cssi/SciSciGPT-SciSciNet huggingface dataset:
Recycling and Endosomal Sorting of Protease-activated Receptor-1 Is Distinctly Regulated by Rab11A and Rab11B Proteins

Protease-activated receptor-1 (PAR1) is a G protein-coupled receptor that undergoes proteolytic irreversible activation by coagulant and anti-coagulant proteases. Given the irreversible activation of PAR1, signaling by the receptor is tightly regulated through desensitization and intracellular trafficking. PAR1 displays both constitutive and agonist-induced internalization. Constitutive internalization of PAR1 is important for generating an internal pool of naive receptors that replenish the cell surface and facilitate resensitization, whereas agonist-induced internalization of PAR1 is critical for terminating G protein signaling. We showed that PAR1 constitutive internalization is mediated by the adaptor protein complex-2 (AP-2), whereas AP-2 and epsin control agonist-induced PAR1 internalization. However, the mechanisms that regulate PAR1 recycling are not known. In the present study we screened a siRNA library of 140 different membrane trafficking proteins to identify key regulators of PAR1 intracellular trafficking. In addition to known mediators of PAR1 endocytosis, we identified Rab11B as a critical regulator of PAR1 trafficking. We found that siRNA-mediated depletion of Rab11B and not Rab11A blocks PAR1 recycling, which enhanced receptor lysosomal degradation. Although Rab11A is not required for PAR1 recycling, depletion of Rab11A resulted in intracellular accumulation of PAR1 through disruption of basal lysosomal degradation of the receptor. Moreover, enhanced degradation of PAR1 observed in Rab11B-deficient cells is blocked by depletion of Rab11A and the autophagy related-5 protein, suggesting that PAR1 is shuttled to an autophagic degradation pathway in the absence of Rab11B recycling. Together these findings suggest that Rab11A and Rab11B differentially regulate intracellular trafficking of PAR1 through distinct endosomal sorting mechanisms.
An Examination of Increasing Protection for Sacred Sites and the Trust Responsibilities of the Federal Government

Native American concerns about development activities adversely affecting sacred sites have emerged in recent years as major impediments to mineral and energy development projects. This article examines legislation, regulations, and other legal efforts designed to add protection to these sacred sites. This article analyzes current legal authorities pertinent to the protection of Native American sacred sites, and addresses issues raised by proposed legislative expansions of these protections. Constitutional issues, including the restriction on the establishment of any religion by the government, are also examined. With various regulatory and legislative initiatives pushing for an increased protection of sacred sites, there will undoubtedly be increased costs for mineral development. The examples discussed in this article focus on protections afforded Native American values outside of Indian sovereign lands. These off-reservation protections have the potential to greatly expand the influence of Native Americans in federal decision making and expand their scope of control. They create increased costs, delay projects, almost surely create an environment for conditions to be placed on many activities that are approved, and increases the risk that some projects will be denied. Congress should continue to recognize the benefits of mineral development activities and avoid creating constitutionally suspect preferences for Native American sacred sites. Agencies must similarly be aware of the potential consequences of allowing purported sacred sites to impede projects which are otherwise valuable to the nation's economy and security. Officials must strike an appropriate balance and consider other values, and indeed property rights, that could be infringed through preferences for sacred site protection.
Influence of electron-beam lithography exposure current level on the transport characteristics of graphene field effect transistors

Many factors have been identified to influence the electrical transport characteristics of graphene field-effect transistors. In this report, we examine the influence of the exposure current level used during electron beam lithography (EBL) for active region patterning. In the presence of a self-assembled hydrophobic residual layer generated by oxygen plasma etching covering the top surface of the graphene channel, we show that the use of low EBL current level results in higher mobility, lower residual carrier density, and charge neutrality point closer to 0 V, with reduced device-to-device variations. We show that this correlation originates from the resist heating dependent release of radicals from the resist material, near its interface with graphene, and its subsequent trapping by the hydrophobic polymer layer. Using a general model for resist heating, we calculate the difference in resist heating for different EBL current levels. We further corroborate our argument through control experiments, where ...
Congress from the Inside: U.S.–Africa Foreign Policy and Black Ethnic Politics

In addition to the ardent call for political scientists to broaden their theories about legislative representation and behavior to include a broader analysis of the everyday operations of Congress, the call for a more nuanced approach to the study of race and ethnic politics resonates just as deeply. With the emergence of black ethnic caucuses such as the Ethiopia and Ethiopian American Congressional Caucus (EEAC) and the subsequent election of President Barack Obama, African immigrants and their progeny have been made visible to the American polity in ways they have never been before. As an Ethiopian American whose personal and professional interest aims to highlight the significance of black ethnic political participation and representation in U.S. politics, I found working for Rep. Barbara Lee (D-CA) as an APSA Congressional Fellow to be an extraordinary opportunity to explore how and why African American members of Congress in particular, and other nonblack legislators more broadly, represent their constituents beyond race.
Is There a Generalized Price-Quality Relationship?

