bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developing an analytical method by HPLC for simultaneous quantification of methylene blue and metformin applied to in vitro skin permeation and retention studies
Authors: de Carvalho Matos Lisa , Calixto Leandro Augusto , Junqueira Garcia Maria Teresa 
Published: March 2021

AbstractThe aim of this study was to develop an HPLC method for simultaneous quantification of metformin (MET) and methylene blue (MB) in in vitro skin permeation/retention studies, in which retention was evaluated in the different layers of the skin [stratum corneum (SC) and the viable epidermis + dermis (VE + D)]. The method was validated considering the following parameters: specificity, linearity, quantitation limit (LOQ), recovery, precision and accuracy. Calibration curves were obtained using the following six matrices: methanol, water, methanolic extracts from the SC and VE + D spiked with the drugs and drugs extracted from the SC and VE + D. The precision, accuracy and LOQ of the method were evaluated in water and in VE + D and SC, applying the drug extraction process. The results show that the method is selective and linear for both drugs. The precision and accuracy values, independent of matrix and drug, were below the limit of 15%. The LOQ of MB was defined as 0.4 μg/ml in the VE + D and SC and 0.8 μg/ml in water. The LOQ of MET was defined as 0.8 μg/ml in the VE + D and SC and 0.4 μg/ml in the water. The recovery of the method was adequate, consistent and reproducible for the concentration range of 0.4–10 μg/ml for MB (73.3–92.1%) and 0.8–10.0 μg/mL for MET (72.4–94.4%). This method has a potential application in the development of formulation for skin delivery of MB and MET.
Astrocyte glutamate uptake coordinates experience‐dependent, eye‐specific refinement in developing visual cortex
Authors: Sipe Grayson O. , Petravicz Jeremy , Rikhye Rajeev V. , Garcia Rodrigo , Mellios Nikolaos , Sur Mriganka 
Published: March 2021

AbstractThe uptake of glutamate by astrocytes actively shapes synaptic transmission, however its role in the development and plasticity of neuronal circuits remains poorly understood. The astrocytic glutamate transporter, GLT1 is the predominant source of glutamate clearance in the adult mouse cortex. Here, we examined the structural and functional development of the visual cortex in GLT1 heterozygous (HET) mice using two‐photon microscopy, immunohistochemistry and slice electrophysiology. We find that though eye‐specific thalamic axonal segregation is intact, binocular refinement in the primary visual cortex is disrupted. Eye‐specific responses to visual stimuli in GLT1 HET mice show altered binocular matching, with abnormally high responses to ipsilateral compared to contralateral eye stimulation and a greater mismatch between preferred orientation selectivity of ipsilateral and contralateral eye responses. Furthermore, we observe an increase in dendritic spine density in the basal dendrites of layer 2/3 excitatory neurons suggesting aberrant spine pruning. Monocular deprivation induces atypical ocular dominance plasticity in GLT1 HET mice, with an unusual depression of ipsilateral open eye responses; however, this change in ipsilateral responses correlates well with an upregulation of GLT1 protein following monocular deprivation. These results demonstrate that a key function of astrocytic GLT1 function during development is the experience‐dependent refinement of ipsilateral eye inputs relative to contralateral eye inputs in visual cortex.
Clinical Implications of HBV PreS/S Mutations and the Effects of PreS2 Deletion on Mitochondria, Liver Fibrosis, and Cancer Development
Authors: Liang Yuh‐Jin , Teng Wei , Chen Chih‐Li , Sun Cheng‐Pu , Teng Rui‐Dung , Huang Yen‐Hua , Liang Kung‐Hao , Chen Yi‐Wen , Lin Chung‐Chih , Su Chien‐Wei , Tao Mi‐Hua , Wu Jaw‐Ching 
Published: March 2021

Background and Aims
PreS mutants of HBV have been reported to be associated with HCC. We conducted a longitudinal study of the role of HBV preS mutations in the development of HCC, particularly in patients with chronic hepatitis B (CHB) having low HBV DNA or alanine aminotransferase (ALT) levels, and investigated the effects of secretion‐defective preS2 deletion mutant (preS2ΔMT) on hepatocyte damage in vitro and liver fibrosis in vivo.

