We describe a new approach to measuring the masses of individual macroions. The method employs a pulsed acceleration tube located between two sensitive image charge detectors. The charge and velocity ...of the macroion are recorded with the first image charge detector. The ion is pulse accelerated through a known voltage drop, and then the charge and velocity are remeasured using the second image charge detector. The mass of the ion is deduced from its charge and its initial and final velocities. The approach has been used to measure masses in the 1010−1014 Da range with z = 103−106 and m/z = 106−109. It should be extendable to masses of <106 Da. We have used the method to determine the size and charge of water droplets transmitted through a capillary interface and an aperture interface. The droplets detected from the aperture interface are ∼1 order of magnitude smaller in mass than those detected from the capillary interface. The droplets from both interfaces have relatively low charges, particularly with the capillary interface where they are only charged to a small fraction of the Rayleigh limit. These results suggest that the aerodynamic breakup of the droplets plays a significant role in the mechanism of electrospray ionization.
Vaccination of children and young people against SARS-CoV-2 is recommended in some countries. Scarce data have been published on immune responses induced by COVID-19 vaccines in people younger than ...18 years compared with the same data that are available in adults.
COV006 is a phase 2, single-blind, randomised, controlled trial of ChAdOx1 nCoV-19 (AZD1222) in children and adolescents at four trial sites in the UK. Healthy participants aged 6–17 years, who did not have a history of chronic respiratory conditions, laboratory-confirmed COVID-19, or previously received capsular group B meningococcal vaccine (the control), were randomly assigned to four groups (4:1:4:1) to receive two intramuscular doses of 5 × 1010 viral particles of ChAdOx1 nCoV-19 or control, 28 days or 84 days apart. Participants, clinical investigators, and the laboratory team were masked to treatment allocation. Study groups were stratified by age, and participants aged 12–17 years were enrolled before those aged 6–11 years. Due to the restrictions in the use of ChAdOx1 nCoV-19 in people younger than 30 years that were introduced during the study, only participants aged 12–17 years who were randomly assigned to the 28-day interval group had received their vaccinations at the intended interval (day 28). The remaining participants received their second dose at day 112. The primary outcome was assessment of safety and tolerability in the safety population, which included all participants who received at least one dose of the study drug. The secondary outcome was immunogenicity, which was assessed in participants who were seronegative to the nucleocapsid protein at baseline and received both prime and boost vaccine. This study is registered with ISRCTN (15638344).
Between Feb 15 and April 2, 2021, 262 participants (150 57% participants aged 12–17 years and 112 43% aged 6–11 years; due to the change in the UK vaccination policy, the study terminated recruitment of the younger age group before the planned number of participants had been enrolled) were randomly assigned to receive vaccination with two doses of either ChAdOx1 nCoV-19 (n=211 n=105 at day 28 and n=106 at day 84) or control (n=51 n=26 at day 28 and n=25 at day 84). One participant in the ChAdOx1 nCoV-19 day 28 group in the younger age bracket withdrew their consent before receiving a first dose. Of the participants who received ChAdOx1 nCoV-19, 169 (80%) of 210 participants reported at least one solicited local or systemic adverse event up to 7 days following the first dose, and 146 (76%) of 193 participants following the second dose. No serious adverse events related to ChAdOx1 nCoV-19 administration were recorded by the data cutoff date on Oct 28, 2021. Of the participants who received at least one dose of ChAdOx1 nCoV-19, there were 128 unsolicited adverse events up to 28 days after vaccination reported by 83 (40%) of 210 participants. One participant aged 6–11 years receiving ChAdOx1 nCoV-19 reported a grade 4 fever of 40·2°C on day 1 following first vaccination, which resolved within 24 h. Pain and tenderness were the most common local solicited adverse events for all the ChAdOx1 nCoV-19 and capsular group B meningococcal groups following both doses. Of the 242 participants with available serostatus data, 14 (6%) were seropositive at baseline. Serostatus data were not available for 20 (8%) of 262 participants. Among seronegative participants who received ChAdOx1 nCoV-19, anti-SARS-CoV-2 IgG and pseudoneutralising antibody titres at day 28 after the second dose were higher in participants aged 12–17 years with a longer interval between doses (geometric means of 73 371 arbitrary units AU/mL 95% CI 58 685–91 733 and 299 half-maximal inhibitory concentration IC50; 95% CI 230–390) compared with those aged 12–17 years who received their vaccines 28 days apart (43 280 AU/mL 95% CI 35 852–52 246 and 150 IC50 95% CI 116–194). Humoral responses were higher in those aged 6–11 years than in those aged 12–17 years receiving their second dose at the same 112-day interval (geometric mean ratios 1·48 95% CI 1·07–2·07 for anti-SARS-CoV-2 IgG and 2·96 1·89–4·62 for pseudoneutralising antibody titres). Cellular responses peaked after a first dose of ChAdOx1 nCoV-19 across all age and interval groups and remained above baseline after a second vaccination.
