State based model of long-term potentiation and synaptic tagging and capture

Recent data indicate that plasticity protocols have not only synapse-specific but also more widespread effects. In particular, in synaptic tagging and capture (STC), tagged synapses can capture plasticity-related proteins, synthesized in response to strong stimulation of other synapses. This leads to long-lasting modification of only weakly stimulated synapses. Here we present a biophysical model of synaptic plasticity in the hippocampus that incorporates several key results from experiments on STC. The model specifies a set of physical states in which a synapse can exist, together with transition rates that are affected by high- and low-frequency stimulation protocols. In contrast to most standard plasticity models, the model exhibits both early- and late-phase LTP/D, de-potentiation, and STC. As such, it provides a useful starting point for further theoretical work on the role of STC in learning and memory

Nicotinic acetylcholine receptors modulate osteoclastogenesis

Background: Our aim was to investigate the role of nicotinic acetylcholine receptors (nAChRs) in in-vitro osteoclastogenesis and in in-vivo bone homeostasis. Methods: The presence of nAChR subunits as well as the in-vitro effects of nAChR agonists were investigated by ex vivo osteoclastogenesis assays, real-time polymerase chain reaction, Western blot and flow cytometry in murine bone marrow-derived macrophages differentiated in the presence of recombinant receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). The bone phenotype of mice lacking various nAChR subunits was investigated by peripheral quantitative computed tomography and histomorphometric analysis. Oscillations in the intracellular calcium concentration were detected by measuring the Fura-2 fluorescence intensity. Results: We could demonstrate the presence of several nAChR subunits in bone marrow-derived macrophages stimulated with RANKL and M-CSF, and showed that they are capable of producing acetylcholine. nAChR ligands reduced the number of osteoclasts as well as the number of tartrate-resistant acidic phosphatase-positive mononuclear cells in a dose-dependent manner. In vitro RANKL-mediated osteoclastogenesis was reduced in mice lacking α7 homomeric nAChR or β2-containing heteromeric nAChRs, while bone histomorphometry revealed increased bone volume as well as impaired osteoclastogenesis in male mice lacking the α7 nAChR. nAChR ligands inhibited RANKL-induced calcium oscillation, a well-established phenomenon of osteoclastogenesis. This inhibitory effect on Ca2+ oscillation subsequently led to the inhibition of RANKL-induced NFATc1 and c-fos expression after long-term treatment with nicotine. Conclusions: We have shown that the activity of nAChRs conveys a marked effect on osteoclastogenesis in mice. Agonists of these receptors inhibited calcium oscillations in osteoclasts and blocked the RANKL-induced activation of c-fos and NFATc1. RANKL-mediated in-vitro osteoclastogenesis was reduced in α7 knockout mice, which was paralleled by increased tibial bone volume in male mice in vivo. © 2016 Mandl et al

Chemokine Transfer by Liver Sinusoidal Endothelial Cells Contributes to the Recruitment of CD4+ T Cells into the Murine Liver

Leukocyte adhesion and transmigration are central features governing immune surveillance and inflammatory reactions in body tissues. Within the liver sinusoids, chemokines initiate the first crucial step of T-cell migration into the hepatic tissue. We studied molecular mechanisms involved in endothelial chemokine supply during hepatic immune surveillance and liver inflammation and their impact on the recruitment of CD4+ T cells into the liver. In the murine model of Concanavalin A-induced T cell-mediated hepatitis, we showed that hepatic expression of the inflammatory CXC chemokine ligands (CXCL)9 and CXCL10 strongly increased whereas homeostatic CXCL12 significantly decreased. Consistently, CD4+ T cells expressing the CXC chemokine receptor (CXCR)3 accumulated within the inflamed liver tissue. In histology, CXCL9 was associated with liver sinusoidal endothelial cells (LSEC) which represent the first contact site for T-cell immigration into the liver. LSEC actively transferred basolaterally internalized CXCL12, CXCL9 and CXCL10 via clathrin- coated vesicles to CD4+ T cells leading to enhanced transmigration of CXCR4+ total CD4+ T cells and CXCR3+ effector/memory CD4+ T cells, respectively in vitro. LSEC-expressed CXCR4 mediated CXCL12 transport and blockage of endothelial CXCR4 inhibited CXCL12-dependent CD4+ T-cell transmigration. In contrast, CXCR3 was not involved in the endothelial transport of its ligands CXCL9 and CXCL10. The clathrin-specific inhibitor chlorpromazine blocked endothelial chemokine internalization and CD4+ T-cell transmigration in vitro as well as migration of CD4+ T cells into the inflamed liver in vivo. Moreover, hepatic accumulation of CXCR3+ CD4+ T cells during T cell-mediated hepatitis was strongly reduced after administration of chlorpromazine. These data demonstrate that LSEC actively provide perivascularly expressed homeostatic and inflammatory chemokines by CXCR4- and clathrin-dependent intracellular transport mechanisms thereby contributing to the hepatic recruitment of CD4+ T-cell populations during immune surveillance and liver inflammation

