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Gain-of-function (GOF) variants give rise to increased/novel protein functions whereas loss-of-function (LOF) variants lead to diminished protein function. Experimental approaches for identifying GOF and LOF are generally slow and costly, whilst available computational methods have not been optimized to discriminate between GOF and LOF variants. We have developed LoGoFunc, a machine learning method for predicting pathogenic GOF, pathogenic LOF, and neutral genetic variants, trained on a broad range of gene-, protein-, and variant-level features describing diverse biological characteristics. LoGoFunc outperforms other tools trained solely to predict pathogenicity for identifying pathogenic GOF and LOF variants and is available at https://itanlab.shinyapps.io/goflof/. [ABSTRACT FROM AUTHOR]

Background: The number of adults requiring prolonged mechanical ventilation (PMV) including those with cognitive impairment or disorders of consciousness is escalating. We aimed to compare in a long-term acute care hospital (LTACH) mortality and length of stay (LOS) among three age groups (40-59y, 60-79y, ≥80y) of hospitalized PMV patients, and according to consciousness and cognitive state at admission. Methods: We obtained data from the health records of 308 adults aged ≥40 years requiring PMV hospitalized at a Chronic Ventilator Dependent Unit in a LTACH between 01/01/2015 to 06/30/2019 and followed-up until discharge or death or until 12/31/2019. Results: At admission to LTACH, 42.2% of PMV patients were in a vegetative state/minimally conscious state (VS/MCS); 32.5% were severely cognitively impaired, 11.0% were mildly to moderately cognitively impaired, 12.3% had no cognitive impairment, and 1.9% had intellectual disability/psychiatric disorder. In-LTACH LOS (months) decreased from 34.6 ±42.6 at age 40-59y, 19.1 ± 22.3 at 60-79y to 14.4 ± 19.3 at age ≥80y (p = .006). In-LTACH mortality was 30.6% for 40-59y, 41.1% for 60-79y and 54.8% for age ≥80y. In-LTACH LOS (months) was 23.8 ± 30.7 for VS/MCS, 15.1 ± 19.5 for the severely cognitively impaired, 10.0 ± 12.8 for mild to moderate cognitive impairment and 18.9 ± 21.9 for those without cognitive impairment (p = .02). In-LTACH mortality was 50.8% for VS/MCS, 58.0% for the severely cognitively impaired, 26.5% for mild to moderate cognitive impairment and 13.2% for those without cognitive impairment (p < .001). Conclusion: In this population requiring PMV, mortality and in-LTACH LOS worsened with age. In-LTACH LOS was longest for VS/MCS patients, who had a mean survival of about two years, followed by those without cognitive impairment and then those with severe cognitive impairment. Mortality was associated with worse consciousness and cognitive state. These findings highlight the importance of discussing end-of-life decisions with patients and family members regarding resuscitation/intubation and the long-term management of these patients. [ABSTRACT FROM AUTHOR]

Well-conditioned boundary integral methods for the solution of elliptic boundary value problems (BVPs) are powerful tools for static and dynamic physical simulations. When there are many close-to-touching boundaries (e.g., in complex fluids) or when the solution is needed in the bulk, nearly singular integrals must be evaluated at many targets. We show that precomputing a linear map from surface density to an effective source representation renders this task highly efficient, in the common case where each object is “simple”, i.e., its smooth boundary needs only moderately many nodes. We present a kernel-independent method needing only an upsampled smooth surface quadrature, and one dense factorization, for each distinct shape. No (near-)singular quadrature rules are needed. The resulting effective sources are drop-in compatible with fast algorithms, with no local corrections nor bookkeeping. Our extensive numerical tests include 2D FMM-based Helmholtz and Stokes BVPs with up to 1000 objects (281000 unknowns), and a 3D Laplace BVP with 10 ellipsoids separated by 1/30 of a diameter. We include a rigorous analysis for analytic data in 2D and 3D. [ABSTRACT FROM AUTHOR]

Background Patients with immunodeficiency-associated antibody disorders are at a higher risk of prolonged/persistent COVID-19 infection, having no viable treatment options. Methods A retrospective analysis of patients with primary and/or secondary immunodeficiency-associated antibody disorders who received casirivimab and imdevimab (REGEN-COV®) under emergency compassionate use. Objective were to describe safety and response to REGEN-COV, focusing on the subset of patients who had COVID-19 duration ≥21 days before treatment. Results Quantitative (change in oxygenation status and/or viral load) and/or qualitative (physician-reported clinical status) outcomes data are reported from 64 patients. Improvement in ≥1 outcome was observed in 90.6% of the overall patient group. Thirty-seven of these had COVID-19 duration ≥21 days before treatment; median time from diagnosis to REGEN-COV treatment was 60.5 days. Of the 29 patients with COVID-19 duration ≥21 days before treatment and available outcome data, 96.6% showed improvement in ≥1 outcome. In the 14 patients with post-treatment reverse transcription–polymerase chain reaction (RT-PCR) results available, 11 (78.6%) reported a negative RT-PCR following treatment, with 5 (45.5%) and 8 (72.7%) patients reporting a negative RT-PCR within 5 days and 21 days of treatment, respectively. Ten of 85 patients (11.8%) experienced serious adverse events; only one was an infusion-related reaction, possibly related to REGEN-COV. Two deaths were reported; neither were attributed to REGEN-COV. Conclusions In this retrospective analysis of immunodeficient patients granted REGEN-COV under emergency compassionate use, REGEN-COV treatment was associated with rapid viral clearance and clinical improvement in patients with longstanding COVID-19. Adverse events were consistent with COVID-19 and its associated complications, and due to patients' concurrent medical conditions. [ABSTRACT FROM AUTHOR]

