FTY720 (fingolimod), an FDA-approved drug for treatment of multiple sclerosis, has beneficial effects in the CNS that are not yet well understood, independent of its effects on immune cell ...trafficking. We show that FTY720 enters the nucleus, where it is phosphorylated by sphingosine kinase 2 (SphK2), and that nuclear FTY720-P binds and inhibits class I histone deacetylases (HDACs), enhancing specific histone acetylations. FTY720 is also phosphorylated in mice and accumulates in the brain, including the hippocampus, inhibits HDACs and enhances histone acetylation and gene expression programs associated with memory and learning, and rescues memory deficits independently of its immunosuppressive actions. Sphk2(-/-) mice have lower levels of hippocampal sphingosine-1-phosphate, an endogenous HDAC inhibitor, and reduced histone acetylation, and display deficits in spatial memory and impaired contextual fear extinction. Thus, sphingosine-1-phosphate and SphK2 play specific roles in memory functions and FTY720 may be a useful adjuvant therapy to facilitate extinction of aversive memories.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Ecological baselines-reference states of species' distributions and abundances-are key to the scientific arguments underpinning many conservation and management interventions, as well as to the ...public support to such interventions. Yet societal as well as scientific perceptions of these baselines are often based on ecosystems that have been deeply transformed by human actions. Despite increased awareness about the pervasiveness and implications of this shifting baseline syndrome, ongoing global assessments of the state of biodiversity do not take into account the long-term, cumulative, anthropogenic impacts on biodiversity. Here, we propose a new framework for documenting such impacts, by classifying populations according to the extent to which they deviate from a baseline in the absence of human actions. We apply this framework to the bowhead whale (
) to illustrate how it can be used to assess populations with different geographies and timelines of known or suspected impacts. Through other examples, we discuss how the framework can be applied to populations for which there is a wide diversity of existing knowledge, by making the best use of the available ecological, historical and archaeological data. Combined across multiple populations, this framework provides a standard for assessing cumulative anthropogenic impacts on biodiversity. This article is part of a discussion meeting issue 'The past is a foreign country: how much can the fossil record actually inform conservation?'
Several cognitive mechanisms have been proposed to account for the relationship between exposure to traumatic life events (TLEs) and the entire psychosis spectrum. However, only few of these ...mechanisms have been empirically tested and those that have been tested have not considered multiple mechanisms simultaneously. The purpose of this study was to examine whether perceived stress, dissociation, negative self-schemas, negative other-schemas, and/or external locus of control mediated the association between TLEs and psychotic-like experiences (PLEs). An undergraduate sample of 945 individuals completed a battery of self-report questionnaires. We found significant indirect effects from TLE exposure to PLEs through perceived stress, dissociation, external locus of control, negative self-schemas, and negative other-schemas. When controlling for comorbid psychological symptoms, only the indirect effect from TLE exposure to PLEs through dissociation continued to be significant. Targeting stress sensitivity, maladaptive schemas, dissociative tendencies, and externalizing attributional styles may prove useful in the amelioration of risk for various psychopathologies (e.g., mood, psychosis) in the aftermath of TLE exposure. Findings underscore the importance of targeting trauma-related cognitions in the prevention or reduction of psychotic-like experiences or disorders.
The Eastern Lau Spreading Center (ELSC) is the southernmost part of the back-arc spreading axis in the Lau Basin, west of the Tonga trench and the active Tofua volcanic arc. Over its 397-km length it ...exhibits large and systematic changes in spreading rate, magmatic/tectonic processes, and proximity to the volcanic arc. In 2005, we collected 81 samples of vent water from six hydrothermal fields along the ELSC. The chemistry of these waters varies both within and between vent fields, in response to changes in substrate composition, temperature and pressure, pH, water/rock ratio, and input from magmatic gases and subducted sediment. Hot-spring temperatures range from 229° to 363
°C at the five northernmost fields, with a general decrease to the south that is reversed at the Mariner field. The southernmost field, Vai Lili, emitted water at up to 334
°C in 1989 but had a maximum venting temperature of only 121
°C in 2005, due to waning activity and admixture of bottom seawater into the subseafloor plumbing system. Chloride varies both within fields and from one field to another, from a low of 528
mmol/kg to a high of 656
mmol/kg, and may be enriched by phase separation and/or leaching of Cl from the rock. Concentrations of the soluble elements K, Rb, Cs, and B likewise increase southward as the volcanic substrate becomes more silica-rich, especially on the Valu Fa Ridge. Iodine and δ
7Li increase southward, and δ
11B decreases as B increases, apparently in response to increased input from subducted sediment as the arc is approached. Species that decrease southward as temperature falls are Si, H
2S, Li, Na/Cl, Fe, Mn, and
87Sr/
86Sr, whereas pH, alkalinity, Ca, and Sr increase. Oxygen isotopes indicate a higher water/rock ratio in the three systems on Valu Fa Ridge, consistent with higher porosity in more felsic volcanic rocks. Vent waters at the Mariner vent field on the Valu Fa Ridge are significantly hotter, more acid and metal-rich, less saline, and richer in dissolved gases and other volatiles, including H
2S, CO
2, and F, than the other vent fields, consistent with input of magmatic gases. The large variations in geologic and geophysical parameters produced by back-arc spreading along the ELSC, which exceed those along mid-ocean ridge spreading axes, produce similar large variations in the composition of vent waters, and thus provide new insights into the processes that control the chemistry of submarine hot springs.
