178 research outputs found
Control of RelB during dendritic cell activation integrates canonical and noncanonical NF-ÎșB pathways.
The NF-ÎșB protein RelB controls dendritic cell (DC) maturation and may be targeted therapeutically to manipulate T cell responses in disease. Here we report that RelB promoted DC activation not as the expected RelB-p52 effector of the noncanonical NF-ÎșB pathway, but as a RelB-p50 dimer regulated by canonical IÎșBs, IÎșBα and IÎșBÉ. IÎșB control of RelB minimized spontaneous maturation but enabled rapid pathogen-responsive maturation. Computational modeling of the NF-ÎșB signaling module identified control points of this unexpected cell type-specific regulation. Fibroblasts that we engineered accordingly showed DC-like RelB control. Canonical pathway control of RelB regulated pathogen-responsive gene expression programs. This work illustrates the potential utility of systems analyses in guiding the development of combination therapeutics for modulating DC-dependent T cell responses
Neuroinflammatory markers associate with cognitive decline after major surgery:Findings of an explorative study
OBJECTIVE
Longâterm cognitive decline is an adverse outcome after major surgery associated with increased risk for mortality and morbidity. We studied the cerebrospinal fluid (CSF) and serum biochemical inflammatory response to a standardized orthopedic surgical procedure and the possible association with longâterm changes in cognitive function. We hypothesized that the CSF inflammatory response pattern after surgery would differ in patients having longâterm cognitive decline defined as a composite cognitive z score of â„1.0 compared to patients without longâterm cognitive decline at 3 months postsurgery.
METHODS
Serum and CSF biomarkers of inflammation and bloodâbrain barrier (BBB) integrity were measured preoperatively and up to 48 hours postoperatively, and cognitive function was assessed preoperatively and at 2 to 5âdays and 3 months postoperatively.
RESULTS
Surgery was associated with a pronounced increase in inflammatory biomarkers in both CSF and blood throughout the 48âhour study period. A principal component (PC) analysis was performed on 52 inflammatory biomarkers. The 2 first PC (PC1 and PC2) construct outcome variables on CSF biomarkers were significantly associated with longâterm cognitive decline at 3 months, but none of the PC construct serum variables showed a significant association with longâterm cognitive decline at 3 months. Patients both with and patients without longâterm cognitive decline showed early transient increases of the astroglial biomarkers Sâ100B and glial fibrillary acidic protein in CSF, and in BBB permeability (CSF/serum albumin ratio).
INTERPRETATION
Surgery rapidly triggers a temporal neuroinflammatory response closely associated with longâterm cognitive outcome postsurgery. The findings of this explorative study require validation in a larger surgical patient cohort. ANN NEUROL 202
Quantitative acoustic differentiation of cryptic species illustrated with King and Clapper rails
Reliable species identification is vital for survey and monitoring programs. Recently, the development of digital technology for recording and analyzing vocalizations has assisted in acoustic surveying for cryptic, rare, or elusive species. However, the quantitative tools that exist for species differentiation are still being refined. Using vocalizations recorded in the course of ecological studies of a King Rail (Rallus elegans) and a Clapper Rail (Rallus crepitans) population, we assessed the accuracy and effectiveness of three parametric (logistic regression, discriminant function analysis, quadratic discriminant function analysis) and six nonparametric (support vector machine, CART, Random Forest, kĂąâŹïżœnearest neighbor, weighted kĂąâŹïżœnearest neighbor, and neural networks) statistical classification methods for differentiating these species by their kek mating call. We identified 480 kek notes of each species and quantitatively characterized them with five standardized acoustic parameters. Overall, nonparametric classification methods outperformed parametric classification methods for species differentiation (nonparametric tools were between 57% and 81% accurate, parametric tools were between 57% and 60% accurate). Of the nine classification methods, Random Forest was the most accurate and precise, resulting in 81.1% correct classification of kek notes to species. This suggests that the mating calls of these sister species are likely difficult for human observers to tell apart. However, it also implies that appropriate statistical tools may allow reasonable speciesĂąâŹïżœlevel classification accuracy of recorded calls and provide an alternative to species classification where other captureĂąâŹïżœ or genotypeĂąâŹïżœbased survey techniques are not possible
Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model
Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis. We hypothesized that radium-223 and bortezomib combination treatment would have additive effects on MM. In vitro experiments revealed that the combination treatment inhibited MM cell proliferation and demonstrated additive efficacy. In the systemic, syngeneic 5TGM1 mouse MM model, both bortezomib and radium-223 decreased the osteolytic lesion area, and their combination was more effective than either monotherapy alone. Bortezomib decreased the number of osteoclasts at the tumor-bone interface, and the combination therapy resulted in almost complete eradication of osteoclasts. Furthermore, the combination therapy improved the incorporation of radium-223 into MM-bearing bone. Importantly, the combination therapy decreased tumor burden and restored body weights in MM mice. These results suggest that the combination of radium-223 with bortezomib could constitute a novel, effective therapy for MM and, in particular, myeloma bone disease
Pathogenic Bacillus anthracis in the progressive gene losses and gains in adaptive evolution
Background: Sequence mutations represent a driving force of adaptive evolution in bacterial pathogens. It is especially evident in reductive genome evolution where bacteria underwent lifestyles shifting from a free-living to a strictly intracellular or host-depending life. It resulted in loss of function mutations and/or the acquisition of virulence gene clusters. Bacillus anthracis shares a common soil bacterial ancestor with its closely related bacillus species but is the only obligate, causative agent of inhalation anthrax within the genus Bacillus. The anthrax-causing Bacillus anthracis experienced the similar lifestyle changes. We thus hypothesized that the bacterial pathogen would follow a compatible evolution path.
