The modern chemotherapy era started with Fleming's discovery of benzylpenicillin. He demonstrated that benzylpenicillin did not kill
In this study, we found that >64 mg/liter of static ...benzylpenicillin concentrations killed 1.16 to 1.43 log
CFU/ml below starting inoculum of extracellular and intracellular
over 7 days. When we added the β-lactamase inhibitor avibactam, benzylpenicillin maximal kill (
) of extracellular log-phase-growth
was 6.80 ± 0.45 log
CFU/ml at a 50% effective concentration (EC
) of 15.11 ± 2.31 mg/liter, while for intracellular
it was 2.42 ± 0.14 log
CFU/ml at an EC
of 6.70 ± 0.56 mg/liter. The median penicillin (plus avibactam) MIC against South African clinical
strains (80% either multidrug or extensively drug resistant) was 2 mg/liter. We mimicked human-like benzylpenicillin and avibactam concentration-time profiles in the hollow-fiber model of tuberculosis (HFS-TB). The percent time above the MIC was linked to effect, with an optimal exposure of ≥65%. At optimal exposure in the HFS-TB, the bactericidal activity in log-phase-growth
was 1.44 log
CFU/ml/day, while 3.28 log
CFU/ml of intracellular
was killed over 3 weeks. In an 8-week HFS-TB study of nonreplicating persistent
, penicillin-avibactam alone and the drug combination of isoniazid, rifampin, and pyrazinamide both killed >7.0 log
CFU/ml. Monte Carlo simulations of 10,000 preterm infants with disseminated disease identified an optimal dose of 10,000 U/kg (of body weight)/h, while for pregnant women or nonpregnant adults with pulmonary tuberculosis the optimal dose was 25,000 U/kg/h, by continuous intravenous infusion. Penicillin-avibactam should be examined for effect in pregnant women and infants with drug-resistant tuberculosis, to replace injectable ototoxic and teratogenic second-line drugs.
It is well established that decreased kidney function can increase blood pressure (BP), but it is unproven whether moderately elevated BP causes chronic kidney disease (CKD) or glomerular ...hyperfiltration.
311 119 White British UK Biobank participants were included in logistic regression analyses to estimate the odds of CKD (defined as long-term kidney replacement therapy, estimated glomerular filtration rate eGFR< 60mL/min/1.73m
, or urinary albumin:creatinine ratio ≥3 mg/mmol) associated with higher genetically predicted BP using genetic risk scores comprising 219 systolic and 223 diastolic BP loci. Analyses estimating associations with clinical categories of eGFR and urinary albumin:creatinine ratio were also conducted, with an eGFR ≥120 mL (min·1.73m
) considered evidence of glomerular hyperfiltration.
21 623 participants had CKD: 7781 with reduced eGFR and 15 500 with albuminuria. 1828 participants had an eGFR ≥120 mL/min/1.73m
. Each genetically predicted 10 mmHg higher systolic BP and 5 mmHg higher diastolic BP were associated with a 37% (95% CI, 1.29-1.45) and 19% (1.14-1.25) higher odds of CKD, respectively. Associations were evident for both the reduced eGFR and albuminuria components of the CKD outcome. The odds of hyperfiltration (versus an eGFR ≥60 and <90 mL/min/1.73m
were 49% higher (95% CI, 1.21-1.84) for each genetically predicted 10 mmHg higher systolic BP. Associations with CKD and hyperfiltration were similar irrespective of preexisting diabetes, vascular disease, or different levels of adiposity.
In this general population, genetic epidemiological evidence supports a causal role of life-long differences in BP for decreased kidney function, glomerular hyperfiltration, and albuminuria. Physiological autoregulation may not afford complete renal protection against the moderate BP elevations.
