Galaxies are believed to evolve through merging, which should lead to some hosting multiple supermassive black holes. There are four known triple black hole systems, with the closest black hole pair ...being 2.4 kiloparsecs apart (the third component in this system is at 3 kiloparsecs), which is far from the gravitational sphere of influence (about 100 parsecs for a black hole with mass one billion times that of the Sun). Previous searches for compact black hole systems concluded that they were rare, with the tightest binary system having a separation of 7 parsecs (ref. 10). Here we report observations of a triple black hole system at redshift z = 0.39, with the closest pair separated by about 140 parsecs and significantly more distant from Earth than any other known binary of comparable orbital separation. The effect of the tight pair is to introduce a rotationally symmetric helical modulation on the structure of the large-scale radio jets, which provides a useful way to search for other tight pairs without needing extremely high resolution observations. As we found this tight pair after searching only six galaxies, we conclude that tight pairs are more common than hitherto believed, which is an important observational constraint for low-frequency gravitational wave experiments.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This work presents results from analyzing position-sensitive capacitive Frisch-grid (PS-CFG) TlBr gamma-ray detectors. As a room-temperature semiconductor detector, TlBr exhibits a high atomic ...number, high density, and low Fano factor compared to other material. The use of the 3D position sensing technique provides information on the crystal uniformity. This technique presents the spatial variation in the histograms of the anode amplitude versus the cathode-to-anode ratio, necessary for depth correction, for detectors fabricated with 5×5×12 mm 3 TlBr crystals at room temperature operating at continuous bias (1.5 kV) over the course of nine months. This work also presents the temperature dependence of the leakage current for a TlBr PS-CFG detector over the temperature range of -20 to +60 °C, which varies from <0.2 to 40 nA, respectively, along with changes in the spectrum from the anode signal measured with 137 Cs irradiation. This work shows the utility of the 3D technique to evaluate the performance and uniformity of PS-CFG detectors for applications that require high-energy resolution gamma-ray spectroscopy, such as radionuclide identification.
Ultrasound measurement of volume blood flow is potentially useful for many clinical situations, yet practical implementation and use are restricted by the many instrumentation and blood flow ...limitations that can arise. Colour velocity imaging offers a number of theoretical advantages over methods based on duplex imaging. We evaluated a colour velocity flow measurement system (CVI-Q, Philips) both in a flow phantom and
in vivo in the extracranial carotid arteries of normal volunteers. Over a range of constant (50–1200 ml/min) and pulsatile (92–366 ml/min) flows and using both steered and unsteered beams with beam angles of 30° and 40°, errors usually within 5% were obtained for constant flow and within 10% for pulsatile flow. However, with a beam angle of 70°, higher errors of 20% were obtained for pulsatile flow. The reproducibility of flow measurements made using both anterior and posterior-lateral scanning approaches was determined in the common (CCA), internal (ICA) and external carotid (ECA) arteries of 18 volunteers. A greater reproducibility was found using the posterior-lateral approach (CCA 6.27%; ICA 9.8%), and mean (SD) flow values were 376 ml/min in the CCA and 255 ml/min in the ICA. The ratio of
(ICA + ECA)
CCA
flow calculated for each subject individually was mean (SD) 0.95 (0.11). Insonation from an anterior approach resulted in lower reproducibility and lower flow values. In conclusion, colour flow velocity imaging allows repeatable reproducible measurements of CCA and ICA flow, but results are optimal if a posterior-lateral scanning approach is used.
Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented pressure on healthcare system globally. Lack of high-quality evidence on the respiratory management of COVID-19-related acute ...respiratory failure (C-ARF) has resulted in wide variation in clinical practice.
Using a Delphi process, an international panel of 39 experts developed clinical practice statements on the respiratory management of C-ARF in areas where evidence is absent or limited. Agreement was defined as achieved when > 70% experts voted for a given option on the Likert scale statement or > 80% voted for a particular option in multiple-choice questions. Stability was assessed between the two concluding rounds for each statement, using the non-parametric Chi-square (χ
) test (p < 0·05 was considered as unstable).
Agreement was achieved for 27 (73%) management strategies which were then used to develop expert clinical practice statements. Experts agreed that COVID-19-related acute respiratory distress syndrome (ARDS) is clinically similar to other forms of ARDS. The Delphi process yielded strong suggestions for use of systemic corticosteroids for critical COVID-19; awake self-proning to improve oxygenation and high flow nasal oxygen to potentially reduce tracheal intubation; non-invasive ventilation for patients with mixed hypoxemic-hypercapnic respiratory failure; tracheal intubation for poor mentation, hemodynamic instability or severe hypoxemia; closed suction systems; lung protective ventilation; prone ventilation (for 16-24 h per day) to improve oxygenation; neuromuscular blocking agents for patient-ventilator dyssynchrony; avoiding delay in extubation for the risk of reintubation; and similar timing of tracheostomy as in non-COVID-19 patients. There was no agreement on positive end expiratory pressure titration or the choice of personal protective equipment.
Using a Delphi method, an agreement among experts was reached for 27 statements from which 20 expert clinical practice statements were derived on the respiratory management of C-ARF, addressing important decisions for patient management in areas where evidence is either absent or limited.
The study was registered with Clinical trials.gov Identifier: NCT04534569.
Objective
To develop updated guidelines for the pharmacologic management of rheumatoid arthritis.
Methods
We developed clinically relevant population, intervention, comparator, and outcomes (PICO) ...questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations.
Results
The guideline addresses treatment with disease‐modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high‐risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional).
