Miracle-dz/UniFAR-FTUs huggingface dataset:
Direct interaction between CEP85 and STIL mediates PLK4-driven directed cell migration

ABSTRACT PLK4 has emerged as a prime target for cancer therapeutics, and its overexpression is frequently observed in various types of human cancer. Recent studies have further revealed an unexpected oncogenic activity of PLK4 in regulating cancer cell migration and invasion. However, the molecular basis behind the role of PLK4 in these processes still remains only partly understood. Our previous work has demonstrated that an intact CEP85–STIL binding interface is necessary for robust PLK4 activation and centriole duplication. Here, we show that CEP85 and STIL are also required for directional cancer cell migration. Mutational and functional analyses reveal that the interactions between CEP85, STIL and PLK4 are essential for effective directional cell motility. Mechanistically, we show that PLK4 can drive the recruitment of CEP85 and STIL to the leading edge of cells to promote protrusive activity, and that downregulation of CEP85 and STIL leads to a reduction in ARP2 (also known as ACTR2) phosphorylation and reorganization of the actin cytoskeleton, which in turn impairs cell migration. Collectively, our studies provide molecular insight into the important role of the CEP85–STIL complex in modulating PLK4-driven cancer cell migration. This article has an associated First Person interview with the first author of the paper. Highlighted Article: Our studies provide molecular insight into the important role of the CEP85-STIL complex in activating ARP2/3-dependent actin reorganization and modulating PLK4-driven cancer cell migration.
Diurnal activity patterns and habitat use of juvenile Pastinachus ater in a coral reef flat environment

Stingrays are thought to play important ecological roles in coral reef ecosystems. However, little is known about juvenile stingray movement patterns and habitat use in coral reefs. This study used active acoustic telemetry to determine fine-scale diel movement patterns and habitat use of juvenile cowtail stingrays (Pastinachus ater) in a coral reef flat environment. Seven cowtail stingrays (4 males and 3 females) were manually tracked between April and December 2016. Each individual was tracked over 2 days, generating a total of 14 active tracks ranging from 4.91 to 9 h. Specimens moved at an average speed of 2.44 m min-1 ± 0.87 SE, with minimum distances travelled ranging from 546 to 1446 m. Tracking data showed that juvenile cowtail stingrays move in response to tidal cycles, moving faster and in straighter pathways during incoming and outgoing tides. Juvenile cowtail stingrays also showed a strong affinity to sand flat areas and mangrove edge areas. These areas provide food resources and potential refuges for juvenile rays to avoid predators. Coral reef flats were identified as secondary refuge for juveniles during the lowest tides. Future research is necessary to fully unveil the major drivers of juvenile cowtail stingray seasonal and ontogenetic movement patterns and habitat use within coral reef flat environments. This information is important to establish a full understanding of juvenile cowtail stingray ecology, but could also improve management and conservation policies.
DNA-Binding and Anticancer Activity of Binuclear Gold(I) Alkynyl Complexes with a Phenanthrenyl Bridging Ligand

3,6-Diethynyl-9,10-diethoxyphenanthrene (4) was synthesized from phenanthrene and employed in the synthesis of the binuclear gold(I) alkynyl complexes (R3P)Au(C≡C–3-[C14H6-9,10-diethoxy]-6–C≡C)Au(PR3) (R = Ph (5a), Cy (5b)). The diyne 4 and complexes 5a and 5b were characterized by NMR spectroscopy, mass spectrometry, and elemental analysis. UV-Vis spectroscopy studies of the metal complexes and precursor diyne show strong π → π* transitions in the near UV region that red shift by ca. 50 nm upon coordination at the gold centers. The emission spectrum of 4 shows an intense fluorescence band centered at 420 nm which red shifts, slightly upon coordination of 4 to gold. Binding studies of 4, 5a, and 5b against calf thymus DNA were carried out, revealing that 4, 5a, and 5b have ≥40% stronger binding affinities than the commonly used intercalating agent ethidium bromide. The molecular docking scores of 4, 5a, and 5b with B-DNA suggest a similar trend in behavior to that observed in the DNA-binding study. Unlike the ligand 4, promising anticancer properties for 5a and 5b were observed against several cell lines; the DNA binding capability of the precursor alkyne was maintained, and its anticancer efficacy enhanced by the gold centers. Such phenanthrenyl complexes could be promising candidates in certain biological applications because the two components (phenanthrenyl bridge and metal centers) can be altered independently to improve the targeting of the complex, as well as the biological and physicochemical properties.
Penicillin allergy testing is cost-saving: An economic evaluation study.