ChAdOx1 nCoV-19 is well tolerated and immunogenic in children aged 6–17 years, inducing concentrations of antibody that are similar to those associated with high efficacy in phase 3 studies in adults. No safety concerns were raised in this trial.
AstraZeneca and the UK Department of Health and Social Care through the UK National Institute for Health and Care Research.
A modified ion funnel is described. Counterintuitively, increased spacing between electrodes results in enhanced “focusing” of the ions through the funnel. Consequently, the internal diameter (i.d.) ...of the funnel need not decrease to the conductance limit (as in previous designs). A simple dc-only lens, which also serves as the conductance limit, combined with the natural flow of gas is used to extract the ions from the funnel. Ions with mass to charge ratios varying between 75 and 3000
m/z are passed through the funnel with no apparent discrimination. The funnel can be operated under mild conditions that preserve weakly bound noncovalent complexes. After testing several designs, a thin closely spaced dc lens was found to be the best solution for extracting ions. A simple method for simulating ion trajectories at nonzero pressures based on ion mobility and explicit diffusion is described. This theoretical approach was used to design and calculate ion trajectories for the modified funnel presented here. Finally, the increased spacing between electrodes in the current funnel significantly relaxes machining constraints, reduces cost, and enhances ease of use versus previous funnel designs.
Objective
To evaluate the ability of SNX‐7081, a novel small molecule inhibitor of Hsp90, to block components of inflammation, including cytokine production, protein kinase activity, and angiogenic ...signaling. A close analog was evaluated in preclinical in vivo models of rheumatoid arthritis (RA).
Methods
SNX‐7081 binding to Hsp90 was characterized in Jurkat cells and RA synovial fibroblasts (RASFs). Inhibition of NF‐κB nuclear translocation was evaluated in cellular systems, using lipopolysaccharide (LPS), tumor necrosis factor α, or interleukin‐1β stimulation. Suppression of cytokine production in THP‐1 cells, human umbilical vein endothelial cells, and RASFs was studied. Disruption of MAPK signaling cascades by SNX‐7081 following growth factor stimulation was assessed. SNX‐7081 was tested in 2 relevant angiogenesis assays: platelet‐derived growth factor activation of fibroblasts and LPS‐induced nitric oxide (NO) release in J774 macrophages. A close analog, SNX‐4414, was evaluated in rat collagen‐induced arthritis and adjuvant‐induced arthritis, following oral treatment.
Results
SNX‐7081 showed strong binding affinity to Hsp90 and expected induction of Hsp70. NF‐κB nuclear translocation was blocked by SNX‐7081 at nanomolar concentrations, and cytokine production was potently inhibited. Growth factor activation of ERK and JNK signaling was significantly reduced by SNX‐7081. NO production was also sharply inhibited. In animal models, SNX‐4414 fully inhibited paw swelling and improved body weight. Scores for inflammation, pannus formation, cartilage damage, and bone resorption returned to normal.
Conclusion
The present results demonstrate that a small molecule Hsp90 inhibitor can impact inflammatory disease processes. The strong in vivo efficacy observed with SNX‐4414 provides preclinical validation for consideration of Hsp90 inhibitors in the treatment of RA.
This study sought to derive age-, sex-, and ethnic-appropriate adult reference values for left atrial (LA) and left ventricular (LV) dimensions and volumes, LV mass, fractional shortening, and ...ejection fraction (EF) derived from geographically diverse population studies.
The current recommended reference values for measurements from echocardiography may not be suitable to the diverse world population to which they are now applied.
