cssi/SciSciGPT-SciSciNet huggingface dataset:
Aplastic anemia and hepatitis C: Molecular biology exonerates another suspect

Objective. – To test the hypothesis that the rare, often fatal, syndrome of hepatitis-associated aplasia is associated with hepatitis C virus infection. Design. – Case series. Setting.-Tertiary referral centers in the United States, Japan, Italy, and Germany. Patients. – Twenty-eight patients with onset of aplastic anemia within 90 days after seeking medical attention for jaundice, or having serum transaminase levels 150% or more of normal (hepatitis-associated aplasia patients) and three patients who developed aplastic anemia following liver transplantation for non-A, non-B, hepatitis. Outcome Measures. - Presence of hepatitis C in serum, bone marrow, and liver samples, detected by the polymerase chain reaction; antibody testing; and percentage of activated peripheral cytotoxic T lymphocytes determined by immunophenotyping. Results. – Hepatitis ribonucleic acid was present in the serum samples of 10 (36%) patients with hepatitis-associated aplasia. However, hepatitic C virus viremia was associated with transfusions received after the onset of aplasia: seven (58%) of 12 patients with hepatitis-associated aplasia who had received 21 or more units of blood products at the time of serum sampling were viremic, compared with only three (19%) of 16 patients with hepatitis-associated aplasia who had received 20 or less units of blood products (P <.05). Hepatitis C virus was not found in blood and bone marrow samples of three National Institutes of Health case patients tested at the time of diagnosis. None of three livers from non-A, non-B hepatitis patients who developed aplastic anemia after liver transplantation contained hepatitis C virus ribonucleic acid. Activated CD8+ T lymphocytes were elevated three- to 20-fold early in the course of hepatitis-associated aplasia. Conclusions. – Our results implicate a novel, non-A, non-B, and non-C agent in both hepatitis-associated aplasia and fulminant hepatitis.
Diversity of ATM gene mutations detected in patients with ataxia‐telangiectasia

The ataxia-telangiectasia mutated (ATM) gene, which is mutated in the autosomal recessive disorder ataxia-telangiectasia (AT), was isolated in 1995 by positional cloning. Although in vitro cell fusion studies had suggested that AT was genetically heterogeneous, all AT patients studied to date have been found to harbor mutations in the ATM gene. More that 100 ATM mutations occurring in AT patients have been documented. The mutations are broadly distributed throughout the ATM gene. Except for patients from families with known consanguinity, most AT patients are compound heterozygotes. The majority (> 70%) of mutations are predicted to lead to protein truncation. A significant number of the reported mutations affect mRNA splicing with at least half of the coding exons (32/62) having been observed to undergo exon skipping. The large size of the ATM gene, 66 exons spanning approximately 150 kb of genomic DNA, together with the diversity and broad distribution of mutations in AT patients greatly limits the utility of direct mutation screening as a diagnostic tool, or method of carrier identification, except where founder effect mutations are involved.
Brain and behavior: 1. Neurohumors, drugs, and behavior.

biochem ist these days. Exciting because he can use his tools and con­ cepts within the service of a new frame of ref erence-behavior. The brain, being an organ like any other in the body, but having it s own particular and specific biochemical properties, has begun to yield some biochemical secrets which prom ise that in the future biochemistry may contribute it s share to an understanding of behavior. The evidence accumulating now demonstrate s that there are a number of substances, metaboli tes, neurohumors, which play an important role in the development, maint enance, and function of the brain. As a fundamental post ulate we can consider that there can be no func­ tion of the brain withou t concom it ant reactions of the chemi cals and chemi­ cal systems of which the brain is composed. The in terrelationships of fats, carbohydrates, proteins,
Expressions and their Representations

It is plausible to think that our knowledge of linguistic types can bejustified by what we know about the tokens of these types. But one then hasto explain what it is about the relation a type bears to its tokens that makespossible the move from knowledge of the concrete to knowledge of theabstract. I argue that the standard solution to this difficulty, that the relevant relation is instantiation and that the transition is inductive generalization, is inadequate. I propose an alternative, according to which tokens are representations of the type they belong to. I also defend this view against the charge that it cannot account for the systematic ambiguity of expressions like ‘word’ or ‘sentence’, and the objection that it leads to an implausible form of Platonism.
Genome-Wide Association Studies: Getting to Pathogenesis, the Role of Inflammation/Complement in Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a chronic, degenerative, and significant cause of visual impairment and blindness in the elderly. Genetic and epidemiological studies have confirmed that AMD has a strong genetic component, which has encouraged the application of increasingly sophisticated genetic techniques to uncover the important underlying genetic variants. Although various genes and pathways have been implicated in the risk for AMD, complement activation has been emphasized repeatedly throughout the literature as having a major role both physiologically and genetically in susceptibility to and pathogenesis of this disease. This article explores the research efforts that brought about the discovery and characterization of the role of inflammatory and immune processes (specifically complement) in AMD. The focus herein is on the genetic evidence for the role of complement in AMD as supported specifically by genome-wide association (GWA) studies, which interrogate hundreds of thousands of variants across the genome in a hypothesis-free approach, and other genetic interrogation methods.
Plant functional traits improve diversity-based predictions of temporal stability of grassland productivity

