bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activity within specific enteric neurochemical subtypes is correlated with distinct patterns of gastrointestinal motility in the murine colon
Authors: Gould Thomas W. , Swope William A. , Heredia Dante J. , Corrigan Robert D. , Smith Terence K. 
Published: July 2019

The enteric nervous system in the large intestine generates two important patterns relating to motility: 1) propagating rhythmic peristaltic smooth muscle contractions referred to as colonic migrating motor complexes (CMMCs) and 2) tonic inhibition, during which colonic smooth muscle contractions are suppressed. The precise neurobiological substrates underlying each of these patterns are unclear. Using transgenic animals expressing the genetically encoded calcium indicator GCaMP3 to monitor activity or the optogenetic actuator channelrhodopsin (ChR2) to drive activity in defined enteric neuronal subpopulations, we provide evidence that cholinergic and nitrergic neurons play significant roles in mediating CMMCs and tonic inhibition, respectively. Nitrergic neurons [neuronal nitric oxide synthase (nNOS)-positive neurons] expressing GCaMP3 exhibited higher levels of activity during periods of tonic inhibition than during CMMCs. Consistent with these findings, optogenetic activation of ChR2 in nitrergic neurons depressed ongoing CMMCs. Conversely, cholinergic neurons [choline acetyltransferase (ChAT)-positive neurons] expressing GCaMP3 markedly increased their activity during the CMMC. Treatment with the NO synthesis inhibitor Nω-nitro-l-arginine also augmented the activity of ChAT-GCaMP3 neurons, suggesting that the reciprocal patterns of activity exhibited by nitrergic and cholinergic enteric neurons during distinct phases of colonic motility may be related. NEW & NOTEWORTHY Correlating the activity of neuronal populations in the myenteric plexus to distinct periods of gastrointestinal motility is complicated by the difficulty of measuring the activity of specific neuronal subtypes. Here, using mice expressing genetically encoded calcium indicators or the optical actuator channelrhodopsin-2, we provide compelling evidence that cholinergic and nitrergic neurons play important roles in mediating coordinated propagating peristaltic contractions or tonic inhibition, respectively, in the murine colon.
Active membrane conductances and morphology of a collision detection neuron broaden its impedance profile and improve discrimination of input synchrony
Authors: Dewell Richard B. , Gabbiani Fabrizio 
Published: July 2019

How neurons filter and integrate their complex patterns of synaptic inputs is central to their role in neural information processing. Synaptic filtering and integration are shaped by the frequency-dependent neuronal membrane impedance. Using single and dual dendritic recordings in vivo, pharmacology, and computational modeling, we characterized the membrane impedance of a collision detection neuron in the grasshopper Schistocerca americana. This neuron, the lobula giant movement detector (LGMD), exhibits consistent impedance properties across frequencies and membrane potentials. Two common active conductances gH and gM, mediated respectively by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and by muscarine-sensitive M-type K+ channels, promote broadband integration with high temporal precision over the LGMD’s natural range of membrane potentials and synaptic input frequencies. Additionally, we found that a model based on the LGMD’s branching morphology increased the gain and decreased the delay associated with the mapping of synaptic input currents to membrane potential. More generally, this was true for a wide range of model neuron morphologies, including those of neocortical pyramidal neurons and cerebellar Purkinje cells. These findings show the unexpected role played by two widespread active conductances and by dendritic morphology in shaping synaptic integration. NEW & NOTEWORTHY Neuronal filtering and integration of synaptic input patterns depend on the electrochemical properties of dendrites. We used an identified collision detection neuron in grasshoppers to examine how its morphology and two conductances affect its membrane impedance in relation to the computations it performs. The neuronal properties examined are ubiquitous and therefore promote a general understanding of neuronal computations, including those in the human brain.
Case studies in neuroscience: subcortical origins of the frequency-following response
Authors: White-Schwoch Travis , Anderson Samira , Krizman Jennifer , Nicol Trent , Kraus Nina 
Published: July 2019