There is much evidence that a relationship exists between a product's price and its perceived quality [8, 9, 12, 13]. However, no study gives evidence that the pricequality relationship can be generalized to various products with varying prices and consumer purchasing patterns. Furthermore, some studies [8, 13] have relied on an implied price-quality relationship derived from a forced choice situation, and only one study [12] did not use price as the sole determinant. The possibility that other factors influence the perception of quality is largely ignored.
Submacular choroidal vascular pattern. Experimental fluorescein fundus angiographic studies.

The submacular choroidal vascular pattern was investigated by experimental occlusion of either one of the temporal short posterior ciliary arteries (SPCAs) or 1, 2, 3 or all of the vortex veins in 87 rhesus monkey eyes and evaluation of their filling defects and anastomoses by fluorescein fundus angiography (FFA). No special artery supplying the submacular choroid was seen. All the temporal SPCAs entered the eyeball in the macular region and each artery supplied a segment of the choroid, with no anastomoses between the adjacent segments. Most of the segments of the choroid supplied by the temporal SPCAs and their watershed zones met in the macular region. Similarly the four quadrants of the uveal tract drained by the four vortex veins and their watershed zones met in the macular region. Since an area where numerous watershed zones meet is most vulnerable to ischaemic disorders, the macular region is likely to show special vulnerability to any generalized chronic ischaemic disorder of the choroid. This, however, would not hold good in occlusion of a single SPCA, because the latter supplies only a small segment of the macular region. It is postulated that senile macular degeneration, senile disciform macular degeneration and allied macular disorders are most probably due to this unusual pattern of the submacular choroid and its special vulnerability to suffer in generalized chronic choroidal ischaemia as compared to the rest of the choroid.
Note on the electrophoresis of thrombin.

SummaryResults of electrophoresis experiments with purified thrombin preparations indicate that thrombic activity is probably associated with 2 proteins. Under the conditions of the experiments one has an isoelectric point of pH 4.1 and the other at pH 4.7. Another substance is derived from prothrombin and is always found in the thrombin preparations. It has a high electrophoretic mobility and its isoelectric point is 3.6. This is called 3.6-protein, and it is very likely devoid of thrombic activity.
A Game with n Numbers

(1978). A Game with n Numbers. The American Mathematical Monthly: Vol. 85, No. 3, pp. 183-185.
Five Mathematicians, a Bunch of Coconuts, a Monkey, and a Coin

(2004). Five Mathematicians, a Bunch of Coconuts, a Monkey, and a Coin. The College Mathematics Journal: Vol. 35, No. 4, pp. 256-257.
ANALYSIS OF THE TENDENCY OF CONSUMPTION DEMAND AND THE COUNTERMEASURES

On the basis of summarizing the features of consumption demand,this paper analyzes the causes of the decrease of consumption demand from the aspects of income increase,income gap,institution reform,supply structure and consumption circumstances,then puts forward the countermeasures,such as improving national income allocation,adjusting supply structure and optimizing consumption circumstances.
Introduction to health physics

Nuclear science and technology have an important bearing on the future and sustainable development of our society.The study of health physics is a comprehensive subject that deals with the safe application of nuclear radiation in all areas.An overview is presented of its history and development,and the special role it plays in many interdisciplinary fields.It is to be hoped that the subject of health physics will be better known in the future.
The epidemiological analysis on surveillance for influenza in Changning District, Shanghai from 2009 to 2010

Objective: The study was conducted to explore the epidemiological characteristics of influenza in Changning District.Method: The epidemiological analyses were conducted based on the surveillance of influenza and influenza like illnes(s ILI) cases and etiological results in Changning District,Shanghai.Results: 355 influenza cases were reported from 2009-2010.The proportion rate of A(H1N1)influenza and seasonal influenza from 2009-2010 had obvious difference(χ2=77.02,P 0.00).2840 ILI cases were observed in 2009-2010 totally,the percentage of the average diagnosis was 0.30%.The cases presented a seasonal character.The peak occurred during week 5-8、week 34-40 in 2009 and week 49 in 2009-week 8 in 2010.The positive rate of etiological surveillance was 37.56%.The epidemic strains of influenza were A(H3)during August to September in 2009 and turned to A(H1N1)during October in 2009 to January in 2010 and turned to B during February to June in 2010.During July to Oct.A(H3)became the main epidemic strains again.Strains A(H1N1)、A(H3)and B were all in vogue during November to December in 2010.Conclusion: The etiological surveillance positive test rate was basically the same as the ILI cases epidemic peak.Strengthening surveillance for ILI cases could avoid outbreaks of influenza.
Biliary Excretion of Apolipoprotein B by the Isolated Perfused Rat Liver: Relationship to Receptor-Mediated Uptake of Human Low-Density Lipoprotein and Biliary Lipid Secretion

