We propose a one-shot, privacy-preserving distributed algorithm to perform logistic regression (ODAL) across multiple clinical sites.
ODAL effectively utilizes the information from the local site ...(where the patient-level data are accessible) and incorporates the first-order (ODAL1) and second-order (ODAL2) gradients of the likelihood function from other sites to construct an estimator without requiring iterative communication across sites or transferring patient-level data. We evaluated ODAL via extensive simulation studies and an application to a dataset from the University of Pennsylvania Health System. The estimation accuracy was evaluated by comparing it with the estimator based on the combined individual participant data or pooled data (ie, gold standard).
Our simulation studies revealed that the relative estimation bias of ODAL1 compared with the pooled estimates was <3%, and the ratio of standard errors was <1.25 for all scenarios. ODAL2 achieved higher accuracy (with relative bias <0.1% and ratio of standard errors <1.05). In real data analysis, we investigated the associations of 100 medications with fetal loss during pregnancy. We found that ODAL1 provided estimates with relative bias <10% for 85% of medications, and ODAL2 has relative bias <10% for 99% of medications. For communication cost, ODAL1 requires transferring p numbers from each site to the local site and ODAL2 requires transferring (p×p+p) numbers from each site to the local site, where p is the number of parameters in the regression model.
This study demonstrates that ODAL is privacy-preserving and communication-efficient with small bias and high statistical efficiency.
Major genomic drivers of hepatocellular carcinoma (HCC) are nowadays well recognized, although models to establish their roles in human HCC initiation remain scarce. Here, we used human liver ...organoids in experimental systems to mimic the early stages of human liver carcinogenesis from the genetic lesions of TP53 loss and L3 loop R249S mutation. In addition, chromatin immunoprecipitation sequencing (ChIP-seq) of HCC cell lines shed important functional insights into the initiation of HCC consequential to the loss of tumor-suppressive function from TP53 deficiency and gain-of-function activities from mutant p53.
Human liver organoids were generated from surgical nontumor liver tissues. CRISPR knockout of TP53 in liver organoids consistently demonstrated tumor-like morphological changes, increased in stemness and unrestricted in vitro propagation. To recapitulate TP53 status in human HCC, we overexpressed mutant R249S in TP53 knockout organoids. A spontaneous increase in tumorigenic potentials and bona fide HCC histology in xenotransplantations were observed. ChIP-seq analysis of HCC cell lines underscored gain-of-function properties from L3 loop p53 mutants in chromatin remodeling and overcoming extrinsic stress. More importantly, direct transcriptional activation of PSMF1 by mutant R249S could increase organoid resistance to endoplasmic reticulum stress, which was readily abrogated by PSMF1 knockdown in rescue experiments. In a patient cohort of primary HCC tumors and genome-edited liver organoids, quantitative polymerase chain reaction corroborated ChIP-seq findings and verified preferential genes modulated by L3 mutants, especially those enriched by R249S.
We showed differential tumorigenic effects from TP53 loss and L3 mutations, which together confer normal hepatocytes with early clonal advantages and prosurvival functions.
Abstract
In this study, we demonstrate three-dimensional (3D) hollow nanosphere electrocatalysts for CO
2
conversion into formate with excellent H-Cell performance and industrially-relevant current ...density in a 25 cm
2
membrane electrode assembly electrolyzer device. Varying calcination temperature maximized formate production via optimizing the crystallinity and particle size of the constituent SnO
2
nanoparticles. The best performing SnO
2
nanosphere catalysts contained ~ 7.5 nm nanocrystals and produced 71–81% formate Faradaic efficiency (FE) between −0.9 V and −1.3 V vs. the reversible hydrogen electrode (RHE) at a maximum formate partial current density of 73 ± 2 mA cm
geo
−2
at −1.3 V vs. RHE. The higher performance of nanosphere catalysts over SnO
2
nanoparticles and commercially-available catalyst could be ascribed to their initial structure providing higher electrochemical surface area and preventing extensive nanocrystal growth during CO
2
reduction. Our results are among the highest performance reported for SnO
2
electrocatalysts in aqueous H-cells. We observed an average 68 ± 8% FE over 35 h of operation with multiple on/off cycles. In situ Raman and time-dependent X-ray diffraction measurements identified metallic Sn as electrocatalytic active sites during long-term operation. Further evaluation in a 25 cm
2
electrolyzer cell demonstrated impressive performance with a sustained current density of 500 mA cm
geo
−2
and an average 75 ± 6% formate FE over 24 h of operation. Our results provide additional design concepts for boosting the performance of formate-producing catalysts.
