Miracle-dz/UniFAR-FTUs huggingface dataset:
Evaluation of efficacy on RANKL induced osteoclast from RAW264.7 cells

Established RAW264.7 cell lines for osteoclastic differentiation has been widely engaged in bone homeostasis research, however, the efficacy of RANKL independently stimulating has rarely been defined, because protocols were usually developed and modified by various laboratories. Otherwise, problematic issues are also lie in the cell's seeding density, RANKL stimulating time point, and distinguishing osteoclastogenesis ability of RANKL‐treated RAW264.7 cells. Therefore, in the current study, we examined the efficacy of various concentrations of RANKL‐treated RAW264.7 for its osteoclastic differentiation with or without pretreated other costimulators such as: LPS and/or M‐CSF. The oteoclastogenesis ability of RANKL‐treated RAW264.7 cells was demonstrated by bone resorption pit, F‐actin, and osteoclastogenesis specific marker studies. Besides that, through tartrate‐resistant acid phosphatase (TRAP) staining, we clarified to start the treatment with 30 ng/ml RANKL at 12 hr after seeded RAW264.7 with the density of 6.25 × 10 3 cells/cm 2 manifested an significantly increased number of multinucleated osteoclastic cells. Overall, our results establishing an optimal method for RANKL independently inducing RAW 264.7 cell osteoclastic differentiation, which could efficiently generate osteoclasts in vitro for significant advances in our understanding of bone biology.
The Paris System for Reporting Urinary Cytology: The Quest to Develop a Standardized Terminology

The main purpose of urine cytology is to detect high-grade urothelial carcinoma (HGUC). With this principle in mind, The Paris System (TPS) Working Group, composed of cytopathologists, surgical pathologists, and urologists, has proposed and published a standardized reporting system that includes specific diagnostic categories and cytomorphologic criteria for the reliable diagnosis of HGUC. This paper outlines the essential elements of TPS and the process that led to the formation and rationale of the reporting system. The Paris System Working Group, organized at the 2013 International Congress of Cytology, conceived a standardized platform on which to base cytologic interpretation of urine samples. The widespread dissemination of this approach to cytologic examination and reporting of urologic samples and the scheme's universal acceptance by pathologists and urologists is critical for its success. For urologists, understanding the diagnostic criteria, their clinical implications, and the limitations of TPS is essential if they are to utilize urine cytology and noninvasive ancillary tests in a thoughtful and practical manner. This is the first international/inclusive attempt at standardizing urinary cytology. The success of TPS will depend on the pathology and urology communities working collectively to improve this seminal paradigm shift, and optimize the impact on patient care.
Combined ultrasound and MR imaging to guide focused ultrasound therapies in the brain

Several emerging therapies with potential for use in the brain, harness effects produced by acoustic cavitation—the interaction between ultrasound and microbubbles either generated during sonication or introduced into the vasculature. Systems developed for transcranial MRI-guided focused ultrasound (MRgFUS) thermal ablation can enable their clinical translation, but methods for real-time monitoring and control are currently lacking. Acoustic emissions produced during sonication can provide information about the location, strength and type of the microbubble oscillations within the ultrasound field, and they can be mapped in real-time using passive imaging approaches. Here, we tested whether such mapping can be achieved transcranially within a clinical brain MRgFUS system. We integrated an ultrasound imaging array into the hemisphere transducer of the MRgFUS device. Passive cavitation maps were obtained during sonications combined with a circulating microbubble agent at 20 targets in the cingulate cortex in three macaques. The maps were compared with MRI-evident tissue effects. The system successfully mapped microbubble activity during both stable and inertial cavitation, which was correlated with MRI-evident transient blood–brain barrier disruption and vascular damage, respectively. The location of this activity was coincident with the resulting tissue changes within the expected resolution limits of the system. While preliminary, these data clearly demonstrate, for the first time, that it is possible to construct maps of stable and inertial cavitation transcranially, in a large animal model, and under clinically relevant conditions. Further, these results suggest that this hybrid ultrasound/MRI approach can provide comprehensive guidance for targeted drug delivery via blood–brain barrier disruption and other emerging ultrasound treatments, facilitating their clinical translation. We anticipate that it will also prove to be an important research tool that will further the development of a broad range of microbubble-enhanced therapies.
Microbiome yarns: The Global Phenotype‐Genotype Survey

Ms. Repor-Tastory: Ani, this evening we will discuss the results of the most ambitious human microbiome survey to date, and some subsequent trials designed to assess whether or not the correlations it uncovered reflect causalities. AND: we will discuss how couples intending to tie the knot are dealing with the knotty (sorry! ) problem of who owns what in terms of their microbiomes. Dr. Noitall-Most: Yes, Abi: this is indeed a perplexing issue that lawyers are cannily turning into a significant new revenue stream. But before we get into this, we need to inform viewers about recent commercial developments in the field of microbiome science, in order to provide important background.
Glutamate Supply and Metabolism in Infants

