Quantitative studies on the uptake of nanoparticles into biological systems should consider simultaneous agglomera tion, sedimentation, and diffusion at physiologically relevant concentrations to ...assess the corresponding risks of nanomaterials to human health. In this paper, the transport and uptake of industrially important cerium oxide nanoparticles, into human lung fibroblasts is measured in vitro after exposing thoroughly characterized particle suspensions to a fibroblast cell culture for particles of four separate size fractions and concentrations ranging from 100 ng g-1 to 100 μg g-1 of fluid (100 ppb to 100 ppm). The unexpected findings at such low but physiologically relevant concentrations reveal a strong dependence of the amount of incorporated ceria on particle size, while nanoparticle number density or total particle surface area are of minor importance. These findings can be explained on the basis of a purely physical model. The rapid formation of agglomerates in the liquid is strongly favored for small particles due to a high number density while larger ones stay mainly unagglomerated. Diffusion (size fraction 25−50 nm) or sedimentation (size fraction 250−500 nm) limits the transport of nanoparticles to the fibroblast cells. The biological uptake processes on the surface of the cell are faster than the physical transport to the cell at such low concentrations. Comparison of the colloid stability of a series of oxide nanoparticles reveals that untreated oxide suspensions rapidly agglomerate in biological fluids and allows the conclusion that the presented transport and uptake kinetics at low concentrations may be extended to other industrially relevant materials.
Carbon is anything but a new material, yet ubiquitously applicable for many catalytic transformations in modern organic chemistry. It is highly versatile, as it occurs as modifications abundantly ...available as 1–3D carbonaceous materials due to technical progress. In addition, materials such as activated charcoal, ordered mesoporous carbon (OMC), graphite and graphene (oxide), carbon nanotubes (CNTs), nanospheres (nano-onions, fullerenes), and many others are no “innocent” supports, as demonstrated by many recent publications within the revitalized field of “carbocatalysis”. By nature, carbon scaffolds offer a perfect link between nanoscaled matter and organic molecules, which makes them an ideal cornerstone for molecular catalysts. Apart from this inherent chemical significance, the physical properties (e.g., different conductivity) are equally important for the performance of heterogeneous or immobilized homogeneous catalysts. Careful selection of the carbon scaffold enables control of reactivity by tuning the electronic interactions of active sites with the support or among each other. Moreover, separation and recycling of “heterogenized” catalysts can be further improved by rendering carbon “magnetic”, that is, by incorporation of magnetic particles or by coating metal nanomagnets with graphene-like shells. Altogether, tuning the properties of carbon supports might lead to catalysts tailored not only in matters of reactivity (electron shuttle), but also to down-to-earth problems such as purification (magnetic separation and recycling). This critical review will highlight how far such concepts have already been implemented in the design of “heterogenized” catalysts and is meant to widen the perspectives where certain concepts have yet to be realized.
Modern scholars often understand 1 Cor 15:29 as a clear reference to the baptism of living individuals as proxies for the departed. Yet before or at the time of 1 Corinthians, there appears to be no ...evidence for this practice or a similar one. A reasonable explanation for its emergence, therefore, is that the tradition derives from 1 Cor 15:29, rather than giving rise to it. Consequently, 1 Cor 15:29 supplies a unique opportunity to see how Paul’s earliest interpreters navigated the conflict between the emergent proxy baptism tradition and others they had inherited. Responses varied from acceptance (Marcion) to tolerance (Ambrosiaster) to rejection (Tertullian, Didymus, Epiphanius, Chrysostom, Eznik) of proxy baptism as being what 1 Cor 15:29 describes. Adopters of proxy baptism found support in Paul for breaking with prior tradition and interpreted 1 Cor 15:29 as a basis for creating a new tradition that fit a distinctive need in their community. By contrast, those who tolerate or reject the proxy baptism interpretation do so by considering both 1 Cor 15:29 and Paul himself as more thoroughly situated within existing prior traditions that rule out proxy baptism. These different responses illustrate the complex interplay between Paul and the conflicting traditions through which his letters have been and continue to be received. These responses also surface key features of the interplay between conflict and tradition, whether that conflict occurs within explicitly religious spheres or not.