Since we previously reported that apolipoproteins, the lipid transport proteins of lipoproteins; are present in human bile, we tested the hypothesis that apolipoproteins in bile are derived from circulating lipoproteins and that they are involved in the biliary excretion of lipids. We perf used isolated rat livers with lipoprotein-free solutions and collected bile before and after addition of human low and high density lipoproteins. When human low density lipoprotein was added to solutions perf using livers isolated from rats previously treated with ethinyl estradiol, a hormone that increases receptor-mediated uptake of low density lipoproteins by hepatocytes, the concentrations in bile of cholesterol and phospholipid, but not bile acids, increased by -25% together with the appearance of small amounts (~ 1% of the amount perf used) of a metabolized form of human apolipoprotein B in bile. Acetylation of low density lipoprotein, a procedure that prevents this lipoprotein from binding to its receptor on hepatocytes, both abolished the appearance of immunoreactive apolipoprotein B in bile and blocked the increase in biliary cholesterol and phospholipid concentrations. Whereas the addition of a high density lipoprotein to solutions perf using isolated livers of normal rats was associated with the appearance of small amounts (~1% of the amount perf used) of apolipoproteins A-I and A-II in bile, there were no accompanying changes in the concentrations of biliary lipids. These results suggest that apolipoproteins or their fragments in bile are derived from circulating lipoproteins; in the case of apolipoprotein B, biliary excretion is dependent upon receptormediated uptake of low density lipoprotein by the hepatocyte. Our data are also consistent with the hypothesis that certain apolipoproteins may be involved in biliary lipid secretion, although in an as yet unclear manner.
The American Southwest: An Urban View

and books have called attention to the urban dimension of the western experience, and urban dwellers have been given as much credit for developing the American West as other pioneers and promoters.1 From the beginning, western cities served as "spearheads of the American frontier." Urban developers worked to reproduce familiar city patterns in the new country, and by 1830 Pittsburgh, Cincinnati, Louisville, and St. Louis represented the paramount influence in the Ohio Valley. A similar process occurred in the Great Lakes area. The builders of Cleveland, Detroit, Chicago, and Milwaukee, like earlier urban pioneers and promoters, were a conspicuous part of the westward movement. By 1870 the lake cities exhibited the same dominant influence over their region that older urban centers exerted over their respective hinterlands, and this rapid city growth in the West was viewed as fundamental to the development of the expanding nation.2 In Texas, too, patterns of urbanization were established during the middle years of the nineteenth century. During the period from 1836 to 1865, Houston, Galveston, Austin, and San Antonio came of age as major centers of cultural, social, economic, and political influence in the state. Texans looked to the cities not only for culture but for vital services. As one urban historian has put it, "They read urban newspapers, sought out urban society, borrowed money, traded raw materials and purchased goods from urban merchants."3 Even the Rocky Mountain mining camps and the Kansas cattle towns served as agents of urban civilization, despite the myth of the "Wild West"
INDEFINITE PUNISHMENT AND THE CRIMINAL RECORD: STIGMA REPORTS AMONG EXPUNGEMENT-SEEKERS IN ILLINOIS*

Although criminal records in the United States are more publicly accessible than ever before, we lack knowledge about how record-bearers seek to overcome the negative consequences associated with a visible criminal record as they apply for jobs, housing, and financial aid. Furthermore, although criminal histories record all arrests—and not just those that result in conviction—researchers have yet to compare how those with more extensive versus minor criminal records cope with criminal record stigma. We present interview data from a comparative study of expungement-seekers (N = 53) who have petitioned the courts to remove their criminal records from public view. One group had extensive criminal records (46 percent); the other group had more minor criminal records (54 percent). Several key findings emerged. First, both groups of participants tried, but failed, to persuade potential employers and landlords to overlook the criminal record. They also faced restricted educational opportunity. Second, participants in both groups expressed distress that criminal justice contact could follow them throughout their lives, subjecting them to ongoing stigma. However, those with extensive versus minor criminal records offered different rationales explaining why the visible criminal record history unfairly burdened them. Implications for reintegration theory and policy are discussed.
Small-Cell Lung Cancer: An Update on Targeted Therapies

Lung cancer is the leading cause of cancer-related deaths world-wide and small-cell lung cancer (SCLC) accounts for up to 25% of lung cancer deaths. There has been a considerable amount of research in the understanding of the depth of biology of SCLC and utilizing this knowledge to develop targeted approaches. The treatment of SCLC remains a challenge, despite remarkable initial efficacy to combination chemotherapy and radiation therapy. The response is usually short-lived and the prognosis of SCLC has not changed over the past few decades, necessitating the critical need for evaluating novel agents/therapies. Several signaling pathways have been found to be activated in SCLC tumor cells, forming a rationale for blocking some of the drugable targets. Molecular changes and biological markers have been identified but remain to be validated. Novel and targeted agents have been evaluated but without much success. Increasing understanding of the biology and potential clinical evaluation of biomarkers will pave the way for more effective treatments.
Subcutaneous extraskeletal osteosarcoma of the forearm: a case report and review of the literature.

