bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interactions Between SNAP-25 and Synaptotagmin-1 Are Involved in Vesicle Priming, Clamping Spontaneous and Stimulating Evoked Neurotransmission
Authors: Schupp Melanie , Malsam Jörg , Ruiter Marvin , Scheutzow Andrea , Wierda Keimpe D.B. , Söllner Thomas H. , Sørensen Jakob B. 
Published: November 2016

Whether interactions between synaptotagmin-1 (syt-1) and the soluble NSF attachment protein receptors (SNAREs) are required during neurotransmission is debated. We examined five SNAP-25 mutations designed to interfere with syt-1 interactions. One mutation, D51/E52/E55A, targeted negative charges within region II of the primary interface (Zhou et al., 2015); two mutations targeted region I (D166A and D166/E170A) and one mutation targeted both (D51/E52/E55/D166A). The final mutation (D186/D193A) targeted C-terminal residues not expected to interact with syt-1. Anin vitroassay showed that the region I, region II, and region I+II (D51/E52/E55/D166A) mutants markedly reduced the attachment between syt-1 and t-SNARE-carrying vesicles in the absence of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. In the presence of PI(4,5)P2, vesicle attachment was unaffected by mutation. When expressed inSnap-25-null mouse autaptic neurons, region I mutations reduced the size of the readily releasable pool of vesicles, whereas the region II mutation reduced vesicular release probability. Combining both in the D51/E52/E55/D166A mutation abrogated evoked release. These data point to a division of labor between region I (vesicle priming) and region II (evoked release). Spontaneous release was disinhibited by region I mutations and found to correlate with defective complexin (Cpx) clamping in anin vitrofusion assay, pointing to an interdependent role of synaptotagmin and Cpx in release clamping. Mutation in region II (D51/E52/E55A) also unclamped release, but this effect could be overcome by synaptotagmin overexpression, arguing against an obligatory role in clamping. We conclude that three synaptic release functions of syt-1, vesicle priming, spontaneous release clamping, and evoked release triggering, depend on direct SNARE complex interaction.SIGNIFICANCE STATEMENTThe function of synaptotagmin-1 (syt-1):soluble NSF attachment protein receptor (SNARE) interactions during neurotransmission remains unclear. We mutated SNAP-25 within the recently identified region I and region II of the primary synaptotagmin:SNARE interface. Usingin vitroassays and rescue experiments in autaptic neurons, we show that interactions within region II of the primary interface are necessary for synchronized calcium-triggered release, whereas region I is involved in vesicle priming. Spontaneous release was disinhibited by region I mutation and found to correlate with defective complexin (Cpx) clampingin vitro, pointing to an interdependent role of synaptotagmin and Cpx in release clamping. Therefore, vesicle priming, clamping spontaneous release, and eliciting evoked release are three different functions of syt-1 that involve different interaction modes with the SNARE complex.
Blocking the Interaction between EphB2 and ADDLs by a Small Peptide Rescues Impaired Synaptic Plasticity and Memory Deficits in a Mouse Model of Alzheimer's Disease
Authors: Shi Xiao-Dong , Sun Kai , Hu Rui , Liu Xiao-Ya , Hu Qiu-Mei , Sun Xiao-Yu , Yao Bin , Sun Nan , Hao Jing-Ru , Wei Pan , Han Yuan , Gao Can 
Published: November 2016

