Miracle-dz/UniFAR-FTUs huggingface dataset:
Exploring the interaction of Peloruside-A with drug resistant αβII and αβIII tubulin isotypes in human ovarian carcinoma using a molecular modeling approach

Abstract Microtubules (MTs) play an essential role in mitosis; hence they are identified as potential targets to design novel anti-mitotic agents. MT’s are composed of α/β-tubulin isotypes that are associated with differential drug-resistant effects against MT-targeting agents. Peloruside-A (PLA) is a potent anti-mitotic agent showing excellent activity against taxol-resistant carcinoma. PLA alters MT dynamics by binding to the ‘non-taxoid’ site of β-tubulin. The abundance of βII and βIII tubulin isotypes in human ovarian carcinoma affects the efficacy of PLA. Nevertheless, the mechanism of PLA resistance due to βII and βIII tubulin isotype is not well understood. Therefore, we investigated the interactions of PLA with αβIIa, αβIIb, and αβIII tubulin isotypes which are predominantly expressed in the human ovarian carcinoma, using a molecular modeling approach. A sequence analysis study shows that the βIII isotype has seven residue variations at the ‘non-taxoid’ site compared to the βIIa and βIIb isotypes. Molecular docking and molecular dynamics simulation revealed that residue variation at the ‘non-taxoid’ site of βIII isotype affect PLA binding. Furthermore, binding energy calculations showed that αβIIa has the highest binding towards PLA, whereas αβIIb and αβIII isotypes shows weaker associations with PLA. Our computational study provides valuable structural and energetic information to increase understanding into the origin of PLA resistance in human ovarian carcinoma and could be helpful to develop potential PLA analogs against specific β-tubulin isotypes expressed in cancer cells. Communicated by Ramaswamy H. Sarma
Pirfenidone Inhibits Cell Proliferation and Collagen I Production of Primary Human Intestinal Fibroblasts

Intestinal fibrosis is a common complication of inflammatory bowel disease. So far, there is no safe and effective drug for intestinal fibrosis. Pirfenidone is an anti-fibrotic compound available for the treatment of idiopathic pulmonary fibrosis. Here, we explored the anti-proliferative and anti-fibrotic properties of pirfenidone on primary human intestinal fibroblasts (p-hIFs). p-hIFs were cultured in the absence and presence of pirfenidone. Cell proliferation was measured by a real-time cell analyzer (xCELLigence) and BrdU incorporation. Cell motility was monitored by live cell imaging. Cytotoxicity and cell viability were analyzed by Sytox green, Caspase-3 and Water Soluble Tetrazolium Salt-1 (WST-1) assays. Gene expression of fibrosis markers was determined by quantitative reverse transcription PCR (RT-qPCR). The mammalian target of rapamycin (mTOR) signaling was analyzed by Western blotting and type I collagen protein expression additionally by immunofluorescence microscopy. Pirfenidone dose-dependently inhibited p-hIF proliferation and motility, without inducing cell death. Pirfenidone suppressed mRNA levels of genes that contribute to extracellular matrix production, as well as basal and TGF-β1-induced collagen I protein production, which was associated with inhibition of the rapamycin-sensitive mTOR/p70S6K pathway in p-hIFs. Thus, pirfenidone inhibits the proliferation of intestinal fibroblasts and suppresses collagen I production through the TGF-β1/mTOR/p70S6K signaling pathway, which might be a novel and safe anti-fibrotic strategy to treat intestinal fibrosis.
Concomitant Intra-Articular Glenohumeral Lesions in Fractures of the Scapula Body

