bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dorsal Hippocampal Actin Polymerization Is Necessary for Activation of G-Protein-Coupled Estrogen Receptor (GPER) to Increase CA1 Dendritic Spine Density and Enhance Memory Consolidation
Authors: Kim Jaekyoon , Schalk Jayson C. , Koss Wendy A. , Gremminger Rachel L. , Taxier Lisa R. , Gross Kellie S. , Frick Karyn M. 
Published: October 2019

Activation of the membrane estrogen receptor G-protein-coupled estrogen receptor (GPER) in ovariectomized mice via the GPER agonist G-1 mimics the beneficial effects of 17β-estradiol (E2) on hippocampal CA1 spine density and memory consolidation, yet the cell-signaling mechanisms mediating these effects remain unclear. The present study examined the role of actin polymerization and c-Jun N-terminal kinase (JNK) phosphorylation in mediating effects of dorsal hippocampally infused G-1 on CA1 dendritic spine density and consolidation of object recognition and spatial memories in ovariectomized mice. We first showed that object learning increased apical CA1 spine density in the dorsal hippocampus (DH) within 40 min. We then found that DH infusion of G-1 increased both CA1 spine density and phosphorylation of the actin polymerization regulator cofilin, suggesting that activation of GPER may increase spine morphogenesis through actin polymerization. As with memory consolidation in our previous work (Kim et al., 2016), effects of G-1 on CA1 spine density and cofilin phosphorylation depended on JNK phosphorylation in the DH. Also consistent with our previous findings, E2-induced cofilin phosphorylation was not dependent on GPER activation. Finally, we found that infusion of the actin polymerization inhibitor, latrunculin A, into the DH prevented G-1 from increasing apical CA1 spine density and enhancing both object recognition and spatial memory consolidation. Collectively, these data demonstrate that GPER-mediated hippocampal spinogenesis and memory consolidation depend on JNK and cofilin signaling, supporting a critical role for actin polymerization in the GPER-induced regulation of hippocampal function in female mice.SIGNIFICANCE STATEMENTEmerging evidence suggests that G-protein-coupled estrogen receptor (GPER) activation mimics effects of 17β-estradiol on hippocampal memory consolidation. Unlike canonical estrogen receptors, GPER activation is associated with reduced cancer cell proliferation; thus, understanding the molecular mechanisms through which GPER regulates hippocampal function may provide new avenues for the development of drugs that provide the cognitive benefits of estrogens without harmful side effects. Here, we demonstrate that GPER increases CA1 dendritic spine density and hippocampal memory consolidation in a manner dependent on actin polymerization and c-Jun N-terminal kinase phosphorylation. These findings provide novel insights into the role of GPER in mediating hippocampal morphology and memory consolidation, and may suggest first steps toward new therapeutics that more safely and effectively reduce memory decline in menopausal women.
Cochlear Efferent Innervation Is Sparse in Humans and Decreases with Age
Authors: Liberman Leslie D. , Liberman M. Charles 
Published: October 2019

