bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response to coincident inputs in electrically coupled primary afferents is heterogeneous and is enhanced by H-current (IH) modulation
Authors: Davoine Federico , Curti Sebastian 
Published: May 2019

Electrical synapses represent a widespread modality of interneuronal communication in the mammalian brain. These contacts, by lowering the effectiveness of random or temporally uncorrelated inputs, endow circuits of coupled neurons with the ability to selectively respond to simultaneous depolarizations. This mechanism may support coincidence detection, a property involved in sensory perception, organization of motor outputs, and improvement signal-to-noise ratio. While the role of electrical coupling is well established, little is known about the contribution of the cellular excitability and its modulations to the susceptibility of groups of neurons to coincident inputs. Here, we obtained dual whole cell patch-clamp recordings of pairs of mesencephalic trigeminal (MesV) neurons in brainstem slices from rats to evaluate coincidence detection and its determinants. MesV neurons are primary afferents involved in the organization of orofacial behaviors whose cell bodies are electrically coupled mainly in pairs through soma-somatic gap junctions. We found that coincidence detection is highly heterogeneous across the population of coupled neurons. Furthermore, combined electrophysiological and modeling approaches reveal that this heterogeneity arises from the diversity of MesV neuron intrinsic excitability. Consistently, increasing these cells’ excitability by upregulating the hyperpolarization-activated cationic current ( IH) triggered by cGMP results in a dramatic enhancement of the susceptibility of coupled neurons to coincident inputs. In conclusion, the ability of coupled neurons to detect coincident inputs is critically shaped by their intrinsic electrophysiological properties, emphasizing the relevance of neuronal excitability for the many functional operations supported by electrical transmission in mammals.NEW & NOTEWORTHY We show that the susceptibility of pairs of coupled mesencephalic trigeminal (MesV) neurons to coincident inputs is highly heterogenous and depends on the interaction between electrical coupling and neuronal excitability. Additionally, upregulating the hyperpolarization-activated cationic current ( IH) by cGMP results in a dramatic increase of this susceptibility. The IHand electrical synapses have been shown to coexist in many neuronal populations, suggesting that modulation of this conductance could represent a common strategy to regulate circuit operation supported by electrical coupling.
Slow oscillatory changes of DPOAE magnitude and phase after exposure to intense low-frequency sounds
Authors: Ueberfuhr Margarete A. , Drexl Markus 
Published: May 2019

Sensitive sound detection within the mammalian cochlea is performed by hair cells surrounded by cochlear fluids. Maintenance of cochlear fluid homeostasis and tight regulation of intracellular conditions in hair cells are crucial for the auditory transduction process but can be impaired by intense sound stimulation. After a short, intense low-frequency sound, the cochlea shows the previously described “bounce phenomenon,” which manifests itself as slow oscillatory changes of hearing thresholds and otoacoustic emissions. In this study, distortion product otoacoustic emissions (DPOAEs) were recorded after Mongolian gerbils were exposed to intense low-frequency sounds (200 Hz, 100 dB SPL) with different exposure times up to 1 h. After all sound exposure durations, a certain percentage of recordings (up to 80% after 1.5-min-long exposure) showed oscillatory DPOAE changes, similar to the bounce phenomenon in humans. Changes were quite uniform with respect to size and time course, and they were independent from sound exposure duration. Changes showed states of hypo- and hyperactivity with either state preceding the other. The direction of changes was suggested to depend on the static position of the cochlear operating point. As assessed with DPOAEs, no indication for a permanent damage after several or long exposure times was detected. We propose that sensitivity changes occur due to alterations of the mechanoelectrical transduction process of outer hair cells. Those alterations could be induced by different challenged homeostatic processes with slow electromotility of outer hair cells being the most plausible source of the bounce phenomenon. NEW & NOTEWORTHY Low-frequency, high-intensity sound can cause slowly cycling activity changes in the mammalian cochlea. We examined the effect of low-frequency sound duration on the degree of these alterations. We found that cochlear changes showed a stereotypical biphasic pattern independent of sound exposure duration, but the probability that significant changes occurred decreased with increasing sound duration. Despite exposure durations of up to 1 h, no permanent or transient impairments of the cochlea were detected.
Inflammatory Breast Cancer Promotes Development of M2 Tumor-Associated Macrophages and Cancer Mesenchymal Cells through a Complex Chemokine Network
Authors: Valeta-Magara Amanda , Gadi Abhilash , Volta Viviana , Walters Beth , Arju Rezina , Giashuddin Shah , Zhong Hua , Schneider Robert J. 
Published: May 2019

