Estimating the polygenicity (proportion of causally associated single nucleotide polymorphisms (SNPs)) and discoverability (effect size variance) of causal SNPs for human traits is currently of ...considerable interest. SNP-heritability is proportional to the product of these quantities. We present a basic model, using detailed linkage disequilibrium structure from a reference panel of 11 million SNPs, to estimate these quantities from genome-wide association studies (GWAS) summary statistics. We apply the model to diverse phenotypes and validate the implementation with simulations. We find model polygenicities (as a fraction of the reference panel) ranging from ≃ 2 × 10-5 to ≃ 4 × 10-3, with discoverabilities similarly ranging over two orders of magnitude. A power analysis allows us to estimate the proportions of phenotypic variance explained additively by causal SNPs reaching genome-wide significance at current sample sizes, and map out sample sizes required to explain larger portions of additive SNP heritability. The model also allows for estimating residual inflation (or deflation from over-correcting of z-scores), and assessing compatibility of replication and discovery GWAS summary statistics.
E‐cigarette‐derived inhaled nicotine may contribute to the pathogenesis of periodontal and pulmonary diseases in particular via lung inflammation, injurious, and dysregulated repair responses. ...Nicotine is shown to have antiproliferative properties and affects fibroblasts in vitro, which may interfere in tissue myofibroblast differentiation in e‐cig users. This will affect the ability to heal wounds by decreasing wound contraction. In periodontics, direct exposure to e‐vapor has been shown to produce harmful effects in periodontal ligament and gingival fibroblasts in culture. This is due to the generation of reactive oxygen species/aldehydes/carbonyls from e‐cig aerosol, leading to protein carbonylation of extracellular matrix and DNA adducts/damage. A limited number of studies regarding the effects of e‐cig in oral and lung health are available. However, no reports are available to directly link the deleterious effects on e‐cigs, inhaled nicotine, and flavorings aerosol on periodontal and pulmonary health in particular to identify the risk of oral diseases by e‐cigarettes and nicotine aerosols. This mini‐review summarizes the recent perspectives on e‐cigarettes including inhaled nicotine effects on several pathophysiological events, such as oxidative stress, DNA damage, innate host response, inflammation, cellular senescence, profibrogenic and dysregulated repair, leading to lung remodeling, oral submucous fibrosis, and periodontal diseases.
The risk of APOE for Alzheimer's disease (AD) is modified by age. Beyond APOE, the polygenic architecture may also be heterogeneous across age. We aim to investigate age-related genetic heterogeneity ...of AD and identify genomic loci with differential effects across age. Stratified gene-based genome-wide association studies and polygenic variation analyses were performed in the younger (60–79 years, N = 14,895) and older (≥80 years, N = 6559) age-at-onset groups using Alzheimer's Disease Genetics Consortium data. We showed a moderate genetic correlation (rg = 0.64) between the two age groups, supporting genetic heterogeneity. Heritability explained by variants on chromosome 19 (harboring APOE) was significantly larger in younger than in older onset group (p < 0.05). APOE region, BIN1, OR2S2, MS4A4E, and PICALM were identified at the gene-based genome-wide significance (p < 2.73 × 10−6) with larger effects at younger age (except MS4A4E). For the novel gene OR2S2, we further performed leave-one-out analyses, which showed consistent effects across subsamples. Our results suggest using genetically more homogeneous individuals may help detect additional susceptible loci.
•Genetic heterogeneity of Alzheimer's disease between the younger and older patients.•Heritability explained by chromosome 19 was markedly larger at younger than older age.•A novel gene, OR2S2, was found in the younger individuals using gene-based genome-wide association studies.•APOE, BIN1, OR2S2, and PICALM had stronger effects in the younger than the older age.•Our strategy may help identify divergent biological mechanisms and Alzheimer's disease subtypes.
The stimulation of secondary metabolite synthesis by the endophytic fungus, Piriformospora indica, was investigated for the production of triterpenoidsâursolic acid (UA), oleanolic acid (OA) and ...betulinic acid (BA)âin the suspension cultures of Lantana camara. Growth and product formation profiles of the cell suspension cultures of L. camara were established for optimum elicitation strategy. The elicitation potential of P. indica was compared with typical elicitors like methyl jasmonate (MJ), chitin and chitosan. MJ at 62.5 µM and 2.5 % (v/v) filter-sterilized culture filtrate of P. indica enhanced the triterpenoids production to similar level. Filter-sterilized culture filtrate of P. indica at 2.5 % (v/v) increased the concentration of UA by 3.5-fold (3869.3 µg/g DW), OA by 5.6-fold (1425.7 µg/g DW) and BA by 7.8-fold (117.02 µg/g DW) in the cell cultures of L. camara.
Phosphorylation of α-synuclein at the serine-129 site (α-syn Ser129P) is an established pathologic hallmark of synucleinopathies and a therapeutic target. In physiologic states, only a fraction of ...α-syn is phosphorylated at this site, and most studies have focused on the pathologic roles of this post-translational modification. We found that unlike wild-type (WT) α-syn, which is widely expressed throughout the brain, the overall pattern of α-syn Ser129P is restricted, suggesting intrinsic regulation. Surprisingly, preventing Ser129P blocked activity-dependent synaptic attenuation by α-syn-thought to reflect its normal function. Exploring mechanisms, we found that neuronal activity augments Ser129P, which is a trigger for protein-protein interactions that are necessary for mediating α-syn function at the synapse. AlphaFold2-driven modeling and membrane-binding simulations suggest a scenario where Ser129P induces conformational changes that facilitate interactions with binding partners. Our experiments offer a new conceptual platform for investigating the role of Ser129 in synucleinopathies, with implications for drug development.
