Miracle-dz/UniFAR-FTUs huggingface dataset:
Validity and power considerations on hypothesis testing under minimization

Minimization, a dynamic allocation method, is gaining popularity especially in cancer clinical trials. Aiming to achieve balance on all important prognostic factors simultaneously, this procedure can lead to a substantial reduction in covariate imbalance compared with conventional randomization in small clinical trials. While minimization has generated enthusiasm, some controversy exists over the proper analysis of such a trial. Critics argue that standard testing methods that do not account for the dynamic allocation algorithm can lead to invalid statistical inference. Acknowledging this limitation, the International Conference on Harmonization E9 guideline suggests that ‘the complexity of the logistics and potential impact on analyses be carefully evaluated when considering dynamic allocation’. In this article, we investigate the proper analysis approaches to inference in a minimization design for both continuous and time‐to‐event endpoints and evaluate the validity and power of these approaches under a variety of scenarios both theoretically and empirically. Published 2016. This article is a U.S. Government work and is in the public domain in the USA
Frequency-Tracking Clock Servo for Time Synchronization in Networked Motion Control Systems

With the application of internet in manufacturing, motion control system is tend to networking. Clock synchronization is a basic requirement to guarantee capability of coordination in networked motion control systems. In this paper, we propose a frequency-tracking clock servo (FTCS) to adjust the local clock to synchronize with the reference clock. The frequency of FTCS can rapidly lock onto the reference frequency and the offset can be fully compensated within a single synchronizing cycle. Simulations and experiments are performed to validate the feasibility and superiority of FTCS. Compared with the proportional-integral clock servo, FTCS can achieve the rapid synchronized speed and better precision with low frequency of sending synchronization messages.
Monte Carlo‐based investigation of absorbed‐dose energy dependence of radiochromic films in high energy brachytherapy dosimetry

Relative absorbed dose energy response correction, R, for various radiochromic films in water phantom is calculated by the use of the Monte Carlo‐based EGSnrc code system for high energy brachytherapy sources 60Co, 137Cs, 192Ir and 169Yb. The corrections are calculated along the transverse axis of the sources (1‐15 cm). The radiochromic films investigated are EBT, EBT2 (lot 020609 and lot 031109), RTQA, XRT, XRQA, and HS. For the 60Co source, the value of R is about unity and is independent of distance in the water phantom for films other than XRT and XRQA. The XRT and XRQA films showed distance‐dependent R values for this source (the values of R at 15 cm from the source in water are 1.845 and 2.495 for the films XRT and XRQA, respectively). In the case of 137Cs and 192Ir sources, XRT, XRQA, EBT2 (lot 031109), and HS films showed distant‐dependent R values. The rest of the films showed no energy dependence (HS film showed R values less than unity by about 5%, whereas the other films showed R values higher than unity). In the case of 169Yb source, the EBT film showed no energy dependence and EBT2 film (lot 031109) showed a distance‐independent R value of 1.041. The rest of the films showed distance‐dependent R values (increases with distance for the films other than HS). The solid phantoms PMMA and polystyrene enhance the R values for some films when compared the same in the water phantom. PACS number: 87.53. Jw
Robotic pick-and-place of novel objects in clutter with multi-affordance grasping and cross-domain image matching

This article presents a robotic pick-and-place system that is capable of grasping and recognizing both known and novel objects in cluttered environments. The key new feature of the system is that it handles a wide range of object categories without needing any task-specific training data for novel objects. To achieve this, it first uses an object-agnostic grasping framework to map from visual observations to actions: inferring dense pixel-wise probability maps of the affordances for four different grasping primitive actions. It then executes the action with the highest affordance and recognizes picked objects with a cross-domain image classification framework that matches observed images to product images. Since product images are readily available for a wide range of objects (e.g., from the web), the system works out-of-the-box for novel objects without requiring any additional data collection or re-training. Exhaustive experimental results demonstrate that our multi-affordance grasping achieves high success rates for a wide variety of objects in clutter, and our recognition algorithm achieves high accuracy for both known and novel grasped objects. The approach was part of the MIT–Princeton Team system that took first place in the stowing task at the 2017 Amazon Robotics Challenge. All code, datasets, and pre-trained models are available online at http://arc.cs. princeton.edu/
Type 3 Adenylyl Cyclase and Somatostatin Receptor 3 Expression Persists in Aged Rat Neocortical and Hippocampal Neuronal Cilia

