cssi/SciSciGPT-SciSciNet huggingface dataset:
Novel approach to enhance oral bioavailability of drugs with poor permeability

T epithelial enterocyte barrier of the gastrointestinal (GI) tract limits the absorption of many oral drugs to the systemic circulation. Modulation of intercellular tight junctions has long been considered a potential tool to enhance drug delivery across these biological barriers. However, early modulators (e.g., Ca2+ chelators, surfactants, modified fatty acids and esters, and polymers) had unspecific modes of action and insufficient separation between efficacy and toxicity, precluding their clinical use. Recent knowledge regarding the molecular composition and mechanisms regulating tight junctions and adherens junctions has led to a new generation of intercellular junction modulators based on junction protein/peptide mimetics and relevant signaling pathways. E-cadherin peptides (ECPs) represent a class of these new modulators and have shown promise in enhancing small molecule drug delivery across the blood-brain barrier via reversible modulation. Here, the potential of ECPs to enhance oral bioavailability of small molecule drugs that have limited gut absorption was investigated. In vitro permeability and in vivo pharmacokinetic studies have been performed to demonstrate the feasibility of the ECP-based oral drug delivery approach. Results showed that ECPs substantially increased the permeability of the model drugs, as well as their systemic exposure after oral administration. In conclusion, ECPs-based formulations should be further developed as a vehicle to enhance oral bioavailability of poorly permeable drugs.
Eye changes with thyroid disease.

Hypothyroidism occasionally produces periorbital myxedema, while hyperthyroidism can lead to exophthalmos. In the latter condition, the patient's upper lids retract, his lids lag when he gazes down, and he blinks infrequently. In its severe form—endocrine exophthalmos—the eyes may bulge forward so much that corneal exposure occurs, leading to possible infection, perforation and loss of an eye.
Lactate and Pyruvate Are Major Sources of Energy for Stallion Sperm with Dose Effects on Mitochondrial Function, Motility, and ROS Production

Stallion sperm rely primarily on oxidative phosphorylation for production of ATP used in sperm motility and metabolism. The objective of the study was to identify which substrates included in Biggers, Whitten, and Whittingham (BWW) media are key to optimal mitochondrial function through measurements of sperm motility parameters, mitochondrial oxygen consumption, and cellular reactive oxygen species (ROS) production. It was expected that mitochondrial substrates, pyruvate and lactate, would support sperm motility and mitochondrial function better than the glycolytic substrate, glucose, due to direct utilization within the mitochondria. Measurements were performed after incubation in modified BWW media with varying concentrations of lactate, pyruvate, and glucose. The effects of media and duration of incubation on sperm motility, ROS production, and oxygen consumption were determined using a linear mixed-effects model. Duplicate ejaculates from four stallions were used in three separate experiments to determine the effects of substrate availability and concentration on sperm motility and mitochondrial function and the relationship of oxygen consumption with cellular ROS production. The present results indicate that lactate and pyruvate are the most important sources of energy for stallion sperm motility and velocity, and elicit a dose-dependent response. Additionally, lactate and pyruvate are ideal for maximal mitochondrial function, as sperm in these media operate at a very high level of their bioenergetic capability due to the high rate of energy metabolism. Moreover, we found that addition of glucose to the media is not necessary for short-term storage of equine sperm, and may even result in reduction of mitochondrial function. Finally, we have confirmed that ROS production can be the result of mitochondrial dysfunction as well as intense mitochondrial activity.
Minimally Invasive Surgery for Pancreatic Head Cancer

An increasing number of reports on minimally-invasive pancreaticoduodenectomy (MIPD) have emerged over the last two decades. Morbidity, oncologic outcomes, and the impact of the learning curve for MIPD are being carefully scrutinized to ensure that safety and efficacy are not compromised, particularly in the setting of periampullary malignancies. Although many of the current adopters of MIPD are still within their learning curve, a number of single institutional series have recently confirmed the non-inferiority of the laparoscopic or robotic PD when performed by experienced pancreatic surgeons at high volume centers. In the absence of randomized controlled trials to address the safety, efficacy and potential advantages of the MIPD, this chapter will examine the available retrospective data on the safety and oncologic oncologic outcomes of the laparoscopic and robotic PD for pancreatic head malignancies.
Effect of Specimen Holder on Static and Fatigue Tests on Titanium/Cement Interfaces

A tension or compression load was applied onto the Ti rod to test the fracture strength and fatigue life of Ti-cement interface under static and fatigue loadings, respectively. These tests are referred as static and fatigue in this study. A customized holder for the cement is required for the static and fatigue experiments, since the typical wedge, pneumatic, or hydraulic gripper are not suitable for static and fatigue tests on the fracture tests of bi-material samples. The objectives of this study are (1) to evaluate the effect of cement thickness on the fracture strength and fatigue life on Ti-cement union by finite element analysis; (2) to evaluate the effect of plastic cement holder and aluminum cement holder on fracture strength and fatigue life on Ti-cement union by experiment and finite element analysis. Ti-cement union model with 0.22 and 0.11 in. cement, Ti-cement-holder union with plastic and aluminum holders were created and validated using ANSYS in this study to develop a suitable specimen holder for static and fatigue tests. Experimental static tests of Ti-cement with both plastic and aluminum specimen holders were conducted as well. The result clearly showed that both plastic and aluminum holders can be used for static test whereas aluminum holder required much larger fracture load compared to the fracture load on plastic holder. Plastic holder is not suitable for fatigue test, because fatigue test required a stronger and more rigid holder such as aluminum.
Considerations in Biomechanical Testing