Structural features of proteins provide powerful insights into biological function and similarity. Specifically, previous work has demonstrated that structural features of tissue and drug-treated cell line samples can be used to predict tissue type and characterize drug relationships, respectively. We have developed structural signatures, a web server for annotating and analyzing protein features from gene sets that are often found in transcriptomic and proteomic data. This platform provides access to a structural feature database derived from normal and disease human tissue samples. We show how analysis using this database can shed light on the relationship between states of single-cell RNA-sequencing lung cancer samples. These various structural feature signatures can be visualized on the server itself or downloaded for additional analysis. The structural signatures server tool is freely available at https://structural-server.kinametrix.com/. [ABSTRACT FROM AUTHOR]

Three new bathyal species of Paraliparis (Liparidae) are described from Tinian and Anatahan Islands, and from Esmeralda Bank, in the Mariana Islands. All were collected in shrimp traps set at 903–1207 m. Although liparids have been found, described, and studied at hadal depths in the Mariana Trench, Paraliparis echongpachot sp. nov., Paraliparis kadadakaleguak sp. nov., and Paraliparis marianae sp. nov. are the first species of the family described from bathyal depths of the Mariana Islands. The existence of three species from collections at three locations in the same archipelago, and their distinctiveness from liparids known from other areas in the western Pacific to the north and south of the Mariana Archipelago, is in accordance with the high degree of endemism in species of Paraliparis. Biogeographic and liparid life-history factors that influence bathyal fish distributions in the Mariana Archipelago and enhance endemism in Paraliparis are discussed. [ABSTRACT FROM AUTHOR]

Identifying whether a given genetic mutation results in a gene product with increased (gain-of-function; GOF) or diminished (loss-of-function; LOF) activity is an important step toward understanding disease mechanisms because they may result in markedly different clinical phenotypes. Here, we generated an extensive database of documented germline GOF and LOF pathogenic variants by employing natural language processing (NLP) on the available abstracts in the Human Gene Mutation Database. We then investigated various gene- and protein-level features of GOF and LOF variants and applied machine learning and statistical analyses to identify discriminative features. We found that GOF variants were enriched in essential genes, for autosomal-dominant inheritance, and in protein binding and interaction domains, whereas LOF variants were enriched in singleton genes, for protein-truncating variants, and in protein core regions. We developed a user-friendly web-based interface that enables the extraction of selected subsets from the GOF/LOF database by a broad set of annotated features and downloading of up-to-date versions. These results improve our understanding of how variants affect gene/protein function and may ultimately guide future treatment options. [ABSTRACT FROM AUTHOR]

Understanding the role of teaching presence in students' learning can help improve online teaching. This study explored the effects of online teaching presence on students' cognitive conflict and engagement by analyzing three rounds of a course taught with different levels of teaching presence. The participants were 132 students enrolled across the three rounds. Content and lag sequential analysis were used to explore the effects of teaching presence on students' cognitive conflict and learning engagement. The results show that design and facilitation can engage students in reflection and involve them in cognitive conflicts and cognitive engagement (p <.001). Moreover, timely facilitation and direct instruction had no significant effect on students' responses to cognitive conflict. These results illuminate the impact of teaching presence on students' learning engagement through cognitive conflict and provide instructors with practical guidance for online teaching. [ABSTRACT FROM AUTHOR]

Globally, grasslands are among the most degraded habitats, and within that category tallgrass prairies are especially threatened. To restore native species in tallgrass prairie, it is often necessary to concurrently remove exotic plant species while restoring the disturbance processes that many prairie taxa depend upon. Here, we coupled one herbicide application and seed mixture addition with tri-annual prescribed fire and annual cattle grazing to explore the consequences for floral resource (i.e. nectar-producing) plant communities and butterfly communities up to four years later. Each site was divided into three equally sized patches which were placed into either control, "spray-only", or "spray-and-seed" treatment groups. We quantified both floral resource plant and butterfly communities in the year prior to herbicide application and the four years following that treatment. In the four years post-treatment, we found that floral resource abundance, richness, and diversity increased over time but did not significantly vary among treatments. No response to treatment was observed in butterflies, but butterfly abundance decreased while richness was stable and diversity increased over time, which may indicate that the changes to floral resources at the patch scale supported more speciose and diverse butterfly communities at the site scale. Butterfly abundance decreasing over time could be an effect of baseline management or unrelated regional factors. Regardless of whether either treatment benefited butterflies, we find support for a one-time herbicide application changing the floral community in desirable ways and at least not harming butterflies. [ABSTRACT FROM AUTHOR]

Differences in how students and teachers understand online teaching presence play a key role in teaching design. To explore how students and teachers perceive teaching presence, this study surveyed 1,041 students and 18 teachers who participated in an online course at a Chinese university. The analysis found students' perceived teaching presence was significantly lower than the teachers', particularly in terms of facilitating discourse (p <.001). Regarding the perceived importance of the five dimensions of teaching presence (Wang et al., 2019), students perceived facilitating discourse to be more important than direct instruction, while the opposite was found to be true for teachers. The divergence creates a challenge for teachers in engaging students in learning. The results indicate that teachers could pay more attention to the following dimensions to improve students' learning experience: making macro-level comments on courses, designing instructional methods, providing formative feedback for homework and discussions, and making full use of technological tools in teaching. [ABSTRACT FROM AUTHOR]

The ternary perovskite system PbTiO3-Bi(Zn1/2Ti1/2)O3-Bi(Mg1/2Ti1/2)O3 was investigated in an attempt to capture the enhanced tetragonality of the PbTiO3-Bi(Zn1/2Ti1/2)O3 binary system at a morphotropic phase boundary (MPB) to improve piezoelectric performance. Results from the (1-x)[0.75 PbTiO3-0.25Bi(Zn1/2Ti1/2)O3]-(x)Bi(Mg1/2Ti1/2)O3 pseudo-binary solution indicate the formation of an MPB-type phase boundary with a high TC (585 °C at x = 0.55). Multiple dielectric transitions were observed in a region of the ternary diagram characterized by high occupancy of the A-site by Bi3+ (>40%) and the B-site by ferroelectrically active cations (>70%). Temperature-dependent diffraction studies revealed the persistence of a tetragonal structure in at least a subset of the crystal to the higher temperature dielectric transition. [ABSTRACT FROM AUTHOR]