Extraskeletal osteosarcoma (ESOS) originating in the subcutaneous tissue is a rare occurrence, accounting for less than 10 % of ESOS cases. Osteosarcoma of extraskeletal origin accounts for approximately 2–4 % of all osteosarcomas, and 1 % of soft tissue sarcomas. We report a case of an 80-year-old female with an isolated primary subcutaneous tumor of the forearm. After imaging, surgical excision, and pathological analysis, the diagnosis of a subcutaneous osteosarcoma was made. This report documents the clinical and pathological findings of subcutaneous ESOS in this case, along with a review of previous cases of subcutaneous ESOS.
Hepatitis C Virus: Pathogenesis of infection

Is hepatitis C cytopathic? There are a number of mechanisms whereby HCV could trigger liver cell injury during infection (Table 5.1). Injury could be triggered directly by the virus (i.e., a cytopathic effect) and/or by immune responses against virus-infected cells. HCV-associated liver cell injury could also result from the interactions of HCV with a variety of environmental agents, some of which are mentioned below. Flaviviruses are often cytopathic (Chambers et al., 1990) in that they damage or destroy the cells in which they are growing; consequently it was initially thought that the related HCV might also be cytopathic (Table 5.2). Some evidence has supported such a cytopathic effect whereas other studies have suggested that HCV is not cytopathic. Cell damage was observed with a minimal inflammatory response in monkeys experimentally infected with selected flaviviruses (Monath, 1990). Early studies with NANBH showed cell rounding, shrinkage, and nuclear pyknosis, which are characteristic, cytopathic effects. Damage was also observed in the membranes of mitochrondria and ER (Omata et al., 1981; Dienes et al., 1982). Following the discovery of HCV, it was shown that HCV RNA in the liver, but not in serum, was associated with severe inflammation (Lau et al., 1993). The likelihood that HCV maturation and replication is membrane associated may provide an explanation for the membrane alterations in HCV infection.
Islands of Empire: Pop Culture and U.S. Power. By Camilla Fojas. (Austin, TX: University of Texas Press, 2014. Pp. vii, 238. $55.00.)

This book is one of a kind, as it weaves together the post‐1898 colonial territories of the United States through popular culture and imperial ideology. The author does an exemplary job documenting...
Chapter One – What can Neuropsychology Teach Us About Intellectual Disability?: Searching for Commonalities in the Memory and Executive Function Profiles Associated With Down, Williams, and Fragile X Syndromes

Abstract In the current chapter, we begin to answer the question of what neuropsychology can teach us about intellectual disability (ID) by closely examining similarities and differences in memory and executive function skills in youth with three genetic syndromes associated with ID – Down (DS), Williams (WS), and Fragile X (FXS) syndromes. In particular, we provide a detailed description of the research literature on short-term, long-term, and working memory as well as inhibition, and cognitive flexibility/shifting in these three groups. In our review, we identify cognitive domains that have the most consistent evidence for impairment (i.e., performance below mental age expectations) across the groups, in an effort to begin to shed light on key cognitive deficits that may underlie ID regardless of etiology. Our review of the literature revealed evidence for impairments in all of the cognitive domains reviewed in at least two of the three ID groups. However, somewhat more consistent support for impairments across groups was found for studies of long-term and working memory. Thus, in the chapter's discussion, we conceptualize long-term and working memory impairments in relation to the neuroanatomical phenotypes associated with these syndromes in an attempt to begin to bridge relations between brain and cognition in these groups, and thus, advance our understanding of the neuropsychology of ID. We conclude the chapter by identifying limitations in the existing literature and directions for future research.
Single cell transcriptomic profiling of mouse pancreatic progenitors

The heterogeneity of the developing pancreatic epithelium and low abundance of endocrine progenitors limit the information derived from traditional expression studies. To identify genes that charac...
Neutrophil-to-lymphocyte ratio as prognostic indicator in gastrointestinal cancers: a systematic review and meta-analysis

// Randy C. Bowen 1 , Nancy Ann B. Little 1 , Joshua R. Harmer 1 , Junjie Ma 2 , Luke G. Mirabelli 1 , Kyle D. Roller 1 , Andrew Mackay Breivik 1 , Emily Signor 1 , Alec B. Miller 1 and Hung T. Khong 1 1 Department of Oncology, University of Utah, Salt Lake City, Utah, USA 2 Department of Pharmacotherapy, University of Utah, Salt Lake City, Utah, USA Correspondence to: Hung T. Khong, email: // Keywords : neutrophil-to-lymphocyte ratio, gastrointestinal cancers, prognostic indicator, overall survival, biomarkers Received : August 19, 2016 Accepted : February 20, 2017 Published : March 16, 2017 Abstract An accurate, time efficient, and inexpensive prognostic indicator is needed to reduce cost and assist with clinical decision making for cancer management. The neutrophil-to-lymphocyte ratio (NLR), which is derived from common serum testing, has been explored in a variety of cancers. We sought to determine its prognostic value in gastrointestinal cancers and performed a meta-analysis of published studies using the Meta-analysis Of Observational Studies in Epidemiology guidelines. Included were randomized control trials and observational studies that analyzed humans with gastrointestinal cancers that included NLR and hazard ratios (HR) with overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and/or cancer-specific survival (CSS). We analyzed 144 studies comprising 45,905 patients, two-thirds of which were published after 2014. The mean, median, and mode cutoffs for NLR reporting OS from multivariate models were 3.4, 3.0, 5.0 (±IQR 2.5-5.0), respectively. Overall, NLR greater than the cutoff was associated with a HR for OS of 1.63 (95% CI, 1.53-1.73; P < 0.001). This association was observed in all subgroups based on tumor site, stage, and geographic region. HR for elevated NLR for DFS, PFS, and CSS were 1.70 (95% CI, 1.52-1.91, P < 0.001), 1.64 (95% CI, 1.36-1.97, P < 0.001), and 1.83 (95% CI, 1.50-2.23, P < 0.001), respectively. Available evidence suggests that NLR greater than the cutoff reduces OS, independent of geographic location, gastrointestinal cancer type, or stage of cancer. Furthermore, DFS, PFS, and CSS also have worse outcomes with elevated NLR.
Methotrexate and cetuximab for metastatic advanced head and neck squamous cell carcinoma.