The mammalian cochlea is innervated by two cholinergic feedback systems called the medial olivocochlear (MOC) and lateral olivocochlear (LOC) pathways, which send control signals from the brainstem back to the outer hair cells and auditory-nerve fibers, respectively. Despite countless studies of the cochlear projections of these efferent fibers in animal models, comparable data for humans are almost completely lacking. Here, we immunostained the cochlear sensory epithelium from 23 normal-aging humans (14 males and 9 females), 0–86 years of age, with cholinergic markers to quantify the normal density of MOC and LOC projections, and the degree of age-related degeneration. In younger ears, the MOC density peaks in mid-cochlear regions and falls off both apically and basally, whereas the LOC innervation peaks near the apex. In older ears, MOC density decreases dramatically, whereas the LOC density does not. The loss of MOC feedback may contribute to the age-related decrease in word recognition in noise; however, even at its peak, the MOC density is lower than in other mammals, suggesting the MOC pathway is less important for human hearing.SIGNIFICANCE STATEMENTThe cochlear epithelium and its sensory innervation are modulated by the olivocochlear (OC) efferent pathway. Although the medial OC (MOC) reflex has been extensively studied in humans, via contralateral sound suppression, the cochlear projections of these cholinergic neurons have not been described in humans. Here, we use immunostaining to quantify the MOC projections to outer hair cells and lateral OC (LOC) projections to the inner hair cell area in humans 0–89 years of age. We show age-related loss of MOC, but not LOC, innervation, which likely contributes to hearing impairments, and a relative paucity of MOC terminals at all ages, which may account for the relative weakness of the human MOC reflex and the difficulty in demonstrating a robust functional role in human experiments.
The LMTK1-TBC1D9B-Rab11A Cascade Regulates Dendritic Spine Formation via Endosome Trafficking
Authors: Nishino Hironori , Saito Taro , Wei Ran , Takano Tetsuya , Tsutsumi Koji , Taniguchi Makoto , Ando Kanae , Tomomura Mineko , Fukuda Mitsunori , Hisanaga Shin-ichi 
Published: October 2019

Dendritic spines are postsynaptic protrusions at excitatory synapses that are critical for proper neuronal synaptic transmission. While lipid and protein membrane components are necessary for spine formation, it is largely unknown how they are recruited to developing spines. Endosomal trafficking is one mechanism that may influence this development. We recently reported that Lemur kinase 1A (LMTK1A), a membrane-bound Ser/Thr kinase, regulates trafficking of endosomes in neurons. LMTK1 has been shown to be a p35 Cdk5 activator-binding protein and a substrate for Cdk5-p35; however, its neuronal function has not been sufficiently studied. Here, we investigate the role of LMTK1 in spine formation. Depletion of LMTK1 increases spine formation, maturation, and density in primary cultured neurons and in mouse brain of either sex. Additionally, expression of kinase-negative LMTK1 stimulates spine formation in primary neurons andin vivo. LMTK1 controls spine formation through Rab11, a regulator of recycling endosome trafficking. We identify TBC1D9B, a Rab11A GTPase-activating protein (Rab11A GAP), as a LMTK1 binding protein, and find that TBC1D9B mediates LMTK1 activity on Rab11A. TBC1D9B inactivates Rab11A under the control of LMTK1A. Further, by analyzing the effect of decreased TBC1D9B expression in primary neurons, we demonstrate that TBC1D9B indeed regulates spine formation. This is the first demonstration of the biological function of TBC1D9B. Together, with the regulation of LMTK1 by Cdk5-p35, we propose the Cdk5-LMTK1-TBC1D9B-Rab11A cascade as a novel signaling mechanism regulating endosomal transport for synapse formation and function.SIGNIFICANCE STATEMENTDendritic spines are postsynaptic specializations essential for synaptic transmission. However, it is not known how critical membrane components are recruited to spines for their formation. Endosomal trafficking is one such mechanism that may mediate this process. Here we investigate regulators of endosomal trafficking and their contribution to spine formation. We identify two novel factors, LMTK1 and TBC1D9B, which regulate spine formation upstream of Rab11A, a small GTPase. LMTK1 is a membrane bound Ser/Thr kinase regulated by Cdk5-p35, and TBC1D9B is a recently identified Rab11 GAP. LMTK1 controls the GAP activity of TBC1D9B on Rab11A, and TBC1D9B mediates the LMTK1 activity on Rab11A. We propose the Cdk5-LMTK1-TBC1D9B-Rab11A cascade as a novel mechanism controlling spine formation and function.
¿Un "imperio ibérico integrado"? El arbitrismo y el imperio ultramarino portugués (1580-1640)
Authors: Almeida Borges Graça 
Published: October 2019