A companion to Chinese art Powers, Martin J; Tsiang, Katherine R; Arnold, Dana
2016/01/01, 2015, 2015-12-18, 2015-10-14, Letnik:
8
eBook
Exploring the history of art in China from its earliest incarnations to the present day, this comprehensive volume includes two dozen newly-commissioned essays spanning the theories, genres, and ...media central to Chinese art and theory throughout its history. * Provides an exceptional collection of essays promoting a comparative understanding of China's long record of cultural production * Brings together an international team of scholars from East and West, whose contributions range from an overview of pre-modern theory, to those exploring calligraphy, fine painting, sculpture, accessories, and more * Articulates the direction in which the field of Chinese art history is moving, as well as providing a roadmap for historians interested in comparative study or theory * Proposes new and revisionist interpretations of the literati tradition, which has long been an important staple of Chinese art history * Offers a rich insight into China's social and political institutions, religious and cultural practices, and intellectual traditions, alongside Chinese art history, theory, and criticism
Abstract
Maintenance of genetic diversity at adaptive loci may facilitate invasions by non-native species by allowing populations to adapt to novel environments, despite the loss of diversity at ...neutral loci that typically occurs during founder events. To evaluate this prediction, we compared genetic diversity at major histocompatibility complex (MHC) and cytochrome b (cytb) loci from 20 populations of the American bullfrog (Rana catesbeiana) across theinvasive and native ranges in North America and quantified the presence of the pathogen Batrachochytrium dendrobatidis (Bd). Compared to native populations, invasive populations had significantly higher Bd prevalence and intensity, significantly higher pairwise MHC and cytb FST, and significantly lower cytb diversity, but maintained similar levels of MHC diversity. The two most common MHC alleles (LiCA_B and Rapi_33) were associated with a significant decreased risk of Bd infection, and we detected positive selection acting on four peptide binding residues. Phylogenetic analysis suggested invasive populations likely arose from a single founding population in the American Midwest with a possible subsequent invasion in the northwest. Overall, our study suggests that the maintenance of diversity at adaptive loci may contribute to invasion success and highlights the importance of quantifying diversity at functional loci to assess the evolutionary potential of invasive populations.
Arthrogryposis multiplex congenita (AMC) also known as multiple joints contracture or Fetal Akinesia Deformation Sequence (FADS) is etiologically a heterogeneous condition with an estimated incidence ...of approximately 1 in 3000 live births and much higher incidence when prenatally diagnosed cases are included. The condition can be acquired or secondary to fetal exposures and can also be caused by a variety of single‐gene disorders affecting the brain, spinal cord, peripheral nerves, neuromuscular junction, muscle, and a variety of disorders affecting the connective tissues (Niles et al., Prenatal Diagnosis, 2019; 39:720–731). The introduction of next‐generation gene sequencing uncovered many genes and causative variants of AMC but also identified genes that cause both dominant and recessive inherited conditions with the variability of clinical manifestations depending on the genes and variants. Molecular diagnosis in these cases is not only important for prognostication but also for the determination of recurrence risk and for providing reproductive options including preimplantation and prenatal diagnosis. TTN, the largest known gene in the human genome, has been known to be associated with autosomal dominant dilated cardiomyopathy. However, homozygote and compound heterozygote pathogenic variants with recessive inheritance have rarely been reported. We report the effect of recessive variants located within the fetal IC and/or N2BA isoforms in association with severe FADS in three families. All parents were healthy obligate carriers and none of them had cardiac or skeletal muscle abnormalities. This report solidifies FADS as an alternative phenotypic presentation associated with homozygote/compound heterozygous pathogenic variants in the TTN.
Abstract
Background
Bystander administration of naloxone is a critical strategy to mitigate opioid overdose mortality. To ensure bystanders’ willingness to carry and administer naloxone in response ...to a suspected overdose, it is critical to select products for community distribution with the highest likelihood of being utilized. This study examines bystanders’ preference for and willingness to administer three naloxone products approved by the FDA for bystander use and identify product features driving preference.
Methods
The population was a convenience sample of individuals who attended the Kentucky State Fair, August 18–28, 2022, in Louisville, Kentucky. Participants (
n
= 503) watched a standardized overdose education and naloxone training video, rated their willingness to administer each of three products (i.e., higher-dose nasal spray, lower-dose nasal spray, intramuscular injection), selected a product to take home, and rated factors affecting choice.
Results
After training, 44.4% chose the higher-dose nasal spray, 30.1% chose the intramuscular injection, and 25.5% chose the lower-dose nasal spray. Factors most influencing choice on a 10-point Likert scale were ease of use (9 7–10), naloxone dose (8 5–10), and product familiarity (5 5–9).
Conclusions
Bystanders expressed high willingness to administer all studied formulations of naloxone products. Product choice preference varied as a function of product features. As the number and variety of available products continue to increase, continuous evaluation of formulation acceptability, in addition to including individuals with lived experience who are receiving and administering overdose reversal agents, is critical to support adoption and save lives.
We are running out of treatments for multidrug-resistant tuberculosis. Minocycline, an old and safe antibiotic, was highly potent against Mycobacterium tuberculosis in preclinical models. It ...potentiated bacterial killing by the immune system and promoted immune pathways associated with healing.
