Two Drosophila suppressors of cytokine signaling (SOCS) differentially regulate JAK and EGFR pathway activities

BACKGROUND: The Janus kinase (JAK) cascade is an essential and well-conserved pathway required to transduce signals for a variety of ligands in both vertebrates and invertebrates. While activation of the pathway is essential to many processes, mutations from mammals and Drosophila demonstrate that regulation is also critical. The SOCS (Suppressor Of Cytokine Signaling) proteins in mammals are regulators of the JAK pathway that participate in a negative feedback loop, as they are transcriptionally activated by JAK signaling. Examination of one Drosophila SOCS homologue, Socs36E, demonstrated that its expression is responsive to JAK pathway activity and it is capable of downregulating JAK signaling, similar to the well characterized mammalian SOCS. RESULTS: Based on sequence analysis of the Drosophila genome, there are three identifiable SOCS homologues in flies. All three are most similar to mammalian SOCS that have not been extensively characterized: Socs36E is most similar to mammalian SOCS5, while Socs44A and Socs16D are most similar to mammalian SOCS6 and 7. Although Socs44A is capable of repressing JAK activity in some tissues, its expression is not regulated by the pathway. Furthermore, Socs44A can enhance the activity of the EGFR/MAPK signaling cascade, in contrast to Socs36E. CONCLUSIONS: Two Drosophila SOCS proteins have some overlapping and some distinct capabilities. While Socs36E behaves similarly to the canonical vertebrate SOCS, Socs44A is not part of a JAK pathway negative feedback loop. Nonetheless, both SOCS regulate JAK and EGFR signaling pathways, albeit differently. The non-canonical properties of Socs44A may be representative of the class of less characterized vertebrate SOCS with which it shares greatest similarity

COVID-19: The Immune Responses and Clinical Therapy Candidates.

The pandemic of coronavirus disease 2019 (COVID-19), with rising numbers of patients worldwide, presents an urgent need for effective treatments. To date, there are no therapies or vaccines that are proven to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several potential candidates or repurposed drugs are under investigation, including drugs that inhibit SARS-CoV-2 replication and block infection. The most promising therapy to date is remdesivir, which is US Food and Drug Administration (FDA) approved for emergency use in adults and children hospitalized with severe suspected or laboratory-confirmed COVID-19. Herein we summarize the general features of SARS-CoV-2's molecular and immune pathogenesis and discuss available pharmacological strategies, based on our present understanding of SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) infections. Finally, we outline clinical trials currently in progress to investigate the efficacy of potential therapies for COVID-19

Outcomes after anti-tumour necrosis factor originator to biosimilar switching in children and young people with juvenile idiopathic arthritis in the UK: a national cohort study

\ua9 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licence. Background: For cost-saving purposes, children and young people with juvenile idiopathic arthritis (JIA) are being switched (for non-medical reasons) from biological originators to biosimilars. Here, we aimed to investigate those who switched from an anti-tumour necrosis factor (TNF) originator to a biosimilar, regarding drug survival and disease activity, compared with a matched cohort who continued the originator. Methods: This analysis included all patients in the UK JIA Biologics Register switching directly from an anti-TNF originator to a biosimilar of the same product. All patients were matched (age, sex, disease duration, calendar year of when patients started originator therapy, line of therapy, and International League of Associations for Rheumatology [ILAR] category) to patients continuing the originator. For those matched successfully, a Cox proportional hazard model assessed whether drug persistence differed between those who switched compared with those who continued the originator. Overall change in the 71-joint juvenile arthritis disease activity score and the proportion of patients with a clinically important worsening score (by ≥1\ub77 units) after 6 months was compared between cohorts. This analysis was designed to address a priority research area set by our patient partners. Findings: There were 224 children and young people with non-systemic JIA (139 [62%] were female, and 85 [38%] were male) identified as switching from a biological originator to a biosimilar of the same product from Jan 1, 2017, to July 7, 2023. 143 (64%) patients were originally on adalimumab, 56 (25%) on etanercept, and 25 (11%) on infliximab. Of these, 164 patients were matched successfully to those continuing the originator. There was no evidence that patients switching were more likely to stop treatment compared with those continuing the originator, with a hazard ratio of 1\ub746 (95% CI 0\ub793–2\ub730). Of the 51 patients in the biosimilar group who stopped treatment, 18 (35%) switched back to the originator (14 in the first year), 28 (55%) started a different biological drug, and five (10%) discontinued all treatment by the last follow-up. Of the 87 matched patients with available disease activity, there was no evidence that JADAS-71 worsened more after 6 months, with an odds ratio of 0\ub771 (95% CI 0\ub734–1\ub751; p=0\ub738). Interpretation: In this matched comparative effectiveness analysis, children and young people with JIA switched from originators to biosimilars. Disease activity was similar between patients switching compared with those continuing the originator. Three quarters of patients were still receiving their biosimilar after 1 year, with switching back to originator uncommon, at only 9% after 1 year, suggesting good tolerability of non-medical switching in this patient population. This information is reassuring to clinicians and patients regarding the effect of non-medical biological switching. Funding: British Society for Rheumatology, Versus Arthritis, and National Institutes for Health Research Manchester Biomedical Research Centre

