Cardiovascular disease (CVD) is a major cause of premature death in patients with psychotic disorders, where dyslipidemia occurs frequently. In the pathogenesis of these serious mental disorders, a ...low-grade inflammation seems to be a possible contributor. Concurrently, systemic inflammation and its interplay with dyslipidemia is a central driver in the pathogenesis of CVD. We hypothesize that evaluation of atherogenic lipid ratios together with inflammatory markers reflecting different inflammatory pathways with relevance for atherogenesis, could give novel information on immune-related mechanisms involved in early CVD risk in patients with psychotic disorders.
As a measure for CVD risk we calculated atherogenic lipid ratios using established sex-specific cut-offs: Total cholesterol/high-density lipoprotein; HDL-c (TC/HDL) and triglyceride/HDL-c (TG/HDL) were evaluated in 571 schizophrenia (SCZ) and 247 bipolar disorder (BD) patients, and in 99 healthy controls (HC). In addition, as a measure of low-grade inflammation, we measured fasting plasma levels of nine stable atherogenic inflammatory markers in patients (SCZ, BD) and in HC. The elevated inflammatory markers and CVD risk in patients, as reflected by TC/HDL and TG/HDL, were further assessed in multivariable analyses adjusting for comorbid cardio-metabolic risk factors.
A markedly higher proportion (26%-31%) of patients had increased TC/HDL and TG/HDL ratios compared with HC. Plasma levels of high-sensitivity C-reactive protein (hs-CRP) and myeloperoxidase (MPO) were higher (p<0.05, p<0.001) in patients with psychotic disorders than in HC, and hs-CRP and MPO were independently associated with atherogenic lipid ratios in the multivariable analyses.
Our findings suggest that low-grade inflammation and abnormal neutrophil activation may cause increased CVD risk in patients with psychotic disorders. These mechanisms should be further examined to determine the potential for development of novel risk evaluation strategies.
The rate of multidrug-resistant infections is rapidly rising. Cationic antibacterial peptides are active against resistant pathogens and have low propensity for resistance development, but because of ...their unfavorable medicinal properties, cationic antibacterial peptides have been a limited clinical success. We have found that introduction of nongenetically coded amino acids and other lipophilic modifications opens the opportunity for development of extremely short and highly active antibacterial peptides with improved medicinal properties.
Idiopathic generalized epilepsy (IGE) is an inherited neurological disorder affecting about 0.4% of the world's population. Mutations in ten genes causing distinct forms of idiopathic epilepsy have ...been identified so far, but the genetic basis of many IGE subtypes is still unknown. Here we report a gene associated with the four most common IGE subtypes: childhood and juvenile absence epilepsy (CAE and JAE), juvenile myoclonic epilepsy (JME), and epilepsy with grand mal seizures on awakening (EGMA; ref. 8). We identified three different heterozygous mutations in the chloride-channel gene CLCN2 in three unrelated families with IGE. These mutations result in (i) a premature stop codon (M200fsX231), (ii) an atypical splicing (del74-117) and (iii) a single amino-acid substitution (G715E). All mutations produce functional alterations that provide distinct explanations for their pathogenic phenotypes. M200fsX231 and del74-117 cause a loss of function of ClC-2 channels and are expected to lower the transmembrane chloride gradient essential for GABAergic inhibition. G715E alters voltage-dependent gating, which may cause membrane depolarization and hyperexcitability.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This review focuses on important structural features affecting the antimicrobial activity of 15-residue derivatives of lactoferricins. Our investigations are based on an alanine-scan of a 15-residue ...bovine lactoferricin derivative that revealed the absolute necessity of two tryptophan residues for antimicrobial activity. This "tryptophan-effect" was further explored in homologous derivatives of human, caprine, and porcine lactoferricins by the incorporation of one additional tryptophan residue, and by increasing the content of tryptophan in the bovine derivative to five residues. Most of the resulting peptides display a substantial increase in antimicrobial activity. To identify which molecular properties make tryptophan so effective, a series of bovine lactoferricin derivatives were prepared containing non-encoded unnatural aromatic amino acids, which represented various aspects of the physicochemical nature of tryptophan. The results clearly demonstrate that tryptophan is not unique since most of the modified peptides were of higher antimicrobial potency than the native peptide. The size and three-dimensional shape of the inserted "super-tryptophans" are the most important determinants for the high antimicrobial activity of the modified peptides. This review also describes the use of a "soft-modeling" approach in order to identify important structural parameters affecting the antimicrobial activity of modified 15-residue murine lactoferricin derivatives. This QSAR-study revealed that the net charge, charge asymmetry, and micelle affinity of the peptides were the most important structural parameters affecting their antimicrobial activity.Key words: antimicrobial peptides, lactoferricin, non-encoded aromatic amino acids, tryptophan.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
15.