The auditory frequency-following response (FFR) reflects synchronized and phase-locked activity along the auditory pathway in response to sound. Although FFRs were historically thought to reflect subcortical activity, recent evidence suggests an auditory cortex contribution as well. Here we present electrophysiological evidence for the FFR’s origins from two cases: a patient with bilateral auditory cortex lesions and a patient with auditory neuropathy, a condition of subcortical origin. The patient with auditory cortex lesions had robust and replicable FFRs, but no cortical responses. In contrast, the patient with auditory neuropathy had no FFR despite robust and replicable cortical responses. This double dissociation shows that subcortical synchrony is necessary and sufficient to generate an FFR. NEW & NOTEWORTHY The frequency-following response (FFR) reflects synchronized and phase-locked neural activity in response to sound. The authors present a dual case study, comparing FFRs and cortical potentials between a patient with auditory neuropathy (a condition of subcortical origin) and a patient with bilateral auditory cortex lesions. They show that subcortical synchrony is necessary and sufficient to generate an FFR.
Disruption of peripheral nerve development in a zebrafish model of hyperglycemia
Authors: Ennerfelt Hannah , Voithofer Gabrielle , Tibbo Morgan , Miller Derrick , Warfield Rebecca , Allen Samantha , Kennett Clark Jessica 
Published: July 2019

Diabetes mellitus-induced hyperglycemia is associated with a number of pathologies such as retinopathy, nephropathy, delayed wound healing, and diabetic peripheral neuropathy (DPN). Approximately 50% of patients with diabetes mellitus will develop DPN, which is characterized by disrupted sensory and/or motor functioning, with treatment limited to pain management. Zebrafish ( Danio rerio) are an emerging animal model used to study a number of metabolic disorders, including diabetes. Diabetic retinopathy, nephropathy, and delayed wound healing have all been demonstrated in zebrafish. Recently, our laboratory has demonstrated that following the ablation of the insulin-producing β-cells of the pancreas (and subsequent hyperglycemia), the peripheral nerves begin to show signs of dysregulation. In this study, we take a different approach, taking advantage of the transdermal absorption abilities of zebrafish larvae to extend the period of hyperglycemia. Following 5 days of 60 mM d-glucose treatment, we observed motor axon defasciculation, disturbances in perineurial glia sheath formation, decreased myelination of motor axons, and sensory neuron mislocalization. This study extends our understanding of the structural changes of the peripheral nerve following induction of hyperglycemia and does so in an animal model capable of potential DPN drug discovery in the future. NEW & NOTEWORTHY Zebrafish are emerging as a robust model system for the study of diabetic complications such as retinopathy, nephropathy, and impaired wound healing. We present a novel model of diabetic peripheral neuropathy in zebrafish in which the integrity of the peripheral nerve is dysregulated following the induction of hyperglycemia. By using this model, future studies can focus on elucidating the underlying molecular mechanisms currently unknown.
ATP-Competitive Inhibitors Midostaurin and Avapritinib Have Distinct Resistance Profiles in Exon 17–Mutant KIT
Authors: Apsel Winger Beth , Cortopassi Wilian A. , Garrido Ruiz Diego , Ding Lucky , Jang Kibeom , Leyte-Vidal Ariel , Zhang Na , Esteve-Puig Rosaura , Jacobson Matthew P. , Shah Neil P. 
Published: July 2019

Abstract

KIT is a type-3 receptor tyrosine kinase that is frequently mutated at exon 11 or 17 in a variety of cancers. First-generation KIT tyrosine kinase inhibitors (TKI) are ineffective against KIT exon 17 mutations, which favor an active conformation that prevents these TKIs from binding. The ATP-competitive inhibitors, midostaurin and avapritinib, which target the active kinase conformation, were developed to inhibit exon 17–mutant KIT. Because secondary kinase domain mutations are a common mechanism of TKI resistance and guide ensuing TKI design, we sought to define problematic KIT kinase domain mutations for these emerging therapeutics. Midostaurin and avapritinib displayed different vulnerabilities to secondary kinase domain substitutions, with the T670I gatekeeper mutation being selectively problematic for avapritinib. Although gatekeeper mutations often directly disrupt inhibitor binding, we provide evidence that T670I confers avapritinib resistance indirectly by inducing distant conformational changes in the phosphate-binding loop. These findings suggest combining midostaurin and avapritinib may forestall acquired resistance mediated by secondary kinase domain mutations.