Accurate assessment and effective feedback are crucial for cultivating learners' abilities of collaborative problem‐solving and critical thinking in online inquiry‐based discussions. Based on quantitative content analysis (QCA), there has been a methodological evolvement from descriptive statistics to sequential mining and to network analysis for mining coded discourse data. Epistemic network analysis (ENA) has recently gained increasing recognition for modelling and visualizing the temporal characteristics of online discussions. However, due to methodological restraints, some valuable information regarding online discussion dynamics remains unexplained, including the directionality of connections between theoretical indicators and the trajectory of thinking development. Guided by the community of inquiry (CoI) model, this study extended generic ENA by incorporating directional connections and stanza‐based trajectory tracking. By examining the proposed extensions with discussion data of an online learning course, this study first verified that the extensions are comparable with QCA, indicating acceptable assessment validity. Then, the directional ENA revealed that two‐way connections between CoI indicators could vary over time and across groups, reflecting different discussion strategies. Furthermore, trajectory tracking effectively detected and visualized the fine‐grained progression of thinking. At the end, we summarize several research and practical implications of the ENA extensions for assessing the learning process.Practitioner notesWhat is already known about this topic Assessment and feedback are crucial for cultivating collaborative problem‐solving and critical thinking in online inquiry‐based discussions. Cognitive presence is an important construct describing the progression of thinking in online inquiry‐based discussions. Epistemic network analysis is gaining increasing recognition for modelling the temporal characteristics of online inquiries. What this paper adds Directional connections between discourses can reflect different online discussion strategies of groups and individuals. A pair of connected discourses coded with the community of inquiry model can have different meanings depending on their temporal order. A trajectory tracking approach can uncover the fine‐grained progression of thinking in online inquiry‐based discussions. Implications for practice and/or policy Besides the occurrences of individual discourses, examining the meanings of directional co‐occurrences of discourses in online discussions is worthwhile. Groups and individuals can employ different discussion strategies and follow diverse paths to thought development. Developmental assessment is crucial for understanding how participants achieve specific outcomes and providing adaptive feedback. Assessment and feedback are crucial for cultivating collaborative problem‐solving and critical thinking in online inquiry‐based discussions. Cognitive presence is an important construct describing the progression of thinking in online inquiry‐based discussions. Epistemic network analysis is gaining increasing recognition for modelling the temporal characteristics of online inquiries. Directional connections between discourses can reflect different online discussion strategies of groups and individuals. A pair of connected discourses coded with the community of inquiry model can have different meanings depending on their temporal order. A trajectory tracking approach can uncover the fine‐grained progression of thinking in online inquiry‐based discussions. Besides the occurrences of individual discourses, examining the meanings of directional co‐occurrences of discourses in online discussions is worthwhile. Groups and individuals can employ different discussion strategies and follow diverse paths to thought development. Developmental assessment is crucial for understanding how participants achieve specific outcomes and providing adaptive feedback. [ABSTRACT FROM AUTHOR]

The Immersed Boundary (IB) method has been widely used to solve fluid-structure interaction problems, including those where the structure interacts with polymeric fluids. In this paper, we examine the convergence of one such scheme for a well known two-dimensional benchmark flow for the Oldroyd-B constitutive model, and we show that the traditional IB-based scheme fails to adequately capture the polymeric stress near to embedded boundaries. We analyze the reason for such failure, and we argue that this feature is not specific to the case study chosen, but a general feature of such methods due to lack of convergence in velocity gradients near interfaces. In order to remedy this problem, we build a different scheme for the Oldroyd-B system using the Immersed Boundary Smooth Extension (IBSE) scheme, which provides convergent viscous stresses near boundaries. We show that this modified scheme produces convergent polymeric stresses through the whole domain, including on embedded boundaries, and produces solutions in good agreement with known benchmarks. [ABSTRACT FROM AUTHOR]

Rare-earth iron garnets (REIGs) are the benchmark systems for magnonics, including the longitudinal spin Seebeck effect (LSSE). While most research has focused on single-crystalline REIGs on complimentary garnet substrates, moving to more, cost-effective complementary metal-oxide semiconductor (CMOS)-compatible substrates is important to integrate REIG thin films with existing technology. In this regard, we grow a 130 nm-thick polycrystalline gadolinium iron garnet (GdIG) film on the Si/SiO2 substrate and investigate the temperature-dependent LSSE. Interestingly, the polycrystalline GdIG film exhibits perpendicular magnetic anisotropy (PMA) at room temperature which is induced by tensile in-plane (IP)-strain originating from the thermal-expansion mismatch between the GdIG film and the substrate during rapid thermal annealing. Further, a spin-reorientation transition from the out-of-plane IP direction below TS = 180 K is observed. Additionally, the film reveals a magnetic compensation temperature, T Comp , of ≈240 K. The LSSE voltage not only demonstrates a sign-inversion around T Comp , but also shows noticeable changes around T S. As compared to a single-crystalline GdIG film, the lower LSSE voltage for the polycrystalline GdIG is attributed to the higher effective magnetic anisotropy and enhanced magnon scattering at the grain boundaries. Our study not only paves the way for the cost-effective growth of CMOS-compatible REIG-based systems with PMA for magnonic memory and information processing applications, but also highlights the fact that the spincaloritronic and spin-insulatronic properties of the polycrystalline REIGs follow those of their single-crystalline counterparts with reduced spin-to-charge conversion efficiency through LSSE which can be tuned further by controlling the average gran size and interface engineering. [ABSTRACT FROM AUTHOR]