Abstract
Regulated antisense RNA (asRNA) expression has been employed successfully in Gram-positive bacteria for genome-wide essential gene identification and drug target determination. However, ...there have been no published reports describing the application of asRNA gene silencing for comprehensive analyses of essential genes in Gram-negative bacteria. In this study, we report the first genome-wide identification of asRNA constructs for essential genes in Escherichia coli. We screened 250 000 library transformants for conditional growth inhibitory recombinant clones from two shotgun genomic libraries of E. coli using a paired-termini expression vector (pHN678). After sequencing plasmid inserts of 675 confirmed inducer sensitive cell clones, we identified 152 separate asRNA constructs of which 134 inserts came from essential genes, while 18 originated from nonessential genes (but share operons with essential genes). Among the 79 individual essential genes silenced by these asRNA constructs, 61 genes (77%) engage in processes related to protein synthesis. The cell-based assays of an asRNA clone targeting fusA (encoding elongation factor G) showed that the induced cells were sensitized 12-fold to fusidic acid, a known specific inhibitor. Our results demonstrate the utility of the paired-termini expression vector and feasibility of large-scale gene silencing in E. coli using regulated asRNA expression.
Parkinson’s disease (PD) is hallmarked by the abnormal intracellular inclusions (Lewy bodies or LBs) in dopaminergic cells. Amyloidogenic protein α-synuclein (α-syn) and iron (including both Fe(III) ...and Fe(II)) are both found to be present in LBs. The interaction between iron and α-syn might have important biological relevance to PD etiology. Previously, a moderate binding affinity between α-syn and Fe(II) (5.8
×
10
3
M
−1) has been measured, but studies on the binding between α-syn and Fe(III) have not been reported. In this work, electrospray mass spectrometry (ES-MS), cyclic voltammetry (CV), and fluorescence spectroscopy were used to study the binding between α-syn and Fe(II) and the redox property of the resultant α-syn–Fe(II) complex. The complex is of a 1:1 stoichiometry and can be readily oxidized electrochemically and chemically (by O
2) to the putative α-syn–Fe(III) complex, with H
2O
2 as a co-product. The reduction potential was estimated to be 0.025
V vs. Ag/AgCl, which represents a shift by −0.550
V vs. the standard reduction potential of the free Fe(III)/Fe(II) couple. Such a shift allows a binding constant between α-syn and Fe(III), 1.2
×
10
13
M
−1, to be deduced. Despite the relatively high binding affinity, α-syn–Fe(III) generated from the oxidation of α-syn–Fe(II) still dissociates due to the stronger tendency of Fe(III) to hydrolyze to Fe(OH)
3 and/or ferrihydrite gel. The roles of α-syn and its interaction with Fe(III) and/or Fe(II) are discussed in the context of oxidative stress, metal-catalyzed α-syn aggregation, and iron transfer processes.
Activating inert substrates is a challenge in nature and synthetic chemistry, but essential for creating functionally active molecules. In this work, we used a combinatorial optimization approach to ...assemble cytochrome P450 monooxygenases (CYPs) and reductases (CPRs) to achieve a target product profile. By creating 110 CYP-CPR pairs and iteratively screening different pairing libraries, we demonstrated a framework for establishing a CYP network that catalyzes six oxidation reactions at three different positions of a chemical scaffold. Target product titer was improved by remodeling endoplasmic reticulum (ER) size and spatially controlling the CYPs’ configuration on the ER. Out of 47 potential products that could be synthesized, 86% of the products synthesized by the optimized network was our target compound quillaic acid (QA), the aglycone backbone of many pharmaceutically important saponins, and fermentation achieved QA titer 2.23 g/L.