The Large Hadron–Electron Collider at the HL-LHC Aksakal, H; Alekhin, S; Allport, P P ...
Journal of physics. G, Nuclear and particle physics,
11/2021, Letnik:
48, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Abstract
The Large Hadron–Electron Collider (LHeC) is designed to move the field of deep inelastic scattering (DIS) to the energy and intensity frontier of particle physics. Exploiting ...energy-recovery technology, it collides a novel, intense electron beam with a proton or ion beam from the High-Luminosity Large Hadron Collider (HL-LHC). The accelerator and interaction region are designed for concurrent electron–proton and proton–proton operations. This report represents an update to the LHeC’s conceptual design report (CDR), published in 2012. It comprises new results on the parton structure of the proton and heavier nuclei, QCD dynamics, and electroweak and top-quark physics. It is shown how the LHeC will open a new chapter of nuclear particle physics by extending the accessible kinematic range of lepton–nucleus scattering by several orders of magnitude. Due to its enhanced luminosity and large energy and the cleanliness of the final hadronic states, the LHeC has a strong Higgs physics programme and its own discovery potential for new physics. Building on the 2012 CDR, this report contains a detailed updated design for the energy-recovery electron linac (ERL), including a new lattice, magnet and superconducting radio-frequency technology, and further components. Challenges of energy recovery are described, and the lower-energy, high-current, three-turn ERL facility, PERLE at Orsay, is presented, which uses the LHeC characteristics serving as a development facility for the design and operation of the LHeC. An updated detector design is presented corresponding to the acceptance, resolution, and calibration goals that arise from the Higgs and parton-density-function physics programmes. This paper also presents novel results for the Future Circular Collider in electron–hadron (FCC-eh) mode, which utilises the same ERL technology to further extend the reach of DIS to even higher centre-of-mass energies.
Caspase-2 is unique among all the mammalian caspases in that it is the only caspase that is present constitutively in the cell nucleus, in addition to other cellular compartments. However, the ...functional significance of this nuclear localization is unknown. Here we show that DNA damage induced by gamma-radiation triggers the phosphorylation of nuclear caspase-2 at the S122 site within its prodomain, leading to its cleavage and activation. This phosphorylation is carried out by the nuclear serine/threonine protein kinase DNA-PKcs and promoted by the p53-inducible death-domain-containing protein PIDD within a large nuclear protein complex consisting of DNA-PKcs, PIDD, and caspase-2, which we have named the DNA-PKcs-PIDDosome. This phosphorylation and the catalytic activity of caspase-2 are involved in the maintenance of a G2/M DNA damage checkpoint and DNA repair mediated by the nonhomologous end-joining (NHEJ) pathway. The DNA-PKcs-PIDDosome thus represents a protein complex that impacts mammalian G2/M DNA damage checkpoint and NHEJ.
The goals of this investigation were to study the temporal relationships between the demands for key resources in the emergency department (ED) and the inpatient hospital, and to develop multivariate ...forecasting models.
Hourly data were collected from three diverse hospitals for the year 2006. Descriptive analysis and model fitting were carried out using graphical and multivariate time series methods. Multivariate models were compared to a univariate benchmark model in terms of their ability to provide out-of-sample forecasts of ED census and the demands for diagnostic resources.