Background: Scapula body fractures are rare injuries with an incidence of 1% of all fractures accounting for 3% to 5% of all upper extremity fractures. Fractures of the scapula commonly result from high-energetic trauma and fall from great height. While several studies focused on concomitant injuries of chest and head as well as the cervical spine, up to now in the common literature, no study exists analyzing the prevalence of concomitant intra-articular glenohumeral injury following extra-articular scapular fracture. Objectives: The aim of this study was to analyze the prevalence of concomitant intra-articular glenohumeral injuries in acute fractures of the scapula by performing magnetic resonance imaging (MRI) of the shoulder joint. Study Design and Methods: This prospective cohort study was performed at our academic Level I trauma center from November 2014 to October 2016. According to our clinical algorithm, all patients suffering from an acute scapula body fracture primarily underwent computed tomography (CT) for assigning the fracture according to the Orthopedic Trauma Association (OTA)-classification and therapy planning. In addition, 3 T MRI-scans of all patients were performed within seven days after trauma. Results: Twenty-one (16 male/5 female, mean age 53 years (25–83 y) patients with scapula body fractures (OTA 14.A3.2 80.1%, OTA 14.A3.1 4.8%, OTA14.B3.1 4.8%, OTA14.C3 9.5%) were enrolled. MRI revealed 11 acute intra-articular injuries in 8 of 21 patients (38%). In all 21 patients, hematoma of the rotator cuff and periarticular muscles was present. Three patients (14.3%) presented a partial bursa sided tear of the supraspinatus tendon, whereas in 5 (23.8%), a partial articular sided supraspinatus tendon tear and in 2 (9.5%) patients, a subtotal tear was observed. One patient (4.8%) showed a complete transmural supraspinatus tendon tear. Conclusions: Traumatic concomitant glenohumeral injuries in scapula body fractures seem to be more frequent than generally expected. Subsequent surgical treatment of these formerly missed but therapy-relevant injuries may increase functional outcome and reduce the postoperative complication rate following scapula body fractures.
The Role of Chondrocyte Hypertrophy and Senescence in Osteoarthritis Initiation and Progression

Osteoarthritis (OA) is the most common joint disease that causes pain and disability in the adult population. OA is primarily caused by trauma induced by an external force or by age-related cartilage damage. Chondrocyte hypertrophy or chondrocyte senescence is thought to play a role in the initiation and progression of OA. Although chondrocyte hypertrophy and cell death are both crucial steps during the natural process of endochondral bone formation, the abnormal activation of these two processes after injury or during aging seems to accelerate the progression of OA. However, the exact mechanisms of OA progression and these two processes remain poorly understood. Chondrocyte senescence and hypertrophy during OA share various markers and processes. In this study, we reviewed the changes that occur during chondrocyte hypertrophy or senescence in OA and the attempts that were made to regulate them. Regulation of hypertrophic or senescent chondrocytes might be a potential therapeutic target to slow down or stop OA progression; thus, a better understanding of the processes is required for management.
Communication issues contributing to medication incidents: Mixed method analysis of hospitals´ incident reports using indicator phrases based on literature.

AIM To identify the types and frequencies of communication issues (communication pairs, person related, institutional, structural, process, and prescription-related issues) detected in medication incident reports and to compare communication issues that caused moderate or serious harm to patients. BACKGROUND Communication issues have been found to be amongst the main contributing factors of medication incidents, thus necessitating communication enhancement. DESIGN A sequential exploratory mixed-method design. METHODS Medication incident reports from Finland (n=500) for the year 2015 in which communication was marked as a contributing factor were used as the data source. Indicator phrases were used for searching communication issues from free texts of incident reports. The detected issues were analysed statistically, qualitatively, and considering the harm caused to the patient. Citations from free texts were extracted as evidence of issues and were classified following main categories of indicator phrases. The EQUATOR´s SRQR checklist was followed in reporting. RESULTS Twenty-eight communication pairs were identified, with nurse-nurse (68.2%; n=341), nurse-physician (41.6%; n=208), and nurse-patient (9.6%; n=48) pairs being the most frequent. Communication issues existed mostly within unit (76.6%, n=383). The most commonly identified issues were digital communication (68.2%; n=341), lack of communication within a team (39.6%; n=198), false assumptions about work processes (25.6%; n=128) and being unaware of guidelines (25.0%; n=125). Collegial feedback, and communication from patients and relatives were the preventing issues. Moderate harm cases were often linked with lack of communication within the unit, digital communication and not following guidelines. CONCLUSIONS The interventions should be prioritized to (a) enhancing communication about work-processes, (b) verbal communication about digital prescriptions between professionals, (c) feedback among professionals, and (f) encouraging patients to communicate about medication. RELEVANCE TO CLINICAL PRACTICE Upon identifying the most harmful and frequent communication issues, interventions to strengthen medication safety can be implemented.
A Randomized Clinical Trial to Compare Plasmodium falciparum Gametocytemia and Infectivity After Blood-Stage or Mosquito Bite–Induced Controlled Malaria Infection

