Miracle-dz/UniFAR-FTUs huggingface dataset:
Hands‐on radiotherapy: Inspiring the next generation of STEM students

Dear Editor, We read with interest the article by Fagerstrom et al. which explored an outreach project aimed at increasing awareness of the role of medical physicists amongst middle school students. Despite being medical students in our penultimate year of study in the UK, we have incredibly limited knowledge of careers involving medical physics and radiation therapy. Only within the last few months have we had our first interactions with these healthcare professionals. We believe that this is an area of medicine which is poorly covered, if not absent, in the university curriculum, let alone at middle school level. On reflection, we feel it is of limited utility to discover the existence of these career opportunities at such a late stage in our education. If we had known about such career opportunities at a younger age, we may have considered them when applying to university; therefore, the outreach project produced by Fagerstrom et al. should be commended, and we would like to see this approach replicated both nationally and internationally. The concept of bringing undergraduate level education into the school classroom has already been explored in the UK. Authentic Biology is a program which has established student‐led undergraduate‐level research projects in seven schools across the UK, with the aim of inspiring the next generation of biomedical researchers. With funding from the Wellcome Trust, and through collaborations with local universities, this project has inspired students to consider medical research by allowing them to experience these careers before enrolling on a university course. Though aimed at slightly older students (16–18‐year‐old) this project doubled the percentage of students interested in biological careers, and 65% of students involved in the initial project have continued to study STEM based courses. We feel that if the outreach project described by Fagerstrom et al. was further developed, it could have a similar impact on developing interest in careers in medical physics, by allowing students to “trial the job” as opposed to learning about it from a career's website. This approach has wider implications for the way in which we deliver careers advice to school students. A “hands‐on experience” of this kind is likely to be far more relevant and useful to students than an afternoon spent in the school counselor's office. We believe that more of these outreach projects should be instigated, to inspire the next generation of STEM students.
Dichlorinated and Brominated Rugulovasines, Ergot Alkaloids Produced by Talaromyces wortmannii

UHPLC-DAD-HRMS based dereplication guided the detection of new halogenated alkaloids co-produced by Talaromyces wortmannii. From the fungal growth in large scale, the epimers 2,8-dichlororugulovasines A and B were purified and further identified by means of a HPLC-SPE/NMR hyphenated system. Brominated rugulovasines were also detected when the microbial incubation medium was supplemented with bromine sources. Studies from 1D/2D NMR and HRMS spectroscopy data allowed the structural elucidation of the dichlorinated compounds, while tandem MS/HRMS data analysis supported the rationalization of brominated congeners. Preliminary genetic studies revealed evidence that FADH2 dependent halogenase can be involved in the biosynthesis of the produced halocompounds.
In vivo toxicity assays in zebrafish embryos: a pre-requisite for xenograft preclinical studies

Abstract The human cancer cell xenograft in zebrafish embryos has become a very useful preclinical tool in oncology research. While many anticancer drugs have been assayed with this model, few studies regarding the toxicity limits of these drugs for the host have been addressed. Here, we evaluated the acute toxicity of five approved and routinely used human anticancer drugs embracing different mechanism action types: Carboplatin (CarboPt), Irinotecan (IT), Doxorubicin (DOX), Paclitaxel (PT) and Chloroquine (CQ). They were tested in zebrafish embryos using the Fish Embryo Acute Toxicity (FET) test at 0 and 72 hours per fertilization (hpf). Additionally, we compared those results with in vitro toxicity assays and could find notable differences between both models. Our results indicate that the toxicity data of a compound evaluated in vitro and in a FET test at 0 hpf do not guarantee a reliable toxicity determination for performing xenografts in zebrafish, being necessary additional toxicity studies using 72 hpf embryos, the starting point of drug treatment in this kind of preclinical assays.
Expression of CD1d by astrocytes corresponds with relative activity in multiple sclerosis lesions