Approach and Results
Association of preS mutations with HCC in 343 patients with CHB was evaluated by a retrospective case–control follow‐up study. Effects of preS2ΔMT on HBsAg retention, endoplasmic reticulum (ER) stress, calcium accumulation, mitochondrial dysfunction, and liver fibrosis were examined. Multivariate analysis revealed a significant association of preS mutations with HCC (HR, 3.210; 95% CI, 1.072‐9.613; P = 0.037) including cases with low HBV DNA or ALT levels (HR, 2.790; 95% CI, 1.133‐6.873; P = 0.026). Antiviral therapy reduced HCC risk, including cases with preS mutations. PreS2ΔMT expression promoted HBsAg retention in the ER and unfolded protein response (UPR). Transmission electron microscopic examination, MitoTracker staining, real‐time ATP assay, and calcium staining of preS2ΔMT‐expressing cells revealed aberrant ER and mitochondrial ultrastructure, reduction of mitochondrial membrane potential and ATP production, and calcium overload. Serum HBV secretion levels were ~100‐fold lower in preS2ΔMT‐infected humanized Fah–/–/ Rag2–/–/Il2rg–/– triple knockout mice than in wild‐type HBV‐infected mice. PreS2ΔMT‐infected mice displayed up‐regulation of UPR and caspase‐3 and enhanced liver fibrosis.

Conclusions
PreS mutations were significantly associated with HCC development in patients with CHB, including those with low HBV DNA or ALT levels. Antiviral therapy reduced HCC occurrence in patients with CHB, including those with preS mutations. Intracellular accumulation of mutated HBsAg induced or promoted ER stress, calcium overload, mitochondrial dysfunction, impaired energy metabolism, liver fibrosis, and HCC.
The hippocampal‐entorhinal system represents nested hierarchical relations between words during concept learning
Authors: Viganò Simone , Piazza Manuela 
Published: March 2021

AbstractA fundamental skill of an intelligent mind is that of being able to rapidly discover the structural organization underlying the relations across the objects or the events in the world. Humans, thanks to language, master this skill. For example, a child learning thatdolphinsandcatscan also be referred to asmammals, not only will infer the presence of a hierarchical organization for which dolphins and cats are subordinate exemplars of the categorymammals, but will also derive that dolphins are, at least at one conceptual level, more similar to cats than to sharks, despite their indisputable higher perceptual similarity to the latter. The hippocampal‐entorhinal system, classically known for its involvement in relational and inferential memory, is a likely candidate to construct and hold these complex relational structures between concepts. To test this hypothesis, we trained healthy human adults to organize a novel audio‐visual object space into categories labeled with novel words. Crucially, a hierarchical taxonomy existed between the object categories, and participants discovered it via inference during a simple associative object‐to‐word training. Using functional MRI after learning, and a combination of ROI‐based multivariate analyses, we found that both the mid‐anterior hippocampus and the entorhinal cortex represented the inferred hierarchical structure between words: subordinate‐level words were represented more similarly to their related superordinate than to unrelated ones. This was paired, in the entorhinal cortex, by an additional signature of internalized structural representation of nested hierarchy: words referring to subordinate concepts belonging to the same superordinate category were represented more similarly compared with those not belonging to the same superordinate level: interestingly, this similarity was never directly taught to subjects nor it was made explicit during the task, but only indirectly derived through a logical inferential process and, crucially, contrasted the evidence coming from the definitional perceptual properties of the concepts. None of these results were observed before learning, when the same words were not yet semantically organized. A whole‐brain searchlight revealed that the effect in the entorhinal cortex extends to a wider network of areas, encompassing the prefrontal, temporal, and parietal cortices, partially overlapping with the semantic network.
PI3 kinase signaling pathway in hematopoietic cancers: A glance in miRNA's role
Authors: Roshandel Elham , Noorazar Leila , Farhadihosseinabadi Behrouz , Mehdizadeh Mahshid , Kazemi Mohammad Hossein , Parkhideh Sayeh 
Published: March 2021