The Immersed Boundary method is a simple, efficient, and robust numerical scheme for solving PDE in general domains, yet for fluid problems it only achieves first-order spatial accuracy near embedded boundaries for the velocity field and fails to converge pointwise for elements of the stress tensor. In a previous work we introduced the Immersed Boundary Smooth Extension (IBSE) method, a variation of the IB method that achieves high-order accuracy for elliptic PDE by smoothly extending the unknown solution of the PDE from a given smooth domain to a larger computational domain, enabling the use of simple Cartesian-grid discretizations. In this work, we extend the IBSE method to allow for the imposition of a divergence constraint, and demonstrate high-order convergence for the Stokes and incompressible Navier–Stokes equations: up to third-order pointwise convergence for the velocity field, and second-order pointwise convergence for all elements of the stress tensor. The method is flexible to the underlying discretization: we demonstrate solutions produced using both a Fourier spectral discretization and a standard second-order finite-difference discretization. [ABSTRACT FROM AUTHOR]

We present a spectrally accurate embedded boundary method for solving linear, inhomogeneous, elliptic partial differential equations (PDE) in general smooth geometries in two dimensions, focusing in this manuscript on the Poisson, modified Helmholtz, and Stokes equations. Unlike several recently proposed methods which rely on function extension, we propose a method which instead utilizes function intension , or the smooth truncation of known function values. Similar to those methods based on extension, once the inhomogeneity is truncated we may solve the PDE using any of the many simple, fast, and robust solvers that have been developed for regular grids on simple domains. Function intension is inherently stable, as are all steps in the proposed solution method, and can be used on domains which do not readily admit extensions. We pay a price in exchange for improved stability and flexibility: in addition to solving the PDE on the regular domain, we must additionally (1) solve the PDE on a small auxiliary domain that is fitted to the boundary, and (2) ensure consistency of the solution across the interface between this auxiliary domain and the rest of the physical domain. We show how these tasks may be accomplished efficiently (in both the asymptotic and practical sense), and compare convergence to two recent high-order embedded boundary schemes. Finally, to demonstrate the wide applicability of the method, we solve a nonlinear predator-prey model, achieving rapid convergence in both space and time. • Embedded boundary scheme for inhomogeneous PDE in general smooth 2D geometries. • Spectrally accurate, stable, and efficient: same scaling as FFT based methods. • Uses 'function intension', i.e. smooth truncation, instead of function extension. • Function intension is stable; solutions converge rapidly to near machine precision. • Demonstrations for Poisson, modified Helmholtz, Stokes, and predator-prey equations. [ABSTRACT FROM AUTHOR]

The Immersed Boundary method is a simple, efficient, and robust numerical scheme for solving PDE in general domains, yet it only achieves first-order spatial accuracy near embedded boundaries. In this paper, we introduce a new high-order numerical method which we call the Immersed Boundary Smooth Extension (IBSE) method. The IBSE method achieves high-order accuracy by smoothly extending the unknown solution of the PDE from a given smooth domain to a larger computational domain, enabling the use of simple Cartesian-grid discretizations (e.g. Fourier spectral methods). The method preserves much of the flexibility and robustness of the original IB method. In particular, it requires minimal geometric information to describe the boundary and relies only on convolution with regularized delta-functions to communicate information between the computational grid and the boundary. We present a fast algorithm for solving elliptic equations, which forms the basis for simple, high-order implicit-time methods for parabolic PDE and implicit–explicit methods for related nonlinear PDE. We apply the IBSE method to solve the Poisson, heat, Burgers', and Fitzhugh–Nagumo equations, and demonstrate fourth-order pointwise convergence for Dirichlet problems and third-order pointwise convergence for Neumann problems. [ABSTRACT FROM AUTHOR]

Background Obesity currently affects more than a third of the United States population and is associated with increased surgical complications. Compared to all other subspecialties, colorectal surgery is the most affected by the increasing trend in obese surgical patients. Operative time has been found to have the greatest impact on hospital costs and physician workload. This study was conducted to determine whether obesity has a direct impact on operative time in elective colorectal procedures using a high-powered, nationally representative patient sample. Methods A retrospective analysis was conducted on 45,362 patients who underwent open and laparoscopic ileocolic resections, partial colectomies, and low pelvic anastomoses using American College of Surgeons National Surgical Quality Improvement Program data from 2005-2009. Operative time was the main outcome variable, whereas body mass index (BMI) was the main independent variable. BMI was divided into three classes as follows: normal (<25), overweight and/or obese (25-35), and morbidly obese (>35). A univariate linear model was used to analyze the relationship while controlling for confounding factors such as demographics and preoperative conditions. Statistical significance was established at P ≤ 0.05. Results Morbidly obese patients were found to have longer operative times than did normal patients across each individual colorectal procedure (P < 0.001), ranging from a mean difference of 17.8 min for open ileocolic resections to 56.6 min for laparoscopic low pelvic anastomoses with colostomies. Conclusions BMI, as an objective measure of obesity, is a direct, statistically significant independent predictor of operative time across elective colorectal procedures. [ABSTRACT FROM AUTHOR]

Atherosclerosis and its consequences like acute myocardial infarction or stroke are highly prevalent in western countries, and the incidence of atherosclerosis is rapidly rising in developing countries. Atherosclerosis is a disease that progresses silently over several decades before it results in the aforementioned clinical consequences. Therefore, there is a clinical need for imaging methods to detect the early stages of atherosclerosis and to better risk stratify patients. In this review, we will discuss how ultrasound imaging can contribute to the detection and risk stratification of atherosclerosis by (a) detecting advanced and early plaques; (b) evaluating the biomechanical consequences of atherosclerosis in the vessel wall; (c) assessing plaque neovascularization and (d) imaging the expression of disease-relevant molecules using molecular imaging. [ABSTRACT FROM AUTHOR]

Reviewed are 31 studies that evaluated recidivism rates from juvenile drug treatment courts relative to a random-assignment or convenience comparison group. Recidivism was defined as re-referral, new charges, or re-arrest. Mean effect sizes and confidence intervals are provided for the three recidivism assessment time frames most often used by researchers (e.g., recidivism occurring “during the drug court program”; “during, plus post-program”; and “post-program only”). Characteristics of youths and programs that were hypothesized to correlate with the size of effect (e.g., gender and ethnic proportions of program participants, methodological quality of studies) were examined in an attempt to account for variation in effect sizes across studies. The average premature termination rate from drug court programs, as a face-valid indicator of typical program effectiveness, is also reported. The results, based on significantly more studies than past reviews, show that juvenile drug court treatment program youths, relative to controls, had slightly more gains than short-term, pre-to-post-program assessments. Results are compared to adult drug court outcomes, and program and participant correlates of effect size are discussed. Suggestions for further research into possible improvements of programs are offered. [ABSTRACT FROM AUTHOR]