Conclusion
This clinical practice guideline is intended to serve as a tool to support clinician and patient decision‐making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision‐making process based on patients’ values, goals, preferences, and comorbidities.
Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE4. APOE4 is a major genetic risk factor for Alzheimer's disease and is associated with Down's syndrome dementia and poor neurological ...outcome after traumatic brain injury and haemorrhage. Neurovascular dysfunction is present in normal APOE4 carriers and individuals with APOE4-associated disorders. In mice, lack of Apoe leads to blood-brain barrier (BBB) breakdown, whereas APOE4 increases BBB susceptibility to injury. How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted APOE3, but not APOE4, suppressed the CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes through a lipoprotein receptor. Our data suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To characterize the spectral Doppler tracing of the normal renal artery.
Doppler tracings were obtained from a phantom of a vessel with variable compliance and from the kidneys of 15 healthy ...volunteers.
In the phantom, vascular compliance had the following effects on systolic flow velocity patterns: low compliance, little change in the sharp appearance of the systolic component of the transmitted pulse; mildly increased compliance, down-stream dampening of early systolic acceleration (ESA) with the appearance of a sharp early systolic transmitted peak and of a more rounded late systolic compliance peak; high compliance, delayed and diminished transmitted peak that eventually disappeared within the enlarging down-stream compliance peak. Healthy subjects with compliant vessels had greater ESA and more frequently visualized early systolic peaks in the renal hilum than in the renal sinus.
Absence of a discrete early systolic peak is a normal finding in young patients, especially in the more distal interlobar arteries. Loss of the early systolic peak may be explained on the basis of vascular compliance.
rHuEPO treatment improves brain and cognitive function of anemic dialysis patients. Twenty-four patients with chronic renal failure, stabilized on hemodialysis, were treated with recombinant human ...erythropoietin. Before treatment, all patients were anemic (mean Hct = 23.7%). Hematocrits reached normal levels (36.5%) after three months of treatment. Brain event-related potentials and neuropyschological tests were used to assess changes in brain and cognitive functions associated with the correction of anemia. Assessments were done prior to and after three and twelve months of rHuEPO treatment. The P3 component of the event-related potential increased in amplitude significantly with treatment, while its latency was unaffected. Of the four neuropsychological tests administered, scores on two improved significantly with treatment, and the other two approached significance. Taken together, these findings suggest that the correction of anemia to hematocrits near normal in uremic patients by rHuEPO treatment improves brain and cognitive function by raising levels of sustained attention, thus increasing speed and efficiency of scanning and perceptual-motor functions and enhancing learning and memory. These findings also suggest that anemia, either directly or indirectly, may impair brain function.
The quantitative relationship between the emission rate of host attractants (whether olfactory or visual) and the host-seeking rate of insect vectors of disease will determine the relationship ...between host group size and the prevalence of vector-borne diseases within each group. A comparative study was carried out to test whether interspecific differences in social behaviour significantly influence the malaria infection rates of different Amazonian primate species. The aetiological agent of monkey malaria in Amazonia is Plasmodium brasilianum Gonder & Berenberg-Gossler, 1908, and blood smear examinations of 3599 Amazonian primates over three decades have demonstrated an average infection rate with P. brasilianum of 10.4%. P. brasilianum has been detected in only 17/33 species examined, and the infection rate of those 17 species ranged from 2.1 to 50.0%. Logistic and standard linear regressions, at three different taxonomic levels, demonstrate that a significant proportion of the interspecific variation in infection rate can be explained by variation in average body weight (W) and average sleeping group size (G). Infection rate could increase with W and G due to enhanced odour production attracting a greater number of anopheline mosquito vectors of monkey malaria per host. Given that parasites reduce host fitness, the results suggest that, contrary to conventional wisdom, mosquito-borne diseases are a significant cost associated with larger group size.
5-HT3 receptors possess a number of highly conserved proline residues. We changed each of these to alanine, expressed the mutants as homomeric 5-HT3Areceptors in HEK293 cells, and analyzed them with ...radioligand binding, electrophysiology, and immunocytochemistry. Mutation of Pro56, Pro104, Pro123, and Pro170 resulted in ablation of radioligand binding, whereas mutation of Pro257 and Pro301 did not. Only the latter were expressed at the plasma membrane but were non-functional. Thus the former, which are in the N-terminal domain, may be involved in forming correct receptor structure, while those in the transmembrane region (Pro257 and Pro301) are necessary for the function of the protein. To explore the conformational preference (propensity) of these residues we examined the proportion ofcis-prolines and the influence of adjacent residues in known protein structures. 4.7% of prolines in the protein data base were in the cis conformation, and the distribution of amino acids adjacent to cis-prolines was not randomly distributed. Comparison of the proportion of each amino acid residue adjacent to acis-proline revealed that aromatic and bend-facilitating residues were favored while those with β-branched chains were not. Thus five residues (Gly, Pro, Tyr, Trp, Phe) and three residues (Pro, Tyr, Phe) were found more frequently than expected before and aftercis-prolines respectively, whereas five residues (Val, Ile, Leu, Asp, Thr) and two residues (Asp, Glu) were found less frequently. Of the 20 proline residues in the 5-HT3A receptor subunit only Pro170 has adjacent residues that are favorable. Mutating these to non-favorable residues resulted in ablation of ligand binding, whereas replacement with alternative favorable residues did not. We therefore propose that Pro170, which is part of the characteristic cys-loop found in this family of proteins, may be in the cis conformation.
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