Este artículo trata sobre arbitristas y arbitrios centrados en el imperio ultramarino portugués durante el periodo de la incorporación de su imperio a la Monarquía Hispánica (1580-1640). El trabajo trata de dar solución a tres problemas: en primer lugar, pretende determinar quiénes eran estos arbitristas que escribían sobre el imperio ultramarino portugués y cuáles eran los objetivos de sus textos y escritos. En segundo lugar, intenta comprender, en la medida de lo posible, cómo se recibian esos documentos en los centros decisorios de la monarquía. En tercer lugar, examina hasta qué punto este conjunto de documentos reflejan la percepción de un "imperio ibérico integrado", en donde los territorios ultramarinos portugueses se presentaban plenamente incorporados a la política global de la monarquía.
Classification-Based Inference of Dynamical Models of Gene Regulatory Networks
Authors: Fehr David A , Handzlik Joanna E , Manu  , Loh Yen Lee 
Published: October 2019

AbstractCell-fate decisions during development are controlled by densely interconnected gene regulatory networks (GRNs) consisting of many genes. Inferring and predictively modeling these GRNs is crucial for understanding development and other physiological processes. Gene circuits, coupled differential equations that represent gene product synthesis with a switch-like function, provide a biologically realistic framework for modeling the time evolution of gene expression. However, their use has been limited to smaller networks due to the computational expense of inferring model parameters from gene expression data using global non-linear optimization. Here we show that the switch-like nature of gene regulation can be exploited to break the gene circuit inference problem into two simpler optimization problems that are amenable to computationally efficient supervised learning techniques. We present FIGR (Fast Inference of Gene Regulation), a novel classification-based inference approach to determining gene circuit parameters. We demonstrate FIGR’s effectiveness on synthetic data generated from random gene circuits of up to 50 genes as well as experimental data from the gap gene system of Drosophila melanogaster, a benchmark for inferring dynamical GRN models. FIGR is faster than global non-linear optimization by a factor of 600 and its computational complexity scales much better with GRN size. On a practical level, FIGR can accurately infer the biologically realistic gap gene network in under a minute on desktop-class hardware instead of requiring hours of parallel computing. We anticipate that FIGR would enable the inference of much larger biologically realistic GRNs than was possible before.
Historical Introgressions from a Wild Relative of Modern Cassava Improved Important Traits and May Be Under Balancing Selection
Authors: Wolfe Marnin D , Bauchet Guillaume J , Chan Ariel W , Lozano Roberto , Ramu Punna , Egesi Chiedozie , Kawuki Robert , Kulakow Peter , Rabbi Ismail , Jannink Jean-Luc 
Published: October 2019

AbstractIntrogression of alleles from wild relatives has often been adaptive in plant breeding. However, the significance of historical hybridization events in modern breeding is often not clear. Cassava (Manihot esculenta) is among the most important staple foods in the world, sustaining hundreds of millions of people in the tropics, especially in sub-Saharan Africa. Widespread genotyping makes cassava a model for clonally propagated root and tuber crops in the developing world, and provides an opportunity to study the modern benefits and consequences of historical introgression. We detected large introgressed Manihot glaziovii genome-segments in a collection of 2742 modern cassava landraces and elite germplasm, the legacy of a 1930s era breeding to combat disease epidemics. African landraces and improved varieties were, on average, 3.8% (max 13.6%) introgressed. Introgressions accounted for a significant (mean 20%, max 56%) portion of the heritability of tested traits. M. glaziovii alleles on the distal 10 Mb of chr. 1 increased dry matter and root number. On chr. 4, introgressions in a 20 Mb region improved harvest index and brown streak disease tolerance. We observed the introgression frequency on chr. 1 double over three cycles of selection, and that later stage trials selectively excluded homozygotes from consideration as varieties. This indicates a heterozygous advantage of introgressions. However, we also found that maintaining large recombination-suppressed introgressions in the heterozygous state allowed the accumulation of deleterious mutations. We conclude that targeted recombination of introgressions would increase the efficiency of cassava breeding by allowing simultaneous fixation of beneficial alleles and purging of genetic load.
Physicochemical Parameters of Magmatism of the Uksichan and Ichinsky Volcanoes (Sredinnyi Ridge, Kamchatka): Data on Melt Inclusions
Authors: Dobretsov N.L. , Simonov V.A. , Kotlyarov A.V. , Karmanov N.S. 
Published: October 2019

