Miracle-dz/UniFAR-FTUs huggingface dataset:
Does Addition of Protein to Hepatocyte or Microsomal In Vitro Incubations Provide a Useful Improvement in In Vitro-In Vivo Extrapolation Predictability?

Accurate prediction of in vivo hepatic clearance is an essential part of successful and efficient drug development; however, many investigators have recognized that there are significant limitations in the predictability of clearance with a tendency for underprediction for primarily metabolized drugs. Here, we examine the impact of adding serum or albumin into hepatocyte and microsomal incubations on the predictability of in vivo hepatic clearance. The addition of protein into hepatocyte incubations has been reported to improve the predictability for high clearance (extraction ratio) drugs and highly protein-bound drugs. Analyzing published data for 60 different drugs and 97 experimental comparisons (with 17 drugs being investigated from two to seven) we confirmed the marked underprediction of clearance. However, we could not validate any relevant improved predictability within twofold by the addition of serum to hepatocyte incubations or albumin to microsomal incubations. This was the case when investigating all measurements, or when subdividing analyses by extraction ratio, degree of protein binding, Biopharmaceutics Drug Disposition Classification System class, examining Extended Clearance Classification System class 1B drugs only, or drug charge. Manipulating characteristics of small data sets of like compounds and adding scaling factors can appear to yield good predictability, but the carryover of these methods to alternate drug classes and different laboratories is not evident. Improvement in predictability of poorly soluble compounds is greater than that for soluble compounds, but not to a meaningful extent. Overall, we cannot confirm that protein addition improves in vitro-in vivo extrapolation predictability to any clinically meaningful degree when considering all drugs and different subsets. SIGNIFICANCE STATEMENT The addition of protein into microsomal or hepatocyte incubations has been widely proposed to improve hepatic clearance predictions. To date, studies examining this phenomenon have not included appropriate negative controls where predictability is achieved without protein addition and have been conducted with small data sets of similar compounds that don’t apply to alternate drug classes. Here, an extensive analysis of published data for 60 drugs and 97 experimental comparisons couldn’t validate any relevant clinically improved clearance predictability with protein addition.
Calibration Approach Study for the Laser Camera Transducer of Track Inspection

Utilizing laser and camera for track geometry inspection,calibration approach for laser photogrammetric transducers is a key issue.The calibration models constructed by the nonlinear least-square method and Gaussian-Newton optimization computational method are presented respectively.The transducer measurement models parameters are acquired by the above-mentioned approaches making use of 200 individual data in the checkerboard plane by the dedicated test platform.Moreover,the other 200 individual data are added for different algorithms calibration errors analysis.The experimental results show that Gaussian-Newton algorithm is more accurate than the nonlinear least-square algorithm in camera calibration.The horizontal and vertical accuracy can improve 1.55 mm and 1.50 mm by use of Gaussian-Newton algorithm.While using laser photogrammetric transducers in track inspection vehicle,Gaussian-Newton calibration algorithm is proposed.Track gauge and bogie tilting angle computational formulations are given by Gaussian-Newton algorithm in the track inspection system.
Patient‐individual phenotypes of glioblastoma stem cells are conserved in culture and associate with radioresistance, brain infiltration and patient prognosis

Identification of prognostic or predictive molecular markers in glioblastoma resection specimens may lead to strategies for therapy stratification and personalized treatment planning. Here, we analyzed in primary glioblastoma stem cell (pGSC) cultures the mRNA abundances of seven stem cell (MSI1, Notch1, nestin, Sox2, Oct4, FABP7 and ALDH1A3), and three radioresistance or invasion markers (CXCR4, IKCa and BKCa). From these abundances, an mRNA signature was deduced which describes the mesenchymal‐to‐proneural expression profile of an individual GSC culture. To assess its functional significance, we associated the GSC mRNA signature with the clonogenic survival after irradiation with 4 Gy and the fibrin matrix invasion of the GSC cells. In addition, we compared the molecular pGSC mRNA signature with the tumor recurrence pattern and the overall survival of the glioblastoma patients from whom the pGSC cultures were derived. As a result, the molecular pGSC mRNA signature correlated positively with the pGSC radioresistance and matrix invasion capability in vitro. Moreover, patients with a mesenchymal (>median) mRNA signature in their pGSC cultures exhibited predominantly a multifocal tumor recurrence and a significantly (univariate log rank test) shorter overall survival than patients with proneural (≤median mRNA signature) pGSCs. The tumors of the latter recurred predominately unifocally. We conclude that our pGSC cultures induce/select those cell subpopulations of the heterogeneous brain tumor that determine disease progression and therapy outcome. In addition, we further postulate a clinically relevant prognostic/predictive value for the 10 mRNAs‐based mesenchymal‐to‐proneural signature of the GSC subpopulations in glioblastoma.
Design and deployment of a monitoring sensor for enterprise's networks

