bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bioengineered miR‐328‐3p modulates SLC2A1/GLUT1‐mediated glucose uptake and metabolism to exert synergistic antiproliferative effects with chemotherapeutics
Authors: Tu Mei-Juan , Yi Wan-Yong , Liu Zhenzhen , Zhang Chao , Yu Ai-Xi , Yu Ai-Ming 
Published: April 2020

MicroRNAs (miRNAs or miRs) are small noncoding RNAs derived from genome to control target gene expresion. Recently we have developed a novel platform that offers high‐yield production of bioengineered miRNA agents (BERAs). This study was to produce and utilize novel fully‐humanized biologic miR‐328‐3p molecule (hBERA/miR‐328) to delineate the role of miR‐328‐3p in the control of nutrient uptake essential for cell metabolism. We first demonstrated successful high‐level expression of hBERA/miR‐328 in bacteria and purification to a high degree of homogeneity (> 98%). Biologic miR‐328‐3p prodrug was selectively processed to miR‐328‐3p to suppress the growth of highly‐proliferative human osteosarcoma (OS) cells. Besides GLUT1/SLC2A1, we identified and verified LAT1/SLC7A5 as a direct target for miR‐328‐3p. While reduction of LAT1 protein levels by miR‐328‐3p did not alter the homeostasis of amino acids within OS cells, suppression of GLUT1 led to a significantly lower glucose uptake and decline in intracellular levels of glucose and glycolytic metabolite lactate. Moreover, combination treatment with hBERA/miR‐328 and cisplatin or doxorubicin exerted a strong synergism in the inhibition of OS cell proliferationin. These findings support the utility of novel bioengineered RNA molecules and establish an important role of miR‐328‐3p in the control of nutrient transport and homeostasis behind cancer metabolism.Support or Funding InformationThis study was supported by grants R01GM133888 and R01CA225958 from the National Institutes of Health.
S1PR1 interacts with endoplasmic reticulum stress sensor, BiP, to regulate calcium homeostasis and endothelial barrier function
Authors: Anwar Mumtaz , Amin Md-Ruhul , Raghunathrao Vijay Avin , Mo Gary , Mehta Dolly 
Published: April 2020

Endothelial–cell surface localized sphingosine 1 phosphate receptor 1 (S1PR1) is well known to enhance barrier function upon ligating S1P. We recently showed that S1P phosphorylation of S1PR1 at tyrosine (Y) 143 residue induces S1PR1 internalization and compromises barrier function. Here, we assessed the mechanism internalizing the Y143‐S1PR1 and how Y143‐S1PR1 disrupts barrier function. Herein, using TIRF and confocal imaging, we show that phosphorylated (Y143D‐S1PR1) S1PR1 mutant localizes at endoplasmic reticulum (ER). Inhibition of dynamin activity, a GTP‐dependent pinchase, rescued Y143D‐S1PR1 expression at the cell surface. However, dynamin inhibition had no effect on cell‐surface retention of S1PR1 or Y143F‐S1PR1. In other studies, we show that Y143D‐S1PR1 bound WT‐dynamin strongly while weakly with GTPase defective dynamin. Cell‐surface retained S1PR1 induces signaling including calcium mobilization and activation of MAP kinases by binding Gi heterotrimeric protein. Intriguingly, we show that internalized Y143D‐S1PR1 augmented Ca2+ entry which was blocked by pertussis toxin. Furthermore, phosphorylated receptor bound Gi indicating that internalized S1PR1 binds cytosolic Gi which then increases Ca2+ entry. We further showed Y143D‐S1PR1 mutant augmented Ca2+ entry by organizing stromal‐interaction molecule 1 (STIM1) dependent ER‐PM junction formation. To address the mediator involved in retaining Y143D‐S1PR1 at the ER, we performed mass spectrometric analysis and identified GRP78 (BiP), an endoplasmic resident protein, as the novel interacting partner of S1PR1. Depletion of BiP or STIM1 rescued barrier function even in presence of Y143D‐S1PR1. Thus, BiP recruits phosphorylated Y143D‐S1PR1 at the ER where S1PR1 mutant organizes ER‐PM junctions to mediate Ca2+ entry disrupting endothelial barrier function.Support or Funding InformationNIH
Understanding Gαq/11 Localization and Trafficking in Uveal Melanoma
Authors: Randolph Clinita , Wedegaertner Philip 
Published: April 2020

