cssi/SciSciGPT-SciSciNet huggingface dataset:
Blocking Indolamine-2,3-Dioxygenase Rebound Immune Suppression Boosts Antitumor Effects of Radio-Immunotherapy in Murine Models and Spontaneous Canine Malignancies.

Purpose: Previous studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing antitumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically upregulate immunosuppressive pathways, a phenomenon we term “rebound immune suppression,” limiting clinical responses. We further hypothesized that the immunosuppressive enzyme indolamine-2,3-dioxygenase (IDO) is a mechanism of rebound immune suppression and that IDO blockade would improve immunotherapy efficacy. Experimental Design: We examined the efficacy and immunologic effects of a novel triple therapy consisting of local radiotherapy, intratumoral CpG, and systemic IDO blockade in murine models and a pilot canine clinical trial. Results: In murine models, we observed marked increase in intratumoral IDO expression after treatment with radiotherapy, CpG, or other immunotherapies. The addition of IDO blockade to radiotherapy + CpG decreased IDO activity, reduced tumor growth, and reduced immunosuppressive factors, such as regulatory T cells in the tumor microenvironment. This triple combination induced systemic antitumor effects, decreasing metastases, and improving survival in a CD8+ T-cell–dependent manner. We evaluated this novel triple therapy in a canine clinical trial, because spontaneous canine malignancies closely reflect human cancer. Mirroring our mouse studies, the therapy was well tolerated, reduced intratumoral immunosuppression, and induced robust systemic antitumor effects. Conclusions: These results suggest that IDO maintains immune suppression in the tumor after therapy, and IDO blockade promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation. Clin Cancer Res; 22(17); 4328–40. ©2016 AACR . This article is featured in Highlights of This Issue, [p. 4275][1] [1]: /lookup/volpage/22/4275?iss=17
Uncovering the Roles of Oxygen in Cr(III) Photoredox Catalysis

A combined experimental and theoretical investigation aims to elucidate the necessary roles of oxygen in photoredox catalysis of radical cation based Diels–Alder cycloadditions mediated by the first-row transition metal complex [Cr(Ph2phen)3]3+, where Ph2phen = bathophenanthroline. We employ a diverse array of techniques, including catalysis screening, electrochemistry, time-resolved spectroscopy, and computational analyses of reaction thermodynamics. Our key finding is that oxygen acts as a renewable energy and electron shuttle following photoexcitation of the Cr(III) catalyst. First, oxygen quenches the excited Cr3+* complex; this energy transfer process protects the catalyst from decomposition while preserving a synthetically useful 13 μs excited state and produces singlet oxygen. Second, singlet oxygen returns the reduced catalyst to the Cr(III) ground state, forming superoxide. Third, the superoxide species reduces the Diels–Alder cycloadduct radical cation to the final product and reforms oxygen. We...
Pentaketide metabolites of Verticillium dahliae. II. Accumulation of naphthol derivatives by the aberrant-melanin mutant BRM-2.

The quinones, juglone, 2-hydroxyjuglone and 3-hydroxyjuglone, and the tetralones, (+)-3,4-dihydro-4,8-dihydroxy-1(2H) naphthalenone and (-)-cis-3,4-dihydro-3,4,8-trihydroxy-1 (2H) naphthalenone wer...
Fiducial marker application method for position alignment of in situ multimodal X-ray experiments and reconstructions

An evolving suite of X-ray characterization methods are presently available to the materials community, providing a great opportunity to gain new insight into material behavior and provide critical validation data for materials models. Two critical and related issues are sample repositioning during an in situ experiment and registration of multiple data sets after the experiment. To address these issues, a method is described which utilizes a focused ion-beam scanning electron microscope equipped with a micromanipulator to apply gold fiducial markers to samples for X-ray measurements. The method is demonstrated with a synchrotron X-ray experiment involving in situ loading of a titanium alloy tensile specimen.
Take Me to Your Leader: The Power of Place in Prehistoric Anatolian Settlements

During the Early Bronze Age in central Anatolia (ca. 3000-2000 b.c.e.), a change in the residential location of houses belonging to elites and/or leaders occurred. In the fourth and early third millennia, various sites feature settlement plans in which village leaders, or higher-ranking residents, inhabited homes in close proximity to main gates. By the later third millennium the trend was to locate homes away from the gates, sometimes behind physical barriers. These changes are concomitant with several plateauwide phenomena, including increases in population and settlement size at emerging regional centers, and the establishment of international trade networks. The reasons underlying this residential adjustment lie in the need for protection against outsiders while also desiring to impress both outsiders and those living within the community. An additional motivating factor, however, was the erosion of trust between community members, i.e., a “fear of the insiders” factor as societies experienced interna...
Proust, the Metaxy, and Transcendence

