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The integration of multiple signalling pathways that co-ordinate T cell metabolism and transcriptional reprogramming is required to drive T cell differentiation and proliferation. One key T cell signalling module is mediated by extracellular signal-regulated kinases (ERKs) which are activated in response to antigen receptor engagement. The activity of ERKs is often used to report antigen receptor occupancy but the full details of how ERKs control T cell activation is not understood. Accordingly, we have used mass spectrometry to explore how ERK signalling pathways control antigen receptor driven proteome restructuring in CD8+ T cells to gain insights about the biological processes controlled by ERKs in primary lymphocytes. Quantitative analysis of >8000 proteins identified 900 ERK regulated proteins in activated CD8+ T cells. The data identify both positive and negative regulatory roles for ERKs during T cell activation and reveal that ERK signalling primarily controls the repertoire of transcription factors, cytokines and cytokine receptors expressed by activated T cells. It was striking that a large proportion of the proteome restructuring that is driven by triggering of the T cell antigen receptor is not dependent on ERK activation. However, the selective targets of the ERK signalling module include the critical effector molecules and the cytokines that allow T cell communication with other immune cells to mediate adaptive immune responses.Friedreich ataxia (FA) is a neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. In primary cultures of dorsal root ganglia neurons, we showed that frataxin depletion resulted in decreased levels of the mitochondrial calcium exchanger NCLX, neurite degeneration and apoptotic cell death. Here, we describe that frataxin-deficient dorsal root ganglia neurons display low levels of ferredoxin 1 (FDX1), a mitochondrial Fe/S cluster-containing protein that interacts with frataxin and, interestingly, is essential for the synthesis of calcitriol, the active form of vitamin D. We provide data that calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both FDX1 and NCLX levels and restores mitochondrial membrane potential indicating an overall mitochondrial function improvement. Accordingly, reduction in apoptotic markers and neurite degeneration was observed and, as a result, cell survival was also recovered. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both, frataxin-deficient DRG neurons and cardiomyocytes; remarkably, this increase also occurs in lymphoblastoid cell lines derived from FA patients. In conclusion, these results provide molecular bases to consider calcitriol for an easy and affordable therapeutic approach for FA patients.Theoretical models explaining serial order processing link order information to specified position markers. However, the precise characteristics of position marking have remained largely elusive. Recent studies have shown that space is involved in marking serial position of items in verbal working memory (WM). Furthermore, it has been suggested, but not proven, that accessing these items involves horizontal shifts of spatial attention. We used continuous electroencephalography recordings to show that memory search in serial order verbal WM involves spatial attention processes that share the same electrophysiological signatures as those operating on the visuospatial WM and external space. Accessing an item from a sequence in verbal WM induced posterior "early directing attention negativity" and "anterior directing attention negativity" contralateral to the position of the item in mental space (i.e., begin items on the left; end items on the right). In the frequency domain, we observed posterior alpha suppression contralateral to the position of the item. Our results provide clear evidence for the involvement of spatial attention in retrieving serial information from verbal WM. Implications for WM models are discussed.Lesbian, gay, bisexual, and transgender (LGBT) older adults are at particular risk for receiving inequitable end-of-life care. Their health care wishes may be ignored or disregarded, their families of choice are less likely to be included in their decision making, and they may experience increased isolation, bullying, mistreatment, or abuse, which ultimately contribute to receipt of poor-quality health care. This is particularly important during sensitive transitions along the care continuum to end-of-life settings; 43% of respondents of a 2018 survey of 865 hospice professionals reported having directly observed discriminatory behavior toward LGBT patients. Lack of visibility and accountability perpetuates vulnerabilities and the potential for discriminatory treatment. Unfortunately, while other areas of health care have prioritized and normalized collecting sexual orientation and gender identity (SOGI) data, hospices do not routinely assess patients' SOGI in the context of end-of-life wishes and decisions. Drawing insight from a sample of 31 in-depth interviews with older LGBT adults, this paper focuses on one participant's story-Esther's. We chose her story to illustrate how care can be compromised at the end of life if an open discussion with patients about what and who matters most to them at the end of life, is avoided.
N-methyl-D-aspartate (NMDA) receptor activation requires the binding of a co-agonist on the glycine-binding site. D-serine is the main endogeneous co-agonist of NMDA receptors, and its availability significantly depends on the activity of the metabolic enzyme D-amino acid oxidase (DAAO). Inhibition of DAAO increases the brain levels of D-serine, and modulates a variety of physiological functions including cognitive behavior.
Here, we examined the effects of a novel 4‑hydroxypyridazin-3(2H)‑one derivative DAAO inhibitor, Compound 30 (CPD30) on passive avoidance learning and on neuronal firing activity in rats.
D-serine administration was applied as reference, which increased cognitive performance and enhanced hippocampal firing activity and responsiveness to NMDA after both local and systemic application. Similarly to D-serine, CPD30 (0.1mg/kg) effectively reversed MK-801 induced memory impairment in the passive avoidance test. Furthermore, local iontophoretic application of CPD30 in the vicinity of hippian brain.
The purpose of this study was to explore associations between physical activity, cardiovascular risk factors, mobility, mood, fatigue, and cognition over 2years following stroke rehabilitation discharge.
