cssi/SciSciGPT-SciSciNet huggingface dataset:
The dual modulatory effects of efavirenz on GABAA receptors are mediated via two distinct sites.

Abstract Efavirenz is a widely prescribed medicine used to treat type 1 human immunodeficiency virus (HIV-1), the most prevalent pathogenic strain of the virus responsible for the acquired immune deficiency syndrome (AIDS) pandemic. Under prescribed dosing conditions, either alone or in combination therapy, efavirenz-induced CNS disturbances are frequently reported. Efavirenz was recently reported to interact in a similar concentration range with a number of receptors, transporters and ion channels including recombinant rat α1β2γ2 GABA A receptors whose actions were potentiated ( Gatch et al., 2013; Dalwadi et al., 2016 ). Now we report on the molecular mechanism of efavirenz on GABA A receptors as a function of concentration and subunit composition via whole-cell recordings of GABA-activated currents from HEK293 cells expressing varying subunit configurations of GABA A receptors. Efavirenz elicited dual effects on the GABA response; it allosterically potentiated currents at low concentrations, whereas it inhibited currents at higher concentrations. The allosteric potentiating action on GABA A receptors was pronounced in the α1β2γ2, α2β2γ2 and α4β2γ2 configurations, greatly diminished in the α6β2γ2 configuration, and completely absent in the α3β2γ2 or α5β2γ2 configuration. In stark contrast, the inhibitory modulation of efavirenz at higher concentrations was evident in all subunit configurations examined. Moreover, efavirenz-induced modulatory effects were dependent on GABA concentration ([GABA]), with a pronounced impact on currents activated by low [GABA] but little effect at saturating [GABA]. Mutation of a highly-conserved threonine to phenylalanine in transmembrane domain 2 of the α1 subunit abolished the inhibitory effect of efavirenz in α1β2 receptors. Finally, mutations of any of the three conserved extracellular residues in α1/2/4 subunits to the conserved residues at the corresponding positions in α3/5 subunits (i.e., R84P, M89L or I120L) completely eliminated the potentiating effect of efavirenz in α1β2γ2 configuration. These findings demonstrate that efavirenz's positive allosteric modulation of the GABA A receptor is mediated via a novel allosteric site associated with the extracellular domain of the receptor.
Engineering Isoprene Synthase Expression and Activity in Cyanobacteria

Efforts to heterologously produce quantities of isoprene hydrocarbons (C5H8) renewably from CO2 and H2O through the photosynthesis of cyanobacteria face barriers, including low levels of recombinant enzyme accumulation compounded by their slow innate catalytic activity. The present work sought to alleviate the “expression level” barrier upon placing the isoprene synthase (IspS) enzyme in different fusion configurations with the cpcB protein, the highly expressed β-subunit of phycocyanin. Different cpcB*IspS fusion constructs were made, distinguished by the absence or presence of linker amino acids between the two proteins. Composition of linker amino acids was variable with lengths of 7, 10, 16, and 65 amino acids designed to test for optimal activity of the IspS through spatial positioning between the cpcB and IspS. Results showed that fusion constructs with the highly expressed cpcB gene, as the leader sequence, improved transgene expression in the range of 61 to 275-fold over what was measured with the...
tSDX: Enabling Impairment-Aware All-Optical Inter-Domain Exchange

Optical transmission systems exist ubiquitously in data center, access, metro and long-haul networks, and are divided into different autonomous domains based on different carrier ownership, network equipment manufacturers, geographical location, etc. Software-defined Internet exchange methods have been proposed to solve the long-standing problem of inter-domain routing and enable control flexibility in layer-3 networks, and software-defined networking (SDN) has also been introduced to optical networks and much progress has been made to enhance optical network control capability. In this paper, we investigate a transparent software-defined exchange (tSDX) with real-time impairment-aware service level agreement (SLA) guarantees for multidomain optical networks. An SDN-based hierarchical control architecture is designed and implemented. End-to-end, impairment-aware wavelength path provisioning is experimentally realized in a multidomain network. Real-time optical signal to noise ratio based optical performance monitoring, together with inter-domain negotiation enabled by our proposed SDN control architecture, serves as an SLA guarantee for 100-Gbps polarization-multiplexed quadrature phase-shift keying signals in dense wavelength division multiplexed transmission.
State estimation codes for perfect secrecy

We study the problem of remote state estimation, in the presence of a passive eavesdropper. An authorized user estimates the state of an unstable linear plant, based on the packets received from a sensor, while the packets may also be intercepted by the eavesdropper. Our goal is to design a coding scheme at the sensor, which encodes the state information, in order to impair the eavesdropper's estimation performance, while enabling the user to successfully decode the sent messages. We introduce a novel class of codes, suitable for real-time dynamical systems, termed State-Secrecy Codes. By using acknowledgment signals from the user, they apply linear time-varying transformations to the current and previously received states. We prove that under minimal conditions, State-Secrecy Codes achieve perfect secrecy, namely the eavesdropper's minimum mean square error grows unbounded almost surely, while the user's estimation performance is optimal. These conditions require that at least once, the user receives the corresponding packet while the eavesdropper fails to intercept it. The theoretical results are illustrated in simulations.
Pareto Front and General Line Coordinates