Justin Dawn, engineering diploma in hand, was hired to work in the Orthopaedic Research Laboratory at Mega General Hospital shortly after Sanza Time was admitted with the broken femoral rod. Having seen such broken rods too many times in her long career, the chief orthopaedic surgeon at Mega General asked the staff of the research laboratory to design a stronger rod. In order to design such a device, the staff immediately recognized that some notion of the strains incurred by the current rod would have to be taken into account. Justin’s first project was thus to determine what such strains might be during normal walking. How would Justin go about doing this?
Banks: Fundamental Concepts

This chapter from our forthcoming book on financial institution regulation identifies the fundamental economic form of a commercial banking firm. We argue that a commercial bank is a financial intermediary that operates as a payments specialist. The intermediation and payment functions are not necessarily linked; many firms operate as financial intermediaries without offering payments services, and many firms and institutions offer payments services without being intermediaries. The linkage of the payment and intermediation functions in the commercial bank is due to the fact that a bank performs the payment function by means of accounts customers place on deposit. Given that the bank has funds on deposit to carry out its payments function, it naturally invests those funds in financial claims and thus becomes an intermediary. What is truly fundamental about banks is not the fact that they are financial intermediaries, but rather that they are payments specialists. The chapter discusses this feature of banks and places bank payment services in a broader context of other payment mechanisms including exotic instruments such as local currencies, MMORPG currencies, LETS systems, and crypto-currencies such as Bitcoin.
Characterization of human translesion DNA synthesis across a UV-induced DNA lesion

Translesion DNA synthesis (TLS) during S-phase uses specialized TLS DNA polymerases to replicate a DNA lesion, allowing stringent DNA synthesis to resume beyond the offending damage. Human TLS involves the conjugation of ubiquitin to PCNA clamps encircling damaged DNA and the role of this post-translational modification is under scrutiny. A widely-accepted model purports that ubiquitinated PCNA recruits TLS polymerases such as pol η to sites of DNA damage where they may also displace a blocked replicative polymerase. We provide extensive quantitative evidence that the binding of pol η to PCNA and the ensuing TLS are both independent of PCNA ubiquitination. Rather, the unique properties of pols η and δ are attuned to promote an efficient and passive exchange of polymerases during TLS on the lagging strand.
Algorithmic Modeling Interface Interoperability Case Study

The Algorithmic Modeling Interface (AMI) defines a standard syntax for modeling the physical layer of high-speed serial interfaces such as PCI Express (PCIe) and Serial Attach SCSI (SAS). Although it has been gathering momentum since it emerged in 2008, the models developed under this standard continue to experience basic functionality and interoperability issues. Many models only run under one simulator and require multiple revisions before they will run in another simulator. Our paper presents a case study of three different AMI models in three different simulators together with recommendations for insuring the quality of these critical elements of serial interface simulation.
Chapter Two – The Complexities of Learning Categories Through Comparisonsa

Abstract Comparisons have been suggested as central to category learning, yet we are only beginning to understand how different types of comparisons affect what people learn. Prior research has established that different ways of learning affect what information learners acquire, suggesting that different types of comparisons may also affect learning in different ways. An important comparison-type distinction in category learning is between-category versus within-category comparisons. The results of prior studies looking at these types of comparisons are mixed, so it remains unclear how each type of comparison affects category learning. This chapter lays out a framework based on the idea that the benefits of comparisons depend on both the type of comparison being made as well as what information needs to be learned. Specifically, between-category comparisons highlight distinguishing information between categories while within-category comparisons highlight commonalities and the relational structure of items.
Grass Cell Walls: A Story of Cross-Linking