Glutamate (Glu) is the most abundant amino acid (AA) in human milk. Available information on Glu supply and metabolism was reviewed, based on an electronic literature search. In 22 cross-sectional global studies with 4,747 women, free Glu increases with lactation duration and contributes to about 38% of total and 63% of dispensable milk AA. Based on these data, a typical breastfed infant obtains a mean free Glu intake of 35.7 mg/kg body weight (bw; upper end of the normal range 134.6 mg/kg), while precisely collected longitudinal data indicate mean intakes of 40 mg/kg and upper range intakes of 70.2 mg/kg. Mean intakes with cows’ milk formula at median concentrations are 0.7 mg/kg (upper range 1.0 mg/kg) and with extensive protein hydrolysate formula 171.7 mg/kg bw (upper range 249.8 mg/kg bw), with no indication of untoward effects. Infants almost entirely utilize dietary Glu in splanchnic organs, with no appreciable effect on plasma Glu concentrations. Estimated free Glu intakes in breastfed infants are up to 4.5-fold higher than the acceptable daily intake (ADI) set by the European Food Safety Authority for the total population including infants, and the respective intakes of infants fed a formula based on an extensive protein hydrolysate are up to 8.3-fold higher. There is no reason to assume that feeding human milk or an extensive protein hydrolysate infant formula would be unsuitable or unsafe for infants. Setting an ADI below the range of the normal intake with a safe diet in generally healthy individuals, that is, below 250 mg/kg per day, seems inappropriate.
Low dose of Bisphenol A enhance the susceptibility of thyroid carcinoma stimulated by DHPN and iodine excess in F344 rats

Thyroid carcinoma (TC) is the most common endocrine neoplasm. The risk of TC as a second primary malignancy (SPM) of breast cancer is significantly increased. Bisphenol A (BPA) is a widely contacted xenoestrogen and increases susceptibility to breast cancer through binding to estrogen receptor alpha (ERα). However, the effect of BPA on thyroid carcinogenesis has not been fully demonstrated. This present study aimed to characterize the effects of BPA on the development of TC using a Fischer 344 (F344) rat model. In this study, we established a TC model using female F344 rats pretreated with N-Bis (2-hydroxypropyl) nitrosamine (DHPN) at a single dose of 2800 mg/kg (the DA group) or without DHPN (the DN group), followed by stimulation with BPA at the level of 250 μg/kg (BPA250) or 1000 μg/kg (BPA1000) and a basic diet containing potassium iodine (KI, 1000 μg/L) for 64 weeks. We demonstrated that the incidence of TC in the BPA250 + KI of DA groups reached the highest at 50%, the incidence of thyroid hyperplasia lesions (including both tumors and focal hyperplasia lesions) in the BPA1000 + KI of DA groups reached 100% (P < 0.05). ERα protein and immunochemistry expression was upregulated in the BPA-exposed groups and the immunochemistry scores were positively correlated with PCNA. Thus, the present results indicate that BPA could enhance the susceptibility to TC stimulated by DHPN and iodine excess. ERα is probably involved in the proliferation effect of BPA. BPA or KI alone could not increase TC incidence.
Comment on: The potential use of rifabutin for treatment of patients diagnosed with rifampicin-resistant tuberculosis.

Background Use of the Xpert MTB/RIF assay has increased the number of people diagnosed with rifampicin-resistant tuberculosis (RR-TB), especially in South Africa where Xpert is now the initial diagnostic for individuals with TB symptoms. We hypothesized that a proportion of RR-TB patients determined by Xpert can be treated with a rifabutin-containing regimen. Methods Rifabutin susceptibility by rpoB mutation was assessed in 349 individuals from South Africa and 172 from Belgium. rpoB polymorphisms were identified by Sanger sequencing. Rifampicin and rifabutin susceptibility was assessed phenotypically. A systematic review was performed to comprehensively collate information on rifabutin susceptibility by rpoB polymorphism. Rifabutin susceptibility was assigned to rpoB polymorphisms based on their positive likelihood ratios and ORs. Results One hundred and twelve rpoB polymorphisms (67.9% from literature) were identified from all 2045 RR-TB patients, of which 17 polymorphisms could be classified as susceptible/resistant to rifabutin. Eleven polymorphisms were associated with rifabutin susceptibility. The 516GTC mutation was the most common, representing 70% (South Africa) and 76% (Belgium) of all rifabutin-susceptible isolates. At a population level, the 11 polymorphisms associated with rifabutin susceptibility occurred in 33.2% and 16.6% of all South African and Belgian patients diagnosed with RR-TB, respectively. Conclusions Identification of the exact rpoB polymorphism leading to the diagnosis of RR-TB has the potential to allow inclusion of rifabutin in the treatment regimen of a substantial proportion of RR-TB patients. A randomized controlled trial evaluating the efficacy of a rifabutin-containing TB treatment regimen in these selected patients is needed to provide the evidence required for a change in policy.
Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide

Background The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors. Methods We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided. Results The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P < .001), mesothelioma (P < .001), cutaneous melanoma (P < .001), and nonmelanoma skin cancer (P < .001). Conclusions This analysis substantially increases the number of pathogenic BAP1 germline variants and refines the phenotype. It highlights the need for a curated registry of germline variant carriers for proper assessment of the clinical phenotype of the BAP1-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research.
Structure and activity of lipid bilayer within a membrane-protein transporter

Significance Membrane proteins function naturally as imbedded in the lipid bilayers of cell membranes, but isolation into homogeneous and soluble preparations is needed for many biochemical studies. Detergents, which are used traditionally to extract and purify membrane proteins from cells, also remove most protein-associated lipid molecules as they disrupt the membranes. We have devised a detergent-free system to prepare native cell-membrane nanoparticles for biochemical analysis. In application to the membrane transporter AcrB, we demonstrate that these detergent-free nanoparticles are suitable for cryo-EM imaging at high resolution and that the natural lipid-bilayer structure so preserved is important for the functional integrity of AcrB. This nanoparticle system should be broadly applicable in membrane-protein research. Membrane proteins function in native cell membranes, but extraction into isolated particles is needed for many biochemical and structural analyses. Commonly used detergent-extraction methods destroy naturally associated lipid bilayers. Here, we devised a detergent-free method for preparing cell-membrane nanoparticles to study the multidrug exporter AcrB, by cryo-EM at 3.2-Å resolution. We discovered a remarkably well-organized lipid-bilayer structure associated with transmembrane domains of the AcrB trimer. This bilayer patch comprises 24 lipid molecules; inner leaflet chains are packed in a hexagonal array, whereas the outer leaflet has highly irregular but ordered packing. Protein side chains interact with both leaflets and participate in the hexagonal pattern. We suggest that the lipid bilayer supports and harmonizes peristaltic motions through AcrB trimers. In AcrB D407A, a putative proton-relay mutant, lipid bilayer buttresses protein interactions lost in crystal structures after detergent-solubilization. Our detergent-free system preserves lipid–protein interactions for visualization and should be broadly applicable.
Efficacy and safety of prothrombin complex concentrate in patients treated with rivaroxaban or apixaban compared to warfarin presenting with major bleeding

This retrospective study investigated the efficacy and safety of prothrombin complex concentrates (PCCs) for management of major bleeding events (MBE) in 344 patients receiving the anticoagulants rivaroxaban, apixaban or warfarin during the period January 2016 to April 2018. Median (range) PCC dose was 2000 units (1000–4500). Intracranial haemorrhage (ICH) was the most common indication (137/344, 39·8%) for PCC use followed by gastrointestinal bleeding (93/344, 27%). ICH patients more frequently received rivaroxaban (62·5%) or apixaban (52·5%) compared to warfarin (34·5%), P = 0·002; and visceral bleeding patients received warfarin more frequently (24·2%) than rivaroxaban (5%) or apixaban (10%), P = 0·003. Median rivaroxaban and apixaban levels were 230 ng/ml (47–759) and 159 ng/ml (45–255). Median International Normalised Ratio pre‐ and post‐PCC in patients on warfarin were 3·4 (1·9–15·4) and 1·2 (1·0–1·9). Blood products use was the same between groups. Thirty‐day mortality and re‐bleeding rates in patients with ICH were 35% (P = 0·50) and 18% (P = 0·90) with no differences between the groups. Thrombosis occurred in 4·1% patients within 30 days with no difference between groups. Two of 91 (2·2%) patients with ICH only (both on warfarin) had ischaemic strokes within 30 days post‐PCC. In conclusion, there was no difference in the safety (thrombosis) or efficacy (30‐day mortality, re‐bleeding) in use of PCC for MBE in patients on warfarin, rivaroxaban or apixaban.
Multiple-therapy-resistant major depressive disorder: a clinically important concept