Analisis Kinerja Ruas Jalan Timor Raya Akibat Aktivitas Pasar Oesao Kabupaten Kupang (Di Masa Pandemi)

Abstrak Kapasitas dan kinerja jalan akan berkurang karena adanya aktivitas pasar pada samping jalan. Saat masa Pandemi Covid-19 jumlah volume kendaraan yang melintas mengalami penurunan sementara yang disebabkan oleh adanya peraturan pemerintah tentang Pembatasan Sosial Berskala Besar. Namun berdasarkan pengamatan dilapangan, peneliti mengemukakan bahwa kondisi ruas jalan Timor Raya sudah kembali ramai karena pemerintah sudah berlakukan era new normal, dan aktivitas lain seperti pertokoan dan kantor pada area pasar sudah kembali beroperasi sehingga lebar jalan yang tersita oleh aktivitas pasar tentu mengurangi kemampuan jalan tersebut atau terjadi penurunan kapasitas ruas jalan. Penelitian ini menggunakan Pedoman Manual Kapasitas Jalan Indonesia 1997. Hasil Penelitian menunjukkan Berdasarkan hasil analisis dan pembahasan dapat disimpulkan bahwa Pengaruh aktivitas pasar pada ruas jalan Timor raya Oesao Pada masa Pandemi Covid 19 menimbulkan adanya hambatan samping sehingga kapasitas ruas jalan menjadi berkurang yaitu kapasitas jalan mempunyai nilai sebesar 2090,02 smp/jam dan Setelah melakukan analisa data akhir dimana diasumsikan penghilangan hambatan samping terbesar berupa kendaraan parkir diperoleh nilai kapasitas sebesar 2859,0288 smp/jam. Kata kunci: Jalan Timor Raya, Kinerja Jalan, Covid 19, MKJI 1997

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

Plant RuBisCo assembly in E. coli with five chloroplast chaperones including BSD2

Plant RuBisCo, a complex of eight large and eight small subunits, catalyzes the fixation of CO2 in photosynthesis. The low catalytic efficiency of RuBisCo provides strong motivation to reengineer the enzyme with the goal of increasing crop yields. However, genetic manipulation has been hampered by the failure to express plant RuBisCo in a bacterial host. We achieved the functional expression of Arabidopsis thaliana RuBisCo in Escherichia coli by coexpressing multiple chloroplast chaperones. These include the chaperonins Cpn60/Cpn20, RuBisCo accumulation factors 1 and 2, RbcX, and bundle-sheath defective-2 (BSD2). Our structural and functional analysis revealed the role of BSD2 in stabilizing an end-state assembly intermediate of eight RuBisCo large subunits until the small subunits become available. The ability to produce plant RuBisCo recombinantly will facilitate efforts to improve the enzyme through mutagenesis

Pressures to Publish: Catalysts for the Loss of Scientific Writing Integrity?