Objective: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS.Methods: Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized.Results: The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion. All mutations were protein-truncating or splicing mutations. We identified 2 recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, 7 of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold.Interpretation: This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy, and regression. [ABSTRACT FROM AUTHOR]

Objective Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na+/H+ exchanger 6 ( NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. Methods Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized. Results The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion. All mutations were protein-truncating or splicing mutations. We identified 2 recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, 7 of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold. Interpretation This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy, and regression. Ann Neurol 2014;76:581-593 [ABSTRACT FROM AUTHOR]

Multi-attribute tradespace exploration for survivability is a system design and analysis methodology that incorporates survivability considerations into the tradespace exploration process (i.e., a solution-generating and decision-making framework that applies decision theory to model-based design). During the concept-generation phase of tradespace exploration, the methodology applies 17 empirically validated survivability design principles spanning susceptibility reduction, vulnerability reduction, and resilience enhancement. During subsequent concept evaluation, the methodology adds value-based survivability metrics to traditional architectural evaluation criteria of mission utility and life-cycle cost. Applied to a satellite radar mission, the methodology allowed operational survivability to be statistically evaluated across representative distributions of naturally occurring disturbances in the space environment and for survivability to be incorporated as a decision factor earlier in the design process. Constellations in the illustrative example are shown to be the most survivable, mitigating disturbances architecturally rather than through additive features. [ABSTRACT FROM AUTHOR]

Dengue viruses (DENV) are endemic pathogens of tropical and subtropical regions that cause significant morbidity and mortality worldwide. To date, no vaccines or antiviral therapeutics have been approved for combating DENV-associated disease. In this paper, we describe a class of tricyclic small-molecule compounds-dihydrodibenzothiepines (DHBTs), identified through highthroughput screening-with potent inhibitory activity against DENV serotype 2. SKI-417616, a highly active representative of this class, displayed activity against all four serotypes of DENV, as well as against a related flavivirus, West Nile virus (WNV), and an alphavirus, Sindbis virus (SINV). This compound was characterized to determine its mechanism of antiviral activity. Investigation of the stage of the viral life cycle affected revealed that an early event in the life cycle is inhibited. Due to the structural similarity of the DHBTs to known antagonists of the dopamine and serotonin receptors, we explored the roles of two of these receptors, serotonin receptor 2A (5HTR2A) and the D4 dopamine receptor (DRD4), in DENV infection. Antagonism of DRD4 and subsequent downstream phosphorylation of epidermal growth factor receptor (EGFR)-related kinase (ERK) were found to impact DENV infection negatively, and blockade of signaling through this network was confirmed as the mechanism of anti- DENV activity for this class of compounds. [ABSTRACT FROM AUTHOR]

This article presents a study on the safety of site-specific modification of the CCR5 gene in autologous CD4 T cells in HIV-positive persons. It discusses the methods used in the study, the adverse event associated with gene editing, and findings on the blood level of HIV DNA in majority of the patients.

We report the safety and tolerability of 87 infusions of lentiviral vector-modified autologous CD4 T cells (VRX496-T; trade name, Lexgenleucel-T) in 17 HIV patients with well-controlled viremia. Antiviral effects were studied during analytic treatment interruption in a subset of 13 patients. VRX496-T was associated with a decrease in viral load set points in 6 of 8 subjects (P = .08). In addition, A→ G transitions were enriched in HIV sequences after infusion, which is consistent with a model in which transduced CD4 T cells exert antisense-mediated genetic pressure on HIV during infection. Engraftment of vector-modified CD4 T cells was measured in gut-associated lymphoid tissue and was correlated with engraftment in blood. The engraftment half-life in the blood was approximately 5 weeks, with stable persistence in some patients for up to 5 years. Conditional replication of VRX496 was detected periodically through 1 year after infusion. No evidence of clonal selection of lentiviral vector-transduced T cells or integration enrichment near oncogenes was detected. This is the first demonstration that gene-modified cells can exert genetic pressure on HIV. We conclude that gene-modified T cells have the potential to decrease the fitness of HIV-1 and conditionally replicative lentiviral vectors have a promising safety profile in T cells. This study is registered at www.clinicaltrials.gov as number NCT00295477. [ABSTRACT FROM AUTHOR]

Abstract: This meta-analysis summarizes 41 studies that examined associations between characteristics of adolescent participants in juvenile drug treatment court and outcomes (i.e., premature termination, recidivism). A summary of within- and post-program recidivism rates was calculated, as was a global estimate of the premature drop-out rate. One clear trend in the available studies was the dramatic difference in recidivism rates for adolescents who succeed in graduating from drug court, relative to those who do not. In addition, the review revealed that behavior patterns evidenced during drug court participation were most strongly associated with both the probability of graduating successfully from drug court and recidivism (e.g., few in-program arrests, citations, detentions, and referrals; greater length of time in program or amount of treatment; lower use of drug and alcohol use, few positive urine screens, greater school attendance). Unfortunately, non-white participants tend to have a lower probability of graduation from drug court and experience higher recidivism during and following the program. Available juvenile drug treatment court studies confirm a number of reputed adolescent risk factors associated with substance abuse, criminality, treatment failure, and recidivism among adolescents (e.g., higher levels of emotional and behavioral problems, higher levels and severity of pre-program substance abuse, male gender). Suggestions for improving the effects of juvenile drug treatment court based on key results of the meta-analysis are offered. [Copyright &y& Elsevier]