Synthesis Aboveground net primary productivity (ANPP) varies in response to temporal fl uctuations in weather. Temporal stability of community ANPP may be increased by increasing plant species richness, but stability often varies at a given richness level implying a dependence on abundances and functional properties of member species. We measured stability in ANPP during 11 years in fi eld plots (Texas, USA) in which we varied the richness and relative abundances of perennial grassland species at planting. We sought to identify species abundance patterns and functional traits linked to the acquisition and processing of essential resources that could be used to improve richness-based predictions of community stability. We postulated that community stability would correlate with abundance-weighted indices of traits that infl uence plant responses to environmental variation. Annual precipitation varied by a factor of three leading to large inter-annual variation in ANPP. Regression functions with planted and realized richness (species with � 1% of community ANPP during the fi nal four years) explained 32% and 25% of the variance in stability, respectively. Regression models that included richness plus the fraction of community ANPP produced by the two most abundant species in combination with abundance-weighted values of either the fraction of sampled root biomass at 20 – 45 cm depth, leaf dry matter content (LDMC), or response to greater-than-average precipitation of plants grown in monocultures explained 58 – 69% (planted richness) and 58 – 64% (realized richness) of the variance in stability. Stability was greatest in communities that were not strongly dominated by only two species and in which plants rooted shallowly, had high values of LDMC, or responded to the wettest year with a minimal increase in ANPP. Our results indicate that the temporal stability of grassland ANPP may depend as much on species abundances and functional traits linked to plant responses to precipitation variability as on species richness alone.
CNT logic knowledge module integrated in digital CMOS logic design course

We present a knowledge module exposing students to novel Nanodevices and computing isuues in the context of CMOS Design. This knowledge module has a two-fold objective. First, it generates interest amongst students regarding the fundamental concept of future nano-devices. This will motivate them to enroll in other elective courses related to Nanotechnology, being offered in most EE and CS departments. Further, this module can be used to let students analyze, synthesize and apply their existing knowledge of digital logic design into revolutionary design context with CNT logic. Assessment included the development of rubrics for grading students understanding of key concepts. Survey results and comments indicate that 89% of the students liked the module and demonstration, as well as were enthusiastic and motivated to learn more on nano devices.
Managing medical equipment used by technology-dependent children: evaluation of an instructional tool for pediatric residents and medical students.

Objectives.To evaluate the effectiveness of a workshop on managing medical devices used in technology-dependent children.Methods.Study participants included residents and medical students rotating in the pediatrics department at the time of the study. A workshop was conducted consisting of learning stations for common medical devices, including brief presentations and opportunities for hands-on practice with each device. Participants completed surveys before and after the workshop assessing their perceived ability to manage medical equipment before and after the workshop and their ongoing learning needs.Results.All participants indicated a substantial need for training on how to manage medical devices used by technology-dependent patients. Scores for perceived ability to manage the devices improved significantly after workshop participation for nearly all devices taught.Conclusions.Medical trainees have significant learning needs for managing devices used by technology-dependent patients. Hands-on, small-...
In search of the functional neuroanatomy of sociality: MRI subdivisions of orbital frontal cortex and social cognition

We examined social cognition in a sample of healthy participants who had prior magnetic resonance imaging (MRI) gray matter volume studies of the orbital frontal cortex (OFC) that was parcellated into three regions: gyrus rectus, middle orbital gyrus and lateral orbital gyrus. These subjects also completed a self-report measure of Machiavelli personality traits, along with psychometric tests of social comprehension and declarative episodic memory, all of which we used as proxy measures to examine various features of social cognition. The data pointed to distinct functional–anatomical relationships highlighted by strong correlations of left lateral orbital gyrus and Machiavellian scores and right middle orbital gyrus with social comprehension and declarative episodic memory. In addition, hierarchical regression analyses revealed statistical evidence of a double dissociation between Machiavellian scores and left lateral orbital gyrus on one hand, and social comprehension with right middle orbital gyrus, on the other hand. To our knowledge, these findings are the first to show evidence linking normal variation in OFC subregions and different aspects of social cognition.
Visual Behavior in Social Interaction

Visual behavior appears to provide information at several different communicational levels in social interaction. As a dependent variable, it has been used to measure stable individual and group differences, the regulation of the flow of conversation, and the search for feedback in an interaction. As an independent variable, it has been shown to influence emotional responses and cognitive attributions. Research efforts to specify and understand the functioning of visual behavior at each level are reviewed. An example of a multi-level approach to an area is provided by a survey of the research on visual behavior in relation to interpersonal attraction and involvement. Finally, some speculations about future questions and concerns are presented.
Electrocapillary at contact: potential-dependent adhesion between a gold electrode and a mica surface.