Constitutively activating mutations in Gαq and Gα11 (Gαq/11) have been reported in up to 93% of uveal melanomas. Although constitutively active Gαq/11 promote uveal melanoma tumorigenesis through activation of multiple downstream pathways, no therapies inhibit constitutively active Gαq/11. Studies suggest that increased palmitate turnover and increased cytoplasmic localization occur upon activation of some Gα subunits. The purpose of our studies is to understand the role of palmitoylation in trafficking and signaling of constitutively active Gαq/11 in uveal melanoma. Using live cell imaging and cellular fractionation of HEK 293 cells and uveal melanoma cells, constitutively active GαqQ209L and GαqQ209P show decreased localization at membranes compared to wild type Gαq, suggesting increased turnover of attached palmitate in constitutively active mutants. Moreover, immunofluorescence microscopy revealed that a palmitoylation‐deficient constitutively active mutant displays a complete loss of plasma membrane localization and an inability to signal as measured by Rho‐ and Rac‐dependent YAP translocation into the nucleus, TEAD‐dependent luciferase activity, and ERK phosphorylation. These studies demonstrate that palmitoylation of mutationally activated Gαq/11 is required for its signaling functions. Although live cell imaging and cellular fractionation experiments reveal decreased membrane localization of constitutively active Gαq compared to wild‐type Gαq, our studies suggest that complete loss of membrane localization abolishes constitutively active Gαq‐dependent signaling. Disruption of constitutively active Gαq/11 palmitoylation and localization may be an effective strategy for inhibiting constitutively active Gαq/11 oncogenic signaling in uveal melanoma.Support or Funding InformationThis research was funded by NIH grants F31CA224803‐Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship to Promote Diversity in Health, R01GM056444‐16, R01GM056444‐16S1‐Research Supplements to Promote Diversity in Health‐Related Research, and T32 GM100836.
Optimizing Extraction of Proteins from Carcinus Maenus After Removal of Low‐Molecular Weight Chitins
Authors: Stevens Rylie , Myracle Angela D. , Grant Jennifer E. 
Published: April 2020

Crab shells as waste products are presently of economic interest only for the value of the chitin polymer present in their shells, which may be used to formulate foods or pharmaceutical products. Other materials in the crab shells, including protein, are discarded as waste. Crab shells have a large protein content A key question to examine is if there are bioactive proteins and/or peptides that have health benefits which could be recovered and utilized as a value added fraction from the waste stream. For example proteins isolated from crab shells have been found to contain antimicrobial and moderate antitumor agents (Sawssen, 2015.)In this work, the procedures used for removal of low molecular weight (LMW) chitin were followed (Ye, 2016). After removal of LMW chitin, the acetic acid extraction of proteins from crab shells was optimized using 50%, 25% and 12% acetic acid. One of the challenges associated with the extraction of proteins from crab shells is the concomitant demineralization of the shells which results in a high calcium carbonate solution in solution. In this project, a variety of different methods for separating the protein from the acidic solution and the calcium carbonate were utilized including dialysis, polyethylene glycol precipitation strategies.These findings will be of value to the community of researchers investigating either bioactive materials in the shells of marine organisms.
The effect of whole‐body skin cooling on dynamic cerebral autoregulation
Authors: Kobayashi Fumino , Kobayashi Maho , Nakata Hiroki , Kamijo Yoshi-ichiro , Crandall Craig , Shibasaki Manabu 
Published: April 2020

The incidence of cerebrovascular accident is elevated during the winter season. Increases in blood pressure associated with an enhanced vasoconstricted state during cold exposure may contribute to this risk. We hypothesized that whole‐body skin cooling would impair dynamic cerebral autoregulation, perhaps due to both systemic and cerebral vasoconstriction. Supine resting data from fifteen young healthy participants were obtained before and during whole‐body skin cooling. In addition, subjects performed a simple cognitive task (Go/No‐go tasks) in each condition. Subjects also performed a separate time control trial while remaining in thermoneutral conditions. Dynamic cerebral autoregulation was assessed by transfer function analysis (TFA) of middle cerebral artery blood velocity and mean arterial pressure. Whole‐body cooling decreased mean skin temperature (P<0.001), while ear canal temperature and respiratory variables were maintained. The cold stress increased mean arterial blood pressure (P<0.01) while heart rate decreased (P<0.05). Vascular conductance of both the internal and external carotid arteries (Doppler ultrasound) decreased during cooling, indicating cerebral and systemic vasoconstriction, respectively. The TFA‐derived low frequency gain increased during the cold stress (P<0.05), indicative of reduced dynamic cerebral autoregulation. The Go/No‐go task did not alter the TFA‐derived gain during cooling. None of these variables were altered during the thermoneutral time control trial. These findings suggest that whole‐body skin cooling impairs dynamic cerebral autoregulation.Support or Funding InformationJapan Society for the Promotion of Science 18H03166
Differences in effects of task repetition in three modalities Go/No‐go paradigams.
Authors: Hirai Minami , Ishikura Keiko , Sawai Norie , Kobayashi Fumino , Nakata Hiroki , Shibasaki Manabu 
Published: April 2020