Abstract
—Thermobarogeochemical study of melt inclusions and investigation of clinopyroxenes and amphiboles from effusive rocks of the Uksichan and Ichinsky Volcanoes gave an insight into the parameters of deep-seated melts and the evolution of magmatic systems during the formation of minerals in intermediate chambers. Study of melt inclusions from the Uksichan volcanic rocks made it possible to estimate the pressure during the liquidus crystallization of clinopyroxenes and plagioclases from basaltic magmas and to establish four depth intervals of the formation of these minerals: ~60, 45–30, 27–18, and from 12 km to the subsurface. Comparison of the results of calculation based on melt inclusion data and of the clinopyroxene and amphibole data helped to establish the evolution paths of the P–T parameters of ascending melts of the Uksichan Volcano. The most high-temperature magmas, generated at a depth of ~60 km, are characterized by a successive temperature decrease during their ascent (1320–1240–1200 °С). Based on the representative data on the compositions of amphiboles from the Uksichan and Ichinsky Volcanoes, we have elucidated the general regularities of the evolution of intermediate and acid magmatic systems, with three depths of crystallization in intermediate chambers. Amphiboles of the Ichinsky Volcano andesites and the Uksichan Volcano latites crystallized at depths of 22.0–18.5 and 18–16 km and at temperatures of 980–930 and 1010–985 °С, respectively. As melt ascended to a depth of 15.5–11.0 km and a temperature decreased from 945 to 880 °С, amphiboles of andesites and dacites of both volcanoes were produced. At the final stage (a temperature decrease to 900–810 °С and ascent of melts to a depth of 3 km), only amphiboles of dacites of both volcanoes crystallized.
CIC Mutation as a Molecular Mechanism of Acquired Resistance to Combined BRAF-MEK Inhibition in Extramedullary Multiple Myeloma with Central Nervous System Involvement
Authors: Da Vià Matteo Claudio , Solimando Antonio Giovanni , Garitano-Trojaola Andoni , Barrio Santiago , Munawar Umair , Strifler Susanne , Haertle Larissa , Rhodes Nadine , Teufel Eva , Vogt Cornelia , Lapa Constantin , Beilhack Andreas , Rasche Leo , Einsele Hermann , Kortüm K. Martin 
Published: October 2019

Abstract

Combined MEK-BRAF inhibition is a well-established treatment strategy in BRAF-mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF-MEK inhibitor treatment are unavailable.
Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1% of patients. It is considered an ultimate high-risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient.

Key Points
BRAF mutations constitute an attractive druggable target in multiple myeloma. This is the first genomic dissection of the central nervous system involvement in a multiple myeloma patient harboring a druggable BRAFV600E mutation. Deep genomic characterization of the extramedullary lesion prompted a personalized therapeutic approach. Acquisition of CIC mutation confers a mechanism of BRAF-MEK inhibitor drug resistance in multiple myeloma. The in silico interrogation of the CoMMpass clinical study revealed 10 patients with somatic mutations of CIC and its downregulation at gene expression level in multiple myeloma. CIC gene silencing decreases the sensitivity of multiple myeloma cells to BRAF-MEK inhibition in vitro. The correlation between CIC downregulation and ETV4/5 nuclear factor expression in multiple myeloma BRAF-mutant cells is shown for the first time. CIC mutation, its downregulation, and the related downstream effect on MMP24 support disseminative potential providing new clues in the extramedullary biology definition.
Contextualizing the Use of Moxetumomab Pasudotox in the Treatment of Relapsed or Refractory Hairy Cell Leukemia
Authors: Kreitman Robert J. , Pastan Ira 
Published: October 2019