﻿﻿﻿﻿﻿﻿The Pareto Front is a mathematically correct solution of multi-objective optimization problems with several conflicting objectives. However, it is only a partial solution for many real-world situations, where only few of the PF alternatives can be implemented, due to resource limitations and other reasons. Commonly Pareto Front is narrowed by linear aggregation of contradictory criteria, where the challenge is assigning weights to criteria. Lossless visualization of multi-dimensional data of the Pareto Front is promising way to assist in interactive selecting appropriate weighs. This chapter shows a way to accomplish this with GLC-L visualization method defined Chap. 7. It also shows a way to visualize the approximation set for the Pareto Front with Collocated Paired Coordinates, defined in Chap. 2 in comparison with Parallel Coordinates to assists in finding “best” Pareto points.
HETEROGENEITY OF PULMONARY PERFUSION CHARACTERIZED BY FRACTALS AND SPATIAL CORRELATIONS

New technologies providing high resolution measurements of organ perfusion, have revealed a large degree of spatial heterogeneity. These new observations provide new insights into the mechanisms of blood flow distribution and are revolutionizing our understanding of normal and pathologic physiology. The concepts of heterogeneity, as they apply to blood flow distribution, span all levels of physiology from the organ system to the mitochondrial level. Mechanisms matching heterogeneous perfusion to organ function and cellular needs encompass the same range of scales. New paradigms of organ perfusion and the matching of local blood flow to function are needed to account for these new observations. Fractal analysis, a revolutionary mathematical science, provides insights and tools for constructing such models. Because fractal analysis is not a familiar tool to most physiologic investigators, principal definitions and concepts will be systematically developed. Concurrently, numerical methods to determine whether a structure or process is fractal and to estimate a fractal dimension will be derived.
Social trust prediction using rank-k matrix recovery

Trust prediction, which explores the unobserved relationships between online community users, is an emerging and important research topic in social network analysis and many web applications. Similar to other social-based recommender systems, trust relationships between users can be also modeled in the form of matrices. Recent study shows users generally establish friendship due to a few latent factors, it is therefore reasonable to assume the trust matrices are of low-rank. As a result, many recommendation system strategies can be applied here. In particular, trace norm minimization, which uses matrix's trace norm to approximate its rank, is especially appealing. However, recent articles cast doubts on the validity of trace norm approximation. In this paper, instead of using trace norm minimization, we propose a new robust rank-k matrix completion method, which explicitly seeks a matrix with exact rank. Moreover, our method is robust to noise or corrupted observations. We optimize the new objective function in an alternative manner, based on a combination of ancillary variables and Augmented Lagrangian Multiplier (ALM) Method. We perform the experiments on three real-world data sets and all empirical results demonstrate the effectiveness of our method.
Critical Values For Dunnett’s Procedure

This table contains critical values da/2,k,v and da,k,v for simultaneous comparisons of each treamtment group with a control group; α is the signficance level, k is the number of treatment groups, and v is the degrees of freedom of the independent estimate s2.
Effect of carbamyl phosphate on the begulation of nitrogenase in Clostridiumpasteurianum

Abstract One mM carbamyl phosphate inhibited the in vitro acetylene reduction activity of nitrogenase 30% whereas at high concentrations a maximum inhibition of 50% was observed. When 1 mM carbamyl phosphate was added to a culture growing of N2 1) nitrogenase synthesis was completely repressed and 2) after a period of 2.5 hrs in the absence of growth, the specific activity decreased to less than 50% of its activity just before the addition of the inhibitor.
The subgenus Stegomyia of Aedes in the Afrotropical Region with keys to the species (Diptera: Culicidae)

The subgenus Stegomyia Theobald of the genus Aedes Meigen in the Afrotropical Region is characterized. Eleven species groups are recognized and diagnosed. The taxonomy, distribution, bionomics and medical importance of the species of the region are discussed and summarized. Keys and illustrations are provided for the identification of the 11 species groups and 59 species and subspecies known to occur in this region. Information on the present status of the species of the African Stegomyia is summarized. Six new species: Aedes ealaensis, ethiopiensis, gandaensis, hogsbackensis, mpusiensis and sampi are recognized. Aedes blacklocki Evans is restored to specific status. One subspecies, denderensis Wolfs is elevated to specific status.
FLUORESCENT ANTIBODY STUDIES IN EXPERIMENTAL MALARIAS. I. STUDIES ON PLASMODIUM GALLINACEUM AND PLASMODIUM BERGHEI

Publisher Summary This chapter discusses fluorescent antibody (FA) studies in experimental malarias focusing on Plasmodium Gallinaceum and Plasmodium Berghei. For the studies on Plasmodium gallinaceum the direct FA method was used; serum was derived from a chicken immunized by multiple inoculations, conjugated with fluorescein isothiocyanate, and fractionated on a DEAE's cellulose column. With this reagent, fluorescent staining could be demonstrated with erythrocytic parasites, both asexual and gametocytes, ookinetes, oocysts, sporozoites, and exoerythrocytic forms in the brain capillaries. Brightly staining masses of fluorescent material appeared to precipitate on some of the sporozoites. These precipitates were located at the tip end and on the lateral wall just distil to the nucleus and these areas appear to correspond with the apical cup and the micropyle of the sporozoites. Thus, there appears to be an antigenic continuity throughout the stages of the parasite life cycle, demonstrable with serum from a vertebrate host immunized only through exposure to blood parasites.
Hypothalamic gene transfer of BDNF promotes healthy aging in mice.