In this longitudinal observational study, survivors of first-ever stroke were evaluated at rehabilitation discharge and 6, 12, and 24months later. Moderate to vigorous physical activity (MVPA) duration (minutes/day) assessed with an electronic monitor was the primary outcome. Further outcomes included step count, the number and duration of MVPA and sedentary bouts, cardiovascular risk factors (eg, blood pressure, fasting lipid profile, body mass index [BMI]), gait speed and endurance, mood, fatigue, and cognition. Associations between physical activity and cardiovascular risk factors over time were assessed with random-effects regression modeling. Associations between baseline characteristics and physical activity at 2years were explored using regression modeling.
Seventy-nine participants (68.4% men) w0 minutes might be challenging, but it could be an important component of treatments to reduce cardiovascular risk after stroke.
VRE are nosocomial pathogens with an increasing incidence in recent decades. Rapid detection is crucial to reduce their spread and prevent infections and outbreaks.
To evaluate a lateral flow immunoassay (LFIA) (called NG-Test VanA) for the rapid and reliable detection of VanA-producing VRE (VanA-VRE) from colonies and broth.
NG-Test VanA was validated on 135 well-characterized enterococcal isolates grown on Mueller-Hinton (MH) agar (including 40 VanA-VRE). Different agar plates and culture broths widely used in routine laboratories for culture of enterococci were tested.
All 40 VanA-VRE clinical isolates were correctly detected in less than 15 min irrespective of the species expressing the VanA ligase and the medium used for bacterial growth. No cross-reaction was observed with any other clinically relevant ligases (VanB, C1, C2, D, E, G, L, M and N). Overall, the sensitivity and specificity of the assay were 100% for VanA-VRE grown on MH agar plates. NG-Test VanA accurately detects VanA-VRE irrespective of the culture medium (agar and broth). Band intensity was increased when using bacteria grown on vancomycin-containing culture media or on MH close to the vancomycin disc as a consequence of VanA induction. The limit of detection of the assay was 6.3 × 106 cfu per test with bacteria grown on MH plates and 4.9 × 105 cfu per test with bacteria grown on ChromID® VRE plates.
NG-Test VanA is efficient, rapid and easy to implement in the routine workflow of a clinical microbiology laboratory for the confirmation of VanA-VRE.
NG-Test VanA is efficient, rapid and easy to implement in the routine workflow of a clinical microbiology laboratory for the confirmation of VanA-VRE.
Intestinal colonization by ESBL Escherichia coli and its association with community-acquired MDR infections is of great concern. This review determined the worldwide prevalence of human faecal ESBL E. coli carriage and its trend in the community over the past two decades.
A systematic literature search was conducted using PubMed, EMBASE and Google Scholar to retrieve articles published between 1 January 2000 and 13 February 2020 that contained data on the prevalence of faecal carriage of ESBL E. coli among healthy individuals. A cumulative (for the whole period) meta-analysis was used to estimate the global and regional pooled prevalence rates. Articles were grouped into study periods of 3 years, and subgroup meta-analyses were undertaken to examine the global pooled prevalence over time.
Sixty-two articles covering 29 872 healthy persons were included in this meta-analysis. The cumulative (2003-18) global pooled prevalence of ESBL E. coli intestinal carriage in the community was 16.5% (95% CI 14.3%-18.7%; P < 0.001). The pooled prevalence showed an upward trend, increasing from 2.6% (95% CI 1.6%-4.0%) in 2003-05 to 21.1% (95% CI 15.8%-27.0%) in 2015-18. Over the whole period, the highest carriage rate was observed in South-East Asia (27%; 95% CI 2.9%-51.3%), while the lowest occurred in Europe (6.0%; 95% CI 4.6%-7.5%).
Globally, an 8-fold increase in the intestinal carriage rate of ESBL E. Selleckchem LY2780301 coli in the community has occurred over the past two decades. Prevention of its spread may require new therapeutic and public health strategies.
Globally, an 8-fold increase in the intestinal carriage rate of ESBL E. coli in the community has occurred over the past two decades. Prevention of its spread may require new therapeutic and public health strategies.
Boronates are of growing interest as β-lactamase inhibitors. The only marketed analogue, vaborbactam, principally targets KPC carbapenemases, but taniborbactam (VNRX-5133, Venatorx) has a broader spectrum.
MICs of cefepime and meropenem were determined combined with taniborbactam or avibactam for carbapenem-resistant UK isolates. β-Lactamase genes and porin alterations were sought by PCR or sequencing.
Taniborbactam potentiated partner β-lactams against (i) Enterobacterales with KPC, other class A, OXA-48-like, VIM and NDM (not IMP) carbapenemases; and (ii) Enterobacterales inferred to have combinations of ESBL or AmpC activity and impermeability. Potentiation of cefepime (the partner for clinical development) by taniborbactam was slightly weaker than by avibactam for Enterobacterales with KPC or OXA-48-like carbapenemases, but MICs of cefepime/taniborbactam were similar to those of ceftazidime/avibactam, and the spectrum was wider. MICs of cefepime/taniborbactam nonetheless remained >8 + 4 mg/L for 22%-32% of NDM-producing Enterobacterales.