Previous studies suggested that learning, habituation, mental fatigue, or reduced motivation due to task repetition (time‐on‐task) decreased the peak amplitude and/or latency of components of event‐related potentials (ERPs), but the mechanism remains unclear. Also, the effect of the sensory modality on those changes has not been clarified. The difference in modality could modify cerebral blood flow or its distribution in the brain. We hypothesized that the effect of task repetition on ERPs was related to the sensory modality, and the changes in cerebral blood flow contributed to the difference. Subjects performed 6 sessions of Go/No‐go paradigms for 5 minutes with visual, auditory, and somatosensory stimuli on different days, and were allowed to rest for 5 minutes between sessions. In addition to electroencephalography, middle cerebral artery blood mean velocity and finger arterial pressure were continuously measured to evaluate dynamic cerebral autoregulation via transfer function analysis. The amplitude of P300 decreased with the time‐on‐task in all three modalities, and the latency of P300 delayed with the time‐ontask only with somatosensory stimuli. The reductions in amplitude were the greatest with the visual stimuli among the three modalities. The reductions in the amplitude of P300 were greater with No‐go stimuli than Go stimuli across the three modalities. Contrary to our hypothesis, dynamic cerebral autoregulation did not change throughout the trials. These results suggest that the effects of task repetition on ERPs were sensory modality‐dependent, while dynamic cerebral autoregulation during cognitive tasks might not contribute to changes in ERPs.Support or Funding InformationJapan Society for the Promotion of Science 18H03166
Racial Disparities in Route of Hysterectomy for Benign Indications Within an Integrated Health Care System
Authors: Zaritsky Eve , Ojo Anthonia , Tucker Lue-Yen , Raine-Bennett Tina R. 
Published: April 2020

(Abstracted from JAMA Network Open 2019;2(12):e1917004)
Over the past 2 decades, gynecologists have been performing fewer hysterectomies and have increased the use of minimally invasive techniques. When used for benign gynecological surgery, minimally invasive hysterectomies (MIHs)—including laparoscopic, vaginal, and robotic procedures)—have been shown to have several advantages compared with open abdominal hysterectomies.
Deep Versus Lobar Intraparenchymal Hemorrhage: Seizures, Hyperexcitable Patterns, and Clinical Outcomes
Authors: Sheikh Zubeda B. , Stretz Christoph , Maciel Carolina B. , Dhakar Monica B. , Orgass Hailey , Petroff Ognen A. , Hirsch Lawrence J. , Gilmore Emily J. 
Published: April 2020

Objectives:
To compare electrographic seizures, hyperexcitable patterns, and clinical outcomes in lobar and deep intraparenchymal hemorrhage. Additionally, to characterize electrographic seizure and hyperexcitable pattern predictors in each group and determine seizure risk with thalamic involvement.

Design:
Retrospective cohort study.

Setting:
Tertiary academic medical center.

Patients:
Consecutive adult patients with nontraumatic intraparenchymal hemorrhage undergoing continuous electroencephalography at our center between January 2013 and December 2016.

Interventions:
Not applicable.

Measurements and Main Results:
Based on head CT closest to the initial continuous electroencephalography session, we classified intraparenchymal hemorrhage as isolated deep (no insular, subarachnoid, subdural extension) or lobar. Hyperexcitable patterns included the following: periodic discharges, spike-wave complexes, any rhythmic delta other than generalized. We used Fisher exact test for categorical and Mann-Whitney U test for continuous variables. Multivariable regression identified predictors of electrographic seizures, hyperexcitable patterns, and poor outcomes (score of 1–2 on Glasgow Outcome Scale) in lobar intraparenchymal hemorrhage. The cohort comprised of 128 patients, 88 lobar, and 40 deep intraparenchymal hemorrhage. Electrographic seizures occurred in 17% of lobar and 5% of deep intraparenchymal hemorrhage (p = 0.09). Hyperexcitable patterns were more frequent in the lobar group (44.3% vs 17.5%; p = 0.005). In multivariable analyses in the lobar group, lateralized rhythmic delta activity predicted electrographic seizures (odds ratio, 6.24; CI, 1.49–26.08; p = 0.012); insular involvement predicted hyperexcitable patterns (odds ratio, 4.88; CI, 1.36–17.57; p = 0.015); coma, temporal lobe involvement, intraparenchymal hemorrhage volume, and electrographic seizures predicted poor outcome. Thalamic involvement did not affect electrographic seizures or hyperexcitable patterns in either group.

