bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute neurotoxicant exposure induces hyperexcitability in mouse lumbar spinal motor neurons
Authors: Sceniak Michael P. , Spitsbergen Jake B. , Sabo Shasta L. , Yuan Yukun , Atchison William D. 
Published: March 2020

Spinal motor neurons (MNs) are susceptible to glutamatergic excitotoxicity, an effect associated with lumbar MN degeneration in amyotrophic lateral sclerosis (ALS). MN susceptibility to environmental toxicant exposure, one prospective contributor to sporadic ALS, has not been systematically studied. The goal of this study was to test the ability of a well-known environmental neurotoxicant to induce hyperexcitability in mouse lumbar MNs. Methylmercury (MeHg) causes neurotoxicity through mechanisms involving elevated intracellular Ca2+ concentration ([Ca2+]i), a hallmark of excitotoxicity. We tested whether acute exposure to MeHg induces hyperexcitability in MNs by altering synaptic transmission, using whole cell patch-clamp recordings of lumbar spinal MNs in vitro. Acute MeHg exposure (20 μM) led to an increase in the frequency of both spontaneous excitatory postsynaptic currents (EPSCs) and miniature EPSCs. The frequency of inhibitory postsynaptic currents (IPSCs) was also increased by MeHg. Action potential firing rates, both spontaneous and evoked, were increased by MeHg, despite increases in both EPSCs and IPSCs, indicating a shift toward hyperexcitability. Also consistent with hyperexcitability, fluo 4-AM microfluorimetry indicated that MeHg exposure induced an increase in [Ca2+]i. Spinal cord hyperexcitability is partially mediated by Ca2+-permeable AMPA receptors, as MeHg-dependent increases in EPSCs were blocked by 1-napthyl spermine. Therefore, spinal MNs appear highly susceptible to MeHg exposure, leading to significant increases in spontaneous network excitability and disruption of normal function. Prolonged hyperexcitability could lead to eventual neurodegeneration and loss of motor function as observed in spinal cord after MeHg exposure in vivo and may contribute to MeHg-induced acceleration of ALS symptoms. NEW & NOTEWORTHY Spinal motor neurons (MN) are susceptible to glutamatergic excitotoxicity, an effect associated with lumbar MN degeneration in amyotrophic lateral sclerosis (ALS). This study investigated MN susceptibility to environmental toxicant exposure, one prospective contributor to sporadic ALS. Spinal MNs appear highly susceptible to methylmercury exposure, leading to significant increases in spontaneous network excitability and disruption of normal function. Prolonged hyperexcitability could lead to neurodegeneration and loss of motor function as observed in ALS spinal cord symptoms.
OMTX705, a Novel FAP-Targeting ADC Demonstrates Activity in Chemotherapy and Pembrolizumab-Resistant Solid Tumor Models
Authors: Fabre Myriam , Ferrer Cristina , Domínguez-Hormaetxe Saioa , Bockorny Bruno , Murias Laura , Seifert Oliver , Eisler Stephan A. , Kontermann Roland E. , Pfizenmaier Klaus , Lee So Young , Vivanco María dM. , López-Casas Pedro P. , Perea Sofia , Abbas Muhammad , Richter Wolfgang , Simon Laureano , Hidalgo Manuel 
Published: March 2020

Abstract

Purpose:
The tumor microenvironment plays a key role in cancer development and progression and is involved in resistance to chemo- and immunotherapy. Cancer-associated fibroblast expressing fibroblast-activating protein α (FAPα) is one of the predominant stroma cell types and is involved in resistance to immunotherapy.

Experimental Design:
We generated OMTX705, a novel antibody–drug conjugate from a humanized anti-FAP antibody linked to a new cytolysin. Here, we studied its antineoplastic activity in vitro and in preclinical mouse models alone and in combination with chemotherapy as well as immunotherapy in PD-1–resistant tumors.