The CD1 protein family present lipid antigens to the immune system. CD1d has been observed in the CNS of MS patients, yet no studies have quantitatively characterized this expression and related it to inflammatory demyelinative activity in MS plaques. In this study, we set out to localize and quantify the presence of CD1d expression by astrocytes in MS brain tissue lesions. Formalin‐fixed, paraffin‐embedded MS and control brain tissues were examined. Lesions were classified as active, chronic active or chronic silent. Using immunofluorescence, the density of CD1d‐positive cells was determined in active lesions, chronic active lesion edges and chronic active lesion centers. The percentage of CD1d‐positive cells that were GFAP‐positive was also determined in each of these regions. CD1d immunoreactivity was significantly increased in MS compared to control tissue, was significantly more prevalent in areas of active demyelination, and colocalized with GFAP‐positive reactive astrocytes. Increases of CD1d immunoreactivity in the CNS of MS patients being greatest in areas of active demyelination and localized to GFAP‐positive astrocytes lend support to the hypothesis of a lipid‐targeted autoimmune process contributing to the pathogenesis of MS.
The Osteogenic Study of Tissue Engineering Bone with BMP2 and BMP7 Gene-Modified Rat Adipose-Derived Stem Cell

To evaluate the feasibility and advantages of constructing a novel tissue engineering bone, using β-tricalcium phosphate (β-TCP) and rat adipose-derived stem cells (ADSCs), modified with BMP2 and BMP7 by lentivirus. In the present study, ADSCs transfected with Lv-BMP2 and Lv-BMP7, alone or together, were seeded on β-TCP scaffold and cultured in vitro. Based on the results of DNA assay, alkaline phosphatase (ALP) activity, alizarin red staining and osteogenic marker genes expression analysis, the BMP2 and BMP7 genes cotransfection group exhibited a higher degree of osteogenic differentiation in vitro. To investigate the in vivo osteogenesis of the tissue engineering bone, the ADSCs/β-TCP constructs were implanted in rat femurs defects for 6 weeks and studied histomorphology and radiography. The results showed that BMP2 and BMP7 genes cotransfection group dramatically enhanced the efficiency of new bone formation than BMP2 group and BMP7 group in vivo. These results demonstrated that it was advantageous to construct tissue engineering bone using ADSCs cotransfected with BMP2 and BMP7 on β-TCP, providing a potential way for treating bone defects.
Waterpipe tobacco smoke distresses cardiovascular biomarkers in mice: alterations in protein expression of metalloproteinases, endothelin and myeloperoxidase

Abstract Introduction: Tobacco use is a major risk factor of cardiovascular diseases (CVD) and atherosclerosis in particular. The use of waterpipe smoking (WPS) is increasing due to the misperception that it is less harmful than cigarette smoking due to its flavor and the use of water as a filter. Thus, research that investigates toxic effects of WPS is essential. The aim of this study was to investigate the effect of WPS on major cardiovascular biomarkers that may develop atherosclerosis in mice. Methods: BALB/c mice were exposed to WPS for either two weeks (acute exposure) or eight weeks (chronic exposure). Then, the heart tissue homogenates were analyzed to elucidate the effects of WPS on matrix metalloproteinase (MMPs: isoforms 1, 3, and 9), metallopeptidase inhibitor (TIMP1), endothelin-1 (ET-1) and myeloperoxidase (MPO) using ELISA technique. Results: Current data showed that acute exposure to WPS significantly enhanced the levels of MMP-3, MMP-9, and MPO (p < 0.05) compared to their corresponding control. However, the body was capable to restore the increased levels of these parameters following chronic exposure to WPS for 8 weeks (p > 0.05). Additionally, the levels of ET-1 were significantly higher upon chronic exposure to WPS compared to both control and acute exposure groups (p < 0.05). Conclusions: Waterpipe exposure has a significant negative effect on the cardiovascular system. The enhancement of the atherosclerotic biomarkers (MMP-3, MMP-9, MPO, and ET-1) might represent an early scavenger of compensatory efforts to maintain cardiovascular function after WPS exposure.
Biological Activities of Bacteroides forsythus Lipoproteins and Their Possible Pathological Roles in Periodontal Disease