The primary cilia of forebrain neurons assemble around birth and become enriched with neuromodulatory receptors. Our understanding of the permanence of these structures and their associated signaling pathways in the aging brain is poor, but they are worthy of investigation because disruptions in neuronal cilia signaling have been implicated in changes in learning and memory, depression-like symptoms, and sleep anomalies. Here, we asked whether neurons in aged forebrain retain primary cilia and whether the staining characteristics of aged cilia for type 3 adenylyl cyclase (ACIII), somatostatin receptor 3 (SSTR3), and pericentrin resemble those of cilia in younger forebrain. To test this, we analyzed immunostained sections of forebrain tissues taken from young and aged male Fischer 344 (F344) and F344 × Brown Norway (F344 × BN) rats. Analyses of ACIII and SSTR3 in young and aged cortices of both strains of rats revealed that the staining patterns in the neocortex and hippocampus were comparable. Virtually every NeuN positive cell examined possessed an ACIII positive cilium. The lengths of ACIII positive cilia in neocortex were similar between young and aged for both strains, whereas in F344 × BN hippocampus, the cilia lengths increased with age in CA1 and CA3, but not in dentate gyrus (DG). Additionally, the percentages of ACIII positive cilia that were also SSTR3 positive did not differ between young and aged tissues in either strain. We also found that pericentrin, a protein that localizes to the basal bodies of neuronal cilia and functions in primary cilia assembly, persisted in aged cortical neurons of both rat strains. Collectively, our data show that neurons in aged rat forebrain possess primary cilia and that these cilia, like those present in younger brain, continue to localize ACIII, SSTR3, and pericentrin. Further studies will be required to determine if the function and signaling pathways regulated by cilia are similar in aged compared to young brain.
Impaired autophagy correlates with golden retriever muscular dystrophy phenotype

Introduction: Duchenne muscular dystrophy (DMD) and golden retriever muscular dystrophy (GRMD) are X‐linked disorders caused by mutations in the DMD gene. Autophagy was recently identified as a secondary therapeutic target for DMD. We hypothesized that autophagy would be reduced in GRMD. Methods: Autophagic gene and protein expression was assessed in normal and GRMD skeletal muscles and correlated with phenotypic biomarkers. Results: Muscles were differentially affected. Autophagy gene levels were lower than normal in the GRMD cranial sartorius (CS) but similar in the vastus lateralis (VL). Protein markers of autophagic flux, LC3B‐II and p62, were higher in both GRMD muscles, in keeping with impaired autophagy. Protein levels correlated with a more severe phenotype. Autophagic structures were found in necrotic, fast‐twitch GRMD myofibers. Discussion: Our data suggest that autophagy is impaired in certain GRMD muscles. Differential GRMD CS involvement emphasizes that therapeutic modulation of autophagy could require specific muscle targeting. Muscle Nerve 58: 418–426, 2018
Model-based local density sharpening of cryo-EM maps

Atomic models based on high-resolution density maps are the ultimate result of the cryo-EM structure determination process. Here, we introduce a general procedure for local sharpening of cryo-EM density maps based on prior knowledge of an atomic reference structure. The procedure optimizes contrast of cryo-EM densities by amplitude scaling against the radially averaged local falloff estimated from a windowed reference model. By testing the procedure using six cryo-EM structures of TRPV1, β-galactosidase, γ-secretase, ribosome-EF-Tu complex, 20S proteasome and RNA polymerase III, we illustrate how local sharpening can increase interpretability of density maps in particular in cases of resolution variation and facilitates model building and atomic model refinement.
Lipopolysaccharide transport to the cell surface: biosynthesis and extraction from the inner membrane

