bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of paroxysmal depolarization in focal seizure activity
Authors: Tryba Andrew K. , Merricks Edward M. , Lee Somin , Pham Tuan , Cho SungJun , Nordli Douglas R. , Eissa Tahra L. , Goodman Robert R. , McKhann Guy M. , Emerson Ronald G. , Schevon Catherine A. , van Drongelen Wim 
Published: August 2019

We analyze the role of inhibition in sustaining focal epileptic seizure activity. We review ongoing seizure activity at the mesoscopic scale that can be observed with microelectrode arrays as well as at the macroscale of standard clinical EEG. We provide clinical, experimental, and modeling data to support the hypothesis that paroxysmal depolarization (PD) is a critical component of the ictal machinery. We present dual-patch recordings in cortical cultures showing reduced synaptic transmission associated with presynaptic occurrence of PD, and we find that the PD threshold is cell size related. We further find evidence that optically evoked PD activity in parvalbumin neurons can promote propagation of neuronal excitation in neocortical networks in vitro. Spike sorting results from microelectrode array measurements around ictal wave propagation in human focal seizures demonstrate a strong increase in putative inhibitory firing with an approaching excitatory wave, followed by a sudden reduction of firing at passage. At the macroscopic level, we summarize evidence that this excitatory ictal wave activity is strongly correlated with oscillatory activity across a centimeter-sized cortical network. We summarize Wilson–Cowan-type modeling showing how inhibitory function is crucial for this behavior. Our findings motivated us to develop a network motif of neurons in silico, governed by a reduced version of the Hodgkin–Huxley formalism, to show how feedforward, feedback, PD, and local failure of inhibition contribute to observed dynamics across network scales. The presented multidisciplinary evidence suggests that the PD not only is a cellular marker or epiphenomenon but actively contributes to seizure activity. NEW & NOTEWORTHY We present mechanisms of ongoing focal seizures across meso- and macroscales of microelectrode array and standard clinical recordings, respectively. We find modeling, experimental, and clinical evidence for a dual role of inhibition across these scales: local failure of inhibition allows propagation of a mesoscopic ictal wave, whereas inhibition elsewhere remains intact and sustains macroscopic oscillatory activity. We present evidence for paroxysmal depolarization as a mechanism behind this dual role of inhibition in shaping ictal activity.
Loose coupling between SK and P/Q-type Ca2+ channels in cartwheel cells of the dorsal cochlear nucleus
Authors: Irie Tomohiko 
Published: August 2019

Small-conductance Ca2+-activated K+ (SK) and large-conductance voltage- and Ca2+-activated K+ (BK) channels are Ca2+-activated K+ channels that control action potential firing in diverse neurons in the brain. In cartwheel cells of the dorsal cochlear nucleus, blockade of either channel type leads to excessive production of spike bursts. In the same cells, P/Q-type Ca2+ channels in plasma membrane and ryanodine receptors in endoplasmic reticulum supply Ca2+ to BK channels through Ca2+ nanodomain signaling. In this study, voltage-clamp experiments were performed in cartwheel cells in mouse brain slices to examine the Ca2+ signaling pathways underlying activation of SK channels. As with BK channels, SK channels required the activity of P/Q-type Ca2+ channels. However, this signaling occurred across Ca2+ micro- rather than nanodomain distances and was independent of Ca2+ release from endoplasmic reticulum. These differential modes of activation may lead to distinct time courses of the two K+ currents and therefore control excitability of auditory neurons across different timescales. NEW & NOTEWORTHY This study has shown for the first time that in cartwheel cells of the dorsal cochlear nucleus, small-conductance Ca2+-activated K+ (SK) channels were triggered by the activation of P/Q-type Ca2+ channels in which SK–P/Q-type coupling is mediated within the Ca2+ microdomains (loose coupling). Although Ca2+-induced Ca2+ release is able to activate large-conductance voltage- and Ca2+-activated K+ (BK) channels in cartwheel cells, it did not contribute to SK activation.
Reproductive Toxicity of Pomegranate Peel Extract Synthesized Gold Nanoparticles: A Multigeneration Study in C. elegans
Authors: Patel Mahnoor , Siddiqi Nikhat J. , Sharma Preeti , Alhomida Abdullah S. , Khan Haseeb A. 
Published: August 2019