Drift Reduced Navigation with Deep Explainable Features Omama, Mohd; Sundar, Sripada V. S.; Chinchali, Sandeep ...
2022 IEEE/RSJ International Conference on Intelligent Robots and Systems (IROS),
2022-Oct.-23
Conference Proceeding
Open access
Modern autonomous vehicles (AVs) often rely on vision, LIDAR, and even radar-based simultaneous localization and mapping (SLAM) frameworks for precise localization and navigation. However, modern ...SLAM frameworks often lead to unacceptably high levels of drift (i.e., localization error) when AVs observe few visually distinct features or encounter occlusions due to dynamic obstacles. This paper argues that minimizing drift must be a key desiderata in AV motion planning, which requires an AV to take active control decisions to move towards feature-rich regions while also minimizing conventional control cost. To do so, we first introduce a novel data-driven perception module that observes LIDAR point clouds and estimates which features/regions an AV must navigate towards for drift minimization. Then, we introduce an interpretable model predictive controller (MPC) that moves an AV toward such feature-rich regions while avoiding visual occlusions and gracefully trading off drift and control cost. Our experiments on challenging, dynamic scenarios in the state-of-the-art CARLA simulator indicate our method reduces drift up to 76.76% compared to benchmark approaches.
Background
Antibodies against ganglioside complexes (GSCs) are associated with various clinical features and subtypes of Guillain‐Barré syndrome (GBS).
Methods
One‐hundred patients were evaluated for ...antibodies to GSCs formed by combination of GM1, GM2, GD1a, GD1b, GT1b, and GQ1b using manual enzyme linked immuno‐sorbent assay (ELISA).
Results
Twenty‐six patients were GSC antibody‐positive, most frequent being against GM1‐containing GSC (76.9%). Gender distribution, mean age, symptom‐duration, antecedent events, electrophysiological subtypes, requirement for mechanical ventilation, and median duration of hospital stay were comparable between the GSC antibody‐positive and negative groups. There was no association between specific GSC antibody and electrophysiological subtypes or clinical variants. After controlling for false discovery rate (FDR) using the Benjamini‐Hochberg method, the number of subjects who improved in overall disability sum score, modified Erasmus GBS outcome score, and neuropathy symptom score at discharge was significantly higher in the GSC antibody‐positive group. Improvements in Medical Research Council sum scores and Hughes Disability Scale during the hospital stay between the GSC antibody‐positive and negative groups were not significantly different after controlling for FDR.
Conclusions
The GSC antibody‐positive group had better outcome at hospital discharge in some of the disability scores. Pathophysiological pathways among patients without GSC antibodies may be different and this requires further evaluation.
Although CO
2 lasers have been widely employed for commercial sheet metal cutting operations, increased recognition of the processing benefits afforded by pulsed Nd:YAG lasers has recently fuelled ...interest in the latter. Pulsed Nd:YAG laser cutting differs from conventional continuous wave laser cutting as it involves overlapping of a series of individual spots generated by each pulse. In this paper, a typical cutting regime for pulsed Nd:YAG laser cutting of 1
mm thick Hastelloy-X sheet has been constructed and explained in terms of extent of spot overlap. The characteristics of single holes drilled employing the same process parameters as those employed for cutting were investigated and correlated with the obtained processing regime. Additionally, the influence of key process parameters like pulse duration on the shift in the constructed processing regime was investigated. Cut quality attributes like kerf width, cut edge kerf profile and surface roughness were also studied and their dependence on process parameters has been discussed.
Protective mechanical ventilation with low tidal volumes is standard of care for patients with acute respiratory distress syndrome. The aim of this individual patient data analysis was to determine ...the association between tidal volume and the occurrence of pulmonary complications in ICU patients without acute respiratory distress syndrome and the association between occurrence of pulmonary complications and outcome in these patients.
Individual patient data analysis.
ICU patients not fulfilling the consensus criteria for acute respiratory distress syndrome at the onset of ventilation.
Mechanical ventilation with low tidal volume.
The primary endpoint was development of a composite of acute respiratory distress syndrome and pneumonia during hospital stay. Based on the tertiles of tidal volume size in the first 2 days of ventilation, patients were assigned to a "low tidal volume group" (tidal volumes ≤ 7 mL/kg predicted body weight), an "intermediate tidal volume group" (> 7 and < 10 mL/kg predicted body weight), and a "high tidal volume group" (≥ 10 mL/kg predicted body weight). Seven investigations (2,184 patients) were included. Acute respiratory distress syndrome or pneumonia occurred in 23% of patients in the low tidal volume group, in 28% of patients in the intermediate tidal volume group, and in 31% of the patients in the high tidal volume group (adjusted odds ratio low vs high tidal volume group, 0.72; 95% CI, 0.52-0.98; p = 0.042). Occurrence of pulmonary complications was associated with a lower number of ICU-free and hospital-free days and alive at day 28 (10.0 ± 10.9 vs 13.8 ± 11.6 d; p < 0.01 and 6.1 ± 8.1 vs 8.9 ± 9.4 d; p < 0.01) and an increased hospital mortality (49.5% vs 35.6%; p < 0.01).
Ventilation with low tidal volumes is associated with a lower risk of development of pulmonary complications in patients without acute respiratory distress syndrome.
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