Soluble amyloid-β (Aβ) oligomers, also known as Aβ-derived diffusible ligands (ADDLs), are thought to be the key pathogenic factor in Alzheimer's disease (AD), but there is still no effective treatment for preventing or reversing the progression of the disease. Targeting NMDA receptor trafficking and regulation is a new strategy for early treatment of AD. Aβ oligomers have been found to bind to the fibronectin (FN) type III repeat domain of EphB2 to trigger EphB2 degradation, thereby impairing the normal functioning of NMDA receptors and resulting in cognitive deficits. Here, we identified for the first time the interaction sites of the EphB2 FN domain with ADDLs by applying the peptide array method to design and synthesize four candidate peptides (Pep21, Pep25, Pep32, and Pep63) that might be able to block the EphB2–ADDL interaction. Among them, Pep63 was found to be the most effective at inhibiting the binding between EphB2 and ADDLs. We found that Pep63 not only rescued the ADDL-induced depletion of EphB2- and GluN2B-containing NMDA receptors from the neuronal surface in cultured hippocampal neurons, but also improved impaired memory deficits in APPswe/PS1dE9 (APP/PS1) transgenic mice and the phosphorylation and surface expression of GluN2B-containing NMDA receptors in cultures. Together, these results suggest that blocking the EphB2–ADDL interaction by small interfering peptides may be a promising strategy for AD treatment.SIGNIFICANCE STATEMENTAlzheimer's disease (AD) is an age-dependent neurodegenerative disorder and amyloid β-derived diffusible ligands (ADDLs) play a key role in triggering the early cognitive deficits that constitute AD. ADDLs may bind EphB2 and alter NMDA receptor trafficking and synaptic plasticity. Here, we identified the interaction sites of the EphB2 FN domain with ADDLs for the first time to develop a small (10 aa) peptide (Pep63) capable of blocking the EphB2–ADDL interaction. We found that Pep63 not only rescued the ADDL-induced depletion of EphB2 and GluN2B-containing NMDA receptors from the neuronal surface in cultured hippocampal neurons, but also improved impaired memory deficits in APPswe/PS1dE9 (APP/PS1) transgenic mice. Our results suggest that blocking the EphB2–ADDL interaction with Pep63 may be a promising strategy for AD treatment.
Low Somatic Sodium Conductance Enhances Action Potential Precision in Time-Coding Auditory Neurons
Authors: Yang Yang , Ramamurthy Bina , Neef Andreas , Xu-Friedman Matthew A. 
Published: November 2016

Auditory nerve fibers encode sounds in the precise timing of action potentials (APs), which is used for such computations as sound localization. Timing information is relayed through several cell types in the auditory brainstem that share an unusual property: their APs are not overshooting, suggesting that the cells have very low somatic sodium conductance (gNa). However, it is not clear howgNainfluences temporal precision. We addressed this by comparing bushy cells (BCs) in the mouse cochlear nucleus with T-stellate cells (SCs), which do have normal overshooting APs. BCs play a central role in both relaying and refining precise timing information from the auditory nerve, whereas SCs discard precise timing information and encode the envelope of sound amplitude. Nucleated-patch recording at near-physiological temperature indicated that the Na current density was 62% lower in BCs, and the voltage dependence ofgNainactivation was 13 mV hyperpolarized compared with SCs. We endowed BCs with SC-likegNausing two-electrode dynamic clamp and found that synaptic activity at physiologically relevant rates elicited APs with significantly lower probability, through increased activation of delayed rectifier channels. In addition, for two near-simultaneous synaptic inputs, the window of coincidence detection widened significantly with increasinggNa, indicating that refinement of temporal information by BCs is degraded bygNa. Thus, reduced somaticgNaappears to be an adaption for enhancing fidelity and precision in time-coding neurons.SIGNIFICANCE STATEMENTProper hearing depends on analyzing temporal aspects of sounds with high precision. Auditory neurons that specialize in precise temporal information have a suite of unusual intrinsic properties, including nonovershooting action potentials and few sodium channels in the soma. However, it was not clear how low sodium channel availability in the soma influenced the temporal precision of action potentials initiated in the axon initial segment. We studied this using dynamic clamp to mimic sodium channels in the soma, which yielded normal, overshooting action potentials. Increasing somatic sodium conductance had major negative consequences: synaptic activity evoked action potentials with lower fidelity, and the precision of coincidence detection was degraded. Thus, low somatic sodium channel availability appears to enhance fidelity and temporal precision.
Attenuation of Responses to Self-Generated Sounds in Auditory Cortical Neurons
Authors: Rummell Brian P. , Klee Jan L. , Sigurdsson Torfi 
Published: November 2016

