Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS ...using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10
with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
Host cell invasion is a major feature of Staphylococcus aureus and contributes to infection development. The intracellular metabolically active bacteria can induce host cell activation and death but ...they can also persist for long time periods. In this study a comparative analysis was performed of different well-characterized S. aureus strains in their interaction with a variety of host cell types. Staphylococcus aureus (strains 6850, USA300, LS1, SH1000, Cowan1) invasion was compared in different human cell types (epithelial and endothelial cells, keratinocytes, fibroblasts, osteoblasts). The number of intracellular bacteria was determined, cell inflammation was investigated, as well as cell death and phagosomal escape of bacteria. To explain strain-dependent differences in the secretome, a proteomic approach was used. Barrier cells took up high amounts of bacteria and were killed by aggressive strains. These strains expressed high levels of toxins, and possessed the ability to escape from phagolysosomes. Osteoblasts and keratinocytes ingested less bacteria, and were not killed, even though the primary osteoblasts were strongly activated by S. aureus. In all cell types S. aureus was able to persist. Strong differences in uptake, cytotoxicity, and inflammatory response were observed between primary cells and their corresponding cell lines, demonstrating that cell lines reflect only partially the functions and physiology of primary cells. This study provides a contribution for a better understanding of the pathomechanisms of S. aureus infections. The proteomic data provide important basic knowledge on strains commonly used in the analysis of S. aureus-host cell interaction.
Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk ...of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
National rates of COVID-19 infection and fatality have varied dramatically since the onset of the pandemic. Understanding the conditions associated with this cross-country variation is essential to ...guiding investment in more effective preparedness and response for future pandemics.
Daily SARS-CoV-2 infections and COVID-19 deaths for 177 countries and territories and 181 subnational locations were extracted from the Institute for Health Metrics and Evaluation's modelling database. Cumulative infection rate and infection-fatality ratio (IFR) were estimated and standardised for environmental, demographic, biological, and economic factors. For infections, we included factors associated with environmental seasonality (measured as the relative risk of pneumonia), population density, gross domestic product (GDP) per capita, proportion of the population living below 100 m, and a proxy for previous exposure to other betacoronaviruses. For IFR, factors were age distribution of the population, mean body-mass index (BMI), exposure to air pollution, smoking rates, the proxy for previous exposure to other betacoronaviruses, population density, age-standardised prevalence of chronic obstructive pulmonary disease and cancer, and GDP per capita. These were standardised using indirect age standardisation and multivariate linear models. Standardised national cumulative infection rates and IFRs were tested for associations with 12 pandemic preparedness indices, seven health-care capacity indicators, and ten other demographic, social, and political conditions using linear regression. To investigate pathways by which important factors might affect infections with SARS-CoV-2, we also assessed the relationship between interpersonal and governmental trust and corruption and changes in mobility patterns and COVID-19 vaccination rates.
The factors that explained the most variation in cumulative rates of SARS-CoV-2 infection between Jan 1, 2020, and Sept 30, 2021, included the proportion of the population living below 100 m (5·4% 4·0–7·9 of variation), GDP per capita (4·2% 1·8–6·6 of variation), and the proportion of infections attributable to seasonality (2·1% 95% uncertainty interval 1·7–2·7 of variation). Most cross-country variation in cumulative infection rates could not be explained. The factors that explained the most variation in COVID-19 IFR over the same period were the age profile of the country (46·7% 18·4–67·6 of variation), GDP per capita (3·1% 0·3–8·6 of variation), and national mean BMI (1·1% 0·2–2·6 of variation). 44·4% (29·2–61·7) of cross-national variation in IFR could not be explained. Pandemic-preparedness indices, which aim to measure health security capacity, were not meaningfully associated with standardised infection rates or IFRs. Measures of trust in the government and interpersonal trust, as well as less government corruption, had larger, statistically significant associations with lower standardised infection rates. High levels of government and interpersonal trust, as well as less government corruption, were also associated with higher COVID-19 vaccine coverage among middle-income and high-income countries where vaccine availability was more widespread, and lower corruption was associated with greater reductions in mobility. If these modelled associations were to be causal, an increase in trust of governments such that all countries had societies that attained at least the amount of trust in government or interpersonal trust measured in Denmark, which is in the 75th percentile across these spectrums, might have reduced global infections by 12·9% (5·7–17·8) for government trust and 40·3% (24·3–51·4) for interpersonal trust. Similarly, if all countries had a national BMI equal to or less than that of the 25th percentile, our analysis suggests global standardised IFR would be reduced by 11·1%.
Efforts to improve pandemic preparedness and response for the next pandemic might benefit from greater investment in risk communication and community engagement strategies to boost the confidence that individuals have in public health guidance. Our results suggest that increasing health promotion for key modifiable risks is associated with a reduction of fatalities in such a scenario.
Bill & Melinda Gates Foundation, J Stanton, T Gillespie, J and E Nordstrom, and Bloomberg Philanthropies.
Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HTT gene that codes for an elongated polyglutamine tract in the huntingtin (HTT) protein. HTT is subject to ...multiple post-translational modifications (PTMs) that regulate its cellular function. Mutating specific PTM sites within mutant HTT (mHTT) in HD mouse models can modulate disease phenotypes, highlighting the key role of HTT PTMs in the pathogenesis of HD. These findings have led to increased interest in developing small molecules to modulate HTT PTMs in order to decrease mHTT toxicity. However, the therapeutic efficacy of pharmacological modulation of HTT PTMs in preclinical HD models remains largely unknown. HTT is palmitoylated at cysteine 214 by the huntingtin-interacting protein 14 (HIP14 or ZDHHC17) and 14-like (HIP14L or ZDHHC13) acyltransferases. Here, we assessed if HTT palmitoylation should be regarded as a therapeutic target to treat HD by (1) investigating palmitoylation dysregulation in rodent and human HD model systems, (2) measuring the impact of mHTT-lowering therapy on brain palmitoylation, and (3) evaluating if HTT palmitoylation can be pharmacologically modulated. We show that palmitoylation of mHTT and some HIP14/HIP14L-substrates is decreased early in multiple HD mouse models, and that mHTT palmitoylation decreases further with aging. Lowering mHTT in the brain of YAC128 mice is not sufficient to rescue aberrant palmitoylation. However, we demonstrate that mHTT palmitoylation can be normalized in COS-7 cells, in YAC128 cortico-striatal primary neurons and HD patient-derived lymphoblasts using an acyl-protein thioesterase (APT) inhibitor. Moreover, we show that modulating palmitoylation reduces mHTT aggregation and mHTT-induced cytotoxicity in COS-7 cells and YAC128 neurons.
•Palmitoylation of mHTT is reduced in multiple transgenic HD mouse models.•HTT palmitoylation decreases with increasing polyQ length in HD patient cells.•mHTT-lowering in mouse brains does not rescue aberrant palmitoylation.•mHTT palmitoylation in HD patient-derived cells can be rescued via APT inhibition.•Promoting palmitoylation reduces mHTT aggregation and cytotoxicity in vitro.
Background:
Intrauterine growth restriction (
IUGR
) is associated with reduced β2 adrenergic sensitivity, which contributes to poor postnatal muscle growth. The objective of this study was to ...determine if stimulating β2 adrenergic activity postnatal would rescue deficits in muscle growth, body composition, and indicators of metabolic homeostasis in IUGR offspring.
Methods:
Time-mated ewes were housed at 40°C from day 40 to 95 of gestation to produce IUGR lambs. From birth, IUGR lambs received daily IM injections of 0.8 μg/kg clenbuterol HCl (
IUGR+CLEN
;
n
= 11) or saline placebo (
IUGR
;
n
= 12). Placebo-injected controls (
n
= 13) were born to pair-fed thermoneutral ewes. Biometrics were assessed weekly and body composition was estimated by ultrasound and bioelectrical impedance analysis (
BIA
). Lambs were necropsied at 60 days of age.
Results:
Bodyweights were lighter (
p
≤ 0.05) for IUGR and IUGR+CLEN lambs than for controls at birth, day 30, and day 60. Average daily gain was less (
p
≤ 0.05) for IUGR lambs than controls and was intermediate for IUGR+CLEN lambs. At day 58, BIA-estimated whole-body fat-free mass and ultrasound-estimated loin eye area were less (
p
≤ 0.05) for IUGR but not IUGR+CLEN lambs than for controls. At necropsy, loin eye area and
flexor digitorum superficialis
muscles were smaller (
p
≤ 0.05) for IUGR but not IUGR+CLEN lambs than for controls.
Longissimus dorsi
protein content was less (
p
≤ 0.05) and fat-to-protein ratio was greater (
p
≤ 0.05) for IUGR but not IUGR+CLEN lambs than for controls.
Semitendinosus
from IUGR lambs had less (
p
≤ 0.05) β2 adrenoreceptor content, fewer (
p
≤ 0.05) proliferating myoblasts, tended to have fewer (
p
= 0.08) differentiated myoblasts, and had smaller (
p
≤ 0.05) muscle fibers than controls. Proliferating myoblasts and fiber size were recovered (
p
≤ 0.05) in IUGR+CLEN lambs compared to IUGR lambs, but β2 adrenoreceptor content and differentiated myoblasts were not recovered.
Semitendinosus
lipid droplets were smaller (
p
≤ 0.05) in size for IUGR lambs than for controls and were further reduced (
p
≤ 0.05) in size for IUGR+CLEN lambs.
Conclusion:
These findings show that clenbuterol improved IUGR deficits in muscle growth and some metabolic parameters even without recovering the deficit in β2 adrenoreceptor content. We conclude that IUGR muscle remained responsive to β2 adrenergic stimulation postnatal, which may be a strategic target for improving muscle growth and body composition in IUGR-born offspring.
We describe the organization of a nascent international effort, the Functional Annotation of Animal Genomes (FAANG) project, whose aim is to produce comprehensive maps of functional elements in the ...genomes of domesticated animal species.
We report on a dark matter search for a Weakly Interacting Massive Particle (WIMP) in the mass range
m
χ
∈
4
,
30
GeV
/
c
2
with the EDELWEISS-III experiment. A 2D profile likelihood analysis is ...performed on data from eight selected detectors with the lowest energy thresholds leading to a combined fiducial exposure of 496 kg-days. External backgrounds from
γ
- and
β
-radiation, recoils from
206
Pb
and neutrons as well as detector intrinsic backgrounds were modelled from data outside the region of interest and constrained in the analysis. The basic data selection and most of the background models are the same as those used in a previously published analysis based on boosted decision trees (BDT)
1
. For the likelihood approach applied in the analysis presented here, a larger signal efficiency and a subtraction of the expected background lead to a higher sensitivity, especially for the lowest WIMP masses probed. No statistically significant signal was found and upper limits on the spin-independent WIMP-nucleon scattering cross section can be set with a hypothesis test based on the profile likelihood test statistics. The 90 % C.L. exclusion limit set for WIMPs with
m
χ
=
4
GeV
/
c
2
is
1.6
×
10
-
39
cm
2
, which is an improvement of a factor of seven with respect to the BDT-based analysis. For WIMP masses above
15
GeV
/
c
2
the exclusion limits found with both analyses are in good agreement.
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