e17033 Background: After the failure of first-line palliative chemotherapy in recurrent non-resectable or metastatic head and neck squamous-cell carcinoma (HNSCC), there is no standard of care seco...
CERTAIN GENERALIZED MORDELL CURVES OVER THE RATIONAL NUMBERS ARE POINTLESS

A conjecture of Scharaschkin and Skorobogatov states that there is a Brauer–Manin obstruction to the existence of rational points on a smooth geometrically irreducible curve over a number field. In this paper, we verify the Scharaschkin–Skorobogatov conjecture for explicit families of generalized Mordell curves. Our approach uses standard techniques from the Brauer–Manin obstruction and the arithmetic of certain threefolds.
Hydrogen Environment Assisted Cracking of a Modern Ultra-High Strength Martensitic Stainless Steel

A modern martensitic stainless steel (Ferrium® PH48S™) resists hydrogen environment assisted cracking (HEAC) in aqueous NaCl at ultra-high yield strengths (1,400 MPa to 1,600 MPa). HEAC is transgra...
Live-cell calcium imaging of adherent and non-adherent GL261 cells reveals phenotype-dependent differences in drug responses.

The tumor-derived GL261 cell line is used as a model for studying glioblastoma and other high-grade gliomas, and can be cultured adherently or as free-floating aggregates known as neurospheres. These different culture conditions give rise to distinct phenotypes, with increased tumorigenicity displayed by neurosphere-cultured cells. An important technique for understanding GL261 pathobiology is live cell fluorescent imaging of intracellular calcium. However, live cell imaging of GL261 neurospheres presents a technical challenge, as experimental manipulations where drugs are added to the extracellular media cause the cells to move during analysis. Here we present a method to immobilize GL261 neurospheres with low melting point agarose for calcium imaging using the fluorescent calcium sensor fura-2. GL261 cells were obtained from the NCI-Frederick Cancer Research Tumor Repository and cultured as adherent cells or induced to form neurospheres by placing freshly trypsinized cells into serum-free media containing fibroblast growth factor 2, epidermal growth factor, and B-27 supplement. Prior to experiments, adherent cells were loaded with fura-2 and cultured on 8-well chamber slides. Non-adherent neurospheres were first loaded with fura-2, placed in droplets onto an 8-well chamber slide, and finally covered with a thin layer of low melting point agarose to immobilize the cells. Ratiometric pseudocolored images were obtained during treatment with ATP, capsaicin, or vehicle control. Cells were marked as responsive if fluorescence levels increased more than 30% above baseline. Differences between treatment groups were tested using Student’s t-tests and one-way ANOVA. We found that cellular responses to pharmacological treatments differ based on cellular phenotype. Adherent cells and neurospheres both responded to ATP with a rise in intracellular calcium. Notably, capsaicin treatment led to robust responses in GL261 neurospheres but not adherent cells. We demonstrate the use of low melting point agarose for immobilizing GL261 cells, a method that is broadly applicable to any cell type cultured in suspension, including acutely trypsinized cells and primary tumor cells. Our results indicate that it is important to consider GL261 phenotype (adherent or neurosphere) when interpreting data regarding physiological responses to experimental compounds.
Single Agent Indirect Herding of Multiple Targets: A Switched Adaptive Control Approach

Indirect herding involves using a set of directly controllable herding agents to indirectly regulate the states of target agents. This letter considers a single herding agent tasked with regulating the states of multiple targets that are repelled from the herder and the goal location. Integral concurrent learning is used to develop an exponentially convergent adaptive controller that is proven to achieve globally uniformly ultimately bounded regulation through a Lyapunov-based analysis. Switched systems methods are used to develop dwell-time conditions that direct the herder to switch between targets. Experimental results with a network of quadcopters are included to illustrate the performance of the developed controller.
Topoisomerase-Induced DNA Damage

Because of their ability to cleave and religate DNA by covalently bonding to one of the ends of the DNA break, topoisomerases are highly susceptible to DNA structure. Here, we will review how topoisomerases can damage the genome when it contains preexisting DNA lesions at the enzyme sites of action. This brief chapter gives an overview of the broad range of lesions that lead to the accumulation of cleavage complexes produced by DNA topoisomerases I and II.
Targeted Clinical Trials