Many of the sounds that we perceive are caused by our own actions, for example when speaking or moving, and must be distinguished from sounds caused by external events. Studies using macroscopic measurements of brain activity in human subjects have consistently shown that responses to self-generated sounds are attenuated in amplitude. However, the underlying manifestation of this phenomenon at the cellular level is not well understood. To address this, we recorded the activity of neurons in the auditory cortex of mice in response to sounds generated by their own behavior. We found that the responses of auditory cortical neurons to these self-generated sounds were consistently attenuated, compared with the same sounds generated independently of the animals' behavior. This effect was observed in both putative pyramidal neurons and in interneurons and was stronger in lower layers of auditory cortex. Downstream of the auditory cortex, we found that responses of hippocampal neurons to self-generated sounds were almost entirely suppressed. Responses to self-generated optogenetic stimulation of auditory thalamocortical terminals were also attenuated, suggesting a cortical contribution to this effect. Further analyses revealed that the attenuation of self-generated sounds was not simply due to the nonspecific effects of movement or behavioral state on auditory responsiveness. However, the strength of attenuation depended on the degree to which self-generated sounds were expected to occur, in a cell-type-specific manner. Together, these results reveal the cellular basis underlying attenuated responses to self-generated sounds and suggest that predictive processes contribute to this effect.SIGNIFICANCE STATEMENTDistinguishing self-generated from externally generated sensory input poses a fundamental problem for behaving organisms. Our study in mice shows for the first time that responses of auditory cortical neurons are attenuated to sounds generated manually by the animals' own behavior. This effect is distinct from the nonspecific effect of behavioral activity on auditory responsiveness that has previously been reported and its magnitude is modulated by the probability with which self-generated sounds occur, suggesting an underlying predictive process. We also reveal how this effect varies across cell types and cortical layers. These findings lay a foundation for studying impairments in the processing of self-generated sounds, which are observed in psychiatric illness, in animal disease models.
A Biophysical Model for Cytotoxic Cell Swelling
Authors: Dijkstra Koen , Hofmeijer Jeannette , van Gils Stephan A. , van Putten Michel J.A.M. 
Published: November 2016

We present a dynamic biophysical model to explain neuronal swelling underlying cytotoxic edema in conditions of low energy supply, as observed in cerebral ischemia. Our model contains Hodgkin—Huxley-type ion currents, a recently discovered voltage-gated chloride flux through the ion exchanger SLC26A11, active KCC2-mediated chloride extrusion, and ATP-dependent pumps. The model predicts changes in ion gradients and cell swelling during ischemia of various severity or channel blockage with realistic timescales. We theoretically substantiate experimental observations of chloride influx generating cytotoxic edema, while sodium entry alone does not. We show a tipping point of Na+/K+-ATPase functioning, where below cell volume rapidly increases as a function of the remaining pump activity, and a Gibbs–Donnan-like equilibrium state is reached. This precludes a return to physiological conditions even when pump strength returns to baseline. However, when voltage-gated sodium channels are temporarily blocked, cell volume and membrane potential normalize, yielding a potential therapeutic strategy.SIGNIFICANCE STATEMENTCytotoxic edema most commonly results from energy shortage, such as in cerebral ischemia, and refers to the swelling of brain cells due to the entry of water from the extracellular space. We show that the principle of electroneutrality explains why chloride influx is essential for the development of cytotoxic edema. With the help of a biophysical model of a single neuron, we show that a tipping point of the energy supply exists, below which the cell volume rapidly increases. We simulate realistic time courses to and reveal critical components of neuronal swelling in conditions of low energy supply. Furthermore, we show that, after transient blockade of the energy supply, cytotoxic edema may be reversed by temporary blockade of Na+channels.
Multivariate Brain Prediction of Heart Rate and Skin Conductance Responses to Social Threat
Authors: Eisenbarth Hedwig , Chang Luke J. , Wager Tor D. 
Published: November 2016