The cell surface of most Gram-negative bacteria is covered with lipopolysaccharide (LPS). The network of charges and sugars provided by the dense packing of LPS molecules in the outer leaflet of the outer membrane interferes with the entry of hydrophobic compounds into the cell, including many antibiotics. In addition, LPS can be recognized by the immune system and plays a crucial role in many interactions between bacteria and their animal hosts. LPS is synthesized in the inner membrane of Gram-negative bacteria, so it must be transported across their cell envelope to assemble at the cell surface. Over the past two decades, much of the research on LPS biogenesis has focused on the discovery and understanding of Lpt, a multi-protein complex that spans the cell envelope and functions to transport LPS from the inner membrane to the outer membrane. This paper focuses on the early steps of the transport of LPS by the Lpt machinery: the extraction of LPS from the inner membrane. The accompanying paper (May JM, Sherman DJ, Simpson BW, Ruiz N, Kahne D. 2015 Phil. Trans. R. Soc. B 370, 20150027. (doi:10.1098/rstb.2015.0027)) describes the subsequent steps as LPS travels through the periplasm and the outer membrane to its final destination at the cell surface.
CARD 2017: expansion and model-centric curation of the comprehensive antibiotic resistance database

The Comprehensive Antibiotic Resistance Database (CARD; http://arpcard.mcmaster.ca) is a manually curated resource containing high quality reference data on the molecular basis of antimicrobial resistance (AMR), with an emphasis on the genes, proteins and mutations involved in AMR. CARD is ontologically structured, model centric, and spans the breadth of AMR drug classes and resistance mechanisms, including intrinsic, mutation-driven and acquired resistance. It is built upon the Antibiotic Resistance Ontology (ARO), a custom built, interconnected and hierarchical controlled vocabulary allowing advanced data sharing and organization. Its design allows the development of novel genome analysis tools, such as the Resistance Gene Identifier (RGI) for resistome prediction from raw genome sequence. Recent improvements include extensive curation of additional reference sequences and mutations, development of a unique Model Ontology and accompanying AMR detection models to power sequence analysis, new visualization tools, and expansion of the RGI for detection of emergent AMR threats. CARD curation is updated monthly based on an interplay of manual literature curation, computational text mining, and genome analysis.
A genome-wide association study identiﬁes nucleotide variants at SIGLEC5 and DEFA1A3 as risk loci for periodontitis

Periodontitis is one of the most common inﬂammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. The disease is characterized by destruction of the alveolar bone due to an aberrant host inﬂammatory response to a dysbiotic oral microbiome. Previous genome-wide association studies (GWAS) have reported several suggestive susceptibility loci. Here, we conducted a GWAS using a German and Dutch case-control sample of aggressive periodontitis (AgP, 896 cases, 7,104 controls), a rare but highly severe and early-onset form of periodontitis, validated the associations in a German sample of severe forms of the more moderate phenotype chronic periodontitis (CP) (993 cases, 1,419 controls). Positive ﬁndings were replicated in a Turkish sample of AgP (223 cases, 564 controls). A locus at SIGLEC5 (sialic acid binding Ig-like lectin 5) and a chromosomal region downstream of the DEFA1A3 locus (defensin alpha 1-3) showed association with both disease phenotypes and were associated with periodontitis at a genome-wide signiﬁcance level in the pooled samples, with P ¼ 1.09E-08 (rs4284742,-G; OR ¼ 1.34, 95% CI ¼ 1.21–1.48) and P ¼ 5.48E-10 (rs2738058,-T; OR ¼ 1.28, 95% CI ¼ 1.18–1.38), respectively. SIGLEC5 is expressed in various myeloid immune cells and classiﬁed as an inhibitory receptor with the potential to mediate tyrosine phosphatases SHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils and mucosal surfaces and a role in phagocyte-mediated host defense. This study identiﬁes the ﬁrst shared genetic risk loci of AgP and CP with genome-wide signiﬁcance and highlights the role of innate and adaptive immunity in the etiology of periodontitis.
Effect of Health Literacy on Decision-Making Preferences among Medically Underserved Patients