Cell wall matrices are complex composites mainly of polysaccharides, phenolics (monomers and polymers), and protein. We are beginning to understand the synthesis of these major wall components individually, but still have a poor understanding of how cell walls are assembled into complex matrices. Valuable insight has been gained by examining intact components to understand the individual elements that make up plant cell walls. Grasses are a prominent group within the plant kingdom, not only for their important roles in global agriculture, but also for the complexity of their cell walls. Ferulate incorporation into grass cell wall matrices (C3 and C4 types) leads to a cross-linked matrix that plays a prominent role in the structure and utilization of grass biomass compared to dicot species. Incorporation of p-coumarates as part of the lignin structure also adds to the complexity of grass cell walls. Feruoylation results in a wall with individual hemicellulosic polysaccharides (arabinoxylans) covalently linked to each other and to lignin. Evidence strongly suggests that ferulates not only cross-link arabinoxylans, but may be important factors in lignification of the cell wall. Therefore, the distribution of ferulates on arabinoxylans could provide a means of structuring regions of the matrix with the incorporation of lignin and have a significant impact upon localized cell wall organization. The role of other phenolics in cell wall formation such as p-coumarates (which can have concentrations higher than ferulates) remains unknown. It is possible that p-coumarates assist in the formation of lignin, especially syringyl rich lignin. The uniqueness of the grass cell wall compared to dicot sepcies may not be so much in the gross composition of the wall, but how the distinctive individual components are organized into a functional wall matrix. These features are discussed and working models are provided to illustrate how changing the organization of feruoylation and p-coumaroylation could lead to differing cell wall properties.
Confidentiality in Biobanking Research: A Comparison of Donor and Nondonor Families' Understanding of Risks

Aims: Confidentiality of personal identifiers potentially linking the genetic results from biobanking participants back to the donor and donor relatives is a concern. The risks associated with a breach of confidentiality should be ascertained when biobanks collect samples requiring the consent of a family decision maker (FDM) from deceased organ and tissue donors. This article explores FDM knowledge and opinions regarding risks associated with participation in biobanking research in the context of the Genotype-Tissue Expression (GTEx) Project. Methods: Data collection included a survey completed by organ procurement organization requesters (n = 37) and semistructured telephone interviews with the FDMs (n = 85). Results: Donor families were more likely to know that there was a risk that a patient's identity could be revealed through a breach of confidentiality (p < 0.05). They also were more likely to understand that researchers using biobanked tissue would not have access to the patient's exact identity (...
Vassiliev invariants of Legendrian, transverse, and framed knots in contact three-manifolds

Abstract We show that for a large class of contact three-manifolds the groups of Vassiliev invariants of Legendrian and of framed knots are canonically isomorphic. As a corollary, we obtain that the group of finite order Arnold's J+-type invariants of wave fronts on a surface F is isomorphic to the group of Vassiliev invariants of framed knots in the spherical cotangent bundle ST ∗ F of F. On the other hand, we construct the first examples of contact manifolds for which Vassiliev invariants of Legendrian knots can distinguish Legendrian knots that realize isotopic framed knots and are homotopic as Legendrian immersions.
Application of stable isotopic tracing in an ex-vivo system to reveal heterogeneous patterns of androgen metabolism in localized, hormone-naïve prostate cancer.

109Background: The 5α-androstanedione (5α-dione) pathway is the demonstrated route through which adrenal precursor steroids bypass testosterone (T) to form dihydrotestosterone (DHT) in metastatic castration-resistant prostate cancer (mCRPC). However, accessible pathways of DHT synthesis are less clear in localized, hormone-naive prostate cancer (HNPCa), where steroidogenic enzyme expression may differ and circulating T and adrenal steroids could act as competing substrates for 5α-reductase. We employed a dual substrate, ex-vivo system with selective stable isotopic labeling of DHT precursors to better understand alterations in androgen synthesis that occur in the transition of HNPCa to mCRPC. Methods: Under IRB approval and patient consent, tumor and adjacent benign prostate tissues were procured from radical prostatectomy specimens of men with HNPCa (n = 16). Tissues were grossly homogenized and incubated ex-vivo in serum-free media spiked with 1 µM of 13C3-AD +/- equimolar unlabeled T. Media was collect...
Validating the 11-Item Revised University of California Los Angeles Scale to Assess Loneliness Among Older Adults: An Evaluation of Factor Structure and Other Measurement Properties

Objective To examine the measurement properties and factor structure of the short version of the Revised University of California Los Angeles (R-UCLA) loneliness scale from the Health and Retirement Study (HRS). Methods Based on data from 3,706 HRS participants aged 65 + who completed the 2012 wave of the HRS and its Psychosocial Supplement, the measurement properties and factorability of the R-UCLA were examined by conducting an exploratory factor analysis (EFA) and the confirmatory factor analysis (CFA) on randomly split halves. Results The average score for the 11-item loneliness scale was 16.4 (standard deviation: 4.5). An evaluation of the internal consistency produced a Cronbach's α of 0.87. Results from the EFA showed that two- and three-factor models were appropriate. However, based on the results of the CFA, only a two-factor model was determined to be suitable because there was a very high correlation between two factors identified in the three-factor model, available social connections and sense of belonging . Conclusion This study provides important data on the properties of the 11-item R-UCLA scale by identifying a two-factor model of loneliness: feeling isolated and available social connections . Our findings suggest the 11-item R-UCLA has good factorability and internal reliability.
Picosecond Vibrational and Electronic Relaxation Processes in Molecules

We describe in this paper an improved picosecond timescale spectrophotometer. As the accuracy of ultrashort kinetic techniques improves so can the sophistication of the models used to describe the responses of systems to picosecond pulses. No less than with traditional kinetic studies, it is vital in picosecond work to have analytical methods that characterize the species that are incorporated into the models. In our case the analytical method is spectrophotometry.
Changes in Time Use and Their Effect on Energy Consumption in the United States