Psychosocial stressors induce autonomic nervous system (ANS) responses in multiple body systems that are linked to health risks. Much work has focused on the common effects of stress, but ANS responses in different body systems are dissociable and may result from distinct patterns of cortical–subcortical interactions. Here, we used machine learning to develop multivariate patterns of fMRI activity predictive of heart rate (HR) and skin conductance level (SCL) responses during social threat in humans (N= 18). Overall, brain patterns predicted both HR and SCL in cross-validated analyses successfully (rHR= 0.54,rSCL= 0.58, bothp< 0.0001). These patterns partly reflected central stress mechanisms common to both responses because each pattern predicted the other signal to some degree (rHR→SCL= 0.21 andrSCL→HR= 0.22, bothp< 0.01), but they were largely physiological response specific. Both patterns included positive predictive weights in dorsal anterior cingulate and cerebellum and negative weights in ventromedial PFC and local pattern similarity analyses within these regions suggested that they encode common central stress mechanisms. However, the predictive maps and searchlight analysis suggested that the patterns predictive of HR and SCL were substantially different across most of the brain, including significant differences in ventromedial PFC, insula, lateral PFC, pre-SMA, and dmPFC. Overall, the results indicate that specific patterns of cerebral activity track threat-induced autonomic responses in specific body systems. Physiological measures of threat are not interchangeable, but rather reflect specific interactions among brain systems.SIGNIFICANCE STATEMENTWe show that threat-induced increases in heart rate and skin conductance share some common representations in the brain, located mainly in the vmPFC, temporal and parahippocampal cortices, thalamus, and brainstem. However, despite these similarities, the brain patterns that predict these two autonomic responses are largely distinct. This evidence for largely output-measure-specific regulation of autonomic responses argues against a common system hypothesis and provides evidence that different autonomic measures reflect distinct, measurable patterns of cortical–subcortical interactions.
Recombinant Haplotypes Narrow the ARMS2/HTRA1 Association Signal for Age-Related Macular Degeneration
Authors: Grassmann Felix , Heid Iris M , Weber Bernhard H F ,   International AMD Genomics Consortium (IAMDGC)
Published: November 2016

Abstract
Age-related macular degeneration (AMD) is the leading cause of blindness in ageing societies, triggered by both environmental and genetic factors. The strongest genetic signal for AMD with odds ratios of up to 2.8 per adverse allele was found previously over a chromosomal region in 10q26 harboring two genes, ARMS2 and HTRA1, although with little knowledge as to which gene or genetic variation is functionally relevant to AMD pathology. In this study, we analyzed rare recombinant haplotypes in 16,144 AMD cases and 17,832 controls from the International AMD Genomics Consortium and identified variants in ARMS2 but not HTRA1 to exclusively carry the AMD risk with P-values between 1.0 × 10−773 and 6.7 × 10−5. This now allows prioritization of the gene of interest for subsequent functional studies.
Inhaled Corticosteroids for Bronchopulmonary Dysplasia: A Meta-analysis
Authors: Shinwell Eric S. , Portnov Igor , Meerpohl Joerg J. , Karen Tanja , Bassler Dirk 
Published: November 2016

CONTEXT:
Bronchopulmonary dysplasia (BPD) in preterm infants remains a major health burden despite many therapeutic interventions. Inhaled corticosteroids (IC) may be a safe and effective therapy.

OBJECTIVE:
To assess the safety and efficacy of IC for prevention or treatment of BPD or death in preterm infants.

DATA SOURCES:
PubMed, the Cochrane Library, Embase, and CINAHL from their inception until November 2015 together with other relevant sources.

STUDY SELECTION:
Randomized controlled trials of ICs versus placebo for either prevention or treatment of BPD.

DATA EXTRACTION:
This meta-analysis used a random-effects model with assessment of quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.

RESULTS:
Thirty-eight trials were identified, and 16 met inclusion criteria. ICs were associated with a significant reduction in death or BPD at 36 weeks’ postmenstrual age (risk ratio [RR] = 0.86, 95% confidence interval [CI] 0.75 to 0.99, I2 = 0%, P = .03; 6 trials, n = 1285). BPD was significantly reduced (RR = 0.77, 95% CI 0.65 to 0.91, I2 = 0%, 7 trials, n = 1168), although there was no effect on death (RR = 0.97, 95% CI 0.42 to 2.2, I2 = 50%, 7 trials, n = 1270). No difference was found for death or BPD at 28 days’ postnatal age. The use of systemic steroids was significantly reduced in treated infants (13 trials, n = 1537, RR = 0.87, 95% CI 0.76 to 0.98 I2 = 3%,). No significant differences were found in neonatal morbidities and other adverse events.

