Cytosolic DNA Promotes Signal Transducer and Activator of Transcription 3 (STAT3) Phosphorylation by TANK-binding Kinase 1 (TBK1) to Restrain STAT3 Activity

Cytosolic DNA can elicit beneficial as well as undesirable immune responses. For example, viral or microbial DNA triggers cell-intrinsic immune responses to defend against infections, whereas aberrant cytosolic accumulation of self-DNA results in pathological conditions, such as autoimmunity. Given the importance of these DNA-provoked responses, a better understanding of their molecular mechanisms is needed. Cytosolic DNA engages stimulator of interferon genes (STING) to activate TANK-binding kinase 1 (TBK1), which subsequently phosphorylates the transcription factor interferon regulatory factor 3 (IRF3) to promote interferon expression. Recent studies have reported that additional transcription factors, including nuclear factor κB (NF-κB) and signal transducer and activator of transcription 6 (STAT6), are also activated by cytosolic DNA, suggesting that cytosolic DNA-induced gene expression is orchestrated by multiple factors. Here we show that cytosolic DNA activates STAT3, another member of the STAT family, via an autocrine mechanism involving interferon β (IFNβ) and IL-6. Additionally, we observed a novel cytosolic DNA-induced phosphorylation at serine 754 in the transactivation domain of STAT3. Upon cytosolic DNA stimulation, Ser 754 is directly phosphorylated by TBK1 in a STING-dependent manner. Moreover, Ser 754 phosphorylation inhibits cytosolic DNA-induced STAT3 transcriptional activity and selectively reduces STAT3 target genes that are up-regulated in response to cytosolic DNA. Taken together, our results suggest that cytosolic DNA-induced STAT3 activation via IFNβ and IL-6 is restrained by Ser 754 phosphorylation of STAT3. Our findings reveal a new signaling axis downstream of the cytosolic DNA pathway and suggest potential interactions between innate immune responses and STAT3-driven oncogenic pathways

Potential commercial application of a bi-layer bone-ligament regeneration scaffold to anterior cruciate ligament replacement

Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2006.Includes bibliographical references (p. 71-74).A business model was created in order to explore the commercial application of a bi-layer bone-ligament scaffold to the treatment of torn anterior cruciate ligaments (ACL) requiring replacement. The two main keys in producing the bone scaffold are triple co-precipitation of type-I collagen, chodroitin-6-sulphate, and calcium phosphate minerals and the use of lyophilization to create a network where all the materials are homogeneously dispersed and present in significant amounts. This process allows the creation of a porous network whose physical characteristics, mechanical properties, and material content can all be changed to create a scaffold that closely mimics natural bone. A collagen and chondroitin-6-sulphate scaffold is used for ligament regeneration. The ACL replacement market was chosen because it is one of the most commonly surgically repaired ligaments in the body and because all of the current treatments have drawbacks.(cont.) The exercise of creating a business model made it clear that the commercial potential of starting a company that focused on marketing a direct ACL replacement scaffold would most likely not be successful mainly because surgeons would hesitate to use this product over current methods that are satisfactory and it would be difficult to separate our product from other newer methods which all boast similar advantages over current treatment options. However, the commercial potential of using the technology to create a scaffold for graft site morbidity in certain ACL replacement surgeries is large because there is no competition, and the implantation procedure for the surgeon would be simple.by Jessica C. Li.M.Eng

Violencia sexual a menores de edad y el derecho a la salud integral, Lima Metropolitana 2022

En estos tiempos es difícil comprender como la violencia sexual a menores de edad se ha vuelto una de las grandes preocupaciones en nuestra sociedad y como tal forma parte de la vulneración en contra del derecho a la salud integral. Es por ello, el acto de conciencia que se fomenta para hacerle frente a este grave problema. Por esa razón, la tesis presentada tiene como objetivo general describir de qué manera la violencia sexual a menores de edad afecta al derecho a la salud integral, Lima Metropolitana 2022. Como también, analizar de qué manera las consecuencias físicas y el trastorno psicológico por efecto de violencia sexual vulnera al derecho a la salud. Asimismo, mediante un profundo análisis doctrinario se buscó amparar el derecho a la salud. Por consiguiente, la investigación emplea metodología de enfoque cualitativo, tipo básico de nivel descriptivo en base a teoría fundamentada, se recopilo información de revistas indexadas como artículos, doctrinas tanto nacionales e internacionales. Finalmente, se obtuvo como resultado que efectivamente la violencia sexual vulnera al derecho a la salud integral y se deberá brindar la seguridad jurídica para disminuir este tipo de violencia para el mejor resguardo y protección a la víctima

