bluuebunny/crossref_metadata_2025 huggingface dataset:
Crystal structure of ethyl 1-(3,4-dimethylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate, C14H17N3O2
Authors: Brito Iván , Kesternich Victor , Pérez-Ferhmann Marcia , Narea Pilar , Cárdenas Alejandro
Published: October 2017

C14H17N3O2, monoclinic, P21/c (no. 14), a = 14.9289(7) Å, b = 7.8070(4) Å, c = 12.4664(7) Å, β = 106.821(4)°, V = 1390.79(13) Å3, Z = 4, R
gt(F) = 0.0646, wR
ref(F
2) = 0.1682, T = 293(2) K.
Crystal structure of ethyl 5-methyl-1-(pyridin-3-yl)-1H-1,2,3-triazole-4-carboxylate, C11H12N4O2
Authors: Brito Iván , Kesternich Victor , Pérez-Fehrmann Marcia , Araneda Catherine , Cárdenas Alejandro
Published: October 2017

C11H12N4O2, monoclinic, P21/c (no. 14), a = 12.0258(15) Å, b = 8.0563(10) Å, c = 12.4478(13) Å, β = 104.157(4)°, V = 1169.4(2) Å3, Z = 4, R
gt(F) = 0.0619, wR
ref(F
2) = 0.1616, T = 293(2) K.
La sémiotique des passions : hier, aujourd’hui, demain
Authors: Biglari Amir
Published: October 2017

This paper presents the semiotics of passions. It first retraces the establishment and evolution of this theory, and sets out its objectives and issues, especially its relationship to tensivity. Next, it highlights devices suggested for approaching textual manifestations of passions, notably the canonical schema of passions and codes of passions: perspective codes, modal codes, somatic codes, rhythmic and aspectual codes, perceptive and figurative codes. Finally, it underlines the importance of concrete analyses in this field, by situating them alongside cultural studies.
Refinanzierung als Organisationsproblem
Authors: Kette Sven
Published: October 2017

Es ist unübersehbar, dass Organisationen auf Geld angewiesen sind – sei es um Mitarbeiter zu bezahlen, Geräte anzuschaffen oder Geschäftsräume zu mieten. Trotz der empirischen Evidenz des Refinanzierungsproblems hat dieses in der organisationssoziologischen Theorie bisher so gut wie keine Beachtung gefunden. Der Beitrag unterbreitet ein heuristisches Angebot, das Fragen des organisationalen Geldbedarfs sichtbar hält. Hierzu arbeitet der Text zunächst die Gründe für die Geldvergessenheit der Organisationssoziologie heraus (Abschnitt 2). Für eine entsprechende Justierung schlägt der Beitrag die Konzeptualisierung von Geld als organisationaler Meta-Ressource sowie die Unterscheidung von vier Refinanzierungsformen vor (Abschnitt 3). Die Abschnitte 4 und 5 präsentieren am Beispiel von Non-Profit-Organisationen Erträge für die empirische Organisationsforschung und am Beispiel des Neo-Institutionalismus sowie der Systemtheorie Konsequenzen für die organisationssoziologische Theorieentwicklung.
Geschlecht und wissenschaftliche Produktivität
Authors: Jaksztat Steffen
Published: October 2017

Dieser Beitrag betrachtet den Zusammenhang zwischen dem Geschlecht und der wissenschaftlichen Produktivität während der Promotionsphase. Es wird untersucht, inwiefern Produktivitätsunterschiede als Folge unterschiedlicher Effekte von Elternschaft oder als Folge einer geschlechterdifferenten Ausstattung mit wissenschaftlichem Sozialkapital betrachtet werden können. Diese Forschungsfragen werden mit Daten des DZHW-Promoviertenpanels bearbeitet. Die Analysen zeigen, dass es Frauen während der Promotionsphase nicht in gleichem Umfang wie Männern gelingt, wissenschaftliche Publikationen zu veröffentlichen. Die in diesem Sinne geringere wissenschaftliche Produktivität von Wissenschaftlerinnen kann teilweise dadurch erklärt werden, dass Frauen von ihrem wissenschaftlichen Umfeld weniger gefördert und unterstützt werden. Entgegen den theoretischen Erwartungen können keine Effekte von Elternschaft auf die Publikationszahlen nachgewiesen werden. Produktivitätsunterschiede dürften einen erheblichen negativen Einfluss auf die Karrierechancen von Frauen innerhalb der Wissenschaft haben.
Unter welchen Bedingungen bilden Betriebe an- und ungelernte Beschäftigte weiter?
Authors: Wotschack Philip
Published: October 2017

Nur knapp ein Drittel der Beschäftigten hat 2014 an betrieblich geförderter Weiterbildung teilgenommen. An- und Ungelernte waren besonders selten vertreten. Im Rahmen einer qualitativen Studie konnten auf Basis von Fallstudien verschiedene institutionelle betriebliche Rahmenbedingungen identifiziert werden, die zur Integration an- und ungelernter Beschäftigter in betriebliche Weiterbildung beitragen. Aufbauend auf den Befunden dieser Studie verfolgt der vorliegende Beitrag das Ziel, den Einfluss des institutionellen betrieblichen Kontextes im Rahmen eines quantitativen Forschungsdesigns zu untersuchen. Dazu werden auf der Basis der Transaktionskostentheorie und des Konzepts der sozialen Einbettung Hypothesen formuliert und getestet. Die Auswertung von Daten des IAB-Betriebspanels (Welle 2011) mittels Cluster- und Regressionsanalysen zeigt, dass Konstellationen der institutionellen Einbettung eine wichtige Rolle für die Integration an- und ungelernter Beschäftigter in betriebliche Weiterbildung spielen. Als förderlich erweisen sich formalisierte Verfahren in der betrieblichen Personalarbeit im Zusammenspiel mit betrieblichen Interessenvertretungsstrukturen und einer mitarbeiterorientierten Personalpolitik.
On the dimorphism of Pr6Mo10O39
Authors: Rudolph Daniel , Laufer Sonja , Hartenbach Ingo
Published: October 2017