Descriptive analyses revealed little temporal interaction between the demand for inpatient resources and the demand for ED resources at the facilities considered. Multivariate models provided more accurate forecasts of ED census and of the demands for diagnostic resources.
Our results suggest that multivariate time series models can be used to reliably forecast ED patient census; however, forecasts of the demands for diagnostic resources were not sufficiently reliable to be useful in the clinical setting.
Ascending vasodilatation is integral to blood flow control in exercising skeletal muscle and is attributable to conduction
from intramuscular arterioles into proximal feed arteries. Passive stretch ...of skeletal muscle can impair muscle blood flow
but the mechanism is not well understood. We hypothesized that the conduction of vasodilatation along feed arteries can be
modulated by changes in muscle length. In anaesthetized hamsters, acetylcholine (ACh) microiontophoresis triggered conducted
vasodilatation along feed arteries (diameter, 50-70 μm) of the retractor muscle secured at 100 % resting length or stretched
by 30 %. At 100 % length, ACh evoked local dilatation (> 30 μm) and this response conducted rapidly along the feed artery
(14 ± 1 μm dilatation at 1600 μm upstream). During muscle stretch, feed arteries constricted â10 μm ( P < 0.05) and local vasodilatation to ACh was maintained while conducted vasodilatation was reduced by half ( P < 0.01). Resting diameter and conduction recovered upon restoring 100 % length. Sympathetic nerve stimulation (4-8 Hz) produced
vasoconstriction and attenuated conduction in the manner observed during muscle stretch, as did noradrenaline or phenylephrine
(10 n m ). Inhibiting nitric oxide production ( N Ï -nitro-L-arginine, 50 μ m ) produced similar vasoconstriction yet had no effect on conduction. Phentolamine, prazosin, or tetrodotoxin (1 μ m ) during muscle stretch abolished vasoconstriction and restored conduction. Inactivation of sensory nerves with capsaicin
had no effect on vasomotor responses. Thus, muscle stretch can attenuate conducted vasodilatation by activating α-adrenoreceptors
on feed arteries through noradrenaline released from perivascular sympathetic nerves. This autonomic feedback mechanism can
restrict muscle blood flow during passive stretch.
To determine the number of CD34+ cells associated with a high probability of rapid engraftment after allogeneic peripheral-blood stem-cell (PBSC) transplant, and to examine the relationship between ...certain donor characteristics and the effectiveness of PBSC mobilization.
Between December 1994 and July 1996, we treated 47 patients who had resistant hematologic neoplasms with myeloablative therapy followed by transplantation of allogeneic PBSC collected from histocompatible siblings after mobilization with granulocyte colony-stimulating factor (G-CSF). Expression of CD34 was determined by flow cytometry.
Engraftment was rapid and similar to that observed following autologous PBSC transplant, with an absolute neutrophil count (ANC) greater than 500/microL and platelet count greater than 20,000/microL on median days +9 and +11, respectively. The pace of hematologic recovery correlated with the number of hematopoietic progenitors transplanted, so that patients who received greater than 5 x 10(6) CD34+ cells/kg recipient weight had a 95% likelihood of neutrophil and platelet recovery by day +15. Baseline (precytokine) CD34+ cells per milliliter of donor peripheral blood and total G-CSF dose (donor weight x 10 micrograms/kg) correlated with the number of CD34+ cells collected (R2 = .24 and P = .0009, and R2 = .24 and P < .0001, respectively). Donor age and sex did not effect mobilization.
Following allogeneic PBSC transplant, patients who received greater than 5 x 10(6) CD34+ cells/ kg recipient weight had a high probability of rapid engraftment. Donors with low baseline levels of circulating progenitors (< 2,000 CD34+ cells/mL blood) and those who received lower total doses of G-CSF were less likely to be effectively mobilized. For donors with low baseline CD34+ counts, higher doses of G-CSF might improve mobilization. Baseline CD34+ counts and total G-CSF dose accounted for less than half of the variation in CD34+ cells collected, which indicates that other, as yet unidentified, factors play an important role in determining the effectiveness of mobilization.
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