Significance:
This study identifies potential problematic kinase domain mutations for next-generation KIT inhibitors midostaurin and avapritinib.
Stearoyl-CoA Desaturase 1 Protects Ovarian Cancer Cells from Ferroptotic Cell Death
Authors: Tesfay Lia , Paul Bibbin T. , Konstorum Anna , Deng Zhiyong , Cox Anderson O. , Lee Jingyun , Furdui Cristina M. , Hegde Poornima , Torti Frank M. , Torti Suzy V. 
Published: July 2019

Abstract

Activation of ferroptosis, a recently described mechanism of regulated cell death, dramatically inhibits growth of ovarian cancer cells. Given the importance of lipid metabolism in ferroptosis and the key role of lipids in ovarian cancer, we examined the contribution to ferroptosis of stearoyl-CoA desaturase (SCD1, SCD), an enzyme that catalyzes the rate-limiting step in monounsaturated fatty acid synthesis in ovarian cancer cells. SCD1 was highly expressed in ovarian cancer tissue, cell lines, and a genetic model of ovarian cancer stem cells. Inhibition of SCD1 induced lipid oxidation and cell death. Conversely, overexpression of SCD or exogenous administration of its C16:1 and C18:1 products, palmitoleic acid or oleate, protected cells from death. Inhibition of SCD1 induced both ferroptosis and apoptosis. Inhibition of SCD1 decreased CoQ10, an endogenous membrane antioxidant whose depletion has been linked to ferroptosis, while concomitantly decreasing unsaturated fatty acyl chains in membrane phospholipids and increasing long-chain saturated ceramides, changes previously linked to apoptosis. Simultaneous triggering of two death pathways suggests SCD1 inhibition may be an effective component of antitumor therapy, because overcoming this dual mechanism of cell death may present a significant barrier to the emergence of drug resistance. Supporting this concept, we observed that inhibition of SCD1 significantly potentiated the antitumor effect of ferroptosis inducers in both ovarian cancer cell lines and a mouse orthotopic xenograft model. Our results suggest that the use of combined treatment with SCD1 inhibitors and ferroptosis inducers may provide a new therapeutic strategy for patients with ovarian cancer.

Significance:
The combination of SCD1 inhibitors and ferroptosis inducers may provide a new therapeutic strategy for the treatment of ovarian cancer patients.
See related commentary by Carbone and Melino, p. 5149
Effects of Switching to a Heat-Not-Burn Tobacco Product on Biologically Relevant Biomarkers to Assess a Candidate Modified Risk Tobacco Product: A Randomized Trial
Authors: Lüdicke Frank , Ansari S. Michael , Lama Nicola , Blanc Nicolas , Bosilkovska Marija , Donelli Andrea , Picavet Patrick , Baker Gizelle , Haziza Christelle , Peitsch Manuel , Weitkunat Rolf 
Published: July 2019

Abstract

Background:
Cigarette smoking increases the risk of chronic diseases; heating instead of burning tobacco can lower these risks, contributing to tobacco harm reduction. This study (with 984 adult American smokers) examined whether favorable changes occur in 8 co-primary endpoints (HDL-C, WBC, FEV1%pred, COHb, Total NNAL, sICAM-1, 11-DTX-B2, 8-epi-PGF2α) indicative of biological and functional effects when cigarette smokers switch to the heat-not-burn Tobacco Heating System 2.2 (THS). Additionally, these biomarkers of exposure (BoExp) were quantified: MHBMA, 3-HPMA, Total NNN, CEMA, 3-OH-B[a]P, HMPMA, Total 1-OHP, NEQ, and CO exhaled.

