Traumatic brain injury (TBI) leaves many survivors with long-term disabilities. A prolonged immune response in the brain may cause neurodegeneration, resulting in chronic neurological disturbances. ...In this study, using a TBI mouse model, we correlate changes in the local immune response with neurodegeneration/neurological dysfunction over an 8-month period. Flow cytometric analysis reveals a protracted increase in effector/memory CD8+ T cells (expressing granzyme B) in the injured brain. This precedes interleukin-17+CD4+ T cell infiltration and is associated with progressive neurological/motor impairment, increased circulating brain-specific autoantibodies, and myelin-related pathology. Genetic deficiency or pharmacological depletion of CD8+ T cells, but not depletion of CD4+ T cells, improves neurological outcomes and produces a neuroprotective Th2/Th17 immunological shift, indicating a persistent detrimental role for cytotoxic T cells post-TBI. B cell deficiency results in severe neurological dysfunction and a heightened immune reaction. Targeting these adaptive immune cells offers a promising approach to improve recovery following TBI.
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•Granzyme B+ CD8+ T cells accumulate in the brain after traumatic brain injury (TBI)•Brain CD8+ T cells contribute to chronic motor deficits and myelin pathology•Deficiency/depletion of CD8+ T cells promotes neurological recovery following TBI•B cells and autoreactive antibodies appear to play a regulatory role in TBI
Daglas et al. show that granzyme B+CD8+ T cells accumulate in the brain after traumatic brain injury, triggering chronic neurological/motor impairment and myelin pathology. Genetic deficiency/pharmacological depletion of CD8+ T cells, but not B cells, promotes recovery post-injury and offers a therapeutic option to minimize long-term disabilities in trauma patients.
Removal of dead cells in the absence of concomitant immune stimulation is essential for tissue homeostasis. We recently identified an injury-induced protein misfolding event that orchestrates the ...plasmin-dependent proteolytic degradation of necrotic cells. As impaired clearance of dead cells by the innate immune system predisposes to autoimmunity, we determined whether plasmin could influence endocytosis and immune cell stimulation by dendritic cells - a critical cell that links the innate and adaptive immune systems. We find that plasmin generated on the surface of necrotic cells enhances their phagocytic removal by human monocyte-derived dendritic cells. Plasmin also promoted phagocytosis of protease-resistant microparticles by diverse mouse dendritic cell sub-types both in vitro and in vivo. Together with an increased phagocytic capacity, plasmin-treated dendritic cells maintain an immature phenotype, exhibit reduced migration to lymph nodes, increase their expression/release of the immunosuppressive cytokine TGF-β, and lose their capacity to mount an allogeneic response. Collectively, our findings support a novel role for plasmin formed on dead cells and other phagocytic targets in maintaining tissue homeostasis by increasing the phagocytic function of dendritic cells while simultaneously decreasing their immunostimulatory capacity consistent with producing an immunosuppressive state.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains ...poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (γ-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Necroptotic cell death has been implicated in many human pathologies and is thought to have evolved as an innate immunity mechanism. The pathway relies on two key effectors: the kinase ...receptor-interacting protein kinase 3 (RIPK3) and the terminal effector, the pseudokinase mixed-lineage kinase-domain-like (MLKL). We identify proteins with high sequence similarity to the pseudokinase domain of MLKL in poxvirus genomes. Expression of these proteins from the BeAn 58058 and Cotia poxviruses, but not swinepox, in human and mouse cells blocks cellular MLKL activation and necroptotic cell death. We show that viral MLKL-like proteins function as dominant-negative mimics of host MLKL, which inhibit necroptosis by sequestering RIPK3 via its kinase domain to thwart MLKL engagement and phosphorylation. These data support an ancestral role for necroptosis in defense against pathogens. Furthermore, mimicry of a cellular pseudokinase by a pathogen adds to the growing repertoire of functions performed by pseudokinases in signal transduction.
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•Some poxviruses encode proteins with homology to mammalian MLKL pseudokinase domains•BAV and Cotia viral MLKL proteins inhibit necroptotic death of human and mouse cells•These viral MLKL proteins target RIPK3 to block activation of cellular MLKL•Viral MLKL proteins inhibit RIPK3 via species-specific mechanisms
Petrie et al. identify proteins encoded by some poxviruses with homology to the pseudokinase domain of the terminal necroptosis effector, MLKL. Via species-specific mechanisms, viral MLKL proteins block necroptotic death in human and mouse cells by sequestering RIPK3 to prevent phosphorylation and activation of MLKL.
To evaluate the association between the dietary inflammatory index (DII
) and incident cardiovascular disease (CVD) in Hispanic women from the Women's Health Initiative (WHI), and to determine if ...body mass index (BMI) interacted with the DII scores.
Secondary analysis of baseline dietary data and long-term CVD outcomes among 3,469 postmenopausal women who self-identified as Hispanic enrolled in WHI. DII scores were calculated from self-administered food frequency questionnaires. The CVD outcomes included coronary heart disease (CHD) and stroke. Stratified Cox regression models were used to assess the relationship between DII scores and CVD in women with and without obesity. Models were adjusted for age, lifestyle risk factors, known risk factors, and neighborhood socioeconomic status.
The incidence of CHD was 3.4 and 2.8% for stroke after a median follow-up of 12.9 years. None of the DIIs were associated with CVD risk in this sample of Hispanic women. BMI interacted with the DII (p < 0.20) and stratified models showed that the associations between the DII and CVD were only significant in women with overweight (p < 0.05). In this group, higher DII scores were associated with a higher risk of CHD (HR 1.27; 95% CI: 1.08, 1.51) and a higher risk of stroke (HR 1.32; 95% CI: 1.07, 1.64).