Publishing research is the final step in the scientific process and is used as the primary means for disseminating research findings to the scientific community. Publishing can embody many personal motivations (e.g., gratification, seeing a finished product in print, desire to further science) for authors as well as professional benefits (e.g., promotion, tenure, future funding opportunities). As the scientific workforce and competition for jobs and funding increase, publishing productivity has become a driving factor for many authors, which may lead to writing practices that violate integrity. In this essay, we discuss writing actions that may be considered a violation of integrity in the context of traditional manuscript sections (introduction and discussion, methods, and results). We define “integrity” as consistency of actions that reflect honesty and truthfulness. Writing the introduction and discussion can be compared to an artistic creation because the rendition of the data may vary depending on the intentions and experience of the author. Some authors may be tempted to relate their research to a hot topic (e.g., climate change, model selection) in an attempt to increase publication success or maximize visibility in search engines, despite not having sufficient data to support their conclusions. Caution must be taken to not overextend the “story” beyond the bounds of the data. Modification of the methods and results sections contains the most extreme cases of scientific integrity violations (e.g., changing an alpha level, only presenting positive results, running numerous tests until desired outcome). Manipulation of methods or results is more difficult to detect by peer review. We believe that however destructive integrity violations may be, despite benefits to the author (e.g., accolades, publication, potential citations, promotion, etc.), the individual scientist should hold him- or herself accountable and to a high standard to avoid sacrificing integrity. Presión para publicar: catalizadores de la pérdida de integridad en la publicación científica Resume: La publicación es la etapa final del proceso científico y se utiliza como el medio principal para diseminar los hallazgos de una investigación. Para los autores, publicar puede implicar distintas motivaciones tanto personales (p.e. satisfacción, ver un producto final impreso, deseo de hacer más ciencia) como profesionales (p.e. promoción interna, basificación, oportunidades de financiamiento). A medida que se incrementa la fuerza laboral científica y la competencia por trabajo y financiamiento, la productividad en cuanto a las publicaciones se ha convertido en un factor determinante para muchos autores, lo cual puede dar pie a prácticas de publicación que comprometen la integridad. En este ensayo se discuten aquellas prácticas de publicación que se considera que comprometen la integridad en el contexto de las secciones habituales que conforman un artículo (introducción y discusión, métodos y resultados). Se define la integridad como la consistencia en acciones que reflejan honestidad y veracidad. Escribir la introducción y discusión se compara con una creación artística en cuanto a que la interpretación de los datos puede variar dependiendo de las intenciones y experiencia del autor. Algunos autores pueden estar tentados a relacionar su investigación a un tópico de actualidad (p.e. cambio climático, selección de modelos) en un intento por incrementar el éxito de la publicación y maximizar la posibilidad de ser encontrados mediante motores de búsqueda, a pesar de que no cuentan con suficientes datos como para apoyar sus conclusiones. Se debe tener cuidado para no extender la historia más allá de los límites que establecen los datos. La modificación de las secciones de métodos y resultados implica los casos más extremos de violaciones a la integridad (p.e. cambiar el nivel de alfa, presentar sólo resultados positivos, realizar numerosas pruebas hasta que salga el resultado esperado). La manipulación de los métodos o los resultados resulta particularmente difícil de detectar durante el proceso de revisión por pares. Creemos que no obstante lo destructivas que puedan ser las violaciones a la integridad y a pesar de los beneficios que obtengan los autores (p.e. premios, potencial de citación, promociones, etc.), el individuo científico debe mantener su sentido de responsabilidad y sus estándares en alto con el fin de evitar sacrificar su integridad

Global distribution of fluoroquinolone and colistin resistance and associated resistance markers in escherichia coli of swine origin – a systematic review and meta-analysis

Background: Fluoroquinolones and polymyxins (colistin) are considered as critical drugs for human medicine. Antimicrobials of these classes are also used in swine production worldwide and this usage can contribute to selection of antimicrobial resistance (AMR), which is a threat to both human and animal health. Given the dynamic epidemiology of AMR, updating our knowledge regarding distribution and trends in the proportion of resistant bacteria is of critical importance. Objectives: The aim of this systematic review and meta-analysis was to describe the global prevalence of phenotypic and genotypic resistance to fluoroquinolones and colistin in Escherichia coli collected from swine. Results: Four databases (PubMed, PubAg, Web of Science, and CAB abstracts) and reports of national surveillance programs were scanned and 360 articles were included in the analysis. We identified higher prevalence levels of fluoroquinolone and colistin resistance in isolates from pig populations in Asia compared to Europe. The heterogeneity of pooled estimates was also higher in Asian countries suggesting that prevalence of AMR is still not fully characterized. There was a major knowledge gap about the situation of AMR in South American and African countries. We also identified key deficiencies in how AMR data was reported in the studies. A meta-analysis using 6, 167 publicly available genomes of swine E. coli established the prevalence and global distribution of genetic determinants that can lead to fluoroquinolone and colistin resistance. Conclusion: This study provides the most comprehensive information on prevalence of phenotypic and genotypic resistance to key antimicrobials in pig populations globally. There is a need to establish national surveillance programs and effective policies, particularly in certain world regions, to curtail the threat of evolution of resistant isolates in swine production that can potentially contribute to public health detrimentally. Copyright © 2022 Hayer, Casanova-Higes, Paladino, Elnekave, Nault, Johnson, Bender, Perez and Alvarez

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio