Nicotinamide riboside rescues dysregulated glycolysis and fatty acid ß-oxidation in a human hepatic cell model of citrin deficiency.

Citrin deficiency (CD) is an inborn error of metabolism caused by loss-of-function of the mitochondrial aspartate/glutamate transporter, CITRIN, which is involved in both the urea cycle and malate-aspartate shuttle. Patients with CD develop hepatosteatosis and hyperammonemia but there is no effective therapy for CD. Currently, there are no animal models that faithfully recapitulate the human CD phenotype. Accordingly, we generated a CITRIN knockout HepG2 cell line using Clustered Regularly Interspaced Short Palindromic Repeats/Cas 9 genome editing technology to study metabolic and cell signaling defects in CD. CITRIN KO cells showed increased ammonia accumulation, higher cytosolic ratio of reduced versus oxidized form of nicotinamide adenine dinucleotide (NAD) and reduced glycolysis. Surprisingly, these cells showed impaired fatty acid metabolism and mitochondrial activity. CITRIN KO cells also displayed increased cholesterol and bile acid metabolism resembling those observed in CD patients. Remarkably, normalizing cytosolic NADH:NAD+ ratio by nicotinamide riboside increased glycolysis and fatty acid oxidation but had no effect on the hyperammonemia suggesting the urea cycle defect was independent of the aspartate/malate shuttle defect of CD. The correction of glycolysis and fatty acid metabolism defects in CITRIN KO cells by reducing cytoplasmic NADH:NAD+ levels suggests this may be a novel strategy to treat some of the metabolic defects of CD and other mitochondrial diseases.

Validity and reliability of artificial intelligence chatbots as public sources of information on endodontics.

AIM: This study aimed to evaluate and compare the validity and reliability of responses provided by GPT-3.5, Google Bard, and Bing to frequently asked questions (FAQs) in the field of endodontics. METHODOLOGY: FAQs were formulated by expert endodontists (n = 10) and collected through GPT-3.5 queries (n = 10), with every question posed to each chatbot three times. Responses (N = 180) were independently evaluated by two board-certified endodontists using a modified Global Quality Score (GQS) on a 5-point Likert scale (5: strongly agree; 4: agree; 3: neutral; 2: disagree; 1: strongly disagree). Disagreements on scoring were resolved through evidence-based discussions. The validity of responses was analysed by categorizing scores into valid or invalid at two thresholds: The low threshold was set at score ≥4 for all three responses whilst the high threshold was set at score 5 for all three responses. Fisher's exact test was conducted to compare the validity of responses between chatbots. Cronbach's alpha was calculated to assess the reliability by assessing the consistency of repeated responses for each chatbot. RESULTS: All three chatbots provided answers to all questions. Using the low-threshold validity test (GPT-3.5: 95%; Google Bard: 85%; Bing: 75%), there was no significant difference between the platforms (p > .05). When using the high-threshold validity test, the chatbot scores were substantially lower (GPT-3.5: 60%; Google Bard: 15%; Bing: 15%). The validity of GPT-3.5 responses was significantly higher than Google Bard and Bing (p = .008). All three chatbots achieved an acceptable level of reliability (Cronbach's alpha >0.7). CONCLUSIONS: GPT-3.5 provided more credible information on topics related to endodontics compared to Google Bard and Bing.

A laboratory study comparing the static navigation technique using a bur with a conventional freehand technique using ultrasonic tips for the removal of fibre posts.