Using the electrochemical surface forces apparatus, we investigated adhesion (from pull-off measurements) between gold and mica as the potential of the gold surface was changed externally. Measurements were performed at different concentrations of KClO4 in a potential window where the gold electrode is ideally polarizable. At applied potentials where the gold−mica interactions are repulsive, we obtain double layer forces that are predictable by the Derjaguin−Landau−Verwey−Overbeek (DLVO) theory of colloid stability but deviate from the theory at short range. At applied potentials where the gold−mica interactions are attractive, we observed a very strong dependence of adhesion on the applied potential, a result that cannot be directly related to DLVO theory. We show, however, that an approach based on electrocapillary thermodynamics can be employed to model the potential dependence of adhesion seen in our measurements. This electrocapillary approach presents evidence of charging at the gold−mica interface ...
Cuticular Hydrocarbons of Adult Pteromalus cerealellae (Hymenoptera: Pteromalidae) and Two Larval Hosts, Angoumois Grain Moth (Lepidoptera: Gelechiidae) and Cowpea weevil (Coleptera: Bruchidae)

The pteromalid parasitoid Pteromalus cerealellae (Ashmead) is nominally a host- specific ectoparasitoid of the stored-product pest the Angoumois grain moth. It is readily cultured, however, on a number of other stored-product pests, including the cowpea weevil. The parasitoids resulting from these different hosts are disparate in size, leading me to ask if the cuticular hydro- carbons of P. cerealellae reared on different hosts would be different. This question is of importance because many parasitoids of stored-product pests use cuticular hydrocarbons as major species- and gender-recognition cues, and moth and beetle hosts differ greatly in their hydrocarbon profiles. The parasitoid hydrocarbon profile reported here was much more complex than the profiles of either host and showed both gender and host effects. Parasitoids reared on the larger cowpea weevils were larger than those reared on moths and contained substantially more hydrocarbon on their cuticle. Re- gardless of host, female wasps were always larger than males and contained more hydrocarbon than males. The hydrocarbon chemistry of wasps reared on different hosts were qualitatively the same, but quantitatively different. Both gender and host are important in the relative abundance of individual hydrocarbons. There are four major hydrocarbons of females constituting 49% of the total female profile: 3-MeC29, 11-MeC31, 3, 7-DiMeC31 and 11, 17-, 11, 19- and 11, 21—DiMeC33. There is one major male-specific hydrocarbon comprising 18% of the total hydrocarbons, 3, 7- and 3, 9—DiMeC33. Although major gender differences occur between hydrocarbon classes, these differ- ences are not host-related.
Parental Report of the Diagnostic Process and Outcome: ASD Compared With Other Developmental Disabilities:

Parents report that the process of getting an autism spectrum disorder (ASD) diagnosis is arduous, lengthy, and fraught with difficulties. This analysis of the Pathways survey data set examined the...
Institutional Factors Matter: Perspectives on China's Outward Direct Investment

In the past three decades, China has transformed itself from a central-planned, agricultural economy to the world’s manufacturing base and growth engine. Expanding at an average annual rate of more than 10 percent, the Chinese economy is now the second-largest in the world. Globalization is undoubtedly one of the most important drivers behind this extraordinary growth. Globalization is not a one-way process. As Chinese businesses grow and mature, they are increasingly turning to outward direct investment (ODI) to diversify their product portfolios, take advantage of cheaper labor in foreign countries, and claim reliable sources of raw materials. In recent years, several instances of Chinese outward direct investment received wide media attention. Among them were Lenovo Group’s purchase of IBM’s personal computer division in 2005 and Wanda Group’s acquisition of AMC Entertainment in 2012. However, acquisitions of assets by state-owned enterprises in natural resource-rich countries — especially African countries — have stirred the most concern. Still, despite the hype, Chinese outward direct investment remains small in relative size. In 2011, China’s ODI stock was 1.7 percent of the world’s total, or 5.2 percent of the nation’s GDP. When measured by direct investment, China is much less globalized than when measured by international trade. Is China’s relatively low outward direct investment level justified by economic fundamentals? What are the determinants of Chinese ODI? This paper uses country-level data to analyze the patterns of these investments.
Serum Antibody Response in Renal Versus Bladder Bacteriuria