Abstract

Hairy cell leukemia (HCL) is an indolent B-cell malignancy characterized by high initial sensitivity to purine analog chemotherapy, minimal residual disease (MRD) frequently accompanying complete remission (CR), and relapses requiring additional treatment. Repeat chemotherapy shows decreasing efficacy and increasing toxicity with each course. Newer therapies targeting BRAF/MEK or Bruton's tyrosine kinase are effective but generally leave MRD. Rituximab has modest activity as a single agent and can achieve MRD-negative CR in combination with purine analogs, but there is significant toxicity from the chemotherapy. Moxetumomab pasudotox-tdfk (Moxe) is a biologic containing an antibody fragment (Fv) binding to CD22, attached to a portion of Pseudomonas exotoxin A. Binding to CD22 enables the toxin to enter and kill cells. Moxe is administered by 30-minute infusions on days 1, 3, and 5 of up to six cycles spaced 4 weeks apart. In phase I testing, 64% of 33 patients at the highest dose level achieved CR, most without MRD. Lack of MRD correlated with prolonged CR duration; of 11 MRD-negative CRs, 10 were still in CR after a median of 42 months of observation. In pivotal testing, 75% of 80 patients had a hematologic response, 41% with CR; 82% (27/33) of CRs were MRD-negative, and only 4 of the 27 MRD-negative patients relapsed during the follow-up period. Hemolytic uremic syndrome and capillary leak syndrome were each observed in 9% of patients, all reversible. In September 2018, the U.S. Food and Drug Administration approved Moxe for the treatment of relapsed/refractory HCL after ≥2 prior therapies. Moxe is undergoing further development in combination with rituximab.
The Relationship of Youth Family Values with Hedonism and Eudemonia
Authors: Anoshkin I. V. , Sychev O. A. 
Published: October 2019

Introduction. A notable trend in modern society is the transformation of family institution, which has long been considered the most important social and personal value. The change of attitudes of young people towards marriage in Russia is slower than in Europe; however, this process is becoming more obvious today and there is an urgent need to study it. So far, very little research has been carried out. In psychology and other social sciences, it is widely believed that the family formation is hampered by a hedonistic worldview. However, it is well known that the family provides the opportunities to meet many important human needs. This contradiction has prompted the direction of the present research.Theaimof this research is to empirically investigate whether there is the conflict of the perceptions of the Russian young people about family values and hedonic and eudemonic orientations.Methodology and research methods.The empirical research was conducted using K. Peterson’s questionnaire “Happiness Orientations”. 173 students (49% female) took part in the research project. To assess the importance of family and different family values, the authors of the present research elaborated a special questionnaire, the reliability of which was confirmed in the course of approbation. The information obtained was processed through the means of correlation, regression analysis and nonparametric statistics in Statistica 10; confirmatory factor analysis of questionnaires was performed in Mplus 7.Results.The results of path analysis of interrelations between hedonism, eudemonia and family values indicated that family values were correlated not only with the orientation to meaningful and dignified life (eudemonia), but also with the orientation to pleasure (hedonism). The orientation hedonism was higher in young women; therefore, multiple regression analysis of the relationship between the studied phenomena was conducted in separate male and female groups of respondents. The results demonstrated that the value of birth and child-rearing in women is correlated with hedonism; the general value of family in male respondents is related with eudemonia.Scientific novelty.This investigation confirms that there is no contradiction between hedonism and family values. The research findings deduce that both eudemonic and hedonic orientations support family values, although the system of relationships between these orientations may vary according to gender. This finding expands our knowledge about hedonism and its role in modern society.Practical significance.The research results expand the understanding of hedonism and its role in modern society, clarifying the content of activities to prepare young people for family life. In order to enhance the effectiveness of such psychological and pedagogical support, one should take into account the hedonic tendencies of young people, revealing the importance of family formation in the context of personal happiness.