AIM: There are currently no high-quality studies comparing the static navigation technique with conventional methods of fibre post removal. The aim of this ex vivo study was to compare the effectiveness of fibre post removal between a static navigation technique and a conventional freehand technique using ultrasonics by experienced and inexperienced operators. METHODOLOGY: Forty-eight extracted single-rooted human premolars were root-filled. A fibre post was cemented in all 48 teeth, which were then divided randomly into the following groups: static navigation group using burs; static navigation-ultrasonic group; and non-guided group using ultrasonic tips. The following parameters were evaluated for both experienced operators and inexperienced operators: reaching the gutta-percha root filling successfully, the time required to remove the entire post, the occurrence of lateral root perforations, and the amount of root dentine removed. The Kolmogorov-Smirnov test was used to examine the normality of the data; the anova test was used to compare the significant differences among groups; and Tukey tests were used for all two-by-two comparisons. The significance level was set at 0.05. RESULTS: In the static navigation group, the gutta-percha was reached significantly more frequently than in the non-guided group (p < .05). The static navigation approach required significantly less time than the non-guided approach to reach the gutta-percha (p < .05). The total removal of posts was significantly different between groups (p < .05), but there was no significant difference between experienced and inexperienced operators in the static navigation group (p > .05). More perforations were associated with the non-guided group than with the other two groups. The total mean loss of dentine in the non-guided group in all directions was 0.39 (±0.17) mm, with 0.25 (±0.09) mm for experienced, and 0.42 (±0.16) mm for inexperienced operators. CONCLUSION: When compared to a conventional ultrasonic technique for the removal of fibre posts, the static navigation method using burs resulted in less dentine removal, more rapid access to the gutta-percha root filling, less overall time to remove the posts, and fewer complications. When using static navigation, there was no difference in performance between experienced and inexperienced operators.

Influence of endodontic access cavity design on mechanical properties of a first mandibular premolar tooth: a finite element analysis study.

OBJECTIVES: This study aimed to investigate the influence of access cavity designs on the mechanical properties of a single-rooted mandibular first premolar tooth under various static loads using a finite element analysis. MATERIALS AND METHODS: 3-dimensional FEA designs were modeled according to the access cavity designs: an intact tooth (control), traditional access cavity (TEC-I), traditional access cavity with Class-II mesio-occlusal cavity design (TEC-II), conservative access cavity (CEC), ninja access cavity (NEC), caries-driven access cavity (Cd-EC), buccal access cavity (BEC) and bucco-occlusal access cavity (BOEC). After the simulated access cavity preparations, root canal treatment was simulated and three different static loads which mimicked oblique and vertical mastication forces were applied to the models. The stress distribution and maximum Von Misses stress values were recorded. The maximum stress values were obtained on both enamel and dentin under multi-point vertical loads. RESULTS: The maximum stress values were obtained on both enamel and dentin under multi-point vertical loads. Under all load types, the minimum stress distribution was observed in the control group, followed by CEC, NEC and BEC designs. The highest stress concentration was detected in Cd-EC and TEC-II designs. Under single-point vertical loading, the stress was mostly concentrated in the lingual PCD area, while under multi-point vertical loading, the entire root surface was stress-loaded except for the lingual apical third of the root. CONCLUSION: Preserving tooth tissue by simulating CEC, NEC and BEC access cavities increased the load capacity of a single-rooted mandibular first premolar following simulated endodontic treatment.

Validation of a 0/1 h Algorithm for Rapid Diagnosis of Myocardial Infarction Using a High-Sensitivity Troponin I Assay.

BACKGROUND: Current guidelines recommend 0/1 h algorithms using high-sensitivity cardiac troponin (hs-cTn) for fast diagnosis of myocardial infarction (MI). Yet, for some assays, existing data is limited. We aimed to evaluate the diagnostic performance and the prognostic value of a rapid 0/1 h algorithm for the Access hs-cTnI assay. METHODS: In consecutive patients presenting with suspected MI, we measured concentrations of Access hs-cTnI at presentation and after 1 hour. Final diagnosis was adjudicated independently by 2 cardiologists. Parameters for diagnostic performance were calculated, applying the recently derived European Society of Cardiology (ESC) 0/1 h algorithm for Access hs-cTnI. Additionally, we assessed the prognostic utility of Access hs-cTnI for the composite end point of all-cause mortality and incident MI at 3 years. RESULTS: In 1879 patients, 257 non-ST-elevation MIs occurred. Application of the 0/1 h algorithm classified 44.5% as rule-out, 20.3% as rule-in, and triaged 35.1% to the observe group. High rule-out safety was confirmed with a sensitivity of 97.7% (95% CI, 95.0%-99.1%) and a negative predictive value of 99.3% (95% CI, 98.4%-99.7%). Rule-in capacity was moderate with a specificity of 88.0% (95% CI, 86.3%-89.6%) and a positive predictive value of 50.8% (95% CI, 45.7%-55.9%). After exclusion of patients with ST-elevation MI the results showed strong prognostic value, even after adjustment for cardiovascular risk factors and comorbidities, with adjusted hazard ratios of 2.51 (95% CI, 1.56-4.04) in the observe and 3.55 (95% CI, 2.18-5.79) in the rule-in group for the composite end point of all-cause mortality and incident MI at 3 years, compared to ruled-out patients. CONCLUSION: The ESC 0/1 h algorithm for Access hs-cTnI allows safe and efficient triage of patients with suspected MI and has strong prognostic utility up to 3 years after the initial evaluation.