AbstractHematopoietic cancers are among the most common malignancies worldwide, which are divided into different types depending on the origin of tumor cells. In recent years, the pivotal role of different signaling pathways in the onset and progression of these cancer types has been well established. One of these pathways, whose role in blood malignancies has been well‐defined, is PI3K/mTOR/AKT axis. The signaling pathway involves in a wide variety of important biological events in cells. It is clear that dysregulation of mediators involved in PI3 kinase signaling takes a pivotal role in cancer development. Considering the undeniable role of miRNAs, as one of the well‐known families of non‐coding RNAs, in gene regulation, we aimed to review the role of miRNAs in regulation of PI3 kinase signaling effectors in hematopoietic cancers.
Targeting the mitochondrial permeability transition pore for neuroprotection in a piglet model of neonatal hypoxic‐ischemic encephalopathy
Authors: Chen May W. , Santos Polan , Kulikowicz Ewa , Koehler Raymond C. , Lee Jennifer K. , Martin Lee J. 
Published: March 2021

AbstractNeonatal hypoxic‐ischemic encephalopathy (HIE) causes significant morbidity despite treatment with therapeutic hypothermia. Mitochondrial dysfunction may drive the mechanisms underlying neuronal cell death, thereby making mitochondria prime targets for neuroprotection. The mitochondrial permeability transition pore (mPTP) is one such target within mitochondria. In adult animal models, mPTP inhibition is neuroprotective. However, evidence for mPTP inhibition in neonatal models of neurologic disease is less certain. We tested the therapeutic efficacy of the mPTP small molecule inhibitor GNX‐4728 and examined the developmental presence of brain mPTP proteins for drug targeting in a neonatal piglet model of hypoxic‐ischemic brain injury. Male neonatal piglets were randomized to hypoxia‐ischemia (HI) or sham procedure with GNX‐4728 (15 mg/kg, IV) or vehicle (saline/cyclodextrin/DMSO, IV). GNX‐4728 was administered as a single dose within 5 min after resuscitation from bradycardic arrest. Normal, ischemic, and injured neurons were counted in putamen and somatosensory cortex using hematoxylin and eosin staining. In separate neonatal and juvenile pigs, western blots of putamen mitochondrial‐enriched fractions were used to evaluate mitochondrial integrity and the presence of mPTP proteins. We found that a single dose of GNX‐4728 did not protect putamen and cortical neurons from cell death after HI. However, loss of mitochondrial matrix integrity occurred within 6h after HI, and while mPTP components are present in the neonatal brain their levels were significantly different compared to that of a mature juvenile brain. Thus, the neonatal brain mPTP may not be a good target for current neurotherapeutic drugs that are developed based on adult mitochondria.
Signal averaged ECG in patients with early repolarization
Authors: Hassanzadeh Mani , Mardani Ehsan , Hosseinpour Alireza , Mehdipour Namdar Zahra , Shahrzad Shahab , Aslani Amir 
Published: March 2021

AbstractBackgroundEarly repolarization (ER) pattern is diagnosed when the J‐point is elevated on the patient's electrocardiogram. The aim of this study was to evaluate signal‐averaged electrocardiography (SAECG) in patients with ER pattern.MethodsSubjects were divided into three groups: 1‐patients with normal ECG pattern (control group); 2‐patients with J‐point elevation in the inferior leads; and 3‐patients with J‐point elevation in non‐inferior leads.ResultsThe mean filtered QRS duration in groups with J‐point elevation in inferior leads and non‐inferior leads and in the control, was 86.4 ± 23.4 msec, 84.8 ± 26.6 msec, and 85.8 ± 24.8 msec, respectively, indicating no significant difference across the three groups. The mean duration of terminal QRS < 40µV was 21.2 ± 4.2 msec, 22.8 ± 4.6 msec, and 23.1 ± 4.5 msec in the mentioned groups, respectively, without a significant difference between the groups. Additionally, the mean root‐mean‐square voltage of terminal 40 msec was 34.5 ± 8.3 µV, 35.3 ± 8.6µV, and 35.7 ± 9.2 µV in patients with increased J‐point in inferior leads, non‐inferior leads, and the control group, respectively, showing no difference between the groups.ConclusionIn conclusion, we found that parameters in SAECG did not have any significant difference between patients with ER pattern and healthy individuals. Moreover, we concluded that SAECG cannot distinguish the patients with elevated J‐point in inferior leads from non‐inferior leads. Overall, SAECG does not appear to be a reliable diagnostic tool for the assessment of ER pattern.
Impact of Using Abdominal Circumference Independently in the Diagnosis of Fetal Growth Restriction
Authors: Pressman Katherine , Odibo Linda , Duncan Jose R. , Odibo Anthony O. 
Published: March 2021