C. elegans is a preferential model for testing environmental toxicity of compounds including nanomaterials. The impact of multigeneration exposure of gold nanoparticles (AuNPs) on the lifespan and fertility of C. elegans is not known and therefore is investigated in this study. We used pomegranate (Punica granatum) peel extracts as a reducing agent to synthesize gold nanoparticles (PPE-AuNPs) from chloroauric acid. Nematodes were grown till adult stage and then exposed to 25, 50, and 100 μg/ml of PPE-AuNPs at 20°C for 72 hours and then assessed for lifespan and fertility. The same protocols were followed for subsequent F1, F2, and F3 generations. The results showed that PPE-AuNPs dose-dependently but insignificantly reduced the lifespan of C. elegans. Exposure of PPE-AuNPs significantly and dose-dependently reduced the fertility of C. elegans in terms of the number of eggs produced. The reproductive toxicity of PPE-AuNPs was found to be minimal in parental generation (F0) and maximal in F3 generation. In conclusion, biologically synthesized PPE-AuNPs adversely affect the fertility of C. elegans while the factors responsible for reproductive toxicity are inherited by subsequent generations.
SRSF3-Regulated RNA Alternative Splicing Promotes Glioblastoma Tumorigenicity by Affecting Multiple Cellular Processes
Authors: Song Xiao , Wan Xuechao , Huang Tianzhi , Zeng Chang , Sastry Namratha , Wu Bingli , James C. David , Horbinski Craig , Nakano Ichiro , Zhang Wei , Hu Bo , Cheng Shi-Yuan 
Published: August 2019

Abstract

Misregulated alternative RNA splicing (AS) contributes to the tumorigenesis and progression of human cancers, including glioblastoma (GBM). Here, we showed that a major splicing factor, serine and arginine rich splicing factor 3 (SRSF3), was frequently upregulated in clinical glioma specimens and that elevated SRSF3 was associated with tumor progression and a poor prognosis for patients with glioma. In patient-derived glioma stem-like cells (GSC), SRSF3 expression promoted cell proliferation, self-renewal, and tumorigenesis. Transcriptomic profiling identified more than 1,000 SRSF3-affected AS events, with a preference for exon skipping in genes involved with cell mitosis. Motif analysis identified the sequence of CA(G/C/A)CC(C/A) as a potential exonic splicing enhancer for these SRSF3-regulated exons. To evaluate the biological impact of SRSF3-affected AS events, four candidates were selected whose AS correlated with SRSF3 expression in glioma tissues, and their splicing pattern was modified using a CRISPR/Cas9 approach. Two functionally validated AS candidates were further investigated for the mechanisms underlying their isoform-specific functions. Specifically, following knockout of SRSF3, transcription factor ETS variant 1 (ETV1) gene showed exon skipping at exon 7, while nudE neurodevelopment protein 1 (NDE1) gene showed replacement of terminal exon 9 with a mutually exclusive exon 9′. SRSF3-regulated AS of these two genes markedly increased their oncogenic activity in GSCs. Taken together, our data demonstrate that SRSF3 is a key regulator of AS in GBM and that understanding mechanisms of misregulated AS could provide critical insights for developing effective therapeutic strategies against GBMs.

Significance:
SRSF3 is a significant regulator of glioma-associated alternative splicing, implicating SRSF3 as an oncogenic factor that contributes to the tumor biology of GBM.
Pooled Genomic Screens Identify Anti-apoptotic Genes as Targetable Mediators of Chemotherapy Resistance in Ovarian Cancer
Authors: Stover Elizabeth H. , Baco Maria B. , Cohen Ofir , Li Yvonne Y. , Christie Elizabeth L. , Bagul Mukta , Goodale Amy , Lee Yenarae , Pantel Sasha , Rees Matthew G. , Wei Guo , Presser Adam G. , Gelbard Maya K. , Zhang Weiqun , Zervantonakis Ioannis K. , Bhola Patrick D. , Ryan Jeremy , Guerriero Jennifer L. , Montero Joan , Liang Felice J. , Cherniack Andrew D. , Piccioni Federica , Matulonis Ursula A. , Bowtell David D.L. , Sarosiek Kristopher A. , Letai Anthony , Garraway Levi A. , Johannessen Cory M. , Meyerson Matthew 
Published: August 2019

