moving dielectrics. In the paper, a way of description of electromagnetic fields in slow-moving media on the basis of the Maxwell theory within the frame of classical mechanics is offered by combining the Hertz approach and the experimental data concerned with the movement of dielectrics in electromagnetic fields. Received Maxwell equations lack asymmetry in the description of the reciprocal electrodynamic action of a magnet and a conductor and conform to known experimental data. Comparative analysis of the Minkowski and Maxwell models is carried out.
Decoding Internally and Externally Driven Movement Plans
Authors: Ariani Giacomo , Wurm Moritz F. , Lingnau Angelika
Published: October 2015

During movement planning, brain activity within parietofrontal networks encodes information about upcoming actions that can be driven either externally (e.g., by a sensory cue) or internally (i.e., by a choice/decision). Here we used multivariate pattern analysis (MVPA) of fMRI data to distinguish between areas that represent (1) abstract movement plans that generalize across the way in which these were driven, (2) internally driven movement plans, or (3) externally driven movement plans. In a delayed-movement paradigm, human volunteers were asked to plan and execute three types of nonvisually guided right-handed reaching movements toward a central target object: using a precision grip, a power grip, or touching the object without hand preshaping. On separate blocks of trials, movements were either instructed via color cues (Instructed condition), or chosen by the participant (Free-Choice condition). Using ROI-based and whole-brain searchlight-based MVPA, we found abstract representations of planned movements that generalize across the way these movements are selected (internally vs externally driven) in parietal cortex, dorsal premotor cortex, and primary motor cortex contralateral to the acting hand. In addition, we revealed representations specific for internally driven movement plans in contralateral ventral premotor cortex, dorsolateral prefrontal cortex, supramarginal gyrus, and in ipsilateral posterior parietotemporal regions, suggesting that these regions are recruited during movement selection. Finally, we observed representations of externally driven movement plans in bilateral supplementary motor cortex and a similar trend in presupplementary motor cortex, suggesting a role in stimulus–response mapping.

SIGNIFICANCE STATEMENTThe way the human brain prepares the body for action constitutes an essential part of our ability to interact with our environment. Previous studies demonstrated that patterns of neuronal activity encode upcoming movements. Here we used multivariate pattern analysis of human fMRI data to distinguish between brain regions containing movement plans for instructed (externally driven) movements, areas involved in movement selection (internally driven), and areas containing abstract movement plans that are invariant to the way these were generated (i.e., that generalize across externally and internally driven movement plans). Our findings extend our understanding of the neural basis of movement planning and have the potential to contribute to the development of brain-controlled neural prosthetic devices.
Laminar Profile and Physiology of the α Rhythm in Primary Visual, Auditory, and Somatosensory Regions of Neocortex
Authors: Haegens Saskia , Barczak Annamaria , Musacchia Gabriella , Lipton Michael L. , Mehta Ashesh D. , Lakatos Peter , Schroeder Charles E.
Published: October 2015

The functional significance of the α rhythm is widely debated. It has been proposed that α reflects sensory inhibition and/or a temporal sampling or “parsing” mechanism. There is also continuing disagreement over the more fundamental questions of which cortical layers generate α rhythms and whether the generation of α is equivalent across sensory systems. To address these latter questions, we analyzed laminar profiles of local field potentials (LFPs) and concomitant multiunit activity (MUA) from macaque V1, S1, and A1 during both spontaneous activity and sensory stimulation. Current source density (CSD) analysis of laminar LFP profiles revealed α current generators in the supragranular, granular, and infragranular layers. MUA phase-locked to local current source/sink configurations confirmed that α rhythms index local neuronal excitability fluctuations. CSD-defined α generators were strongest in the supragranular layers, whereas LFP α power was greatest in the infragranular layers, consistent with some of the previous reports. The discrepancy between LFP and CSD findings appears to be attributable to contamination of the infragranular LFP signal by activity that is volume-conducted from the stronger supragranular α generators. The presence of α generators across cortical depth in V1, S1, and A1 suggests the involvement of α in feedforward as well as feedback processes and is consistent with the view that α rhythms, perhaps in addition to a role in sensory inhibition, may parse sensory input streams in a way that facilitates communication across cortical areas.