Summary Lifestyles are changing due to information technology and other socio-technological trends. We study the energy effects induced by lifestyle shifts via tradeoffs in time spent in performing activities. We use the American Time Use Survey to find changes in times performing different activities from 2003 to 2012. The results show that Americans are spending considerably more time at home (7.8 days more in 2012 compared with 2003). This increased home time is counterbalanced by decreased time spent traveling (1.2 days less in 2012 versus 2003) and in non-residential buildings (6.7 days less in 2012 versus 2003). Increased residential time is mainly due to increased work at home, video watching, and computer use. Decomposition analysis is then used to estimate effects on energy consumption, indicating that more time at home and less on travel and in non-residential buildings reduced national energy demand by 1,700 trillion BTU in 2012, 1.8% of the national total.
Working With Young Children With OCD

Abstract Family-based cognitive behavioral therapy using exposure with response prevention (E/RP) is the treatment of choice when working with young children with obsessive-compulsive disorder (OCD). This chapter provides an overview of how to treat OCD in young children using E/RP as the primary intervention. Treatment elements discussed include initial screening and diagnostic assessment, psychoeducation about OCD and E/RP, functional assessment of symptoms, hierarchy building, implementation of E/RP, contingency behavioral management, and relapse prevention. Particular emphasis is given to developmental modifications for using E/RP with young children as well as involving caregivers in treatment. Delivery of E/RP is described using a habituation and distress tolerance framework. Lastly, common treatment barriers are addressed.
Hyperoxia-induced macrophage dysfunction and acute lung injury are attenuated by modulation of α7nAChR via reduced HMGB1 hyperacetylation and release

Prolonged exposure to hyperoxia during mechanical ventilation (MV) can result in acute lung injury (ALI) and is associated with HMGB1 accumulation in the airways. The aim of this study was to determine whether modulation of α7 nicotinic acetylcholine receptor (α7nAChR) with either GTS-21 (partial agonist) or GAT107 (ago-PAM) could inhibit hyperoxia-induced HMGB1 accumulation in the airways and improve innate immunity and clinical outcomes. RAW 264.7 cells, treated with either GTS-21 or GAT107 in the presence of 95% O2 exhibited decreased levels of HMGB1 in culture media and enhanced phagocytic ability. Hyperacetylation of nuclear HMGB1 can lead to its release into the extracellular milieu and is observed in cells exposed to hyperoxia. Activation of α7nAChR is effective in reducing both hyperoxia-induced HMGB1 accumulation and hyperacetylation. To determine whether activation of α7nAChR-mediated macrophage function can be translated into clinical outcomes, mice were exposed to >99% O2 for 3 d with GTS-21 treatment. GTS-21 significantly decreased both the accumulation of airway levels and hyperacetylation of HMGB1, protein content and neutrophil infiltration. Therefore, α7nAChRs represent a possible pharmacological target for the treatment of HALI in patients receiving MV.
EVALUATING NONTARGET EFFECTS OF CLASSICAL BIOLOGICAL CONTROL: FRUIT FLY PARASITOIDS IN HAWAII AS A CASE STUDY

Classical biological control is a method of pest management that employs the deliberate introduction of exotic living organisms to suppress pest species. The ecological basis of classical biological control rests on the principle that many invasive pest populations are limited in their native habitat by the action of upper trophic level organisms (often termed natural enemies), or in some cases, by competitors within the same trophic level (Van Driesche and Bellows 1996). Many species achieve pest status when they are moved (accidentally or intentionally) to a new location without their natural enemies, and where local natural enemies are ineffective in suppressing them. The anticipated outcome of a biological control introduction is the establishment of a new balance with both the pests and natural enemies coexisting at low densities.
How Fate Taught Me the Violin

Have you ever wondered how many of us got interested in playing a musical instrument at an early age?
Drug-Eluting Stents: A Potential Preemptive Treatment Choice for Vulnerable Coronary Plaques

Restenosis, a major limitation of percutaneous transluminal coronary angioplasty, has been dramatically reduced by the use of drug-eluting stents (DES). Because the majority of acute coronary events occur at nonobstructive lesions that are vulnerable, it has been suggested that prophylactic stenting of vulnerable plaques (VP) to prevent further plaque instability, thereby preventing future coronary events, is as a reasonable strategy. The use of DES in treating intermediate coronary lesions has been shown to be safe and effective. Clinical trials evaluating different intracoronary imaging modalities for the detection of VP and to define its association with subsequent coronary events are ongoing. Risk stratification of such intermediate lesions by VP imaging can help to identify appropriate lesions for preemptive treatment in patients who are at high risk for acute coronary events or recurrent events. Such a strategy should help to improve outcomes in these patients. Current limitations of DES include the long-term risk of stent thrombosis and the need for prolonged dual antiplatelet therapy. Several other transcatheter-based approaches for the stabilization of VP to overcome the limitations of DES are under development. These include drug-eluting balloons, bioabsorbable stents, photodynamic therapy, and cyroenergy. These improvements in technology hopefully will reduce or eliminate the long-term risk of stent thrombosis associated with DES, thus shifting the risk-benefit ratio toward prophylactic stenting of nonobstructive VP in the future.
GRNN: Low-Latency and Scalable RNN Inference on GPUs