This paper explores how Marcel Proust, in his long novel *In Search of Lost Time,* presents at explicit length an account of human existence that shows it to be a simultaneous participation in both time and eternity, and that one of Proust's intentions is to show, in the mode of literary art, that any human existence and any work of profound literary art can only be revealed to have a unified narrative meaning, as a whole, because human conscious existence participates in eternal reality. In this regard, Proust presents a vision of existence that corresponds to Eric Voegelin's philosophical account of human life as "existence in the metaxy," that is to say, existence as always lived in the "in-between" of immanence (world) and transcendence (eternity). On the other hand, Proust is careful not to "personalize" transcendence, the dimension of eternity, that he affirms humans to participate in - he never refers to it as "God." Some reasons for this, drawn from examination of the novel's long account of Proust's development (though Proust and the novel's Narrator are not precisely identical), are explored. They include Proust's experiences of and descriptions of "love," and his confessed unconcern for any "notion of justice." Given the Proustian existential development and anthropology both implicit and explicit in the novel, it is not surprising to find that experiences of "the eternal"--though conducive in the novel to experiences of deep "joy" - are never experiences of an "I-Thou" encounter with a divine reality. None of this detracts from the importance of Proust's masterly "modern" presentation of human life as only making sense if we understand it as a simultaneous participation in worldly and timeless meaning.
446 CONCEPTIONS OF MOTHER-TO-CHILD TRANSMISSION OF HIV AMONG WOMEN FROM THE NSO TRIBE OF NORTHWESTERN CAMEROON.

Background The northwestern province of Cameroon has the highest rate of HIV infection in the country with 8.7% of adults infected. An estimated 20-30% of women between the ages of 15 and 30 are infected. The high rate of HIV among women of childbearing age makes mother-to-child transmission (MTCT) of HIV a major concern. The goal of the research was to explore conceptions of MTCT of HIV among women in the context of differing access to HIV testing during pregnancy. Study Design and Methods 62 semi-structured, open-ended interviews with Nso women from 9 villages in the northwest province. The villages were grouped based on access to HIV testing during pregnancy: high access (N = 23), medium access (N = 21), low access (N = 18). All of the interviews were conducted with a local interpreter and each of the participants was asked to respond freely to questions about their knowledge and beliefs about MTCT of HIV. Data were recorded by hand during the interview by the author. Results Women from all access groups stressed the importance of antenatal care mainly to check the position of the baby in the womb. All women said they would be willing to take an HIV test and receive the results during pregnancy, but very few said they would pay extra money or travel extra distance just for an HIV test. Knowledge about MTCT of HIV was high in all groups. Witchcraft was almost always simultaneously cited as a way for infants to acquire HIV and was not correlated to a low level of awareness of or knowledge about MCTC of HIV. Conclusions Despite high awareness of and knowledge about MTCT of HIV and high perceived importance of antenatal care, perceived importance of HIV testing during pregnancy was low, indicating that including HIV testing in the cost of antenatal care at rural health centers would be an effective way to increase the amount of women getting tested for HIV during pregnancy.
The Underlying Chemical Nature of Life

All known life depends on molecular interactions of a small number of different polymers. The two main groups are polynucleotides, such as DNA and various types of RNA, and polypeptides that comprise most of the catalysts controlling the rates of various biochemical reactions essential to maintaining life. DNA is the site of storage of the genetic information, coded as sequences of a small number of nucleotide monomers attached to one another in particular orders. DNA is transcribed in cells to messenger RNA which then serves as a template for manufacture of proteins, mediated by a small RNA molecule known as transfer RNA. The proteins can then modulate a large variety of metabolic reactions to release energy and to direct the synthesis of important cell components. These complicated interactions highlight the complexity of even the simplest forms of extant life. Presumably the emergence of life from a non-living prebiotic “soup” of potential biomolecules must have had some kind of simpler, but no longer present form. Phylogenetic trees showing the relatedness of various organisms can be constructed using sequences of nucleotides found in certain vital RNA molecules common to all living forms. Such trees clearly demonstrate the close relationship of macroscopic multicellular organisms like plants and animals, especially compared to the much more distant relationships not only between them and simpler forms such as bacteria, but even between different groups of bacteria. It is clear that the common ancestor of all living forms was at least superficially similar to some kind of bacterium, but also that the first “living entity” most likely was even simpler in makeup. The transition from a prebiotic soup to life is a critical, but mostly hidden step in the history of life.
Generalized linear models with covariate measurement error and unknown link function

Generalized linear models (GLMs) with error-in-covariates are useful in epidemiological research due to the ubiquity of non-normal response variables and inaccurate measurements. The link function in GLMs is chosen by the user depending on the type of response variable, frequently the canonical link function. When covariates are measured with error, incorrect inference can be made, compounded by incorrect choice of link function. In this article we propose three flexible approaches for handling error-in-covariates and estimating an unknown link simultaneously. The first approach uses a fully Bayesian (FB) hierarchical framework, treating the unobserved covariate as a latent variable to be integrated over. The second and third are approximate Bayesian approach which use a Laplace approximation to marginalize the variables measured with error out of the likelihood. Our simulation results show support that the FB approach is often a better choice than the approximate Bayesian approaches for adjusting for mea...
Assessing Cyberbullying in Higher Education.

This project aims to expose information educators to various aspects of cyberbullying for the purpose of policy development in an environment of higher education. The preponderance of nation-wide research on cyberbullying is concentrated on adolescents; such efforts in college campuses are limited to individual endeavors. Cyberbullying research on college campuses lacks a unified definition of the concept. Although the states mandated most school districts to develop and enact some sort of policy, the law is silent on the college level cyberbullying. According to the literature, cyberbullying is reserved for adolescents; however, cyber-harassment or cyberstalking are related to adults. While cyberbullying shares with conventional bullying intimidation, aggression, and harm, it is unique because 1) the encounter is not face-to-face; 2) the perpetrator can employ varied means (e.g., cellphones, texts, blogs, Internet, social media, etc.), and 3) the act can be undisclosed. The data was collected from a random sample of 511 students (out of a student population of approximately 6,000) in a Midwestern town by employing self-administered questionnaire. It was found that engagement with different social network groups and online communications with those with questionable identity are good predictor of increased vulnerability to the risks of being victimized. The data suggests being victimized leads to victimization. Although males differ from females in terms of the type and the extent of cyberbullying, no significant difference was found among the categories of student status or their class ranks.
Germany as Number Two

The distinctions between politics and economics, and between domestic and foreign policy, have always been more blurred in the Federal Republic than in most other countries. At the same time, German decision makers have consistently used economic policy for political purposes, which explains why Germany's economic success is evaluated by Germany's allies as well as by its opponents mostly in political rather than economic terms. During the 1950s, there existed a striking correspondence between the principles of Germany's domestic economic order and the principles of the international economic order, which were guided by the United States and supplemented by the fledgling institutions of West European integration. These complementarities unraveled in the 1960s and 1970s, during a period when increasing economic and monetary interdependence was beginning to supplant, at least in part, such measures of power as military capacity. As a consequence, international elements of power were shifted in areas where the major sources of German capacity are located, creating opportunities as well as difficulties for the Federal Republic's diplomacy. Depending on the future evolution of the European political order, German economic capacity can be expected to remain an important component of the Federal Republic's foreign policy efforts.
Abstract LB-102: A pro-proliferative function of centriole duplication regulator, polo-like kinase-4 in human melanoma

Malignant melanoma is one of the deadliest forms of skin cancer that remains resistant to existing therapeutic strategies. According to the SEER (Surveillance, Epidemiology, and End Results) program database of the National Cancer Institute, the 5-year survival rate for metastatic melanoma is a dismal 16%. Further, of the seven most common cancers in the USA, melanoma is the only neoplasm with constantly increasing incidence. Therefore, it is important to intensify our efforts to better-understand the genetics and biology of melanoma. This may lead to development of novel targets and biomarkers for management of this hard-to-treat neoplasm. This study was undertaken to determine the role and potential significance of polo-like kinase 4 (PLK4) in human melanoma. PLK4 is a serine/threonine kinase that has been shown to localize to centrioles and regulate centriole duplication during the cell cycle. While the potential role of PLK4 in cancer is beginning to be appreciated, there are evidence for its function as a tumor suppressor as well as tumor promoter. However, the role of PLK4 in melanoma is not known. Here, we employed in vitro and ex vivo experiments to determine the role of PLK4 in melanoma. Our data demonstrated that PLK4 was significantly overexpressed, both at mRNA and protein levels in human melanoma cells viz. A375, Hs294T, G361, 451Lu; when compared to the normal human epidermal melanocytes (NHEM). We also found a significant increase in PLK4 immunostaining in clinical melanoma tissues, compared to normal skin and nevus tissues. Further, treatment of melanoma cells with a selective small molecule PLK4 inhibitor, centrinone-B, was found to cause a significant decrease in the cell growth/viability and clonogenic survival in multiple melanoma cell lines. The observed anti-proliferative effects of centrinone-B were found to be accompanied with i) a G0/G1 phase arrest of cell cycle, and ii) induction of apoptosis, in human melanoma cells. Taken together, our study suggests a pro-proliferative role of PLK4 in human melanoma. Additional studies are ongoing in our laboratory to determine the functional significance of PLK4 in melanoma. We suggest that PLK4 should be further evaluated as a potential ‘druggable target’ and biomarker, for the management of melanoma. Citation Format: Maria Shabbir, Minakshi Nihal, Chandra K. Singh, B Jack Longley, Nihal Ahmad. A pro-proliferative function of centriole duplication regulator, polo-like kinase-4 in human melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-102.
Comparative study of connected vehicle simulators

Contemporary studies of Intelligent Transportation Systems (ITS) use simulations of vehicular and communications traffic, due to the ethical and practical infeasibility of conducting experiments on real transportation networks. Different simulators have been developed for modeling real-time vehicular mobility and inter-vehicular communication under varying traffic and roadway conditions. While most model the effect of mobility on communications, only a few simulate the impact of inter-vehicular communication on vehicular mobility. None, moreover, are implemented as parallel or distributed frameworks: an essential requirement for the study of ITS applications in large-scale urban environments. As a starting point for developing such a framework, one contemporary simulator, VNetInetSim, was tested to determine its behavior under large loads. Testing determined that VNetInetSim's memory usage and execution time increase exponentially in the number of simulated vehicles while remaining relatively constant under increased communication traffic.
Diamond Crystal for DACs