SIGNIFICANCE STATEMENTThe α rhythm is thought to reflect sensory inhibition and/or a temporal parsing mechanism. Here, we address two outstanding issues: (1) whether α is a general mechanism across sensory systems and (2) which cortical layers generate α oscillations. Using intracranial recordings from macaque V1, S1, and A1, we show α band activity with a similar spectral and laminar profile in each of these sensory areas. Furthermore, α generators were present in each of the cortical layers, with a strong source in superficial layers. We argue that previous findings, locating α generators exclusively in the deeper layers, were biased because of use of less locally specific local field potential measurements. The laminar distribution of α band activity appears more complex than generally assumed.
Rapid Feedforward Inhibition and Asynchronous Excitation Regulate Granule Cell Activity in the Mammalian Main Olfactory Bulb
Authors: Burton Shawn D. , Urban Nathaniel N.
Published: October 2015

Granule cell-mediated inhibition is critical to patterning principal neuron activity in the olfactory bulb, and perturbation of synaptic input to granule cells significantly alters olfactory-guided behavior. Despite the critical role of granule cells in olfaction, little is known about how sensory input recruits granule cells. Here, we combined whole-cell patch-clamp electrophysiology in acute mouse olfactory bulb slices with biophysical multicompartmental modeling to investigate the synaptic basis of granule cell recruitment. Physiological activation of sensory afferents within single glomeruli evoked diverse modes of granule cell activity, including subthreshold depolarization, spikelets, and suprathreshold responses with widely distributed spike latencies. The generation of these diverse activity modes depended, in part, on the asynchronous time course of synaptic excitation onto granule cells, which lasted several hundred milliseconds. In addition to asynchronous excitation, each granule cell also received synchronous feedforward inhibition. This inhibition targeted both proximal somatodendritic and distal apical dendritic domains of granule cells, was reliably recruited across sniff rhythms, and scaled in strength with excitation as more glomeruli were activated. Feedforward inhibition onto granule cells originated from deep short-axon cells, which responded to glomerular activation with highly reliable, short-latency firing consistent with tufted cell-mediated excitation. Simulations showed that feedforward inhibition interacts with asynchronous excitation to broaden granule cell spike latency distributions and significantly attenuates granule cell depolarization within local subcellular compartments. Collectively, our results thus identify feedforward inhibition onto granule cells as a core feature of olfactory bulb circuitry and establish asynchronous excitation and feedforward inhibition as critical regulators of granule cell activity.

SIGNIFICANCE STATEMENTInhibitory granule cells are involved critically in shaping odor-evoked principal neuron activity in the mammalian olfactory bulb, yet little is known about how sensory input activates granule cells. Here, we show that sensory input to the olfactory bulb evokes a barrage of asynchronous synaptic excitation and highly reliable, short-latency synaptic inhibition onto granule cells via a disynaptic feedforward inhibitory circuit involving deep short-axon cells. Feedforward inhibition attenuates local depolarization within granule cell dendritic branches, interacts with asynchronous excitation to suppress granule cell spike-timing precision, and scales in strength with excitation across different levels of sensory input to normalize granule cell firing rates.
Human Frontal–Subcortical Circuit and Asymmetric Belief Updating
Authors: Moutsiana Christina , Charpentier Caroline J. , Garrett Neil , Cohen Michael X. , Sharot Tali
Published: October 2015

How humans integrate information to form beliefs about reality is a question that has engaged scientists for centuries, yet the biological system supporting this process is not well understood. One of the most salient attributes of information is valence. Whether a piece of news is good or bad is critical in determining whether it will alter our beliefs. Here, we reveal a frontal–subcortical circuit in the left hemisphere that is simultaneously associated with enhanced integration of favorable information into beliefs and impaired integration of unfavorable information. Specifically, for favorable information, stronger white matter connectivity within this system, particularly between the left inferior frontal gyrus (IFG) and left subcortical regions (including the amygdala, hippocampus, thalamus, putamen, and pallidum), as well as insular cortex, is associated with greater change in belief. However, for unfavorable information, stronger connectivity within this system, particularly between the left IFG and left pallidum, putamen, and insular cortex, is associated with reduced change in beliefs. These novel results are consistent with models suggesting that partially separable processes govern learning from favorable and unfavorable information.