The aging process and age-related diseases all involve perturbed energy adaption and impaired ability to cope with adversity. Brain-derived neurotrophic factor (BDNF) in the hypothalamus plays important role in regulation of energy balance. Our previous studies show that recombinant adeno-associated virus (AAV)-mediated hypothalamic BDNF gene transfer alleviates obesity, diabetes, and metabolic syndromes in both diet-induced and genetic models. Here we examined the efficacy and safety of a built-in autoregulatory system to control transgene BDNF expression mimicking the body's natural feedback systems in middle-aged mice. Twelve-month-old mice were treated with either autoregulatory BDNF vector or yellow fluorescence protein (YFP) control, maintained on normal diet, and monitored for 28 weeks. BDNF gene transfer prevented the development of aging-associated metabolic declines characterized by: preventing aging-associated weight gain, reducing adiposity, reversing the decline of brown fat activity, increasing adiponectin while reducing leptin and insulin in circulation, improving glucose tolerance, increasing energy expenditure, alleviating hepatic steatosis, and suppressing inflammatory genes in the hypothalamus and adipose tissues. Moreover, BDNF treatment reduced anxiety-like and depression-like behaviors. These safety and efficacy data provide evidence that hypothalamic BDNF is a target for promoting healthy aging.
THE OVERUSE OF TRANSESOPHAGEAL ECHOCARDIOGRAPHY IN PATIENTS WITH CONFIRMED ISCHEMIC STROKE

The role of transesophageal echocardiography (TEE) in identifying ischemic stroke etiology is debated. In 2009, the American Heart Association/American Stroke Association issued a scientific statement for echocardiography, providing a class IIa recommendation. However, this recommendation came with
Misclassification and linkage of hereditary sensory and autonomic neuropathy type 1 as Charcot-Marie-Tooth disease, Type 2B

Recently Kwon et al. published in the Journal their work describing linkage of a single large family with an inherited axonal neuropathy to chromosome 3, which they suggest is a second locus for Charcot-Marie-Tooth (CMT) type 2 and subsequently named {open_quotes}CMT2B.{close_quotes} We think that the diagnostic classification of this family as CMT2 is incorrect, since the subjects have a severe sensory neuropathy that fits within the hereditary sensory and autonomic neuropathy (HSAN) type 1 classification of Dyck (1993). Abnormal sensory findings in CMT2 separate it from distal spinal muscular atrophy but are a minor component of clinical symptoms in most CMT patients, as CMT is primarily a motor neuropathy. When Kwon et al. state that {open_quotes}all [patients] had characteristic findings in their physical examinations, including... evidence of foot sores that were slow to heal, or amputated limbs related to the poorly healing foot ulcers,{close_quotes} it suggests that a different diagnosis is more appropriate. In our experience collecting data on >950 individuals in >60 CMT1, CMT2, CMTX and CMT4 families, we have not seen foot ulcers, osteomyelitis, or amputations. Ulcerations leading to osteomyelitis and amputations are usually associated with severe sensory neuropathies. 16 refs., 1 tab.
The Futility of Walls: How Traveling Corporations Threaten State Sovereignty

Inversions — mergers in which one firm merges with another abroad to avoid taxes in its home country — have spread as globalization has reduced many of the transactional costs associated with relocating. As firms acquire the power to choose the laws that govern them, they challenge the sovereignty of nation-states, who find their ability to tax and regulate firms depleted. States and firms compete in a game of cat and mouse to adapt to this new global reality. The subversion of state power by these firms reveals the futility of walls, both literal and regulatory. This Essay describes the phenomenon of these “traveling corporations” and analyzes several remedies that could limit future mergers. We conclude by arguing that inversions provoke deglobalization and yet may continue to flourish despite it as firms take the lead in dictating global norms.
Hu Shi’s Model of Rhetorical Pragmatic Argumentation

ABSTRACTDuring China’s Republican Period, scholar and reformer Hu Shi advanced a rhetorical pragmatic project for democratic reform. In this essay, I argue that the dissertation Hu wrote under the ...
Importance and feasibility of an adapted set of implementation strategies in schools