Abstract

Inflammatory breast cancer (IBC) is a highly aggressive form of breast cancer that displays profound cancer stem cell (CSC) and mesenchymal features that promote rapid metastasis. Another hallmark of IBC is high infiltration of M2 tumor-associated (immune-suppressing) macrophages. The molecular mechanism that drives these IBC phenotypes is not well understood. Using patient breast tumor specimens, breast cancer cell lines, and a patient-derived xenograft model of IBC, we demonstrate that IBC strongly expresses IL8 and growth-regulated oncogene (GRO) chemokines that activate STAT3, which promotes development of high levels of CSC-like cells and a mesenchymal phenotype. We also show that IBC expresses high levels of many monocyte recruitment and macrophage polarization factors that attract and differentiate monocytes into tumor-promoting, immune-suppressing M2-like macrophages. The M2 macrophages in turn were found to secrete high levels of IL8 and GRO chemokines, thereby creating a feed-forward chemokine loop that further drives an IBC epithelial-to-mesenchymal transition. Our study uncovers an intricate IBC-initiated autocrine–paracrine signaling network between IBC cells and monocytes that facilitates development of this highly aggressive form of breast cancer.

Significance:
This study uncovers a signaling network in which IBC cells commandeer macrophages to become tumor-promoting, and they in turn drive IBC cells to be more cancer stem-like, mesenchymal, and aggressive.
Stromal Support of Metabolic Function through Mitochondrial Transfer in Multiple Myeloma
Authors: Boise Lawrence H. , Shanmugam Mala 
Published: May 2019

Abstract
Marlein and colleagues demonstrate in multiple myeloma, bone marrow stromal cells transfer mitochondria to myeloma cells to increase cellular respiration, resulting in increased proliferation. The intercellular transfer occurs through the formation of tunneling nanotubes that connect the myeloma cell to the stromal cell and is dependent on surface CD38 expression on myeloma cells. CD38 is an important therapeutic target in myeloma, therefore, regulation of myeloma metabolism may play a role in the activity of this therapeutic approach. The study reinforces the importance of intercellular interactions in the tumor microenvironment and sheds new light on the control of metabolism in myeloma.
See related article by Marlein et al., p. 2285
TFE3 Xp11.2 Translocation Renal Cell Carcinoma Mouse Model Reveals Novel Therapeutic Targets and Identifies GPNMB as a Diagnostic Marker for Human Disease
Authors: Baba Masaya , Furuya Mitsuko , Motoshima Takanobu , Lang Martin , Funasaki Shintaro , Ma Wenjuan , Sun Hong-Wei , Hasumi Hisashi , Huang Ying , Kato Ikuma , Kadomatsu Tsuyoshi , Satou Yorifumi , Morris Nicole , Karim Baktiar O. , Ileva Lilia , Kalen Joseph D. , Wilan Krisna Luh Ade , Hasumi Yukiko , Sugiyama Aiko , Kurahashi Ryoma , Nishimoto Koshiro , Oyama Masafumi , Nagashima Yoji , Kuroda Naoto , Araki Kimi , Eto Masatoshi , Yao Masahiro , Kamba Tomomi , Suda Toshio , Oike Yuichi , Schmidt Laura S. , Linehan W. Marston 
Published: May 2019

