Janus Kinase 1 Is Required for Transcriptional Reprograming of Murine Astrocytes in Response to Endoplasmic Reticulum Stress

Neurodegenerative diseases are associated with the accumulation of misfolded proteins in the endoplasmic reticulum (ER), leading to ER stress. To adapt, cells initiate the unfolded protein response (UPR). However, severe or unresolved UPR activation leads to cell death and inflammation. The UPR is initiated, in part, by the transER membrane kinase PKR-like ER kinase (PERK). Recent evidence indicates ER stress and inflammation are linked, and we have shown that this involves PERKdependent signaling via Janus Kinase (JAK) 1. This signaling provokes the production of soluble inflammatory mediators such as interleukin-6 (IL-6) and chemokine C-C motif ligand 2 (CCL2). We, therefore, hypothesized that JAK1 may control widespread transcriptional changes in response to ER stress. Here, using RNA sequencing of primary murine astrocytes, we demonstrate that JAK1 regulates approximately 10% of ER stress-induced gene expression and is required for a subset of PERK-dependent genes. Additionally, ER stress synergizes with tumor necrosis factor-α (TNF-α) to drive inflammatory gene expression in a JAK1-dependent fashion. We identified that JAK1 contributes to activating transcription factor (ATF) 4-dependent gene expression, including expression of the genes growth arrest and DNA damage (GADD) 45α and tribbles (TRIB) 3 that have not previously been associated with JAK signaling. While these genes are JAK1 dependent in response to ER stress, expression of GADD45α and TRIB3 are not induced by the JAK1-activating cytokine, oncostatin M (OSM). Transcriptomic analysis revealed that JAK1 drives distinct transcriptional programs in response to OSM stimulation versus ER stress. Interestingly, JAK1-dependent genes induced by ER stress in an ATF4-dependent mechanism were unaffected by small molecule inhibition of JAK1, suggesting that, in response to UPR activation, JAK1 initiates gene expression using non-canonical mechanisms. Overall, we have identified that JAK1 is a major regulator of ER stress-induced gene expression

Endoplasmic Reticulum Stress Differentially Modulates the IL-6 Family of Cytokines in Murine Astrocytes and Macrophages

In many diseases, misfolded proteins accumulate within the endoplasmic reticulum (ER), leading to ER stress. In response, the cell initiates the unfolded protein response (UPR) to reestablish homeostasis. Additionally, in response to ER stress, various cell types mount an inflammatory response involving interleukin (IL)-6. While IL-6 has been widely studied, the impact of ER stress on other members of the IL-6 cytokine family, including oncostatin (OSM), IL-11, ciliary neurotrophic factor (CNTF), and leukemia inhibitor factor (LIF) remains to be elucidated. Here, we have examined the expression of the IL-6 family cytokines in response to pharmacologically-induced ER stress in astrocytes and macrophages, which express IL-6 in response to ER stress through different mechanisms. Our findings indicate that, in astrocytes, ER stress regulates mRNA expression of the IL-6 family of cytokines that is, in part, mediated by PKR-like ER kinase (PERK) and Janus kinase (JAK) 1. Additionally, in astrocytes, CNTF expression was suppressed through a PERK-dependent mechanism. Macrophages display a different profile of expression of the IL-6 family that is largely independent of PERK. However, IL-6 expression in macrophages was dependent on JAK signaling. Overall, this study demonstrates the cell-specific and differential mechanisms controlling expression of the IL-6 family of cytokines in response to ER stress

Endoplasmic reticulum stress and inflammation in the central nervous system

Persistent endoplasmic reticulum (ER) stress is thought to drive the pathology of many chronic disorders due to its potential to elicit aberrant inflammatory signaling and facilitate cell death. In neurodegenerative diseases, the accumulation of misfolded proteins and concomitant induction of ER stress in neurons contributes to neuronal dysfunction. In addition, ER stress responses induced in the surrounding neuroglia may promote disease progression by coordinating damaging inflammatory responses, which help fuel a neurotoxic milieu. Nevertheless, there still remains a gap in knowledge regarding the cell-specific mechanisms by which ER stress mediates neuroinflammation. In this review, we will discuss recently uncovered inflammatory pathways linked to the ER stress response. Moreover, we will summarize the present literature delineating how ER stress is generated in Alzheimer?s disease, Parkinson?s disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis, and highlight how ER stress and neuroinflammation intersect mechanistically within the central nervous system. The mechanisms by which stress-induced inflammation contributes to the pathogenesis and progression of neurodegenerative diseases remain poorly understood. Further examination of this interplay could present unappreciated insights into the development of neurodegenerative diseases, and reveal new therapeutic targets