•Combinatorial screening of P450 and CPR enzymes for target product profile.•Spatial control of P450 enzymes on endoplasmic reticulum.•Optimized production of quillaic acid in yeast by P450 enzyme network.
Highlights • Intranasal immunization protects mice against lethal respiratory Acinetobacter baumannii infection. • Immunization limits bacterial extrapulmonary dissemination and the development of ...bacteremia. • B cells are essential for the protection while FcRγ and antibodies play no or little roles. • Neutrophils are key effector cells in vaccine-induced protection.
Abstract
Objective
We developed and evaluated a privacy-preserving One-shot Distributed Algorithm to fit a multicenter Cox proportional hazards model (ODAC) without sharing patient-level information ...across sites.
Materials and Methods
Using patient-level data from a single site combined with only aggregated information from other sites, we constructed a surrogate likelihood function, approximating the Cox partial likelihood function obtained using patient-level data from all sites. By maximizing the surrogate likelihood function, each site obtained a local estimate of the model parameter, and the ODAC estimator was constructed as a weighted average of all the local estimates. We evaluated the performance of ODAC with (1) a simulation study and (2) a real-world use case study using 4 datasets from the Observational Health Data Sciences and Informatics network.
Results
On the one hand, our simulation study showed that ODAC provided estimates nearly the same as the estimator obtained by analyzing, in a single dataset, the combined patient-level data from all sites (ie, the pooled estimator). The relative bias was <0.1% across all scenarios. The accuracy of ODAC remained high across different sample sizes and event rates. On the other hand, the meta-analysis estimator, which was obtained by the inverse variance weighted average of the site-specific estimates, had substantial bias when the event rate is <5%, with the relative bias reaching 20% when the event rate is 1%. In the Observational Health Data Sciences and Informatics network application, the ODAC estimates have a relative bias <5% for 15 out of 16 log hazard ratios, whereas the meta-analysis estimates had substantially higher bias than ODAC.
Conclusions
ODAC is a privacy-preserving and noniterative method for implementing time-to-event analyses across multiple sites. It provides estimates on par with the pooled estimator and substantially outperforms the meta-analysis estimator when the event is uncommon, making it extremely suitable for studying rare events and diseases in a distributed manner.
•Acinetobacter baumannii is an important human pathogen.•LPS is one of the bacterial virulence factors.•The structure of the polysaccharide part of the LPS from a hypervirulent for mice strain LAC-4 ...was studied.•8-epi-Legionaminic acid was found in the polysaccharide.
The structure of the surface polysaccharide from a hypervirulent for mice Acinetobacter baumannii strain LAC-4 was studied. The polysaccharide was built of trisaccharide repeating units containing α-l-fucosamine, α-d-glucosamine, and α-8-epi-legionaminic acid. The structure interpretation was based mostly on NMR data. Polysaccharide was obtained using a procedure of LPS O-chain preparation, although whether it is an LPS O-chain or capsular polysaccharide remained unclear.
This letter aims to understand the impact of stochastic arrivals on the peak age of information (PAoI) of non-orthogonal multiple access (NOMA) based Internet of Things (IoT) networks. Particularly, ...the concurrent transmissions of devices under NOMA provoke interactions of queues, which renders an entangled stochastic process to the analysis of PAoI. To this end, we first present an algorithmic solution to calculate the queue service rate, and then we derive analytical expression for the distribution of PAoI, which can be utilized to evaluate the statistics and the violation probability of PAoI. Based on the analysis, which is validated by simulations, we show that in terms of network average PAoI, NOMA considerably outperforms orthogonal multiple access (OMA) in the regime of more frequent update arrivals. We also find that the discrepancy on PAoI violation probability among different NOMA devices heavily hinges on the update arrival rate, demonstrating the critical role of the update dynamic in PAoI performance. The derived results allows us to extract valuable insights from the problem.
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