Introduction. Participation in the decision-making process and health literacy may both affect health outcomes; data on how these factors are related among diverse groups are limited. This study examined the relationship between health literacy and decision-making preferences in a medically underserved population. Methods. We analyzed a sample of 576 primary care patients. Multivariable logistic regression was used to examine the independent association of health literacy (measured by the Rapid Estimate of Adult Literacy in Medicine–Revised) and patients’ decision-making preferences (physician directed or patient involved), controlling for age, race/ethnicity, and gender. We tested whether having a regular doctor modified this association. Results. Adequate health literacy (odds ratio [OR] = 1.7; P = 0.009) was significantly associated with preferring patient-involved decision making, controlling for age, race/ethnicity, and gender. Having a regular doctor did not modify this relationship. Males were significantly less likely to prefer patient-involved decision making (OR = 0.65; P = 0.024). Discussion. Findings suggest health literacy affects decision-making preferences in medically underserved patients. More research is needed on how factors, such as patient knowledge or confidence, may influence decision-making preferences, particularly for those with limited health literacy.
Shared decision-making following disclosure of coronary heart disease genetic risk: results from a randomized clinical trial

Whether disclosure of genetic risk for coronary heart disease (CHD) influences shared decision-making (SDM) regarding use of statins to reduce CHD risk is unknown. We randomized 207 patients, age 45–65 years, at intermediate CHD risk, and not on statins, to receive the 10-year risk of CHD based on conventional risk factors alone (n=103) or in combination with a genetic risk score (n=104). A genetic counselor disclosed this information followed by a physician visit for SDM regarding statin therapy. A novel decision aid was used in both encounters to disclose the CHD risk estimates and facilitate SDM regarding statin use. Patients reported their decision quality and physician visit satisfaction using validated surveys. There were no statistically significant differences between the two groups in the SDM score, satisfaction with the clinical encounter, perception of the quality of the discussion or of participation in decision-making and physician visit satisfaction scores. Quantitative analyses of a random subset of 80 video-recorded encounters using the OPTION5 scale also showed no significant difference in SDM between the two groups. Disclosure of CHD genetic risk using an electronic health record-linked decision aid did not adversely affect SDM or patients’ satisfaction with the clinical encounter. Trial registration number NCT01936675; Results.
Plasticity in copper thin films: An experimental investigation of the effect of microstructure

The mechanical behavior of freestanding Cu thin films is investigated using the plane-strain bulge test. Finite element analysis of the bulge test technique confirms that the measurement is highly accurate and reliable. A versatile specimen fabrication process using Si micromachining is developed and an automated bulge test apparatus with high displacement and pressure measurement resolutions is constructed. The elastic-plastic behavior of Cu films is studied with emphasis on the effects of microstructure, film thickness, and surface passivation on the plastic response of the films. For that purpose, Cu films with a range of thickness and microstructure and with different surface passivation conditions are prepared by electroplating or sputtering. The microstructure is carefully characterized and the stress–strain curves are measured. The mechanical properties are determined as a function of film thickness and microstructure for films both with and without surface passivation. The stiffness of the Cu films varies with film thickness because of changes in the crystallographic texture of the films and the elastic anisotropy of Cu. No modulus deficit is observed. The yield stress of unpassivated films varies mainly with the average grain size, while film thickness and texture have a
Toll-Like Receptor 9–Dependent AMPKα Activation Occurs via TAK1 and Contributes to RhoA/ROCK Signaling and Actin Polymerization in Vascular Smooth Muscle Cells