Characteristics of various types of diamonds are summarized and selection of a diamond for a diamond anvil cell (DAC) is discussed. A diamond crystal with little internal strain and few crystal defects must be selected for generating ultra high pressure. The selection of a diamond is also based on other factors, such as a need for transparency in ultraviolet or infrared for optical studies or a need for low luminescence for Raman studies. Synthetic type II a diamond is most appropriate for diamond anvils, because it has a high crystalline quality, high transparency and low luminescence.
Application of LOS microwave propagation data to channel modeling and outage prediction issues

Propagation data collected on a 99.4-km link that is part of the US Defense Communications System in Europe is discussed. Propagation data recorded during the 18-month experiment included received signal level on each of the two space diversity receivers, several measures of in-band power difference, and data from a dual-channel line-of-sight (LOS) channel probe. Despite the extensive research which has been conducted in the development of LOS channel models and in outage prediction methodology for digital microwave radio links, a number of technical issues remain. The application of an extensive LOS microwave propagation database to these issues is described. The nature of these unresolved technical issues is discussed, and additional propagation data relevant to the resolution of these issues is provided. >
Optical Properties of Small Gold Clusters Au8L82+ (L = PH3, PPh3): Magnetic Circular Dichroism Spectra

A theoretical study of the optical and electronic properties of small phosphine-protected centered gold clusters with gold core symmetry C3v was performed using density functional theory (DFT) and time-dependent density functional theory (TDDFT) methods. It is well-known that magnetic circular dichroism (MCD) spectroscopy yields more detailed information about electronic structure and optical properties with respect to optical absorption spectroscopy. In this work, we combine electronic absorption and MCD spectroscopy for gold nanoclusters to gain a better understanding of their electronic states. These results can be used to help with interpretation of the experimentally measured MCD spectra, which is a very complicated process, especially for low-symmetry systems. In the present paper, absorption and MCD spectra were calculated for ligand-protected gold clusters Au8(PPh3)82+ and Au8(PH3)82+, in addition to bare Au82+. The influence of the nature of the ligands on the optical properties of gold cluster w...
Extending the Work of Cowen and Fowles: A Historical Analysis of Kentucky Teacher Contracts:

We extend the work of Cowen and Fowles by examining contracts in Kentucky school districts with collective bargaining. Using document analysis, we sought to answer the following research question: ...
Titration of Medication and the Management of Suffering at the End of Life

When ventilator support is being withdrawn from a dying child, responsive titration of sedative medications by the ICU team can relieve suffering without anesthetizing the child completely or hastening death.
Assessment of Blood Flow Patterns Distal to Aortic Occlusion Using CT in Patients with Resuscitative Endovascular Balloon Occlusion of the Aorta.

Background Resuscitative endovascular balloon occlusion of the aorta (REBOA) is used to decrease hemorrhage below the level of aortic occlusion (AO); however, the amount of collateral blood flow below the level of occlusion is unknown. Our aim was to investigate blood flow patterns during complete AO in patients who underwent CT scan after REBOA. Study Design Between February 2013 and January 2017, patients who received REBOA and underwent CT scan with intravenous contrast during full AO were included. Patients were excluded if they had a CT scan performed with the balloon partially or fully deflated. Results Nine patients (8 men) were included; all had blunt trauma. Mean Injury Severity Score (±SD) was 48 ± 8 and mean age was 45 ± 19 years. Four had supra-celiac AO, and 5 had infra-renal AO. Arterial contrast enhancement was noted below the level of AO in all patients, and distal to REBOA sheath placement in 5. Collateralization from arteries above and below the AO was identified in all patients. Contrast extravasation distal to AO was identified in 4 patients, and hematomas in 8. Distal vascular enhancement patterns varied by level of AO and contrast administration site. Conclusions Aortic occlusion appears to dramatically decrease, but does not completely impede, distal perfusion during REBOA due to multiple pathways of collateralization. Active extravasation and hematomas can still be detected in the setting of full AO, with purposefully timed contrast and image acquisition. Blood flow persists below the level of both the AO and in-dwelling sheath. Dynamic flow studies are needed to determine the contribution of AO and sheath placement to distal tissue ischemia.
Regulating animals with gene drive systems: lessons from the regulatory assessment of a genetically engineered mosquito

For the purposes of conservation or suppression of species, gene drive technology has significant potential. Theoretically speaking, with the release of even relatively few animals with gene drive ...
A rapid review of treatment literacy materials for tuberculosis patients.

Objective To assess available treatment literacy materials for patients undergoing treatment for tuberculosis (TB). Design We conducted a rapid review by searching the US Centers for Disease Control's Find TB Resources website and the websites of health departments and TB-focused organizations. We included English-language documents intended to educate TB patients about anti-tuberculosis treatment. We evaluated the format, readability, and content of documents, and audience. We defined 12 essential content elements based on those previously identified as facilitating human immunodeficiency virus treatment literacy. Results Of the 205 documents obtained, 45 were included in our review. The median reading grade level was 7 (IQR 5-8). The median number of essential content elements present was 6 (IQR 4-8), with the most comprehensive document containing 11 of the 12 elements. Only two documents were written for children with TB or their care givers, and two for patients with drug-resistant TB. Many documents contained paternalistic and non-patient-centered language. Conclusion We found few examples of comprehensive, patient-centered documents. Work is needed to achieve consensus as to the essential elements of TB treatment literacy and to create additional materials for children, patients with drug-resistant TB, and those with lower literacy levels.
Unskilled Labour Migrants in Qatar: Issues and Policy Developments

Much of the literature on migrants in the GCC has focusses primarily on the treatment of construction labourers who have relocated from mostly South Asia. Fottrell (2015). Okaz News (2017). Their plight has been published in many newspapers and journals and countries within the GCC have made some headway into introducing legislation to address the protection of migrant workers to bring about policy change. BBC News (2016), BBC News (2017), Piper (2014), Martin and Malit (2017), The Guardian (2017), Mohammad and Sidaway (2016). Surprisingly, stemming from the present Gulf crisis, there have been accusations by the blockading countries of abuses to migrant labour in Qatar. This applied, non-experimental and quasi-evaluative research uses both primary and secondary sources to conduct an investigation to obtain information about the issues of migrant labour in Qatar and the extent to which their problems have been addressed in terms of legislation. Wickramasekara (2015), Wickramasekara and Baruah (2017), Kamrava (2015), Ulrichsen (2009). The purpose of this work is to establish an evidence base regarding the issues of migrant workers and what positive actions have been undertaken to address the issues surrounding migrant management. It also aims to report on the effectiveness of the legislation and suggest possible amendment.
Middle East and North Africa: Sociocultural Aspects

The entry begins by discussing the different ways in which this geographical expanse has been delimited as a unit of analysis in Orientalist and social science scholarship. It critically examines the notion of Islam as a unifying force, and as providing the sociocultural cohesion of the region. The discussion then turns to the ways in which modernization theory and developmentalism set agendas of scholarship, to be followed by critiques rooted in political economy, a new historiography, and anthropological reflexivity. Scholarship from the region itself also poses challenges, whether through providing different interpretations and emphases in research or in attempting to develop alternative epistemologies as in the call for the Islamization of the social sciences. New interpretive frameworks adopting cultural, feminist, and postcolonial perspectives are more cognizant of the circulation and power of such discourses, seeing in them examples of the multiple sites of modernity. The enduring interest in the study of Islam and gender in the region is now supplemented by research into new areas such as diasporic populations and public spheres, intersections of history and ethnography, refugee studies, popular culture, and everyday life.
Disruption of brain-derived neurotrophic factor production from individual promoters generates distinct body composition phenotypes in mice

Brain-derived neurotrophic factor (BDNF) is a key neuropeptide in the central regulation of energy balance. The Bdnf gene contains nine promoters, each producing specific mRNA transcripts that enco...
The allosteric activation of cGAS underpins its dynamic signaling landscape

Cyclic G/AMP synthase (cGAS) initiates type-1 interferon responses against cytosolic double-stranded (ds)DNA, which range from antiviral gene expression to apoptosis. The mechanism by which cGAS shapes this diverse signaling landscape remains poorly defined. We find that substrate-binding and dsDNA length-dependent binding are coupled to the intrinsic dimerization equilibrium of cGAS, with its N-terminal domain potentiating dimerization. Notably, increasing the dimeric fraction by raising cGAS and substrate concentrations diminishes duplex length-dependent activation, but does not negate the requirement for dsDNA. These results demonstrate that reaction context dictates the duplex length dependence, reconciling competing claims on the role of dsDNA length in cGAS activation. Overall, our study reveals how ligand-mediated allostery positions cGAS in standby, ready to tune its signaling pathway in a switch-like fashion.
Burden and Cost of Outpatient Hemorrhoids in the United States Employer-Insured Population, 2014.

INTRODUCTION:Although hemorrhoids are a common indication for seeking health care, there are no contemporary estimates of burden and cost. We examined data from an administrative claims database to estimate health care use and aggregate costs.METHODS:We conducted a cross-sectional study using the Ma
Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3-dependent mechanism in male mice

Nicotinamide adenine dinucleotide (NAD+) is a central signaling molecule and enzyme cofactor that is involved in a variety of fundamental biological processes. NAD+ levels decline with age, neurodegenerative conditions, acute brain injury, and in obesity or diabetes. Loss of NAD+ results in impaired mitochondrial and cellular functions. Administration of NAD+ precursor, nicotinamide mononucleotide (NMN), has shown to improve mitochondrial bioenergetics, reverse age associated physiological decline, and inhibit post-ischemic NAD+ degradation and cellular death. In this study we identified a novel link between NAD+ metabolism and mitochondrial dynamics. A single dose (62.5mg/kg) of NMN, administered to male mice, increases hippocampal mitochondria NAD+ pools for up to 24 hours post-treatment and drives a sirtuin 3 (SIRT3) mediated global decrease in mitochondrial protein acetylation. This results in a reduction of hippocampal reactive oxygen species levels via SIRT3 driven deacetylation of mitochondrial manganese superoxide dismutase. Consequently, mitochondria in neurons become less fragmented due to lower interaction of phosphorylated fission protein, dynamin-related protein 1 (pDrp1 (S616)), with mitochondria. In conclusion, manipulation of mitochondrial NAD+ levels by NMN results in metabolic changes that protect mitochondria against reactive oxygen species and excessive fragmentation, offering therapeutic approaches for pathophysiologic stress conditions.
The normal microbial flora: comparative bacterial flora of animals and man.

In a qualitative and quantitative study of bacteria, the mid small intestine and colon of rabbits and dogs, and the upper jejunum and terminal ileum of surgical patients were sampled at laparotomy.
Reduced arterial compliance along the cerebrovascular tree predicts cognitive slowing in multiple sclerosis: Evidence for a neurovascular uncoupling hypothesis:

Background:Cognitive slowing occurs in ~70% of multiple sclerosis (MS) patients. The pathophysiology of this slowing is unknown. Neurovascular coupling, acute localized blood flow increases followi...
The role of hydrogen in hot-salt stress corrosion cracking of titanium-aluminum alloys

Additional support is presented for the previously proposed role of hydrogen as an embrittling agent in hot-salt stress corrosion cracking of titanium-aluminum alloys. The main source of hydrogen formed during the reactions of titanium alloys with hot salt was identified as water associated with the salt. Hydrogen is produced by the reaction of an intermediate (hydrogen halide) with the alloy rather than from metal-water reactions. The fracture mode of precracked tensile specimens was ductile when the specimens were tested in air, and brittle when tests were made in high-pressure hydrogen. Stressed titanium-aluminum alloys also were cracked by bombardment with hydrogen ions produced in a proton accelerator. The approximate concentrations of the hydrogen ions in the alloys were calculated.
Imaging and Diagnostic Challenges in a Patient With Refractory Hypoglycemia Caused by Insulinomas Related to Multiple Endocrine Neoplasia Type 1.

Insulinoma is a rare neuroendocrine tumor. It may occur sporadically or as part of the genetic tumor syndrome multiple endocrine neoplasia type 1 (MEN1). Diagnosis is challenging because of the small size of insulin producing tumors that lead to hyperinsulinemia. Advances in imaging modalities may provide more accurate diagnosis of primary tumors, metastasis, and tumor functional status. Advances allow for improved medical and surgical management with new tools for research of neuroendocrine tumors. Surgical excision of the primary tumor is often curative; however, insulinomas in MEN1 syndrome are often multifocal with a high rate of recurrence presenting unique challenges in management. Here, we present the case of a 34-year-old male with recurrent hypoglycemic episodes and hyperparathyroidism diagnosed with multiple pancreatic insulinomas secondary to MEN1. Furthermore, we provide a brief review of the literature and discuss the approach to diagnosis and management in patients with MEN1 syndrome and future areas of investigation.
Hepatic NADH reductive stress underlies common variation in metabolic traits

The cellular NADH/NAD+ ratio is fundamental to biochemistry, but the extent to which it reflects versus drives metabolic physiology in vivo is poorly understood. Here we report the in vivo application of Lactobacillus brevis (Lb)NOX1, a bacterial water-forming NADH oxidase, to assess the metabolic consequences of directly lowering the hepatic cytosolic NADH/NAD+ ratio in mice. By combining this genetic tool with metabolomics, we identify circulating α-hydroxybutyrate levels as a robust marker of an elevated hepatic cytosolic NADH/NAD+ ratio, also known as reductive stress. In humans, elevations in circulating α-hydroxybutyrate levels have previously been associated with impaired glucose tolerance2, insulin resistance3 and mitochondrial disease4, and are associated with a common genetic variant in GCKR5, which has previously been associated with many seemingly disparate metabolic traits. Using LbNOX, we demonstrate that NADH reductive stress mediates the effects of GCKR variation on many metabolic traits, including circulating triglyceride levels, glucose tolerance and FGF21 levels. Our work identifies an elevated hepatic NADH/NAD+ ratio as a latent metabolic parameter that is shaped by human genetic variation and contributes causally to key metabolic traits and diseases. Moreover, it underscores the utility of genetic tools such as LbNOX to empower studies of ‘causal metabolism’. The authors identify an increased hepatic NADH/NAD+ ratio as an underlying metabolic parameter that is shaped by human genetic variation and contributes causally to key metabolic traits and diseases.
A Review of Online Rehabilitation Protocols Designated for Rotator Cuff Repairs