Implementation strategies are methods or techniques used to enhance the adoption, implementation, and sustainment of a new program or practice. Recent studies have facilitated implementation strategy prioritization by mapping strategies based on their feasibility and importance, but these efforts have not been replicated across distinct service delivery contexts. The aim of the current project was to evaluate the feasibility and importance of an education-adapted taxonomy of implementation strategies and to directly compare feasibility and importance ratings to the original Expert Recommendations for Implementing Change (ERIC) taxonomy, the leading compilation of implementation strategies in healthcare. A sample of 200 school-based consultants who support social, emotional, and mental health services provided ratings of feasibility and importance for each of the 75 strategies included in the adapted School Implementation Strategies, Translating ERIC Resources (SISTER) compilation. Results identified strategies rated as: (a) both feasible and important, (b) important but not feasible, (c) feasible but not important, and (d) neither feasible nor important. When mapped onto scatterplots using feasibility and importance ratings, comparison of ERIC and SISTER ratings indicated that approximately one third of the strategies shifted from one quadrant of the feasibility and importance axis to another. Findings demonstrate the value of efforts to adapt and generalize existing implementation products to novel service settings, such as schools. Additionally, findings assist implementation researchers and practitioners in prioritizing the selection of actionable and practically relevant implementation strategies to advance the quality of school mental health services.
NaF rinse and dentifrice concentrations on enamel lesion demineralization.

Purpose To compare the in vitro effectiveness of two mouthrinses containing different concentrations of NaF to reduce enamel lesion demineralization. Methods Nine extracted caries-free molars were selected and cleaned. The teeth were painted with acid resistant varnish, leaving a 1 mm × 4 mm window exposed. The teeth were cycled in a demineralizing solution at pH 4.5 for a total for 96 hours. The teeth were sectioned longitudinally through the unpainted window using a hard-tissue microtome, producing 96 sections. The sections were measured and photographed under polarized light microscopy using water and Thoulet's 1.47 as imbibing mediums. Six treatment groups were randomly created: (A) water control group, (B) 0.05% rinse group once a day (C) 0.02% rinse group twice a day, (D) 1,500 ppm paste group used twice a day, (E) combination group containing 0.05% rinse once a day, and 1,500 ppm paste twice a day, and (F) combination group containing 0.02% rinse and 1,500 ppm paste twice a day. A 10-day cycling protocol was carried out. All sections were then re-measured and re-photographed. A statistical analysis was performed to detect any differences between pre- and post-treatment groups. Results There was a statistically significant difference in lesion depth between the water control group and the 1,500 ppm paste group as well as the 0.05% rinse in combination with 1,500 ppm paste group (P= 0.0184). No statistically significant differences were found between the control group and any other groups. A statistically significant difference was found in lesion area between the two rinse groups alone and the 1,500 ppm paste group, as well as the 0.05% rinse in combination with the 1,500 ppm paste group (P= 0.0002). An analysis of the results suggested that both rinse concentrations performed equally well in reducing lesion demineralization when used alone. However, only the 0.05% rinse used in combination with 1,500 ppm paste decreased lesion demineralization as compared to the water control group, and was equally as effective as the 1,500 ppm paste alone. Clinical significance Within the limitations of this in vitro study, it was found that a fluoride containing dentifrice (1,500 ppm) and a combination of a fluoride containing dentifrice (1,500 ppm) and a 0.05% (210 ppm) fluoride rinse were more effective at reducing demineralization of enamel lesions than sodium fluoride rinses at concentrations of 0.02% and 0.05% alone or the combination of 0.02% NaF rinse with fluoride toothpaste.
Socioeconomic and Demographic Variation in Insurance Coverage Among Patients With Head and Neck Cancer After the Affordable Care Act.

Importance Health insurance status has a significant association with early diagnosis and stage at presentation, which are the most important predictors of survival among patients with head and neck cancer (HNC). Literature on the association of the Patient Protection and Affordable Care Act (ACA) with changes in insurance status among patients with HNC remains limited. To our knowledge, no studies have evaluated changes in insurance rates across sociodemographic subgroups of patients with HNC. Objective To assess the association of the implementation of the ACA with insurance status across socioeconomic and demographic subpopulations of patients with HNC. Design, Setting, and Participants A retrospective cohort study using data from the National Cancer Database (NCDB), a hospital-based cancer registry (2011-2015) for adults diagnosed with a malignant primary HNC was carried out. The analyses were conducted from November 2018 through December 2018. Main Outcomes and Measures Changes in the percentage of patients with insurance. Results A total of 131 779 patients with HNC were identified in the pre-ACA (77 071) and post-ACA (54 708) periods. Overall, 98 207 (74.5%) participants were men and 33 572 (25.5) were women, with 73 124 (55.5%) being aged between 50 to 64 years. There was a 2.68 percentage point decrease (PPD) (95% CI, 2.93-2.42) in the percentage of patients with HNC without insurance from the pre-ACA to the post-ACA period. Changes in the percentage of uninsured patients varied significantly by age, with the largest reduction in uninsured status among patients with HNC aged 18 to 34 years (5.12 PPD; 95% CI, 3.18-7.06) and the smallest reduction in uninsured among those aged 65 to 74 years (0.24 PPD; 95% CI, 0.03-0.45). There was a significantly greater reduction in uninsured status in low-income zip codes (3.45 PPD; 95% CI, 2.76-4.14) than in high-income zip codes (1.99 PPD; 95% CI, 1.63-2.36). Conclusions and Relevance There was a significant association between ACA implementation and percentage decrease in uninsured patients. Young adults and those residing in low-income zip codes experienced a significantly higher rate of insurance uptake compared with older adults and residents of high-income areas. This suggests that coverage expansions enacted through the ACA are not only associated with increased access to care among the broader HNC population, but that they may also yield a greater benefit among subpopulations with historically limited insurance coverage.
Spatial and temporal trends in physiological biomarkers of adult eastern oysters, Crassostrea virginica, within an urban estuary