Abstract

Renal cell carcinoma (RCC) associated with Xp11.2 translocation (TFE3-RCC) has been recently defined as a distinct subset of RCC classified by characteristic morphology and clinical presentation. The Xp11 translocations involve the TFE3 transcription factor and produce chimeric TFE3 proteins retaining the basic helix–loop–helix leucine zipper structure for dimerization and DNA binding suggesting that chimeric TFE3 proteins function as oncogenic transcription factors. Diagnostic biomarkers and effective forms of therapy for advanced cases of TFE3-RCC are as yet unavailable. To facilitate the development of molecular based diagnostic tools and targeted therapies for this aggressive kidney cancer, we generated a translocation RCC mouse model, in which the PRCC-TFE3 transgene is expressed specifically in kidneys leading to the development of RCC with characteristic histology. Expression of the receptor tyrosine kinase Ret was elevated in the kidneys of the TFE3-RCC mice, and treatment with RET inhibitor, vandetanib, significantly suppressed RCC growth. Moreover, we found that Gpnmb (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that GPNMB is the direct transcriptional target of TFE3 fusions. While GPNMB IHC staining was positive in 9/9 cases of TFE3-RCC, Cathepsin K, a conventional marker for TFE3-RCC, was positive in only 67% of cases. These data support RET as a potential target and GPNMB as a diagnostic marker for TFE3-RCC. The TFE3-RCC mouse provides a preclinical in vivo model for the development of new biomarkers and targeted therapeutics for patients affected with this aggressive form of RCC.

Implications:
Key findings from studies with this preclinical mouse model of TFE3-RCC underscore the potential for RET as a therapeutic target for treatment of patients with TFE3-RCC, and suggest that GPNMB may serve as diagnostic biomarker for TFE3 fusion RCC.
Evaluation of Tumor Cell–Tumor Microenvironment Component Interactions as Potential Predictors of Patient Response to Napabucasin
Authors: Chang An-Yun , Hsu Eric , Patel Jaimin , Li Yiqun , Zhang Minjie , Iguchi Haruhisa , Rogoff Harry A. 
Published: May 2019

Abstract

Napabucasin is an NAD(P)H:quinone oxidoreductase 1 (NQO1)-bioactivatable small molecule hypothesized to affect multiple oncogenic pathways. In a prespecified, retrospective analysis of the napabucasin phase III CO.23 study, overall survival was longer for napabucasin versus placebo in patients expressing phosphorylated STAT3 (pSTAT3) in tumor cells and cells of the tumor microenvironment (TME). We hypothesized that a connection may exist between NQO1 expression in cancer cells and pSTAT3 in tumor cells and the TME. In 3D spheroid cocultures of cancer cells and cancer-associated fibroblasts, the antitumor activity of napabucasin was NQO1 dependent. The levels of cytokines such as IL6, CXCL10, and GM-CSF were higher in NQO1-positive versus NQO1-deleted cocultures. These differentially secreted cytokines promoted STAT3 phosphorylation in tumor cells and the TME. NQO1-expressing, napabucasin-sensitive tumor cells can modify tumor cells and the TME to promote STAT3 phosphorylation, suggesting that pSTAT3 may be used to identify a subpopulation of patients who would likely respond to napabucasin.

Implications:
pSTAT3 is a potential biomarker for patient response to the anticancer drug napabucasin.
Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/7/1429/F1.large.jpg.
Paracrine Interaction of Cancer Stem Cell Populations Is Regulated by the Senescence-Associated Secretory Phenotype (SASP)
Authors: Lagunas Angelica M. , Francis Marybeth , Maniar Nisha B. , Nikolova Gergana , Wu Jianchun , Crowe David L. 
Published: May 2019