Randomized clinical trials (RCTs) are the most reliable scientific tool for the identification of safe and effective therapies for cancer. Indeed, it can be argued that such trials are indispensible for this purpose. The design and analysis of these trials are generally aimed at differences in overall population parameters. The trials compare outcome measures such as response rates, progression-free survival (PFS), disease-free survival, and overall survival (OS) for patients assumed to be representative of the population under study, determined by the specified eligibility criteria on the trial. Although no assumption of homogeneity of the patients studied or of the relative effects of treatment is required, major conclusions and, for new agents, subsequent regulatory approvals are generally based on the overall population. For example, a conclusion might be that some new therapy is better than a standard therapy in some population with respect to PFS, if the observed hazard ratio is significantly less than unity (in favor of the new therapy), even if the “average” benefit on other scales (e.g., difference in the PFS medians) is quite small. This is a legitimate and reasonable approach, one that has over time yielded major advances in cancer treatments. However, if the eligibility criteria are sufficiently broad, a generally desirable feature of traditional RCTs, unrecognized heterogeneity may have a substantial effect on the power of the trial (Betensky et al. 2002; Zhang et al. 2006). Indeed, there may be reasons to suspect that the treatment under study might benefit only a subset of patients in the population and that any observed difference is due solely or largely to the results in this subset.If this is true and if such patients can be reliably identified beforehand, major benefits could accrue by targeting the subset population rather than the broader one. Benefits include more efficient clinical trials, avoidance of unnecessary treatment of patients who will not benefit from treatment, faster drug development times, and so on. Indeed, the concept of “personalized” medicine is predicated on the existence of such exploitable patient differences. Of course, the reliable identification of the subset population, assuming such exists, is not easy, but is of critical importance (George 2008).
Prosecuting Violence, Performing Sovereignty: The Trial of Dusko Tadic

This article is a critical reading of the contemporary international legal regulation of warfare and an analysis of war crimes trials as ``sovereignty-producing practices''. Whereas proponents of international law optimistically presume that the advent of war crimes tribunals signifies a humanitarian-inspired erosion of sovereignty in the international system, this article shows that legislating violence in war exemplifies an international commitment to structures which normalize war and violence while individualizing, dehistoricizing and depoliticizing criminal acts. This analysis focuses on the first trial of the International Criminal Tribunal for the Former Yugoslavia which convicted Dusko Tadic of war crimes and crimes against humanity.
Parent–Child Relationships

For many smokers, the act of smoking is enough to indict them as bad parents, and many recount instances when subjected to the humiliation and abuse of public indictment. It is difficult for smoking parents who must deal with personal pressures to quit as well as the guilt and shame of addiction to be constantly vulnerable to public abuse from strangers.
Induced pluripotent stem cell–based mapping of β-globin expression throughout human erythropoietic development

Robust β-globin expression in erythroid cells derived from induced pluripotent stem cells (iPSCs) increases the resolution with which red blood cell disorders such as sickle cell disease and β thalassemia can be modeled in vitro. To better quantify efforts in augmenting β-globin expression, we report the creation of a β-globin reporter iPSC line that allows for the mapping of β-globin expression throughout human erythropoietic development in real time at single-cell resolution. Coupling this tool with single-cell RNA sequencing (scRNAseq) identified features that distinguish β-globin-expressing cells and allowed for the dissection of the developmental and maturational statuses of iPSC-derived erythroid lineage cells. Coexpression of embryonic, fetal, and adult globins in individual cells indicated that these cells correspond to a yolk sac erythromyeloid progenitor program of hematopoietic development, representing the onset of definitive erythropoiesis. Within this developmental program, scRNAseq analysis identified a gradient of erythroid maturation, with β-globin-expressing cells showing increased maturation. Compared with other cells, β-globin-expressing cells showed a reduction in transcripts coding for ribosomal proteins, increased expression of members of the ubiquitin-proteasome system recently identified to be involved in remodeling of the erythroid proteome, and upregulation of genes involved in the dynamic translational control of red blood cell maturation. These findings emphasize that definitively patterned iPSC-derived erythroblasts resemble their postnatal counterparts in terms of gene expression and essential biological processes, confirming their potential for disease modeling and regenerative medicine applications.
Introduction and Main Findings

Nontariff Measures (NTMs) encompass all policy instruments other than tariffs, from labeling requirements to macro-policies affecting trade. These measures have been growing as tariffs have been greatly reduced and sometimes eliminated through numerous global and preferential trade agreements such as those of the World Trade Organization (WTO) and its predecessor, as well as regional trade agreements (RTAs). Among NTMs particularly, sanitary and phytosanitary (SPS) measures and technical barriers to trade (TBTs) have been proliferating. These measures have much in common as they act as standards affecting cost and potentially demand by addressing market imperfections (asymmetric information, external effects) (Bacchetta & Beverelli, 2012).
Age differences in the association of nonmedical prescription opioid use and suicidality.