BACKGROUND Having a penicillin allergy label is associated with the use of less appropriate and more expensive antibiotics and increased healthcare utilization. Penicillin allergy testing results in delabeling most allergy claimants and may be cost-saving. This study aimed to project whether penicillin allergy testing in patients reporting a penicillin allergy is cost-saving. METHODS In this economic evaluation study, we built decision models to project the economic impact of two strategies for the patient with a penicillin allergy label: (1) Perform diagnostic testing (drug challenges, with or without skin tests) and (2) Do not perform diagnostic testing. The health service perspective was adopted, considering costs with penicillin allergy tests, and with hospital bed-days/outpatient visits, antibiotic use, and diagnostic testing. Twenty-four base case decision models were built, accounting for differences in the diagnostic workup, setting (inpatient versus outpatient) and geographic region. Uncertainty was explored via probabilistic sensitivity analyses. RESULTS Penicillin allergy testing was cost-saving in all decision models built. For models assessing the performance of both skin tests and drug challenges, allergy testing resulted in average savings of $657 for inpatients (United States of America: $1444, Europe: $489) and $2746 for outpatients (United States of America: $256, Europe: $6045). 75% of simulations obtained through probabilistic sensitivity analysis identified testing as the less costly option. CONCLUSION Penicillin allergy testing was projected to be cost-saving across different scenarios. These results are devised to inform guidelines, supporting the adoption of policies promoting widespread testing of patients with a penicillin allergy label.
Assessment of Lesion Detectability in Dynamic Whole-Body PET Imaging Using Compartmental and Patlak Parametric Mapping

Purpose Hybrid dynamic imaging allows not only the estimation of whole-body (WB) macroparametric maps but also the estimation of microparameters in the initial bed position targeting the blood pool region containing the pathology owing to the limited axial field of view of PET scanners. In this work, we assessed the capability of multipass WB 18F-FDG PET parametric imaging in terms of lesion detectability through qualitative and quantitative evaluation of simulation and clinical studies. Methods Simulation studies were conducted by generating data incorporating 3 liver and 3 lung lesions produced by 3 noise levels and 20 noise realizations for each noise level to estimate bias and lesion detection features. The total scan time for the clinical studies of 8 patients addressed for lung and liver lesions staging, including dynamic and static WB imaging, lasted 80 minutes. An in-house–developed MATLAB code was utilized to derive the microparametric and macroparametric maps. We compared lesion detectability and different image-derived PET metrics including the SUVs, Patlak-derived influx rate constant (Ki) and distribution volume (V) and K1, k2, k3, blood volume (bv) microparameters, and Ki estimated using the generalized linear least square approach. Results In total, 104 lesions were detected, among which 47 were located in the targeted blood pool bed position where all quantitative parameters were calculated, thus enabling comparative analysis across all parameters. The evaluation encompassed visual interpretation performed by an expert nuclear medicine specialist and quantitative analysis. High correlation coefficients were observed between SUVmax and Kimax derived from the generalized linear least square approach, as well as Ki generated by Patlak graphical analysis. Moreover, 3 contrast-enhanced CT-proven malignant lesions located in the liver and a biopsy-proven malignant liver lesion not visible on static SUV images and Patlak maps were clearly pinpointed on K1 and k2 maps. Conclusions Our results demonstrate that full compartmental modeling for the region containing the pathology has the potential of providing complementary information and, in some cases, more accurate diagnosis than conventional static SUV imaging, favorably comparing to Patlak graphical analysis.
Success of Hypoglossal Nerve Stimulation Using Mandibular Advancement During Sleep Endoscopy