SIGNIFICANCE STATEMENTBeliefs of what may happen in the future are important, because they guide decisions and actions. Here, we illuminate how structural brain connectivity is related to the generation of subjective beliefs. We focus on how the valence of information is related to people's tendency to alter their beliefs. By quantifying the extent to which participants update their beliefs in response to desirable and undesirable information and relating those measures to the strength of white matter connectivity using diffusion tensor imaging, we characterize a left frontal–subcortical system that is associated simultaneously with greater belief updating in response to favorable information and reduced belief updating in response to unfavorable information. This neural architecture may allow valence to be incorporated into belief updating.
Nurr1 and Retinoid X Receptor Ligands Stimulate Ret Signaling in Dopamine Neurons and Can Alleviate α-Synuclein Disrupted Gene Expression
Authors: Volakakis Nikolaos , Tiklova Katarina , Decressac Mickael , Papathanou Maria , Mattsson Bengt , Gillberg Linda , Nobre André , Björklund Anders , Perlmann Thomas
Published: October 2015

α-synuclein, a protein enriched in Lewy bodies and highly implicated in neurotoxicity in Parkinson's disease, is distributed both at nerve terminals and in the cell nucleus. Here we show that a nuclear derivative of α-synuclein induces more pronounced changes at the gene expression level in mouse primary dopamine (DA) neurons compared to a derivative that is excluded from the nucleus. Moreover, by RNA sequencing we analyzed the extent of genome-wide effects on gene expression resulting from expression of human α-synuclein in primary mouse DA neurons. The results implicated the transcription factor Nurr1 as a key dysregulated target of α-synuclein toxicity. Forced Nurr1 expression restored the expression of hundreds of dysregulated genes in primary DA neurons expressing α-synuclein, and therefore prompted us to test the possibility that Nurr1 can be pharmacologically targeted by bexarotene, a ligand for the retinoid X receptor that forms heterodimers with Nurr1. Although our data demonstrated that bexarotene was ineffective in neuroprotection in ratsin vivo, the results revealed that bexarotene has the capacity to coregulate subsets of Nurr1 target genes including the receptor tyrosine kinase subunit Ret. Moreover, bexarotene was able to restore dysfunctional Ret-dependent neurotrophic signaling in α-synuclein-overexpressing mouse DA neurons. These data highlight the role of the Nurr1–Ret signaling pathway as a target of α-synuclein toxicity and suggest that retinoid X receptor ligands with appropriate pharmacological properties could have therapeutic potential in Parkinson's disease.

SIGNIFICANCE STATEMENTHow α-synuclein, a protein enriched in Lewy bodies in Parkinson's disease, is causing neuropathology in dopamine neurons remains unclear. This study elucidated how α-synuclein is influencing gene expression and how Nurr1, a transcription factor known to protect dopamine neurons against α-synuclein toxicity, can counteract these effects. Moreover, given the protective role of Nurr1, this study also investigated how Nurr1 could be pharmacologically targeted via bexarotene, a ligand of Nurr1's heterodimerization partner retinoid X receptor (RXR). The results showed that RXR ligands could increase neurotrophic signaling, but provided a mixed picture of its potential in a Parkinson's disease rat modelin vivo. However, this study clearly emphasized Nurr1's neuroprotective role and indicated that other RXR ligands could have therapeutic potential in Parkinson's disease.
There Is a “U” in Clutter: Evidence for Robust Sparse Codes Underlying Clutter Tolerance in Human Vision
Authors: Cox Patrick H. , Riesenhuber Maximilian
Published: October 2015