Among postmenopausal Hispanic women with overweight, greater adherence to pro-inflammatory diets was associated with higher risk of CVD. Additional research is needed to understand how to promote long-term heart-healthy dietary habits to reduce inflammation and prevent CVD in at-risk Hispanic women.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
We report more than 1400 proteins of the secretory-pathway proteome and provide spatial information on the relative presence of each protein in the rough and smooth ER Golgi cisternae and ...Golgi-derived COPI vesicles. The data support a role for COPI vesicles in recycling and cisternal maturation, showing that Golgi-resident proteins are present at a higher concentration than secretory cargo. Of the 1400 proteins, 345 were identified as previously uncharacterized. Of these, 230 had their subcellular location deduced by proteomics. This study provides a comprehensive catalog of the ER and Golgi proteomes with insight into their identity and function.
Extracellular proteolysis of platelet plasma membrane proteins is an event that ensues platelet activation. Shedding of surface receptors such as glycoprotein (GP) Ibα, GPV and GPVI as well as ...externalized proteins P-selectin and CD40L releases soluble ectodomain fragments that are subsequently detectable in plasma. This results in the irreversible functional downregulation of platelet receptor-mediated adhesive interactions and the generation of biologically active fragments. In this review, we describe molecular insights into the regulation of platelet receptor and ligand shedding in health and disease. The scope of this review is specially focused on GPIbα, GPV, GPVI, P-selectin and CD40L where we: (1) describe the basic physiological regulation of expression and shedding of these proteins in hemostasis illustrate alterations in receptor expression during (2) apoptosis and (3) ex vivo storage relevant for blood banking purposes; (4) discuss considerations to be made when analyzing and interpreting shedding of platelet membrane proteins and finally; (5) collate clinical evidence that quantify these platelet proteins during disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract Background Few studies have assessed the dietary quality of children who eat meals from home compared with school meals according to the 2010 Dietary Guidelines for Americans. Objective The ...objective of this study was to examine diet quality for elementary school students in relation to source of breakfast and lunch (whether school meal or from an outside source). Design An observational study was conducted of students in 43 schools in San Diego, CA, during the 2011-2012 school year. Participants/setting Fourth- and fifth-grade students (N=3,944) completed a diary-assisted 24-hour food recall. Main outcome measures The Healthy Eating Index-2010 (HEI-2010) scores of children who ate breakfast and lunch at school were compared with the HEI-2010 scores of children who obtained their meals from home and a combination of both school and home. Statistical analysis Analysis of variance, χ2 test, and generalized estimating equation models adjusted for age, sex, race/ethnicity, grade, language, and school level clustering were performed. Results School lunch eaters had a higher mean±standard deviation overall diet quality score (HEI-2010=49.0±11.3) compared with students who ate a lunch obtained from home (46.1±12.2; P =0.02). There was no difference in overall diet quality score by breakfast groups. Students who ate school breakfast had higher total fruit ( P =0.01) and whole fruit ( P =0.0008) scores compared with students who only ate breakfast obtained from home. Students who ate school foods had higher scores for dairy ( P =0.007 for breakfast and P <0.0001 for lunch) and for empty calories from solid fats and added sugars ( P =0.01 for breakfast and P =0.007 for lunch). Conclusions Eating school lunch was associated with higher overall diet quality compared with obtaining lunch from home. Future studies are needed that assess the influence of the Healthy Hunger-Free Kids Act on children’s diet quality.
Children eat more fruits and vegetables when more are available at home, but less is known about how the neighborhood food environment relates to children’s diet and weight outcomes. The goal of this ...study was to determine whether parental perception of the food environment (neighborhood and home) is associated with children’s fruit and vegetable (F&V) intake and weight outcomes, and to assess differences by household food security status and household income. Cross-sectional data from the 2013–2015 U.S. Healthy Communities Study included 5138 children, aged 4 to 15 years old, from 130 U.S. communities. Neighborhood and home food environments were assessed with parent-reported, perceived F&V availability scores. Associations were tested with multi-level linear regression models. Parents’ perception of produce availability was associated with household F&V availability ratings (β = 0.09 points, p < 0.001). Household F&V availability was associated with child F&V intake (β = 0.32 cups/day or 25.6 g/day, p < 0.001). A higher child F&V intake was associated with a lower child BMI z-score (β = −0.05, p = 0.002). Weaker relationships were seen for children living in food insecure or low-income households. Optimizing neighborhood and home access to F&V may help children improve diet quality, but may not be as effective for children living in food insecure or low-income households.
The molecular basis of changes in structure, cellular location, and function of the Golgi apparatus during male germ cell differentiation is unknown. To deduce cognate Golgi proteins, we isolated ...germ cell Golgi fractions, and 1318 proteins were characterized, with 20 localized in situ. The most abundant protein, GL54D of unknown function, is characterized as a germ cell-specific Golgi-localized type II integral membrane glycoprotein. TM9SF3, also of unknown function, was revealed to be a universal Golgi marker for both somatic and germ cells. During acrosome formation, several Golgi proteins (GBF1, GPP34, GRASP55) localize to both the acrosome and Golgi, while GL54D, TM9SF3, and the Golgi trafficking protein TMED7/p27 are segregated from the acrosome. After acrosome formation, GL54D, TM9SF3, TMED4/p25, and TMED7/p27 continue to mark Golgi identity as it migrates away from the acrosome, while the others (GBF1, GPP34, GRASP55) remain in the acrosome and are progressively lost in later steps of differentiation. Cytoplasmic HSP70.2 and the endoplasmic reticulum luminal protein-folding enzyme PDILT are also Golgi recruited but only during acrosome formation. This resource identifies abundant Golgi proteins that are expressed differentially during mitosis, meiosis, and postacrosome Golgi migration, including the last step of differentiation.
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