Mengyang Gu.

Source: Bayesian Analysis, Volume 14, Number 3, 877--905.

Abstract:
Gaussian stochastic process (GaSP) has been widely used in two fundamental problems in uncertainty quantification, namely the emulation and calibration of mathematical models. Some objective priors, such as the reference prior, are studied in the context of emulating (approximating) computationally expensive mathematical models. In this work, we introduce a new class of priors, called the jointly robust prior, for both the emulation and calibration. This prior is designed to maintain various advantages from the reference prior. In emulation, the jointly robust prior has an appropriate tail decay rate as the reference prior, and is computationally simpler than the reference prior in parameter estimation. Moreover, the marginal posterior mode estimation with the jointly robust prior can separate the influential and inert inputs in mathematical models, while the reference prior does not have this property. We establish the posterior propriety for a large class of priors in calibration, including the reference prior and jointly robust prior in general scenarios, but the jointly robust prior is preferred because the calibrated mathematical model typically predicts the reality well. The jointly robust prior is used as the default prior in two new R packages, called “RobustGaSP” and “RobustCalibration”, available on CRAN for emulation and calibration, respectively.

Two men are charged in connection with an illegal drug distribution operation after Winnipeg police seized more than $2.2 million worth of methamphetamine, cocaine and ecstasy.

Businesses in Cape Breton are helping customers get creative with DIY take-home kits to make everything from mermaid-themed terrariums to bubble tea.

Online learning holds great potential to transform rural education by ensuring that every student has access to great instruction.

A strong Delaware watermelon season is now under way, with First State melons now reaching customers in grocery stores and markets along the East Coast, from New England to Florida. This season is featuring good yields and excellent quality for Delaware watermelon growers, said Secretary of Agriculture Ed Kee. The First State produces both seeded and seedless watermelon.

The US 10-year Treasury bond yield fell 0.7 percent in response to the latest report of jobless claims. That comes a week after the Treasury said it would borrow a record $2.99 trillion this quarter, and launch a 20-year bond.
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ESPN's colleges writers and reporters reflect on the phenoms they had a chance to cover before they were famous.

Lulzbuster is a very fast and smart web directory and file enumeration tool written in C.

Lulzbuster is a very fast and smart web directory and file enumeration tool written in C.

Lulzbuster is a very fast and smart web directory and file enumeration tool written in C.

Lulzbuster is a very fast and smart web directory and file enumeration tool written in C.

Earlier this month, when EPA proposed a new health-protective air quality standard for the pollutants that form “ozone,” some critics predictably pounced on it as another example of a long string of “job-killing EPA regulations.” Yet last week, we learned that the U.S. economy created about 320,000 new jobs in November, and average wages are starting to rise as the labor market tightens.

A man involved in a $2.5 million meth bust in Hawke's Bay has had his three and a half year prison sentence dropped to 12 months of home detention.Uriah Whetu Monty Wirihana received a prison sentence of three years and seven months...

A Hong Kong police officer arrested in connection with the seizure of 25kg of drugs worth HK$12 million is believed to have orchestrated its theft from the scene of a bust he was personally in charge of last week, according to police sources.If true, it would mean the announced record seizure of 296kg of Ice, a form of methamphetamine, actually involved 321kg.Sources said the station sergeant, who was arrested along with a constable in connection with the missing drugs, was in charge of the…

A high school teacher in Kisii County was arrested on Tuesday for impersonating a 20-year old girl during a KCSE exam.

Hrithik Roshan had an extraordinary 2019, having made two hit movies in a row

Usually the kingdom of water tanks and satellite dishes, Lebanon's rooftops have recently been graced by unlikely scenes of locked-down residents fleeing their flats.

Sara Pauly is not one of those small business owners scrambling to fill out paperwork for part of the more than $350 billion in government aid available through the Paycheck Protection Program or the...

While President Donald Trump traveled to the battleground state of Arizona this week, his Democratic opponent for the White House, Joe Biden, campaigned from his basement as he has done throughout the coronavirus pandemic.

ABSTRACT

In Escherichia coli, the chemotaxis response regulator CheY-P binds to FliM, a component of the switch complex at the base of the bacterial flagellar motor, to modulate the direction of motor rotation. The bacterial flagellar motor is ultrasensitive to the concentration of unbound CheY-P in the cytoplasm. CheY-P binds to FliM molecules both in the cytoplasm and on the motor. As the concentration of FliM unavoidably varies from cell to cell, leading to a variation of unbound CheY-P concentration in the cytoplasm, this raises the question whether the flagellar motor is robust against this variation, that is, whether the rotational bias of the motor is more or less constant as the concentration of FliM varies. Here, we showed that the motor is robust against variations of the concentration of FliM. We identified adaptive remodeling of the motor as the mechanism for this robustness. As the level of FliM molecules changes, resulting in different amounts of the unbound CheY-P molecules, the motor adaptively changes the composition of its switch complex to compensate for this effect.