Hypervirulent K. pneumoniae (hvKp) is a distinct pathotype that causes invasive community-acquired infections in healthy individuals. Hypermucoviscosity (hmv) is a major phenotype associated with ...hvKp characterized by copious capsule production and poor sedimentation. Dissecting the individual functions of CPS production and hmv in hvKp has been hindered by the conflation of these two properties. Although hmv requires capsular polysaccharide (CPS) biosynthesis, other cellular factors may also be required and some fitness phenotypes ascribed to CPS may be distinctly attributed to hmv. To address this challenge, we systematically identified genes that impact capsule and hmv. We generated a condensed, ordered transposon library in hypervirulent strain KPPR1, then evaluated the CPS production and hmv phenotypes of the 3,733 transposon mutants, representing 72% of all open reading frames in the genome. We employed forward and reverse genetic screens to evaluate effects of novel and known genes on CPS biosynthesis and hmv. These screens expand our understanding of core genes that coordinate CPS biosynthesis and hmv, as well as identify central metabolism genes that distinctly impact CPS biosynthesis or hmv, specifically those related to purine metabolism, pyruvate metabolism and the TCA cycle. Six representative mutants, with varying effect on CPS biosynthesis and hmv, were evaluated for their impact on CPS thickness, serum resistance, host cell association, and fitness in a murine model of disseminating pneumonia. Altogether, these data demonstrate that hmv requires both CPS biosynthesis and other cellular factors, and that hmv and CPS may serve distinct functions during pathogenesis. The integration of hmv and CPS to the metabolic status of the cell suggests that hvKp may require certain nutrients to specifically cause deep tissue infections.
Background
OnabotulinumtoxinA is approved for the prevention of headache in those with chronic migraine (CM); however, more clinical data on the risk-benefit profile for treatment beyond one year is ...desirable.
Methods
The
C
hronic Migraine
O
nabotulinu
M
toxinA
P
rolonged
E
fficacy open
L
abel (COMPEL) Study (
ClinicalTrials.gov
, NCT01516892) is an international, multicenter, open-label long-term prospective study. Adults with CM received 155 U of onabotulinumtoxinA (31 sites in a fixed-site, fixed-dose paradigm across 7 head/neck muscles) every 12 weeks (±7 days) for 9 treatment cycles (108 weeks). The primary outcome was headache day reductions at 108 weeks; secondary outcomes were headache day reductions at 60 weeks and change in the 6-item Headache Impact Test (HIT-6) score. Safety and tolerability were assessed by reviewing the frequency and nature of adverse events (AEs). AEs were determined at each visit through patient self-report, general non-directed and, for specific AEs, directed questioning, and physical examination. Subgroup analyses for safety and efficacy included, but were not limited to, patients with/without concomitant oral preventive treatment and acute medication overuse at baseline.
Results
Enrolled patients (
N
= 716) were 18–73 years old and most were female (
n
= 607, 84.8%). At baseline, patients reported an average 22.0 (SD = 4.8) headache days per month. 52.1% of patients (
n
= 373) completed the study. By 60 and 108 weeks, a significant reduction in headache days (− 9.2 days and − 10.7 days, respectively,
P
< 0.0001) was observed. Significant improvements (
P
< 0.0001) in HIT-6 scores (− 7.1 point change at week 108) were also demonstrated. 131 patients (18.3%) reported ≥1 treatment-emergent adverse events; most frequently reported was neck pain (
n
= 29, 4.1%). One patient reported a serious treatment-related adverse event (rash). No deaths were reported.
Conclusions
The COMPEL Study provides additional clinical evidence for the consistency of the efficacy and for the long-term safety and tolerability of onabotulinumtoxinA for the prevention of headache in those with CM who have been treated with onabotulinumtoxinA every 12 weeks over 2 years (9 treatments) with the fixed-site, fixed-dose injection paradigm.
Trial registration
Trial registration number:
NCT01516892
. Name of registry:
clinicaltrials.gov
. Date of registration: January 20 2012. Date of enrollment of first patient: December 2011.
At the start of the 2019-2020 influenza season, concern arose that circulating B/Victoria viruses of the globally emerging clade V1A.3 were antigenically drifted from the strain included in the ...vaccine. Intense B/Victoria activity was followed by circulation of genetically diverse A(H1N1)pdm09 viruses that were also antigenically drifted. We measured vaccine effectiveness (VE) in the United States against illness from these emerging viruses.
We enrolled outpatients aged ≥6 months with acute respiratory illness at 5 sites. Respiratory specimens were tested for influenza by reverse-transcriptase polymerase chain reaction (RT-PCR). Using the test-negative design, we determined influenza VE by virus subtype/lineage and genetic subclades by comparing odds of vaccination in influenza cases versus test-negative controls.