AbstractDyskeratosis congenita is a telomere DNA damage syndrome characterized by defective telomere maintenance, bone marrow failure, and increased head and neck cancer risk. The Pot1b−/−;Terc+/− mouse exhibits some features of dyskeratosis congenita, but head and neck cancer was not reported in this model. To model the head and neck cancer phenotype, we created unique Pot1b- and p53-null–mutant models which allow genetic lineage tracing of two distinct stem cell populations. Loss of Pot1b expression depleted stem cells via ATR/Chk1/p53 signaling. Tumorigenesis was inhibited in Pot1b−/−;p53+/+ mice due to cellular senescence. Pot1b−/−;p53−/− tumors also exhibited senescence, but proliferated and metastasized with expansion of Lgr6+ stem cells indicative of senescence-associated secretory phenotype. Selective depletion of the small K15+ stem cell fraction resulted in reduction of Lgr6+ cells and inhibition of tumorigenesis via senescence. Gene expression studies revealed that K15+ cancer stem cells regulate Lgr6+ cancer stem cell expansion via chemokine signaling. Genetic ablation of the chemokine receptor Cxcr2 inhibited cancer stem cell expansion and tumorigenesis via senescence. The effects of chemokines were primarily mediated by PI3K signaling, which is a therapeutic target in head and neck cancer.Implications:Paracrine interactions of cancer stem cell populations impact therapeutic options and patient outcomes.
Smoking Cessation and the Risk of Bladder Cancer among Postmenopausal Women
Authors: Li Yueyao , Tindle Hilary A. , Hendryx Michael S. , Xun Pengcheng , He Ka , Liang Xiaoyun , Luo Juhua 
Published: May 2019

Abstract
Smoking is the strongest established risk factor for bladder cancer. Former smokers have a lower risk of bladder cancer compared with current smokers, but findings on the dose–response relationship between years after quitting and the risk of bladder cancer are inconsistent. A total of 143,279 postmenopausal women from the Women's Health Initiative Study were included. Cox proportional hazards regression models were applied for estimating age- and multivariable-adjusted HRs and their 95% confidence intervals (CI). There were 870 bladder cancer cases identified over an average of 14.8 years of follow-up. After adjusting for pack-years of smoking, bladder cancer risk among former smokers declined by 25% within the first 10 years of cessation and continued to decrease as cessation time increased but remained higher than never smokers after 30 years of quitting (HR, 1.92; 95% CI, 1.43–2.58). Smokers who quit smoking had a lower risk of bladder cancer compared with current smokers (HR, 0.61; 95% CI, 0.40–0.94). We conclude that among postmenopausal women, there is a significant reduction in the risk of bladder cancer after quitting smoking. In addition to primary prevention, smoking cessation is critical to prevent the incidence of bladder cancer in older women.
Poor Response to Neoadjuvant Chemotherapy Correlates with Mast Cell Infiltration in Inflammatory Breast Cancer
Authors: Reddy Sangeetha M. , Reuben Alexandre , Barua Souptik , Jiang Hong , Zhang Shaojun , Wang Linghua , Gopalakrishnan Vancheswaran , Hudgens Courtney W. , Tetzlaff Michael T. , Reuben James M. , Tsujikawa Takahiro , Coussens Lisa M. , Wani Khalida , He Yan , Villareal Lily , Wood Anita , Rao Arvind , Woodward Wendy A. , Ueno Naoto T. , Krishnamurthy Savitri , Wargo Jennifer A. , Mittendorf Elizabeth A. 
Published: May 2019