IMPORTANCE The bacterial flagellar motor is an ultrasensitive motor. Its output, the probability of the motor turning clockwise, depends sensitively on the occupancy of the protein FliM (a component on the switch complex of the motor) by the input CheY-P molecules. With a limited cellular pool of CheY-P molecules, cell-to-cell variation of the FliM level would lead to large unwanted variation of the motor output if not compensated. Here, we showed that the motor output is robust against the variation of FliM level and identified the adaptive remodeling of the motor switch complex as the mechanism for this robustness.

ABSTRACT

Hepatitis C virus (HCV) infects millions of people worldwide, causing chronic liver disease that can lead to cirrhosis, hepatocellular carcinoma, and liver transplant. In the last several years, the advent of direct-acting antivirals, including NS3/4A protease inhibitors (PIs), has remarkably improved treatment outcomes of HCV-infected patients. However, selection of resistance-associated substitutions and polymorphisms among genotypes can lead to drug resistance and in some cases treatment failure. A proactive strategy to combat resistance is to constrain PIs within evolutionarily conserved regions in the protease active site. Designing PIs using the substrate envelope is a rational strategy to decrease the susceptibility to resistance by using the constraints of substrate recognition. We successfully designed two series of HCV NS3/4A PIs to leverage unexploited areas in the substrate envelope to improve potency, specifically against resistance-associated substitutions at D168. Our design strategy achieved better resistance profiles over both the FDA-approved NS3/4A PI grazoprevir and the parent compound against the clinically relevant D168A substitution. Crystallographic structural analysis and inhibition assays confirmed that optimally filling the substrate envelope is critical to improve inhibitor potency while avoiding resistance. Specifically, inhibitors that enhanced hydrophobic packing in the S4 pocket and avoided an energetically frustrated pocket performed the best. Thus, the HCV substrate envelope proved to be a powerful tool to design robust PIs, offering a strategy that can be translated to other targets for rational design of inhibitors with improved potency and resistance profiles.

IMPORTANCE Despite significant progress, hepatitis C virus (HCV) continues to be a major health problem with millions of people infected worldwide and thousands dying annually due to resulting complications. Recent antiviral combinations can achieve >95% cure, but late diagnosis, low access to treatment, and treatment failure due to drug resistance continue to be roadblocks against eradication of the virus. We report the rational design of two series of HCV NS3/4A protease inhibitors with improved resistance profiles by exploiting evolutionarily constrained regions of the active site using the substrate envelope model. Optimally filling the S4 pocket is critical to avoid resistance and improve potency. Our results provide drug design strategies to avoid resistance that are applicable to other quickly evolving viral drug targets.

ABSTRACT

The profiling of gene expression by RNA sequencing (RNA-seq) has enabled powerful studies of global transcriptional patterns in all organisms, including bacteria. Because the vast majority of RNA in bacteria is rRNA, it is standard practice to deplete the rRNA from a total RNA sample such that the reads in an RNA-seq experiment derive predominantly from mRNA. One of the most commonly used commercial kits for rRNA depletion, the Ribo-Zero kit from Illumina, was recently discontinued abruptly and for an extended period of time. Here, we report the development of a simple, cost-effective, and robust method for depleting rRNA that can be easily implemented by any lab or facility. We first developed an algorithm for designing biotinylated oligonucleotides that will hybridize tightly and specifically to the 23S, 16S, and 5S rRNAs from any species of interest. Precipitation of these oligonucleotides bound to rRNA by magnetic streptavidin-coated beads then depletes rRNA from a complex, total RNA sample such that ~75 to 80% of reads in a typical RNA-seq experiment derive from mRNA. Importantly, we demonstrate a high correlation of RNA abundance or fold change measurements in RNA-seq experiments between our method and the Ribo-Zero kit. Complete details on the methodology are provided, including open-source software for designing oligonucleotides optimized for any bacterial species or community of interest.

IMPORTANCE The ability to examine global patterns of gene expression in microbes through RNA sequencing has fundamentally transformed microbiology. However, RNA-seq depends critically on the removal of rRNA from total RNA samples. Otherwise, rRNA would comprise upward of 90% of the reads in a typical RNA-seq experiment, limiting the reads coming from mRNA or requiring high total read depth. A commonly used kit for rRNA subtraction from Illumina was recently unavailable for an extended period of time, disrupting routine rRNA depletion. Here, we report the development of a "do-it-yourself" kit for rapid, cost-effective, and robust depletion of rRNA from total RNA. We present an algorithm for designing biotinylated oligonucleotides that will hybridize to the rRNAs from a target set of species. We then demonstrate that the designed oligonucleotides enable sufficient rRNA depletion to produce RNA-seq data with 75 to 80% of reads coming from mRNA. The methodology presented should enable RNA-seq studies on any species or metagenomic sample of interest.