Hypoglossal nerve stimulation (HGNS) effectively treats obstructive sleep apnea in select patients. Drug‐induced sleep endoscopy (DISE) is required for HGNS candidacy. Data suggest that mandibular advancement (MA) devices and HGNS share similar target populations. We aimed to test the association between MA's effect on the velum and lateral walls during DISE in relation to the improvement in the apnea‐hypopnea index (AHI) with HGNS.
Fatal Case of Legionnaires’ Disease After Home Exposure to Legionella pneumophila Serogroup 3 — Wisconsin, 2018

In January 2018, the Wisconsin Department of Health Services, Division of Public Health (DPH), received a report of a culture-confirmed case of Legionnaires' disease. The patient, who was immunocompromised, had died at a local hospital 10 days after being admitted. DPH and an infection preventionist from the hospital investigated to determine the source of the infection and prevent additional cases. Because the case was suspected to be nosocomial, health care facility water samples were tested for Legionella. When these samples were negative, water sources in the patient's home were tested. These tested positive for Legionella pneumophila, and the bacteria remained after an attempt to remediate. The patient and home isolates were identified as L. pneumophila serogroup 3, sequence type 93, by whole-genome multilocus sequence typing. A second resident of the home did not become ill. This case highlights the potential for immunocompromised persons and others at risk for Legionnaires' disease to be exposed to Legionella through home water systems containing the bacteria and demonstrates the difficulty of home remediation. This case also illustrates the role of lower respiratory tract specimens in the identification of less common Legionella infections (e.g., L. pneumophila serogroup 3) and confirmation of the infection source.
Effective Photodynamic Inactivation of 26 Escherichia coli Strains with Different Antibiotic Susceptibility Profiles: A Planktonic and Biofilm Study

The emergence of multidrug-resistant bacteria is a growing problem and alternative therapies are being sought to effectively address this issue. The aim of this study is to assess a range of Escherichia coli strains’ susceptibility to Methylene Blue-mediated antimicrobial photodynamic therapy and determine if this is affected by their antibiotic-resistance profile. Two reference and twenty-four uropathogenic clinical E. coli strains were used in this study. All were tested in vitro for antimicrobial susceptibility against sixteen antibiotics. Strains underwent photodynamic treatments using the photosensitizer Methylene Blue with red light and tested in both planktonic and biofilm state. It was found that reference strain ATCC 25922 was susceptible to all tested antibiotics whereas reference strain ATCC 35218 showed resistance only to Ampicillin. With the exception of strains number 16 and 22, all of the isolated strains were multidrug-resistant according to the criteria established by the European Centre for Disease Prevention and Control and the Centre for Disease Control and Prevention, where acquired non-susceptibility to at least one agent in three or more antimicrobial categories is outlined. Photodynamic therapy induced more than 3 log10 colony-forming units’ reduction to all strains in planktonic state. Whereas when tested in biofilm state, two and a half times the original dose of methylene blue was necessary to cause a 3 log10 antimicrobial effect. There were statistically significant differences in susceptibility among the strains tested in both the planktonic and biofilm experiments. Nevertheless, antimicrobial photodynamic therapy could inactivate all multidrug-resistant strains in the planktonic and biofilm state.
Effect of exercise stress upon the acute toxicity of adriamycin in mice.

: The effect of an acute exercise stress upon the acute toxicity of adriamycin was tested. Mice were forced to swim for 30 min following 18 or 23 mg/kg ip of adriamycin. Survival was checked daily for 30 days. The exercise stress did not appear to increase the toxicity of adriamycin in these animals.
Lornoxicam controlled release transdermal gel patch: Design, characterization and optimization using co-solvents as penetration enhancers