Conclusions:
Electrographic seizures are frequent in lobar intraparenchymal hemorrhage, occurring in one in six monitored patients, as opposed to only 5% in isolated deep intraparenchymal hemorrhage not extending to cortex/insula, subarachnoid, or subdural spaces. Patients with lobar intraparenchymal hemorrhage and lateralized rhythmic delta activity were six times as likely to have electrographic seizures, which were associated with 5.47 higher odds of a poor outcome. Coma, temporal lobe involvement, hematoma volume, and electrographic seizures predicted poor outcome in lobar intraparenchymal hemorrhage.
Subtle Motor Signs as a Biomarker for Mindful Movement Intervention in Children with Attention-Deficit/Hyperactivity Disorder
Authors: Clark Dav , Seymour Karen E. , Findling Robert L. , Mostofsky Stewart H. 
Published: April 2020

Abstract:

Objective:
Previous studies of Tai Chi or mindfulness-based interventions in attention-deficit/hyperactivity disorder (ADHD) have relied on self- or parent-reported outcome measures; however, there is a critical need for the validation of objective biomarkers of treatment. Therefore, we implemented a mindful movement intervention for children with ADHD, hypothesizing that an ADHD-relevant motor control measure could serve as a predictive biomarker of treatment-related improvement.

Methods:
Thirty-four participants were included, 8 to 12 year olds diagnosed with DSM-5 ADHD. Participants engaged in the mindful movement treatment, an 8-week program with 2 classes a week for 60 minutes. At pre- and post-treatment, ADHD symptoms and associated impairment and motor control via the Physical and Neurological Examination for Subtle Signs (PANESS) were assessed.

Results:
The results showed a significant reduction for PANESS Gaits and Station (p ≤ 0.001), total overflow (p = 0.009), and total score (p = 0.001) after treatment, with the largest effect for Gaits and Stations. The results also showed a significant reduction in symptoms of inattention (p ≤ 0.001), hyperactivity/impulsivity (p ≤ 0.001), oppositional defiant disorder (p = 0.001), and executive dysfunction (p ≤ 0.001). There were significant positive correlations between change in PANESS Gaits and Stations and change in both inattentive (p = 0.02) and hyperactive/impulsive symptoms (p = 0.02). There was also a significant positive correlation between change in the PANESS total score and change in inattentive (p = 0.007) and hyperactive/impulsive symptoms (p = 0.042). The change in the PANESS total score (β = 0.295, p = 0.002) predicted post-treatment ADHD severity above the change in inattentive or hyperactive/impulsive symptoms.

Conclusion:
The results suggest the effectiveness of a mindful movement treatment on ADHD symptoms and suggest the PANESS as a candidate motor biomarker for future mindful movement trials.

Clinical Trial Registration:

ClinicalTrials.gov, NCT02234557, https://clinicaltrials.gov/ct2/show/NCT02234557.
THE INCIDENCE OF NEOVASCULARIZATION IN CENTRAL SEROUS CHORIORETINOPATHY BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY
Authors: Savastano M. Cristina , Rispoli Marco , Lumbroso Bruno 
Published: April 2020

Purpose:
To evaluate the incidence of neovascularization (NV) secondary to central serous chorioretinopathy (CSC)—a condition belonging to the spectrum of pachychoroid disorders by means of optical coherence tomography angiography.

Methods:
One hundred and seventy five eyes with CSC were evaluated in this retrospective observational study. The eyes with acute or chronic CSC with no NV were included in Group 1, and those with NV were evaluated in Group 2. Only eyes that had undergone structural optical coherence tomography and optical coherence tomography angiography were included. Age, best-corrected visual acuity, and subfoveal choroidal thickness were evaluated in all eyes. In Group 2, the type and morphology of NV and the occurrence of exudation were considered.

Results:
Of a total of 175 eyes with CSC, 86 had the acute form and 89 the chronic. Approximately 140 belonged to Group 1 (80%) and 35 to Group 2 (20%). Approximately 39.2% of all patient with chronic CSC developed NV. Mean age in Groups 1 and 2 was 53.3 years (±10.9) and 66.6 years (±10.2), respectively. Mean best-corrected visual acuity in Groups 1 and 2 was 45.7 (±11.7) and 30.9 (±17.9) early treatment diabetic retinopathy study letters, respectively. Mean CCT in Group 1 and 2 was 417.5 µm (±123) and 344.2 µm (±165.9), respectively. In Group 2, all patients had Type 1 NV (100%); 29 eyes (83%) had filamentous feature, and 6 eyes (17%) had irregular shape. Silent nonexudative NV was observed in 7 eyes (20%), all belonging to Group 2.