Results:
In Avatar models, OMTX705 showed a 100% tumor growth inhibition and prolonged tumor regressions as single agent and in combination with chemotherapy. Treatment rechallenge following treatment discontinuation induced additional tumor regression, suggesting lack of treatment resistance. In a mouse model with a humanized immune system resistant to PD-1 inhibition, OMTX705 increased tumor infiltration by CD8+ T cells, induced complete regressions, and delayed tumor recurrence.

Conclusions:
These data suggest that FAP targeting with OMTX705 represents a novel and potent strategy for cancer treatment, including tumors resistant to immunotherapy, and support its clinical development.
Integrative Analysis of Multi-omics Data Identified EGFR and PTGS2 as Key Nodes in a Gene Regulatory Network Related to Immune Phenotypes in Head and Neck Cancer
Authors: Feng Bohai , Shen Ying , Pastor Hostench Xavier , Bieg Matthias , Plath Michaela , Ishaque Naveed , Eils Roland , Freier Kolja , Weichert Wilko , Zaoui Karim , Hess Jochen 
Published: March 2020

AbstractPurpose:Malignant progression exhibits a tightly orchestrated balance between immune effector response and tolerance. However, underlying molecular principles that drive the establishment and maintenance of the tumor immune phenotype remain to be elucidated.Experimental Design:We trained a novel molecular classifier based on immune cell subsets related to programmed death-ligand 1 (PD-L1) and interferon γ (IFNγ) expression, which revealed distinct subgroups with higher (cluster A) or lower (subcluster B3) cytotoxic immune phenotypes. Integrative analysis of multi-omics data was conducted to identify differences in genetic and epigenetic landscapes as well as their impact on differentially expressed genes (DEG) among immune phenotypes. A prognostic gene signature for immune checkpoint inhibition (ICI) was established by a least absolute shrinkage and selection operator (LASSO)-Cox regression model.Results:Mutational landscape analyses unraveled a higher frequency of CASP8 somatic mutations in subcluster A1, while subcluster B3 exhibited a characteristic pattern of copy-number alterations affecting chemokine signaling and immune effector response. The integrative multi-omics approach identified EGFR and PTGS2 as key nodes in a gene regulatory network related to the immune phenotype, and several DEGs related to the immune phenotypes were affected by EGFR inhibition in tumor cell lines. Finally, we established a prognostic gene signature by a LASSO-Cox regression model based on DEGs between nonprogressive disease and progressive disease subgroups for ICI.Conclusions:Our data highlight a complex interplay between genetic and epigenetic events in the establishment of the tumor immune phenotype and provide compelling experimental evidence that a patient with squamous cell carcinoma of the head and neck at higher risk for ICI treatment failure might benefit from a combination with EGFR inhibition.
Interactions between Moisture and Tropical Convection. Part I: The Coevolution of Moisture and Convection
Authors: Wolding Brandon , Dias Juliana , Kiladis George , Ahmed Fiaz , Powell Scott W. , Maloney Eric , Branson Mark 
Published: March 2020

AbstractRealistically representing the multiscale interactions between moisture and tropical convection remains an ongoing challenge for weather prediction and climate models. In this study, we revisit the relationship between precipitation and column saturation fraction (CSF) by investigating their tendencies in CSF–precipitation space using satellite and radar observations, as well as reanalysis. A well-known, roughly exponential increase in precipitation occurs as CSF increases above a “critical point,” which acts as an attractor in CSF–precipitation space. Each movement away from and subsequent return toward the attractor results in a small net change of the coupled system, causing it to evolve in a cyclical fashion around the attractor. This cyclical evolution is characterized by shallow and convective precipitation progressively moistening the environment and strengthening convection, stratiform precipitation progressively weakening convection, and drying in the nonprecipitating and lightly precipitation regime. This behavior is evident across a range of spatiotemporal scales, suggesting that shortcomings in model representation of the joint evolution of convection and large-scale moisture will negatively impact a broad range of spatiotemporal scales. Novel process-level diagnostics indicate that several models, all implementing versions of the Zhang–McFarlane deep convective parameterization, exhibit unrealistic coupling between column moisture and convection.
Interactions between Moisture and Tropical Convection. Part II: The Convective Coupling of Equatorial Waves
Authors: Wolding Brandon , Dias Juliana , Kiladis George , Maloney Eric , Branson Mark 
Published: March 2020