Abstract: This exploratory study examined the effect of a coaching and feedback intervention in teaching presence and social presence on higher-order thinking in an online community of inquiry. Coaching occurred before each chat, and feedback was provided immediately afterwards. The findings suggest that over time, the frequency of higher-order thinking will increase more in a group that receives coaching and feedback than in a group that does not receive coaching and feedback. In addition, the findings suggest that the Community of Inquiry framework has benefits beyond its use in course design, facilitation, and assessment to include serving as a guide to coaching. [Copyright &y& Elsevier]

Providing coaching to participants in inquiry‐based online discussions contributes to developing cognitive presence (CP) and higher‐order thinking. However, a primary issue limiting quality and timely coaching is instructors' lack of tools to efficiently identify CP phases in massive discussion transcripts and effectively assess learners' cognitive development. This study examined a computational approach integrating text mining and co‐occurrence analysis for assessing CP and cognitive development in online discussions based on the community of inquiry (CoI) framework. First, text classifiers trained on different language models were evaluated for identifying and coding the CP phases. Second, epistemic network analysis (ENA) was employed to model cognitive patterns reflected by co‐occurrences between the coding elements. Results indicated that text classifiers trained on the state‐of‐the‐art language model Bidirectional Encoder Representations from Transformers (BERT) can address the efficiency issue in coding CP phases in discussion transcripts and obtain substantial agreements (Cohen's k = 0.76) with humans, which outperformed other baseline classifiers. Furthermore, compared to traditional quantitative content analysis, ENA can effectively model the temporal characteristics of online discourse and detect fine‐grained cognitive patterns. Overall, the findings suggest a feasible path for applying learning analytics to tracking learning progression and informing theory‐based assessments. Practitioner notesWhat is already known about this topic Cognitive presence is an important construct describing the progression of thinking in online inquiry‐based discussions.Most studies used self‐report instruments or quantitative content analysis to measure and assess cognitive presence.More efficient and effective approaches were needed by instructors to support assessment of cognitive development and determine coaching strategies.What this paper adds An integrated computational approach for the developmental and formative assessment of cognitive presence was proposed and evaluated.A BERT‐based text classification model could efficiently code massive transcripts and achieve substantial agreements with human coders.Epistemic network analysis effectively revealed the process of cognitive development and identified representative discussion patterns and behaviours.Implications for practice and/or policy The proposed approach can considerably reduce the pressure on instructors, enabling them to focus on quality coaching and feedback.Compared to frequencies of individual codes, the connective features between codes carry more insights for assessing cognitive patterns.Learners in a discussion group play different roles and produce diverse paths of cognitive development. [ABSTRACT FROM AUTHOR]

Like the religions and creation myths that predated it, contemporary science provides a framework for attempting to understand the universe. Replacing faith-based dogma with a new consensus-based authority grounded in repeatable experiment and observation, science itself is based on a protocol known as the scientific method. Yet now, science, mathematics, and even logic are shaking their own foundations, with profound implications not only for the scientific method as a means of understanding the universe, but also for the relationship between science, religion, and mysticism. For example, recent advances in quantum physics, and continual reinterpretations of earlier findings, are calling into question the notion of the detached observer-a notion fundamental to the contemporary scientific method-as well as the reductionistic approach of attempting to understand an entirety in terms of its components. Other findings indicate that uncertainty~ randomness, and inconsistency may be basic to nature, with pervasive implications to the predictive and descriptive capability of science. Science, in turn, is underpinned by mathematics and logic, which are axiomatic in nature and thus limited by Gädel's theorem, an implication of which is that axioms are ultimately unprovable. In a striking parallel with some Western religions, the axioms themselves are accepted by consensus and "on faith" Beyond these gatekeepers to knowledge lies yet another. Stated differently, "This far and no further' Like religion, science may hold mysteries that are beyond human reach. Increasing studies of consciousness, intuitive processes, and some of the healing modalities can be expected to magnify the self-impacts of scientific research. This is because these studies generally do not yield the repeatable results that the scientific method demands. It is envisioned that the scientific method will need to evolve to encompass subjective experiences that have traditionally been regarded as outside its realm-perhaps starting with a framework that recognizes the interconnectedness of the observer and the observed. This paper explores the scientific findings that will shape the research protocols of tomorrow and the parallel and synergistic cultural, social, and academic trends. [ABSTRACT FROM AUTHOR]

Developmental and behavioral disorders including intellectual disability, learning disabilities, and attention-deficit/hyperactivity disorder are highly prevalent, chronic health conditions. Despite being versed in caring for children with these conditions, pediatricians might be less prepared for challenging questions from families about the long-term course of these conditions and what can be done to improve outcomes. Through this state-of-the-art review, we provide clinicians with an understanding of the course of these conditions and adult outcomes in several areas including vocational, social, and health domains. We also provide a review of the most current research examining factors that predict or mediate adult outcomes for people with intellectual disability, learning disabilities, and attention-deficit/hyperactivity disorder. On the basis of the current literature, we offer practice recommendations aimed at optimizing adult outcomes for those with these disorders. [ABSTRACT FROM AUTHOR]

This study investigated the small-group, learner-led discussion process in synchronous discussions. Transcripts from online chats and face-to-face discussions were analyzed within the context of the Community of Inquiry framework to examine the relationship of teaching presence, social presence, and cognitive presence to one another and for evidence of changes in frequency of teaching, social, and cognitive presence over time. Findings suggest that social presence and cognitive presence are highly positively correlated and that teaching presence and social presence are moderately positively correlated in learner-led synchronous environments. The frequency of teaching, social, and cognitive presence did not change over time for either group. Findings also indicate that neither the group meeting online nor the group meeting face-to-face attained high levels of cognitive presence integration or resolution. [ABSTRACT FROM AUTHOR]