Attempts to synthesize Pr4Mo7O27 using Pr, Pr6O11 and MoO3 in a molar ratio of 8:6:77 led to a main product of scheelite-type Pr0.667[MoO4] and few single crystals of the triclinic A-type Pr6Mo10O39. The latter crystallizes in space group P1̅ (a=945.25(1), b=1058.49(2), c=1815.16(3) pm; α=104.149(1), β=95.220(1), γ=102.617(1)°, Z=2). Its crystal structure comprises six crystallographically independent Pr3+ cations, eight tetrahedral [MoO4]2− units, and one [Mo2O7]2− entity. The cations display coordination numbers of seven (1×) and eight (5×), while the [MoO4]2− tetrahedra are surrounded by five Pr3+ cations each. The [Mo2O7]2− anions exhibit a coordination environment of seven Pr3+ cations. The attempt to synthesize PrF[MoO4] using PrOF (from in situ thermal decomposition of PrF[CO3]) as reagent did not lead to the desired product but to monoclinic B-type Pr6Mo10O39. This slightly less dense modification compared to its triclinic analogue crystallizes in space group C2/c (a=1247.93(3), b=1989.68(6), c=1392.52 (4) pm, β=100.505(2)°, Z=4) with three crystallographically independent Pr3+ cations, four [MoO4]2− tetrahedra, and again one [Mo2O7]2− unit in the crystal structure. Thus, both Pr6Mo10O39 modifications are better described with the structured formula Pr6[MoO4]8[Mo2O7]. The coordination numbers around the Pr3+ cations are seven (1×) and eight (2×) while all four [MoO4]2− anions are again surrounded by five Pr3+ cations each. Six of the latter represent the coordination environment around the [Mo2O7]2− entities. Besides the thorough comparison of the crystal structures single crystal Raman spectra were recorded for both Pr6Mo10O39 phases.
Coordination of the ambiphilic phosphinoborane tBu2PCH2BPh2 to Cu(I)Cl
Authors: Boom Devin H.A. , Ehlers Andreas W. , Nieger Martin , Slootweg J. Chris
Published: October 2017

A chloro-bridged dimeric copper(I) complex with the ambiphilic phosphinoborane ligand tBu2PCH2BPh2 is reported. The molecular structure was determined by single-crystal X-ray diffraction analysis, revealing a secondary η
1-C interaction of the ligand with the metal center. The complex exhibits green fluorescence when exposed to UV light at 366 nm.
Unique Configurations of Compression and Truncation of Neuronal Activity Underlie l-DOPA–Induced Selection of Motor Patterns inAplysia
Authors: Neveu Curtis L. , Costa Renan M. , Homma Ryota , Nagayama Shin , Baxter Douglas A. , Byrne John H.
Published: October 2017

A key issue in neuroscience is understanding the ways in which neuromodulators such as dopamine modify neuronal activity to mediate selection of distinct motor patterns. We addressed this issue by applying either low or high concentrations ofl-DOPA (40 or 250 μM) and then monitoring activity of up to 130 neurons simultaneously in the feeding circuitry ofAplysiausing a voltage-sensitive dye (RH-155).l-DOPA selected one of two distinct buccal motor patterns (BMPs): intermediate (lowl-DOPA) or bite (highl-DOPA) patterns. The selection of intermediate BMPs was associated with shortening of the second phase of the BMP (retraction), whereas the selection of bite BMPs was associated with shortening of both phases of the BMP (protraction and retraction). Selection of intermediate BMPs was also associated with truncation of individual neuron spike activity (decreased burst duration but no change in spike frequency or burst latency) in neurons active during retraction. In contrast, selection of bite BMPs was associated with compression of spike activity (decreased burst latency and duration and increased spike frequency) in neurons projecting through specific nerves, as well as increased spike frequency of protraction neurons. Finally, large-scale voltage-sensitive dye recordings delineated the spatial distribution of neurons active during BMPs and the modification of that distribution by the two concentrations ofl-DOPA.
Anatomical and Electrophysiological Clustering of Superficial Medial Entorhinal Cortex Interneurons
Authors: Martínez Joan José , Rahsepar Bahar , White John A.
Published: October 2017