Enterprise’s computers that are connected to the Internet are often targets for attacks and need to be protected. Using sensors, a network security monitoring system can collect traffic patterns from different locations in the network, analyze them and give indications of possible network attacks. However, it is still not clear how a sensor can be designed and how can the sensors be managed. This paper presents an approach for modeling a security monitoring sensor within an enterprise’s network. We present an overall architecture of a sensor as well as a model for anomaly traffic behaviour detection and show possible applications to anomaly traffic detection and quality of service monitoring. Index Terms – Network Security Monitoring, Anomaly Traffic Detection, Quality of Service Monitoring.
Biotransformation Enables Innovations toward Green Synthesis of Steroidal Pharmaceuticals.

Steroids have been widely used in birth-control, prevention and treatment of various diseases, representing the largest sector after antibiotics in the global pharmaceutical market. The steroidal active pharmaceutical ingredients (APIs) have been produced via partial synthetic processes first mainly from sapogenins, which was converted into 16-dehydropregnenolone by the famous "Marker Degradation". Traditional mutation and screening, and process engineering have resulted in the industrial production of 4-androstene-3,17-dione (AD), androst-1,4-diene-3,17-dione (ADD), 9a-hydroxy-androsta-4-ene-3,17-dione (9a-OH-AD), etc., which serve as the key intermediates for the synthesis of steroidal APIs. Recently, genetic and metabolic engineering have generated highly efficient microbial strains for the production of these precursors, leading to the replacement of sapogenins with phytosterols as the starting materials. Further advances in synthetic biology hold promise in the design and construction of microbial cell factories for the industrial production of steroidal intermediates and/or APIs from simple carbon sources such as glucose. Integration of biotransformation into the synthesis of steroidal APIs can greatly reduce the number of reaction steps, achieve lower waste discharge and higher production efficiency, thus enabling a greener steroidal pharmaceutical industry.
Impact of supplemental essential phospholipids on treatment outcome and quality of life of patients with psoriasis with moderate severity

Aim of this study was to evaluate effect of supplemental of essential phospholipids (EPL) on the treatment efficacy in patients with moderate psoriasis. One hundred and thirty‐two subjects over 18 years of age with diagnosed psoriasis participated in this study. Patients were randomly assigned two treatment groups. Two types of treatment were used for the treatment of the patients. First group of patients received conventional treatment which included systemic immunosuppressant, antihistamine, calcium gluconate, and topical salicylic acid. Second group (n = 67) received same treatment with supplemental EPL. Data was comprised of age, gender, psoriasis area and severity index (PASI) and dermatological life quality index (DLQI) scores, other clinical/laboratory characteristics including TNF‐α, IL‐1α, IL‐2, INF‐γ, IL‐10, and TGF‐β. All measurements were done before and after treatments. After treatment in the treatment groups the PASI scores decreased to 4.5 (SD ± 2.66) and 2.09 (SD ± 1.09) respectively. The observed difference was statistically significant (p < 0.001). Change of PASI score was greater in group II on average by 2.81 (SD ± 0.38). After treatment in both groups the DLQI scores decreased to 4.42 (SD ± 1.23) and 3.91 (SD ± 0.34), respectively. The observed difference was statistically significant (p < 0.001). Change of DLQI score was greater in group II on average by 4.29 (SD ± 0.44). We can state that addition of EPL to the standard treatment can improve treatment outcomes and quality of life in patients with moderate psoriasis.
From Gondwana to the Yellow Sea, evolutionary diversifications of true toads Bufo sp. in the Eastern Palearctic and a revisit of species boundaries for Asian lineages