Traditionally, Toll-like receptor 9 (TLR9) signals through an MyD88-dependent cascade that results in proinflammatory gene transcription. Recently, it was reported that TLR9 also participates in a stress tolerance signaling cascade in nonimmune cells. In this noncanonical pathway, TLR9 binds to and inhibits sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2), modulating intracellular calcium handling, and subsequently resulting in the activation of 5′-AMP–activated protein kinase α (AMPKα). We have previously reported that TLR9 causes increased contraction in isolated arteries; however, the mechanisms underlying this vascular dysfunction need to be further clarified. Therefore, we hypothesized that noncanonical TLR9 signaling was also present in vascular smooth muscle cells (VSMCs) and that it mediates enhanced contractile responses through SERCA2 inhibition. To test these hypotheses, aortic microsomes, aortic VSMCs, and isolated arteries from male Sprague-Dawley rats were incubated with vehicle or TLR9 agonist (ODN2395). Despite clear AMPKα activation after treatment with ODN2395, SERCA2 activity was unaffected. Alternatively, ODN2395 caused the phosphorylation of AMPKα via transforming growth factor β–activated kinase 1 (TAK1), a kinase involved in TLR9 inflammatory signaling. Downstream, we hypothesized that that TLR9 activation of AMPKα may be important in mediating actin cytoskeleton reorganization. ODN2395 significantly increased the filamentous-to-globular actin ratio, as well as indices of RhoA/Rho-associated protein kinase (ROCK) activation, with the latter being prevented by AMPKα inhibition. In conclusion, AMPKα phosphorylation after TLR9 activation in VSMCs appears to be an extension of traditional inflammatory signaling via TAK1, as opposed to SERCA2 inhibition and the noncanonical pathway. Nonetheless, TLR9-AMPKα signaling can mediate VSMC function via RhoA/ROCK activation and actin polymerization.
The Implementation and Validation of a Virtual Environment for Training Powered Wheelchair Manoeuvres

Navigating a powered wheelchair and avoiding collisions is often a daunting task for new wheelchair users. It takes time and practice to gain the coordination needed to become a competent driver and this can be even more of a challenge for someone with a disability. We present a cost-effective virtual reality (VR) application that takes advantage of consumer level VR hardware. The system can be easily deployed in an assessment centre or for home use, and does not depend on a specialized high-end virtual environment such as a Powerwall or CAVE. This paper reviews previous work that has used virtual environments technology for training tasks, particularly wheelchair simulation. We then describe the implementation of our own system and the first validation study carried out using thirty three able bodied volunteers. The study results indicate that at a significance level of 5 percent then there is an improvement in driving skills from the use of our VR system. We thus have the potential to develop the competency of a wheelchair user whilst avoiding the risks inherent to training in the real world. However, the occurrence of cybersickness is a particular problem in this application that will need to be addressed.
Chemoselective Alteration of Fluorophore Scaffolds as a Strategy for the Development of Ratiometric Chemodosimeters.

Ratiometric sensors generally couple binding events or chemical reactions at a distal site to changes in the fluorescence of a core fluorophore scaffold. However, such approaches are often hindered by spectral overlap of the product and reactant species. We provide a strategy to design ratiometric sensors that display dramatic spectral shifts by leveraging the chemoselective reactivity of novel functional groups inserted within fluorophore scaffolds. As a proof-of-principle, fluorophores containing a borinate (RF620 ) or silanediol (SiOH2R) functionality at the bridging position of the xanthene ring system are developed as endogenous H2 O2 sensors. Both these fluorophores display far-red to near-infrared excitation and emission prior to reaction. Upon oxidation by H2 O2 both sensors are chemically converted to tetramethylrhodamine, producing significant (≥66 nm) blue-shifts in excitation and emission maxima. This work provides a new concept for the development of ratiometric probes.
Automatic Modulation Classification for MIMO-OFDM Systems with Imperfect Timing Synchronization

Automatic modulation classification (AMC) plays a pivotal role for spectrum monitoring in cognitive radio (CR). The objective of this work is to investigate the AMC problem for multiple-input multiple-output (MIMO) systems employing orthogonal frequency division multiplexing (OFDM) under imperfect timing synchronization scenarios. Two major contributions are made in this work: i) specific higher-order cumulants (HOC) are proved to be robust to symbol timing offset (STO). ii) with the feature of multiple HOCs, a random forest based AMC algorithm is proposed for MIMO-OFDM systems, which is robust to timing synchronization error. Numerical simulations are conducted to verify the validation of the algorithm.