Here, the Major Atmospheric Gamma-ray Imaging Cherenkov (MAGIC) telescopes observed S2 0109+22 in 2015 July during its flaring activity in high-energy gamma-rays observed by Fermi-Large Area ...Telescope. We analyse the MAGIC data to characterize the very high energy (VHE) gamma-ray emission of S2 0109+22, which belongs to the subclass of intermediate synchrotron peak (ISP) BL Lacertae (BL Lac) objects. We study the multifrequency emission in order to investigate the source classification. Finally, we compare the source long-term behaviour to other VHE gamma-ray emitting (TeV) blazars. We performed a temporal and spectral analysis of the data centred around the MAGIC interval of observation (MJD 57225–57231). Long-term radio and optical data have also been investigated using the discrete correlation function. The redshift of the source is estimated through optical host-galaxy imaging and also using the amount of VHE gamma-ray absorption. The quasi-simultaneous multifrequency spectral energy distribution (SED) is modelled with the conventional one-zone synchrotron self-Compton (SSC) model. MAGIC observations resulted in the detection of the source at a significance level of 5.3σ. The VHE gamma-ray emission of S2 0109+22 is variable on a daily time scale. VHE gamma-ray luminosity of the source is lower than the average of TeV BL Lacs. The optical polarization and long-term optical/radio behaviour of the source are different from the general population of TeV blazars. All these findings agree with the classification of the source as an ISP BL Lac object. As a result, we estimate the source redshift as z = 0.36 ± 0.07. The SSC parameters describing the SED are rather typical for blazars.
Objective
Genetic variation in the first intron of FTO (e.g., single‐nucleotide polymorphism SNP rs9939609) is strongly associated with adiposity. This effect is thought to be mediated (at least in ...part) via increasing caloric intake, although the precise molecular genetic mechanisms are not fully understood. Prior pediatric studies of FTO have included youth with overweight and obesity; however, they have not informed whether a genotypic effect on ingestive behavior is present prior to obesity onset. Therefore, this study investigated the association between FTO and caloric intake in children aged 5 to 10 years without obesity (adiposity ≤ 95th percentile).
Methods
A total of 122 children were genotyped for rs9939609 and ate ad libitum from a laboratory lunch buffet following a standardized breakfast. Linear regressions, adjusting for body mass, were used to examine the association between FTO “dose” (number of copies of SNP rs9939609) and intake variables.
Results
There was a significant association between FTO and total intake. Each risk allele predicted an additional 64 calories, accounting for 3% of the variance. There were no associations between FTO and macronutrient preference, energy density, or diet variety. Results were influenced by race.
Conclusions
Results corroborate and extend prior work by showing a dose‐dependent effect on food intake in children without obesity.
The activity and/or expression of the mitogen-activated protein kinases c-Jun N-terminal kinase 1, p38 and extracellular signal-regulated kinases 1/2, as well as their substrates, the transcription ...factors c-Jun and activating transcription factor-2, were examined following systemic application of kainate in the cortex and hippocampus of the adult rat brain. The protein expression levels of all three mitogen-activated protein kinases remained constant during the observation period. Unexpectedly, c-Jun N-terminal kinase 1 was the only mitogen-activated protein kinase activated in this model of excitotoxicity, its activity raised from between 1 and 3
h moderate basal to maximal levels between 6 and 12
h. In contradistinction, activity of extracellular signal-regulated kinases 1/2 fell from their substantial basal levels and did not recover; activity of p38 was characterized by a high basal level that almost entirely disappeared and did not return to basal levels even 10
days after kainate application. c-Jun protein was rapidly expressed, with a maximum after 3
h and a slow decline after 12
h. Supershift assays revealed that, during the early induction phase of the
c-
jun gene, the proximal
activator protein-
1 (
jun1) site of the
c-
jun promoter was mainly occupied by the constitutively expressed activating transcription factor-2, whereas the late induction correlated with the predominant binding of c-Jun and, to a lesser extent, activating transcription factor-2 to the distal
activator protein-
1 (
jun2) site. The time-course of the N-terminal phosphorylation of c-Jun as determined by immunocytochemistry paralleled the activity of c-Jun N-terminal kinase 1 and showed a compartment-specific regulation between 3 and 12
h. A second set of supershift experiments demonstrated that c-Jun, but not activating transcription factor 2, bound to
activator protein-
1 sites in the promoter of
substance P and
collagenase genes, but not of the
cyclo-
oxygenase-
2 gene.
Our results demonstrate that activation of c-Jun N-terminal kinase 1, phosphorylation of c-Jun and selective occupation of the
c-
jun promoter by activating transcription factor-2 or c-Jun are part of the neuronal response following excitotoxicity that is considered as the mechanism for neuronal apoptosis
in vivo. Some of these findings differ substantially from
in vitro experiments and underline the necessity to analyse the neuronal stress pathways in the adult brain.