Abstract Background For malaria elimination efforts, it is important to better understand parasite transmission to mosquitoes and develop models for early-clinical evaluation of transmission-blocking interventions. Methods In a randomized open-label trial, 24 participants were infected by bites from Plasmodium falciparum 3D7-infected mosquitoes (mosquito bite [MB]; n = 12) or by induced blood-stage malaria (IBSM) with the same parasite line (n = 12). After subcurative piperaquine treatment, asexual parasite and gametocytes kinetics were assessed, and mosquito feeding experiments were performed. Results Study procedures were well tolerated. The median peak gametocyte density was 1304/mL (interquartile range, 308–1607/mL) after IBSM, compared with 14/mL (10–64/mL) after MB inoculation (P < .001), despite similar peak asexual parasite densities (P = .48). Peak gametocyte density was correlated with preceding pfap2-g transcripts, indicative of gametocyte commitment (ρ = 0.62; P = .002). Direct feeding assays resulted in mosquito infections from 9 of 12 participants after IBSM versus 0 of 12 after MB inoculation (P < .001). Conclusions We observed a striking effect of inoculation method on gametocyte production, suggesting higher gametocyte commitment after IBSM. Our direct comparison of MB and IBSM establishes the controlled human malaria infection transmission model, using intravenous administration of P. falciparum–infected erythrocytes as a model for early-clinical evaluation of interventions that aim to interrupt malaria transmission. Clinical Trial Registration NCT03454048
Interleukin 6: An Important Mediator of Allograft Injury.

Interleukin 6 (IL-6) is a cytokine with critical innate and adaptive immunity functions. It's diverse immunologic and physiologic actions include direction of immune cell differentiation, initial response to invading pathogens and ischemic injury, sustained plasma cell growth, and immunoglobulin production. IL-6 transcriptional dysregulation is commonly seen in patients with autoimmune or inflammatory disorders. Emerging information suggests IL-6 transcription is upregulated in patients with kidney and heart transplant rejection and may account for perpetuation of inflammatory responses in the allograft, leading to allograft rejection and vasculopathy. IL-6 directed therapeutics include monoclonal antibodies directed at IL-6, the IL-6 receptor (IL-6R) and Janus Kinase (JAK) inhibitors. IL-6 mediated signaling to cell targets is unique, involving classic signaling (IL-6->IL-6R) cell membrane receptors, trans signaling (IL-6->soluble IL-6R->gp130) which activates any cell, and the recently discovered IL-6/IL-6R transpresentation where antigen presenting cells (APC) synthesize and express IL-6/IL-6R complexes which are transported through the cell membrane subsequently interacting with gp130 to costimulate T-cells. Currently, there are new trials in autoimmunity and heart and kidney transplantation to determine effectiveness of inhibiting IL-6/IL-6R to ameliorate chronic allograft rejection and coronary allograft vasculopathy. Therapeutic trials aimed at prevention of ischemia/reperfusion injury (IRI) to allografts based on animal data should be considered.
A nuclear localization signal is required for the nuclear translocation of Fign and its microtubule-severing function

