bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional characterization of the antiepileptic drug candidate, padsevonil, on GABAA receptors
Authors: Niespodziany Isabelle , Ghisdal Philippe , Mullier Brice , Wood Martyn , Provins Laurent , Kaminski Rafal M. , Wolff Christian 
Published: April 2020

AbstractObjectiveThe antiepileptic drug candidate, padsevonil, is the first in a novel class of drugs designed to interact with both presynaptic and postsynaptic therapeutic targets: synaptic vesicle 2 proteins and γ‐aminobutyric acid type A receptors (GABAARs), respectively. Functional aspects of padsevonil at the postsynaptic target, GABAARs, were characterized in experiments reported here.MethodsThe effect of padsevonil on GABA‐mediated Cl− currents was determined by patch clamp on recombinant human GABAARs (α1β2γ2) stably expressed in a CHO‐K1 cell line and on native GABAARs in cultured rat primary cortical neurons. Padsevonil selectivity for GABAAR subtypes was evaluated using a two‐electrode voltage clamp on recombinant human GABAARs (α1‐5/β2/γ2) in Xenopus oocytes.ResultsIn recombinant GABAARs, padsevonil did not evoke Cl− currents in the absence of the agonist GABA. However, when co‐administered with GABA at effective concentration (EC)20, padsevonil potentiated GABA responses by 167% (EC50 138 nmol/L) and demonstrated a relative efficacy of 41% compared with zolpidem, a reference benzodiazepine site agonist. Similarly, padsevonil demonstrated GABA‐potentiating activity at native GABAARs (EC50 208 nmol/L) in cultured rat cortical neurons. Padsevonil also potentiated GABA (EC20) responses in GABAARs expressed in oocytes, with higher potency at α1‐ and α5‐containing receptors (EC50 295 and 281 nmol/L) than at α2‐ and α3‐containing receptors (EC50 1737 and 2089 nmol/L). Compared with chlordiazepoxide—a nonselective, full GABAAR agonist—the relative efficacy of padsevonil was 60% for α1β2γ2, 26% for α2β2γ2, 56% for α3β2γ2, and 41% for α5β2γ2; no activity was observed at benzodiazepine‐insensitive α4β2γ2 receptors.SignificanceResults of functional investigations on recombinant and native neuronal GABAARs show that padsevonil acts as a positive allosteric modulator of these receptors, with a partial agonist profile at the benzodiazepine site. These properties may confer better tolerability and lower potential for tolerance development compared with classic benzodiazepines currently used in the clinic.
Deep brain stimulation reduces evoked potentials with a dual time course in freely moving rats: Potential neurophysiological basis for intermittent as an alternative to continuous stimulation
Authors: Sprengers Mathieu , Raedt Robrecht , Larsen Lars Emil , Delbeke Jean , Wadman Wytse Jan , Boon Paul , Vonck Kristl 
Published: April 2020