AbstractThe exponential increase in precipitation with increasing column saturation fraction (CSF) is used to investigate the role of moisture in convective coupling. This simple empirical relationship between precipitation and CSF is shown to capture nearly all MJO-related variability in TRMM precipitation, ~80% of equatorial Rossby wave–related variability, and ~75% of east Pacific easterly wave–related variability. In contrast, this empirical relationship only captures roughly half of TRMM precipitation variability associated with Kelvin waves, African easterly waves, and mixed Rossby–gravity waves, suggesting coupling mechanisms other than moisture are playing leading roles in these phenomena. These latter phenomena have strong adiabatically forced vertical motions that could reduce static stability and convective inhibition while simultaneously moistening, creating a more favorable convective environment. Cross-spectra of precipitation and column-integrated dry static energy show enhanced coherence and an out-of-phase relationship in the Kelvin wave, mixed Rossby–gravity wave, and eastward inertio-gravity wave bands, supporting this narrative. The cooperative modulation of precipitation by moisture and temperature anomalies is shown to shorten the convective adjustment time scale (i.e., time scale by which moisture and precipitation are relaxed toward their “background” state) of these phenomena. Speeding the removal of moisture anomalies relative to that of temperature anomalies may allow the latter to assume a more important role in driving moist static energy fluctuations, helping promote the gravity wave character of these phenomena.
Oceanic Density/Pressure Gradients and Slope Currents
Authors: Huthnance John M. , Inall Mark E. , Fraser Neil J. 
Published: March 2020

AbstractEastern boundary currents are some of the most energetic features of the global ocean, contributing significantly to meridional mass, heat, and salt transports. We take a new look at the form of an oceanic slope current in equilibrium with oceanic density gradients. We depth integrate the linearized x and y momentum and continuity equations and assume an equilibrium force balance in the along-slope direction (no along-slope variation in the along-slope flow) and zero cross-slope flow at a coastal boundary. We relate the bottom stress to a bottom velocity via a simple boundary friction law (the precise details are easily modified) and then derive an expression for the slope current velocity by integrating upward including thermal wind shear. This provides an expression for the slope current as a function of depth and of cross-slope coordinate, dependent on the oceanic density field and surface and bottom stresses. This new expression for the slope current allows for more general forms of oceanic density fields than have been treated previously. Wind stress is also now considered. The emphasis here is on understanding the simplified equilibrium force balance rather than the evolution toward that balance. There is a direct relationship between the slope current strength, friction, and along-slope forcing (e.g., wind), and also between the total along-slope forcing and bottom Ekman transport, illustrating that “slippery” bottom boundaries in literature are a direct consequence of unrealistically assuming zero along-slope pressure gradient. We demonstrate the utility of the new expression by comparison with a high-resolution hydrodynamic numerical model.
Instabilities and Multiscale Interactions Underlying the Loop Current Eddy Shedding in the Gulf of Mexico
Authors: Yang Yang , Weisberg Robert H. , Liu Yonggang , San Liang X. 
Published: March 2020

AbstractA recently developed tool, the multiscale window transform, along with the theory of canonical energy transfer is used to investigate the roles of multiscale interactions and instabilities in the Gulf of Mexico Loop Current (LC) eddy shedding. A three-scale energetics framework is employed, in which the LC system is reconstructed onto a background flow window, a mesoscale eddy window, and a high-frequency eddy window. The canonical energy transfer between the background flow and the mesoscale windows plays an important role in LC eddy shedding. Barotropic instability contributes to the generation/intensification of the mesoscale eddies over the eastern continental slope of the Campeche Bank. Baroclinic instability favors the growth of the mesoscale eddies that propagate downstream to the northeastern portion of the well-extended LC, eventually causing the shedding by cutting through the neck of the LC. These upper-layer mesoscale eddies lose their kinetic energy back to the background LC through inverse cascade processes in the neck region. The deep eddies obtain energy primarily from the upper layer through vertical pressure work and secondarily from baroclinic instability in the deep layer. In contrast, the canonical energy transfer between the mesoscale and the high-frequency frontal eddy windows accounts for only a small fraction in the mesoscale eddy energy balance, and this generally acts as a damping mechanism for the mesoscale eddies. A budget analysis reveals that the mesoscale eddy energy gained through the instabilities is balanced by horizontal advection, pressure work, and dissipation.
The Contrasting Dynamics of the Buoyancy-Forced Lofoten and Greenland Basins
Authors: Ypma S. L. , Spall M. A. , Lambert E. , Georgiou S. , Pietrzak J. D. , Katsman C. A. 
Published: March 2020