Taxa with vast distribution ranges often display unresolved phylogeographic structures and unclear taxonomic boundaries resulting in hidden diversity. This hypothesis-driven study reveals the evolutionary history of Bufonidae, covering the phylogeographic patterns found in Holarctic bufonids from the West Gondwana to the phylogenetic taxonomy of Asiatic true toads in the Eastern Palearctic. We used an integrative approach relying on fossilized birth-death calibrations, population dynamics, gene-flow, species distribution, and species delimitation modeling to resolve the biogeography of the clade and highlight cryptic lineages. We verified the near-simultaneous Miocene radiations within Western and Eastern Palearctic Bufo, c. 14.49–10.00 Mya, temporally matching with the maximum dust outflows in Central Asian deserts. Contrary to earlier studies, we demonstrated that the combined impacts of long dispersal and ice-age refugia equally contributed to the current genetic structure of Bufo in East Asia. Our findings reveal a climate-driven adaptation in septentrional Eastern Asian Bufo, explaining its range shifts toward northern latitudes. We resolve species boundaries within the Eastern Palearctic Bufo, and redefine the taxonomic and conservation units of the northeastern species: B. sachalinensis and its subspecies.
Single-cell atlas of early chick development reveals gradual segregation of neural crest lineage from the neural plate border during neurulation

The epiblast of vertebrate embryos is comprised of neural and non-neural ectoderm, with the border territory at their intersection harboring neural crest and cranial placode progenitors. Here, we a generate single-cell atlas of the developing chick epiblast from late gastrulation through early neurulation stages to define transcriptional changes in the emerging ‘neural plate border’ as well as other regions of the epiblast. Focusing on the border territory, the results reveal gradual establishment of heterogeneous neural plate border signatures, including novel genes that we validate by fluorescent in situ hybridization. Developmental trajectory analysis infers that segregation of neural plate border lineages only commences at early neurulation, rather than at gastrulation as previously predicted. We find that cells expressing the prospective neural crest marker Pax7 contribute to multiple lineages, and a subset of premigratory neural crest cells shares a transcriptional signature with their border precursors. Together, our results suggest that cells at the neural plate border remain heterogeneous until early neurulation, at which time progenitors become progressively allocated toward defined neural crest and placode lineages. The data also can be mined to reveal changes throughout the developing epiblast.
Exploring Uniformity of Clinical Judgment: A Vignette Approach to Understanding Healthcare Professionals’ Suicide Risk Assessment Practices

Objectives Suicide risk assessment often requires health professionals to consider a complex interplay of multiple factors, with a significant reliance on judgment, which can be influenced by factors such as education and experience. Our study aimed at assessing the uniformity of decision making around suicide risk within healthcare professionals. Methods We used a factorial survey approach to gather information on healthcare professionals’ demographics, clinical experience, and their decision on 3 vignettes of patients with suicidal ideation. We used Kruskal-Wallis tests for determining if there were significant differences between groups for continuous variables and Spearman rank correlation for measuring the association between continuous variables. Content analysis was used for analyzing free-text comments. Results Responses were gathered from 79 healthcare professionals (nurses, nurse practitioners, physicians) who worked in primary care, mental health, or emergency department settings. Median suicide risk rates across all respondents were 90%, 50%, and 53% for vignettes 1, 2, and 3, respectively. Confidence in healthcare professionals’ decisions was significantly associated with the clinical designation and personal risk profile of the healthcare professional in certain vignettes, with nurses and those willing to take more risks having a higher confidence in their decisions for vignettes 1 and 3, respectively. Treatment decision was significantly associated with mental health experience (i.e., those with lengthier mental health experiences were less likely to choose “admit to psychiatry ward” for vignette 2), clinical designation (i.e., nurses were more likely to “admit to psychiatry ward” for vignette 1), and practice setting. It should be noted that these associations were not consistent across all 3 vignettes, and results for each association were only specific to 1 of the 3 vignettes. Discussion Findings compare decision-making practices for suicide risk assessment across several types of healthcare professions over a range of practice settings, with the high-risk vignette showing the least variability. Insights from this study are relevant when building clinical decision support systems for suicide risk assessment. Designers should think about incorporating tailored messaging and alerts to health professionals’ mental health experience and/or designation. Conclusions Within our Canadian sample, there was considerable variability among healthcare professionals assessing the risk of suicide, with important implications for tailoring education and decision support.
Whole exome sequencing studies in epilepsy: A deep analysis of the published literature