Recurrent neural networks (RNNs) have gained significant attention due to their effectiveness in modeling sequential data, such as text and voice signal. However, due to the complex data dependencies and limited parallelism, current inference libraries for RNNs on GPUs produce either high latency or poor scalability, leading to inefficient resource utilization. Consequently, companies like Microsoft and Facebook use CPUs to serve RNN models. This work demonstrates the root causes of the unsatisfactory performance of existing implementations for RNN inference on GPUs from several aspects, including poor data reuse, low on-chip resource utilization, and high synchronization overhead. We systematically address these issues and develop a GPU-based RNN inference library, called GRNN, that provides low latency, high throughput, and efficient resource utilization. GRNN minimizes global memory accesses and synchronization overhead, as well as balancing on-chip resource usage through novel data reorganization, thread mapping, and performance modeling techniques. Evaluated on extensive benchmarking and real-world applications, we show that GRNN outperforms the state-of-the-art CPU inference library by up to 17.5X and state-of-the-art GPU inference libraries by up to 9X in terms of latency reduction.
New developments in the diagnosis of fibrillary glomerulonephritis.

Fibrillary glomerulonephritis is a glomerular disease historically defined by glomerular deposition of Congo red–negative, randomly oriented straight fibrils that lack a hollow center and stain with antisera to immunoglobulins. It was initially considered to be an idiopathic disease, but recent studies highlighted association in some cases with autoimmune disease, malignant neoplasm, or hepatitis C viral infection. Prognosis is poor with nearly half of patients progressing to end-stage renal disease within 4 years. There is currently no effective therapy, aside from kidney transplantation, which is associated with disease recurrence in a third of cases. The diagnosis has been hampered by the lack of biomarkers for the disease and the necessity of electron microscopy for diagnosis, which is not widely available. Recently, through the use of laser microdissection–assisted liquid chromatography–tandem mass spectrometry, a novel biomarker of fibrillary glomerulonephritis, DnaJ homolog subfamily B member 9, has been identified. Immunohistochemical studies confirmed the high sensitivity and specificity of DnaJ homolog subfamily B member 9 for this disease; dual immunofluorescence showed its colocalization with IgG in glomeruli; and immunoelectron microscopy revealed its localization to individual fibrils of fibrillary glomerulonephritis. The identification of this tissue biomarker has already entered clinical practice and undoubtingly will improve the diagnosis of this rare disease, particularly in developing countries where electron microscopy is less available. Future research is needed to determine whether DnaJ homolog subfamily B member 9 is an autoantigen or just an associated protein in fibrillary glomerulonephritis, whether it can serve as a noninvasive biomarker, and whether therapies that target this protein are effective in improving prognosis.
Management of epidural hematomas in pediatric patients presenting with a GCS of 14 or better.

Abstract Object Guidelines for the management of pediatric epidural hematoma (PEDH) remain poorly defined. Here we seek to characterize the disease course of PEDH in patients with presenting Glasgow Coma Scale (GCS) of 14+, and suggest high-risk characteristics for progression to surgery. Methods A prospectively maintained, single-institution, level-1 trauma hospital admission database was queried to identify patients ages 6 months to 18 years presenting with PEDH between 2006 and 2016. Selected charts were reviewed for clinical information and treatment. Head imaging was reviewed for hematoma size, location, fractures, and midline shift. Results Of 210 cases reviewed, 117 presented with a GCS of 14+. Of these, 24 required surgery while 93 were managed conservatively. Factors leading to surgery included decline in GCS (40%), size alone (21%), localizing neurological deficit (20%), progression on repeat imaging (12%), and other (7%). Hematomas involving the temporal lobe plus an adjacent lobe were more likely to proceed to surgery than those involving the temporal lobe alone (OR: 24.8, 95% CI (4.74, 129.26)). Hematomas in proximity to the superior sagittal and transverse sinuses proceeded to surgery in 33.3% and 37.5% of cases, respectively. Of the 93 patients with a thickness:biparietal skull diameter ratio of ≤0.15, 89 (95.7%) were managed conservatively. Conclusion In this single-institution experience, 21% of pediatric patients presenting with a GCS of 14+ proceeded to surgery. High-risk features include large hematoma thickness, proximity to the transverse sinus, and multilobar location. A thickness:biparietal skull diameter ratio less than 0.15 was highly unlikely to proceed to surgery.
Missing from the Conversation: Sexual Risk Factors Across Young People by Gender Identity and Sexual Orientation

AbstractObjectives: Lesbian, gay, bisexual, and queer/questioning (LGBQ), and transgender/nonbinary (trans/NB) youth experience health disparities. Much research combines gender identity with sexua...
Addressing power dynamics in interprofessional health care teams