Facial thermal response to non-painful stressor in premature and term neonates.

BACKGROUND: This study is a preliminary clinical investigation with the objective to evaluate the facial thermal response of premature and term neonates to a non-painful stressor (hunger) using infrared thermography (IRT). The development of objective and reliable parameters to monitor pain and stress is of relevance for optimal neonatal outcome and achieving a better management of patient comfort. METHODS: We enrolled 12 neonates ranging from 27 to 39 weeks gestation (median: 34) and aged 3-79 days (median: 13). Recordings were performed before and after feeding, with and without hunger. Six regions of interest were chosen for evaluation (nose tip, periorbital and corrugator region, forehead, perioral and chin region). RESULTS: There was an increase in the facial temperature in infants immediately prior to their next feed relative to infants who were not hungry, with the nasal tip being the facial evaluation site with the greatest temperature change. CONCLUSIONS: The IRT appears to be a feasible and suitable method to detect changes in the neonatal patient. The thermal variations observed seem to reflect an arousal mediated by the parasympathetic nervous system, which has been described in existing infant stress research. IMPACT: This is the first study to examine the use of infrared thermography (IRT) in monitoring the facial thermal response to a mild stressor (hunger) in premature and term neonates. Hunger as a mild, non-pain-associated stressor showed a significant effect on the facial temperature. The thermal signature of the regions of interest chosen showed hunger-related thermal variations. Results suggest the feasibility and suitability of IRT as an objective diagnostic tool to approach stress and changes in the condition of the neonatal patient.

Effects of Air Pollutants from Wildfires on Downwind Ecosystems: Observations, Knowledge Gaps, and Questions for Assessing Risk.

Wildfires have increased in frequency and area burned, trends expected to continue with climate change. Among other effects, fires release pollutants into the atmosphere, representing a risk to human health and downwind terrestrial and aquatic ecosystems. While human health risks are well studied, the ecological impacts to downwind ecosystems are not, and this gap may present a constraint on developing an adequate assessment of the ecological risks associated with downwind wildfire exposure. Here, we first screened the scientific literature to assess general knowledge about pathways and end points of a conceptual model linking wildfire generated pollutants and other materials to downwind ecosystems. We found a substantial body of literature on the composition of wildfire derived pollution and materials in the atmosphere and subsequent transport, yet little observational or experimental work on their effects on downwind ecological end points. This dearth of information raises many questions related to adequately assessing the ecological risk of downwind exposure, especially given increasing wildfire trends. To guide future research, we pose eight questions within the well-established US EPA ecological risk assessment paradigm that if answered would greatly improve ecological risk assessment and, ultimately, management strategies needed to reduce potential wildfire impacts.

Critical analysis of the reporting quality of animal studies within Endodontics using the Preferred Reporting Items for Animal Studies in Endodontics (PRIASE) 2021 quality standard checklist.

AIM: To critically evaluate the reporting quality of a random sample of animal studies within the field of endodontics against the Preferred Reporting Items for Animal Studies in Endodontics (PRIASE) 2021 checklist and to investigate the association between the quality of reporting and several characteristics of the selected studies. METHODOLOGY: Fifty animal studies related to endodontics were randomly selected from the PubMed database with publication dates from January 2017 to December 2021. For each study, a score of '1' was given when the item of the PRIASE 2021 checklist was fully reported, whereas a score of '0' was given when an item was not reported; when the item was inadequately or partially reported, a score of '0.5' was given. Based on the overall scores allocated to each manuscript, they were allocated into three categories of reporting quality: low, moderate and high. Associations between study characteristics and reporting quality scores were also analysed. Descriptive statistics and Fisher's exact tests were used to describe the data and determine associations. The probability value of .05 was selected as the level of statistical significance. RESULTS: Based on the overall scores, four (8%) and 46 (92%) of the animal studies evaluated were categorized as 'High' and 'Moderate' reporting quality, respectively. A number of items were adequately reported in all studies related to background (Item 4a), relevance of methods/results (7a) and interpretation of images (11e), whereas only one item related to changes in protocol (6d) was not reported in any. No associations were confirmed between reporting quality scores and number of authors, origin of the corresponding author, journal of publication (endodontic specialty vs. non- specialty), impact factor or year of publication. CONCLUSIONS: Animal studies published in the specialty of endodontics were mostly of 'moderate' quality in terms of the quality of reporting. Adherence to the PRIASE 2021 guidelines will enhance the reporting of animal studies in the expectation that all future publications will be high quality.