To evaluate the quality of whole‐exome sequencing (WES) reporting in the epilepsy literature. We aimed to assess the quality of reporting of WES in epilepsy. We compared studies based on journal type and if outcome reporting biases exist. We used a self‐constructed benchmark to quantitatively analyze studies. We included 451 publications. Reporting was heterogeneous with poor reporting of (1) ACMG guideline application 13% and (2) Human Phenotype Ontology (HPO) numbers in 3% of studies, 3) VUS in 19%. Predictors of reporting included journal type and journal impact factor. Date of publication and publication type were not predictors of poor reporting. Pairwise comparisons of genetics versus neurology journals using relative risks yielded significant differences in reporting of ACMG guideline application (RR 1.88, 95% CI 1.04–3.38); HPO numbers (RR 8.62, 95% CI 1.08–63.37) and deposition of findings to ClinVar (RR 2.50, 95% CI 1.03–6.1). Reporting of WES literature is heterogeneous in quality, and poor reporting hinders collaboration and accession of data into large databases like OMIM and OrphaNet. This study highlights reporting bias in this area and, formal structural guidelines like the CONSORT guidelines used in the reporting of clinical trials are needed to address the issue.
Postoperative anti-inflammatory efficacy of 2% saline rinses and a herbal- mouthwash after non-surgical periodontal therapy for the management of periodontal inflammation in young adults with chlorhexidine allergy: A randomized controlled trial.

AIM The present randomized controlled trial assessed the postoperative anti-inflammatory efficacy of 2% saline rinses (SR) and a herbal- mouthwash (HMW) after non-surgical periodontal therapy (NSPT) for the management of periodontal inflammation in patients with chlorhexidine (CHX) allergy. MATERIALS AND METHODS Patients with periodontal inflammation with and without self-reported CHX-allergy were included. All patients underwent non-surgical periodontal therapy (NSPT). Patients were randomly divided into three groups. In the SR and HMW groups, 2% SR, and a HMW, respectively were prescribed. In Group-3 (CHX-group), patients without CHX allergy were included and were prescribed 0.12% CHX. In all groups, plaque index (PI), gingival index (GI), probing depth (PD), clinical attachment loss (AL) and marginal bone loss were measured at baseline. Clinical periodontal parameters were re-assessed at 6-weeks' follow-up. P<0.01 were considered statistically significant. RESULTS Thirteen, 12 and 12 patients were included in the SR, HMW and CHX groups, respectively. At baseline clinical and radiographic periodontal parameters were comparable in all groups. In all groups, PI (P<0.01), GI (P<0.01) and PD (P<0.01) were significantly higher at baseline compared with their respective values at 6-weeks of follow-up. There was no significant difference in clinical AL at all time intervals in all groups. There was no significant correlation between periodontal parameters and age, gender and daily toothbrushing/flossing in all groups. CONCLUSION In young adults with self-reported CHX-allergy, herbal-mouthwashes and/or 2% SR are suitable postoperative prescriptions after NSPT.
Ocular signs, visual and general developmental outcome in Indian children with radiologically proven periventricular leukomalacia