Abstract Heavy metal contamination and water quality may alter reproductive capacity of oysters in highly urbanized, eutrophic ecosystems. This study assessed physiological biomarkers and heavy metal body burdens in adult oysters, Crassostrea virginica, placed at a highly urban and reference site. Condition index and Vitellogenin-like proteins were significantly different between sites, but protein concentration and activity of the electron transport system were not. Accumulation of Cd and Hg occurred at both sites, and Cd body burden was greater at the urban site. There was a negative relationship between condition index and Cd body burden at the urban site, while no relationship was found between physiological biomarkers and metal burden at the reference site. The results suggest that oyster condition and reproductive potential may be negatively influenced by the biotic and abiotic factors typically found within urban, eutrophic ecosystems.
Delegation with Technology Migration: An Empirical Analysis of Mobile Virtual Network Operators

This study examines the impact of mobile virtual network operators (MVNOs) on the performance of mobile network operators (MNOs) in the presence of overlapping generations of wireless mobile technologies (2G and 3G). MVNOs distribute MNOs’ mobile services to customers without owning any spectrum or network infrastructures. Some MVNOs are wholly owned by MNOs with a revenue-sharing mechanism (branded MVNOs), while others operate through wholesale agreements with MNOs (third-party MVNOs). By focusing on the impact of MVNOs on MNOs’ performance, we investigate governance issues, e.g., delegation vs. ownership, in value chains with overlapping generations of technologies. Using proprietary data, we design a quasi-experiment to analyze branded and third-party MVNOs. First, we use a sliding window adjusted difference-in-differences model as an exploratory analysis. Next, in the main analysis, we employ dynamic propensity score matching, which allows us to explore the variation of the impact over time. We find that branded and third-party MVNO launches both increase an MNO's 2G market share, whereas its 3G market share increases only with a branded MVNO launch. In addition, the positive effects diminish over time for branded MVNOs, but strengthen for third-party MVNOs. These results suggest that, when launching MVNOs, managers should decide on value chain governance based on technology migration and market maturity. If the focus is to quickly seize the market share with new mobile technologies, branded MVNOs are preferred. On the other hand, if the focus is to expand in a niche, mature market, delegating to third-party MVNOs may be more effective.
Reporting and Availability of COVID-19 Demographic Data by US Health Departments (April to October 2020): Observational Study.

Background: There is an urgent need for consistent collection of demographic data on COVID-19 morbidity and mortality and sharing it with the public in open and accessible ways. Due to the lack of consistency in data reporting during the initial spread of COVID-19, the Equitable Data Collection and Disclosure on COVID-19 Act was introduced into the Congress that mandates collection and reporting of demographic COVID-19 data on testing, treatments, and deaths by age, sex, race and ethnicity, primary language, socioeconomic status, disability, and county. To our knowledge, no studies have evaluated how COVID-19 demographic data have been collected before and after the introduction of this legislation. Objective: This study aimed to evaluate differences in reporting and public availability of COVID-19 demographic data by US state health departments and Washington, District of Columbia (DC) before (pre-Act), immediately after (post-Act), and 6 months after (6-month follow-up) the introduction of the Equitable Data Collection and Disclosure on COVID-19 Act in the Congress on April 21, 2020. Methods: We reviewed health department websites of all 50 US states and Washington, DC (N=51). We evaluated how each state reported age, sex, and race and ethnicity data for all confirmed COVID-19 cases and deaths and how they made this data available (ie, charts and tables only or combined with dashboards and machine-actionable downloadable formats) at the three timepoints. Results: We found statistically significant increases in the number of health departments reporting age-specific data for COVID-19 cases (P=.045) and resulting deaths (P=.002), sex-specific data for COVID-19 deaths (P=.003), and race- and ethnicity-specific data for confirmed cases (P=.003) and deaths (P=.005) post-Act and at the 6-month follow-up (P<.05 for all). The largest increases were race and ethnicity state data for confirmed cases (pre-Act: 18/51, 35%; post-Act: 31/51, 61%; 6-month follow-up: 46/51, 90%) and deaths due to COVID-19 (pre-Act: 13/51, 25%; post-Act: 25/51, 49%; and 6-month follow-up: 39/51, 76%). Although more health departments reported race and ethnicity data based on federal requirements (P<.001), over half (29/51, 56.9%) still did not report all racial and ethnic groups as per the Office of Management and Budget guidelines (pre-Act: 5/51, 10%; post-Act: 21/51, 41%; and 6-month follow-up: 27/51, 53%). The number of health departments that made COVID-19 data available for download significantly increased from 7 to 23 (P<.001) from our initial data collection (April 2020) to the 6-month follow-up, (October 2020). Conclusions: Although the increased demand for disaggregation has improved public reporting of demographics across health departments, an urgent need persists for the introduced legislation to be passed by the Congress for the US states to consistently collect and make characteristics of COVID-19 cases, deaths, and vaccinations available in order to allocate resources to mitigate disease spread.
BET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma

Richter Transformation (RT) develops in CLL as an aggressive, therapy-resistant, diffuse large B cell lymphoma (RT-DLBCL), commonly clonally-related (CLR) to the concomitant CLL. Lack of available pre-clinical human models has hampered the development of novel therapies for RT-DLBCL. Here, we report the profiles of genetic alterations, chromatin accessibility and active enhancers, gene-expressions and anti-lymphoma drug-sensitivity of three newly established, patient-derived, xenograft (PDX) models of RT-DLBCLs, including CLR and clonally-unrelated (CLUR) to concomitant CLL. The CLR and CLUR RT-DLBCL cells display active enhancers, higher single-cell RNA-Seq-determined mRNA, and protein expressions of IRF4, TCF4, and BCL2, as well as increased sensitivity to BET protein inhibitors. CRISPR knockout of IRF4 attenuated c-Myc levels and increased sensitivity to a BET protein inhibitor. Co-treatment with BET inhibitor or BET-PROTAC and ibrutinib or venetoclax exerted synergistic in vitro lethality in the RT-DLBCL cells. Finally, as compared to each agent alone, combination therapy with BET-PROTAC and venetoclax significantly reduced lymphoma burden and improved survival of immune-depleted mice engrafted with CLR-RT-DLBCL. These findings highlight a novel, potentially effective therapy for RT-DLBCL.
The Fourth's Estate

The news industry in the United States faces a funding crisis because the tech giants, particularly Google and Facebook, have acceded to the advertising monopolies once enjoyed by the newspaper industry itself. Despite the best efforts of the news industry to paint the tech giants as rapacious monopolists, however, these big firms won by offering better services to users and better advertising opportunities to advertisers, so breakup is not appropriate, and is unlikely to restore the news industry’s profits anyway, because search and social media will remain better ad distribution channels than the news. A better solution to the funding crisis would be for government to divide the advertising distribution market, reallocating to the news industry some of the ad impressions taken from it by the tech giants. This indirect, property-rights-based approach to government subsidization would address concerns, however misguided, that direct subsidization a la the BBC might lead to political interference in newsgathering. An important collateral benefit would be the opportunity to limit the total amount of advertising consumed by the economy, by licensing fewer total ad impressions than are currently consumed. This would lead to an efficiency gain because advertising’s information function has withered in the information age, making advertising almost entirely manipulative in character, and therefore a threat to consumer sovereignty. Ad distribution revenues would not fall, however, because advertising cancels—firms advertise because others advertise, not because advertising increases sales—and so firms will bid up prices in proportion to the decline in available impressions. The proposed division and reduction of the advertising market would be constitutional because the purpose of First Amendment commercial speech doctrine is to protect consumer sovereignty, and restrictions on advertising that has become almost entirely manipulative in the information age do that.
The use of random search and genetic algorithms to optimize stochastic robustness functions

Stochastic robustness synthesis is a framework for designing practical compensators. It uses Monte Carlo simulation to evaluate the quality of control laws, and it searches a parameter space for the best law. Search methods must find the global minimum of a probabilistic design criterion function, ideally with minimum numbers of Monte Carlo evaluations. This paper examines two approaches to minimizing the probabilistic function: random search and a genetic algorithm. The genetic algorithm is similar to previously published algorithms but has several modifications to improve its performance, most notably a clustering analysis at the beginning of each generation. Statistical tools are incorporated into the search algorithms, allowing intelligent search decisions to be based on the "noisy" Monte Carlo estimates. Performance of the two methods is demonstrated by application to a 24-dimensional test function. The genetic algorithm is shown to be significantly better than the random search for this application. The genetic algorithm is then used to design compensators for a benchmark problem and produces control laws with excellent levels of stability and performance robustness.
Wideband optical parametric frequency comb applications in real-time signal processing

A set of phase-locked wideband optical parametric frequency combs are presented as a core of a photonics aided signal processor allowing for the real-time spectral analysis of a 10 Gbps data stream.
Categorical Abstract Algebraic Logic Metalogical Properties

Metalogical properties that have traditionally been studied in the deductive system context (see, e.g., [21]) and transferred later to the institution context [33], are here formulated in the π-institution context. Preservation under deductive equivalence of π-institutions is investigated. If a property is known to hold in all algebraic π-institutions and is preserved under deductive equivalence, then it follows that it holds in all algebraizable π-institutions in the sense of [36].
Spermiogenesis and exchange of basic nuclear proteins are impaired in male germ cells lacking Camk4.