AbstractObjectiveDeep brain stimulation (DBS) is an increasingly applied treatment for various neuropsychiatric disorders including drug‐resistant epilepsy, and it may be optimized by rationalizing the stimulation protocol based on increased knowledge of its mechanism of action. We evaluated the effects of minutes to hours of hippocampal DBS on hippocampal evoked potentials (EPs) and local field potentials (LFPs) in freely moving male rats to further investigate some of the previously proposed mechanisms of action.MethodsHippocampal high‐frequency (130 Hz) DBS was administered for 0, 1, or 6 min every 10 min for 160 min. Stimulation parameter settings were similar to those that had previously been shown to reduce seizures in epileptic rats. EPs and LFPs were recorded in the stimulation‐free intervals. We investigated both the immediate temporary effects of 1 or 6 min of DBS and the effects of 160 min of intermittent DBS. Input specificity was investigated by using two different stimulation electrodes.ResultsRelatively low DBS intensities corresponding to only 1.8% of the intensity evoking a maximum EP were required to prevent unintended seizure occurrence in healthy rats. Both 1 and 6 min of DBS caused input‐specific short‐lasting (<60 s) reductions (5%‐7%) of the field excitatory postsynaptic potential (fEPSP) slope (P = .005). We observed longer‐lasting, input‐specific EP reductions during the 160 min intermittent DBS, with statistically significant reductions (3%‐4%) of the fEPSP slope (P = .009‐.018). The LFP spectrogram remained unaltered.SignificanceDeep brain stimulation induced both acute temporary effects compatible with axonal block and/or synaptic depression, and longer‐lasting potentially cumulative EP reductions, suggesting the involvement of homeostatic plasticity or long‐term depression. This dual time course may parallel the different temporal patterns of improvement observed in clinical trials. The longer‐lasting reductions provide a potential neurophysiological basis for the use of intermittent DBS—as typically used in epilepsy patients—as an alternative to continuous DBS.
Integrin αvβ3‐Akt signalling plays a role in radioresistance of melanoma
Authors: Im Hyuntaik , Lee Jeeyong , Ryu Kwon‐Yul , Yi Jae Youn 
Published: April 2020

AbstractMelanoma is a deadly type of skin cancer that is particularly difficult to treat owing to its resistance to radiation therapy. Here, we attempted to determine the key proteins responsible for melanoma radioresistance, with the aim of improving disease response to radiation therapy. Two melanoma cell lines, SK‐Mel5 and SK‐Mel28, with different radiosensitivities were analysed via RNA‐Seq (Quant‐Seq) and target proteins with higher abundance in the more radioresistant cell line, SK‐Mel28, identified. Among these proteins, integrin αvβ3, a well‐known molecule in cell adhesion, was selected for analysis. Treatment of SK‐Mel28 cells with cilengitide, an integrin αvβ3 inhibitor, as well as γ‐irradiation resulted in more significant cell death than γ‐irradiation alone. In addition, Akt, a downstream signal transducer of integrin αvβ3, showed high basic activation in SK‐Mel28 and was significantly decreased upon co‐treatment with cilengitide and γ‐irradiation. MK‐2206, an Akt inhibitor, exerted similar effects on the SK‐Mel28 cell line following γ‐irradiation. Our results collectively demonstrate that the integrin αvβ3‐Akt signalling pathway contributes to radioresistance in SK‐Mel28 cells, which may be manipulated to improve therapeutic options for melanoma.
A C‐terminal fragment of adhesion protein fibulin‐7 inhibits growth of murine breast tumor by regulating macrophage reprogramming
Authors: Chakraborty Papiya , Dash Shiba Prasad , Dalpati Nibedita , Kumar Puneet , Jain Deepali , Sarangi Pranita P. 
Published: April 2020

Recent reports have shown that a C‐terminal fragment of adhesion protein Fibulin7 (Fbln7‐C) could demonstrate both antiangiogenic and anti‐inflammatory activities. The current study investigated the potential of Fbln7‐C as a modulator of tumor‐associated macrophages (TAMs) and its potential as an anticancer therapeutic. Our in vitro data show that Fbln7‐C could inhibit the tumor cell line (MDA‐MB‐231) supernatant‐induced reprogramming of human monocytes into immunosuppressive TAMs as indicated by higher expression of pERK1/2 and pSTAT1 molecules, and reduced expression of CD206 protein and arg1, ido, and vegf transcripts in monocytes cultured in the presence of Fbln7‐C compared to controls. Interestingly, Fbln7‐C‐treated macrophages retained their altered phenotype even after the removal of Fbln7‐C, and their secretome demonstrated anticancer activities. Finally, in a 4T1‐induced murine breast tumor model, intravenous administration of Fbln7‐C, following the appearance of measurable tumors, significantly reduced the growth and weight of the tumors. Detailed phenotypic analysis of the infiltrated monocyte/macrophage populations (F480+Ly6G−CD11b+) at day 23 postinduction showed a higher percentage of inflammatory monocytes (F480+Ly6ChiCD11b+) and a delayed differentiation into anti‐inflammatory TAMs as evident by their reduced levels of CD206 expression. In conclusion, the above data suggest that Fbln7‐C could regulate the tumor environment‐induced macrophage reprogramming and has the potential for cancer therapeutics.
Hybrid additive manufacturing of the modified electrolyte‐electrode surface of planar solid oxide fuel cells
Authors: Salari Farid , Badihi Najafabadi Alireza , Ghatee Mojtaba , Golmohammad Mohammad 
Published: April 2020