Methods:
Participants were randomized to continued smoking of their preferred cigarette brand (n = 496) or to using THS (IQOS brand; n = 488) for 6 months. THS has a maximum heating temperature of 350°C, delivering 1.21 mg nicotine/stick and 3.94 mg glycerin/stick under the Health Canada Intense smoking regimen.

Results:
The main outcome was a favorable change 6 months after baseline, with statistically significant improvements in 5 of 8 biomarkers of effect (HDL-C, WBC, FEV1%pred, COHb, Total NNAL) when smokers switched to THS compared with those who continued to smoke cigarettes. Likewise, BoExp were markedly reduced.

Conclusions:
All endpoints showed favorable changes in the same direction as with smoking cessation and improved biological effects were observed in smokers who predominantly used THS compared with continued cigarette smoking, with similar nicotine levels in both groups.

Impact:
Improvements in 5 of 8 biomarkers of effect are supportive of the research hypothesis, suggestive of disease risk reduction potential for smokers switching to THS instead of continuing to smoke cigarettes.
Evaluation of Rare and Common Variants from Suspected Familial or Sporadic Nasopharyngeal Carcinoma (NPC) Susceptibility Genes in Sporadic NPC
Authors: Liu Zhiwei , Goldstein Alisa M. , Hsu Wan-Lun , Yu Kelly J. , Chien Yin-Chu , Ko Jenq-Yuh , Jian James Jer-Min , Tsou Yung-An , Leu Yi-Shing , Liao Li-Jen , Chang Yen-Liang , Wang Cheng-Ping , Wu Jia-Shing , Hua Chun-Hung , Lee Jehn-Chuan , Yang Tsung-Lin , Hsiao Chuhsing Kate , Wu Ming-Shiang , Tsai Ming-Hsui , Huang Kuei-Kang , Yu Kai , Jones Kristie , Zhu Bin , Yeager Meredith , Yu Guoqin , Lou Pei-Jen , Chen Chien-Jen , Hildesheim Allan 
Published: July 2019

Abstract

Background:
Genetic susceptibility is associated with nasopharyngeal carcinoma (NPC). We previously identified rare variants potentially involved in familial NPC and common variants significantly associated with sporadic NPC.

Methods:
We conducted targeted gene sequencing of 20 genes [16 identified from the study of multiplex families, three identified from a pooled analysis of NPC genome-wide association study (GWAS), and one identified from both studies] among 819 NPC cases and 938 controls from two case–control studies in Taiwan (independent from previous studies). A targeted, multiplex PCR primer panel was designed using the custom Ion AmpliSeq Designer v4.2 targeting the regions of the selected genes. Gene-based and single-variant tests were conducted.

Results:
We found that NPC was associated with combined common and rare variants in CDKN2A/2B (P = 1.3 × 10−4), BRD2 (P = 1.6 × 10−3), TNFRSF19 (P = 4.0 × 10−3), and CLPTM1L/TERT (P = 5.4 × 10−3). Such associations were likely driven by common variants within these genes, based on gene-based analyses evaluating common variants and rare variants separately (e.g., for common variants of CDKN2A/2B, P = 4.6 × 10−4; for rare variants, P = 0.04). We also observed a suggestive association with rare variants in HNRNPU (P = 3.8 × 10−3) for NPC risk. In addition, we validated four previously reported NPC risk–associated SNPs.

Conclusions:
Our findings confirm previously reported associated variants and suggest that some common variants in genes previously linked to familial NPC are associated with the development of sporadic NPC.

Impact:
NPC-associated genes, including CLPTM1L/TERT, BRD2, and HNRNPU, suggest a role for telomere length maintenance in NPC etiology.
Atovaquone: An Antiprotozoal Drug Suppresses Primary and Resistant Breast Tumor Growth by Inhibiting HER2/β-Catenin Signaling
Authors: Gupta Nehal , Srivastava Sanjay K. 
Published: July 2019

Abstract
Breast cancer is the second leading cause of cancer-related mortality in women. In the current study, we evaluated the anticancer effects of an antiprotozoal drug, atovaquone, against several breast cancer cell lines. Our results showed that atovaquone treatment induced apoptosis and inhibited the growth of all the breast cancer cell lines tested, including several patient-derived cells. In addition, atovaquone treatment significantly reduced the expression of HER2, β-catenin, and its downstream molecules such as pGSK-3β, TCF-4, cyclin D1, and c-Myc in vitro. Efficacy of atovaquone was further evaluated in an in vivo tumor model by orthotropic implantation of two highly aggressive 4T1 and CI66 breast cancer cells in the mammary fat pad of female mice. Our results demonstrated that oral administration of atovaquone suppressed the growth of CI66 and 4T1 tumors by 70% and 60%, respectively. Paclitaxel is the first-line chemotherapeutic agent for metastatic breast cancer. We demonstrate that atovaquone administration suppressed the growth of 4T1 paclitaxel-resistant tumors by 40%. Tumors from atovaquone-treated mice exhibited reduced HER2, β-catenin, and c-Myc levels alongside an increase in apoptosis in all the three tumor models when analyzed by Western blotting, IHC, and TUNEL assay. Taken together, our results indicate that atovaquone effectively reduces the growth of primary and paclitaxel-resistant breast tumors. Atovaquone is already in the clinics with high safety and tolerability profile. Therefore, the findings from our studies will potentially prompt further clinical investigation into repurposing atovaquone for the treatment of patients with advanced breast cancer.
Mechanisms of Resistance to EGFR Inhibition Reveal Metabolic Vulnerabilities in Human GBM
Authors: McKinney Andrew , Lindberg Olle R. , Engler Jane R. , Chen Katharine Y. , Kumar Anupam , Gong Henry , Lu Kan V. , Simonds Erin F. , Cloughesy Timothy F. , Liau Linda M. , Prados Michael , Bollen Andrew W. , Berger Mitchel S. , Shieh Joseph T.C. , James C. David , Nicolaides Theodore P. , Yong William H. , Lai Albert , Hegi Monika E. , Weiss William A. , Phillips Joanna J. 
Published: July 2019

Abstract
Amplification of the epidermal growth factor receptor gene (EGFR) represents one of the most commonly observed genetic lesions in glioblastoma (GBM); however, therapies targeting this signaling pathway have failed clinically. Here, using human tumors, primary patient-derived xenografts (PDX), and a murine model for GBM, we demonstrate that EGFR inhibition leads to increased invasion of tumor cells. Further, EGFR inhibitor–treated GBM demonstrates altered oxidative stress, with increased lipid peroxidation, and generation of toxic lipid peroxidation products. A tumor cell subpopulation with elevated aldehyde dehydrogenase (ALDH) levels was determined to comprise a significant proportion of the invasive cells observed in EGFR inhibitor–treated GBM. Our analysis of the ALDH1A1 protein in newly diagnosed GBM revealed detectable ALDH1A1 expression in 69% (35/51) of the cases, but in relatively low percentages of tumor cells. Analysis of paired human GBM before and after EGFR inhibitor therapy showed an increase in ALDH1A1 expression in EGFR-amplified tumors (P &lt; 0.05, n = 13 tumor pairs), and in murine GBM ALDH1A1-high clones were more resistant to EGFR inhibition than ALDH1A1-low clones. Our data identify ALDH levels as a biomarker of GBM cells with high invasive potential, altered oxidative stress, and resistance to EGFR inhibition, and reveal a therapeutic target whose inhibition should limit GBM invasion.
A Novel Technique to Intelligently Monitor and Control Renal Pelvic Pressure during Minimally Invasive Percutaneous Nephrolithotomy
Authors: Deng Xiaolin , Xie Donghua , Du Chuance , Song Leming , Huang Jianrong , Tan Wanlong 
Published: July 2019