The ability to recognize objects in clutter is crucial for human vision, yet the underlying neural computations remain poorly understood. Previous single-unit electrophysiology recordings in inferotemporal cortex in monkeys and fMRI studies of object-selective cortex in humans have shown that the responses to pairs of objects can sometimes be well described as a weighted average of the responses to the constituent objects. Yet, from a computational standpoint, it is not clear how the challenge of object recognition in clutter can be solved if downstream areas must disentangle the identity of an unknown number of individual objects from the confounded average neuronal responses. An alternative idea is that recognition is based on a subpopulation of neurons that are robust to clutter, i.e., that do not show response averaging, but rather robust object-selective responses in the presence of clutter. Here we show that simulations using the HMAX model of object recognition in cortex can fit the aforementioned single-unit and fMRI data, showing that the averaging-like responses can be understood as the result of responses of object-selective neurons to suboptimal stimuli. Moreover, the model shows how object recognition can be achieved by a sparse readout of neurons whose selectivity is robust to clutter. Finally, the model provides a novel prediction about human object recognition performance, namely, that target recognition ability should show a U-shaped dependency on the similarity of simultaneously presented clutter objects. This prediction is confirmed experimentally, supporting a simple, unifying model of how the brain performs object recognition in clutter.

SIGNIFICANCE STATEMENTThe neural mechanisms underlying object recognition in cluttered scenes (i.e., containing more than one object) remain poorly understood. Studies have suggested that neural responses to multiple objects correspond to an average of the responses to the constituent objects. Yet, it is unclear how the identities of an unknown number of objects could be disentangled from a confounded average response. Here, we use a popular computational biological vision model to show that averaging-like responses can result from responses of clutter-tolerant neurons to suboptimal stimuli. The model also provides a novel prediction, that human detection ability should show a U-shaped dependency on target–clutter similarity, which is confirmed experimentally, supporting a simple, unifying account of how the brain performs object recognition in clutter.
A Critical Gating Switch at a Modulatory Site in Neuronal Kir3 Channels
Authors: Adney Scott K. , Ha Junghoon , Meng Xuan-Yu , Kawano Takeharu , Logothetis Diomedes E.
Published: October 2015

Inwardly rectifying potassium channels enforce tight control of resting membrane potential in excitable cells. The Kir3.2 channel, a member of the Kir3 subfamily of G-protein-activated potassium channels (GIRKs), plays several roles in the nervous system, including key responsibility in the GABABpathway of inhibition, in pain perception pathways via opioid receptors, and is also involved in alcoholism. PKC phosphorylation acts on the channel to reduce activity, yet the mechanism is incompletely understood. Using the heterologousXenopusoocyte system combined with molecular dynamics simulations, we show that PKC modulation of channel activity is dependent on Ser-196 in Kir3.2 such that, when this site is phosphorylated, the channel is less sensitive to PKC inhibition. This reduced inhibition is dependent on an interaction between phospho-Ser (SEP)-196 and Arg-201, reducing Arg-201 interaction with the sodium-binding site Asp-228. Neutralization of either SEP-196 or Arg-201 leads to a channel with reduced activity and increased sensitivity to PKC inhibition. This study clarifies the role of Ser-196 as an allosteric modulator of PKC inhibition and suggests that the SEP-196/Arg-201 interaction is critical for maintaining maximal channel activity.

SIGNIFICANCE STATEMENTThe inwardly rectifying potassium 3.2 (Kir3.2) channel is found principally in neurons that regulate diverse brain functions, including pain perception, alcoholism, and substance addiction. Activation or inhibition of this channel leads to changes in neuronal firing and chemical message transmission. The Kir3.2 channel is subject to regulation by intracellular signals including sodium, G-proteins, ethanol, the phospholipid phosphatidylinositol bis-phosphate, and phosphorylation by protein kinases. Here, we take advantage of the recently published structure of Kir3.2 to provide an in-depth molecular view of how phosphorylation of a specific residue previously thought to be the target of PKC promotes channel gating and acts as an allosteric modulator of PKC-mediated inhibition.
Internalized Tau Oligomers Cause Neurodegeneration by Inducing Accumulation of Pathogenic Tau in Human Neurons Derived from Induced Pluripotent Stem Cells
Authors: Usenovic Marija , Niroomand Shahriar , Drolet Robert E. , Yao Lihang , Gaspar Renee C. , Hatcher Nathan G. , Schachter Joel , Renger John J. , Parmentier-Batteur Sophie
Published: October 2015