[DEEP ORBITAL DERMOID CYSTS].

INTRODUCTION: Orbital dermoid cysts are benign choristomas that arise from the entrapment of ectodermal elements adjacent to the fetal bony suture lines. They are considered congenital, but not all are diagnosed at birth. They are the most common orbital tumors in children. While superficial dermoid cysts appear early in life, deep dermoid cysts remain clinically occult until adolescence or adulthood, when they enlarge and may cause proptosis, ocular and orbital symptoms, and even neurological symptoms. In addition, many deep orbital dermoid cysts present with chronic inflammation resulting from lipid leakage from the cysts. They pose a diagnostic and therapeutic challenge, require radiological imaging for planning the surgical approach and may be difficult to remove. Early diagnosis and complete surgical removal of the cysts are the recommended therapeutic approach. In this paper, we present a literature review of deep orbital dermoid cysts to provide useful guidance for their diagnosis and management.

Vitamin B12 and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation.

BACKGROUND & AIMS: Several recent clinical studies have shown that serum homocysteine (Hcy) levels are positively correlated, while vitamin B12 (B12) and folate levels are negative correlated, with non-alcoholic steatohepatitis (NASH) severity. However, it is not known whether hyperhomocysteinemia (HHcy) plays a pathogenic role in NASH. METHODS: We examined the effects of HHcy on NASH progression, metabolism, and autophagy in dietary and genetic mouse models, patients, and primates. We employed vitamin B12 (B12) and folate (Fol) to reverse NASH features in mice and cell culture. RESULTS: Serum Hcy correlated with hepatic inflammation and fibrosis in NASH. Elevated hepatic Hcy induced and exacerbated NASH. Gene expression of hepatic Hcy-metabolizing enzymes was downregulated in NASH. Surprisingly, we found increased homocysteinylation (Hcy-lation) and ubiquitination of multiple hepatic proteins in NASH including the key autophagosome/lysosome fusion protein, Syntaxin 17 (Stx17). This protein was Hcy-lated and ubiquitinated, and its degradation led to a block in autophagy. Genetic manipulation of Stx17 revealed its critical role in regulating autophagy, inflammation and fibrosis during HHcy. Remarkably, dietary B12/Fol, which promotes enzymatic conversion of Hcy to methionine, decreased HHcy and hepatic Hcy-lated protein levels, restored Stx17 expression and autophagy, stimulated ß -oxidation of fatty acids, and improved hepatic histology in mice with pre-established NASH. CONCLUSIONS: HHcy plays a key role in the pathogenesis of NASH via Stx17 homocysteinylation. B12/folate also may represent a novel first-line therapy for NASH. LAY SUMMARY: The incidence of non-alcoholic steatohepatitis, for which there are no approved pharmacological therapies, is increasing, posing a significant healthcare challenge. Herein, based on studies in mice, primates and humans, we found that dietary supplementation with vitamin B12 and folate could have therapeutic potential for the prevention or treatment of non-alcoholic steatohepatitis.

A Consensus Statement on the Terminology for Automated Visual Field Abnormalities.