Burst suppression probability algorithms: state-space methods for tracking EEG burst suppression

Objective. Burst suppression is an electroencephalogram pattern in which bursts of electrical activity alternate with an isoelectric state. This pattern is commonly seen in states of severely reduced brain activity such as profound general anesthesia, anoxic brain injuries, hypothermia and certain developmental disorders. Devising accurate, reliable ways to quantify burst suppression is an important clinical and research problem. Although thresholding and segmentation algorithms readily identify burst suppression periods, analysis algorithms require long intervals of data to characterize burst suppression at a given time and provide no framework for statistical inference. Approach. We introduce the concept of the burst suppression probability (BSP) to define the brain's instantaneous propensity of being in the suppressed state. To conduct dynamic analyses of burst suppression we propose a state-space model in which the observation process is a binomial model and the state equation is a Gaussian random walk. We estimate the model using an approximate expectation maximization algorithm and illustrate its application in the analysis of rodent burst suppression recordings under general anesthesia and a patient during induction of controlled hypothermia. Main result. The BSP algorithms track burst suppression on a second-to-second time scale, and make possible formal statistical comparisons of burst suppression at different times. Significance. The state-space approach suggests a principled and informative way to analyze burst suppression that can be used to monitor, and eventually to control, the brain states of patients in the operating room and in the intensive care unit.National Institutes of Health (U.S.) (Award DP1-OD003646)National Institutes of Health (U.S.) (Award DP2-OD006454)National Institutes of Health (U.S.) (Award K08-GM094394)Burroughs Wellcome Fund (Award 1010625

Growth mindset in young people awaiting treatment in a paediatric mental health service: a mixed methods pilot of a digital single-session intervention

BACKGROUND: Wait times are significant in child mental health services but may offer opportunity to promote growth mindsets in young people with physical and mental health needs. A digital growth mindset single-session intervention is effective in young people, but its use in paediatric settings has not been examined. This mixed methods pilot aimed to assess the intervention’s feasibility, acceptability, and impact in this population. METHOD: Patients aged 8–18 on waiting lists in a paediatric hospital’s specialist mental health service were offered the intervention remotely. Treatment completion and retention rates, symptoms of depression and anxiety, perceived control, and personality mindset were assessed at baseline, post-treatment, and follow-ups. Semi-structured interviews to explore the intervention’s acceptability were conducted post-treatment. RESULTS: Twenty-five patients completed the intervention and 17 patients and three carers/parents were interviewed. Outcomes showed small to large improvements across time-points. Most patients reported finding the intervention enjoyable, accessible, and instilled a hope for change. They valued elements of the intervention but made suggestions for improvement. CONCLUSIONS: The digital growth mindset single-session intervention is feasible, acceptable, and potentially beneficial for young people with physical and mental health needs on waiting lists. Further research is warranted to examine its effectiveness and mechanism of change

Structural Characterization of Tick Cement Cones Collected From \u3ci\u3ein vivo\u3c/i\u3e and Artifical Membrane Blood-Fed Lone Star Ticks (\u3ci\u3eAmbylomma americanum\u3c/i\u3e)

The Lone Star tick, Amblyomma americanum, is endemic to the southeastern United States and capable of transmitting pathogenic diseases and causing non-pathogenic conditions. To remain firmly attached to the host, the tick secretes a proteinaceous matrix termed the cement cone which hardens around the tick’s mouthparts to assist in the attachment of the tick as well as to protect the mouthparts from the host immune system. Cement cones collected from ticks on a host are commonly contaminated with host skin and hair making analysis of the cone difficult. To reduce the contamination found in the cement cone, we have adapted an artificial membrane feeding system used to feed long mouthpart ticks. Cones collected from in vivo and membrane fed ticks are analyzed to determine changes in the cone morphology. Comparisons of the cement cones using light microscopy shows similar structures and color however using scanning electron microscopy the cones have drastically different structures. The in vivo cones contain fibrils, sheets, and are heavily textured whereas cones from membrane fed ticks are remarkably smooth with no distinct structures. Analysis of the secondary protein structures using FTIR-ATR show both in vivo and membrane fed cement cones contain β sheets but only in vivo cement cones contain helical protein structures. Additionally, proteomic analysis using LC–MS/MS identifies many proteins including glycine rich proteins, metalloproteases, and protease inhibitors. Proteomic analysis of the cones identified both secreted and non-secreted tick proteins. Artificial membrane feeding is a suitable model for increased collection of cement cones for proteomic analysis however, structurally there are significant differences

Mechanical feedback through E-cadherin promotes direction sensing during collective cell migration.