Purpose To compare publicly available rehabilitation protocols designated for rotator cuff (RTC) repairs published online by academic residency programs and private practice institutions. Methods A systematic electronic search using the Fellowship and Residency Electronic Interactive Database Access System (FREIDA) was performed for RTC repair rehabilitation protocols. Private practice programs with published rehabilitation protocols that were discovered during the Google search were also included for review, but no comprehensive search for private practice protocols was performed. The main exclusion criteria consisted of non–English-language protocols and protocols without any of the time-based components in question. Included protocols were assessed independently based on the specified RTC tear size (small [≤1 cm], medium [1-4 cm], large or massive [≥5 cm], or no mention of size). Protocols were compared based on the inclusion, exclusion, and timing of certain rehabilitation components. Results A total of 96 rehabilitation protocols were included for review, from 39 academic institutions and 28 private practice programs. Specific instructions for concomitant biceps tenodesis were included in 26 protocols (27.1%). Of the 96 protocols, 88 (91.7%) did not place restrictions on early postoperative passive range of motion (PROM) of the shoulder. Isolated PROM with restrictions on active range of motion was most commonly recommended for the first 4 or 6 weeks postoperatively (80.2%). Use of a sling or immobilizer was most frequently recommended for the first 4 or 6 weeks postoperatively (78.1%). Wide variation was noted in recommendations for returning to resistance strengthening, with the highest incidence being 27 protocols recommending returning at 12 weeks (28.1%); this further varied based on the size of the tear. A total of 21 protocols (21.9%) recommended the use of cryotherapy postoperatively. Conclusions Although certain rehabilitation components were common, such as duration of PROM and sling or immobilizer use, a large degree of variation remains among published rehabilitation protocols after RTC repair, and this variability is still seen even when subdividing by the size or severity of the RTC tear. Clinical Relevance Rehabilitation after RTC repair is crucial to patient outcomes. This study summarizes the variability among online rehabilitation protocols for RTC repair in the United States and emphasizes the importance of appropriate rehabilitation after RTC surgery.
Cromosomas B mitoticamente inestables en el saltamontes Sphingonotus Haitiensis Saus (Orthoptera : Acrididae)

Este texto describe el estudio citogenetico de la espermatogenesis en dos poblaciones dominicanas del saltamones "Sphingonotus haitiensis Sauss", este estudio revelo la existencia de individuos portadores de cromosomas B mitoticamente inestables, adicionales al careotipo normal de las especies.
Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response.

Background Minimally invasive radiofrequency ablation (RFA) is used as a first-line treatment option for hepatocellular cancer (HCC) with the weaknesses of incomplete ablation, tumor recurrence, and inferior outcomes. To overcome this limitation, we proposed to develop sunitinib-RFA integrated therapy with a potential of activating anti-HCC immune response. Methods Using our unique murine model, we developed a novel RFA platform with a modified human cardiac RF generator. Therapeutic efficacy of sunitinib–RFA combined treatment in HCC was tested in this platform. Tumor progression was monitored by MRI; tumor necrosis and apoptosis were detected by HE immune reaction was defined by flow cytometry; and signaling molecules were examined with real-time PCR (qPCR), western blot, and immunohistochemical staining. Results A significantly reduced tumor growth and extended lift span were observed in the mice receiving combined treatment with RFA and sunitinib. This combined treatment significantly increased the frequency of CD8+ T cell, memory CD8+ T cell, and dendritic cells (DCs); decreased the frequency of regulatory T cells; and activated tumor-specific antigen (TSA) immune response in tumor microenvironment. We found that RFA caused PD-1 upregulation in tumor-infiltrated T cells by boosting hepatocyte growth factor (HGF) expression, which was suppressed by sunitinib treatment. We have also demonstrated that sunitinib suppressed VEGF’s effect in enhancing PD-L1 expression in DCs and attenuated heat-sink effect. The results indicate that RFA induced tumor destruction and release of in situ TSAs which can activate a tumoricidal immune response in sunitinib-treated mice, significantly improving anti-HCC therapeutic efficacy. Conclusions Sunitinib enables RFA-released in situ TSA to ignite an effective anti-tumor immune response by suppressing HGF and VEGF signaling pathways. Sunitinib–RFA as a synergistic therapeutic approach significantly suppresses HCC growth.
Situated Learning-Based Robotics Education

This Innovative Practice Work-In-Progress Paper presents a situated learning-based robotics education pedagogy for computing students. Different from traditional textbook-directed robotics courses, in this work, we develop a hands-on, project-oriented robotics curriculum based on the situated learning methodology for undergraduate and graduate students. The innovative pedagogical framework and curriculum development are presented. Preliminary results and evaluations suggest that our situated learning-based pedagogy and developed robotics curriculum provide an effective solution for computing students to learn robotics.
Evolution of risk stratification and sudden death prevention in hypertrophic cardiomyopathy: Twenty years with the implantable cardioverter-defibrillator