Local GABAergic interneurons regulate the activity of spatially-modulated principal cells in the medial entorhinal cortex (MEC), mediating stellate-to-stellate connectivity and possibly enabling grid formation via recurrent inhibitory circuitry. Despite the important role interneurons seem to play in the MEC cortical circuit, the combination of low cell counts and functional diversity has made systematic electrophysiological studies of these neurons difficult. For these reasons, there remains a paucity of knowledge on the electrophysiological profiles of superficial MEC interneuron populations. Taking advantage of glutamic acid decarboxylase 2 (GAD2)-IRES-tdTomato and PV-tdTomato transgenic mice, we targeted GABAergic interneurons for whole-cell patch-clamp recordings and characterized their passive membrane features, basic input/output properties and action potential (AP) shape. These electrophysiologically characterized cells were then anatomically reconstructed, with emphasis on axonal projections and pial depth. K-means clustering of interneuron anatomical and electrophysiological data optimally classified a population of 106 interneurons into four distinct clusters. The first cluster is comprised of layer 2- and 3-projecting, slow-firing interneurons. The second cluster is comprised largely of PV+ fast-firing interneurons that project mainly to layers 2 and 3. The third cluster contains layer 1- and 2-projecting interneurons, and the fourth cluster is made up of layer 1-projecting horizontal interneurons. These results, among others, will provide greater understanding of the electrophysiological characteristics of MEC interneurons, help guide future in vivo studies, and may aid in uncovering the mechanism of grid field formation.
Dendritic and Axonal L-Type Calcium Channels Cooperate to Enhance Motoneuron Firing Output duringDrosophilaLarval Locomotion
Authors: Kadas Dimitrios , Klein Aylin , Krick Niklas , Worrell Jason W. , Ryglewski Stefanie , Duch Carsten
Published: October 2017

Behaviorally adequate neuronal firing patterns are critically dependent on the specific types of ion channel expressed and on their subcellular localization. This study combinesin situelectrophysiology with genetic and pharmacological intervention in larvalDrosophila melanogasterof both sexes to address localization and function of L-type like calcium channels in motoneurons. We demonstrate that Dmca1D (Cav1 homolog) L-type like calcium channels localize to both the somatodendritic and the axonal compartment of larval crawling motoneurons.In situpatch-clamp recordings in genetic mosaics reveal that Dmca1D channels increase burst duration and maximum intraburst firing frequencies during crawling-like motor patterns in semi-intact animals. Genetic and acute pharmacological manipulations suggest that prolonged burst durations are caused by dendritically localized Dmca1D channels, which activate upon cholinergic synaptic input and amplify EPSPs, thus indicating a conserved function of dendritic L-type channels fromDrosophilato vertebrates. By contrast, maximum intraburst firing rates require axonal calcium influx through Dmca1D channels, likely to enhance sodium channel de-inactivation via a fast afterhyperpolarization through BK channel activation. Therefore, in unmyelinatedDrosophilamotoneurons different functions of axonal and dendritic L-type like calcium channels likely operate synergistically to maximize firing output during locomotion.

SIGNIFICANCE STATEMENTNervous system function depends on the specific excitabilities of different types of neurons. Excitability is largely shaped by different combinations of voltage-dependent ion channels. Despite a high degree of conservation, the huge diversity of ion channel types and their differential localization pose challenges in assigning distinct functions to specific channels across species. We find a conserved role, from fruit flies to mammals, for L-type calcium channels in augmenting motoneuron excitability. As in spinal cord, dendritic L-type channels amplify excitatory synaptic input. In contrast to spinal motoneurons, axonal L-type channels enhance firing rates in unmyelinatedDrosophilamotoraxons. Therefore, enhancing motoneuron excitability by L-type channels seems an old strategy, but localization and interactions with other channels are tuned to species-specific requirements.
The Reduction of Ventrolateral Prefrontal Cortex Gray Matter Volume Correlates with Loss of Economic Rationality in Aging
Authors: Chung Hui-Kuan , Tymula Agnieszka , Glimcher Paul
Published: October 2017

The population of people above 65 years old continues to grow, and there is mounting evidence that as humans age they are more likely to make errors. However, the specific effect of neuroanatomical aging on the efficiency of economic decision-making is poorly understood. We used whole-brain voxel-based morphometry analysis to determine where reduction of gray matter volume in healthy female and male adults over the age of 65 years correlates with a classic measure of economic irrationality: violations of the Generalized Axiom of Revealed Preference. All participants were functionally normal with Mini-Mental State Examination scores ranging between 26 and 30. While our elders showed the previously reported decline in rationality compared with younger subjects, chronological age per se did not correlate with rationality measures within our population of elders. Instead, reduction of gray matter density in ventrolateral prefrontal cortex correlates tightly with irrational behavior. Interestingly, using a large fMRI sample and meta-analytic tool with Neurosynth, we found that this brain area shows strong coactivation patterns with nearly all of the value-associated regions identified in previous studies. These findings point toward a neuroanatomic locus for economic rationality in the aging brain and highlight the importance of understanding both anatomy and function in the study of aging, cognition, and decision-making.

SIGNIFICANCE STATEMENTAge is a crucial factor in decision-making, with older individuals making more errors in choices. Using whole-brain voxel-based morphometry analysis, we found that reduction of gray matter density in ventrolateral prefrontal cortex correlates with economic irrationality: reduced gray matter volume in this area correlates with the frequency and severity of violations of the Generalized Axiom of Revealed Preference. Furthermore, this brain area strongly coactivates with other reward-associated regions identified with Neurosynth. These findings point toward a role for neuroscientific discoveries in shaping long-standing economic views of decision-making.
Hebbian Learning in a Random Network Captures Selectivity Properties of the Prefrontal Cortex
Authors: Lindsay Grace W. , Rigotti Mattia , Warden Melissa R. , Miller Earl K. , Fusi Stefano
Published: October 2017

Complex cognitive behaviors, such as context-switching and rule-following, are thought to be supported by the prefrontal cortex (PFC). Neural activity in the PFC must thus be specialized to specific tasks while retaining flexibility. Nonlinear “mixed” selectivity is an important neurophysiological trait for enabling complex and context-dependent behaviors. Here we investigate (1) the extent to which the PFC exhibits computationally relevant properties, such as mixed selectivity, and (2) how such properties could arise via circuit mechanisms. We show that PFC cells recorded from male and female rhesus macaques during a complex task show a moderate level of specialization and structure that is not replicated by a model wherein cells receive random feedforward inputs. While random connectivity can be effective at generating mixed selectivity, the data show significantly more mixed selectivity than predicted by a model with otherwise matched parameters. A simple Hebbian learning rule applied to the random connectivity, however, increases mixed selectivity and enables the model to match the data more accurately. To explain how learning achieves this, we provide analysis along with a clear geometric interpretation of the impact of learning on selectivity. After learning, the model also matches the data on measures of noise, response density, clustering, and the distribution of selectivities. Of two styles of Hebbian learning tested, the simpler and more biologically plausible option better matches the data. These modeling results provide clues about how neural properties important for cognition can arise in a circuit and make clear experimental predictions regarding how various measures of selectivity would evolve during animal training.