Neuronal inclusions of hyperphosphorylated and aggregated tau protein are a pathological hallmark of several neurodegenerative tauopathies, including Alzheimer's disease (AD). The hypothesis of tau transmission in AD has emerged from histopathological studies of the spatial and temporal progression of tau pathology in postmortem patient brains. Increasing evidence in cellular and animal models supports the phenomenon of intercellular spreading of tau. However, the molecular and cellular mechanisms of pathogenic tau transmission remain unknown. The studies described herein investigate tau pathology propagation using human neurons derived from induced pluripotent stem cells. Neurons were seeded with full-length human tau monomers and oligomers and chronic effects on neuronal viability and function were examined over time. Tau oligomer-treated neurons exhibited an increase in aggregated and phosphorylated pathological tau. These effects were associated with neurite retraction, loss of synapses, aberrant calcium homeostasis, and imbalanced neurotransmitter release. In contrast, tau monomer treatment did not produce any measureable changes. This work supports the hypothesis that tau oligomers are toxic species that can drive the spread of tau pathology and neurodegeneration.

SIGNIFICANCE STATEMENTSeveral independent studies have implicated tau protein as central to Alzheimer's disease progression and cell-to-cell pathology propagation. In this study, we investigated the ability of different tau species to propagate pathology in human neurons derived from induced pluripotent stem cells, which to date has not been shown. We demonstrated that tau oligomers, but not monomers, induce accumulation of pathological, hyperphosphorylated tau. This effect was accompanied with neurite degeneration, loss of synapses, aberrant calcium homeostasis, imbalanced neurotransmitter release, and ultimately with neuronal death. This study bridges various tau pathological phenotypes into a single and relevant induced pluripotent stem cell neuronal model of human disease that can be applied to the discovery of the mechanisms of tau-induced neurodegeneration.
The Krüppel-Like Factor Dar1 Determines Multipolar Neuron Morphology
Authors: Wang Xin , Zhang Macy W. , Kim Jung Hwan , Macara Ann Marie , Sterne Gabriella , Yang Tao , Ye Bing
Published: October 2015

Neurons typically assume multipolar, bipolar, or unipolar morphologies. Little is known about the mechanisms underlying the development of these basic morphological types. Here, we show that the Krüppel-like transcription factor Dar1 determines the multipolar morphology of postmitotic neurons inDrosophila. Dar1 is specifically expressed in multipolar neurons and loss ofdar1gradually converts multipolar neurons into the bipolar or unipolar morphology without changing neuronal identity. Conversely, misexpression of Dar1 or its mammalian homolog in unipolar and bipolar neurons causes them to assume multipolar morphologies. Dar1 regulates the expression of several dynein genes andnuclear distribution protein C(nudC), which is an essential component of a specialized dynein complex that positions the nucleus in a cell. We further show that these genes are required for Dar1-induced multipolar neuron morphology.Dar1likely functions as a terminal selector gene for the basic layout of neuron morphology by regulating both dendrite extension and the dendrite–nucleus coupling.

SIGNIFICANCE STATEMENTThe three basic morphological types of neurons—unipolar, bipolar, and multipolar—are important for information processing and wiring of neural circuits. Little progress has been made toward understanding the molecular and cellular programs that generate these types since their discovery over a century ago. It is generally assumed that basic morphological types of neurons are determined by the number of dendrites growing out from the cell body. Here, we show that this model alone is insufficient. We introduce the positioning of nucleus as a critical factor in this process and report that the transcription factor Dar1 determines multipolar neuron morphology in postmitotic neurons by regulating genes involved in nuclear positioning.
Frizzled3 Controls Axonal Polarity and Intermediate Target Entry during Striatal Pathway Development
Authors: Morello Francesca , Prasad Asheeta A. , Rehberg Kati , Vieira de Sá Renata , Antón-Bolaños Noelia , Leyva-Diaz Eduardo , Adolfs Youri , Tissir Fadel , López-Bendito Guillermina , Pasterkamp R. Jeroen
Published: October 2015