Objectives: To examine age differences in the associations of nonmedical prescription opioid use (NMPOU) and suicidality. Design: This is a population health study using the 2016 National Survey on Drug Use and Health. Participants: The sample included 38,136 persons 18 and older. Main outcome measures: Weighted logistic regression analyses were used to examine the odds of past year NMPOU with suicidality (suicidal thoughts, plans, and attempts in the past year), stratified by age groups. Results: Overall, the prevalence of suicidality was higher for persons who reported past year NMPOU across all age groups. For the full sample, NMPOU was associated with increased odds of suicidal thoughts (OR = 1.71, 95% CI = 1.36, 2.14), plans (OR = 1.95, 95% CI = 1.33, 2.84), and attempts (OR = 2.25, 95% CI = 1.27, 4.00). Users 18 to 34 had greater odds for reporting yes on all three suicidality measures. Users 50 and older had greater odds for suicidal thoughts in the past year. Conclusions: Among younger and older age groups, there is a higher prevalence and associated odds of suicidality for those who report any misuse within the 12-month period .
In vivo electrophysiological recordings of the effects of antidepressant drugs.

Antidepressant drugs are a standard biological treatment for various neuropsychiatric disorders, yet relatively little is known about their electrophysiologic and synaptic effects on mood systems that set moment-to-moment emotional tone. In vivo electrical recording of local field potentials (LFPs) and single neuron spiking has been crucial for elucidating important details of neural processing and control in many other systems, and yet electrical approaches have not been broadly applied to the actions of antidepressants on mood-related circuits. Here we review the literature encompassing electrophysiologic effects of antidepressants in animals, including studies that examine older drugs, and extending to more recently synthesized novel compounds, as well as rapidly acting antidepressants. The existing studies on neuromodulator-based drugs have focused on recording in the brainstem nuclei, with much less known about their effects on prefrontal or sensory cortex. Studies on neuromodulatory drugs have moreover focused on single unit firing patterns with less emphasis on LFPs, whereas the rapidly acting antidepressant literature shows the opposite trend. In a synthesis of this information, we hypothesize that all classes of antidepressants could have common final effects on limbic circuitry. Whereas NMDA receptor blockade may induce a high powered gamma oscillatory state via direct and fast alteration of glutamatergic systems in mood-related circuits, neuromodulatory antidepressants may induce similar effects over slower timescales, corresponding with the timecourse of response in patients, while resetting synaptic excitatory versus inhibitory signaling to a normal level. Thus, gamma signaling may provide a biomarker (or “neural readout”) of the therapeutic effects of all classes of antidepressants.
A blockchain enabled Cyber-Physical System architecture for Industry 4.0 manufacturing systems

Abstract Cyber-Physical Production Systems (CPPSs) are complex manufacturing systems which aim to integrate and synchronize machine world and manufacturing facility to the cyber computational space. However, having intensive interconnectivity and a computational platform is crucial for real-world implementation of CPPSs. In this paper, the potential impacts of blockchain technology in development and realization of real-world CPPSs are discussed. A unified three-level blockchain architecture is proposed as a guideline for researchers and industries to clearly identify the potentials of blockchain and adapt, develop, and incorporate this technology with their manufacturing developments towards Industry 4.0.
The P300 in alcohol use disorder: A meta-analysis and meta-regression.

Abstract Objective The P300 ERP component is a marker of reduced capacity in alcohol use disorder (AUD) to engage attentional mechanisms and update memory representations. No meta-analysis to date has been completed comparing effect size estimates of auditory vs. visual stimuli in AUD. In addition, there is a lack of consensus on whether the P3b in women is reduced, or whether the P3a – an earlier, more frontally distributed component – is reduced in AUD. Methods Strict inclusion criteria and data-analysis plans were implemented. Eligible studies needed to diagnose AUD using DSM or ICD-10 and exclude patients with any psychiatric co-morbidities. Data analysis was completed using a refined variance estimator of the random effects model. Results Effect size estimates were large for both auditory (Hedges' g = 1.01, p = .056) and visual (Hedges' g = 0.77, p = .040) P300 amplitudes, but only marginally significant for the auditory modality. Auditory P300 latency was significantly increased in AUD patients (Hedges' g = 0.73, p = .027). The moderator analysis did not show significant sex differences for either auditory (p = .97) or visual (p = .45) P3b. Finally, the P3a was not reduced in patients with AUD (Hedges' g = 1.01; p = .59). Conclusion This meta-analysis clarifies important questions related to P300 in AUD. By resolving inconsistencies, it is hoped that this information will facilitate the design of futurestudies.
Multiplex isolation and profiling of extracellular vesicles using a microfluidic DICE device