Cooking Hand Multi-Tool

The purpose of this project was to devise a solution for Jorge Segura, a US Marine who was wounded in Afghanistan and had to have his non-dominant arm amputated above the elbow. His current prosthetic attachments are not suited to cooking tasks, so he needed a way to cook more effectively with either prosthetic attachments or accessibility devices. The main tasks that he needed help with was holding down food on cutting boards and stabilizing pots, pans, and bowls especially when stirring. After background research, exploring commercially available devices, and talking with our challenger, our solution was to design three prosthetic attachments with a quick-change wrist to enable Jorge to stabilize pots, pans, and bowls, as well as hold food down on a cutting board and switch between the attachments efficiently. The quick-change wrist operates in a twist-and-lock fashion, with the wrist inserts mating into the wrist receiver and locking into place with magnets on each component. The wrist receiver easily mates with Jorge’s current wrist so that he can efficiently and easily install our quick-change wrist into his existing wrist. The wrist is predominantly made from delrin to reduce weight and improve component machinability. The prototyping process for the wrist cost $144.58 to develop our functional prototypes, while the estimated mass production cost is only$13.99 per wrist assembly. The clamp attachment interfaces with Jorge’s current body powered prosthetic arm through a connector plate mounted on the attachment body. Jorge is able to engage the cable to open the clamp so that it can fit over various sizes of pots and bowls, and release the tension in the cable to allow it to close over the pot or bowl. The clamp is also fully adjustable, with a trifold face designed with springs to conform to different diameters, and an angled guide that is adjustable with thumb screws to allow Jorge to angle the trifold to fit on curved bowls. It also includes a set of angled and straight inner prongs that can be removed for easier cleaning. The clamp is predominantly made from aluminum to reduce weight, and has an estimated cost of $209.55 to develop our functional prototypes, while the estimated mass production cost is only$43.25 per clamp assembly. The sleeve attachment allows Jorge to stabilize shallow pans with long handles. The design includes a simple diamond-shaped opening to fit over a variety of pan sizes, and has no moving parts for simplicity. Made from a 3D printed core and sheet metal inserts and connections, the sleeve is relatively lightweight and easy to manufacture. Design development to make our sleeve prototypes cost $124.91, while the estimated mass production cost of one sleeve is only$8.05. The cutting tool attachment enables Jorge to secure various sizes of food onto a cutting board. It is made of clear acrylic to allow Jorge to receive visual feedback from what he is cutting. The design of the cutting tool attachment includes several ridges to allow for better grip, and a narrow slit on the base to allow for perpendicular knife cuts. The cutting tool has an estimated development cost of $70.86 for the prototypes, with an estimated mass production cost of$4.72 per assembly. For future manufacturing of the wrist, we recommend that the wrist inserts be made from aluminum instead of delrin to improve the strength of the epoxied and press-fit joints. This would increase the weight of the device and decrease the cost slightly. We recommend that future iterations of the clamp include a more robust prong design, and a more secure connection for the angle guides. To manufacture more copies of the sleeve, we recommend adding a key to both sides of the connecting rod to fully restrain the rotation of the connecting rod. This would increase the weight and cost of the sleeve marginally. Finally, for future iterations of the cutting tool we recommend looking into a solid construction cast from food-safe resin in order to improve cutting tool durability with respect to impact loads

Effect of genotype and pretreatment of field peas (Pisum sativum) on their dehulling and cooking quality

Field peas (Pisum sativum), an important pulse crop in Australia, are consumed as human food either as whole seeds or as splits after decortication. The yield of splits is an important economic factor for processors and the cooking quality is important for consumers. Effects of genotype, other physical characteristics and pretreatment in various solutions on both dehulling and cooking quality were studied for 23 known genotypes and are market sample of unknown genotype. Large variations were found for most characteristics. Seed size was positively correlated with yield of splits while husk content and broken seeds were negatively correlated with yield. Preconditioning seeds in salt solutions improved yield of splits. Variation in cooking quality among genotypes was reduced following splitting and cooking time was reduced by decortication and splitting and by presoaking in salt solutions (10 or 20 g kg-1), particularly with sodium tripolyphosphate. Loss of seed material into cooking water was correlated with cooking time. No characteristic was found that could be used to predict cooking tim

Assessing Depression in Childhood and Adolescence: A Guide for Social Work Practice

Depression is relatively common in children and adolescents, and if left undetected and untreated, can have long-term negative consequences. Social workers providing services to families, children and adolescents need to understand the characteristics, and conduct developmentally appropriate assessments, of depressive symptoms. This paper provides a review of current literature related to the definition, prevalence, co-occurrence, and measurement of depression in childhood and adolescence. It also highlights relevant gender, race, and ethnic influences.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44242/1/10560_2004_Article_457005.pd

Screening for Meares-Irlen sensitivity in adults: can assessment methods predict changes in reading speed?