Ca2+/calmodulin-dependent protein kinase IV (Camk4; also known as CaMKIV), a multifunctional serine/threonine protein kinase with limited tissue distribution, has been implicated in transcriptional regulation in lymphocytes, neurons and male germ cells1,2,3,4,5,6. In the mouse testis, however, Camk4 is expressed in spermatids and associated with chromatin and nuclear matrix7. Elongating spermatids are not transcriptionally active8, raising the possibility that Camk4 has a novel function in male germ cells. To investigate the role of Camk4 in spermatogenesis, we have generated mice with a targeted deletion of the gene Camk4. Male Camk4−/− mice are infertile with impairment of spermiogenesis in late elongating spermatids. The sequential deposition of sperm basic nuclear proteins on chromatin is disrupted, with a specific loss of protamine-2 and prolonged retention of transition protein-2 (Tnp2) in step-15 spermatids. Protamine-2 is phosphorylated by Camk4 in vitro, implicating a connection between Camk4 signalling and the exchange of basic nuclear proteins in mammalian male germ cells. Defects in protamine-2 have been identified in sperm of infertile men, suggesting that our results may have clinical implications for the understanding of human male infertility.
A Combustion Test Program to Establish Design Criteria for Liquid-Hydrogen-Fueled Space Vehicles

Recent development of liquid hydrogen as a fuel for space vehicles has created a requirement to establish design criteria which will eliminate potential hazards due to propellant leakage or venting into confined areas.
Aging and the Prevalence of Cardiovascular Disease Risk Factors in Older American Indians: The Strong Heart Study

OBJECTIVES: To describe longitudinal changes in the prevalence of major cardiovascular disease (CVD) risk factors in aging American Indians. DESIGN: Population-based ongoing epidemiological study. SETTING: The Strong Heart Study is a study of CVD and its risk factors. Standardized examinations were repeated in 1993 to 1995 and again in 1997 to 1999. PARTICIPANTS: A diverse cohort of 4,549 American Indians aged 45 to 74 at the initial examinations in 1989 to 1991. MEASUREMENTS: Changes in the prevalence of hypertension, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), current smoking, and type 2 diabetes mellitus. RESULTS: The prevalence of hypertension rose rapidly and steadily with aging. A nonsignificant decrease in LDL-C was seen in men, and men and women initially had rapid increases in the prevalence of low HDL-C. The prevalence of smoking decreased, but the prevalence of diabetes mellitus continued to rise for men and women. CONCLUSION: Overall, unfavorable changes in CVD risk factors were seen in the aging participants and will likely be reflected in worsening morbidity and mortality.
Three-Parameter Probability Distributions

The lognormal, Weibull, Pearson type 3, and log Pearson type 3, each a three-parameter distribution, were evaluated in a generalized fashion in terms of the dimensionless variate K (K=X/υ\N\dx, in which X equals randon variable, and υ\N\dn equals its mean) which has a population mean of unity. The bounds of the distributions, areas of the portions of distributions in the negative region of variate when they enter such regions, and the differences in some important quantiles among the four distributions, are presented. The four distributions become less applicable for hydrologic frequency analysis as they deviate more and more from their two-parameter counterparts (lognormal in the case of log Pearson). When they have well-applicable properties, their quantile values differ little for some or all distributions indicating that choice of a distribution makes little difference. Some guidelines are provided for selecting the best applicable distribution for a given hydrologic sample.
Chemical relaxation of cyclic enzyme systems. V. The Michaelis and Henri schemes.

Abstract The Michaelis and the Henri schemes represent alternate models, which cannot be differentiated by steady state kinetics. Viale showed that presteady state kinetics can differentiate between the models. He derived further that differentiation between the two models on the basis of kinetics of chemical relaxation is not possible. It is shown here that differentiation between the two alternate models is possible, if thermodynamics of chemical relaxation is considered in addition. Further refinements are added by taking into account the relations between observed signals and individual concentration changes.
Strong Intermolecular Forces: Covalent and Coulomb Interactions

This chapter discusses covalent and Coulomb interactions as the strong forces operating within molecules. Covalent forces tightly bind the atoms together within the molecule. They are of short range, that is, they operate over very short distances of the order of interatomic separations. Covalently bonded atoms make up molecules and crystals with well-defined structures that cannot normally melt or liquify without totally breaking the bonds. They tend to sublimate, decompose, or undergo a chemical reaction above some temperature rather than going through the conventional solid-liquid-gas states that are characteristic of physically bonded molecules. This chapter starts with a discussion on covalent or chemical bonding forces, and the differences between physical and chemical bonds. The chapter then explains Coulomb forces (charge–charge interactions). Concepts of ionic crystals and reference states are explained. The chapter gives detailed discussion on the Born energy as well as solubility of ions in different solvents. The chapter concludes with presenting computer simulations and integral equations of many-body systems.
Distributed target tracking