Influenza A viruses constitute a major and ongoing global public health concern. Current antiviral strategies target viral gene products; however, the emergence of drug-resistant viruses highlights the need for novel antiviral approaches. Cleavage of the influenza virus hemagglutinin (HA) by host cell proteases is crucial for viral infectivity and therefore presents a potential drug target. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) are single-stranded-DNA-like antisense agents that readily enter cells and can act as antisense agents by sterically blocking cRNA. Here, we evaluated the effect of PPMO targeted to regions of the pre-mRNA or mRNA of the HA-cleaving protease TMPRSS2 on proteolytic activation and spread of influenza viruses in human Calu-3 airway epithelial cells. We found that treatment of cells with a PPMO (T-ex5) designed to interfere with TMPRSS2 pre-mRNA splicing resulted in TMPRSS2 mRNA lacking exon 5 and consequently the expression of a truncated and enzymatically inactive form of TMPRSS2. Altered splicing of TMPRSS2 mRNA by the T-ex5 PPMO prevented HA cleavage in different human seasonal and pandemic influenza A viruses and suppressed viral titers by 2 to 3 log10 units, strongly suggesting that TMPRSS2 is responsible for HA cleavage in Calu-3 airway cells. The data indicate that PPMO provide a useful reagent for investigating HA-activating proteases and may represent a promising strategy for the development of novel therapeutics to address influenza infections. [ABSTRACT FROM AUTHOR]

Summary: Drosophila embryonic dorsal-ventral polarity is generated by a series of serine protease processing events in the egg perivitelline space. Gastrulation Defective processes Snake, which then cleaves Easter, which then processes Spätzle into the activating ligand for the Toll receptor []. seele was identified in a screen for mutations that, when homozygous in ovarian germline clones, lead to the formation of progeny embryos with altered embryonic patterning; maternal loss of seele function leads to the production of moderately dorsalized embryos []. By combining constitutively active versions of Gastrulation Defective, Snake, Easter, and Spätzle with loss-of-function alleles of seele, we find that Seele activity is dispensable for Spätzle-mediated activation of Toll but is required for Easter, Snake, and Gastrulation Defective to exert their effects on dorsal-ventral patterning. Moreover, Seele function is required specifically for secretion of Easter from the developing embryo into the perivitelline space and for Easter processing. Seele protein resides in the endoplasmic reticulum of blastoderm embryos, suggesting a role in the trafficking of Easter to the perivitelline space, prerequisite to its processing and function. Easter transport to the perivitelline space represents a previously unappreciated control point in the signal transduction pathway that controls Drosophila embryonic dorsal-ventral polarity. [Copyright &y& Elsevier]

From its inception, psychology has sought recognition as a science, but, unfortunately, this is not happening, especially in the clinical arena. It is all too often referred to as "junk science." Eloquent arguments are constantly made defending psychology as different because it is dealing with unknowns, such as the mind and the soul. However, the fact remains that psychology is not progressing well, with extremely poor treatment efficacy rates and with its tenacious clinging to psychological tests that are repeatedly shown to be unreliable and invalid. Thus, psychology is not policing itself. However, change and reformation may be forced on it because the federal courts and 33 state courts have based new laws for more rigorous standards for trial testimony, and it appears that the new laws are aimed at cleansing the courts of "junk science," namely, psychological testimony. This article reviews the changes that thus far few psychologists, lawyers, or even judges know about. However, slowly the new laws will permeate the courts and perhaps exert a strong influence for psychology to adapt. [ABSTRACT FROM AUTHOR]

Abstract: A significant consequence of equine arteritis virus (EAV) infection of horses is persistence of the virus in a variable percentage of infected stallions. We recently established an in vitro model of EAV persistence in cell culture for the purpose of furthering our understanding of EAV biology in general and viral persistence in the stallion in particular. In this study we investigated whether persistently infected HeLa cells could be cured of EAV infection by treatment with an antisense peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) designed to target the 5′-terminal region of the EAV genome. We found that persistently infected HeLa cells passaged three times in the presence of 5–10μM EAV-specific PPMO produced no detectable virus. The PPMO-cured HeLa cells were free of infectious virus, viral antigen and EAV RNA as measured by plaque assay, indirect immunofluorescence assay and RT-PCR, respectively. Furthermore, when re-challenged with EAV at several passages after discontinuation of PPMO treatments, PPMO-cured HeLa cells were found to be refractory to re-infection and to the re-establishment of viral persistence. While these findings demonstrate that PPMO can be used to eliminate persistent EAV infection in cell culture, the efficacy of PPMO against EAV in vivo remains to be addressed. [Copyright &y& Elsevier]

Background: Japanese encephalitis virus (JEV) has a significant impact on public health throughout Asia, and there is a pressing need for development of new therapeutics against it. Methods: Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) are antisense agents that enter cells readily and interfere with gene expression. Four PPMOs, targeting various locations in the JEV genome, were evaluated for antiviral activity against JEV in cultured cells and the mouse model of JEV infection. Results: A PPMO (P10882) targeting the JEV 3′ cyclization sequence (3′CSI) had significant antiviral activity in Vero (epithelial), Neuro2A (neuronal) and J774E (macrophage) cells at concentrations that were not cytotoxic. P10882 added before infection suppressed JEV replication to an undetectable level in Vero cells and produced a 93% and 66% reduction in titre in J774E and Neuro2A cells, respectively, when measured at 24 h postinfection. In uninfected cells, fluorescein-labelled PPMOs entered J774E cells most efficiently, followed by Vero and Neuro2A cells. The antiviral effect of P10882 was also demonstrated in vivo, where 60%-80% of 1-week-old mice treated intracerebrally with a 20 mg/kg dose of P10882 every 12 h for 5 days were protected from a lethal dose of JEV and showed an undetectable level of virus in brain tissue at 2 days post-infection. Conclusions: P10882, which targets sequence that is highly conserved across members of the JEV serocomplex, was previously shown to be effective in a mouse model of West Nile disease, and represents a candidate antiviral agent against members of the JEV serocomplex. [ABSTRACT FROM AUTHOR]

The article presents the pyramid model (PM) as a representation of the functioning of the mind. The authors say the PM aims to integrate the four basic responses studied by psychologists, namely behavior, physiology, cognition and affect. They add that the model explains how external events are filtered through the belief system, producing the consequences of the responses. The authors discuss depression triggers, Deepok Chopra's views on thoughts, and the different models and theories of psychology including Ellis and Harper's, and Barlow and Durrand's.