Population-based datasets of echocardiographic measurements from 22,404 adults without clinical cardiovascular or renal disease, hypertension, or diabetes were combined in an individual person data meta-analysis. Quantile regression was used to derive reference values at the 95th percentile (upper reference value URV) and fifth percentile (lower reference value LRV) of each measurement against age (treated as linear), separately within sex and ethnic groups.
The URVs for left ventricular end-diastolic volume (LVEDV), LV end-systolic volume, and LV stroke volume (SV) were highest in Europeans and lowest in South Asians. Important sex and ethnic differences remained after indexation by body surface area or height for these measurements, as well as for the LRV for SV. LVEDV and SV decreased with increasing age for all groups. Importantly, the LRV for EF differed by ethnicity; there was a clear apparent difference between Europeans and Asians. The URVs for LV end-diastolic diameter and LV end-systolic diameter were higher for Europeans than those for East Asian, South Asian, and African people, particularly among men. Similarly, the URVs for LA diameter and volume were highest for Europeans.
Sex- and/or ethnic-appropriate echocardiographic reference values are indicated for many measurements of LA and LV size, LV mass, and EF. Reference values for LV volumes and mass also differ across the age range.
The reduction of Tc(VII), Cr(VI) Se(IV) and Te(IV) by representatives of three genera of sulphate-reducing bacteria was studied with respect to the specificity of electron donor and acceptor. Tc(VII) ...and Cr(VI) were reduced by different mechanisms involving a hydrogenase. Cr(VI) reduction was achieved using a new isolate with lactate as the electron donor or by using H
2 in the presence of bicarbonate ion. Te(IV) and Se(IV) were reduced to base metals. The removal of Se(IV) was enhanced under sulphidogenic conditions, with metal sulphide identified by energy dispersive X-ray microanalysis. The order of preference of the electron acceptors was Te(IV)>S(VI)>Se(IV), which is in sharp contrast to that predicted by the redox potentials alone.
Abstract In asymptomatic bacteriuria (ABU), bacteria colonize the urinary tract without provoking symptoms. Here, we compared the virulence properties of a collection of ABU Escherichia coli strains ...to cystitis and pyelonephritis strains. Specific urinary tract infection (UTI)-associated virulence genes, hemagglutination characteristics, siderophore production, hemolysis, biofilm formation, and the ability of strains to adhere to and induce cytokine responses in epithelial cells were analyzed. ABU strains were phylogenetically related to strains that cause symptomatic UTI. However, the virulence properties of the ABU strains were variable and dependent on a combination of genotypic and phenotypic factors. Most ABU strains adhered poorly to epithelial cells; however, we also identified a subgroup of strongly adherent strains that were unable to stimulate an epithelial cell IL-6 cytokine response. Poor immune activation may represent one mechanism whereby ABU E. coli evade immune detection after the establishment of bacteriuria.
Urinary tract infections (UTIs) are among the most common infectious diseases of humans, with Escherichia coli being responsible for >80% of all cases. Asymptomatic bacteriuria (ABU) occurs when ...bacteria colonize the urinary tract without causing clinical symptoms and can affect both catheterized patients (catheter-associated ABU CA-ABU) and noncatheterized patients. Here, we compared the virulence properties of a collection of ABU and CA-ABU nosocomial E. coli isolates in terms of antibiotic resistance, phylogenetic grouping, specific UTI-associated virulence genes, hemagglutination characteristics, and biofilm formation. CA-ABU isolates were similar to ABU isolates with regard to the majority of these characteristics; exceptions were that CA-ABU isolates had a higher prevalence of the polysaccharide capsule marker genes kpsMT II and kpsMT K1, while more ABU strains were capable of mannose-resistant hemagglutination. To examine biofilm growth in detail, we performed a global gene expression analysis with two CA-ABU strains that formed a strong biofilm and that possessed a limited adhesin repertoire. The gene expression profile of the CA-ABU strains during biofilm growth showed considerable overlap with that previously described for the prototype ABU E. coli strain, 83972. This is the first global gene expression analysis of E. coli CA-ABU strains. Overall, our data suggest that nosocomial ABU and CA-ABU E. coli isolates possess similar virulence profiles.
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