The aim of the current study was to develop membrane-based transdermal patches of lornoxicam gel using oleic acid (OA)and propylene glycol (PG) as penetration enhancers to improve drug delivery across the skin and to evaluate in vivo analgesic and anti-inflammatory activity. For this purpose, nine formulations were developed in accordance with 32 factorial design using Design Expert® 11. The concentration of propylene glycol (X1) and oleic acid (X2) were selected as independent variable whereas Q10 (Y1), flux (Y2) and lag time (Y3) were considered as the response variables. The impact of drug loading, surface area, gel concentration, membrane variation and agitation speed on drug release and permeation was also studied. The skin sensitivity reaction, analgesic activity and anti-inflammatory action of the optimized patch were also determined in Albino Wistar rats. Stability studies were performed for three months at three different temperature conditions. The result suggests that a membrane-based system with controlled zero-order drug release of 95.8 ± 1.121% for 10 h exhibiting flux of 126.51±1.19 μg/cm2/h and lag time of 0.908 ±0.57h was optimized with the desired analgesic and anti-inflammatory effect can be obtained by using propylene glycol and oleic acid co-solvents as a penetration enhancer. The patch was also found stable at 4˚C for a period of 6.44 months. Formulation F9 comprising of 10% PG and 3% OA was selected as an optimized formulation. The study demonstrates that the fabricated transdermal system of lornoxicam can deliver the drug through the skin in a controlled manner with desired analgesic and anti-inflammatory activity and can be considered as a suitable alternative of the oral route.
Beyond 'find and fix': improving quality and safety through resilient healthcare systems.

OBJECTIVE The aim was to develop a method based on resilient healthcare principles to proactively identify system vulnerabilities and quality improvement interventions. DESIGN Ethnographic methods to understand work as it is done in practice using concepts from resilient healthcare, the Concepts for Applying Resilience Engineering model and the four key activities that are proposed to underpin resilient performance-anticipating, monitoring, responding and learning. SETTING Accident and Emergency Department (ED) and the Older People's Unit (OPU) of a large teaching hospital in central London. PARTICIPANTS ED-observations 104 h, and 14 staff interviews. OPU-observations 60 h, and 15 staff interviews. RESULTS Data were analysed to identify targets for quality improvement. In the OPU, discharge was a complex and variable process that was difficult to monitor. A system to integrate information and clearly show progress towards discharge was needed. In the ED, patient flow was identified as a complex high-intensity activity that was not supported by the existing data systems. The need for a system to integrate and display information about both patient and organizational factors was identified. In both settings, adaptive capacity was limited by the absence of systems to monitor the work environment. CONCLUSIONS The study showed that using resilient healthcare principles to inform quality improvement was feasible and focused attention on challenges that had not been addressed by traditional quality improvement practices. Monitoring patient and workflow in both the ED and the OPU was identified as a priority for supporting staff to manage the complexity of the work.
Pulmonary arteries in a fix

167 chest [Figures 1 and 2]. Transthoracic echocardiography was done which showed evidence of mild pulmonary hypertension with a pulmonary artery systolic pressure of 45 mmHg. On further questioning, she gave a history of undergoing spinal decompression and fixation for L5-S1 spondylolisthesis immediately before the onset of dyspnea. Based on this temporal relationship, a diagnosis was suspected which was further reinforced by a lumbosacral radiograph [Figure 3].
A Novel Tool for the Assessment of Sport Climbers' Movement Performance.

PURPOSE To assess the validity and reliability of a novel movement-performance assessment tool for climbing/sport climbing. METHODS First, salient climbing movement-performance factors were identified through an iterative consultation process with 10 expert climbing coaches; the resulting Climber's Movement Performance Assessment Tool (CM-PAT) contained 14 items in 5 categories. Second, 61 intermediate to advanced climbers ascended a single route, which was video recorded. Subsequently, 4 experienced (>10 y coaching) coaches used the CM-PAT to observe and score the climbers' performance. Interrater reliability and comparisons with existing measures of climbing performance (6-mo self-reported ability, success and failure, climbing pace [m·min-1], and geometric entropy) were made. RESULTS Intraclass correlation coefficient (2,k) for the 4 raters demonstrated excellent reliability (>.81) between observers and good to excellent test-retest reliability (.71-.91). Pearson correlations between self-reported ability and CM-PAT scores explained 61% of the variance in self-reported climbing performance compared with 16% for geometric entropy and 52% for climbing pace. Considering differences in successful and unsuccessful climbers, the CM-PAT (P < .0005; d = 2.14), geometric entropy (P = .014; d = 0.67), and pace (P < .0005; d = 1.88) were able to differentiate between groups. CONCLUSIONS The CM-PAT is the first sport climbing performance observational instrument to be developed through a thorough iterative process with expert coaches. Excellent interrater and test-retest reliability and excellent agreement with self-reported ability and with existing quantitative measures of performance support its recommendation for use in coaching and research contexts. Notably, a key advantage over existing measures is the identification of coachable elements of performance.
Lactose monohydrate flow characterization using shear cell method