Traumatic brain injury (TBI) produces axotomy, deafferentation and reactive synaptogenesis. Inflammation influences synaptic repair, and the novel brain cytokine osteopontin (OPN) has potential to ...support axon regeneration through exposure of its integrin receptor binding sites. This study explored whether OPN secretion and proteolysis by matrix metalloproteinases (MMPs) mediate the initial degenerative phase of synaptogenesis, targeting reactive neuroglia to affect successful repair. Adult rats received unilateral entorhinal cortex lesion (UEC) modeling adaptive synaptic plasticity. Over the first week postinjury, hippocampal OPN protein and mRNA were assayed and histology was performed. At 1–2d, OPN protein increased up to 51 fold, and was localized within activated, mobilized glia. OPN transcript also increased over 50 fold, predominantly within reactive microglia. OPN fragments known to be derived from MMP proteolysis were elevated at 1d, consistent with prior reports of UEC glial activation and enzyme production. Postinjury minocycline immunosuppression attenuated MMP-9 gelatinase activity, which was correlated with the reduction of neutrophil gelatinase-associated lipocalin (LCN2) expression, and reduced OPN fragment generation. The antibiotic also attenuated removal of synapsin-1 positive axons from the deafferented zone. OPN KO mice subjected to UEC had similar reduction of hippocampal MMP-9 activity, as well as lower synapsin-1 breakdown over the deafferented zone. MAP1B and N-cadherin, surrogates of cytoarchitecture and synaptic adhesion, were not affected. OPN KO mice with UEC exhibited time dependent cognitive deficits during the synaptogenic phase of recovery. This study demonstrates that OPN can mediate immune response during TBI synaptic repair, positively influencing synapse reorganization and functional recovery.
•Cortical deafferentation produces time-dependent increase in hippocampal osteopontin.•Osteopontin production by reactive microglia mediates synapse reorganization.•Loss of osteopontin through immunosuppression or knock out attenuates synapse repair.•Metalloproteinase lysis of osteopontin supports glial integrin signaling with synaptogenesis.•Increased lipocalin 2 is correlated with matrix metalloproteinase-9 proteolysis of osteopontin.
The aim of this study was to determine the extent to which socioeconomic characteristics of the home and neighborhood are associated with racial inequalities in brain outcomes.
We performed a ...cross-sectional analysis of the baseline dataset (v.2.0.1) from the Adolescent Brain and Cognitive Development (ABCD) Study. Cognitive performance was assessed using the National Institutes of Health Toolbox (NIH-TB) cognitive battery. Standard socioeconomic indicators of the family and neighborhood were derived from census-related statistics. Cortical morphometric measures included MRI-derived thickness, area, and volume.
9638 children were included. Each NIH-TB cognitive measure was negatively associated with household and neighborhood socioeconomic characteristics. Differences in cognitive scores between Black or Hispanic children and other racial groups were mitigated by higher household income. Most children from lowest-income families or residents in impoverished neighborhoods were Black or Hispanic. These disparities were associated with racial differences in NIH-TB measures and mediated by smaller cortical brain volumes.
Neighborhood socioeconomic characteristics are associated with racial differences in preadolescent brain outcomes and mitigated by greater household income. Household income mediates racial differences more strongly than neighborhood-level socioeconomic indicators in brain outcomes. Highlighting these socioeconomic risks may direct focused policy-based interventions such as allocation of community resources to ensure equitable brain outcomes in children.
Neighborhood socioeconomic characteristics are associated with racial differences in preadolescent brain outcomes and mitigated by greater household income. Household income mediates racial differences more strongly than neighborhood-level socioeconomic indicators in brain outcomes. Highlighting these disparities related to socioeconomic risks may direct focused policy-based interventions such as allocation of community resources to ensure equitable brain outcomes in children.