ObjectiveSociety for Maternal‐Fetal Medicine guidelines for diagnosing fetal growth restriction (FGR) have broadened the definition to include abdominal circumference (AC) <10th percentile for gestational age (GA) regardless of estimated fetal weight (EFW). We aimed to compare the ability of three definitions of FGR to predict small for gestational age (SGA) neonates and adverse outcomes.MethodsWe performed a secondary analysis of a prospective cohort of patients who underwent assessment of fetal growth between GA of 26 and 36 weeks. We compared three definitions of FGR: EFW <10th percentile; AC <10th percentile; either EFW or AC <10th percentile. The primary outcome was successful prediction of neonatal SGA. Secondary outcomes included a composite adverse neonatal outcome (CANO). We further compared these definitions of FGR using area under receiver operative curves (AUC) to measure their discriminatory abilities.ResultsAbout 1054 women met inclusion criteria. Ninety‐one (8.6%) had EFW <10th percentile, 122 (11.6%) had AC <10th percentile, and 137 (12.9%) had either EFW or AC <10th percentile. SGA was seen in 139 (13.2%); CANO was seen in 139 (13.2%). Ability for detecting neonatal SGA was significantly better when the definition included both EFW or AC <10th percentile compared to either variable independently. The AUC were: 0.74, 0.73, 0.69; P = .0003. There was no statistical significance in ability for predicting CANO (AUC 0.51, 0.51, 0.50; P = .7447).ConclusionsAddition of AC as a criterion for diagnosing FGR improves our ability to predict neonatal SGA compared to using EFW alone. All three definitions were poorly predictive of neonates at risk for adverse outcomes.
Hyperbranched Rigid Aromatic Phosphorus‐Containing Flame Retardants for Epoxy Resins
Authors: Battig Alexander , Müller Patrick , Bertin Annabelle , Schartel Bernhard 
Published: March 2021

AbstractA rigid aromatic phosphorus‐containing hyperbranched flame retardant structure is synthesized from 10‐(2,5‐dihydroxyphenyl)‐10H‐9‐oxa‐10‐phosphaphenanthrene‐10‐oxide (DOPO‐HQ), tris(4‐hydroxyphenyl)phosphine oxide (THPPO), and 1,4‐terephthaloyl chloride (TPC). The resulting poly‐(DOPO‐HQ/THPPO‐terephthalate) (PDTT) is implemented as a flame retardant into an epoxy resin (EP) at a 10 wt% loading. The effects on EP are compared with those of the monomer DOPO‐HQ and triphenylphosphine oxide (OPPh3) as low molar mass flame retardants. The glass transition temperature, thermal decomposition, flammability (reaction to small flame), and burning behavior of the thermosets are investigated using differential scanning calorimetry, thermogravimetric analysis, pyrolysis combustion flow calorimetry, UL 94‐burning chamber testing, and cone calorimeter measurements. Although P‐contents are low at only 0.6 wt%, the study aims not at attaining V‐0, but at presenting a proof of principle: Epoxy resinswith PDTT show promising fire performance, exhibiting a 25% reduction in total heat evolved (THE), a 30% reduction in peak heat release rate (PHRR) due to flame inhibition (21% reduction in effective heat of combustion (EHC)), and an increase in Tg at the same time. This study indicates that rigid aromatic hyperbranched polymeric structures offer a promising route toward multifunctional flame retardancy.
Women are started on a lower daily dose of metoprolol than men irrespective of dose recommendations: A potential source of confounding by contraindication in pharmacoepidemiology
Authors: Hendriksen Linda C. , Verhamme Katia M. C. , Van der Linden Paul D. , Stricker Bruno H. , Visser Loes E. 
Published: March 2021

AbstractPurposeCurrent guidelines have no sex‐specific dosage advice for metoprolol. To evaluate whether women and men are prescribed the same dose a cohort analysis was performed in the population‐based Rotterdam Study (RS). Results were replicated in the Integrated Primary Care Information (IPCI) database of automated general practice data.MethodsThe mean daily starting doses of metoprolol in both sexes were compared with independent‐samples t‐tests and a linear regression analysis was used to adjust in the RS for co‐variables, notably, cardiovascular comorbidity, migraine, age, SBP, DBP, BMI, socioeconomic status, use of other antihypertensive drugs, smoking, and alcohol. In the IPCI‐database, adjustment was for age only.ResultsThe mean daily starting dose was statistically significantly lower in women than in men in both the RS and IPCI database, with a mean difference of 4.8 mg (95%CI −7.8, −1.8) and 4.6 mg (95%CI −5.3,‐4.0), respectively. Statistical significance remained after adjustment in both databases.ConclusionsWomen received lower starting doses of metoprolol than men in two independent data collections despite non‐sex specific cardiovascular guideline recommendations. This example of real‐life pharmacotherapy can lead to a form of confounding by contraindication in pharmacoepidemiology.
Theoretical investigation of Prolyl‐Histidine‐catalyzed intermolecular aldol reaction
Authors: Zhang Peihuan , Zhang Yufeng , Li Zhewei , Gao Yang , Lei Ming , Yang Zuoyin , Pu Min 
Published: March 2021

AbstractThe mechanism of aldol reaction of acetone and benzaldehyde catalyzed by Prolyl‐Histidine dipeptide was studied using density functional theory (DFT) method at ωB97XD/6‐31G(d,p) level. The calculated results indicated that this reaction consisted of the following processes: (I) the formation of alcohol intermediate with acetone and Pro‐His by water assistance; (II) the formation of enamine by alcohol dehydration; (III) the formation of imine complexes by electrophilic addition of enamine and benzaldehyde; and (IV) the formation of aldol products by imine complex combining with water to obtain S or R type products after removing the catalyst. The calculated results show that the generation of enamine is the rate‐determining step, and the main product is cis‐enamine with a free energy barrier of 19.6 kcal/mol. The calculated enantiomeric excess (ee) value of aldol product is 100%.
Matrix decomposition in meta‐analysis for extraction of adverse event pattern and patient‐level safety profile
Authors: Matsuura Kentaro , Tsuchida Jun , Ando Shuji , Sozu Takashi 
Published: March 2021

AbstractThe purpose of assessing adverse events (AEs) in clinical studies is to evaluate what AE patterns are likely to occur during treatment. In contrast, it is difficult to specify which of these patterns occurs in each patient. To tackle this challenging issue, we constructed a new statistical model including nonnegative matrix factorization by incorporating background knowledge of AE‐specific structures such as severity and drug mechanism of action. The model uses a meta‐analysis framework for integrating data from multiple clinical studies because insufficient information is derived from a single trial. We demonstrated the proposed method by applying it to real data consisting of three Phase III studies, two mechanisms of action, five anticancer treatments, 3317 patients, 848 AE types, and 99,546 AEs. The extracted typical treatment‐specific AE patterns coincided with medical knowledge. We also demonstrated patient‐level safety profiles using the data of AEs that were observed by the end of the second cycle.
A bird in the hand is worth two in the bush: Technology search strategies and competition due to import penetration
Authors: Morandi Stagni Raffaele , Fosfuri Andrea , Santaló Juan 
Published: March 2021

AbstractResearch SummaryDo firms respond to tougher competition by searching for completely new technological solutions (exploration), or do they work to defend their position by improving current technologies (exploitation)? Considering the different times to fruition for exploration versus exploitation, in the presence of heightened competition, we argue that firms might not be able to wait for the benefits of technological exploration to materialize. With a panel data set of U.S. manufacturing firms, we show that tougher competition, due to import penetration, leads to a decrease in technological exploration and an increase in technological exploitation. These effects are heterogeneous across industries, firms, and time. To obtain exogenous variation in competition we rely on both instrumental variable regressions and a difference‐in‐differences design exploiting large changes in import tariffs.Managerial SummaryA firm's R&D strategy is one of the fundamental determinants of success or failure when responding to competitive threats. In this study, we examine how firms change the knowledge sources used in their R&D efforts in response to substantial increases in import penetration in their domestic market. We find that in the years that immediately follow an increase in import penetration, firms tend to rely more on familiar knowledge in the development of innovations and less on knowledge sources that were not previously used. This switch in R&D strategy also appears to be temporary (reversed in later years), and it is positively associated with an increased likelihood of survival.