AbstractHigh-grade serous ovarian cancer (HGSOC) is often sensitive to initial treatment with platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy-resistant disease. To systematically identify genes modulating chemotherapy response, we performed pooled functional genomic screens in HGSOC cell lines treated with cisplatin, paclitaxel, or cisplatin plus paclitaxel. Genes in the intrinsic pathway of apoptosis were among the top candidate resistance genes in both gain-of-function and loss-of-function screens. In an open reading frame overexpression screen, followed by a mini-pool secondary screen, anti-apoptotic genes including BCL2L1 (BCL-XL) and BCL2L2 (BCL-W) were associated with chemotherapy resistance. In a CRISPR-Cas9 knockout screen, loss of BCL2L1 decreased cell survival whereas loss of proapoptotic genes promoted resistance. To dissect the role of individual anti-apoptotic proteins in HGSOC chemotherapy response, we evaluated overexpression or inhibition of BCL-2, BCL-XL, BCL-W, and MCL1 in HGSOC cell lines. Overexpression of anti-apoptotic proteins decreased apoptosis and modestly increased cell viability upon cisplatin or paclitaxel treatment. Conversely, specific inhibitors of BCL-XL, MCL1, or BCL-XL/BCL-2, but not BCL-2 alone, enhanced cell death when combined with cisplatin or paclitaxel. Anti-apoptotic protein inhibitors also sensitized HGSOC cells to the poly (ADP-ribose) polymerase inhibitor olaparib. These unbiased screens highlight anti-apoptotic proteins as mediators of chemotherapy resistance in HGSOC, and support inhibition of BCL-XL and MCL1, alone or combined with chemotherapy or targeted agents, in treatment of primary and recurrent HGSOC.Implications:Anti-apoptotic proteins modulate drug resistance in ovarian cancer, and inhibitors of BCL-XL or MCL1 promote cell death in combination with chemotherapy.
A Bispecific Molecule Targeting CD40 and Tumor Antigen Mesothelin Enhances Tumor-Specific Immunity
Authors: Ye Shiming , Cohen Diane , Belmar Nicole A. , Choi Donghee , Tan Siu Sze , Sho Mien , Akamatsu Yoshiko , Kim Han , Iyer Ramesh , Cabel Jean , Lake Marc , Song Danying , Harlan John , Zhang Catherine , Fang Yuni , Wahl Alan F. , Culp Patricia , Hollenbaugh Diane , Chao Debra T. 
Published: August 2019

Abstract
Agonistic CD40 monoclonal antibodies (mAb) have demonstrated some clinical activity, but with dose-limiting toxicity. To reduce systemic toxicity, we developed a bispecific molecule that was maximally active in the presence of a tumor antigen and had limited activity in the absence of the tumor antigen. LB-1 is a bispecific molecule containing single-chain Fv domains targeting mouse CD40 and the tumor antigen mesothelin. LB-1 exhibited enhanced activity upon binding to cell-surface mesothelin but was less potent in the absence of mesothelin binding. In a mouse model implanted with syngeneic 4T1 tumors expressing cell-surface mesothelin, LB-1 demonstrated comparable antitumor activity as an agonistic CD40 mAb but did not cause elevation of serum cytokines and liver enzymes, as was observed in anti-CD40–treated mice. The results from our study of LB-1 were used to develop a human cross-reactive bispecific molecule (ABBV-428) that targeted human CD40 and mesothelin. ABBV-428 demonstrated enhanced activation of antigen-presenting cells and T cells upon binding to cell-surface mesothelin, and inhibition of cultured or implanted PC3 tumor cell growth after immune activation. Although expression of cell-surface mesothelin is necessary, the bispecific molecules induced immune-mediated antitumor activity against both mesothelin+ and mesothelin− tumor cells. ABBV-428 represents a class of bispecific molecules with conditional activity dependent on the binding of a tumor-specific antigen, and such activity could potentially maximize antitumor potency while limiting systemic toxicity in clinical studies.
STING Signaling in Melanoma Cells Shapes Antigenicity and Can Promote Antitumor T-cell Activity
Authors: Falahat Rana , Perez-Villarroel Patricio , Mailloux Adam W. , Zhu Genyuan , Pilon-Thomas Shari , Barber Glen N. , Mulé James J. 
Published: August 2019

AbstractSTING (stimulator of IFN genes) signaling is an innate immune pathway for induction of a spontaneous antitumor T-cell response against certain immunogenic tumors. Although antigen-presenting cells are known to be involved in this process, insight into the participation of tumor cell–intrinsic STING signaling remains weak. In this study, we find diversity in the regulation of STING signaling across a panel of human melanoma cell lines. We show that intact activation of STING signaling in a subset of human melanoma cell lines enhances both their antigenicity and susceptibility to lysis by human melanoma tumor-infiltrating lymphocytes (TIL) through the augmentation of MHC class I expression. Conversely, defects in the STING signaling pathway protect melanoma cells from increased immune recognition by TILs and limit their sensitivity to TIL lysis. Based on these findings, we propose that defects in tumor cell–intrinsic STING signaling can mediate not only tumor immune evasion but also resistance to TIL-based immunotherapies.
The Americanization of Orthodox Christians’ Promotion of Religious Freedom
Authors: Herbel Dellas Oliver 
Published: August 2019