Abstract
Our understanding is limited concerning the tumor immune microenvironment of inflammatory breast cancer (IBC), an aggressive form of primary cancer with low rates of pathologic complete response to current neoadjuvant chemotherapy (NAC) regimens. We retrospectively identified pretreatment (N = 86) and matched posttreatment tissue (N = 27) from patients with stage III or de novo stage IV IBC who received NAC followed by a mastectomy. Immune profiling was performed including quantification of lymphoid and myeloid infiltrates by IHC and T-cell repertoire analysis. Thirty-four of 86 cases in this cohort (39.5%) achieved a pathologic complete response. Characterization of the tumor microenvironment revealed that having a lower pretreatment mast cell density was significantly associated with achieving a pathologic complete response to NAC (P = 0.004), with responders also having more stromal tumor-infiltrating lymphocytes (P = 0.035), CD8+ T cells (P = 0.047), and CD20+ B cells (P = 0.054). Spatial analysis showed close proximity of mast cells to CD8+ T cells, CD163+ monocytes/macrophages, and tumor cells when pathologic complete response was not achieved. PD-L1 positivity on tumor cells was found in fewer than 2% of cases and on immune cells in 27% of cases, but with no correlation to response. Our results highlight the strong association of mast cell infiltration with poor response to NAC, suggesting a mechanism of treatment resistance and a potential therapeutic target in IBC. Proximity of mast cells to immune and tumor cells may suggest immunosuppressive or tumor-promoting interactions of these mast cells.
Encontros e diferenças: gêneros, sexualidades e racialidades no fazer científico da geografia. Resenha de SILVA, J. M.; ORNAT, M. J.; CHIMIN JR., A. B. Geografias feministas e das sexualidades: encontros e diferenças
Authors: Silva Elisabete de Fátima Farias 
Published: May 2019

“Geografias Feministas e das Sexualidades: encontros e diferenças”, organizado pelos geógrafos Joseli Maria Silva (UEPG), Marcio Jose Ornat (UEPG) e Alides Baptista Chimin Junior (Unicentro), é uma obra preciosa à geografia brasileira. Composta por dez artigos, sendo nove traduções anglófonas, a coletânea é fruto de uma decisão de pronunciamento sobre escolhas e escalas espaciais, com o objetivo de produzir uma geografia capaz de trazer sujeitos generificados, sexualizados e racializados para o centro do debate científico.O subtítulo encontros e diferenças está presente tanto no conjunto da obra, quanto nas bases teóricas bem articuladas nos artigos. Publicado em 2016, este livro é parte da produção científica do Grupo de Estudos Territoriais (GETE), formado em 2003, na Universidade Estadual de Ponta Grossa, Paraná. O GETE trouxe novas questões para a análise espacial, pautadas no gênero e nas sexualidades, em contraponto às abordagens heteronormativas, confirma Miguel Angelo Ribeiro no prefácio. Além da organização dos artigos proporcionar uma vasta e, sobretudo, consistente aproximação com a diversidade de pesquisas já realizadas no campo das geografias feministas e sexualidades, o primeiro artigo de autoria dos brasileiros organizadores da obra traz à luz discussões muito pertinentes e atuais em “Sobre as desobediências epistemológicas e o testamento intelectual de Milton Santos”.
O sagrado e o profano na poesia de Mário de Andrade
Authors: Natal Caion Meneguello 
Published: May 2019

O artigo aborda a relação entre sagrado e profano na poesia de Mário de Andrade em princípios da década de 1920. São analisados seis poemas: “Noturno”, “Jorobabel”, “XXXIII”, “XXXIII (bis) Platão”, “Carnaval carioca” e “Religião”. Para tanto, dialogamos com o conceito de “verso harmônico”, tal como exposto no manifesto vanguardista “Prefácio interessantíssimo”, publicado no livro Pauliceia desvairada (1922). O objetivo é mostrar como o eixo sagrado-profano relaciona-se a dualidades mais gerais presentes nos versos do autor modernista, como vida e escrita, humano e divino, linguagem e realidade, entre outros.
Litofácies, ambientes deposicionais e ciclicidade do Grupo Paranoá: exemplo da região da Serra de São Domingos, Minas Gerais
Authors: Feitosa Icília De Lima , Alvarenga Carlos José Souza de , Martinho Caroline Thaís 
Published: May 2019