AbstractThe Nordic seas are commonly described as a single basin to investigate their dynamics and sensitivity to environmental changes when using a theoretical framework. Here, we introduce a conceptual model for a two-basin marginal sea that better represents the Nordic seas geometry. In our conceptual model, the marginal sea is characterized by both a cyclonic boundary current and a front current as a result of different hydrographic properties east and west of the midocean ridge. The theory is compared to idealized model simulations and shows good agreement over a wide range of parameter settings, indicating that the physics in the two-basin marginal sea is well captured by the conceptual model. The balances between the atmospheric buoyancy forcing and the lateral eddy heat fluxes from the boundary current and the front current differ between the Lofoten and the Greenland Basins, since the Lofoten Basin is more strongly eddy dominated. Results show that this asymmetric sensitivity leads to opposing responses depending on the strength of the atmospheric buoyancy forcing. Additionally, the front current plays an essential role for the heat and volume budget of the two basins, by providing an additional pathway for heat toward the interior of both basins via lateral eddy heat fluxes. The variability of the temperature difference between east and west influences the strength of the different flow branches through the marginal sea and provides a dynamical explanation for the observed correlation between the front current and the slope current of the Norwegian Atlantic Current in the Nordic seas.
Electrically Active Diurnal Pulses in Hurricane Harvey (2017)
Authors: Ditchek Sarah D. , Corbosiero Kristen L. , Fovell Robert G. , Molinari John 
Published: March 2020

Abstract
Recent research has found that diurnal pulses are ubiquitous features of tropical cyclones. To gain further insight into the characteristics of these pulses, a case study of an electrically active (ACT) cooling pulse and an off-the-clock ACT cooling pulse that occurred in Hurricane Harvey (2017) was conducted. Using GridSat-B1 IR brightness temperatures, World Wide Lightning Location Network (WWLLN) lightning data, the 85–91-GHz channels on microwave satellite imagers, and Level-II Doppler radar reflectivity data from WSR-88D stations (i.e., NEXRAD), these pulses were found to share many similar characteristics: both propagated outward on the right-of-shear side of Harvey and were associated with elevated cloud ice content and high reflectivity. Additionally, using HRRR model output, both pulses were found to be associated with 1) column-deep total condensate, 2) a surface cold pool, 3) an overturning circulation, and 4) an enhanced low-level jet. These characteristics are similar to those found in tropical squall lines, supporting the tropical squall-line interpretation of diurnal pulses put forth in recent studies. A hypothesis for ACT pulse initiation was then introduced, tested, and confirmed: inner rainbands that propagated outward into a more favorable environment for deep convection reinvigorated into ACT pulses that had tropical squall-line characteristics.
Recovery of activity level following total hip arthroplasty in patients less than 60 years of age
Authors: Takeuchi Kazuhiro , Hashimoto Shingo , Matsumoto Tomoyuki , Hayashi Shinya , Takayama Koji , Kuroda Ryosuke 
Published: March 2020

Background: Total hip arthroplasty (THA) is a useful treatment for pain relief and functional improvement. THA indications now include younger, more active patients, with improved implant design and bearing materials. We aimed to investigate daily activity level and return to work after THA, about which limited information is available. Moreover, differences in patient background and clinical parameters including size of femoral head and surgical approach were evaluated. Methods: A multicentre survey was carried out in patients below 60 years, undergoing THA between 2007 and 2012, at least 1 year after surgery. Primary THA patients with osteoarthritis, avascular necrosis, rheumatoid arthritis, hip dysplasia, and no history of postoperative complications were included. The questionnaire included daily activity and occupation levels before and after surgery. University of California, Los Angeles (UCLA) activity score and occupational classification index were defined, and statistical analysis was performed. Results: The mean preoperative UCLA score in 204 patients was 4.55 which improved to 6.17 after surgery. Pre- as well as postoperative UCLA scores in males were significantly higher than that in females. No differences were observed in other parameters. Return to work rate in males was 94.4%; significantly higher than that in females (52.3%). Younger patients with large head THA were more likely to return to work. Conclusions: Most patients showed improved activity levels. Satisfaction levels were higher in young males with large femoral head size. Patients with a higher preoperative work level are expected to have a higher return to work rate.
Coding and noncoding drivers of mantle cell lymphoma identified through exome and genome sequencing
Authors: Pararajalingam Prasath , Coyle Krysta M. , Arthur Sarah E. , Thomas Nicole , Alcaide Miguel , Meissner Barbara , Boyle Merrill , Qureshi Quratulain , Grande Bruno M. , Rushton Christopher , Slack Graham W. , Mungall Andrew J. , Tam Constantine S. , Agarwal Rishu , Dawson Sarah-Jane , Lenz Georg , Balasubramanian Sriram , Gascoyne Randy D. , Steidl Christian , Connors Joseph , Villa Diego , Audas Timothy E. , Marra Marco A. , Johnson Nathalie A. , Scott David W. , Morin Ryan D. 
Published: March 2020

AbstractMantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established, and the features that contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes and 34 genomes alongside previously published exome cohorts. To confirm our findings, we resequenced the genes identified in the exome cohort in 191 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations. Our sequencing revealed novel recurrent noncoding mutations surrounding a single exon of the HNRNPH1gene. In RNA-seq data from 103 of these cases, MCL tumors with these mutations had a distinct imbalance of HNRNPH1 isoforms. This altered splicing of HNRNPH1 was associated with inferior outcomes in MCL and showed a significant increase in protein expression by immunohistochemistry. We describe a functional role for these recurrent noncoding mutations in disrupting an autoregulatory feedback mechanism, thereby deregulating HNRNPH1 protein expression. Taken together, these data strongly imply a role for aberrant regulation of messenger RNA processing in MCL pathobiology.
Epigenetic reprogramming sensitizes immunologically silent EBV+ lymphomas to virus-directed immunotherapy
Authors: Dalton Tanner , Doubrovina Ekaterina , Pankov Dmitry , Reynolds Raymond , Scholze Hanna , Selvakumar Annamalai , Vizconde Teresa , Savalia Bhumesh , Dyomin Vadim , Weigel Christoph , Oakes Christopher C. , Alonso Alicia , Elemento Olivier , Pan Heng , Phillip Jude M. , O’Reilly Richard J. , Gewurz Benjamin E. , Cesarman Ethel , Giulino-Roth Lisa 
Published: March 2020

Abstract
Despite advances in T-cell immunotherapy against Epstein-Barr virus (EBV)-infected lymphomas that express the full EBV latency III program, a critical barrier has been that most EBV+ lymphomas express the latency I program, in which the single Epstein-Barr nuclear antigen (EBNA1) is produced. EBNA1 is poorly immunogenic, enabling tumors to evade immune responses. Using a high-throughput screen, we identified decitabine as a potent inducer of immunogenic EBV antigens, including LMP1, EBNA2, and EBNA3C. Induction occurs at low doses and persists after removal of decitabine. Decitabine treatment of latency I EBV+ Burkitt lymphoma (BL) sensitized cells to lysis by EBV-specific cytotoxic T cells (EBV-CTLs). In latency I BL xenografts, decitabine followed by EBV-CTLs results in T-cell homing to tumors and inhibition of tumor growth. Collectively, these results identify key epigenetic factors required for latency restriction and highlight a novel therapeutic approach to sensitize EBV+ lymphomas to immunotherapy.