The striatum is a large brain nucleus with an important role in the control of movement and emotions. Medium spiny neurons (MSNs) are striatal output neurons forming prominent descending axon tracts that target different brain nuclei. However, how MSN axon tracts in the forebrain develop remains poorly understood. Here, we implicate the Wnt binding receptor Frizzled3 in several uncharacterized aspects of MSN pathway formation [i.e., anterior–posterior guidance of MSN axons in the striatum and their subsequent growth into the globus pallidus (GP), an important (intermediate) target]. InFrizzled3knock-out mice, MSN axons fail to extend along the anterior–posterior axis of the striatum, and many do not reach the GP. Wnt5a acts as an attractant for MSN axonsin vitro, is expressed in a posterior high, anterior low gradient in the striatum, andWnt5aknock-out mice phenocopy striatal anterior–posterior defects observed inFrizzled3mutants. This suggests that Wnt5a controls anterior–posterior guidance of MSN axons through Frizzled3. Axons that reach the GP inFrizzled3knock-out mice fail to enter this structure. Surprisingly, entry of MSN axons into the GP non–cell-autonomously requires Frizzled3, and our data suggest that GP entry may be contingent on the correct positioning of “corridor” guidepost cells for thalamocortical axons by Frizzled3. Together, these data dissect MSN pathway development and reveal (non)cell-autonomous roles for Frizzled3 in MSN axon guidance. Further, they are the first to identify a gene that provides anterior–posterior axon guidance in a large brain nucleus and link Frizzled3 to corridor cell development.

SIGNIFICANCE STATEMENTStriatal axon pathways mediate complex physiological functions and are an important therapeutic target, underscoring the need to define how these connections are established. Remarkably, the molecular programs regulating striatal pathway development remain poorly characterized. Here, we determine the embryonic ontogeny of the two main striatal pathways (striatonigral and striatopallidal) and identify novel (non)cell-autonomous roles for the axon guidance receptor Frizzled3 in uncharacterized aspects of striatal pathway formation (i.e., anterior–posterior axon guidance in the striatum and axon entry into the globus pallidus). Further, our results link Frizzled3 to corridor guidepost cell development and suggest that an abnormal distribution of these cells has unexpected, widespread effects on the development of different axon tracts (i.e., striatal and thalamocortical axons).
A Post-Docking Role of Synaptotagmin 1-C2B Domain Bottom Residues R398/399 in Mouse Chromaffin Cells
Authors: Kedar Girish H. , Munch Anders S. , van Weering Jan R.T. , Malsam Jörg , Scheutzow Andrea , de Wit Heidi , Houy Sébastien , Tawfik Bassam , Söllner Thomas H. , Sørensen Jakob B. , Verhage Matthijs
Published: October 2015

Synaptotagmin-1 (Syt1) is the principal Ca2+sensor for vesicle fusion and is also essential for vesicle docking in chromaffin cells. Docking depends on interactions of the Syt1-C2B domain with the t-SNARE SNAP25/Syntaxin1 complex and/or plasma membrane phospholipids. Here, we investigated the role of the positively charged “bottom” region of the C2B domain, proposed to help crosslink membranes, in vesicle docking and secretion in mouse chromaffin cells and in cell-free assays. We expressed a double mutation shown previously to interfere with lipid mixing between proteoliposomes and with synaptic transmission, Syt1-R398/399Q (RQ), insyt1null mutant cells. Ultrastructural morphometry revealed that Syt1-RQ fully restored the docking defect observed previously insyt1null mutant cells, similar to wild type Syt1 (Syt1-wt). Small unilamellar lipid vesicles (SUVs) that contained the v-SNARE Synaptobrevin2 and Syt1-R398/399Q also docked to t-SNARE-containing giant vesicles (GUVs), similar to Syt1-wt. However, unlike Syt1-wt, Syt1-RQ-induced docking was strictly PI(4,5)P2-dependent. Unlike docking, neither synchronized secretion in chromaffin cells nor Ca2+-triggered SUV–GUV fusion was restored by the Syt1 mutants. Finally, overexpressing the RQ-mutant inwild typecells produced no effect on either docking or secretion. We conclude that the positively charged bottom region in the C2B domain—and, by inference, Syt1-mediated membrane crosslinking—is required for triggering fusion, but not for docking. Secretory vesicles dock by multiple, PI(4,5)P2-dependent and PI(4,5)P2-independent mechanisms. The R398/399 mutations selectively disrupt the latter and hereby help to discriminate protein regions involved in different aspects of Syt1 function in docking and fusion.