Summary Many novel therapeutic options for depression exist that are either not mentioned in clinical guidelines or recommended only for use in highly specialist services. The challenge faced by clinicians is when it might be appropriate to consider such ‘non-standard’ interventions. This analysis proposes a framework to aid this decision. Declaration of interest In the past 3 years R.H. M.W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, LivaNova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. D.M. B.C. has received fees from LivaNova for attending an advisory board. In the past 3 years A.J.C. has received fees for lecturing from Astra Zeneca and Lundbeck; fees for consulting from LivaNova, Janssen and Allergan; and research grant support from Lundbeck. In the past 3 years A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. In the past 3 years A.L. M. has received support for attending seminars and fees for consultancy work (including advisory board) from Medtronic Inc and LivaNova. R.M. holds joint research grants with a number of digital companies that investigate devices for depression including Alpha-stim, Big White Wall, P1vital, Intel, Johnson and Johnson and Lundbeck through his mindTech and CLAHRC EM roles. M.S. is an associate at Blueriver Consulting providing intelligence to NHS organisations, pharmaceutical and devices companies. He has received honoraria for presentations and advisory boards with Lundbeck, Eli Lilly, URGO, AstraZeneca, Phillips and Sanofi and holds shares in Johnson and Johnson. In the past 3 years P.R. A.S. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending an advisory board) from life sciences companies including Corcept Therapeutics, Indivior and LivaNova. In the past 3 years P.S. T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. A.H. Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has received funding for investigator initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth.
Proceedings of the EXPERT Scientific and Technological Workshop

This paper presents results of a user survey for professional translators, which was aimed at identifying their needs regarding translation technologies. It focuses specifically on machine translation (MT), which user groups are more likely to adopt it and how they perceive technological advancements in this field. Based on the data, some connections could be made between the use of machine translation and translators’ domain of specialisation. However, future advancements of MT technology are perceived independently of the domain. Translators with advanced knowledge in IT tend to use MT more than the ones with less IT skills. Similarly, education in IT also has an effect on MT usage rate. Finally, we identified that more freelance translators who work with an agency tend to use MT more than those who work without an agency.
Family‐level variation in early life‐cycle traits of kelp

Temperate kelp forests (Laminarians) are threatened by temperature stress due to ocean warming and photoinhibition due to increased light associated with canopy loss. However, the potential for evolutionary adaptation in kelp to rapid climate change is not well known. This study examined family‐level variation in physiological and photosynthetic traits in the early life‐cycle stages of the ecologically important Australasian kelp Ecklonia radiata and the response of E. radiata families to different temperature and light environments using a family × environment design. There was strong family‐level variation in traits relating to morphology (surface area measures, branch length, branch count) and photosynthetic performance (Fv/Fm) in both haploid (gametophyte) and diploid (sporophyte) stages of the life‐cycle. Additionally, the presence of family × environment interactions showed that offspring from different families respond differently to temperature and light in the branch length of male gametophytes and oogonia surface area of female gametophytes. Negative responses to high temperatures were stronger for females vs. males. Our findings suggest E. radiata may be able to respond adaptively to climate change but studies partitioning the narrow vs. broad sense components of heritable variation are needed to establish the evolutionary potential of E. radiata to adapt under climate change.
Half As Sad: A Plea for Narrative Medicine in Pediatric Residency Training

During my third year of general pediatrics residency training, a patient well known to me and my fellow residents died unexpectedly. The child was an extremely bright and mature 8-year-old who had spent much of the last year of her life in our hospital being treated for cancer. Seemingly overnight, she became “too” sick (ICU sick, intubated and ventilated, on dialysis sick). She began to have intractable seizures, and with her family by her side, she died. The next morning, a colleague in his first year of residency asked how I was. I said that it had been a difficult week and I felt profoundly sad about the death of our patient. A look of relief came over his face. He told me that he was feeling despair. This was the first child he had cared for that had died. He had never felt such sadness before and felt guilty for feeling sad. He said that in medical school he had been told by a senior physician that it was the professional responsibility of a physician to “never feel more than 50% as sad as a patient’s family. ” Faced with the reality of the death of a child, my colleague was left feeling confused, distressed, and disenfranchised from his own emotional response. “You put on the waterworks and it makes the parents feel better,” my genetics attending said. She seemed proud to have arrived at this simple remedy. She had just finished counseling a couple whose child had been diagnosed with a lethal genetic condition. Were the tears an act simulating empathy for … Address correspondence to Malgorzata Nowaczyk, MD, FRCPC, FCCMG, FACMG, Department of Pediatrics, McMaster Children’s Hospital, 1200 Main St W, Hamilton, ON L8N 3Z5, Canada. E-mail: nowaczyk{at}hhsc.ca
Evaluation Measures for Partitioning based Aspect Mining Techniques

Aspect mining is a research direction that tries to identify crosscutting concerns in already developed software systems, without using aspect oriented programming. The goal is to identify them and then to refactor them to aspects, to achieve a system that can be easily understood, maintained and modified. In this paper we propose two new evaluation measures for evaluating the results of partitioning based aspect mining techniques. A small example on how to compute them is provided. The applicability of these measures to different aspect mining techniques is also discussed.