Capture bioprocessing unit operations were previously shown to clear or kill several log₁₀ of a model mycoplasma Acholeplasma laidlawii in lab-scale spike/removal studies. Here, we confirm this observation with two additional mollicute species relevant to biotechnology products for human use: Mycoplasma orale and Mycoplasma arginini. Clearance of M. orale and M. arginini from protein A column purification was similar to that seen with A. laidlawii, though some between cycle carryover was evident, especially for M. orale. However, on-resin growth studies for all three species revealed that residual mycoplasma in a column slowly die off over time rather than expanding further. Solvent/detergent exposure completely inactivated M. arginini though detectable levels of M. orale remained. A small-scale model of a commercial low-pH hold step did inactivate live M. orale, but this inactivation required a lower pH set point and occurred with slower kinetics than previously seen with A. laidlawii. Additionally, ultraviolet-C irradiation was shown to be effective for A. laidlawii and M. orale inactivation whereas virus-retentive filters for upstream and downstream processes, as expected, cleared A. laidlawii. These data argue that M. orale and M. arginini overall would be largely cleared by early bioprocessing steps as shown previously for A. laidlawii, and that barrier technologies can effectively reduce the risk from media components. For some unit operations, M. orale and M. arginini may be hardier, and require more stringent processing or equipment cleaning conditions to assure effective mycoplasma reduction. By exploring how some of the failure modes in commercial antibody manufacturing processes can still eliminate mycoplasma burden, we demonstrate that required best practices assure biotechnology products will be safe for patients.

The Oscar-winning sword-and-sandals Russell Crowe vehicle refreshed old cliches, before ushering in a spate of copycats

“Joey, do you like movies about gladiators?” the creepy pilot asks the small boy in Airplane!. To younger audiences, the joke no longer makes any sense. In Airplane!’s day, sword-and-sandals movies had become an outdated, unwittingly homoerotic joke. But then came Gladiator, and the joke was on us. Released 20 years ago this month, Ridley Scott’s Roman epic gave the old cliches a new lease of life. It was all here: Colosseum action! Rippling man-flesh! Tigers! But Gladiator had its cheesecake and ate it. It served up crowd-pleasing spectacle and airline-ad visuals but also solemn, Oscar-worthy drama (and, in retrospect, a fair degree of camp).

Related: The Guide: Staying In – sign up for our home entertainment tips

While President Donald Trump traveled to the battleground state of Arizona this week, his Democratic opponent for the White House, Joe Biden, campaigned from his basement as he has done throughout the coronavirus pandemic.

While President Donald Trump traveled to the battleground state of Arizona this week, his Democratic opponent for the White House, Joe Biden, campaigned from his basement as he has done throughout the coronavirus pandemic.

Sean S. Cunningham's slasher 'Friday the 13th' is celebrating its 40th anniversary this week. Its effect on the horror genre defined the 1980s.

The Thor star was thankful to finally be on a well-deserved break from his hectic schedule.

Owners of apartments affected by the combustible cladding crisis in Victoria tell researchers of the emotional and financial toll it has taken on them and their neighbours.

In the days before the virus, strolling down Broadway felt like swimming through a sea of people. Now it feels like wandering around a forsaken movie set.

Flattering comparisons with other leading sports officials have also helped elevate the ARL chairman's current status as the can-do man of Australian sport, but as Richard Hinds asks, is he about to make a huge mistake?

Tokyo’s Daiichi Sankyo has submitted a supplemental New Drug Application (sNDA) for trastuzumab deruxtecan…

The Justice Department today announced a settlement agreement under the Americans with Disabilities Act (ADA) with Blockbuster Inc. to ensure equal access to its stores nationwide for individuals with disabilities who use service animals.

Editor's note: This story was originally published Friday morning, and has been updated to reflect the FDA's decision regarding the drug later that day. A U.S. approval decision for a major drug planned to be marketed by Cambridge-based Sanofi Genzyme that had been expected last Friday has been delayed due to “deficiencies” found during a manufacturing site inspection in France. In its third quarter report, released Friday morning, French drugmaker Sanofi (NYSE: SNY) disclosed that “manufacturing…

Yokogawa Electric Corporation (TOKYO: 6841) announces the release of artificial intelligence (AI)-enabled versions of the GX series panel-mount type paperless recorders, GP series portable paperless recorders, and GA10 data logging software, which are components of the highly operable and expandable SMARTDAC+data acquisition and control system. This new AI functionality includes the future pen, a function developed by Yokogawa that enables the drawing of predicted waveforms. Yokogawa is also releasing a new CPU module for the e-RT3 Plus edge computing platform that is environmentally robust and Python compatible. The GX/GP and e-RT3 release is set for April 8, and the GA10 software will be released on May 13. The SMARTDAC+ system is a product in the OpreX Data Acquisition family, and the e-RT3 Plus is part of the OpreX Control Devices family.