BACKGROUND: A multitude of terms have been used to describe automated visual field abnormalities. To date, there is no universally accepted system of definitions or guidelines. Variability among clinicians creates the risk of miscommunication and the compromise of patient care. The purposes of this study were to 1) assess the degree of consistency among a group of neuro-ophthalmologists in the description of visual field abnormalities and 2) to create a consensus statement with standardized terminology and definitions. METHODS: In phase one of the study, all neuro-ophthalmologists in Israel were asked to complete a survey in which they described the abnormalities in 10 selected automated visual field tests. In phase 2 of the study, the authors created a national consensus statement on the terminology and definitions for visual field abnormalities using a modified Delphi method. In phase 3, the neuro-ophthalmologists were asked to repeat the initial survey of the 10 visual fields using the consensus statement to formulate their answers. RESULTS: Twenty-six neuro-ophthalmologists participated in the initial survey. On average, there were 7.5 unique descriptions for each of the visual fields (SD 3.17), a description of only the location in 24.6% (SD 0.19), and an undecided response in 6.15% (SD 4.13). Twenty-two neuro-ophthalmologists participated in the creation of a consensus statement which included 24 types of abnormalities with specific definitions. Twenty-three neuro-ophthalmologists repeated the survey using the consensus statement. On average, in the repeated survey, there were 5.9 unique descriptions for each of the visual fields (SD 1.79), a description of only the location in 0.004% (SD 0.01), and an undecided response in 3.07% (SD 2.11%). Relative to the first survey, there was a significant improvement in the use of specific and decisive terminology. CONCLUSIONS: The study confirmed a great degree of variability in the use of terminology to describe automated visual field abnormalities. The creation of a consensus statement was associated with improved use of specific terminology. Future efforts may be warranted to further standardize terminology and definitions.

Optical stimulation of cardiac cells with a polymer-supported silicon nanowire matrix.

Electronic pacemakers can treat electrical conduction disorders in hearts; however, they are invasive, bulky, and linked to increased incidence of infection at the tissue-device interface. Thus, researchers have looked to other more biocompatible methods for cardiac pacing or resynchronization, such as femtosecond infrared light pulsing, optogenetics, and polymer-based cardiac patches integrated with metal electrodes. Here we develop a biocompatible nongenetic approach for the optical modulation of cardiac cells and tissues. We demonstrate that a polymer-silicon nanowire composite mesh can be used to convert fast moving, low-radiance optical inputs into stimulatory signals in target cardiac cells. Our method allows for the stimulation of the cultured cardiomyocytes or ex vivo heart to beat at a higher target frequency.

A Tunable Hyperspectral Imager for Detection and Quantification of Marine Biofouling on Coated Surfaces.

Fouling control coatings (FCCs) are used to prevent the accumulation of marine biofouling on, e.g., ship hulls, which causes increased fuel consumption and the global spread of non-indigenous species. The standards for performance evaluations of FCCs rely on visual inspections, which induce a degree of subjectivity. The use of RGB images for objective evaluations has already received interest from several authors, but the limited acquired information restricts detailed analyses class-wise. This study demonstrates that hyperspectral imaging (HSI) expands the specificity of biofouling assessments of FCCs by capturing distinguishing spectral features. We developed a staring-type hyperspectral imager using a liquid crystal tunable filter as the wavelength selective element. A novel light-emitting diode illumination system with high and uniform irradiance was designed to compensate for the low-filter transmittance. A spectral library was created from reflectance-calibrated optical signatures of representative biofouling species and coated panels. We trained a neural network on the annotated library to assign a class to each pixel. The model was evaluated on an artificially generated target, and global accuracy of 95% was estimated. The classifier was tested on coated panels (exposed at the CoaST Maritime Test Centre) with visible intergrown biofouling. The segmentation results were used to determine the coverage percentage per class. Although a detailed taxonomic description might be complex due to spectral similarities among groups, these results demonstrate the feasibility of HSI for repeatable and quantifiable biofouling detection on coated surfaces.

Quantifying the strength of heterointeractions among receptor tyrosine kinases from different subfamilies: Implications for cell signaling.

Receptor tyrosine kinases (RTKs) are single-pass membrane proteins that control vital cell processes such as cell growth, survival, and differentiation. There is a growing body of evidence that RTKs from different subfamilies can interact and that these diverse interactions can have important biological consequences. However, these heterointeractions are often ignored, and their strengths are unknown. In this work, we studied the heterointeractions of nine RTK pairs, epidermal growth factor receptor (EGFR)-EPH receptor A2 (EPHA2), EGFR-vascular endothelial growth factor receptor 2 (VEGFR2), EPHA2-VEGFR2, EPHA2-fibroblast growth factor receptor 1 (FGFR1), EPHA2-FGFR2, EPHA2-FGFR3, VEGFR2-FGFR1, VEGFR2-FGFR2, and VEGFR2-FGFR3, using a FRET-based method. Surprisingly, we found that RTK heterodimerization and homodimerization strengths can be similar, underscoring the significance of RTK heterointeractions in signaling. We discuss how these heterointeractions can contribute to the complexity of RTK signal transduction, and we highlight the utility of quantitative FRET for probing multiple interactions in the plasma membrane.