Hypertrophic cardiomyopathy (HCM) is a relatively common inherited myocardial disorder, once regarded as largely untreatable with ominous prognosis and most visibly as a common cause of sudden death (SD) in the young. Over the last several years, HCM has been transformed into a contemporary treatable disease with management options that significantly alter clinical course. With the use of implantable cardioverter-defibrillators (ICDs) in the HCM patient population, a new paradigm has emerged, with primary prevention device therapy reliably terminating potentially lethal ventricular tachyarrhythmias (3%-4% per year) and being largely responsible for a >10-fold decrease in disease-related mortality (to 0.5% per year), independent of age. An evidenced-based and guideline directed clinical risk stratification algorithm has evolved, including variables identified with cardiac magnetic resonance. One or more risk markers judged major and relevant within a patient's clinical profile can be considered sufficient to recommend a primary prevention implant (associated with a measure of physician judgment and shared decision-making). ICD decisions using the prospective individual risk marker strategy have been associated with 95% sensitivity for identifying patients who subsequently experienced appropriate ICD therapy, (albeit often delayed substantially for >5 or >10 years after implant), but without heart failure deterioration or HCM death following device intervention. A rigid mathematically derived statistical risk model proposed by the European Society of Cardiology is associated with low sensitivity (ie, 33%) for predicting SD events. Introduction of prophylactically inserted ICDs to HCM 20 years ago has significantly altered the clinical course and landscape of this disease. SD prevention has reduced HCM mortality significantly, making preservation of life and the potential for normal longevity a reality for most patients.
In vivo dissection of Rhoa function in vascular development using zebrafish

ABSTRACT Rationale The small monomeric GTPase RHOA acts as a master regulator of signal transduction cascades by activating effectors of cellular signaling, including the Rho-associated protein kinases ROCK1/2. Previous in vitro cell culture studies suggest that RHOA can regulate many critical aspects of vascular endothelial cell (EC) biology, including focal adhesion, stress fiber formation, and angiogenesis. However, the specific in vivo roles of RHOA during vascular development and homeostasis are still not well understood. Objective In this study we examine the in vivo functions of RHOA in regulating vascular development and integrity in zebrafish. Methods and Results We use zebrafish RHOA-ortholog (rhoaa) mutants, transgenic embryos expressing wild type, dominant-negative, or constitutively active forms of rhoaa in ECs, and a pharmacologic inhibitor of ROCK1/2 to study the in vivo consequences of RHOA gain- and loss-of-function in the vascular endothelium. Our findings document roles for RHOA in vascular integrity, developmental angiogenesis, and vascular morphogenesis. Conclusions Our results indicate that either too much or too little RHOA activity leads to vascular dysfunction in vivo.
Validation of the nine item ARFID screen (NIAS) subscales for distinguishing ARFID presentations and screening for ARFID.

Objective The Nine Item Avoidant/Restrictive Food Intake Disorder (ARFID) Screen (NIAS) has three subscales aligned with ARFID presentations but clinically validated cutoff scores have not been identified. We aimed to examine NIAS subscale (picky eating, appetite, fear) validity to: (1) capture clinically-diagnosed ARFID presentations; (2) differentiate ARFID from other eating disorders (other-ED); and (3) capture ARFID symptoms among individuals with ARFID, individuals with other-ED, and nonclinical participants. Method Participants included outpatients (ages 10-76 years; 75% female) diagnosed with ARFID (n = 49) or other-ED (n = 77), and nonclinical participants (ages 22-68 years; 38% female, n = 40). We evaluated criterion-related concurrent validity by conducting receiver operating curve (ROC) analyses to identify potential subscale cutoffs and by testing if cutoffs could capture ARFID with and without use of the Eating Disorder Examination-Questionnaire (EDE-Q). Results Each NIAS subscale had high AUC for capturing those who fit versus do not fit each ARFID presentation, resulting in proposed cutoffs of ≥10 (sensitivity = .97, specificity = .63), ≥9 (sensitivity = .86, specificity = .70), and ≥ 10 (sensitivity = .68, specificity = .89) on the NIAS-picky eating, NIAS-appetite, and NIAS-fear subscales, respectively. ARFID versus other-ED had high AUC on the NIAS-picky eating (≥10 proposed cutoff), but not NIAS-appetite or NIAS-fear subscales. NIAS subscale cutoffs had a high association with ARFID diagnosis, but only correctly classified other-ED in combination with EDE-Q Global Discussion To screen for ARFID, we recommend using a screening tool for other-ED (e.g., EDE-Q) in combination with a positive score on any NIAS subscale (i.e., ≥10, ≥9, and/or ≥10 on the NIAS-picky eating, NIAS-appetite, and NIAS-fear subscales, respectively).
Investor Myopia and CEO Compensation

We examine the impact of investor horizon on the design of compensation contracts. Using a sample of IPO firms, we contrast long-term incentives provided to CEOs across firms with venture capital (VC) investors who are myopic and other firms where shareholders have relatively longer investment horizons. We construct several new measures of long-term incentives that capture the horizon of the compensation. We find that VC-backed firms reduce long-term incentives when the lockup expires whereas non-VC-backed firms increase their long-term incentives to mitigate the high level of managerial myopia in the period following the IPO. Specifically VC backed firms grant a greater proportion of annual compensation in the form of cash and vested equity-based compensation, the duration of the compensation is lower, and the proportion of vested options to total option holdings is higher in the lockup expiration year. We also explore the long-run consequences of myopic contracts. We find that the long-run (short-run) stock performance is lower (higher) when contracts are myopic consistent with myopic managers maximizing short run performance at the cost of long run performance.