Na Serra de São Domingos (SSD) afloram mais de 1.000 m de espessura de rochas mesoproterozoicas dominantemente siliciclásticas do Grupo Paranoá. Duas seções estratigráficas foram medidas e descritas na escala 1:300 e individualizadas em 11 litofácies nas seções estudadas: De (dolomito com estromatólitos), Dl (dolomito laminado), AFl (arenito fino laminado), AFm (arenito fino com marcas onduladas de onda e corrente), AFh (arenito fino com estratificação cruzada hummocky), AMc1 (arenito médio com estratificações cruzadas unidirecionais), AMc2 (arenito médio com estratificações cruzadas bidirecionais e/ou multidirecionais), AMe (arenito médio estratificado), AMs (arenito médio com geometria sigmoidal), Pl (pelito laminado) e PAht (pelito e arenito com laminação heterolítica). Cinco associações de fácies foram identificadas: FA-I caracterizada pelas litofácies PAht e AFm em subsistema de intermaré; FA-II caracterizada pelas AMc1, AMc2, AMs, AMe em subsistema de inframaré; FA- III caracterizada pela associação de litofácies AFm, AFl, AFh e Pl em subsistema de plataforma (offshore proximal) com influência de onda, maré e de tempestade; FA-IV caracterizada pelas litofácies AFl, Pl, AFh, Dl e De em subsistema de plataforma (offshore intermediáriadistal); FA-V caracterizada pela associação de litofácies Dl e De em subsistema de zona de plataforma rasa. As associações de fácies, FA-III, FA-IV e FA-V são típicas de sistema deposicional de plataforma marinha mista carbonática-siliciclástica, enquanto FA-I e FA-II caracterizam depósitos de planície de maré. Os sistemas deposicionais ao longo da SSD variam de depósitos de plataforma offshore proximal na sua base, passando em direção ao topo para o domínio de uma plataforma proximal com influência de maré (inframaré-intermaré), evidenciando um gradual e contínuo raseamento para o topo.
Petrografia e química do Granito Aripuanã, sul do Cráton Amazônico
Authors: Godoy Antonio Misson , Vieira Otávio Augusto Ruiz Paccola , Silva Jesué Antonio da , Manzano Jefferson Cassu , Araújo Larissa Marques Barbosa de , Mello Júnior Antônio Ferreira de 
Published: May 2019

O termo Granito Aripuanã refere-se a um conjunto de corpos graníticos circunscritos não deformados, intrusivos em rochas da sequência metavulcanossedimentar do Grupo Roosevelt, reconhecidos na porção sul do Cráton Amazônico. O corpo granítico principal constitui um batólito ovalado com diâmetro menor que 15 km, que ocorre a norte da cidade de Aripuanã, no noroeste do estado do Mato Grosso. É constituído de hornblenda-biotita sieno a monzogranitos porfiríticos grossos, de coloração cinza ou vermelha e localmente com texturas rapakivi. Nas áreas marginais é observada uma redução de granulação das feições porfiríticas com predomínio da fácies equigranular fina, associada a resfriamento rápido. As fácies tardias comuns são constituídas de diques equigranulares de cor cinza, aplitos róseos e cinza e veios pegmatíticos. Ocorrem veios pós-magmáticos de quartzo, fluorita, muscovita em zonas de deformação rúptil, em que as rochas mostram intensa alteração hidrotermal. Esse hidrotermalismo afeta de forma heterogênea as rochas encaixantes e as rochas magmáticas, facilitando a circulação de fluidos e favorecendo a concentração de sulfetos de zinco disseminados, sempre relacionados ao fraturamento. Os granitos hospedam xenólitos de rochas paraderivadas encaixantes, de granodioritos, quartzo dioritos e rochas micáceas. Nas bordas, ocorrem veios e apófises graníticas, além de metamorfismo de contato nas rochas encaixantes. Os monzogranitos são peraluminosos e pertencem à série de alto potássio a shoshonítica, similares a granitos “ferroan”, apresentando assinatura de granito tipo A, pós-colisionais a anorogênicos e associado à evolução do Arco Magmático Jamari.