The balance of power among interprofessional healthcare teams influences their effectiveness. In this study, the researcher assessed the factors that influence power dynamics in interprofessional h...
Signifying “Americanness”: Narrative Collective Identification Work in the Undocumented Youth Movement:

This article examines the narrative identity work that undocumented youth activists used to shift the boundary of and claim membership in the social category “American.” Despite the seemingly infle...
Genome-Wide Screening Reveals CSDE1 as a Novel Regulator of the LDL Receptor

In humans, clearance of LDL cholesterol, which causes atherosclerotic heart disease, is mediated by the hepatic LDL receptor (LDLR)1. As a result, therapies that upregulate the LDLR are highly effective treatments for atherosclerosis2. Since cardiovascular disease remains the leading cause of death in Western countries3, we sought to identify regulators of the LDLR beyond the known genetic causes of familial hypercholesterolemia. Here we show that CSDE1, an RNA-binding protein involved in mRNA stability4, enhances LDLR mRNA degradation to modulate LDLR expression and function. Using parallel phenotypic genome-wide screens, based on the CRISPR interference platform5, we identified over 100 specific regulators of surface LDLR expression in HepG2 cells, characterized their effects on LDLR function, and leveraged pharmacologic strategies to probe their mechanistic pathways. Among our hits, we found that CSDE1 participates in post-translational control of the LDLR independent from well-established, and clinically exploited, transcriptional and lysosomal regulatory mechanisms. Overall, our results reveal a network of novel LDLR modulators left undiscovered by human genetics, many of which have phenotypic strengths similar to bona fide targets in the clinic, offering hope for new therapeutic strategies against atherosclerosis. We anticipate that our approach of modelling a clinically relevant phenotype in an in vitro experimental system amenable to a forward genetic screen, followed by high throughput validation and mechanistic pharmacologic dissection, will serve as a template for the identification of novel therapeutic targets for other disease states. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/235028v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1b9bfb0org.highwire.dtl.DTLVardef@1d7d136org.highwire.dtl.DTLVardef@1e86269org.highwire.dtl.DTLVardef@194ebdc_HPS_FORMAT_FIGEXP M_FIG C_FIG
Enema-Induced spastic left colon syndrome: An unintended consequence of chronic enema use.

Abstract Background/purpose Enemas have become a common practice for treating fecal incontinence and severe constipation. Several patients receiving enemas complained of severe, colicky, abdominal pain during enema administration and complained that the duration for fluid to pass was progressively increasing. Contrast studies showed a startling picture of severe right colon dilatation and a spastic, narrow, left colon. An investigation was started to seek the origin and possible management of this condition. Methods Medical and radiologic records were reviewed retrospectively, with emphasis on the type and ingredients of enemas used, the duration the patients had been receiving enemas, and their original diagnosis. A literature review was done on previous reports of this condition and publications related to long-term use of enemas. Results This series included 22 patients (average age, 19.6 years; range, 8–54) with fecal incontinence due to anorectal malformations (10 cases), myelomeningocele (5), cloaca (2), severe colonic dysmotility (2), Hirschsprung's disease (2), and sacrococcygeal teratoma (1). The average duration of enema use was 13.7 years (range, 4–45). The composition of the enemas included saline/glycerin (six cases), only saline solution (five), saline/glycerin/soap (four), plain water (three), and one case each of molasses/milk, saline/glycerin/soap/phosphate, saline/phosphate, and only phosphate. The enemas were performed in an antegrade fashion in 21 cases and rectally in 1. All patients had a dilated right colon and a narrow, spastic, left, transverse, and descending colon. Four patients underwent colonoscopy, colonic manometry, and mucosal biopsies, which did not help in explaining the etiology of the problem. In the literature, 43 reports mentioned a “long-term follow-up” for the administration of enemas, but we could not find a description of symptoms, such as in our cases. Conclusions An intriguing and, to our knowledge, previously unreported complication of chronic enema use is presented. We call attention to an overly concerning complication and report our findings in the hope that they will aid and stimulate more investigations into this condition. Several hypotheses to explain the cause are presented, as well as potential treatment options.
Exemplifying Power Matters: The Impact of Power Exemplification of Transgender People in the News on Issue Attribution, Dehumanization, and Aggression Tendencies

Despite the enormous rise in the transgender media visibility in recent years, the news media in particular still predominantly exemplify powerful elite transgender people or exclusively quote thei...
Risk management of Bitcoin futures with GARCH models

Abstract In this article, we investigate the quantitative risk management of Bitcoin futures by using the GARCH models. We first found that it is crucial to introduce a heavy-tailed distribution into the GARCH models to explain return volatilities of Bitcoin futures. Then, we compare the VaR estimates based on the parametric methods, namely the GARCH model with the normal distribution (GARCH-Normal) and the GARCH model with the normal inverse Gaussian distribution (GARCH-NIG), and the nonparametric method. Our results illustrate that although the VaR estimates based on the nonparametric method are overall accurate and even more accurate than the VaR estimates based on the GARCH-Normal model, the VaR estimates based on the GARCH-NIG model perform the best. Overall, we conclude that the GARCH-NIG model could generate accurate VaR estimates for the Bitcoin futures return series. In addition, we found that in contrast to Bitcoin cash, the return volatilities of the Bitcoin futures do not increase by more in response to positive shocks than in response to negative shocks.
Combined Deficiency of the Melanocortin 5 Receptor and Adenosine 2A Receptor Unexpectedly Provides Resistance to Autoimmune Disease in a CD8+ T Cell-Dependent Manner

