Cell membrane softening in human breast and cervical cancer cells

Biomechanical properties are key to many cellular functions such as cell division and cell motility and thus are crucial in the development and understanding of several diseases, for instance cancer. The mechanics of the cellular cytoskeleton have been extensively characterized in cells and artificial systems. The rigidity of the plasma membrane, with the exception of red blood cells, is unknown and membrane rigidity measurements only exist for vesicles composed of a few synthetic lipids. In this study, thermal fluctuations of giant plasma membrane vesicles (GPMVs) directly derived from the plasma membranes of primary breast and cervical cells, as well as breast cell lines, are analyzed. Cell blebs or GPMVs were studied via thermal membrane fluctuations and mass spectrometry. It will be shown that cancer cell membranes are significantly softer than their non-malignant counterparts. This can be attributed to a loss of fluid raft forming lipids in malignant cells. These results indicate that the reduction of membrane rigidity promotes aggressive blebbing motion in invasive cancer cells

What factors in rural and remote extended clinical placements may contribute to preparedness for practice, from the perspective of students and clinicians?

What factors in rural and remote extended clinical placements may contribute to preparedness for practice, from the perspective of students and clinicians? Michele Daly, David Perkins, Koshila Kumar, Chris Roberts and Malcolm Moore Background: Community based rural education opportunities have expanded in Australia, attracting more medical students to placements in rural and remote settings. Aim: To identify the factors in an integrated, community engaged rural placement that may contribute to preparedness for practice (P4P), from the perspective of students and clinicians Methods: Forty two semi-structured interviews with medical students, supervisors and clinicians analysed thematically. Results: Opportunities for clinical learning, personal and professional development and cultural awareness were reported by students and clinicians as key factors that contribute to preparedness for practice. Potential barriers in rural and remote settings included geographical and academic isolation, perceived educational risk and differing degrees of program engagement. Conclusions: A longitudinal clinical placement in a rural setting may enable development of enhanced competencies leading to P4P. A rural setting can help provide a unique experience through hands-on learning, enhanced personal and professional development opportunities and observation of the cultural and contextual impact on health

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update

Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at >50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to—or adding—another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies

Rheumatoid arthritis - treatment: 180. Utility of Body Weight Classified Low-Dose Leflunomide in Japanese Rheumatoid Arthritis

Background: In Japan, more than 20 rheumatoid arthritis (RA) patients died of interstitial pneumonia (IP) caused by leflunomide (LEF) were reported, but many of them were considered as the victims of opportunistic infection currently. In this paper, efficacy and safety of low-dose LEF classified by body weight (BW) were studied. Methods: Fifty-nine RA patients were started to administrate LEF from July 2007 to July 2009. Among them, 25 patients were excluded because of the combination with tacrolimus, and medication modification within 3 months before LEF. Remaining 34 RA patients administered 20 to 50 mg/week of LEF were followed up for 1 year and enrolled in this study. Dose of LEF was classified by BW (50 mg/week for over 50 kg, 40 mg/week for 40 to 50 kg and 20 to 30 mg/week for under 40 kg). The average age and RA duration of enrolled patients were 55.5 years old and 10.2 years. Prednisolone (PSL), methotrexate (MTX) and etanercept were used in 23, 28 and 2 patients, respectively. In case of insufficient response or adverse effect, dosage change or discontinuance of LEF were considered. Failure was defined as dosages up of PSL and MTX, or dosages down or discontinuance of LEF. Last observation carried forward method was used for the evaluation of failed patients at 1 year. Results: At 1 year after LEF start, good/ moderate/ no response assessed by the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score, including a 28-joint count (DAS28)-C reactive protein (CRP) were showed in 14/ 10/ 10 patients, respectively. The dosage changes of LEF at 1 year were dosage up: 10, same dosage: 5, dosage down: 8 and discontinuance: 11 patients. The survival rate of patients in this study was 23.5% (24 patients failed) but actual LEF continuous rate was 67.6% (11 patients discontinued) at 1 year. The major reason of failure was liver dysfunction, and pneumocystis pneumonia was occurred in 1 patient resulted in full recovery. One patient died of sepsis caused by decubitus ulcer infection. DAS28-CRP score was decreased from 3.9 to 2.7 significantly. Although CRP was decreased from 1.50 to 0.93 mg/dl, it wasn't significant. Matrix metalloproteinase (MMP)-3 was decreased from 220.0 to 174.2 ng/ml significantly. Glutamate pyruvate transaminase (GPT) was increased from 19 to 35 U/l and number of leukocyte was decreased from 7832 to 6271 significantly. DAS28-CRP, CRP, and MMP-3 were improved significantly with MTX, although they weren't without MTX. Increase of GPT and leukopenia were seen significantly with MTX, although they weren't without MTX. Conclusions: It was reported that the risks of IP caused by LEF in Japanese RA patients were past IP history, loading dose administration and low BW. Addition of low-dose LEF is a potent safe alternative for the patients showing unsatisfactory response to current medicines, but need to pay attention for liver function and infection caused by leukopenia, especially with MTX. Disclosure statement: The authors have declared no conflicts of interes