Emergence of structural and dynamical properties of ecological mutualistic networks

Mutualistic networks are formed when the interactions between two classes of species are mutually beneficial. They are important examples of cooperation shaped by evolution. Mutualism between animals and plants plays a key role in the organization of ecological communities. Such networks in ecology have generically evolved a nested architecture independent of species composition and latitude - specialists interact with proper subsets of the nodes with whom generalists interact. Despite sustained efforts to explain observed network structure on the basis of community-level stability or persistence, such correlative studies have reached minimal consensus. Here we demonstrate that nested interaction networks could emerge as a consequence of an optimization principle aimed at maximizing the species abundance in mutualistic communities. Using analytical and numerical approaches, we show that because of the mutualistic interactions, an increase in abundance of a given species results in a corresponding increase in the total number of individuals in the community, as also the nestedness of the interaction matrix. Indeed, the species abundances and the nestedness of the interaction matrix are correlated by an amount that depends on the strength of the mutualistic interactions. Nestedness and the observed spontaneous emergence of generalist and specialist species occur for several dynamical implementations of the variational principle under stationary conditions. Optimized networks, while remaining stable, tend to be less resilient than their counterparts with randomly assigned interactions. In particular, we analytically show that the abundance of the rarest species is directly linked to the resilience of the community. Our work provides a unifying framework for studying the emergent structural and dynamical properties of ecological mutualistic networks.Comment: 10 pages, 4 figure

Inverse planned stereotactic intensity modulated radiotherapy (IMRT) in the treatment of incompletely and completely resected adenoid cystic carcinomas of the head and neck: initial clinical results and toxicity of treatment

BACKGROUND: Presenting the initial clinical results in the treatment of complex shaped adenoid cystic carcinomas (ACC) of the head and neck region by inverse planned stereotactic IMRT. MATERIALS: 25 patients with huge ACC in different areas of the head and neck were treated. At the time of radiotherapy two patients already suffered from distant metastases. A complete resection of the tumor was possible in only 4 patients. The remaining patients were incompletely resected (R2: 20; R1: 1). 21 patients received an integrated boost IMRT (IBRT), which allow the use of different single doses for different target volumes in one fraction. All patients were treated after inverse treatment planning and stereotactic target point localization. RESULTS: The mean folllow-up was 22.8 months (91 – 1490 days). According to Kaplan Meier the three year overall survival rate was 72%. 4 patients died caused by a systemic progression of the disease. The three-year recurrence free survival was according to Kaplan Meier in this group of patients 38%. 3 patients developed an in-field recurrence and 3 patient showed a metastasis in an adjacent lymph node of the head and neck region. One patient with an in-field recurrence and a patient with the lymph node recurrence could be re-treated by radiotherapy. Both patients are now controlled. Acute side effects >Grade II did only appear so far in a small number of patients. CONCLUSION: The inverse planned stereotactic IMRT is feasible in the treatment of ACC. By using IMRT, high control rates and low side effects could by achieved. Further evaluation concerning the long term follow-up is needed. Due to the technical advantage of IMRT this treatment modality should be used if a particle therapy is not available

Survey of the quality of experimental design, statistical analysis and reporting of research using animals

For scientific, ethical and economic reasons, experiments involving animals should be appropriately designed, correctly analysed and transparently reported. This increases the scientific validity of the results, and maximises the knowledge gained from each experiment. A minimum amount of relevant information must be included in scientific publications to ensure that the methods and results of a study can be reviewed, analysed and repeated. Omitting essential information can raise scientific and ethical concerns. We report the findings of a systematic survey of reporting, experimental design and statistical analysis in published biomedical research using laboratory animals. Medline and EMBASE were searched for studies reporting research on live rats, mice and non-human primates carried out in UK and US publicly funded research establishments. Detailed information was collected from 271 publications, about the objective or hypothesis of the study, the number, sex, age and/or weight of animals used, and experimental and statistical methods. Only 59% of the studies stated the hypothesis or objective of the study and the number and characteristics of the animals used. Appropriate and efficient experimental design is a critical component of high-quality science. Most of the papers surveyed did not use randomisation (87%) or blinding (86%), to reduce bias in animal selection and outcome assessment. Only 70% of the publications that used statistical methods described their methods and presented the results with a measure of error or variability. This survey has identified a number of issues that need to be addressed in order to improve experimental design and reporting in publications describing research using animals. Scientific publication is a powerful and important source of information; the authors of scientific publications therefore have a responsibility to describe their methods and results comprehensively, accurately and transparently, and peer reviewers and journal editors share the responsibility to ensure that published studies fulfil these criteria

Combining estimates of interest in prognostic modelling studies after multiple imputation: current practice and guidelines