<b><i>Objective:</i></b> To introduce a novel technique for intelligently monitoring and controlling renal pelvic pressure (RPP) in minimally invasive percutaneous nephrolithotomy (MPCNL) and to investigate its reliability and stability. <b><i>Materials and Methods:</i></b> A total of 63 kidney stone patients (41 males and 22 females) were enrolled in the study. The average stone size was 3.7 ± 1.1 cm. The average age was 41.6 ± 15.6 years old. All patients underwent MPCNL under combined spinal and epidural anesthesia in prone position. A ureteral catheter connected to an invasive blood pressure monitor was retrogradely placed to measure renal pelvic outlet pressure. The MPCNL was performed with the aid of the patented device, including an irrigation and suctioning platform and a pressure-measuring suctioning sheath. On the platform, the RPP control value was set at –5 mm Hg, and the RPP warning value was set at 20 mm Hg. RPP was measured during the irrigation and suctioning period (ISP), and therapeutic period (TP) when the infusion flow was set at 300, 400, and 500 mL/min, respectively, for 5 min. <b><i>Results:</i></b> Sixty-three patients successfully underwent the procedure without serious complications. The mean operative time was 67 min (range 31–127 min). Three patients had residual stones &#x3e;2 mm in size. No statistical significance was observed between the renal pelvic outlet pressure, platform RPP values, and RPP control values for the 300, 400, and 500 mL/min groups during the ISP and TP (<i>p</i> &#x3e; 0.05). <b><i>Conclusion:</i></b> The patented devices including the platform and the sheath can reliably and stably monitor and control RPP in real time and within a safe range during MPCNL.
Association of Glasgow Coma Scale with Total Homocysteine Levels in Patients with Hemorrhagic Stroke
Authors: Dai Dapeng , Sun Yong , Liu Chengzhang , Xing Houxun , Wang Binyan , Qin Xianhui , Liu Xiguang , Li Aimin 
Published: July 2019

<b><i>Objectives:</i></b> We aimed to evaluate the association between Glasgow Coma Scale (GCS) and total homocysteine (tHcy) levels and examine the possible effect modifiers in patients with hemorrhagic stroke. <b><i>Methods:</i></b> A total of 1,516 participants with hemorrhagic stroke and having the complete data on baseline GCS and tHcy measurements were included in the final analysis. <b><i>Results:</i></b> The mean (SD) of age, tHcy, and GCS levels were 61.5 (11.3) years, 17.0 (10.3) μmol/L, and 13.9 (2.2), respectively. Compared with participants with severe damage (GCS &#x3c;9), those with mild damage (GCS ≥13) had significantly lower transformed tHcy levels (β = –2.46; 95% CI –4.80 to –0.12). Consistently, a significantly lower transformed tHcy levels were found in participants with mild damage (GCS ≥13; β = –1.37; 95% CI –2.66 to –0.08) compared with those with moderate to severe damage (GCS &#x3c;13). In the stratified analysis, a stronger inverse association between GCS categories (≥13 vs. &#x3c;13) and tHcy concentrations was observed in ever smokers (vs. never; <i>p</i> for interaction = 0.045), and in participants with systolic blood pressure (SBP) ≥160 mm Hg (vs. &#x3c;160 mm Hg; <i>p</i> for interaction = 0.031), or total cholesterol (TC) ≥5.2 mmol/L (vs. &#x3c;5.2 mmol/L; <i>p</i> for interaction = 0.025). <b><i>Conclusion:</i></b> There was an inverse association between GCS level and tHcy concentration among patients with hemorrhagic stroke, especially in ever smokers or in participants with higher SBP or TC levels.