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with average lifespan of 2–5 years after diagnosis. The identification of novel prognostic and pharmacodynamic ...biomarkers are needed to facilitate therapeutic development. Metalloprotein human superoxide dismutase 1 (SOD1) is known to accumulate and form aggregates in patient neural tissue with familial ALS linked to mutations in their
SOD1
gene. Aggregates of SOD1 have also been detected in other forms of ALS, including the sporadic form and the most common familial form linked to abnormal hexanucleotide repeat expansions in the Chromosome 9 open reading frame 72 (
C9ORF72
) gene. Here, we report the development of a real-time quaking-induced conversion (RT-QuIC) seed amplification assay using a recombinant human SOD1 substrate to measure SOD1 seeding activity in postmortem spinal cord and motor cortex tissue from persons with different ALS etiologies. Our SOD1 RT-QuIC assay detected SOD1 seeds in motor cortex and spinal cord dilutions down to 10
–5
. Importantly, we detected SOD1 seeding activity in specimens from both sporadic and familial ALS cases, with the latter having mutations in either their
SOD1
or
C9ORF72
genes. Analyses of RT-QuIC parameters indicated similar lag phases in spinal cords of sporadic and familial ALS patients, but higher ThT fluorescence maxima by
SOD1
familial ALS specimens and sporadic ALS thoracic cord specimens. For a subset of sporadic ALS patients, motor cortex and spinal cords were examined, with seeding activity in both anatomical regions. Our results suggest SOD1 seeds are in ALS patient neural tissues not linked to
SOD1
mutation, suggesting that SOD1 seeding activity may be a promising biomarker, particularly in sporadic ALS cases for whom genetic testing is uninformative.
Purpose: The use of primary health care personnel to identify cases of epilepsy and initiate simple treatment protocols has been advocated as a solution to the numeric inadequacy and uneven ...distribution of medical manpower available for the management of epilepsy in developing countries. This study sought to evaluate the effectiveness of primary health care nurses in the diagnosis and management of epilepsy, as well as the impact of patient‐information pamphlets on drug compliance and clinic attendance of patients with epilepsy.
Methods: Primary health care workers from 24 clinics in the Zvimba district in Zimbabwe attended a workshop to improving their knowledge in the diagnosis and management of generalized tonic‐clonic seizures. Half of these clinics (experimental group) subsequently received patient‐information pamphlets for distribution to patients and relatives, whereas the other half (control group) did not. Frequency of clinic attendance, mean seizure frequencies, and mean serum levels of phenobarbitone were compared at baseline and at 6 months after intervention in patients within each group, and at 6 months after intervention between both groups.
Results: Community health worker education led to a 74% increase in patient recruitment as well as a marked improvement in patient drug compliance over the 6‐month study period. The use of patient‐information pamphlets led to a marked reduction in patient default from clinic follow‐up, but did not appear to influence drug compliance or seizure frequency.
Conclusions: The benefits of these simple and inexpensive interventions make a strong case for their widespread implementation for improved epilepsy care not only in Zimbabwe, but also in other developing countries.
The c-Jun N-terminal kinases (JNKs, also called stress activated protein kinases. SAPKs) and p38 kinases constitute together with extracellular signal-regulated kinases (ERKs) the family of MAP ...kinases. Whereas the functions of JNKs under physiological conditions are largely unknown, there is raising evidence that JNKs are potent effectors of apoptosis or degeneration of neurons in vitro and in the brain. The activation of the inducible transcription factor c-Jun by N-terminal phosphorylation is a central event in JNK-mediated degenerative processes that depend on de novo protein synthesis. At the post-translational level, cytoplasmic degenerative actions of JNKs might comprise inhibition of Bcl-2 and steroid hormone-receptor signaling or hyperphosphorylation of tau; and at transcriptional level, JNKs might trigger the induction of the apoptotic effectors p53 and Fas-Ligand by phosphorylation of c-Jun. The role of p38 is the nervous system is poorly understood, but its activation is also considered as part of the neuronal stress response. This review informs about the genetic processing, the regulation of activity and the biochemical actions of JNK and p38 isoforms in general. In the second part, we summarize the findings on expression and activation of JNKs and p38 under neurodegenerative condition. A particular focus is also put on the putative function of JNK under physiological conditions and for neuroprotection.
A neutrino with energy ∼290 TeV, IceCube-170922A, was detected in coincidence with the BL Lac object TXS 0506+056 during enhanced gamma-ray activity, with chance coincidence being rejected at ∼3 ...level. We monitored the object in the very-high-energy (VHE) band with the Major Atmospheric Gamma-ray Imaging Cherenkov (MAGIC) telescopes for ∼41 hr from 1.3 to 40.4 days after the neutrino detection. Day-timescale variability is clearly resolved. We interpret the quasi-simultaneous neutrino and broadband electromagnetic observations with a novel one-zone lepto-hadronic model, based on interactions of electrons and protons co-accelerated in the jet with external photons originating from a slow-moving plasma sheath surrounding the faster jet spine. We can reproduce the multiwavelength spectra of TXS 0506+056 with neutrino rate and energy compatible with IceCube-170922A, and with plausible values for the jet power of . The steep spectrum observed by MAGIC is concordant with internal γγ absorption above ∼100 GeV entailed by photohadronic production of a ∼290 TeV neutrino, corroborating a genuine connection between the multi-messenger signals. In contrast to previous predictions of predominantly hadronic emission from neutrino sources, the gamma-rays can be mostly ascribed to inverse Compton upscattering of external photons by accelerated electrons. The X-ray and VHE bands provide crucial constraints on the emission from both accelerated electrons and protons. We infer that the maximum energy of protons in the jet comoving frame can be in the range ∼1014 - 1018 eV.
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