Two methods of assessing candidates for coloured overlays were compared with the aim of determining which method had the most practical utility. A total of 58 adults were assessed as potential candidates for coloured overlays, using two methods; a questionnaire, which identified self-reported previous symptoms, and a measure of perceptual distortions immediately prior to testing. Participants were classified as normal, Meares-Irlen sensitive, and borderline sensitive. Reading speed was measured with and without coloured overlays, using the Wilkins Rate of Reading Test and the change in speed was calculated. Participants classified as normal did not show any significant benefit from reading with an overlay. In contrast, a significant reading advantage was found for the borderline and Meares-Irlen participants. Current symptom rating was found to be a significant predictor of the change in reading speed, however the previous symptom rating was not found to be a reliable predictor. These data indicate that the assessment of perceptual distortions immediately prior to measuring colour preference and reading speed is the most meaningful method of assessing pattern glare and determining the utility of coloured overlays

MicroRNA-31 is required for astrocyte specification

Previously, we determined microRNA-31 (miR-31) is a noncoding tumor suppressive gene frequently deleted in glioblastoma (GBM); miR-31 suppresses tumor growth, in part, by limiting the activity of NF-κB. Herein, we expand our previous studies by characterizing the role of miR-31 during neural precursor cell (NPC) to astrocyte differentiation. We demonstrate that miR-31 expression and activity is suppressed in NPCs by stem cell factors such as Lin28, c-Myc, SOX2 and Oct4. However, during astrocytogenesis, miR-31 is induced by STAT3 and SMAD1/5/8, which mediate astrocyte differentiation. We determined miR-31 is required for terminal astrocyte differentiation, and that the loss of miR-31 impairs this process and/or prevents astrocyte maturation. We demonstrate that miR-31 promotes astrocyte development, in part, by reducing the levels of Lin28, a stem cell factor implicated in NPC renewal. These data suggest that miR-31 deletions may disrupt astrocyte development and/or homeostasis

Food meanings in HIV and AIDS caregiving trajectories: Ritual, optimism and anguish among caregivers in Lesotho

The article describes the caregiving responsibility to provide food for chronically ill family members and the meanings attached to food and eating when ill created stress for family caregivers. The results come from a qualitative phenomenological study using in-depth interviews with 21 family caregivers of chronically ill HIV and AIDS patients in one district in Lesotho. Analysis of the interview data showed that the caregivers attached profound meanings to food and feeding care recipients. Their perceptions about food as part of family life and caring, the role of food and eating in curbing disease progression, the link between food and medical efficacy and the link between food and life led to ritualised behaviour around food, and moments of optimism and anguish in caregiving. Patients’ behaviour in relation to food was in most instances inconsistent with the caregivers’ goals, thus leading this aspect of caregiving to induce stress. Services intended to support home-based caregivers and patients could contribute to the reduction of stress associated with food through suitably tailored food assistance and professional support to caregivers to enhance their competences and understanding of the dynamics of food intake as AIDS progressed

Comparison between two methods of working length determination and its effect on radiographic extent of root canal filling: a clinical study [ISRCTN71486641]

BACKGROUND: Obtaining a correct working length is critical to the success of endodontic therapy. Different methods have been used to identify this crucial measurement. The Aim of this clinical study was to compare the effect of working length determination using apex locator alone or in combination with working length radiograph on the apical extent of root canal filling. METHODS: A total number of 66 patients, 151 canals were randomized into two groups, In group (I) working length was determined by apex locator alone, while in group (II) working length was determined by apex locator confirmed by working length radiograph, length of obturation was assessed, and the total number of radiographs was recorded. The data were analyzed using SAS system and T. tests were carried out. Statistical significance was considered to be P ≤ 0.05. RESULTS: Sixty seven canals in group I were treated with a mean distance from the tip of root canal filling to radiographic apex -0.5 mm ± 0.5 and a mean of a total number of radiographs of 2.0, while in group II eighty four canals were treated with a mean distance from the tip of root canal filling to radiographic apex -0.4 mm ± 0.5 and a mean of a total number of radiographs of 3.2. There was no statistically significant difference in the mean distance from the tip of root filling to radiographic apex between group I and group II (P > 0.05). CONCLUSION: The practice of using electronic apex locator in the determination of working length is useful and reliable with no statistical difference of the radiographic extent of root canal filling when using apex locator alone or in combination with working length radiograph. Under the clinical conditions of this study, it is suggested that the correct use of an apex locator alone could prevent the need for further diagnostic radiographs for determination of working length. This method can be useful in patients who need not to be exposed to repeated radiation because of mental, medical or oral conditions