This article explores several issues surrounding the American Psychological Association's accredited doctoral training of clinical psychologists. There is a movement to combat the use of psychiatric drugs with psycho-social treatments. However, as will be examined, such treatments seem to not work well. If there is to be a sincere challenge to the growing use of toxic psychiatric drugs then better psycho-social treatment efficacy rates are critical. [ABSTRACT FROM AUTHOR]

This article explores several issues surrounding the American Psychological Association's accredited doctoral training of clinical psychologists. There is a movement to combat the use of psychiatric drugs with psycho-social treatments. However, as will be examined, such treatments seem to not work well. If there is to be a sincere challenge to the growing use of toxic psychiatric drugs then better psycho-social treatment efficacy rates are critical. [ABSTRACT FROM AUTHOR]

Abstract: Alternative therapies are needed for HSV-1 infections in patients refractory to treatment with Acyclovir (ACV) and its derivatives. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) are single-stranded DNA analogues that enter cells readily and reduce target gene expression through steric blockage of complementary RNA. When applied before or soon after infection PPMO targeting the translation-start-site regions of HSV-1 ICP0 or ICP27 mRNA reduced HSV-1 plaque formation by 70–98% in vitro. The ICP0 PPMO also reduced ACV-resistant HSV-1 (strain 615.9) plaque formation by 70–90%, while an equivalent dose of ACV produced only 40–50% inhibition when the treatment was applied between 1 and 3hpi. Seven daily topical treatments of 100μg ICP0 PPMO caused no gross or microscopic damage to the corneas of uninfected mice. Topical application of 10μg ICP0 PPMO to the eyes of HSV-1 infected mice reduced the incidence of eye disease by 37.5–50% compared to controls. This study demonstrates that topically applied PPMO holds promise as an antiviral drug candidate against HSV-1 ocular infection. [Copyright &y& Elsevier]

This naturalistic inquiry explored the theory of transactional distance by investigating how a novice adult learner experiences an online environment. Three themes that are related to how the novice learner reduces the transactional distance space emerged from an analysis of interview transcripts: creating a voice for learning, connecting in a space for learning, and creating a time for learning. Initially, instructors play a critical role in helping novice learners develop identities as online learners and work in that dialogic space. [ABSTRACT FROM AUTHOR]

The article presents an obituary for Russian ichthyologist Anatole Petrovich Andriashev.

A universally accepted operational definition for the term "disease" is not yet established in contemporary psychiatry. In clinical psychology and psychiatry, disease has been used indiscriminately. The term disease has been invoked (even when no systemic etiology or pathology has existed) to describe addictions, a cluster of bizarre symptoms, and to justify crude medically based treatments (e.g., electroshock, lobotomy, involuntary commitment, medication prescription). More recently, sophisticated machines such as CAT scans, PET scans, and MRIs have been used for questionable research conducted to try to identify supposed diseases, to justify the overuse of psychotropic drugs. Economic and industry interests have superseded scientific concerns. To establish scientific rigor in psychiatry and clinical psychology research, an operational definition of disease is proposed. [ABSTRACT FROM AUTHOR]

In this study, infection of 293/ACE2 cells with severe acute respiratory syndrome coronavirus (SARS-CoV) activated several apoptosis-associated events, namely, cleavage of caspase-3, caspase-8, and poly(ADP-ribose) polymerase 1 (PARP), and chromatin condensation and the phosphorylation and hence inactivation of the eukaryotic translation initiation factor 2α (eIF2α). In addition, two of the three cellular eIF2α kinases known to be virus induced, protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK), were activated by SARS-CoV. The third kinase, general control nonderepressible-2 kinase (GCN2), was not activated, but late in infection the level of GCN2 protein was significantly reduced. Reverse transcription-PCR analyses revealed that the reduction of GCN2 protein was not due to decreased transcription or stability of GCN2 mRNA. The specific reduction of PKR protein expression by antisense peptide-conjugated phosphorodiamidate morpholino oligomers strongly reduced cleavage of PARP in infected cells. Surprisingly, the knockdown of PKR neither enhanced SARS-CoV replication nor abrogated SARS-CoV-induced eIF2α phosphorylation. Pretreatment of cells with beta interferon prior to SARS-CoV infection led to a significant decrease in PERK activation, eIF2α phosphorylation, and SARS-CoV replication. The various effects of beta interferon treatment were found to function independently on the expression of PKR. Our results show that SARS-CoV infection activates PKR and PERK, leading to sustained eIF2α phosphorylation. However, virus replication was not impaired by these events, suggesting that SARS-CoV possesses a mechanism to overcome the inhibitory effects of phosphorylated eIF2α on viral mRNA translation. Furthermore, our data suggest that viral activation of PKR can lead to apoptosis via a pathway that is independent of eIF2α phosphorylation. [ABSTRACT FROM AUTHOR]

Abstract: Measles virus (MeV) is a highly contagious human pathogen. Despite the success of measles vaccination programs, measles is still responsible for an estimated 245,000 deaths each year. There are currently no antiviral compounds available for the treatment of measles. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) are antisense compounds that enter cells readily and can interfere with mRNA function by steric blocking. A panel of PPMO was designed to target various sequences of MeV RNA that are known to be important for viral replication. Five PPMO, targeting MeV genomic RNA or mRNA, inhibited the replication of MeV, in a dose-responsive and sequence-specific manner in cultured cells. One of the highly active PPMO (PPMO 454), targeting a conserved sequence in the translation start site of the mRNA coding for the nucleocapsid protein, inhibited multiple genotypes of MeV. This report provides evidence that PPMO treatment represents a promising approach for developing antiviral agents against measles and other paramyxoviruses. [Copyright &y& Elsevier]