AbstractDigital Control of the surface patterning of functional layers of solid oxide fuel cells (SOFCs), via the inkjet printing technique, offers better efficiency in performance. A combination of inkjet printing and tape casting in a single machine system defines as hybrid additive manufacturing, facilitates printing complex structures. Also, implementing this idea removes the blocking of the print head nozzle orifice issue.In this paper, a highly dispersed and long‐term stable colloidal zirconia‐based suspension, with optimal printability characteristics, is designed to be prepared in approximately three hours to fabricate the macro patterned structure of the SOFC electrolyte. Hybrid Additive Manufacturing is successfully employed to make a symmetric cathode side cell with a modified electrolyte‐electrode surface to reduce the electron resistivity.
Valorisation of olive oil pomace extracts for a functional pear beverage formulation
Authors: Spizzirri Umile Gianfranco , Carullo Gabriele , Aiello Francesca , Paolino Donatella , Restuccia Donatella 
Published: April 2020

SummaryOlive pomaces from Southern Italy autochthonous cultivars (Carolea, Nocellara and Roggianella) were eco‐friendly extracted to reach value‐added ingredients for the production of fortified pear beverages. Chemical composition of the extracts was carried out by 1H‐NMR analysis, while antioxidant features were in vitro evaluated. The extracts displayed remarkable scavenger properties against DPPH (IC50 values in the range 0.051–0.171 mg mL−1) and ABTS (IC50 values in the range 0.035–0.047 mg mL−1) radical species. Reactive species in the extracts and inulin chains were involved in an eco‐friendly radical process by grafting reaction to obtain macromolecular conjugates with outstanding antioxidant features, in terms of both antioxidant and scavenging performances, representing an attractive source in the design of functional foods. In this context, the conjugates were employed to enrich pear juice, to achieve reinforced beverages displaying remarkable antioxidant properties in comparison with its non‐functional counterparts, as well as its maintenance over time (20 days).
Evaluation of activated partial thromboplastin time coagulation waveform analysis for identification of patients with acquired factor VIII inhibitors
Authors: McGinnis Eric , Wong Steven K. W. , Smith Tyler W. 
Published: April 2020

AbstractIntroductionActivated partial thromboplastin time (PTT) coagulation waveforms produced by optical detection system coagulation analyzers provide additional potentially useful and routinely underutilized information for the evaluation of a patient's coagulation system. We aimed to identify features of PTT coagulation waveforms, available for all PTT assays performed in our hospital laboratories, that may prove useful in directing early investigations in patients with unexplained prolonged PTT.MethodsWe retrospectively reviewed 211 PTT coagulation waveforms from patient testing and categorized them based on the underlying hemostatic abnormality: normal, therapeutic anticoagulation, lupus anticoagulant, congenital factor deficiency, or acquired factor VIII inhibitor. We compared quantitative waveform parameters and the frequency of qualitatively abnormal double‐peaked first derivative waveform curves between these groups.ResultsPartial thromboplastin time and derivative curve maxima and minima differed significantly between acquired factor VIII inhibitors and other diagnostic categories, and the second derivative curve minimum demonstrated the highest area under the receiver operator characteristic curve for identification of acquired factor VIII inhibitors (0.860; maximum accuracy: 79.5% for 2Dmin> −39.3 mAbs/s2 [sensitivity 90.5%; specificity 77.2%]). The presence of an abnormal double‐peaked first derivative curve had a sensitivity of 83.3% and specificity of 81.6% for identification of acquired factor VIII inhibitors in cases with PTT >50 seconds.ConclusionPartial thromboplastin time coagulation waveform analysis can aid in identification of patients with acquired factor VIII inhibitors and may be of clinical utility in directing early laboratory investigations to identify patients at risk of severe bleeding without prompt intervention.
Catheter ablation of the parahisian accessory pathways from the aortic cusps—Experience of 20 cases—Improving the mapping strategy for better results
Authors: Chokr Muhieddine O. , de Moura Lucas G. , Aiello Vera D. , dos Santos Sousa Ítalo B. , Lopes Hugo B. , do Carmo Andre A. L. , Pisani Cristiano F. , Hardy Carina A. , de Melo Sissy L. , Scanavacca Mauricio I. 
Published: April 2020