Since the initial recognition of hemagglutinating antibody to coliform bacteria by Neter and coworkers [1, 2], much has been done to define further the relationship between infection due to coliforms and immune response in the host. For example, several workers have demonstrated that hemagglutinating antibody is present in higher titers to an infecting strain of Escherichia coli than to strains not recovered from the urine of patients with urinary tract infection [3-6]; it has also been reported that renal infection is associated with higher titers of antibody than is infection confined to the bladder [7-10]. In addition, Percival and colleagues [11] have used a direct bacterial agglutination system and obtained similar findings. More recently, Vosti and Remington [12] have defined the physicochemical characteristics of anti-O antibody to coliform bacteria, and they recognized an apparent correlation between renal parenchymal involvement and high titers of 75 antibody. These earlier studies have been limited because
Laser-Initiated, Microwave Driven Ignition in Methane/Air Mixtures

We have recently demonstrated the use of a pre-ionization laser pulse and a second microwave heating pulse to achieve ignition in near-stoichiometric methane/air mixtures. An ultrashort, 800nm non-resonant laser pulse (200 fs, 200 μJ) for seed ionization in combination with a 3GHz microwave pulse (2 μs, 50 mJ) achieved ignition in a premixed methane/air mixture with an equivalence ratio of 0.8. Microwave energy deposition— limited to only the region of laser interaction—was observed by shadowgraph in both air and methane/air mixtures. In addition, ignition of volumetric regions and multiple ignition points has been demonstrated using single laser and microwave pulses. We also present a numerical simulation of initial microwave heating corresponding to experimental conditions. The goal of moving towards a real combustor implementation is promoted through the design of a novel open microwave resonator configuration allowing a large access area for diagnostics and combustor access not limited to a specific geometry.
Self-Healing Grid and Distributed Energy Resource

The developing of bulk grid based on super high voltage and the researching of self-healing grid(SHG) including distributed energy resource(DER) are two distinctive highlights recently.Having presented the developing trend of power system security control,the emergence background,research process and key technique of SHG and DER as well as its relationship with bulk grid are analyzed and discussed in this paper.Finally the suggestion on applying some SHG methodology to current bulk grid construction and operation is put forward.
Endoscopic Screening and Surveillance for Gastrointestinal Malignancy

In the US, the cumulative lifetime risk of developing carcinoma of the upper gastrointestinal tract is less than 1 per cent, premalignant conditions are uncommon, and esophageal and gastric malignancies are rarely curable even when identified early. Endoscopic screening of the upper gastrointestinal tract in asymptomatic persons thus cannot be justified. Surveillance of persons with certain uncommon conditions associated with a higher risk of upper gastrointestinal cancer may be of benefit. These conditions include achalasia, Barrett's esophagus, chronic atrophic gastritis with intestinal metaplasia, familial polyposis coli, gastric polyps, lye stricture, Plummer-Vinson syndrome, and tylosis. In the lower gastrointestinal tract, however, the lifetime risk of developing carcinoma is 5 per cent, premalignant conditions and lesions are common, and carcinoma is curable when detected at an early stage. Sigmoidoscopic screening of asymptomatic adults has been advocated by the American Cancer Society but has not become widely practiced because of its cost, required physician effort, low overall yield, and poor patient compliance. Surveillance by flexible sigmoidoscopy is recommended for persons at slightly increased risk of colorectal carcinoma who have prior breast or gynecologic malignancy or a family history of colorectal malignancy. Colonoscopic surveillance is recommended for patients with high risk of colorectal cancer who have had prior colorectal carcinoma or adenoma or who have inflammatory bowel disease or a ureterosigmoidostomy.
Tactics to Ensure Durability of Behavior Change Following the Removal of an Intervention Specialist: A Review of Temporal Generality Within Organizational Behavior Management

ABSTRACTThe endurance of behavior change over time, including the time period after a behavior specialist has ceased to offer direct services, is an important consideration for both organizational behavior management and behavior analysis in general. This article considers a dozen strategies labelled temporal generality tactics that may foster the maintenance and institutionalization of intervention efforts in organizational settings. The use of such tactics was examined by conducting a comprehensive review of articles published between 1977 and 2014 in the Journal of Organizational Behavior Management. The results of this review suggest that although follow-up measures are frequently collected, explicit and proactive strategies to systematically increase the success of long-term behavior change are rarely used or researched.
Prospects and Limitations of Spatial Resolution

Our sense of vision permanently captures, transmits and interprets enormous amounts of visual information. The amount of visual information that can be transmitted to the brain by the means of visual prosthesis will be severely limited and thus also limit the rehabilitation prospects of such devices. While several parameters contribute to the information content of visual stimuli, this chapter concentrates essentially on spatial resolution.
The Role of Social Networks and Information Sources on Hurricane Evacuation Decision Making

AbstractHurricanes often threaten to have catastrophic impacts on the lives of residents in coastal areas of the U.S. Timely evacuation limits this impact, but people may choose to evacuate or not ...
Host-microbial Cross-talk in Inflammatory Bowel Disease