LIMITATIONS:
Long-term follow-up data are awaited from a recent large randomized controlled trial.

CONCLUSIONS:
Very preterm infants appear to benefit from ICs with reduced risk for BPD and no effect on death, other morbidities, or adverse events. Data on long-term respiratory, growth, and developmental outcomes are eagerly awaited.
Transformation of Sulfonamides and Tetracyclines during Anaerobic Fermentation of Liquid Manure
Authors: Spielmeyer Astrid , Stahl Franziska , Petri Madeleine S. , Zerr Walter , Brunn Hubertus , Hamscher Gerd 
Published: November 2016

Liquid manure is frequently used as soil fertilizer due to its high nutrient content. It can also contain residues of pharmaceuticals, such as antibiotics, if farm animals are medicated. The anaerobic fermentation process in biogas plants is discussed as one way to reduce the input of antibiotics into the environment. Therefore, 10 worldwide‐applied sulfonamides (sulfachloropyridazine, sulfadiazine, sulfadimethoxine, sulfaguanidine, sulfamerazine, sulfamethazine, sulfamethoxazole, sulfamethoxypyridazine, sulfapyridine, and sulfathiazole) and four frequently used tetracyclines (chlortetracycline, doxycycline, oxytetracycline, and tetracycline) were investigated concerning their elimination pattern during anaerobic fermentation. Batch fermenters with autoclaved and non‐autoclaved inoculum were utilized to distinguish between biotic and abiotic elimination pathways. Overall, sulfadimethoxine, sulfamethoxypyridazine, and sulfamethoxazole showed the highest elimination, which was considerably reduced by autoclaving before inoculation. Structure elucidation via nuclear magnetic resonance and different mass spectrometry techniques revealed only minor structural modifications such as O‐demethylation and hydrogenation, which did not result in a considerably reduced antimicrobial activity. These results show that, especially, sulfonamides are more persistent than expected. Future studies should deal with the elucidation of relevant process parameters for an enhanced compound degradation.Core Ideas
Veterinary antibiotics were incubated in both active and autoclaved inoculum.
Substance‐related elimination profiles were found for sulfonamides and tetracyclines.
Autoclaving of the inoculum reduced the elimination of the sulfonamides.
O‐Demethylation and hydrogenation led to various transformation products.
Some transformation products showed a reduced antimicrobial activity.
Comparative Evaluation of Phosphate Spectrophotometric Methods in Soil Test Phosphorus Extracting Solutions
Authors: Miller Anthony P. , Arai Yuji 
Published: November 2016

Core Ideas
Original ascorbic acid methods are sensitive in STP solutions at phosphate <2 mg L−1.
New optimum wavelengths for the Dick and Tabatabai method in STP extraction solutions.
A new optimum wavelength of 888 nm for Asher's methods is recommended.
Phosphate spectrophotometric methods are valuable in agro‐environmental research because of the orthophosphate‐specific detection. While optimum wavelength and detection limits for these methods are suggested in ultrapure water, they have rarely been evaluated in soil test P (STP) extracting solutions such as Bray P‐1 and Mehlich III. When four different phosphate spectrophotometric methods (Murphy and Riley, He et al., Dick and Tabatabai, and Asher) were evaluated in these STP extracting solutions, we found (i) that the methods of Murphy and Riley and He et al. are still sensitive at P concentrations <2 mg L−1 in STP solutions, (ii) a new optimum wavelength (886–888 nm) in STP solutions for the Dick and Tabatabai method, and (iii) a new optimum wavelength and limit of detection for Asher's methods in ultrapure water and STP solutions. The new optimum wavelengths and detection limit reported in this study should be useful for colorimetric‐based orthophosphate analysis.