SIGNIFICANCE STATEMENTThis study provides new insights in how the two opposite sides of the C2B domain of Synaptotagmin-1 participate in secretory vesicle fusion, and in more upstream steps, especially vesicle docking. We show that the “bottom” surface of the C2B domain is required for triggering fusion, but not for docking. Synaptotagmin-1 promotes docking by multiple, PI(4,5)P2-dependent and PI(4,5)P2-independent mechanisms. Mutations in the C2B bottom surface (R398/399) selectively disrupt the latter. These mutations help to discriminate protein regions involved in different aspects of Synaptotagmin-1 function in docking and fusion.
Distinct Contributions of Ventromedial and Dorsolateral Subregions of the Human Substantia Nigra to Appetitive and Aversive Learning
Authors: Pauli Wolfgang M. , Larsen Tobias , Collette Sven , Tyszka Julian M. , Seymour Ben , O'Doherty John P.
Published: October 2015

The role of neurons in the substantia nigra (SN) and ventral tegmental area (VTA) of the midbrain in contributing to the elicitation of reward prediction errors during appetitive learning has been well established. Less is known about the differential contribution of these midbrain regions to appetitive versus aversive learning, especially in humans. Here we scanned human participants with high-resolution fMRI focused on the SN and VTA while they participated in a sequential Pavlovian conditioning paradigm involving an appetitive outcome (a pleasant juice), as well as an aversive outcome (an unpleasant bitter and salty flavor). We found a degree of regional specialization within the SN: Whereas a region of ventromedial SN correlated with a temporal difference reward prediction error during appetitive Pavlovian learning, a dorsolateral area correlated instead with an aversive expected value signal in response to the most distal cue, and to a reward prediction error in response to the most proximal cue to the aversive outcome. Furthermore, participants' affective reactions to both the appetitive and aversive conditioned stimuli more than 1 year after the fMRI experiment was conducted correlated with activation in the ventromedial and dorsolateral SN obtained during the experiment, respectively. These findings suggest that, whereas the human ventromedial SN contributes to long-term learning about rewards, the dorsolateral SN may be particularly important for long-term learning in aversive contexts.

SIGNIFICANCE STATEMENTThe role of the substantia nigra (SN) and ventral tegmental area (VTA) in appetitive learning is well established, but less is known about their contribution to aversive compared with appetitive learning, especially in humans. We used high-resolution fMRI to measure activity in the SN and VTA while participants underwent higher-order Pavlovian learning. We found a regional specialization within the SN: a ventromedial area was selectively engaged during appetitive learning, and a dorsolateral area during aversive learning. Activity in these areas predicted affective reactions to appetitive and aversive conditioned stimuli over 1 year later. These findings suggest that, whereas the human ventromedial SN contributes to long-term learning about rewards, the dorsolateral SN may be particularly important for long-term learning in aversive contexts.
Multifunctional and Context-Dependent Control of Vocal Acoustics by Individual Muscles
Authors: Srivastava Kyle H. , Elemans Coen P.H. , Sober Samuel J.
Published: October 2015

The relationship between muscle activity and behavioral output determines how the brain controls and modifies complex skills. In vocal control, ensembles of muscles are used to precisely tune single acoustic parameters such as fundamental frequency and sound amplitude. If individual vocal muscles were dedicated to the control of single parameters, then the brain could control each parameter independently by modulating the appropriate muscle or muscles. Alternatively, if each muscle influenced multiple parameters, a more complex control strategy would be required to selectively modulate a single parameter. Additionally, it is unknown whether the function of single muscles is fixed or varies across different vocal gestures. A fixed relationship would allow the brain to use the same changes in muscle activation to, for example, increase the fundamental frequency of different vocal gestures, whereas a context-dependent scheme would require the brain to calculate different motor modifications in each case. We tested the hypothesis that single muscles control multiple acoustic parameters and that the function of single muscles varies across gestures using three complementary approaches. First, we recorded electromyographic data from vocal muscles in singing Bengalese finches. Second, we electrically perturbed the activity of single muscles during song. Third, we developed anex vivotechnique to analyze the biomechanical and acoustic consequences of single-muscle perturbations. We found that single muscles drive changes in multiple parameters and that the function of single muscles differs across vocal gestures, suggesting that the brain uses a complex, gesture-dependent control scheme to regulate vocal output.
Influence of Tinnitus on Auditory Spectral and Temporal Resolution and Speech Perception in Tinnitus Patients
Authors: Moon Il Joon , Won Jong Ho , Kang Hyun Woo , Kim Dong Hyun , An Yong-Hwi , Shim Hyun Joon
Published: October 2015