A vast community of commensal microorganisms, commonly referred to as the gut microbiota, colonizes the gastrointestinal tract (GI). The involvement of the gut microbiota in the maintenance of the gut ecosystem is two-fold: it educates host immune cells and protects the host from pathogens. However, when healthy microbial composition and function are disrupted (dysbiosis), the dysbiotic gut microbiota can trigger the initiation and development of various GI diseases, including inflammatory bowel disease (IBD). IBD, primarily includes ulcerative colitis (UC) and Crohn's disease (CD), is a major global public health problem affecting over 1 million patients in the United States alone. Accumulating evidence suggests that various environmental and genetic factors contribute to the pathogenesis of IBD. In particular, the gut microbiota is a key factor associated with the triggering and presentation of disease. Gut dysbiosis in patients with IBD is defined as a reduction of beneficial commensal bacteria and an enrichment of potentially harmful commensal bacteria (pathobionts). However, as of now it is largely unknown whether gut dysbiosis is a cause or a consequence of IBD. Recent technological advances have made it possible to address this question and investigate the functional impact of dysbiotic microbiota on IBD. In this review, we will discuss the recent advances in the field, focusing on host-microbial cross-talk in IBD.
Pharmacodynamic study of neoadjuvant vemurafenib (VEM) in patients (pts) with BRAF mutated, locally advanced papillary thyroid cancer (PTC).

TPS6100 Background: BRAF mutations are found in 40% of pts with newly diagnosed PTC but much more prevalent in recurrent PTC, ranging from 78-86%, suggesting they play an active role in tumor progr...
Oxidative Stress Markers of Alzheimer's Disease in Peripheral Cell Mitochondria

Alzheimer's disease (AD) represents a neurodegenerative disease leading to progressive dementia in the elderly. AD has been associated with increased oxidative stress and mitochondrial dysfunction. Hence, markers for oxidative stress are expected to accumulate not only in brain mitochondria, but also in mitochondria of peripheral cells. We have developed and optimized a method for the rapid and selective fluorogenic derivatization and enrichment of specific protein oxidation products, 3-nitrotyrosine and 3,4-dihydroxyphenylalanine (DOPA), in order to quantitatively compare protein oxidation in the mitochondria of peripheral, white blood cells obtained from healthy donors, patients with mild cognitive impairment (MCI), and AD patients. Double blind studies reveal a ca. two-fold increase of protein nitration/oxidation between mitochondrial proteins derived from healthy volunteers and MCI patients, with no further increase between MCI and AD patients. Proteomic studies will show whether specific proteins are target for nitration/oxidation during the pathogenesis of MCI and AD. Mitochondrial protein nitration/oxidation may be used for early screening of patients with the genetic risk for the development of AD or as companion diagnostic for pharmacological interventions.
Infrared-Enhanced Fluorescence-Gain Spectroscopy: Conformation-Specific Excited-State Infrared Spectra of Alkylbenzenes

An ultraviolet–infrared (UV-IR) double-resonance method for recording conformation-specific excited-state infrared spectra is described. The method takes advantage of an increase in fluorescence signal in phenylalkanes produced by infrared excitation of the S1 origin levels of different conformational isomers. The shorter lifetimes of these IR-excited molecules, combined with their red-shifted emission, provides a way to discriminate the fluorescence due to the infrared-excited molecules from the S1 origin fluorescence, resulting in spectra with high signal-to-noise ratios. Spectra for a series of phenylalkanes and a capped phenylalanine derivative (Ac-Phe-NHMe) demonstrate the potential of the method. The excited-state spectrum in the alkyl CH stretch region of ethylbenzene is well-fit by an anharmonic model developed for the ground electronic state, which explicitly takes into account stretch–bend Fermi resonance.
Progressing Pakistan should ensure Quality Education for All

The paper analyses the dynamics of education sector in Pakistan in comparison to other developing countries in larger Asia and Latin America. The lessons of history in these regions suggest that those countries have been able to develop on sustainable basis that have invested in education for all and also ensured quality by allocating sufficient funds to all levels of education.
Extensor Carpi Ulnaris Tenodesis Versus No Stabilization After Wide Resection of Distal Ulna Giant Cell Tumors