Regulatory immunity that provides resistance to relapse emerges during resolution of experimental autoimmune uveitis (EAU). This post-EAU regulatory immunity requires a melanocortin 5 receptor (MC5r)-dependent suppressor antigen presenting cell (APC), as shown using a MC5r single knock-out mouse. The MC5r-dependent APC activates an adenosine 2A receptor (A2Ar)-dependent regulatory Treg cell, as shown using an A2Ar single knock-out mouse. Unexpectedly, when MC5r-/- post-EAU APC were used to activate A2Ar-/- post-EAU T cells the combination of cells significantly suppressed EAU, when transferred to EAU mice. In contrast, transfer of the reciprocal activation scheme did not suppress EAU. In order to explain this finding, MC5r-/-A2Ar-/- double knock-out (DKO) mice were bred. Naive DKO mice had no differences in the APC populations, or inflammatory T cell subsets, but did have significantly more Treg cells. When we examined the number of CD4 and CD8 T cell subsets, we found significantly fewer CD8 T cells in the DKO mice compared to WT and both single knock-out mice. DKO mice also had significantly reduced EAU severity and accelerated resolution. In order to determine if the CD8 T cell deficiency contributed to the resistance to EAU in the DKO mice, we transferred naive CD8 T cells from WT mice, that were immunized for EAU. Susceptibility to EAU was restored in DKO mice that received a CD8 T cell transfer. While the mechanism that contributed to the CD8 T cell deficiency in the DKO mice remains to be determined, these observations indicate an importance of CD8 T cells in the initiation of EAU. The involvement of CD4 and CD8 T cells suggests that both class I and class II antigen presentation can trigger an autoimmune response, suggesting a much wider range of antigens may trigger autoimmune disease.
The Instability of Pipe Poiseuille Flow with Respect to Finite Amplitude Disturbances

The stability with respect to finite amplitude disturbances of Hagen-Poiseuille flow is studied, and it is found that for a disturbance velocity amplitude of 5% (scaled to the unperturbed velocity in the pipe center) and a wave number of unity (scaled to the pipe radius), a wall mode of an azimuthally periodic disturbance of periodicity unity is neutrally stable at a Reynolds number of 2 900. A linear wall mode is used to calculate the Reynolds stress and the modified steady flow thereby obtained is then examined for instability with respect to the same mode. Although it is found that a particular finite amplitude mode predisposes the flow towards instability with respect to the same mode, the same may be true for other modes and there may also exist important interactions between modes.
Cell Biological Studies of Learning in Simple Vertebrate and Invertebrate Systems

The sections in this article are: 1 Conceptual Issues in Study of Learning 2 Methodological Approaches to Study of Learning 3 Nonassociative Learning 3.1 Introduction 3.2 Simple Vertebrate System 3.3 Invertebrates 4 Associative Learning 4.1 Introduction 4.2 Simple Vertebrate Systems 4.3 Invertebrates 5 Conclusion 5.1 General Principles in Study of Learning 5.2 Coda
Vectorial representations of meaning for a computational model of language comprehension

This thesis aims to define and extend a line of computational models for text comprehension that are humanly plausible. Since natural language is human by nature, computational models of human language will always be just that — models. To the degree that they miss out on information that humans would tap into, they may be improved by considering the human process of language processing in a linguistic, psychological, and cognitive light. Approaches to constructing vectorial semantic spaces often begin with the distributional hypothesis, i.e., that words can be judged ‘by the company they keep.’ Typically, words that occur in the same documents are similar, and will have similar vectorial meaning representations. However, this does not in itself provide a way for two distinct meanings to be composed, and it ignores syntactic context. Both of these problems are solved in Structured Vectorial Semantics (SVS), a new framework that fully unifies vectorial semantics with syntactic parsing. Most approaches that try to combine syntactic and semantic information will either lack a cohesive semantic component or a full-fledged parser, but SVS integrates both. Thus, in the SVS framework, interpretation is interactive, considering both syntax and semantics simultaneously. Cognitively-plausible language models would also be incremental, support linear-time inference, and operate in only a bounded store of short-term memory. Each of these characteristics is supported by right-corner Hierarchical Hidden Markov Model (HHMM) parsing; therefore, SVS will be transformed into right-corner form and mapped to an HHMM parser. The resulting representation will then encode a psycholinguistically plausible incremental SVS language model.
6'7'-Dihydroxybergamottin contributes to the grapefruit juice effect.