ABSTRACT Bacteroides forsythus is a gram-negative, anaerobic, fusiform bacterium and is considered to be an etiological agent in periodontal disease. A lipoprotein fraction prepared from B. forsythus cells by Triton X-114 phase separation (BfLP) activated human gingival fibroblasts and a human monocytic cell line, THP-1, to induce interleukin-6 production and tumor necrosis factor alpha production. BfLP was found to be capable of inducing nuclear factor-κB translocation in human gingival fibroblasts and THP-1 cells. By using Chinese hamster ovary K1 cells transfected with Toll-like receptor genes together with a nuclear factor-κB-dependent CD25 reporter plasmid, it was found that signaling by BfLP was mediated by Toll-like receptor 2 but not by CD14 or Toll-like receptor 4. BfLP induced apoptotic cell death in human gingival fibroblasts, KB cells (an oral epithelial cell line), HL-60 cells (a human myeloid leukemia cell line), and THP-1 cells but not in MOLT4 cells (a T-cell leukemia cell line). Caspase-8, an initiator caspase in apoptosis, was found to be activated in these cells in response to BfLP stimulation. Thus, this study suggested that BfLP plays some etiological roles in oral infections, especially periodontal disease, by induction of cell activation or apoptosis.
Coexpression of ABCB1 and ABCG2 in a Cell Line Model Reveals Both Independent and Additive Transporter Function

Although overexpression of multiple ATP-binding cassette transporters has been reported in clinical samples, few studies have examined how coexpression of multiple transporters affected resistance to chemotherapeutic drugs. We therefore examined how coexpression of ABCB1 (P-glycoprotein) and ABCG2 contributes to drug resistance in a cell line model. HEK293 cells were transfected with vector-encoding full-length ABCB1, ABCG2, or a bicistronic vector containing both genes, each under the control of a separate promoter. Cells transfected with both transporters (B1/G2 cells) demonstrated high levels of both transporters, and uptake of both the ABCB1-specific substrate rhodamine 123 and the ABCG2-specific substrate pheophorbide a was reduced when examined by flow cytometry. B1/G2 cells were also cross-resistant to the ABCB1 substrate doxorubicin, the ABCG2 substrate topotecan, as well as mitoxantrone and the cell cycle checkpoint kinase 1 inhibitor prexasertib, both of which were found to be substrates of both ABCB1 and ABCG2. When B1/G2 cells were incubated with both rhodamine 123 and pheophorbide a, transport of both compounds was observed, suggesting that ABCB1 and ABCG2, when coexpressed, can function independently to transport substrates. ABCB1 and ABCG2 also functioned additively to transport the common fluorescent substrates mitoxantrone and BODIPY-prazosin, as it was necessary to inhibit both transporters to prevent efflux from B1/G2 cells. ABCG2 expression was also found to decrease the efficacy of the ABCB1 inhibitor tariquidar in B1/G2 cells. Thus, ABCB1 and ABCG2 can independently and additively confer resistance to substrates, underscoring the need to inhibit multiple transporters when they are coexpressed.
An Efficient Algorithm for Computing Optimal (s, S) Policies

This paper presents an algorithm to compute an optimal s, S policy under standard assumptions stationary data, well-behaved one-period costs, discrete demand, full backlogging, and the average-cost criterion. The method is iterative, starting with an arbitrary, given s, S policy and converging to an optimal policy in a finite number of iterations. Any of the available approximations can thus be used as an initial solution. Each iteration requires only modest computations. Also, a lower bound on the true optimal cost can be computed and used in a termination test. Empirical testing suggests very fast convergence.
Detergent‐free caveolae proteome suggests an interaction with ER and mitochondria

Recent proteomic studies of detergent resistant membrane fractions have begun to characterize the protein composition of caveolae and lipid rafts. The methods used in most of these studies, however, are not able to distinguish between plasma membrane and internal membrane lipid domains. Here we used a non‐detergent method for obtaining fractions enriched in caveolae derived from the plasma membrane of multiple cell types. Unexpectedly, the proteins in the caveolae proteome suggest these lipid domains may interact with elements of ER and mitochondria. A comparison of the partial proteome we obtained with other published reports identifies 26 proteins that are candidate marker proteins for identifying caveolae in multiple cell types.
Skin Barrier Homeostasis in Atopic Dermatitis: Feedback Regulation of Kallikrein Activity