BACKGROUND The necessity of stabilizing the residual ulnar stump after distal ulna tumor resection remains controversial. The authors retrospectively compared the outcome of patients who underwent wide resection of distal ulna giant cell tumors (GCTs) and reconstruction with tenodesis of the extensor carpi ulnaris (ECU) or without reconstruction. METHODS Between 2007 and 2015, 9 patients (6 females, 3 males; mean age, 36.8 years; range, 24-65 years) who underwent distal ulna resection for GCT of bone were retrospectively reviewed. The mean resection length was 8.1 cm. Five patients had no reconstruction, whereas 4 patients had stabilization of the ulnar stump using ECU tenodesis. With a mean follow-up of 3.6 years (2-9 years), the functional outcome using the quick Disability of Arm, Shoulder and Hand (DASH) score; Musculoskeletal Tumor Society score and grip strength; as well as the oncological outcome were evaluated. RESULTS Musculoskeletal Tumor Society functional scores were more than 24 in 7 patients and 20 to 24 in 2 patients (mean, 27.6 or 92%). Quick DASH scores ranged from 0 to 27.3 (mean, 11.1). In both groups, similar scores were observed ( P > .5). No patient had instability or pain related to the stump. There was no ulnar translation or subluxation of the radiocarpal joint. Grip strength in the operated hand, controlled for handedness, was 11% less than in the contralateral hand, although there was no difference between groups ( P > .4). All patients were disease-free at the latest follow-up. CONCLUSIONS The distal ulna may be widely resected with or without stabilization of the residual ulnar stump, yielding satisfactory local disease control and functional outcome.
IV Infiltration and Latex Allergy in an Infant: Early Recognition is Key to Prevent Lasting Disability

Latex allergy confounded by IV infiltration presents a serious problem for pediatric patients. If unrecognized, it can lead to serious neurologic deficits, loss of limb mobility, compartment syndrome, and ultimately lasting disability. Appropriate early recognition can prevent progression to these devastating outcomes. In this case report, we present an infant with IV infiltration and latex allergy. The case is used to highlight important clinical diagnostic criteria, treatment approaches, and how to prevent detrimental outcomes. We provide a detailed review of the literature and highlight the key teaching points in a reader-friendly reference table.
Test data reuse for evaluation of adaptive machine learning algorithms: over-fitting to a fixed 'test' dataset and a potential solution

After the initial release of a machine learning algorithm, the subsequently gathered data can be used to augment the training dataset in order to modify or fine-tune the algorithm. For algorithm performance evaluation that generalizes to a targeted population of cases, ideally, test datasets randomly drawn from the targeted population are used. To ensure that test results generalize to new data, the algorithm needs to be evaluated on new and independent test data each time a new performance evaluation is required. However, medical test datasets of sufficient quality are often hard to acquire, and it is tempting to utilize a previously-used test dataset for a new performance evaluation. With extensive simulation studies, we illustrate how such a "naive" approach to test data reuse can inadvertently result in overfitting the algorithm to the test data, even when only a global performance metric is reported back from the test dataset. The overfitting behavior leads to a loss in generalization and overly optimistic conclusions about the algorithm performance. We investigate the use of the Thresholdout method of Dwork et. al. (Ref. 1) to tackle this problem. Thresholdout allows repeated reuse of the same test dataset. It essentially reports a noisy version of the performance metric on the test data, and provides theoretical guarantees on how many times the test dataset can be accessed to ensure generalization of the reported answers to the underlying distribution. With extensive simulation studies, we show that Thresholdout indeed substantially reduces the problem of overfitting to the test data under the simulation conditions, at the cost of a mild additional uncertainty on the reported test performance. We also extend some of the theoretical guarantees to the area under the ROC curve as the reported performance metric.
Structures and dynamics of β-barrel oligomer intermediates of amyloid-beta16-22 aggregation

Accumulating evidence suggests that soluble oligomers are more toxic than final fibrils of amyloid aggregations. Among the mixture of inter-converting intermediates with continuous distribution of sizes and secondary structures, oligomers in the β-barrel conformation - a common class of protein folds with a closed β-sheet - have been postulated as the toxic species with well-defined three-dimensional structures to perform pathological functions. A common mechanism for amyloid toxicity, therefore, implies that all amyloid peptides should be able to form β-barrel oligomers as the aggregation intermediates. Here, we applied all-atom discrete molecular dynamics (DMD) simulations to evaluate the formation of β-barrel oligomers and characterize their structures and dynamics in the aggregation of a seven-residue amyloid peptide, corresponding to the amyloid core of amyloid-β with a sequence of 16KLVFFAE22 (Aβ16-22). We carried out aggregation simulations with various numbers of peptides to study the size dependence of aggregation dynamics and assembly structures. Consistent with previous computational studies, we observed the formation of β-barrel oligomers in all-atom DMD simulations. Using a network-based approach to automatically identify β-barrel conformations, we systematically characterized β-barrels of various sizes. Our simulations revealed the conformational inter-conversion between β-barrels and double-layer β-sheets due to increased structural strains upon forming a closed β-barrel while maximizing backbone hydrogen bonds. The potential of mean force analysis further characterized the free energy barriers between these two states. The obtained structural and dynamic insights of β-barrel oligomers may help better understand the molecular mechanism of oligomer toxicities and design novel therapeutics targeting the toxic β-barrel oligomers. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.
Ten surprising facts about stressful life events and disease risk