A decentralized tracking technique of a target in clutter is discussed. The coordinator must reconstruct the trajectory of a moving object based on the return histories of N geographically distributed sensors. The coordinator can only access the (local) statistics produced by local processing of the sensors' return histories, not the sensors' returns themselves. The local processing models may be different from the coordinator's models of the distributed observation dynamics as long as these local models meet algebraic constraints. To account for the uncertainties in the origin of the sensors' returns, the probabilistic data association technique is used. >
Concluding Remarks at the 12th Potsdam Cosmology Workshop

Research in cosmology traditionally divided into two separate lines. On the one hand was the search for initial conditions: the cosmological parameters H, Omega, Omega_b, and Lambda, and the power spectrum P(k). On the other hand was the study of the formation and evolution of structures, from globular-cluster sized objects to large-scale structures. These lines of investigation are now becoming increasingly intertwined, and this tendency manifested itself in this conference. Following is my personal perspective on where we stand today. I also discuss some technological developments that I think will affect the field. My concluding remarks are very informal. They are not a review paper, and I omit references altogether rather than give a partial list.
Human Factors in Digital Telecommunications

To assure maximum effectiveness, digital system design parameters must be chosen to optimize human perception. An experimental methodology is described which relates human visual performance and electronic design parameters. These relationships are then used to show how to specify optimal encoder design parameters. To illustrate this experimental procedure, tradeoffs were determined for a digitally encoded television system. These relationships were determined by measuring subjects' minimum perceptible acuities for various length lines and spatial orientations. Visual performance was determined for points along four noise-bandwidth curves representing different information capacities and system costs. Optimum system performance was achieved by maximizing the sampling frequency (bandwidth) of the encoder.
Los círculos de calidad en una estrategia corporativa antisindical: un estudio de caso

Este estudio de caso explora la manera como la tecnica organizacional de los circulos de calidad (CC) fue utilizada por una compania del suroeste de los Estados Unidos como parte de su estrategia antisindical global durante una campana de organizacion de un sindicato. El autor explora como la organizacion del proceso social de produccion dentro de esta tecnica de relaciones humanas de grupos pequenos, un componente comun de muchos programas de calidad de vida en el trabajo en centenares de industrias norteamericanas, aumento el control que los supervisores y gerentes tenian sobre la actitud y el comportamiento de los empleados durante la campana de organizacion de un importante sindicato. Este tipo de tecnica de "gerencia participativa" sirvio al proposito corporativo de permanecer sin sindicato al afectar elementos vitales de la cultura de la planta. Especificamente, el programa de CC permitio a la gerencia ejercer un control creciente sobre la seleccion y la socializacion de la fuerza de trabajo asi como sobre las relaciones de trabajo y los modelos de liderazgo que surgieron en la planta durante la campana. El autor sostiene que en vez de ser una tecnica escogida para la planta basicamente en razon de su potencial de democratizacion y beneficios de productividad, el programa de circulo de calidad fue escogido especificamente como una alternativa a la sindicalizacion de la planta y, como tal, se desarrollo como una efectiva y sofisticada herramienta para "reventar al sindicato" durante la campana.
Quorum Sensing Protects Pseudomonas aeruginosa against Cheating by Other Species in a Laboratory Coculture Model

ABSTRACT Many species of bacteria use a cell-cell communication system called quorum sensing (QS) to coordinate group activities. QS systems frequently regulate the production of exoproducts. Some of these products, such as proteases, are “public goods” that are shared among the population and vulnerable to cheating by nonproducing members of the population. Because the QS system of the opportunistic pathogen Pseudomonas aeruginosa regulates several public goods, it can serve as a model for studying cooperation. Bacteria also commonly regulate antimicrobial production through QS. In this study, we focused on the hypothesis that QS-regulated antimicrobials may be important for P. aeruginosa to protect against cheating by another bacterial species, Burkholderia multivorans. We assessed laboratory cocultures of P. aeruginosa and B. multivorans and investigated the importance of three P. aeruginosa QS-regulated antimicrobials, hydrogen cyanide, rhamnolipids, and phenazines, for competition. We found that P. aeruginosa dominates cocultures with B. multivorans and that the three antimicrobials together promote P. aeruginosa competitiveness, with hydrogen cyanide contributing the greatest effect. We show that these QS-regulated antimicrobials are also critical for P. aeruginosa to prevent B. multivorans from cheating under nutrient conditions where both species require a P. aeruginosa quorum-regulated protease for growth. Together our results highlight the importance of antimicrobials in protecting cooperating populations from exploitation by other species that can act as cheaters. IMPORTANCE Cooperative behaviors are threatened by social cheating, wherein individuals do not produce but nonetheless benefit from shared public goods. Bacteria have been shown to use several genetic mechanisms to restrain the emergence of cheaters from within the population, but public goods might also be used by other bacterial species in the vicinity. We demonstrate that a public good produced by Pseudomonas aeruginosa can be used by another species, Burkholderia multivorans, to obtain carbon and energy. We also show that P. aeruginosa antimicrobials that are coregulated with the public good prevent invasion by the cheating species. Our results demonstrate that cross-species cheating can occur and that coregulation of public goods with antimicrobials may stabilize cooperative behavior in mixed microbial communities.