Atopic dermatitis (AD) is a widely spread cutaneous chronic disease characterised by sensitive reactions (eg. eczema) to normally innocuous elements. Although relatively little is understood about its underlying mechanisms due to its complexity, skin barrier dysfunction has been recognised as a key factor in the development of AD. Skin barrier homeostasis requires tight control of the activity of proteases, called kallikreins (KLKs), whose activity is regulated by a complex network of protein interactions that remains poorly understood despite its pathological importance. Characteristic symptoms of AD include the outbreak of inflammation triggered by external (eg. mechanical and chemical) stimulus and the persistence and aggravation of inflammation even if the initial stimulus disappears. These characteristic symptoms, together with some experimental data, suggest the presence of positive feedback regulation for KLK activity by inflammatory signals. We developed simple mathematical models for the KLK activation system to study the effects of feedback loops and carried out bifurcation analysis to investigate the model behaviours corresponding to inflammation caused by external stimulus. The model analysis confirmed that the hypothesised core model mechanisms capture the essence of inflammation outbreak by a defective skin barrier. Our models predicted the outbreaks of inflammation at weaker stimulus and its longer persistence in AD patients compared to healthy control. We also proposed a novel quantitative indicator for inflammation level by applying principal component analysis to microarray data. The model analysis reproduced qualitative AD characteristics revealed by this indicator. Our results strongly implicate the presence and importance of feedback mechanisms in KLK activity regulation. We further proposed future experiments that may provide informative data to enhance the system-level understanding on the regulatory mechanisms of skin barrier in AD and healthy individuals.
Chemical vapor deposition grown graphene DNA field-effect transistor biosensor with gold nanoparticles signal amplification

This paper presents a graphene-based bio-field-effect transistor (bioFET) for the detection of avian influenza A virus subtype H7 gene. This bioFET was realized by directly assembling capture probes on graphene surface via n-n stacking interaction. The extended long capture probes is a simple and stable biofunctionalization strategy. Reporter probes conjugated to AuNPs were then applied to hybridize with H7 target in a sandwich assay format for signal amplification. Transfer curves were recorded to demonstrate the improved analytical performance with AuNPs-reporter probes signal amplification. This bioFET biosensor exhibited lower limit of detect (LOD) of 64 fM, which is yet the lowest among other graphene-based bioFET for DNA detection.
Correlates of HIV-infection among men who have sex with men: results from a community-based, cross-sectional study in Tianjin, China

ABSTRACT China has 747,000 confirmed HIV/AIDS cases and sexual transmission between men who have sex with men (MSM) is the most prevalent mode of transmission. Our study aims to (a) examine HIV prevalence and behavioral risk factors for HIV infection among 1900 MSM recruited from a community-based organization in Tianjin, China, and (b) describe HIV treatment outcomes for those diagnosed with HIV. We used multivariable logistic regression to identify which socio-demographics and behaviors were associated with HIV infection. The overall HIV prevalence was 3.95%. Key behavioral risk factors included: receptive sex role, older age at first sex with man, condomless anal sex, and having used 2+ drugs. Of those living with HIV, 83% were successfully enrolled in antiretroviral therapy and those enrolled were all virally suppressed after one year. These findings highlight key behavioral risk factors for HIV infection in Tianjin, China and can inform interventions to preventing further HIV transmission.
A Randomized Controlled Study Comparing the Efficacy of Topical 5% Tranexamic Acid Solution versus 3% Hydroquinone Cream in Melasma