SIGNIFICANCE STATEMENTThe prefrontal cortex is a brain region believed to support the ability of animals to engage in complex behavior. How neurons in this area respond to stimuli—and in particular, to combinations of stimuli (“mixed selectivity”)—is a topic of interest. Even though models with random feedforward connectivity are capable of creating computationally relevant mixed selectivity, such a model does not match the levels of mixed selectivity seen in the data analyzed in this study. Adding simple Hebbian learning to the model increases mixed selectivity to the correct level and makes the model match the data on several other relevant measures. This study thus offers predictions on how mixed selectivity and other properties evolve with training.
SK Channels Regulate Resting Properties and Signaling Reliability of a Developing Fast-Spiking Neuron
Authors: Zhang Yihui , Huang Hai
Published: October 2017

Reliable and precise signal transmission is essential in circuits of the auditory brainstem to encode timing with submillisecond accuracy. Globular bushy cells reliably and faithfully transfer spike signals to the principal neurons of the medial nucleus of the trapezoid body (MNTB) through the giant glutamatergic synapse, the calyx of Held. Thus, the MNTB works as a relay nucleus that preserves the temporal pattern of firing at high frequency. Using whole-cell patch-clamp recordings, we observed a K+conductance mediated by small-conductance calcium-activated potassium (SK) channels in the MNTB neurons from rats of either sex. SK channels were activated by intracellular Ca2+sparks and mediated spontaneous transient outward currents in developing MNTB neurons. SK channels were also activated by Ca2+influx through voltage-gated Ca2+channels and synaptically activated NMDA receptors. Blocking SK channels with apamin depolarized the resting membrane potential, reduced resting conductance, and affected the responsiveness of MNTB neurons to signal inputs. Moreover, SK channels were activated by action potentials and affected the spike afterhyperpolarization. Blocking SK channels disrupted the one-to-one signal transmission from presynaptic calyces to postsynaptic MNTB neurons and induced extra postsynaptic action potentials in response to presynaptic firing. These data reveal that SK channels play crucial roles in regulating the resting properties and maintaining reliable signal transmission of MNTB neurons.

SIGNIFICANCE STATEMENTReliable and precise signal transmission is required in auditory brainstem circuits to localize the sound source. The calyx of Held synapse in the mammalian medial nucleus of the trapezoid body (MNTB) plays an important role in sound localization. We investigated the potassium channels that shape the reliability of signal transfer across the calyceal synapse and observed a potassium conductance mediated by small-conductance calcium-activated potassium (SK) channels in rat MNTB principal neurons. We found that SK channels are tonically activated and contribute to the resting membrane properties of MNTB neurons. Interestingly, SK channels are transiently activated by calcium sparks and calcium influx during action potentials and control the one-to-one signal transmission from presynaptic calyces to postsynaptic MNTB neurons.
GFP-Mutant Human Tau Transgenic Mice Develop Tauopathy Following CNS Injections of Alzheimer's Brain-Derived Pathological Tau or Synthetic Mutant Human Tau Fibrils
Authors: Gibbons Garrett S. , Banks Rachel A. , Kim Bumjin , Xu Hong , Changolkar Lakshmi , Leight Susan N. , Riddle Dawn M. , Li Chi , Gathagan Ronald J. , Brown Hannah J. , Zhang Bin , Trojanowski John Q. , Lee Virginia M.-Y.
Published: October 2017

Neurodegenerative proteinopathies characterized by intracellular aggregates of tau proteins, termed tauopathies, include Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-tau), and related disorders. Pathological tau proteins derived from human AD brains (AD-tau) act as proteopathic seeds that initiate the templated aggregation of soluble tau upon intracerebral injection into tau transgenic (Tg) and wild-type mice, thereby modeling human tau pathology. In this study, we found that aged Tg mice of both sexes expressing human tau proteins harboring a pathogenic P301LMAPTmutation labeled with green fluorescent protein (T40PL-GFP Tg mouse line) exhibited hyperphosphorylated tau mislocalized to the somatodentritic domain of neurons, but these mice did not developde novoinsoluble tau aggregates, which are characteristic of human AD and related tauopathies. However, intracerebral injections of either T40PL preformed fibrils (PFFs) or AD-tau seeds into T40PL-GFP mice induced abundant intraneuronal pathological inclusions of hyperphosphorylated T40PL-GFP. These injections of pathological tau resulted in the propagation of tau pathology from the injection site to neuroanatomically connected brain regions, and these tau inclusions consisted of both T40PL-GFP and WT endogenous mouse tau. Primary neurons cultured from the brains of neonatal T40PL-GFP mice provided an informativein vitromodel for examining the uptake and localization of tau PFFs. These findings demonstrate the seeded aggregation of T40PL-GFPin vivoby synthetic PFFs and human AD-tau and the utility of this system to study the neuropathological spread of tau aggregates.