Abstract The flow properties of pharmaceutical powders have a great importance in the manufacturing of solid dosage forms. In order to ensure the performance in the production line this parameter must be determined. There are several methods described in European Pharmacopeia that are used to measure these properties. Some of them were used in this study and the results obtained from conventional methods (Conv) and shear cell using the powder flow tester (PFT) showed differences that were more evident in fractions with smaller particle size (F < 63) and for bulk powder (FTotal). The various powder behaviors showed to be related with the size of the particles. An increase of the ffc (Flow Index) was observed with the increase of the particle size. It was also found for the different fractions that the ffc always increases with increasing major principal consolidation stress (σ1). This study shown to be predictive because it also allowed the behavior profiles of other LactMN fractions to be known by interpolation of the median size (Dv50) or σ1 values ranged between the studied intervals. Furthermore, it was also observed that ffc of the FTotal was similar to the F < 63, showing the same behavior under σ1. The occurrence of caking was not observed. Graphical Abstract
Intraspecific variation in sensitivity to food availability and temperature-induced phenotypic plasticity in the rotifer Keratella cochlearis

ABSTRACT Organisms with wide environmentally induced morphological plasticity and cosmopolitan distribution, e.g. the common freshwater rotifer Keratella cochlearis, are ideal models to study the evolution of plastic polymorphisms and the capacity of zooplankton to adapt to local selection conditions. We investigated population-level differences (population-by-environment interaction) in sensitivity to food availability and temperature-induced phenotypic plasticity between two clones of K. cochlearis isolated from neighboring populations in Ruidera Natural Park (Spain) with different trophic statuses: Tinaja lake (mesotrophic) and Cueva Morenilla lake (eutrophic). Using common-garden experiments, each clone proved to have a different sensitivity to food availability, with substantial phenotypic differences between them. When rotifers grew at moderate temperature (15.6°C), low food levels were more efficiently used by the Tinaja versus Cueva Morenilla clone, whereas high food levels were more efficiently used by the Cueva Morenilla versus Tinaja clone. The posterior spine was much longer and the lorica wider in the Tinaja versus Cueva Morenilla clone, with no difference in lorica length. Phylogenetic analysis based on cytochrome c oxidase subunit I (COI) gene sequences showed that the two populations have the same haplotype. This is the first study to show possible local adaptation by a rotifer species to habitats that consistently differ in food availability. We also detected an intriguing deviation from the expected negative relationship between posterior spine length and temperature. Our experimental results indicate that intermediate temperatures may activate the gene responsible for spine elongation in K. cochlearis. This suggests that rotifers in nature could use water temperature as proxy signal of a change in predation risk before defense is needed. Summary: Two neighboring populations of the widespread rotifer Keratella cochlearis exhibit differences in sensitivity to food availability with substantial phenotypic differences between them.
Pathomechanisms of Posttraumatic Osteoarthritis: Chondrocyte Behavior and Fate in a Precarious Environment

Traumatic injuries of the knee joint result in a wide variety of pathomechanisms, which contribute to the development of so-called posttraumatic osteoarthritis (PTOA). These pathogenetic processes include oxidative stress, excessive expression of catabolic enzymes, release of damage-associated molecular patterns (DAMPs), and synovial inflammation. The present review focuses on the underlying pathomechanisms of PTOA and in particular the behavior and fate of the surviving chondrocytes, comprising chondrocyte metabolism, regulated cell death, and phenotypical changes comprising hypertrophy and senescence. Moreover, possible therapeutic strategies, such as chondroanabolic stimulation, anti-oxidative and anti-inflammatory treatment, as well as novel therapeutic targets are discussed.