Hybrid cosmic ray measurements using the IceAct telescopes in coincidence with the IceCube and IceTop detectors

IceAct is a proposed surface array of compact (50 cm diameter) and cost-effective Imaging Air Cherenkov Telescopes installed at the site of the IceCube Neutrino Observatory at the geographic South Pole. Since January 2019, two IceAct telescope demonstrators, featuring 61 silicon photomultiplier (SiPM) pixels have been taking data in the center of the IceTop surface array during the austral winter. We present the first analysis of hybrid cosmic ray events detected by the IceAct imaging air-Cherenkov telescopes in coincidence with the IceCube Neutrino Observatory, including the IceTop surface array and the IceCube in-ice array. By featuring an energy threshold of about 10 TeV and a wide field-of-view, the IceAct telescopes show promising capabilities of improving current cosmic ray composition studies: measuring the Cherenkov light emissions in the atmosphere adds new information about the shower development not accessible with the current detectors, enabling significantly better primary particle type discrimination on a statistical basis. The hybrid measurement also allows for detailed feasibility studies of detector cross-calibration and of cosmic ray veto capabilities for neutrino analyses. We present the performance of the telescopes, the results from the analysis of two years of data, and an outlook of a hybrid simulation for a future telescope array

Three-year performance of the IceAct telescopes at the IceCube Neutrino Observatory

IceAct is an array of compact Imaging Air Cherenkov Telescopes at the ice surface as part of the IceCube Neutrino Observatory. The telescopes, featuring a camera of 61 silicon photomultipliers and fresnel-lens-based optics, are optimized to be operated in harsh environmental conditions, such as at the South Pole. Since 2019, the first two telescopes have been operating in a stereoscopic configuration in the center of IceCube\u27s surface detector IceTop. With an energy threshold of about 10 TeV and a wide field-of-view, the IceAct telescopes show promising capabilities of improving current cosmic-ray composition studies: measuring the Cherenkov light emissions in the atmosphere adds new information about the shower development not accessible with the current detectors. First simulations indicate that the added information of a single telescope leads, e.g., to an improved discrimination between flux contributions from different primary particle species in the sensitive energy range. We review the performance and detector operations of the telescopes during the past 3 years (2020-2022) and give an outlook on the future of IceAct

BLOOM: A 176B-Parameter Open-Access Multilingual Language Model

Large language models (LLMs) have been shown to be able to perform new tasks based on a few demonstrations or natural language instructions. While these capabilities have led to widespread adoption, most LLMs are developed by resource-rich organizations and are frequently kept from the public. As a step towards democratizing this powerful technology, we present BLOOM, a 176B-parameter open-access language model designed and built thanks to a collaboration of hundreds of researchers. BLOOM is a decoder-only Transformer language model that was trained on the ROOTS corpus, a dataset comprising hundreds of sources in 46 natural and 13 programming languages (59 in total). We find that BLOOM achieves competitive performance on a wide variety of benchmarks, with stronger results after undergoing multitask prompted finetuning. To facilitate future research and applications using LLMs, we publicly release our models and code under the Responsible AI License

Brown rats (Rattus norvegicus) in urban ecosystems: are the constraints related to fieldwork a limit to their study?