SIGNIFICANCE STATEMENTThe stereotypical spread of pathological tau protein aggregates have recently been attributed to the transmission of proteopathic seeds. Despite the extensive use of transgenic mouse models to investigate the propagation of tau pathologyin vivo, details of the aggregation process such as the early seeding events leading to new tau pathology have remained elusive. This study validates the use of GFP-labeled tau expressed by neuronsin vivoandin vitroas models for investigating mechanisms underlying the seeded transmission of tau pathology as well as tau-focused drug discovery to identify disease-modifying therapies for AD and related tauopathies.
The Lateral Habenula and Its Input to the Rostromedial Tegmental Nucleus Mediates Outcome-Specific Conditioned Inhibition
Authors: Laurent Vincent , Wong Felix L. , Balleine Bernard W.
Published: October 2017

Animals can readily learn that stimuli predict the absence of specific appetitive outcomes; however, the neural substrates underlying such outcome-specific conditioned inhibition remain largely unexplored. Here, using female and male rats as subjects, we examined the involvement of the lateral habenula (LHb) and of its inputs onto the rostromedial tegmental nucleus (RMTg) in inhibitory learning. In these experiments, we used backward conditioning and contingency reversal to establish outcome-specific conditioned inhibitors for two distinct appetitive outcomes. Then, using the Pavlovian-instrumental transfer paradigm, we assessed the effects of manipulations of the LHb and the LHb–RMTg pathway on that inhibitory encoding. In control animals, we found that an outcome-specific conditioned inhibitor biased choice away from actions delivering that outcome and toward actions earning other outcomes. Importantly, this bias was abolished by both electrolytic lesions of the LHb and selective ablation of LHb neurons using Cre-dependent Caspase3 expression in Cre-expressing neurons projecting to the RMTg. This deficit was specific to conditioned inhibition; an excitatory predictor of a specific outcome-biased choice toward actions delivering the same outcome to a similar degree whether the LHb or the LHb–RMTg network was intact or not. LHb lesions also disrupted the ability of animals to inhibit previously encoded stimulus–outcome contingencies after their reversal, pointing to a critical role of the LHb and of its inputs onto the RMTg in outcome-specific conditioned inhibition in appetitive settings. These findings are consistent with the developing view that the LHb promotes a negative reward prediction error in Pavlovian conditioning.

SIGNIFICANCE STATEMENTStimuli that positively or negatively predict rewarding outcomes influence choice between actions that deliver those outcomes. Previous studies have found that a positive predictor of a specific outcome biases choice toward actions delivering that outcome. In contrast, a negative predictor of an outcome biases choice away from actions earning that outcome and toward other actions. Here we reveal that the lateral habenula is critical for negative predictors, but not positive predictors, to affect choice. Furthermore, these effects were found to require activation of lateral habenula inputs to the rostromedial tegmental nucleus. These results are consistent with the view that the lateral habenula establishes inhibitory relationships between stimuli and food outcomes and computes a negative prediction error in Pavlovian conditioning.
A Role of Endogenous Progesterone in Stroke Cerebroprotection Revealed by the Neural-Specific Deletion of Its Intracellular Receptors
Authors: Zhu Xiaoyan , Fréchou Magalie , Liere Philippe , Zhang Shaodong , Pianos Antoine , Fernandez Neïké , Denier Christian , Mattern Claudia , Schumacher Michael , Guennoun Rachida
Published: October 2017

Treatment with progesterone protects the male and female brain against damage after middle cerebral artery occlusion (MCAO). However, in both sexes, the brain contains significant amounts of endogenous progesterone. It is not known whether endogenously produced progesterone enhances the resistance of the brain to ischemic insult. Here, we used steroid profiling by gas chromatography-tandem mass spectrometry (GC-MS/MS) for exploring adaptive and sex-specific changes in brain levels of progesterone and its metabolites after MCAO. We show that, in the male mouse brain, progesterone is mainly metabolized via 5α-reduction leading to 5α-dihydroprogesterone (5α-DHP), also a progesterone receptor (PR) agonist ligand in neural cells, then to 3α,5α-tetrahydroprogesterone (3α,5α-THP). In the female mouse brain, levels of 5α-DHP and 3α,5α-THP are lower and levels of 20α-DHP are higher than in males. After MCAO, levels of progesterone and 5α-DHP are upregulated rapidly to pregnancy-like levels in the male but not in the female brain. To assess whether endogenous progesterone and 5α-DHP contribute to the resistance of neural cells to ischemic damage, we inactivated PR selectively in the CNS. Deletion of PR in the brain reduced its resistance to MCAO, resulting in increased infarct volumes and neurological deficits in both sexes. Importantly, endogenous PR ligands continue to protect the brain of aging mice. These results uncover the unexpected importance of endogenous progesterone and its metabolites in cerebroprotection. They also reveal that the female reproductive hormone progesterone is an endogenous cerebroprotective neurosteroid in both sexes.

SIGNIFICANCE STATEMENTThe brain responds to injury with protective signaling and has a remarkable capacity to protect itself. We show here that, in response to ischemic stroke, levels of progesterone and its neuroactive metabolite 5α-dihydroprogesterone are upregulated rapidly in the male mouse brain but not in the female brain. An important role of endogenous progesterone in cerebroprotection was demonstrated by the conditional inactivation of its receptor in neural cells. These results show the importance of endogenous progesterone, its metabolites, and neural progesterone receptors in acute cerebroprotection after stroke. This new concept could be exploited therapeutically by taking into account the progesterone status of patients and by supplementing and reinforcing endogenous progesterone signaling for attaining its full cerebroprotective potential.
Activation of CD4+ and CD8+ T-lymphocytes by insulin and GAD in patients with type 1 or 2 diabetes mellitus
Authors: Arneth Borros
Published: October 2017

Background

The origin of autoimmune disease type 1 diabetes is still unknown.