Purpose: Owing to the paucity of literature on Indian children with periventricular leukomalacia (PVL), this retrospective study aimed to describe the visual and associated developmental abnormalities in a series of affected children attending a tertiary level eye care facility. Methods: Children with radiologically confirmed PVL who attended the Pediatric Department of a tertiary eye hospital were included and underwent a detailed ocular and general developmental assessment. Results: Of the 75 children, the mean age was 2.3 years, the mean follow-up was 3.1 years, 68% were males and 43% were born preterm. Grade I PVL was identified in 13 children (17%), Grade 2 PVL in 39 (52%), and Grade 3 PVL in 23 (31%). Premies with ≤2 kg (72.5%) and term babies with >2 kg (75%) had a greater association of PVL occurrence with a preponderance to severe PVL; 46% of the children were visually impaired which was significantly higher in the children with Grade 3 PVL (74%) than those with Grade 2 PVL (15%). Strabismus was common (80%) with a change in deviation over time. Seventy-one percent of the children had a refractive error, frequently myopic astigmatism. All the children except two had a delay in one or more general developmental milestones. Conclusion: PVL occurrence is observed both in the babies born at term and premies, resulting in significant ocular and systemic morbidities. We recommend a system in place for early identification and referral to initiate an early intervention program which goes a long way toward improving the quality of life in these children.
Impact of prior infection status on antibody response to the BNT162b2 mRNA COVID-19 vaccine in healthcare workers at a COVID-19 referral hospital in Milan, Italy

ABSTRACT In Italy, SARS-CoV-2 vaccination campaign prioritized healthcare workers (HCWs) to receive two doses of BNT162b2 vaccine, irrespective of a previous SARS-CoV-2 infection. In this real-life study, we compared the humoral response to BNT162b2 vaccine in HCWs with and without a previous SARS-CoV-2 infection. Of the 407 HCWs enrolled, 334 (82.1%) were SARS-CoV-2-naive and 73 (17.9%) SARS-CoV-2-experienced. Post-vaccine humoral response was detectable in more than 98% of HCWs. Overall, the median level of anti-S IgG in SARS-COV-2-experienced HCWs was twice as high as those of SARS-CoV-2-naive subjects (24641.0 AU/mL [IQR: 15273.0–>40000.0] versus 13053.8 [IQR: 7303.3–20105.8]; p < .001), irrespective of the time elapsed from SARS-CoV-2 previous infection. In a subgroup of SARS-CoV-2-naive and -experienced subjects who received only one dose of the vaccine, the latter showed 32 times higher levels of anti-S IgG compared to the former. Although no serious adverse events have been reported, mild to moderate side effects occurred more frequently after the first dose in the SARS-CoV-2-experienced than in naive subjects (67% versus 42%, respectively; p < .001). Notably, post-vaccination anti-SARS-CoV-2 spike IgG levels ≥20,000 AU/mL were independently associated with the risk of fever ≥38°C (adjusted odds ratio [aOR] 5.122, 95% CI 2.368–11.080, p < .0001). Our study showed high responsiveness of BNT162b2 vaccine and a relationship between levels of antibody response and reactogenicity. It suggests that a single dose of mRNA vaccine might evoke effective protection in SARS-CoV-2-experienced subjects.
Splice variants denote differences between a cancer stem cell side population of EWSR1-ERG-based Ewing sarcoma cells, its main population and EWSR1-FLI-based cells

Ewing sarcoma is a challenging cancer entity, which, besides the characteristic presence of a fusion gene, is driven by multiple alternative splicing events. So far, splice variants in Ewing sarcoma cells were mainly analyzed for EWSR1-FLI1. The present study provided a comprehensive alternative splicing study on CADO-ES1, an Ewing model cell line for an EWSR1-ERG fusion gene. Based on a well- characterized RNA-sequencing dataset with extensive control mechanisms across all levels of analysis, the differential spliced genes in Ewing cancer stem cells were ATP13A3 and EPB41, while the main population was defined by ACADVL, NOP58 and TSPAN3. All alternatively spliced genes were further characterized by their Gene Ontology (GO) terms and by their membership in known protein complexes. These results confirm and extend previous studies towards a systematic whole-transcriptome analysis. A highlight is the striking segregation of GO terms associated with five basic splice events. This mechanistic insight, together with a coherent integration of all observations with prior knowledge, indicates that EWSR1-ERG is truly a close twin to EWSR1-FLI1, but still exhibits certain individuality. Thus, the present study provided a measure of variability in Ewing sarcoma, whose understanding is essential both for clinical procedures and basic mechanistic insight.