Among 8845 enrollees, 2722 (31%) tested positive for influenza, including 1209 (44%) for B/Victoria and 1405 (51%) for A(H1N1)pdm09. Effectiveness against any influenza illness was 39% (95% confidence interval CI: 32-44), 45% (95% CI: 37-52) against B/Victoria and 30% (95% CI: 21-39) against A(H1N1)pdm09-associated illness. Vaccination offered no protection against A(H1N1)pdm09 viruses with antigenically drifted clade 6B.1A 183P-5A+156K HA genes (VE 7%; 95% CI: -14 to 23%) which predominated after January.
Vaccination provided protection against influenza illness, mainly due to infections from B/Victoria viruses. Vaccine protection against illness from A(H1N1)pdm09 was lower than historically observed effectiveness of 40%-60%, due to late-season vaccine mismatch following emergence of antigenically drifted viruses. The effect of drift on vaccine protection is not easy to predict and, even in drifted years, significant protection can be observed.
Chronic stress induces anhedonia in susceptible but not resilient individuals, a phenomenon observed in humans as well as animal models, but the molecular mechanisms underlying susceptibility and ...resilience are not well understood. We hypothesized that the serotonergic system, which is implicated in stress, reward, and antidepressant therapy, may play a role. We found that plasticity of the serotonergic system contributes to the differential vulnerability to stress displayed by susceptible and resilient animals. Stress-induced anhedonia was assessed in adult male rats using social defeat and intracranial self-stimulation, while changes in serotonergic phenotype were investigated using immunohistochemistry and
hybridization. Susceptible, but not resilient, rats displayed an increased number of neurons expressing the biosynthetic enzyme for serotonin, tryptophan-hydroxylase-2 (TPH2), in the ventral subnucleus of the dorsal raphe nucleus (DRv). Further, a decrease in the number of DRv glutamatergic (VGLUT3+) neurons was observed in all stressed rats. This neurotransmitter plasticity is activity-dependent, as was revealed by chemogenetic manipulation of the central amygdala, a stress-sensitive nucleus that forms a major input to the DR. Activation of amygdalar corticotropin-releasing hormone (CRH)+ neurons abolished the increase in DRv TPH2+ neurons and ameliorated stress-induced anhedonia in susceptible rats. These findings show that activation of amygdalar CRH+ neurons induces resilience, and suppresses the gain of serotonergic phenotype in the DRv that is characteristic of susceptible rats. This molecular signature of vulnerability to stress-induced anhedonia and the active nature of resilience could be targeted to develop new treatments for stress-related disorders like depression.
Depression and other mental disorders can be induced by chronic or traumatic stressors. However, some individuals are resilient and do not develop depression in response to chronic stress. A complete picture of the molecular differences between susceptible and resilient individuals is necessary to understand how plasticity of limbic circuits is associated with the pathophysiology of stress-related disorders. Using a rodent model, our study identifies a novel molecular marker of susceptibility to stress-induced anhedonia, a core symptom of depression, and a means to modulate it. These findings will guide further investigation into cellular and circuit mechanisms of resilience, and the development of new treatments for depression.
Abstract
Palladium promotion and deposition on
monoclinic
zirconia are effective strategies to boost the performance of bulk In
2
O
3
in CO
2
-to-methanol and could unlock superior reactivity if well ...integrated into a single catalytic system. However, harnessing synergic effects of the individual components is crucial and very challenging as it requires precise control over their assembly. Herein, we present ternary Pd-In
2
O
3
-ZrO
2
catalysts prepared by flame spray pyrolysis (FSP) with remarkable methanol productivity and improved metal utilization, surpassing their binary counterparts. Unlike established impregnation and co-precipitation methods, FSP produces materials combining low-nuclearity palladium species associated with In
2
O
3
monolayers highly dispersed on the ZrO
2
carrier, whose surface partially transforms from a
tetragonal
into a
monoclinic-
like structure upon reaction. A pioneering protocol developed to quantify oxygen vacancies using in situ electron paramagnetic resonance spectroscopy reveals their enhanced generation because of this unique catalyst architecture, thereby rationalizing its high and sustained methanol productivity.
Synthesis in a day! Carbon‐coated metal nanoparticles can be covalently functionalized by diazonium chemistry. These colloidal reagents can now serve as a basis to magnetically functionalize ...molecules during synthesis, enabling their recovery within seconds.
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