Aim

This study assessed the activation of CD4+ and CD8+ T-lymphocytes by human insulin and human glutamate decarboxylase (GAD) in patients with type 1 or type 2 diabetes mellitus (DM) and healthy volunteers.

Materials and methods

The expression of CD69, a marker of T-lymphocyte activity, was determined in whole blood samples by flow cytometry after 12 h of incubation with or without insulin or GAD. The analysis included samples from 12 type 1 DM patients, 14 type 2 DM patients and 12 healthy volunteers.

Results

Significant increases in the number of activated CD4+ and CD8+ T-lymphocytes following pre-incubation of whole blood samples with human insulin or GAD were observed in samples from patients with type 1 DM, whereas no activation of these cells was detected in samples from either type 2 DM patients or healthy subjects.

Discussion

These results indicated that latent pre-activation of CD4+ and CD8+ T-lymphocytes in response to insulin or GAD epitopes occurred in type 1 DM patients.

Conclusion

These findings suggest that pre-immunization against insulin and/or GAD might be associated with the development of type 1 DM. Alternatively, these results might reflect a non-specific, bystander autoimmune response.
Preoperative selective vs non-selective α-blockade in PPGL patients undergoing adrenalectomy
Authors: Liu Caojie , Lv Qingguo , Chen Xinlei , Ni Guangcheng , Hu Liru , Tong Nanwei , Zhang Yuwei
Published: October 2017

Purpose

Preoperative preparation for adrenalectomy for pheochromocytomas and paragangliomas (PPGL) is universally recognized as necessary, while the optimal strategy remains controversial. Our aims were to increase intraoperative hemodynamic stability, expedite postoperative recovery, decrease side effects and reduce costs for patients with PPGL undergoing adrenalectomy.

Methods

We identified 526 patients undergoing open adrenalectomy for PPGL in the West China Hospital of Sichuan University between May, 2007 and December, 2016. 149 patients received preoperative selective α-blockade with phenoxybenzamine, and 377 patients received non-selective α-blockade with prazosin, doxazosin or terazosin. There were no statistical differences between groups regarding preoperative patient and tumor characteristics. Operations were planned once hypertensive patients were well-controlled with blood pressure ≤130/85 mmHg. Intraoperatively, all patients received arterial blood pressure monitoring, and indwelling urinary catheters to record urine output. We recorded intraoperative hemodynamics, status in the postanesthesia or intensive care unit, postoperative recovery and complications.

Results

Patients in the non-selective group showed a more significant decline in postoperative systolic blood pressure than the selective group (P = 0.041). Also, patients in the non-selective group appeared to receive a long-term anti-hypertensive effect, especially for diastolic blood pressure (P = 0.037), which was a novel finding, based on the current literature.

Conclusions

Our results confirmed that non-selective α-blockade produced a more significant anti-hypertensive effect than selective α-blockade. However, we found no significant difference in intraoperative hemodynamic instability, postoperative recovery and postoperative complications between groups.
MicroRNA expression profiles and type 1 diabetes mellitus: systematic review and bioinformatic analysis
Authors: Assmann Taís S , Recamonde-Mendoza Mariana , De Souza Bianca M , Crispim Daisy
Published: October 2017

Growing evidence indicates that microRNAs (miRNAs) have a key role in processes involved in type 1 diabetes mellitus (T1DM) pathogenesis, including immune system functions and beta-cell metabolism and death. Although dysregulated miRNA profiles have been identified in T1DM patients, results are inconclusive; with only few miRNAs being consistently dysregulated among studies. Thus, we performed a systematic review of the literature on the subject, followed by bioinformatic analysis, to point out which miRNAs are dysregulated in T1DM-related tissues and in which pathways they act. PubMed and EMBASE were searched to identify all studies that compared miRNA expressions between T1DM patients and non-diabetic controls. Search was completed in August, 2017. Those miRNAs consistently dysregulated in T1DM-related tissues were submitted to bioinformatic analysis, using six databases of miRNA–target gene interactions to retrieve their putative targets and identify potentially affected pathways under their regulation. Thirty-three studies were included in the systematic review: 19 of them reported miRNA expressions in human samples, 13 in murine models and one in both human and murine samples. Among 278 dysregulated miRNAs reported in these studies, 25.9% were reported in at least 2 studies; however, only 48 of them were analyzed in tissues directly related to T1DM pathogenesis (serum/plasma, pancreas and peripheral blood mononuclear cells (PBMCs)). Regarding circulating miRNAs, 11 were consistently dysregulated in T1DM patients compared to controls: miR-21-5p, miR-24-3p, miR-100-5p, miR-146a-5p, miR-148a-3p, miR-150-5p, miR-181a-5p, miR-210-5p, miR-342-3p, miR-375 and miR-1275. The bioinformatic analysis retrieved a total of 5867 validated and 2979 predicted miRNA–target interactions for human miRNAs. In functional enrichment analysis of miRNA target genes, 77 KEGG terms were enriched for more than one miRNA. These miRNAs are involved in pathways related to immune system function, cell survival, cell proliferation and insulin biosynthesis and secretion. In conclusion, eleven circulating miRNAs seem to be dysregulated in T1DM patients in different studies, being potential circulating biomarkers of this disease.
EZH2 deletion promotes spermatogonial differentiation and apoptosis
Authors: Jin Cheng , Zhang Yan , Wang Zhi-Peng , Wang Xiu-Xia , Sun Tie-Cheng , Li Xiao-Yu , Tang Ji-Xin , Cheng Jin-Mei , Li Jian , Chen Su-Ren , Deng Shou-Long , Liu Yi-Xun
Published: October 2017