Nowadays, the majority of human beings live in urban ecosystems, with this proportion expected to continue increasing in the future. With the growing importance of urban rat-associated issues (e.g. damages to urban infrastructures, costs of rat-control programs, rat-associated health risks), it is becoming indispensable to fill the identified gaps in knowledge on the urban brown rat regarding, among others, its density, home range, genetic structure, and infectious status. In this context, live-trapping is a crucial prerequisite to any scientific investigation. This paper assesses the main constraints and challenges regarding the urban field and describes the major steps to be considered when planning research on urban rats. The primary challenges are i) the characteri zation of the urban experimental unit; ii) the choice of a trapping design: the use of live-trapping in capture-mark-recapture design, in association with modern statistics, is highly recommended to answer ecological questions (although these methods, mostly developed in natural ecosystems, need to be implemented for the urban field); iii) the potential ethical considerations with regard to animal welfare and field-worker safety; iv) the building of mutually-beneficial collaborations with city stakeholders, pest control professionals, and citizens. Emphasis must be put on communication to the public and education of field-workers. One major need of modern urban rat research is a peer-validated field methodology allowing reproducibility, repeatability, and inference from urban field studies and enabling researchers to answer long-standing key questions about urban rat ecology.Hoy en día, la mayoría de los seres humanos viven en ecosistemas urbanos, y se espera que esta proporción siga aumentando en el futuro. Con la creciente importancia de los problemas asociados a las ratas urbanas (por ejemplo, daños a las infraestructuras urbanas, costes de los programas de control de ratas, riesgos para la salud asociados a las ratas), se hace indispensable llenar las lagunas identificadas en el conocimiento de la rata. de control de ratas, riesgos para la salud asociados a las ratas), se hace indispensable llenar las lagunas identificadas en el conocimiento de la rata parda urbana en lo que respecta, entre otras cosas, a su densidad, área de distribución, estructura genética y estado infeccioso. En este contexto, la captura de animales vivos es un En este contexto, el trampeo en vivo es un prerrequisito crucial para cualquier investigación científica. En este artículo se evalúan las principales limitaciones y retos en el ámbito urbano y se describe los principales pasos a tener en cuenta a la hora de planificar la investigación sobre las ratas urbanas. Los principales retos son: i) la caracterización de la unidad experimental urbana; ii) la elección de un diseño de trampeo: el uso de trampas vivas en un diseño de captura-marcado-recaptura de captura-marcado-recaptura, en asociación con la estadística moderna, es muy recomendable para responder a cuestiones ecológicas (aunque estos métodos (aunque estos métodos, desarrollados en su mayoría en ecosistemas naturales, deben aplicarse en el ámbito urbano); iii) las posibles consideraciones éticas con iii) las posibles consideraciones éticas en relación con el bienestar de los animales y la seguridad de los trabajadores sobre el terreno; iv) la creación de colaboraciones mutuamente beneficiosas con las partes interesadas de la ciudad, los profesionales del control de plagas y los ciudadanos. Hay que hacer hincapié en la comunicación con el público y la educación de los trabajadores de campo. Una de las principales necesidades de la investigación moderna sobre las ratas urbanas es una metodología de campo validada por pares que permita la reproducibilidad, repetibilidad y y permitir a los investigadores responder a las preguntas clave sobre la ecología de las ratas urbanas.Universidad Nacional, Costa RicaEscuela de Medicina Veterinari