Abstract
Drug-resistant tuberculosis represents a global emergency, requiring new drugs. We found that minocycline was highly potent in laboratory strains of Mycobacterium tuberculosis and that 30 drug-susceptible and multidrug/extensively drug-resistant clinical strains were susceptible to clinically achievable concentrations. In the hollow fiber system model, lung concentration-time profiles of 7 mg/kg/day human-equivalent minocycline dose achieved bacterial kill rates equivalent to those of first-line antituberculosis agents. Minocycline killed extracellular bacilli directly. Minocycline also killed intracellular bacilli indirectly, via concentration-dependent granzyme A–driven apoptosis. Moreover, minocycline demonstrated dose-dependent antiinflammatory activity and downregulation of extracellular matrix-based remodeling pathways and, thus, could protect patients from tuberculosis immunopathology. In RNA sequencing of repetitive samples from the hollow fiber system and in independent protein abundance experiments, minocycline demonstrated dose-dependent inhibition of sonic hedgehog–patched–gli signaling. These findings have implications for improved lung remodeling and for dual immunomodulation and direct microbial kill-based treatment shortening regimens for drug-susceptible and drug-resistant latent and active M. tuberculosis infection.
Geostationary satellite measurements of aerosol optical depth (AOD) over East Asia from the Geostationary Ocean Color Imager (GOCI) and Advanced Himawari Imager (AHI) instruments can augment surface ...monitoring of fine particulate matter (PM2.5) air quality, but this requires better understanding of the AOD–PM2.5 relationship. Here we use the GEOS-Chem chemical transport model to analyze the critical variables determining the AOD–PM2.5 relationship over East Asia by simulation of observations from satellite, aircraft, and ground-based datasets. This includes the detailed vertical aerosol profiling over South Korea from the KORUS-AQ aircraft campaign (May–June 2016) with concurrent ground-based PM2.5 composition, PM10, and AERONET AOD measurements. The KORUS-AQ data show that 550 nm AOD is mainly contributed by sulfate–nitrate–ammonium (SNA) and organic aerosols in the planetary boundary layer (PBL), despite large dust concentrations in the free troposphere, reflecting the optically effective size and high hygroscopicity of the PBL aerosols. We updated SNA and organic aerosol size distributions in GEOS-Chem to represent aerosol optical properties over East Asia by using in situ measurements of particle size distributions from KORUS-AQ. We find that SNA and organic aerosols over East Asia have larger size (number median radius of 0.11 µm with geometric standard deviation of 1.4) and 20 % larger mass extinction efficiency as compared to aerosols over North America (default setting in GEOS-Chem). Although GEOS-Chem is successful in reproducing the KORUS-AQ vertical profiles of aerosol mass, its ability to link AOD to PM2.5 is limited by under-accounting of coarse PM and by a large overestimate of nighttime PM2.5 nitrate. The GOCI–AHI AOD data over East Asia in different seasons show agreement with AERONET AODs and a spatial distribution consistent with surface PM2.5 network data. The AOD observations over North China show a summer maximum and winter minimum, opposite in phase to surface PM2.5. This is due to low PBL depths compounded by high residential coal emissions in winter and high relative humidity (RH) in summer. Seasonality of AOD and PM2.5 over South Korea is much weaker, reflecting weaker variation in PBL depth and lack of residential coal emissions.
Neocortex expansion during evolution is linked to higher numbers of neurons, which are thought to result from increased proliferative capacity and neurogenic potential of basal progenitor cells ...during development. Here, we show that
EREG
, encoding the growth factor EPIREGULIN, is expressed in the human developing neocortex and in gorilla cerebral organoids, but not in the mouse neocortex. Addition of EPIREGULIN to the mouse neocortex increases proliferation of basal progenitor cells, whereas
EREG
ablation in human cortical organoids reduces proliferation in the subventricular zone. Treatment of cortical organoids with EPIREGULIN promotes a further increase in proliferation of gorilla but not of human basal progenitor cells. EPIREGULIN competes with the epidermal growth factor (EGF) to promote proliferation, and inhibition of the EGF receptor abrogates the EPIREGULIN-mediated increase in basal progenitor cells. Finally, we identify putative cis-regulatory elements that may contribute to the observed inter-species differences in
EREG
expression. Our findings suggest that species-specific regulation of EPIREGULIN expression may contribute to the increased neocortex size of primates by providing a tunable pro-proliferative signal to basal progenitor cells in the subventricular zone.
Synopsis
Growth factors have been hypothesized to regulate the proliferative capacity of basal progenitor cells during neocortex development. This study reveals that expression of the growth factor EPIREGULIN, encoded by
EREG
, supports proliferation of basal progenitor cells in the developing neocortex of primates.
EREG
is expressed in the developing neocortex of primates but not of mice.
Addition of EPIREGULIN to the developing mouse neocortex promotes basal progenitor proliferation.
EREG
ablation in human cortical organoids reduces basal progenitor proliferation.
EPIREGULIN signals via the EGF receptor and competes with EGF to promote proliferation.
Several putative cis-regulatory elements may contribute to the inter-species differences in EREG expression.
EPIREGULIN competes with EGF to promote proliferation of basal progenitor cells in primates, which may contribute to their neocortex expansion.
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