Spermatogenesis is crucial for male fertility and is therefore tightly controlled by a variety of epigenetic regulators. However, the function of enhancer of zeste homolog 2 (EZH2) in spermatogenesis and the molecular mechanisms underlying its activity remain poorly defined. Here, we demonstrate that deleting EZH2 promoted spermatogonial differentiation and apoptosis. EZH2 is expressed in spermatogonia, spermatocytes and round and elongated spermatids from stage 9 to 11 but not in leptotene and zygotene spermatocytes. Knocking downEzh2 in vitrousing a lentivirus impaired self-renewal in spermatogonial stem cells (SSCs), and the conditional knockout ofEzh2in spermatogonial progenitors promoted precocious spermatogonial differentiation. EZH2 functions to balance self-renewal and differentiation in spermatogonia by suppressing NEUROG3 and KIT via a direct interaction that is independent of its histone methyltransferase activity. Moreover, deletingEzh2enhanced the activation of CASP3 in spermatids, resulting in reduced spermatozoa production. Collectively, these data demonstrate that EZH2 plays a nonclassical role in the regulation of spermatogonial differentiation and apoptosis in murine spermatogenesis.
Different co-culture systems have the same impact on bovine embryo transcriptome
Authors: Carvalho A Vitorino , Canon E , Jouneau L , Archilla C , Laffont L , Moroldo M , Ruffini S , Corbin E , Mermillod P , Duranthon V
Published: October 2017

During the last few years, several co-culture systems using either BOEC or VERO feeder cells have been developed to improve bovine embryo development and these systems give better results at high oxygen concentration (20%). In parallel, the SOF medium, used at 5% O2, has been developed to mimic the oviduct fluid. Since 2010s, the SOF medium has become popular in improving bovine embryo development and authors have started to associate this medium to co-culture systems. Nevertheless, little is known about the putative benefit of this association on early development. To address this question, we have compared embryo transcriptomes in four different culture conditions: SOF with BOEC or VERO at 20% O2, and SOF without feeders at 5% or 20% O2. Embryos have been analyzed at 16-cell and blastocyst stages. Co-culture systems did not improve the developmental rate when compared to 5% O2. Direct comparison of the two co-culture systems failed to highlight major differences in embryo transcriptome at both developmental stages. Both feeder cell types appear to regulate the same cytokines and growth factors pathways, and thus to influence embryo physiology in the same way. In blastocysts, when compared to culture in SOF at 5% O2, BOEC or VERO seems to reduce cell survival and differentiation by, at least, negatively regulating STAT3 and STAT5 pathways. Collectively, in SOF medium both blastocysts rate and embryo transcriptome suggest no influence of feeder origin on bovine early development and no beneficial impact of co-culture systems when compared to 5% O2.
Metabolomic Analysis Reveals That the Drosophila melanogaster Gene lysine Influences Diverse Aspects of Metabolism
Authors: St. Clair Samantha L , Li Hongde , Ashraf Usman , Karty Jonathan A , Tennessen Jason M
Published: October 2017

The fruit fly Drosophila melanogaster has emerged as a powerful model for investigating the molecular mechanisms that regulate animal metabolism. However, a major limitation of these studies is that many metabolic assays are tedious, dedicated to analyzing a single molecule, and rely on indirect measurements. As a result, Drosophila geneticists commonly use candidate gene approaches, which, while important, bias studies toward known metabolic regulators. In an effort to expand the scope of Drosophila metabolic studies, we used the classic mutant lysine (lys) to demonstrate how a modern metabolomics approach can be used to conduct forward genetic studies. Using an inexpensive and well-established gas chromatography-mass spectrometry-based method, we genetically mapped and molecularly characterized lys by using free lysine levels as a phenotypic readout. Our efforts revealed that lys encodes the Drosophila homolog of Lysine Ketoglutarate Reductase/Saccharopine Dehydrogenase, which is required for the enzymatic degradation of lysine. Furthermore, this approach also allowed us to simultaneously survey a large swathe of intermediate metabolism, thus demonstrating that Drosophila lysine catabolism is complex and capable of influencing seemingly unrelated metabolic pathways. Overall, our study highlights how a combination of Drosophila forward genetics and metabolomics can be used for unbiased studies of animal metabolism, and demonstrates that a single enzymatic step is intricately connected to diverse aspects of metabolism.
Competitive Ability of Maize Pollen Grains Requires Paralogous Serine Threonine Protein Kinases STK1 and STK2
Authors: Huang Jun T , Wang Qinghua , Park Wonkeun , Feng Yaping , Kumar Dibyendu , Meeley Robert , Dooner Hugo K
Published: October 2017