Profiling of extracellular vesicles (EVs) is an emerging area in the field of liquid biopsies because of their innate significance in diseases and abundant information reflecting disease status. However, unbiased enrichment of EVs and thorough profiling of EVs is challenging. In this paper, we present a simple strategy to immobilize and analyze EVs for multiple markers on a single microfluidic device and perform differentiated immunostaining-based characterization of extracellular vesicles (DICE). This device, composed of four quadrants with a single inlet, captures biotinylated EVs efficiently and facilitates multiplexed immunostaining to profile their extracellular proteins, allowing for a multiplexed approach for non-invasive cancer diagnostics in the future. From controlled sample experiments using cancer cell line derived EVs and specific fluorescence staining with lipophilic dyes, we identified that the DICE device is capable of isolating biotinylated EVs with 84.4% immobilization efficiency. We extended our study to profile EVs of 9 clinical samples from non-small cell lung cancer (NSCLC) patients and healthy donors and found that the DICE device successfully facilitates immunofluorescent staining for both the NSCLC patients and the healthy control. This versatile and simple method to profile EVs could be extended to EVs of any biological origin, promoting discoveries of the role of EVs in disease diagnostics and monitoring.
Gliomas arising in the setting of Li-Fraumeni syndrome stratify into two molecular subgroups with divergent clinicopathologic features.

Author(s): Sloan, Emily A; Hilz, Stephanie; Gupta, Rohit; Cadwell, Cathryn; Ramani, Biswarathan; Hofmann, Jeffrey; Kline, Cassie N; Banerjee, Anu; Reddy, Alyssa; Oberheim Bush, Nancy Ann; Chang, Susan; Braunstein, Steve; Chang, Edward F; Raffel, Corey; Gupta, Nalin; Sun, Peter P; Kim, John YH; Moes, Gregory; Alva, Elizabeth; Li, Rong; Bruggers, Carol S; Alashari, Mouied; Wetmore, Cynthia; Garg, Shipra; Dishop, Megan; Van Ziffle, Jessica; Onodera, Courtney; Devine, Patrick; Grenert, James P; Lee, Julieann C; Phillips, Joanna J; Pekmezci, Melike; Tihan, Tarik; Bollen, Andrew W; Berger, Mitchel S; Costello, Joseph F; Perry, Arie; Solomon, David A
Empirical medical therapy for idiopathic male infertility.

Objective To determine if there has been a change in empirical medical therapy (EMT) practices since a 2010 American Urological Association survey reported that 25% of urologists treated infertile men who were pursuing a pregnancy with testosterone (T). Design Survey-based cohort study of AUA members. Setting Practice patterns were evaluated of urologists in academic and nonacademic hospital centers. Patient(s) Practice patterns were evaluated in the treatment of men with idiopathic infertility. Interventions(s) None. Main Outcome Measure(s) Subgroup analysis by means of univariate analysis between means (Fisher exact test) and descriptive proportions was used to compare male infertility fellowship–trained urologists (RUs) to general urologists (non-RUs). Result(s) A total of 191 urologists responded (4.7%). Excluding trainees, 164 responses (85.9%) were analyzed: 134 (82.3%) were from non-RUs and 29 from (17.7%) RUs. Over all, 65.9% treated male infertility with a combination of EMT and surgery (93.1% of RU vs. 60.4% of non-RUs). The most common medications used by RUs were clomiphene (100%), anastrozole (85.7%), and hCG/LH (82.1%). Non-RUs used these less frequently. Overall, 24.4% of the urologists reported that they would use T to treat male infertility: 14.4% (n = 4) of RUs and 24.4% (n = 30) of non-RUs. Conclusion(s) A total of 65.9% of urologists would treat male infertility with the use of EMT and surgery. The most common EMTs were clomiphene, anastrozole, and hCG/LH. Of concern, 24.4% of urologists considered T to treat male infertility, a medication with known contraceptive potential. This is unchanged from the 2010 survey, and confirms the need for reproductive medicine guidelines that include the topic of EMT use in infertile men.
Effects of Optimization Technique on Simulated Muscle Activations and Forces

Two optimization techniques, static optimization (SO) and computed muscle control (CMC), are often used in OpenSim to estimate the muscle activations and forces responsible for movement. Although differences between SO and CMC muscle function have been reported, the accuracy of each technique and the combined effect of optimization and model choice on simulated muscle function is unclear. The purpose of this study was to quantitatively compare the SO and CMC estimates of muscle activations and forces during gait with the experimental data in the Gait2392 and Full Body Running models. In OpenSim (version 3.1), muscle function during gait was estimated using SO and CMC in 6 subjects in each model and validated against experimental muscle activations and joint torques. Experimental and simulated activation agreement was sensitive to optimization technique for the soleus and tibialis anterior. Knee extension torque error was greater with CMC than SO. Muscle forces, activations, and co-contraction indices tended to be higher with CMC and more sensitive to model choice. CMC's inclusion of passive muscle forces, muscle activation-contraction dynamics, and a proportional-derivative controller to track kinematics contributes to these differences. Model and optimization technique choices should be validated using experimental activations collected simultaneously with the data used to generate the simulation.
Evolving Threat Perceptions and Changing Regional Dynamics in a “Post-GCC” Era

Rather than isolating Qatar regionally and internationally, the crisis that began with the blockade of Qatar by four regional states in June 2017 has widened existing cracks in the Gulf into a chasm and has generated unintended consequences that risk inflicting generational damage on its political and social fabric.