Conclusion:
The use of optical coherence tomography angiography in everyday clinical practice allows for the accurate analysis of the chorioretinal vascular setting, with the identification of new vessels that could remain misdiagnosed.
A Prospective Cohort Study on the Safety of Infant Pentavalent (DTwP-HBV-Hib) and Oral Polio Vaccines in Two South Indian Districts
Authors: Arora Narendra Kumar , Das Manoja Kumar , Poluru Ramesh , Kashyap Neeraj Kumar , Mathew Thomas , Mathai John , Aggarwal Mahesh Kumar , Haldar Pradeep , Verstraeten Thomas , Zuber Patrick L. F. ,   the INCLEN Vaccine Safety Study Group
Published: April 2020

Background:
Safety of pentavalent (DTwP-HBV-Hib) vaccine has been a public concern in India and other countries. This study attempted to document the association of serious adverse events following immunization (AEFI, including hospitalizations and deaths of all causes) with the 3 doses of pentavalent and oral poliovirus (OPV) vaccines.

Methods:
A cohort of 30,688 infants in 2 south Indian districts were enrolled and followed-up between October 2014 and May 2016, following their first vaccination with DTwP-HBV-Hib and OPV at public health facilities. During weekly follow-ups, by telephone or home visits, the serious AEFIs (hospitalizations and deaths) occurring any time after each vaccination until 4 weeks after third dose were documented. The incidence risk ratios (IRRs) of serious AEFIs in the first (days 0–6) and fourth weeks (days 21–27) after the vaccine doses were compared using the poisson regression analysis.

Results:
Of the 30,688 infants enrolled, 30,208 received their third doses of vaccines. During the 4-week periods following each vaccination, there were 365 hospitalizations and 17 deaths. Adjusted incidence risk ratio of 3 doses combined for post-vaccination serious AEFIs during the first week compared with fourth week was 0.8 [95% confidence interval: 0.6–1.0].

Conclusions:
There was no increased risk of a serious AEFIs during the first week after any of the 3 doses of pentavalent and OPV vaccination compared with the fourth week. In the absence of any temporal clustering, mortality and hospitalization rates observed in vaccinated infants probably reflects the natural occurrence of such events.
Induction of Meal-related Symptoms as a Novel Mechanism of Action of the Duodenal-Jejunal Bypass Sleeve
Authors: McMaster Jessica J. , Rich Graeme G. , Shanahan Erin R. , Do Anh T. , Fletcher Linda M. , Kutyla Marguerite J. , Tallis Caroline , Jones Mike P. , Talley Nicholas J. , Macdonald Graeme A. , Chachay Veronique S. , Holtmann Gerald J. 
Published: April 2020

Background:
Treatment with a duodenal-jejunal bypass sleeve (DJBS) induces clinically significant weight loss, but little is known about the mechanisms of action of this device.

Aim:
The aim of this study was to characterize the mechanisms of action of the DJBS and determine the durability of weight loss and metabolic improvements.

Materials and Methods:
We studied a cohort of 19 subjects with severe obesity and type 2 diabetes (baseline body mass index: 43.7±5.3 kg/m2). Anthropometry, body composition, blood pressure, biochemical measures, and dietary intake were monitored for 48 weeks after DJBS implantation, and then for 1 year after device removal. Gastric emptying and triglyceride absorption were measured at baseline, 8 weeks after implant, and within 3 weeks of device explant. Visceral sensory function was assessed at baseline, 4 weeks after implant, and within 3 weeks after explant.

Results:
Significant weight loss (P<0.01) occurred following DJBS placement, with a mean weight reduction of 17.0±6.5% at 48 weeks. The symptom burden following a standardized nutrient challenge was increased after DJBS implantation (P<0.05), returning to baseline after DJBS removal. Neither gastric emptying nor triglyceride absorption changed with the device in situ. A significant reduction in energy intake was observed [baseline: 7703±2978 kJ (1841±712 kcal), 24 weeks: 4824±2259 kJ (1153±540 kcal), and 48 weeks: 4474±1468 kJ (1069±351 kcal)]. After 1 year, anthropometry remained significantly improved, but there was no durable impact on metabolic outcomes.

Conclusions:
DJBS treatment resulted in substantial weight loss. Weight loss is related to reduced caloric intake, which seems linked to an augmented upper gastrointestinal symptom response, but not altered fat absorption.