Although cochlear damage is believed to trigger the perception of tinnitus in the central auditory system, its pathophysiological mechanism is still unclear. We aimed to investigate the pathophysiology of tinnitus using psychoacoustic assessments of auditory spectral and temporal resolution and speech perception in noise. Human subjects with tinnitus and symmetric hearing thresholds were divided into three groups: nine unilateral tinnitus subjects with normal hearing thresholds (Group 1), 12 unilateral tinnitus subjects with hearing loss (HL; Group 2), and nine bilateral tinnitus subjects with HL. Fifteen normal-hearing subjects without tinnitus were also tested as a control group. Four different tests were administered: (1) the spectral-ripple discrimination (SRD) test, (2) the temporal modulation detection (TMD) test, (3) the Schroeder-phase discrimination (SPD) test, and (4) the speech recognition threshold (SRT) in noise test. There were no significant differences in SRD, TMD, and SPD between the tinnitus-affected ears (TEs) and non-tinnitus ears (NTEs) in Groups 1 and 2 (p> 0.05). In contrast, the TEs showed poorer SRTs than the NTEs in these two subject groups (p= 0.022 and 0.049). No inferiority of spectral/temporal resolution in TEs compared with NTEs suggests that there may be no more outer hair cell (OHC) damage on the tinnitus side given that damaged OHCs are associated with broadening the auditory filters. The decoupling of the SRT results from the spectral/temporal resolution data could imply that the occurrence of tinnitus does not depend upon the degree of damage to the OHCs, but rather upon different plastic changes in the central auditory system after cochlear damage.

SIGNIFICANCE STATEMENTWe can easily find unilateral tinnitus patients who have symmetric hearing thresholds. Our research question was what kind of difference would be responsible for the tinnitus in the tinnitus-affected ears but not in the non-tinnitus ears of subjects with symmetric hearing thresholds. The answer to this fundamental question could help us to understand the pathophysiology of tinnitus. We evaluated the potential influence of tinnitus upon the subjects' auditory spectral and temporal resolution and speech perception in noise by comparing these psychoacoustic performances between tinnitus-affected ears and non-tinnitus ears in the same subjects.
Kommunale Swap-Verträge: Wirksamkeit und Beratungspflichten nach neuer BGH-Rechtsprechung
Authors: Lehmann Matthias
Published: October 2015

In seinem Urteil vom 28. 4. 2015 hat sich der BGH erstmals ausführlich mit kommunalen Swap-Verträgen befasst. Er nimmt deren grundsätzliche Wirksamkeit an. Neues gibt es auch für Swap-Verträge allgemein. Der BGH schränkt die Pflicht zur Aufklärung über den negativen Marktwert u. a. dann ein, wenn der Swap eine „konnexe“ Grundforderung absichert. Überraschend ist zudem, dass der BGH nicht mehr bei allen Derivateverträgen automatisch eine Beratungspflicht annimmt, sondern diese von den jeweiligen Vertragsklauseln abhängig macht. Außerdem nimmt er zu grundsätzlichen Fragen der Vorteilsausgleichung und der Verjährung bei verschiedenen Ansprüchen unter einem Rahmenvertrag Stellung.
How Risk-Return Efficient is the DAX 30? An Analysis of Risk Based Weighting Strategies
Authors: Grabellus Markus , Mager Ferdinand , Reinschmidt Timo
Published: October 2015

More than 25 years ago the DAX 30 was introduced as capitalization weighted performance index. We take a German perspective and replicate the DAX 30. We analyze alternative risk based weighting strategies using different minimum-variance estimators and low beta strategies. We find that the out-of-sample risk-return characteristics of the market capitalization weighted index can be substantially improved with quantitative portfolio selection rules. The results are robust to various specifications. They challenge the common practice of passive index investing and support recent trends of risk based investment strategies.