After over 70 years of research on the association between stressful life events and health, it is generally accepted that we have a good understanding of the role of stressors in disease risk. In this review, we highlight that knowledge but also emphasize misunderstandings and weaknesses in this literature with the hope of triggering further theoretical and empirical development. We organize this review in a somewhat provocative manner, with each section focusing on an important issue in the literature where we feel that there has been some misunderstanding of the evidence and its implications. Issues that we address include the definition of a stressful event, characteristics of diseases that are impacted by events, differences in the effects of chronic and acute events, the cumulative effects of events, differences in events across the life course, differences in events for men and women, resilience to events, and methodological challenges in the literature.
Modeling Fire Expenditures with Spatially Descriptive Data

A regression model of suppression expenditures based on spatially descriptive fire characteristics in the United States Forest Service, Northern Region (Region 1) is expanded to include all six regions of the western United States. Spatially descriptive landscape and fire characteristics are calculated using available final burned area perimeters for large wildfires (greater than approx. 121 hectares). These characteristics are used as independent variables to describe variations in total suppression expenditures for 419 fires. Hierarchical partitioning is employed to develop a parsimonious regression model, and results are checked for spatial autocorrelation. Results suggest that spatially descriptive data is useful for explaining variations in suppression expenditures, and spatial data with regional controls can account for spatial error patterns observed in the dependent variable. Spatially descriptive models have the potential to be used for a variety of applications where expenditure estimates are needed and planning and management activities rely on spatially explicit information that can be used in expenditure models. However, finer-scale geospatial data is necessary to integrate spatially descriptive expenditure models with spatially explicit fire management planning tools (such as outputs from fire simulations).
Clinical interpretation of statistical significance

In any clinical study which compares versus an established therapy, the results will be expressed in terms of statistical significance. For this reason, it is important that every clinician interested in a judicious interpretation of the scientific literature, understands the origin and interpretation of statistical significance. The present paper addresses physicians attempting to give practical meaning to research results by discriminative and critical reading. The main aim is to explain in a simple way the meaning of the P-value, confidence intervals, and the required number to treat. Using practical examples, the most common mistakes in the interpretation of statistical significance are analyzed. The difference between statistical and clinical significance is emphasized and a new way to express and compare the practical utility of clinical trial results and the required number to treat is given.
A STUDY OF THE NONLINEAR RESPONSE OF A RESONANT MICRO-BEAM TO AN ELECTRIC ACTUATION

An investigation into the response of a resonant microbeam to anelectric actuation is presented. A nonlinear model is used to accountfor the mid-plane stretching, a DC electrostatic force, and an ACharmonic force. Design parameters are included in the model by lumpingthem into nondimensional parameters. A perturbation method, the methodof multiple scales, is used to obtain two first-order nonlinearordinary-differential equations that describe the modulation of theamplitude and phase of the response and its stability. The model and theresults obtained by the perturbation analysis are validated by comparingthem with published experimental results. The case of three-to-oneinternal resonance is treated. The effect of the design parameters on the dynamic responses isdiscussed. The results show that increasing the axial force improves thelinear characteristics of the resonance frequency and decreases theundesirable frequency shift produced by the nonlinearities. In contrast,increasing the mid-plane stretching has the reverse effect. Moreover,the DC electrostatic load is found to affect the qualitative andquantitative nature of the frequency-response curves, resulting ineither a softening or a hardening behavior. The results also show thatan inaccurate representation of the system nonlinearities may lead to anerroneous prediction of the frequency response.
Optimal seeding in knockout tournaments

Optimal seeding in balanced knockout tournaments has only been studied in very limited settings, for example, maximizing predictive power for up to 8 players using only the relative ranking of the players (ordinal information). We broaden the scope of the analysis along several dimensions: tournaments of size up to 128, different player models, ordinal as well as cardinal solutions, and two additional objective functions.
Reconstitution of water channel function of aquaporins 1 and 2 by expression in yeast secretory vesicles

Aquaporins 1 (AQP1) and 2 (AQP2) were expressed in the yeast secretory mutant sec6-4. The mutant accumulates post-Golgi, plasma membrane-targeted vesicles and may be used to produce large quantitie...
Stata command for calculating adverse event and efficacy stopping boundaries for phase II single-arm trials

Many programs and functions in statistical packages focus on the final stage of clinical trials, that is, the data analysis. In this article, I aim to assist in the early stages of clinical trials, specifically, the design of phase II single-arm trials. I present the new command stopbound, which calculates stopping boundaries and operating characteristics based on monitoring an adverse event, efficacy, or an adverse event and efficacy.
Inhibition of endocytosis suppresses the nitric oxide-dependent release of Cl- in retinal amacrine cells