E-cadherin is a major homophilic cell-cell adhesion molecule that inhibits motility of individual cells on matrix. However, its contribution to migration of cells through cell-rich tissues is less clear. We developed an in vivo sensor of mechanical tension across E-cadherin molecules, which we combined with cell-type-specific RNAi, photoactivatable Rac, and morphodynamic profiling, to interrogate how E-cadherin contributes to collective migration of cells between other cells. Using the Drosophila ovary as a model, we found that adhesion between border cells and their substrate, the nurse cells, functions in a positive feedback loop with Rac and actin assembly to stabilize forward-directed protrusion and directionally persistent movement. Adhesion between individual border cells communicates direction from the lead cell to the followers. Adhesion between motile cells and polar cells holds the cluster together and polarizes each individual cell. Thus, E-cadherin is an integral component of the guidance mechanisms that orchestrate collective chemotaxis in vivo

Image guidance and inter-fractional anatomical variation in paediatric abdominal radiotherapy

OBJECTIVES: To identify variables predicting inter fractional anatomical variationsmeasured with cone-beam CT (CBCT) throughout abdominal paediatric radiotherapy, and to assess the potential of surface-guided radiotherapy (SGRT) to monitor these changes. METHODS: Metrics of variation in gastrointestinal (GI) gas volume andseparation of the body contour and abdominal wallwere calculated from 21 planning CTs and 77 weekly CBCTs for 21 abdominal neuroblastoma patients (median 4y, range: 2 -19y). Age, sex, feeding tubes, and general anaesthesia (GA) were explored as predictive variables for anatomical variation. Furthermore,GI gas variationwas correlated with changes in body and abdominal wall separation, as well as simulated SGRT metrics of translational and rotationalcorrections between CT/CBCT. RESULTS: GI gas volumes varied 74 ± 54 ml across all scans, while body and abdominal wall separationvaried 2.0 ± 0.7 mm and4.1±1.5mmfrom planning, respectively. Patients < 3.5y (p = 0.04) and treated under GA (p < 0.01) experienced greater GI gas variation; GA was the strongest predictor in multivariate analysis (p < 0.01). Absence of feeding tubes was linked to greater body contour variation (p = 0.03). GI gas variation correlated with body (R = 0.53) and abdominal wall (R = 0.63) changes. The strongest correlations with SGRT metrics were found for anteroposterior translation (R = 0.65) androtation of the left-right axis (R = -0.36). CONCLUSIONS: Young age, GA, and absence of feeding tubes were linked to stronger inter fractional anatomical variation and are likely indicative of patients benefiting from adaptive/robust planning pathways.Our data suggests a role for SGRT toinformthe need for CBCT at each treatment fractionin this patient group. ADVANCES IN KNOWLEDGE: This is the first study to suggest the potential role of SGRT for the management of internal inter fractional anatomical variation in paediatric abdominal radiotherapy

Incidental Ring-Hyperenhancing Liver Micronodules at CT Hepatic Arteriography-Guided Percutaneous Thermal Ablation of Colorectal Liver Metastases

CT during hepatic arteriography (CTHA) is a highly sensitive imaging method for detecting colorectal liver metastases (CLMs), which supports its use during percutaneous thermal liver ablation. In contrast to its high sensitivity, its specificity for incidental small CLMs not detected at preablation cross-sectional imaging is believed to be low given the absence of specific imaging signatures and the common presence of pseudolesions. In this retrospective study of 22 patients (mean age, 55 years ± 10.6 [SD]; 63.6% male, 36.4% female) with CLMs undergoing CTHA-guided microwave percutaneous thermal ablation between November 2017 and October 2022, the authors provided a definition of incidental ring-hyperenhancing liver micronodules (RHLMs) and investigated whether there is a correlation of RHLMs with histologic analysis or intrahepatic tumor progression at imaging follow-up after applying a biomechanical deformable image registration method. The analysis revealed 25 incidental RHLMs in 41.7% (10 of 24) of the CTHA images from the respective guided ablation sessions. Of those, four RHLMs were ablated. Among the remaining 21 RHLMs, 71.4% (15 of 21) were confirmed to be CLM with either histology