AbstractIntroductionCatheter ablation of the parahisian accessory pathways (PHAP) has been established as the definitive therapy for this type of arrhythmia. However, the PHAP proximity to the normal atrioventricular conduction system makes the procedure technically challenging.Here, we have reported a case series of 20 patients with PHAP who underwent aortic access ablation to evaluate the safety and efficacy of this approach in the PHAP ablation.Methods and ResultsThe ablation through the aortic cusps was the successful approach in 13 of 20 (65%) of the cases. In 11 patients, the aortic approach was the initial strategy for ablation, and the accessory pathway was eliminated in seven (63.6%) of them. The aortic approach followed a failed right‐sided attempt in nine patients. In six (66.7%) patients, the ablation was successful with the aortic approach.The only independent predictor for the successful ablation with each approach was the earliest ventricular activation before delta wave (predelta time) and a right‐sided earliest ventricular activation of more than 23 ms had high sensitivity and specificity for right‐sided success.Systematically using the two strategies (right and left approaches), the ablation of the PHAP was successful in 18 (90%) patients.ConclusionThe aortic approach seems to be a safe and effective strategy for the ablation of PHAP. It can be used when the right‐sided approach fails or even considered as an initial strategy when the predelta time is less than 23 ms in the right septal region. When combining the right‐ and left‐sided approaches, the success rate is high. We believe that the retrograde aortic approach remains a key tool for this challenging ablation.
Unique electrophysiological properties of fast‐slow atrioventricular nodal reentrant tachycardia characterized by a shortening of retrograde conduction time via a slow pathway manifested during atrial induction
Authors: Tamura Shuntaro , Nakajima Tadashi , Iizuka Takashi , Hasegawa Hiroshi , Kobari Takashi , Kurabayashi Masahiko , Kaneko Yoshiaki 
Published: April 2020

AbstractIntroductionElectrophysiological properties of reentry circuits of fast‐slow atrioventricular nodal reentrant tachycardia (F/S‐AVNRT) may contribute to cyclic variability after atrial induction.MethodsIn 156 atrial inductions of 33 patients with F/S‐AVNRT, we measured the atrio‐His (AH) and His‐atrial (HA) intervals in the first cycle after the induction (AH[1] and HA[1], respectively), those in the second cycle (AH [2] and HA [2], respectively), and those during tachycardia that maintained a stable cycle length AH[T] and HA[T], respectively), and calculated the value of AH(1) minus AH(T) [ΔAH] and the value of HA(1) minus HA(T) [ΔHA] in each induction. According to the sum of ΔAH and ΔHA, tachycardia variability was classified as incremental (<−20), balanced (−20 to 20), or decremental (>20).ResultsΔAH and ΔHA were significantly different between the three responses: 6 ± 28 and −67 ± 39 in 55 inductions (35%) with an incremental response, 20 ± 10 and −23 ± 28 in 59 (38%) with a balanced response, and 54 ± 44 and 4 ± 50 in 42 (27%) with a decremental response, respectively. Incremental response was reproducibly and consistently observed in 33% of patients. HA(2) was similar to HA(T) in inductions with an incremental response. These results suggest that incremental response can be manifested only in the first cycle when HA(1) is excessively shortened, approximating a retrograde conduction time over a slow pathway, in contrast, and far superior to a decremental delay of AH(1).ConclusionIn specific patients with F/S‐AVNRT, poorly recognized, electrophysiological properties of shortening a retrograde conduction time over a slow pathway was manifested during atrial induction.
Performance of modified blood pressure‐to‐height ratio for diagnosis of hypertension in children: The CASPIAN‐V study
Authors: Yazdi Maryam , Assadi Farahnak , Daniali Seyed S. , Heshmat Ramin , Mehrkash Mehryar , Motlagh Mohammad E. , Qorbani Mostafa , Kelishadi Roya 
Published: April 2020