It is commonly known that the specific function of a given ATPase associated with diverse cellular activities protein (i.e., a member of the AAA superfamily of proteins) depends primarily on its subcellular location. The microtubule-severing protein fidgetin (Fign) possesses a nuclear localization signal (NLS) that facilitates its translocation to the nucleus, where its assembly is finalized; here, Fign contributes to the regulation of microtubule configuration by cutting and trimming microtubule polymers. In the present study, Fign was found to be a nuclear protein, whose N-terminal sequence (SSLKRKAFYM; residues 314–323) acts as an NLS. Following substitution (KR to NN; 317–318) or deletion (NT; 314–323) mutations within the NLS, Fign, which is predominantly expressed in the nucleus, was found to reside in the cytoplasm of transfected cells. Furthermore, Fign was found to have an essential role in microtubule severing by preferentially targeting highly-tyrosinated microtubules (tyr-MTs). Mutation of the Fign NLS did not affect its microtubule-severing function or the cleavage of tyr-MTs, but did affect the cellular distribution of the Fign protein itself. Taken altogether, an NLS for Fign was identified, and it was demonstrated that the basic amino acids K317 and R318 are necessary for regulating its entry into the nucleus, whereas an increase in Fign in the cytosol due to mutations of the NLS did not affect its cleavage function.
Using Deep Learning to Forecast Maritime Vessel Flows

Forecasting vessel flows is important to the development of intelligent transportation systems in the maritime field, as real-time and accurate traffic information has favorable potential in helping a maritime authority to alleviate congestion, mitigate emission of GHG (greenhouse gases) and enhance public safety, as well as assisting individual vessel users to plan better routes and reduce additional costs due to delays. In this paper, we propose three deep learning-based solutions to forecast the inflow and outflow of vessels within a given region, including a convolutional neural network (CNN), a long short-term memory (LSTM) network, and the integration of a bidirectional LSTM network with a CNN (BDLSTM-CNN). To apply those solutions, we first divide the given maritime region into M×N grids, then we forecast the inflow and outflow for all the grids. Experimental results based on the real AIS (Automatic Identification System) data of marine vessels in Singapore demonstrate that the three deep learning-based solutions significantly outperform the conventional method in terms of mean absolute error and root mean square error, with the performance of the BDLSTM-CNN-based hybrid solution being the best.
A randomized trial comparing the effects of sternal band and plate fixation of the sternum with that of figure-of-8 wires on sternal edge motion and quality of recovery after cardiac surgery.

OBJECTIVES We sought to compare the effects of conventional wire cerclage with that of the band and plate fixation of the sternum. METHODS A parallel randomized open-label trial with 1:1 allocation ratio compared healing after adult cardiac surgery using 'figure-of-8' stainless steel wire cerclage or a band and plate system (plates). The primary end point was maximal sternal edge displacement during active coughing of ≥2 mm in ≥2 of 4 sites measured with ultrasound by 2 assessors blinded to the other at 6 weeks postoperatively. Secondary end points at 12 weeks included ultrasound assessment, computed tomography (CT) scan and multidimensional assessment of quality of recovery using the Postoperative Quality of Recovery Scale. RESULTS Of 50 patients, 26 received plates and 24 wires. Two patients died and 1 withdrew consent leaving 25 plates and 22 wires for primary end point analysis. Operations included 37 coronary, 5 valve and 8 combined coronary and valve procedures. At 6 weeks, less sternal movement was observed in patients with plates than those with wires, 4% (1/25) vs 32% (7/22), P = 0.018. Agreement between observers was high, kappa = 0.850. At 12 weeks, less ultrasound motion was seen in patients with plates, 0% (0/23) than those with wires, 25% (5/20), P = 0.014. Recovery from pain was higher for patients with plates 92% (22/24) than those with wires 67% (14/21), P = 0.004. CT bone edge separation was less for plates 38% (9/24) than wires 71% (15/21), P = 0.036. CT mild bone synthesis or greater was similar between patients with plates 21% (5/24) and wires 14% (3/21), P = 0.71. CONCLUSIONS Patients receiving the band and plate system had significantly less sternal edge motion than those receiving wires, 6 and 12 weeks after cardiac surgery and experienced less pain. CLINICAL TRIAL REGISTRATION clinicaltrials.gov NCT03282578.
Molecular Drivers of Lymphocyte Organization in Vertebrate Mucosal Surfaces: Revisiting the TNF Superfamily Hypothesis