Results: In this study, a cluster-based evolution scheme was devised to analyze genes that are gained by or lost from B. anthracis. The study detected gene losses/gains at two separate evolutionary stages. The stage I is when B. anthracis and its sister species within the Bacillus cereus group diverged from other species in genus Bacillus. The stage II is when B. anthracis differentiated from its two closest relatives: B. cereus and B. thuringiensis. Many genes gained at these stages are homologues of known pathogenic factors such those for internalin, B. anthracis-specific toxins and large groups of surface proteins and lipoproteins.
Conclusion: The analysis presented here allowed us to portray a progressive evolutionary process during the lifestyle shift of B. anthracis, thus providing new insights into how B. anthracis had evolved and bore a promise of finding drug and vaccine targets for this strategically important pathogen
Nuclear Translocation of Jacob in Hippocampal Neurons after Stimuli Inducing Long-Term Potentiation but Not Long-Term Depression
Background: In recent years a number of potential synapto-nuclear protein messengers have been characterized that are thought to be involved in plasticity-related gene expression, and that have the capacity of importin- mediated and activity-dependent nuclear import. However, there is a surprising paucity of data showing the nuclear import of such proteins in cellular models of learning and memory. Only recently it was found that the transcription factor cyclic AMP response element binding protein 2 (CREB2) transits to the nucleus during long-term depression (LTD), but not during long-term potentiation (LTP) of synaptic transmission in hippocampal primary neurons. Jacob is another messenger that couples NMDA-receptor-activity to nuclear gene expression. We therefore aimed to study whether Jacob accumulates in the nucleus in physiological relevant models of activity-dependent synaptic plasticity. Methodology/Principal Findings: We have analyzed the dynamics of Jacobâs nuclear import following induction of NMDA-receptor dependent LTP or LTD at Schaffer collateral-CA1 synapses in rat hippocampal slices. Using time-lapse imaging of neurons expressing a Jacob-Green-Fluorescent-Protein we found that Jacob rapidly translocates from dendrites to the nucleus already during the tetanization period of LTP, but not after induction of LTD. Immunocytochemical stainings confirmed the nuclear accumulation of endogenous Jacob in comparison to apical dendrites after induction of LTP but not LTD. Complementary findings were obtained after induction of NMDA-receptor dependent chemical LTP and LTD i
IMI : global trends in myopia management attitudes and strategies in clinical practice : 2022 update
PURPOSE. Surveys in 2015 and 2019 identified a high level of eye care practitioner concern/activity about myopia, but the majority still prescribed single vision interventions to young myopes. This research aimed to provide updated information. METHODS. A self-administered, internet-based questionnaire was distributed in 13 languages, through professional bodies to eye care practitioners globally. The questions examined awareness of increasing myopia prevalence, perceived efficacy and adoption of available strategies, and reasons for not adopting specific strategies. RESULTS. Of the 3195 respondents, practitionersâ concern about the increasing frequency of pediatric myopia in their practices differed between continents (P < 0.001), being significantly higher in Asia (9.0 ± 1.5 of 10) than other continents (range 7.7â8.2; P †0.001). Overall, combination therapy was perceived by practitioners to be the most effective method of myopia control, followed by orthokeratology and pharmaceutical approaches. The least effective perceived methods were single vision distance undercorrection, spectacles and contact lenses, as well as bifocal spectacles. Practitioners rated their activity in myopia control between (6.6 ± 2.9 in South America to 7.9 ± 1.2/2.2 in Australasia and Asia). Single-vision spectacles are still the most prescribed option for progressing young myopia (32.2%), but this has decreased since 2019, and myopia control spectacles (15.2%), myopia control contact lenses (8.7%) and combination therapy (4.0%) are growing in popularity. CONCLUSIONS. More practitioners across the globe are practicing myopia control, but there are still significant differences between and within continents. Practitioners reported that embracing myopia control enhanced patient loyalty, increasing practice revenue and improving job satisfaction
MERS-CoV 4b protein interferes with the NF-ÎșB-dependent innate immune response during infection
This work is licensed under a Creative Commons Attribution 4.0 International License.Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel human coronavirus that emerged in 2012, causing severe pneumonia and acute respiratory distress syndrome (ARDS), with a case fatality rate of ~36%. When expressed in isolation, CoV accessory proteins have been shown to interfere with innate antiviral signaling pathways. However, there is limited information on the specific contribution of MERS-CoV accessory protein 4b to the repression of the innate antiviral response in the context of infection. We found that MERS-CoV 4b was required to prevent a robust NF-ÎșB dependent response during infection. In wild-type virus infected cells, 4b localized to the nucleus, while NF-ÎșB was retained in the cytoplasm. In contrast, in the absence of 4b or in the presence of cytoplasmic 4b mutants lacking a nuclear localization signal (NLS), NF-ÎșB was translocated to the nucleus leading to the expression of pro-inflammatory cytokines. This indicates that NF-ÎșB repression required the nuclear import of 4b mediated by a specific NLS. Interestingly, we also found that both in isolation and during infection, 4b interacted with α-karyopherin proteins in an NLS-dependent manner. In particular, 4b had a strong preference for binding karyopherin-α4 (KPNA4), which is known to translocate the NF-ÎșB protein complex into the nucleus. Binding of 4b to KPNA4 during infection inhibited its interaction with NF-ÎșB-p65 subunit. Thereby we propose a model where 4b outcompetes NF-ÎșB for KPNA4 binding and translocation into the nucleus as a mechanism of interference with the NF-ÎșB-mediated innate immune response
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