Our lab has previously shown that nitric oxide (NO) can alter the synaptic response properties of amacrine cells by releasing Cl- from internal acidic compartments. This alteration in the Cl- gradient brings about a positive shift in the reversal potential of the GABA-gated current, which can convert inhibitory synapses into excitatory synapses. Recently, we have shown that the cystic fibrosis transmembrane regulator (CFTR) Cl- channel is involved in the Cl- release. Here, we test the hypothesis that (acidic) synaptic vesicles are a source of NO-releasable Cl- in chick retinal amacrine cells. If SVs are a source of Cl-, then depleting synaptic vesicles should decrease the nitric oxide-dependent shift in the reversal potential of the GABA-gated current. The efficacy of four inhibitors of dynamin (dynasore, Dyngo 4a, Dynole 34–2, and MiTMAB) were evaluated. In order to deplete synaptic vesicles, voltage-steps were used to activate V-gated Ca2+ channels and stimulate the synaptic vesicle cycle either under control conditions or after treatment with the dynamin inhibitors. Voltage-ramps were used to measure the NO-dependent shift in the reversal potential of the GABA-gated currents under both conditions. Our results reveal that activating the synaptic vesicle cycle in the presence of dynasore or Dyngo 4a blocked the NO-dependent shift in EGABA. However, we also discovered that some dynamin inhibitors reduced Ca2+ signaling and L-type Ca2+ currents. Conversely, dynasore also increased neurotransmitter release at autaptic sites. To further resolve the mechanism underlying the inhibition of the NO-dependent shift in the reversal potential for the GABA-gated currents, we also tested the effects of the clathrin assembly inhibitor Pitstop 2 and found that this compound also inhibited the shift. These data provide evidence that dynamin inhibitors have multiple effects on amacrine cell synaptic transmission. These data also suggest that inhibition of endocytosis disrupts the ability of NO to elicit Cl- release from internal stores which may in part be due to depletion of synaptic vesicles.
Propagating, Evanescent, and Complex Wavenumber Guided Waves in High-Performance Composites

The study of propagating, evanescent and complex wavenumbers of guided waves (GWs) in high-performance composites using a stable and robust semi-analytical finite element (SAFE) method is presented. To facilitate understanding of the wavenumber trajectories, an incremental material change study is performed moving gradually from isotropic aluminum alloy to carbon fiber reinforced polymer (CFRP) composites. The SAFE results for an isotropic aluminum alloy plate are compared with the exact analytical solutions, which shows that N = 20 SAFE elements across the thickness provides <0.5% error in the highest evanescent wavenumber for the given frequency-wavenumber range. The material change study reveals that reducing the transverse and shear moduli moves the wavenumber solution towards one similar to composite material. The comparison of the propagating, evanescent and complex wavenumber trajectories between composites and aluminum alloy show that antisymmetric imaginary Lamb wave modes always exist in composites although they may not exist in isotropic aluminum alloy at some frequencies. The wavenumber trajectories for a unidirectional CFRP plate show that the range of real wavenumber is much smaller than in the isotropic aluminum alloy. For laminated CFRP composite plates (e.g., unidirectional, off-axis, transverse, cross-ply and quasi-isotropic laminates), the quasi Lamb wave and shear horizontal (SH) wave trajectories are also identified and discussed. The imaginary SH wave trajectories in laminated composites are distorted due to the presence of ±45 plies. The convergence study of the SAFE method in various CFRP laminates indicates that sufficient accuracy can always be achieved by increasing the number of SAFE elements. Future work will address the stress-continuity between composite layers.
Promoting individual and community health in the library

In this time of information access, literally in our pockets via our smartphones, understanding where and how to find good information about health can be confusing. While drug companies are requir...
Transduction of gluconeogenic enzymes prolongs cone photoreceptor survival and function in models of retinitis pigmentosa

Abstract The hereditary nature of many retinal degenerative disorders makes them potentially amenable to corrective gene therapies. Numerous clinical trials are ongoing with the goal to rectify the genetic defect in the afflicted cell types. However, the personalized nature of these approaches excludes many patients for whom the underlying mutation is not mapped, or the number of affected individuals is too few to develop a commercially viable therapy (vide infra). Thus, a therapy that can delay visual impairment irrespective of the underlying genetic etiology can satisfy this unmet medical need. Here, we demonstrate the utility of such an approach in retinitis pigmentosa (RP) by promoting survival of cone photoreceptors by targeting metabolic stress. These cells are not primarily affected by the inherited mutation, but their non-autonomous demise leads to a decline in daylight vision, greatly reducing the quality of life. We designed adeno-associated virus (AAV) vectors that promote gluconeogenesis- a pathway found in the liver which produces glucose in response to hypoglycemia. Retinal transduction with these vectors resulted in improved cone survival and delayed a decline in visual acuity in three different RP mouse models. Because this approach extended visual function independent of the primary mutation, therapies emanating from this approach could be used as a treatment option for a genetically heterogenous cohort of patients.
Ibrutinib and Venetoclax - Doubling Down on CLL.

Chronic lymphocytic leukemia (CLL) is a clonal expansion of mature B cells in blood, bone marrow, and lymphoid tissues that usually manifests as a high lymphocyte count in the circulating blood. Ce...