serine threonine kinase1 (stk1) and serine threonine kinase2 (stk2) are closely related maize paralogous genes predicted to encode serine/threonine protein kinases. Pollen mutated in stk1 or stk2 competes poorly with normal pollen, pointing to a defect in pollen tube germination or growth. Both genes are expressed in pollen, but not in most other tissues. In germination media, STK1 and STK2 fluorescent fusion proteins localize to the plasma membrane of the vegetative cell. RNA-seq experiments identified 534 differentially expressed genes in stk1 mutant pollen relative to wild type. Gene ontology (GO) molecular functional analysis uncovered several differentially expressed genes with putative ribosome initiation and elongation functions, suggesting that stk1 might affect ribosome function. Of the two paralogs, stk1 may play a more important role in pollen development than stk2, as stk2 mutations have a smaller pollen transmission effect. However, stk2 does act as an enhancer of stk1 because the double mutant combination is only infrequently pollen-transmitted in double heterozygotes. We conclude that the stk paralogs play an essential role in pollen development.
Histone H3 Threonine 11 Phosphorylation Is Catalyzed Directly by the Meiosis-Specific Kinase Mek1 and Provides a Molecular Readout of Mek1 Activity in Vivo
Authors: Kniewel Ryan , Murakami Hajime , Liu Yan , Ito Masaru , Ohta Kunihiro , Hollingsworth Nancy M , Keeney Scott
Published: October 2017

Saccharomyces cerevisiae Mek1 is a CHK2/Rad53-family kinase that regulates meiotic recombination and progression upon its activation in response to DNA double-strand breaks (DSBs). The full catalog of direct Mek1 phosphorylation targets remains unknown. Here, we show that phosphorylation of histone H3 on threonine 11 (H3 T11ph) is induced by meiotic DSBs in S. cerevisiae and Schizosaccharomyces pombe. Molecular genetic experiments in S. cerevisiae confirmed that Mek1 is required for H3 T11ph and revealed that phosphorylation is rapidly reversed when Mek1 kinase is no longer active. Reconstituting histone phosphorylation in vitro with recombinant proteins demonstrated that Mek1 directly catalyzes H3 T11 phosphorylation. Mutating H3 T11 to nonphosphorylatable residues conferred no detectable defects in otherwise unperturbed meiosis, although the mutations modestly reduced spore viability in certain strains where Rad51 is used for strand exchange in place of Dmc1. H3 T11ph is therefore mostly dispensable for Mek1 function. However, H3 T11ph provides an excellent marker of ongoing Mek1 kinase activity in vivo. Anti-H3 T11ph chromatin immunoprecipitation followed by deep sequencing demonstrated that H3 T11ph was highly enriched at presumed sites of attachment of chromatin to chromosome axes, gave a more modest signal along chromatin loops, and was present at still lower levels immediately adjacent to DSB hotspots. These localization patterns closely tracked the distribution of Red1 and Hop1, axis proteins required for Mek1 activation. These findings provide insight into the spatial disposition of Mek1 kinase activity and the higher order organization of recombining meiotic chromosomes.
Job safety analysis and hazard identification for work accident prevention in para rubber wood sawmills in southern Thailand
Authors: Thepaksorn Phayong , Thongjerm Supawan , Incharoen Salee , Siriwong Wattasit , Harada Kouji , Koizumi Akio
Published: October 2017

Objective

We utilized job safety analysis (JSA) and hazard identification for work accident prevention in Para rubber wood sawmills, which aimed to investigate occupational health risk exposures and assess the health hazards at sawmills in the Trang Province, located in southern Thailand.

Methods

We conducted a cross-sectional study which included a walk-through survey, JSA, occupational risk assessment, and environmental samplings from March through September 2015 at four Para rubber wood sawmills.

Results

We identified potential occupational safety and health hazards associated with six main processes, including: 1) logging and cutting, 2) sawing the lumber into sheets, 3) planing and rearranging, 4) vacuuming and wood preservation, 5) drying and planks rearranging, and 6) grading, packing, and storing. Working in sawmills was associated with high risk of wood dust and noise exposure, occupational accidents injuring hands and feet, chemicals and fungicide exposure, and injury due to poor ergonomics or repetitive work.

Discussion

Several high-risk areas were identified from JSA and hazard identification of the working processes, especially high wood dust and noise exposure when sawing lumber into sheets and risk of occupational accidents of the hands and feet when struck by lumber. All workers were strongly recommended to use personal protective equipment in any working processes. Exposures should be controlled using local ventilation systems and reducing noise transmission. We recommend that the results from the risk assessment performed in this study be used to create an action plan for reducing occupational health hazards in Para rubber sawmills.
Assessing Surgical Residents; Challenges and Future Options
Authors: Sandher Sukhjot , Gibber Marc
Published: October 2017

This article was migrated. The article was not marked as recommended. Surgical education has changed significantly since the first formal program was established by William Halstead. Specifically, in the last ten years, surgical education has moved from the popular "See One, Do One, Teach One" model to a competency based model using distinct milestones. While these milestones and competencies have been successfully implemented in many fields, including Otolaryngology, there remains significant problems that need to be addressed. Specifically, the lack of assessment tools able to accurately measure whether trainee surgeons can perform steps or indeed an entire operation is a significant and underreported problem.
Legal Obligations, Obstacles and Alternative Theories to Admission of Syrian Refugees in the United States
Authors: Stopher Lynn , Kinsel Kourtney , Rothbaum Aaron , Foerschler Susi
Published: October 2017

This paper addresses the historical development and current context of the United States’ obligation to Syrian refugees. Part I discusses the historical context of the domestic approach to accepting refugees and displaced persons. Part II addresses the role of domestic courts in enforcing international obligations to accept refugees. Part III reflects additional obstacles facing Syrians who seek legal protection in the United States. Part IV provides commentary on an alternative to admission, Syrian safe zones.
US Obligations Towards Syrian Refugees
Authors: Fletcher Jessica
Published: October 2017

position paper
Empathy and Refugees
Authors: Owusu Daniella
Published: October 2017

Position paper