AbstractThis study aimed to evaluate the accuracy and performance of modified blood pressure‐to‐height ratio (MBPHR) for identifying high blood pressure (HBP) in a large population of children. This multicentric cross‐sectional study was conducted on a nationally representative sample of 7349 Iranian students aged 7‐12 years living in 30 provinces in Iran. High systolic blood pressure and diastolic blood pressure were defined according to the 2017 American Academy of Pediatrics (AAP) guidelines. The BP‐to height ratio (BPHR) was calculated as BP (mmHg)/height (cm), MBPHR3 as BP (mmHg)/(height (cm) + 3 (13‐age)), and MBPHR7 as BP (mmHg)/(height (cm) + 7 (13‐age). The receiver‐operating characteristic curve analysis was used to evaluate the performance of these three ratios for identification of HBP in children compared to the 2017 AAP guidelines as the gold standard. Mean age of participants was 12.29 ± 3.15 years and 3736 (50.8%) were girls. The prevalence of HBP was 11.9% (11.5% in boys, 12.3% in girls). The area under the curve (AUC) was higher for MSBPHR3/MDBPHR3 (0.97/0.98) than MSBPHR7/MDBPHR7 (0.96/0.97) and SBPHR/DBPHR (0.96/0.95) for identifying high Systolic and diastolic BP. The optimal cut‐off points for MSBPHR3/MDBPH, MSBPHR7/MDBPHR7, and SBPHR/DBPHR were 0.76/0.50, 0.69/0.46, and 0.81/0.52 respectively. Negative predictive value was nearly perfect for three ratios (≥98%). Positive predictive value was higher for MBPHR3 (52.7%) than MBPHR7 (51.0%) and BPHR (39.8%). Overall, MBPHR3 had better performance than MBPHR7 and BPHR for identification of HBP in Iranian children and it may improve early hypertension recognition and control in primary screening.
Polydatin promotes the neuronal differentiation of bone marrow mesenchymal stem cells in vitro and in vivo: Involvement of Nrf2 signalling pathway
Authors: Zhan Jiheng , Li Xing , Luo Dan , Hou Yu , Hou Yonghui , Chen Shudong , Xiao Zhifeng , Luan Jiyao , Lin Dingkun 
Published: April 2020