Background and Aims: Melasma is a common, relapsing, acquired, symmetrical facial hypermelanosis with no universally effective therapy. Hydroquinone (HQ) is considered the gold standard in the treatment of melasma till date. Tranexamic acid (TA) is an upcoming molecule being explored in melasma therapy and has shown optimistic results in preliminary trials. This study aimed to compare the efficacy of topical 5% TA solution with 3% HQ cream in the treatment of melasma in Indian skin. Material and Methods: This was a prospective, randomized, single-blind study of 12 weeks’ duration. Hundred eligible patients randomly divided into two intervention groups were analyzed after screening 346 patients with melasma. Serial photographs, Melasma Area Severity Index (MASI), and adverse effects were documented at monthly intervals. Patient satisfaction score was noted at the end of 12 weeks. A repeated measurement analysis of variance, independent t-test, and χ2 tests were used for statistical analysis. A P-value of <0.05 was considered to be statistically significant. Results: Our study population consisted of 84 females and 16 males. Mixed melasma had the highest prevalence (63%) followed by epidermal (22%) and dermal types (15%). Percentage reduction of MASI was 27% and 26.7% in the TA and HQ group, respectively, at the end of 12 weeks, and the difference between the two groups was not significant (P > 0.05). However, patient satisfaction score was significantly higher in TA group (P value = 0.03) in view of lesser adverse effects. Conclusions: Topical 5% TA solution is as effective as 3% HQ cream in melasma with enhanced patient satisfaction.
Protocol Speci cation and Analysis in Maude

This paper proposes rewriting logic as an executable speciication formalism for security protocols that ooers some novel advantages. A message-passing object-oriented approach seems particularly natural for communication protocols and can be naturally formalized in rewriting logic. This is illustrated by using the Needham-Schroeder Public-Key protocol as a running example. The rewriting logic-based Maude interpreter CELM96] offers also some useful advantages. EEcient executability allows prototyping and debugging of protocol speciications. But since a concurrent system can have many diierent behaviors, to properly analyze the system it becomes important to explore not just the single execution provided by some default strategy, but many other executions. Maude supports user-deened execution strategies, including strategies such as breadth-rst-search that can exhaustively explore all the executions of a system. This is very helpful in uncovering security aws under unforeseen attack scenarios such as those found for NSPK. We also discuss future developments along of this work, including (1) narrowing using symbolic execution techniques, (2) modularity and compositionality issues in formal reasoning, and (3) combination of rewriting logic and temporal logic.
Knowledge, attitude and practices of clinical quality and performance assessment among emergency medical services personnel in South Africa: A mixed methods study

Deficits in healthcare quality are becoming an increasing concern globally. Within the low‐ to middle‐income country (LMIC) setting insufficient quality has become a bigger barrier to reducing mortality than insufficient access, where 60% of deaths from conditions amenable to healthcare, are due to poor quality care. Measuring quality is key towards improving the effectiveness of healthcare in this setting.
p53 shapes genome-wide and cell type-specific changes in microRNA expression during the human DNA damage response

The human DNA damage response (DDR) triggers profound changes in gene expression, whose nature and regulation remain uncertain. Although certain micro-(mi)RNA species including miR34, miR-18, miR-16 and miR-143 have been implicated in the DDR, there is as yet no comprehensive description of genome-wide changes in the expression of miRNAs triggered by DNA breakage in human cells. We have used next-generation sequencing (NGS), combined with rigorous integrative computational analyses, to describe genome-wide changes in the expression of miRNAs during the human DDR. The changes affect 150 of 1523 miRNAs known in miRBase v18 from 4–24 h after the induction of DNA breakage, in cell-type dependent patterns. The regulatory regions of the most-highly regulated miRNA species are enriched in conserved binding sites for p53. Indeed, genome-wide changes in miRNA expression during the DDR are markedly altered in TP53-/- cells compared to otherwise isogenic controls. The expression levels of certain damage-induced, p53-regulated miRNAs in cancer samples correlate with patient survival. Our work reveals genome-wide and cell type-specific alterations in miRNA expression during the human DDR, which are regulated by the tumor suppressor protein p53. These findings provide a genomic resource to identify new molecules and mechanisms involved in the DDR, and to examine their role in tumor suppression and the clinical outcome of cancer patients.