Background: Multiple imputation (MI) provides an effective approach to handle missing covariate data within prognostic modelling studies, as it can properly account for the missing data uncertainty. The multiply imputed datasets are each analysed using standard prognostic modelling techniques to obtain the estimates of interest. The estimates from each imputed dataset are then combined into one overall estimate and variance, incorporating both the within and between imputation variability. Rubin's rules for combining these multiply imputed estimates are based on asymptotic theory. The resulting combined estimates may be more accurate if the posterior distribution of the population parameter of interest is better approximated by the normal distribution. However, the normality assumption may not be appropriate for all the parameters of interest when analysing prognostic modelling studies, such as predicted survival probabilities and model performance measures. Methods: Guidelines for combining the estimates of interest when analysing prognostic modelling studies are provided. A literature review is performed to identify current practice for combining such estimates in prognostic modelling studies. Results: Methods for combining all reported estimates after MI were not well reported in the current literature. Rubin's rules without applying any transformations were the standard approach used, when any method was stated. Conclusion: The proposed simple guidelines for combining estimates after MI may lead to a wider and more appropriate use of MI in future prognostic modelling studies

Electrophysiological Heterogeneity of Fast-Spiking Interneurons: Chandelier versus Basket Cells

In the prefrontal cortex, parvalbumin-positive inhibitory neurons play a prominent role in the neural circuitry that subserves working memory, and alterations in these neurons contribute to the pathophysiology of schizophrenia. Two morphologically distinct classes of parvalbumin neurons that target the perisomatic region of pyramidal neurons, chandelier cells (ChCs) and basket cells (BCs), are generally thought to have the same "fast-spiking" phenotype, which is characterized by a short action potential and high frequency firing without adaptation. However, findings from studies in different species suggest that certain electrophysiological membrane properties might differ between these two cell classes. In this study, we assessed the physiological heterogeneity of fast-spiking interneurons as a function of two factors: species (macaque monkey vs. rat) and morphology (chandelier vs. basket). We showed previously that electrophysiological membrane properties of BCs differ between these two species. Here, for the first time, we report differences in ChCs membrane properties between monkey and rat. We also found that a number of membrane properties differentiate ChCs from BCs. Some of these differences were species-independent (e.g., fast and medium afterhyperpolarization, firing frequency, and depolarizing sag), whereas the differences in the first spike latency between ChCs and BCs were species-specific. Our findings indicate that different combinations of electrophysiological membrane properties distinguish ChCs from BCs in rodents and primates. Such electrophysiological differences between ChCs and BCs likely contribute to their distinctive roles in cortical circuitry in each species. © 2013 Povysheva et al

The effective action of D6-branes in N=1 type IIA orientifolds

We use a Kaluza-Klein reduction to compute the low-energy effective action for the massless modes of a spacetime-filling D6-brane wrapped on a special Lagrangian 3-cycle of a type IIA Calabi-Yau orientifold. The modifications to the characteristic data of the N=1 bulk orientifold theory in the presence of a D6-brane are analysed by studying the underlying Type IIA supergravity coupled to the brane worldvolume in the democratic formulation and performing a detailed dualisation procedure. The N=1 chiral coordinates are found to be in agreement with expectations from mirror symmetry. We work out the Kahler potential for the chiral superfields as well as the gauge kinetic functions for the bulk and the brane gauge multiplets including the kinetic mixing between the two. The scalar potential resulting from the dualisation procedure can be formally interpreted in terms of a superpotential. Finally, the gauging of the Peccei-Quinn shift symmetries of the complex structure multiplets reproduces the D-term potential enforcing the calibration condition for special Lagrangian 3-cycles.Comment: 48 pages, v2: typos corrected, references adde

The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin

Tetherin (CD317/BST2) is an interferon-induced membrane protein that inhibits the release of diverse enveloped viral particles. Several mammalian viruses have evolved countermeasures that inactivate tetherin, with the prototype being the HIV-1 Vpu protein. Here we show that the human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is sensitive to tetherin restriction and its activity is counteracted by the KSHV encoded RING-CH E3 ubiquitin ligase K5. Tetherin expression in KSHV-infected cells inhibits viral particle release, as does depletion of K5 protein using RNA interference. K5 induces a species-specific downregulation of human tetherin from the cell surface followed by its endosomal degradation. We show that K5 targets a single lysine (K18) in the cytoplasmic tail of tetherin for ubiquitination, leading to relocalization of tetherin to CD63-positive endosomal compartments. Tetherin degradation is dependent on ESCRT-mediated endosomal sorting, but does not require a tyrosine-based sorting signal in the tetherin cytoplasmic tail. Importantly, we also show that the ability of K5 to substitute for Vpu in HIV-1 release is entirely dependent on K18 and the RING-CH domain of K5. By contrast, while Vpu induces ubiquitination of tetherin cytoplasmic tail lysine residues, mutation of these positions has no effect on its antagonism of tetherin function, and residual tetherin is associated with the trans-Golgi network (TGN) in Vpu-expressing cells. Taken together our results demonstrate that K5 is a mechanistically distinct viral countermeasure to tetherin-mediated restriction, and that herpesvirus particle release is sensitive to this mode of antiviral inhibition