Ligand bias in receptor tyrosine kinase signaling.

Ligand bias is the ability of ligands to differentially activate certain receptor signaling responses compared with others. It reflects differences in the responses of a receptor to specific ligands and has implications for the development of highly specific therapeutics. Whereas ligand bias has been studied primarily for G protein-coupled receptors (GPCRs), there are also reports of ligand bias for receptor tyrosine kinases (RTKs). However, the understanding of RTK ligand bias is lagging behind the knowledge of GPCR ligand bias. In this review, we highlight how protocols that were developed to study GPCR signaling can be used to identify and quantify RTK ligand bias. We also introduce an operational model that can provide insights into the biophysical basis of RTK activation and ligand bias. Finally, we discuss possible mechanisms underpinning RTK ligand bias. Thus, this review serves as a primer for researchers interested in investigating ligand bias in RTK signaling.

The RTK Interactome: Overview and Perspective on RTK Heterointeractions.

Receptor tyrosine kinases (RTKs) play important roles in cell growth, motility, differentiation, and survival. These single-pass membrane proteins are grouped into subfamilies based on the similarity of their extracellular domains. They are generally thought to be activated by ligand binding, which promotes homodimerization and then autophosphorylation in trans. However, RTK interactions are more complicated, as RTKs can interact in the absence of ligand and heterodimerize within and across subfamilies. Here, we review the known cross-subfamily RTK heterointeractions and their possible biological implications, as well as the methodologies which have been used to study them. Moreover, we demonstrate how thermodynamic models can be used to study RTKs and to explain many of the complicated biological effects which have been described in the literature. Finally, we discuss the concept of the RTK interactome: a putative, extensive network of interactions between the RTKs. This RTK interactome can produce unique signaling outputs; can amplify, inhibit, and modify signaling; and can allow for signaling backups. The existence of the RTK interactome could provide an explanation for the irreproducibility of experimental data from different studies and for the failure of some RTK inhibitors to produce the desired therapeutic effects. We argue that a deeper knowledge of RTK interactome thermodynamics can lead to a better understanding of fundamental RTK signaling processes in health and disease. We further argue that there is a need for quantitative, thermodynamic studies that probe the strengths of the interactions between RTKs and their ligands and between different RTKs.

Spatio-temporal and -spectral feature maps in photoplethysmography imaging and infrared thermograph.

BACKGROUND: Only a small fraction of the information available is generally used in the majority of camera-based sensing approaches for vital sign monitoring. Dedicated skin pixels, for example, fall into this category while other regions are often disregarded early in the processing chain. METHODS: We look at a simple processing chain for imaging where a video stream is converted to several other streams to investigate whether other image regions should also be considered. These streams are generated by mapping spatio-temporal and -spectral features of video segments and, thus, compressing the information contained in several seconds of video and encoding these in a new image. Two typical scenarios are provided as examples to study the applicability of these maps: face videos in a laboratory setting and measurements of a baby in the neonatal intensive care unit. Each measurement consists of the synchronous recording of photoplethysmography imaging (PPGI) and infrared thermography (IRT). We report the results of a visual inspection of those maps, evaluate the root mean square (RMS) contrast of foreground and background regions, and use histogram intersections as a tool for similarity measurements. RESULTS: The maps allow us to distinguish visually between pulsatile foreground objects and an image background, which is found to be a noisy pattern. Distortions in the maps could be localized and the origin could be discovered. The IRT highlights subject contours for the heart frequency band, while silhouettes show strong signals in PPGI. Reflections and shadows were found to be sources of signals and distortions. We can testify advantages for the use of near-infrared light for PPGI. Furthermore, a difference in RMS contrast for pulsatile and non-pulsatile regions could be demonstrated. Histogram intersections allowed us to differentiate between the background and foreground. CONCLUSIONS: We introduced new maps for the two sensing modalities and presented an overview for three different wavelength ranges. The maps can be used as a tool for visualizing aspects of the dynamic information hidden in video streams without automation. We propose focusing on an indirect method to detect pulsatile regions by using the noisy background pattern characteristic, for example, based on the histogram approach introduced.

The biophysical basis of receptor tyrosine kinase ligand functional selectivity: Trk-B case study.

Tropomyosin receptor kinase B (Trk-B) belongs to the second largest family of membrane receptors, Receptor Tyrosine Kinases (RTKs). Trk-B is known to interact with three different neurotrophins: Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-4 (NT-4), and Neurotrophin-3 (NT-3). All three neurotrophins are involved in survival and proliferation of neuronal cells, but each induces distinct signaling through Trk-B. We hypothesize that the different biological effects correlate with differences in the interactions between the Trk-B receptors, when bound to different ligands, in the plasma membrane. To test this hypothesis, we use quantitative FRET to characterize Trk-B dimerization in response to NT-3 and NT-4 in live cells, and compare it to the previously published data for Trk-B in the absence and presence of BDNF. Our study reveals that the distinct Trk-B signaling outcomes are underpinned by both different configurations and different stabilities of the three ligand-bound Trk-B dimers in the plasma membrane.

School-based education to prevent bullying in high schools in Indonesia.

BACKGROUND: The Global School-based Health Survey showed that 20.6% of Indonesian students aged 13-17 years old were bullied. The proportion was lower than those reported from Southeast Asian countries (28.3-51.0%). School education was reported to contribute to the reduction of bullying, but no similar study has been done in Indonesia. This study aimed to explore the role of school-based education in preventing bullying in high schools in Indonesia. METHODS: In-depth interviews with principals and focus group discussions with teachers from five schools in Mataram City were conducted in 2018. Data were transcribed and analyzed using thematic analysis. Participant observations and document reviews were conducted to verify the data. RESULTS: Seven themes emerged: (i) Bullying as a problem; (ii) Causes of bullying; (iii) Effects of bullying; (iv) Curricular interventions; (v) Cultural interventions; (vi) Institutional interventions; and (vii) Challenges and recommendations regarding current interventions. Curricular interventions include Pancasila (state ideology or principles of the state's philosophy) and civic education, and religious education, while cultural interventions include cultural practices and extracurricular activities. The schools provide an enabling environment by maintaining a good physical environment and implementing policies to prevent bullying. These activities promote the prevention of school bullying. CONCLUSIONS: This study demonstrated that moral education in curriculum and cultural activities are avenues for the prevention of school bullying. The implementation of both religious education and civic education encouraged the creation of values among students. In Indonesia, current interventions should be continued and must be modified to respond with societal changes.

Revitalizing previously treated teeth with open apices: A case report and a literature review.

Revitalizing the root canals of previously treated teeth with open apices is appealing to clinicians and patients. However, there are fundamental differences in the microbiome and the microenvironment between a canal with a primary endodontic infection and a canal with a persistent endodontic infection. The aims of this report are to report a case where a previously treated tooth with an open apex and a large apical radiolucency was treated successfully using regenerative endodontic treatment (RET) and to review and critically appraise the literature on procedures and outcomes of RET that result in revitalization of canal(s) in previously treated teeth with open apices. A maxillary central incisor with poor-quality root filling, a large apical radiolucency and an open apex was retreated using RET using platelet-rich fibrin as the scaffold. After 24 months, there was complete healing of the periapical lesion and obvious radiographic signs of apical root closure. Electronic searches were performed in MEDLINE, Scopus and Embase, and the baseline, procedural and outcome data of qualified articles were collected. An assessment tool was developed to rate the quality of evidence reported in these case report/series. Nine articles, three case series and six case reports, with a total of 17 teeth of all types, were included in the reports identified. The age of patients ranged from 7 to 48 years (mean: 19.4 years). The recall period ranged from 12 to 72 months (mean: 29 months). All 17 teeth survived and were functional with healing/healed outcomes. "Apical closure" was the most common radiographic finding regarding root development. The quality of evidence using the new assessment tool was rated "Excellent" in three case reports but only "Fair" in the other six articles. The present case report, as well as the review of the literature, suggests that revitalizing the root canal system of teeth with open apices and post-treatment disease using RET is a potentially valid treatment option. However, more clinical studies with higher levels of evidence and higher quality of evidence are required to confirm the viability of this treatment approach.