Key Points Lymphotoxin axis is not essential for formation of O-MALT in ectotherms and birds. Vertebrate O-MALT structures are enriched in neuroactive ligand/receptor genes. Mammalian PPs and LNs are enriched in genes involved in olfactory transduction. The adaptive immune system of all jawed vertebrates relies on the presence of B and T cell lymphocytes that aggregate in specific body sites to form primary and secondary lymphoid structures. Secondary lymphoid organs include organized MALT (O-MALT) such as the tonsils and Peyer patches. O-MALT became progressively organized during vertebrate evolution, and the TNF superfamily of genes has been identified as essential for the formation and maintenance of O-MALT and other secondary and tertiary lymphoid structures in mammals. Yet, the molecular drivers of O-MALT structures found in ectotherms and birds remain essentially unknown. In this study, we provide evidence that TNFSFs, such as lymphotoxins, are likely not a universal mechanism to maintain O-MALT structures in adulthood of teleost fish, sarcopterygian fish, or birds. Although a role for TNFSF2 (TNF-α) cannot be ruled out, transcriptomics suggest that maintenance of O-MALT in nonmammalian vertebrates relies on expression of diverse genes with shared biological functions in neuronal signaling. Importantly, we identify that expression of many genes with olfactory function is a unique feature of mammalian Peyer patches but not the O-MALT of birds or ectotherms. These results provide a new view of O-MALT evolution in vertebrates and indicate that different genes with shared biological functions may have driven the formation of these lymphoid structures by a process of convergent evolution.
Anatomical Considerations When Treating Compensatory Hypertrophy of the Upper Part of the Masseter after Long-Term Botulinum Neurotoxin Type A Injections

The masseter is the most targeted muscle when treating hypertrophy to produce a smooth face shape. Compensatory hypertrophy is a well known clinical sequela that occurs in botulinum neurotoxin (BoNT) treatments and is limited to the lower part of the masseter. Based on the masseteric hypertrophy procedure, which targets a confined area, we predicted the possibility of compensatory hypertrophy occurring in the upper part of the masseter. If the patient complains about an unexpected result, additional injections must be performed, but the involved anatomical structures have not been revealed yet. The aim of this study was to identify the morphological patterns of the masseter. Deep tendons were observed in most specimens of the upper part of the masseter and mostly appeared in a continuous pattern (69.7%). The superficial and deep tendons could be classified into a simply connected form and forms surrounding part of the muscle. In 45.5% of cases there were tendon capsules that completely enclosed the muscle, which can interfere with how the injected toxin spreads. Interdigitation patterns in which the tendons could be identified independently between the muscles were present in 9.1% of cases. The present findings provide anatomical knowledge for use when injecting BoNT into the masseter.
Primate Version of Modified Rankin Scale for Classifying Dysfunction in Rhesus Monkeys

Supplemental Digital Content is available in the text. Background and Purpose— Nonhuman primates are increasingly used in translational studies of ischemic stroke. However, current scoring systems in monkeys (eg, Nonhuman Primate Stroke Scale) do not focus on impairments in activities of daily living, so clinically relevant data are scarce for evaluating functional deficits in this model. Methods— Here, we referenced the modified Rankin Scale to provide a primate version of Rankin Scale (pRS) for ranking neurological dysfunction in monkeys following stroke. We selected hand function and strength, level of activity, and general mobility as the main components of pRS. We also analyzed interobserver variability. Results— pRS is a simple scale with only 6 levels. Functional deficit can be easily classified into none (category 0), slight (categories 1–2), moderate (category 3–4), and severe disabilities (category 5) based on pRS. We validated this scoring system on 11 monkeys, all with varying levels of neurological dysfunction following stroke, assessed by blinded testers. After a short training period, both technicians and neurology residents were able to achieve a high level of consistency using this scoring system. Conclusions— pRS is a simple and reliable functional scale, similar to the widely used modified Rankin Scale, for evaluating long-term neurological dysfunction in nonhuman primates. We recommend further validation studies and analyses.