Tuberculosis (TB) is a major public health concern worldwide with over 2 billion people currently infected. The rise of strains of Mycobacterium tuberculosis (Mtb) that are resistant to some or all ...first and second line antibiotics, including multidrug-resistant (MDR), extensively drug resistant (XDR) and totally drug resistant (TDR) strains, is of particular concern and new anti-TB drugs are urgently needed. Curcumin, a natural product used in traditional medicine in India, exhibits anti-microbial activity that includes Mtb, however it is relatively unstable and suffers from poor bioavailability. To improve activity and bioavailability, mono-carbonyl analogs of curcumin were synthesized and screened for their capacity to inhibit the growth of Mtb and the related Mycobacterium marinum (Mm). Using disk diffusion and liquid culture assays, we found several analogs that inhibit in vitro growth of Mm and Mtb, including rifampicin-resistant strains. Structure activity analysis of the analogs indicated that Michael acceptor properties are critical for inhibitory activity. However, no synergistic effects were evident between the monocarbonyl analogs and rifampicin on inhibiting growth. Together, these data provide a structural basis for the development of analogs of curcumin with pronounced anti-mycobacterial activity and provide a roadmap to develop additional structural analogs that exhibit more favorable interactions with other anti-TB drugs.
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•Monocarbonyl curcumin analogs inhibit growth of Mycobacterium marinum.•Analogs' Michael acceptors are critical for inhibitory effects.•The lead compound UBS-109 inhibits Mycobacterium tuberculosis.•UBS-109 blocks growth of drug resistant strains of Mycobacteria.
Poor preoperative nutritional status is associated with a higher complication rate after radical cystectomy in patients with bladder cancer. Given the short interval between diagnosis and radical ...cystectomy, we compared the effect of short-term specialized immunonutrition to that of a standard oral nutritional supplement on the acute inflammatory response and arginine status in patients treated with radical cystectomy.
In this prospective, randomized study in 29 men 14 received specialized immunonutrition and 15 received oral nutritional supplement. Each group drank 3 cartons per day for 5 days before and 5 days after radical cystectomy. The Th1-Th2 balance, plasma interleukin-6 and plasma amino acids were measured at baseline, intraoperatively and on postoperative days 2, 14 and 30. Body composition was measured by dual energy x-ray absorptiometry at baseline and on postoperative days 14 and 30. Differences in outcomes were assessed using the generalized linear mixed model.
In the specialized immunonutrition group there was a 54.3% average increase in the Th1-Th2 balance according to the tumor necrosis factor-α-to-interleukin-13 ratio from baseline to intraoperative day, representing a shift toward a Th1 response. In the oral nutritional supplement group the Th1-Th2 balance decreased 4.8%. The change in the Th1-Th2 balance between the specialized immunonutrition and oral nutritional supplement groups significantly differed (p <0.027). Plasma interleukin-6 was 42.8% lower in the specialized immunonutrition group compared to the oral nutritional supplement group on postoperative day 2 (p = 0.020). In the specialized immunonutrition group plasma arginine was maintained from baseline to postoperative day 2 and yet the oral nutritional supplement group showed a 26.3% reduction from baseline to postoperative day 2 (p = 0.0003). The change in appendicular muscle loss between the groups was not statistically significant.
Th1-to-Th2 ratios, peak interleukin-6 levels and plasma arginine suggest that consuming specialized immunonutrition counteracts the disrupted T-helper balance, lowers the inflammatory response and prevents arginine depletion due to radical cystectomy.
Abstract After radical cystectomy (RC), patients are at risk for complications including infections. The expansion of myeloid-derived suppressor cells (MDSCs) after surgery may contribute to the ...lower resistance to infection. Immune response and postoperative complications were compared in men consuming either specialized immunonutrition (SIM; n = 14) or an oral nutrition supplement (ONS; n = 15) before and after RC. MDSC count (Lin− CD11b+ CD33+) was significantly different between the groups over time ( p = 0.005) and significantly lower in SIM 2 d after RC ( p < 0.001). MDSC count expansion from surgery to 2 d after RC showed a weak association with an increase in infection rate 90 d after surgery ( p = 0.061). Neutrophil:lymphocyte ratio was significantly lower in SIM compared with ONS 3 h after the first incision ( p = 0.039). Participants receiving SIM had a 33% reduction in postoperative complication rate (95% confidence interval CI, 1–64; p = 0.060) and a 39% reduction in infection rate (95% CI, 8–70; p = 0.027) during late-phase recovery. The small sample size limits the study findings. Patient summary Results show that the immune response to surgery and late infection rates differ between radical cystectomy patients receiving specialized immunonutrition versus oral nutrition supplement in the perioperative period. Trial registration ClinicalTrials.gov NCT01868087.
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