AbstractBone marrow mesenchymal stem cell (BMSC) transplantation represents a promising repair strategy following spinal cord injury (SCI), although the therapeutic effects are minimal due to their limited neural differentiation potential. Polydatin (PD), a key component of the Chinese herb Polygonum cuspidatum, exerts significant neuroprotective effects in various central nervous system disorders and protects BMSCs against oxidative injury. However, the effect of PD on the neuronal differentiation of BMSCs, and the underlying mechanisms remain inadequately understood. In this study, we induced neuronal differentiation of BMSCs in the presence of PD, and analysed the Nrf2 signalling and neuronal differentiation markers using routine molecular assays. We also established an in vivo model of SCI and assessed the locomotor function of the mice through hindlimb movements and electrophysiological measurements. Finally, tissue regeneration was evaluated by H&E staining, Nissl staining and transmission electron microscopy. PD (30 μmol/L) markedly facilitated BMSC differentiation into neuron‐like cells by activating the Nrf2 pathway and increased the expression of neuronal markers in the transplanted BMSCs at the injured spinal cord sites. Furthermore, compared with either monotherapy, the combination of PD and BMSC transplantation promoted axonal rehabilitation, attenuated glial scar formation and promoted axonal generation across the glial scar, thereby enhancing recovery of hindlimb locomotor function. Taken together, PD augments the neuronal differentiation of BMSCs via Nrf2 activation and improves functional recovery, indicating a promising new therapeutic approach against SCI.
BTB/TAZ protein MdBT2 integrates multiple hormonal and environmental signals to regulate anthocyanin biosynthesis in apple
Authors: An Jian‐Ping , Wang Xiao‐Fei , Hao Yu‐Jin 
Published: April 2020

AbstractBT2 is a BTB/TAZ domain protein with key roles in multiple stress responses and the plant development of Arabidopsis (Figueroa et al. 2005; Ren et al. 2007; Mandadi et al. 2009). Recent studies have demonstrated that apple MdBT2 functions as a negative regulator in diverse hormonal and environmental signal‐induced anthocyanin biosynthesis, suggesting that MdBT2 integrates stress signals and anthocyanin biosynthesis.
Noncutaneous considerations of COVID‐19 for dermatology practices
Authors: Ali Faisal R. , Al‐Niaimi Firas 
Published: April 2020

AbstractCOVID‐19 presents many pressing challenges to the global dermatological community and our patients with ongoing skin needs, which must be considered by every dermatology provider. Many of these are logistical and administrative, distinct from physical manifestations, and could be summarized by the acronym COVID (Consultations, Operations, Videoconferencing, Immunosuppressive medications, Drug and equipment shortages). While the pandemic may represent a threat to many parts of our existence, dermatologists can help the patients we care for by considering noncutaneous implications of COVID‐19 upon our practice.
Rituximab in maintaining remission in adults with podocytopathy
Authors: Ramachandran Raja , Bharati Joyita , Nada Ritambhra , Minz Ranjana , Kohli Harbir S. 
Published: April 2020

AbstractRituximab is currently used after the conventional agents have failed in the management of steroid‐dependent (SD)/ steroid‐resistant (SR) podocytopathies and have a safer toxicity profile. We report 53 adults with podocytopathies who were managed effectively with CD19‐targeted rituximab therapy.MethodsThis was a prospective study carried out at a tertiary care centre in India between January 2014 and June 2019. Adults between 16 and 60 years with SD, frequently relapsing (FR), and SR nephrotic syndrome (NS) due to podocytopathy received rituximab in a CD19‐targeted approach. Primary outcome: Percentage of patients who were in remission at 6 and 12 months. Secondary outcome: Percentage of patients in remission at the last follow‐up, rituximab dose and adverse events of rituximab therapy.ResultsFifty‐three adults with SD/FR/SR NS received CD19‐targeted rituximab. The median age at the time of first rituximab injection was 30.09 ± 13.21 (16.53) years. At the time of first rituximab infusion, all patients were in remission with steroids and/or calcineurin inhibitors (CNIs). Fifty (94.33%) patients were in remission at the end of 6 and 12 months and the last follow‐up (median: 36 months). The mean total dose of rituximab at 1 year was 788.7 ± 128.1 (6 001 100) mg. At last follow‐up (median 36 months), 42 (79%) patients did not require any additional CNI or steroids therapy. No serious adverse events to rituximab were noted.ConclusionCD19‐targeted rituximab therapy is safe and efficacious in the management of SD/SR adult podocytopathy. Also, rituximab is effective in maintaining remission in treatment naïve adult SD or FR podocytopathy.