Objective ur objective was to assess the contribution of 6′,7′-dihydroxybergamottin (DHB) to the inhibitory effect of grapefruit juice toward intestinal cytochrome P450 (CYP) 3A4. Methods An aqueous extract was prepared from grapefruit juice by centrifugation, filtration, and repeated washing of the particulate with water. The concentrations of various furanocoumarins in this grapefruit juice “serum” and in whole grapefruit juice were measured by HPLC and their identities confirmed by liquid chromatography–tandem mass spectrometry. Five healthy volunteers were given a single tablet of felodipine (10 mg) with whole grapefruit juice, orange juice–containing serum, or plain orange juice (control). The pharmacokinetic outcomes of felodipine were evaluated by noncompartmental methods. The effects of serum and purified DHB (at the same concentrations as those measured in the orange juice–containing serum used in the clinical study) were compared, in vitro, with regard to (1) the reversible and mechanism-based inhibition of the catalytic activity of complementary deoxyribonucleic acid–expressed CYP3A4 and (2) the time-dependent loss of immunoreactive CYP3A4 protein in modified Caco-2 cells. Results The concentration of DHB in serum was comparable to that measured in whole grapefruit juice (38 μmol/L versus 43 μmol/L), and the concentrations of other known furanocoumarins were well below the lowest published concentration required to inhibit catalytic activity by 50%. Relative to plain orange juice, orange juice–containing serum significantly increased the median felodipine area under the plasma concentration–time curve by 1.9-fold (P = .04) and increased the maximum concentration by 1.7-fold (P = .01). In vitro, serum and purified DHB had similar inhibitory effects toward CYP3A4 activity with respect to both reversible inhibition (95% confidence interval, 85% ± 5.7% and 75% ± 4.5%, respectively) and mechanism-based inhibition after a 15-minute preincubation (95% confidence interval, 79% ± 6.8% and 78% ± 5.7%, respectively). In Caco-2 cells the time-averaged extents of CYP3A4 protein loss caused by serum and purified DHB were identical (43%). Conclusion The interaction between grapefruit juice serum and felodipine can be attributed largely to DHB. This establishes DHB as an important contributor to the grapefruit juice effect. Clinical Pharmacology & Therapeutics (2004) 75, 569–579; doi: 10.1016/j.clpt.2004.02.007
Time Empirical Ionospheric Correction Model (STORM) response in IRI2000 and challenges for empirical modeling in the future

[1] IRI2000 [Bilitza, 2001] now contains a geomagnetic activity dependence based on the Time Empirical Ionospheric Correction Model (STORM) [Araujo-Pradere and Fuller-Rowell, 2002; Araujo-Pradere et al., 2002]. The storm correction is driven by the previous time history of ap and is designed to scale the quiet time F layer critical frequency (foF2) to account for storm-time changes in the ionosphere. The quality of the storm-time correction was recently evaluated by comparing the model with the observed ionospheric response during all the significant geomagnetic storms in 2000 and 2001. The model output was compared with the actual ionospheric response at 15 stations for each storm. These quantitative comparisons using statistical metrics showed that the model captures the decreases in electron density particularly well in summer and equinox conditions, but is not so good during winter conditions. To further assess the capabilities of the model, STORM has been compared in detail with observations during the Bastille Day storm in July 2000. This storm, considered to be on the extreme end of the statistical scale of storm magnitude, highlights two main areas were challenges remain for the empirical storm-time ionospheric model. The first is the rapid onset of the positive storm phase; the second is the regional composition changes that can affect one longitude sector at the expense of another for a particular storm. Both these challenges, although appreciated during the development of STORM, remain to be addressed.
Web and Web Security

Web services are self-contained modular applications that provide a computation upon request. These services can be described, published, located, and invoked over a network, generally over the Internet. However, intranets, extranets, and LANs can also be used. as well. In using web services for its information systems needs, a firm may open access to its information assets. This action can become an attractive target for malicious hackers, industrial espionage, and fraud. The assurance of security of web services is necessary for a firm to be willing to adopt the web services technology as a means of running its information systems
Challenge/Skill Balance, Flow, and Performance Anxiety

The study longitudinally tracked the relationship among challenge/skill balance, flow, and performance anxiety in 27 student musicians over the course of a semester as they worked toward a recital of a piece of music. Using hierarchical linear modeling, the balance between the challenge of a passage of music and the perceived skills necessary to play that music was found to be significantly and consistently correlated with optimal experience. Results of moderated multiple regression indicated that skill level moderated the relationship between challenge, flow, and performance anxiety. Results also indicated that flow and performance anxiety were antithetical experiences, such that when flow was highest, performance anxiety was lowest and vice versa. These findings are discussed in terms of the application of flow theory to understanding performance, and the practical implications for reducing task-specific anxiety.
Multiple roles of CD4 and CD8 in T cell activation.

The field of T cell biology was ushered in with a series of discoveries in the 1960s demonstrating that the thymus was not a vestigial organ lacking important biologic function but instead was critical for the host to mount both humoral and cell-mediated immune effector functions ([1][1]). Why the