Abstract
Throughout their history in America, Orthodox Christians have promoted their religious freedom primarily through legal changes (e.g., executive orders, court decisions, or legislation). More recently, some Orthodox Christian leaders have begun to respond to the issue of religious freedom by engaging in American political discourse as established by larger conservative religious groups. Orthodox Christians now find themselves utilizing both approaches, exhibiting an Americanization of their faith by accepting the behavior patterns of native-born Americans as valid and authentic. This article explores the three distinct shifts that occurred in this process: self preservation to self-promotion, self-promotion to promoting the religious freedoms of Orthodox overseas, and the adoption of the religious rhetoric and tactics of some American religious conservatives.
Effects of Rotation on the Multiscale Organization of Convection in a Global 2D Cloud-Resolving Model
Authors: Yang Qiu , Majda Andrew J. , Brenowitz Noah D. 
Published: August 2019

Abstract
Atmospheric convection exhibits distinct spatiotemporal variability at different latitudes. A good understanding of the effects of rotation on the multiscale organization of convection from the mesoscale to synoptic scale to planetary scale is still lacking. Here cloud-resolving simulations with fixed surface fluxes and radiative cooling are implemented with constant rotation in a two-dimensional (2D) planetary domain to simulate multiscale organization of convection from the tropics to midlatitudes. All scenarios are divided into three rotation regimes (weak, order-one, and strong) to represent the idealized ITCZ region (0°–6°N), the Indian monsoon region (6°–20°N), and the midlatitude region (20°–45°N), respectively. In each rotation regime, a multiscale asymptotic model is derived systematically and used as a diagnostic framework for energy budget analysis. The results show that planetary-scale organization of convection only arises in the weak rotation regime, while synoptic-scale organization dominates (vanishes) in the order-one (strong) rotation regime. The depletion of planetary-scale organization of convection as the magnitude of rotation increases is attributed to the reduced planetary kinetic energy of zonal winds, mainly due to the decreasing acceleration effect by eddy zonal momentum transfer from mesoscale convective systems (MCSs) and the increasing deceleration effect by the Coriolis force. Similarly, the maintenance of synoptic-scale organization is related to the acceleration effect by MCSs. Such decreasing acceleration effects by MCSs on both planetary and synoptic scales are further attributed to less favorable conditions for convection provided by weaker background vertical shear of the zonal winds, resulting from the increasing magnitude of rotation.
Subtropical South American Hailstorm Characteristics and Environments
Authors: Bruick Zachary S. , Rasmussen Kristen L. , Cecil Daniel J. 
Published: August 2019

AbstractHailstorms in subtropical South America are known to be some of the most frequent anywhere in the world, causing significant damage to the local agricultural economy every year. Convection in this region tends to be orographically forced, with moisture supplied from the Amazon rain forest by the South American low-level jet. Previous climatologies of hailstorms in this region have been limited to localized and sparse observational networks. Because of the lack of sufficient ground-based radar coverage, objective radar-derived hail climatologies have also not been produced for this region. As a result, this study uses a 16-yr dataset of TRMM Precipitation Radar and Microwave Imager observations to identify possible hailstorms remotely, using 37-GHz brightness temperature as a hail proxy. By combining satellite instruments and ERA-Interim reanalysis data, this study produces the first objective study of hailstorms in this region. Hailstorms in subtropical South America have an extended diurnal cycle, often occurring in the overnight hours. In addition, they tend to be multicellular in nature, rather than discrete. High-probability hailstorms (≥50% probability of containing hail) tend to be deeper by 1–2 km and horizontally larger by greater than 15 000 km2 than storms having a low probability of containing hail (&lt;25% probability of containing hail). Hailstorms are supported synoptically by strong upper- and lower-level jets, anomalously warm and moist low levels, and enhanced instability. The findings of this study will support the forecasting of these severe storms and mitigation of their damage within this region.
Access to Subsidised Packing Credit for Financing Export: Who are the Gainers?
Authors: Sanati Gargi 
Published: August 2019

This study examines the packing credit or pre-shipment credit (PC) as a key determinant factor for the export growth in India. PC is considered to be an important means of financing export if advance payment is not received by the exporter prior to the shipment of goods. The Government of India’s (GoI) scheme of interest subsidy in PC is mostly to boost the export growth in India. In this backdrop, this article is having threefold objectives: (a) to examine the distribution pattern of PC across various exporting sectors; (b) to analyse the availability of export financing at different interest rate range; and (c) to estimate the sensitivity of export growth of India to its utilisation of PC in small, medium and large exporting sectors. Our preliminary analysis reveals that natural elimination takes place, and the present practice of disbursing PC is not able to fulfil the goal of establishing a level playing field for the exporters. Per capita utilisation of PC shows highly skewed preference of the banks to large borrowers, even if they are not subject to the benefit of interest subvention. This study also reveals that small exporters hold the maximum number of PC account, although having the least outstanding amount per account. On the contrary, our Arellano–Bond Dynamic panel analysis for the period 1996–1997 to 2015–2016 shows that the utilisation of PC by medium and small exporters respectively are more sensitive to boost the export growth of India. This study also finds that the effect of the interest subvention scheme was dampened due to the financial crisis and concludes that the export growth would have been much worse affected in the absence of the subvention scheme. Our empirical examination concludes that interest subvention plays a positive and significant role to boost the export growth and additional reduction in the cost of production may add to the export growth of India. This study recommends that the government may introduce a differential interest subsidy for different creditworthy exporters within the entitled sectors to reduce the cost of fund effectively for more needy and sensitive exporters. Given the resource constraint, it may be ensured that large exporters are restricted from receiving the subsidised export finance. JEL: F49, F30, G01, G18, G32
Translational value of partial resection of the pulmonary artery wall for congenital heart disease-induced bronchial compression
Authors: Wu Xiangyang , Zhu Jie , Liu Hao , Chen Wensheng , Wei Yalin , Guan Xinqiang , Zhang Yanchun , Tao Pengxian , Gao Bingren 
Published: August 2019

Objective This study was performed to evaluate the clinical efficacy and safety of a novel surgical procedure in treating tracheal or bronchial compression related to severe congenital heart disease. Methods The clinical data of 28 patients with tracheal or bronchial compression related to severe congenital heart disease were retrospectively analyzed. In the control group, 12 patients underwent surgery for congenital cardiac malformations. In the treatment group, 16 patients underwent surgery for congenital cardiac malformations combined with partial resection of the pulmonary artery wall. The cardiothoracic ratio, pulmonary arterial pressure, left ventricular end-diastolic dimension, diameter of the pulmonary artery, and diameter of the trachea in the stenotic segment were quantitatively measured before and 9 days after the operation. Results The diameter of the pulmonary artery and diameter of the trachea in the stenotic segment were almost restored to the normal range in the treatment group. Patients in the treatment group recovered more rapidly and effectively than those in the control group. Conclusion Partial resection of the pulmonary artery wall is an efficacious and safe technique in the treatment of tracheal or bronchial compression related to severe congenital heart disease.
Coblation tonsillectomy versus coblation tonsillectomy with ties in adults
Authors: Zhou Xuanchen , Xu Anting , Zhen Xiaoyue , Gao Kun , Cui Zhaoyang , Yue Zhiyong , Han Jie 
Published: August 2019

Objective This study was performed to compare the intraoperative and postoperative courses of coblation tonsillectomy and coblation tonsillectomy with ties in adults. Methods All patients who underwent tonsillectomy from July 2012 to September 2016 were retrospectively reviewed. Intraoperative and postoperative bleeding, pain, and return to normal food intake were compared between patients who underwent coblation tonsillectomy and those who underwent coblation tonsillectomy with ties. Results Of 515 patients, 300 (58.3%) underwent coblation tonsillectomy and 215 (41.7%) underwent coblation tonsillectomy with ties. Twenty-five (4.9%) patients developed postoperative hemorrhage, 22 (88.0%) of whom had undergone coblation tonsillectomy and 3 (12.0%) of whom had undergone coblation tonsillectomy with ties. Patients who underwent coblation tonsillectomy reported less pain than those who underwent coblation tonsillectomy with ties. Patients who underwent coblation tonsillectomy with ties resumed a normal diet significantly later than those who underwent coblation tonsillectomy (10.0 ± 3.2 vs. 8.2 ± 1.9 days, respectively). Conclusion Coblation tonsillectomy is associated with less intraoperative bleeding, a shorter surgery time, less postoperative pain, and fewer days to recovery of a normal diet than is coblation tonsillectomy with ties. However, coblation tonsillectomy with ties is associated with remarkably reduced postoperative hemorrhage.