cssi/SciSciGPT-SciSciNet huggingface dataset:
Thin Wafer Handling of 300mm Wafer for 3D IC Integration

In this study, thin wafer handling of 300mm wafer for 3D IC Integration is investigated. Emphasis is placed on the determination of the effect of a dicing tape on thin-wafer handling of wafers with Cu-Au pads, Cu-Ni-Au UBM, and TSV interposer with RDL. Also, thin-wafer handling critical issues such as the chip/interposer wafer, carrier wafer, temporary bonding, thinning, backside process, de-bonding, and assembly are presented and their potential solutions are discussed. Finally, state-of-the-art of materials and equipments for thin-wafer handling are examined.
Oronasal and Tracheostomy Delivery of Soft Mist and Pressurized Metered-Dose Inhalers with Valved Holding Chamber

BACKGROUND: Some pediatric tracheostomized patients who receive inhaled drugs undergo decannulation, and it is unknown whether the dose has to be adjusted. Pressurized metered-dose inhalers (pMDIs) and soft mist inhalers (SMIs) used with valved holding chambers (VHCs) made of non-electrostatic material are available. We hypothesized that using an SMI and changing the delivery route from tracheostomy to oronasal would increase lung dose. METHODS: Four units of a metallic VHC were studied with albuterol hydrofluoroalkane (pMDI) and albuterol/ipratropium bromide with an SMI using an anatomically correct in vitro model of a 5-y-old spontaneously breathing tracheostomized child. The drug was captured in a filter and was termed lung dose. We tested breathing patterns with tidal volumes of 50, 155, and 300 mL. A mask and a special adapter were used as interfaces for oronasal and tracheostomy delivery, respectively. Spectrophotometry (276 nm) was used to determine albuterol concentration. RESULTS: The use of SMI resulted in a higher lung dose than the pMDI for all tested conditions except delivery through tracheostomy with tidal volume of 155 mL ( P = .69). Switching from oronasal to tracheostomy delivery increased the lung dose for all tested conditions except for the pMDI with the 300-mL tidal volume ( P = .83). The use of SMI resulted in higher deposition in the tracheostomy tube than the pMDI. CONCLUSIONS: In general, an SMI delivers a higher lung dose than a pMDI when using a metallic spacer during oronasal and tracheostomy route with the latter providing a higher lung dose.
Decentralized Mean Orbit-Element Formation Guidance, Navigation, and Control: Part 1

ight about an estimated weighted mean orbit element formation barycenter is investigated. Consensus over random directed graphs in the presence of time delays is reviewed and applied to the problem. On-orbit spacecraft formations are considered random directed graphs with time delays and agreement over formation parameters is shown. Consensus of formation state estimates and formation barycenter using a distributed formation sensor network is proven. A simulation is described, demonstrating the functionality and applicability of the approach. Conclusions and future work are discussed.
Religion and beliefs about treating medically unexplained symptoms: a survey of primary care physicians and psychiatrists.

Objective:Historical evidence and prior research suggest that psychiatry is biased against religion, and religious physicians are biased against the mental health professions. Here we examine whether religious and non-religious physicians differ in their treatment recommendations for a patient with medically unexplained symptoms.Method:We conducted a national survey of primary care physicians and psychiatrists. We presented a vignette of a patient with medically unexplained symptoms, and experimentally varied whether the patient was religiously observant. We asked whether physicians would recommend six interventions: antidepressant medication, in-office counseling, referral to a psychiatrist, referral to a psychologist or licensed counselor, participation in meaningful relationships and activities, and involvement in religious community. Predictors included the physician's specialty and the physician's attendance at religious services.Results:The response rate was 63% (896 of 1427) primary care physicians...
Hour of darkness : vulnerability, security and globalization

Abstract. The events of September 11th in New York and Washington DC have compelled us to focus on the links between globalization and security. I focus on this relationship by exploring the links between food security, vulnerability to hunger and the world market. Using the new book by Mike Davis on late Victorian famines, I show how his political ecology of famine challenges the work of Amartya Sen on entitlements. My contribution examines how and why entitlements need to be deepened and expanded and grounded in a sophisticated understanding of global political economy. Case materials from Africa and India are deployed to illustrate this argument.
Of Origin: Toward a History of Contemporary Legal Thought

A conventional conception of “contemporary legal thought” would have it stand for the universe of expressions of legal consciousness, plural and contradictory, that abound in our present and compete to determine the trajectory of the future. Contemporary legal thought might, however, stand for something more – a conceptual vocabulary, organizational scheme, or mode of reasoning and arguing that the preponderance of current expressions of legal consciousness share. In the first case, “contemporary” carries no significance other than “current,” and contemporary legal thought stands for nothing more than the aggregation of legal discourses that are “contemporaneous” with each other – existing at the same time. In the second, it becomes (in Duncan Kennedy’s semiotic formulation) a langue – a structure of categories, concepts, conventionally understood procedures and typical legal arguments – within which the present’s plural parole expressions of legal consciousness occur. My objective in this essay is to determine whether or not, in order to write a history of “contemporary legal thought,” it is sensible, or even possible, to posit its existence in the second sense; and, if not, what (if any) historical meaning lies in the aggregate of the first sense. I undertake this exercise not by surveying the field of current legal discourse in search of commonalities that might be restated as structural generalizations. Instead I consider whether something we can call “contemporary legal thought” can be conceived of as such by resorting to a historical concept of origin.
Cyber War versus Cyber Realities: Cyber Conflict in the International System

In February 2015, US Director of National Intelligence James Clapper in his annual report to Congress named the cyber threat as the number one strategic threat to the United States, placing it ahea...
Epidemiological characteristics of hand,foot and mouth disease in Changping District of Beijing in 2012

[Objective]To understand the epidemiological characteristics and regularity of hand,foot and mouth disease( HFMD)in Changping District of Beijing in 2012,provide a basis for reducing the incidence rate of HFMD,and controlling the severe cases and death cases. [Methods]The epidemic data of HFMD from the National disease supervision information management system were investigated by the descriptive analysis,and the pathogen detection was conducted in some patients.[Results]A total of 4 317HFMD cases were reported in 2012,and the incidence rate was 259. 98 / lakh( 4 317 /1 660 512),while the fatality rate was 0. Most of patients were children under 5 years old,accounting for 92. 47% of total cases. There was significant difference in incidence rate between males and females(χ2= 52. 925,P 0. 01). The top three areas of incidence rate were Huilongguan Town,Beiqijia Town and Dongxiaokou Town.[Conclusion]HFMD is the main infectious disease with high incidence rate is in Changping District of Beijing. It is necessary to actively carry out the publicity and education during the epidemic seasons,strengthen the management of childcare institutions,implement the patriotic public health campaign,conduct the pathogen real-time monitoring,and properly adjust the prevention and control strategies.
Restoring strength of incisors with veneers and full ceramic crowns.

PURPOSE The aim was to determine the in vitro fracture resistance of incisors restored with veneers and full ceramic crowns compared to unrestored teeth. MATERIALS AND METHODS Seventy intact, extracted human maxillary central incisors were randomized and assigned to 7 groups (n = 10). The teeth in group 1 remained intact (control). The teeth in groups 2 to 6 were prepared and IPS Empress restorations were conditioned and bonded using an adhesive luting cement, Variolink II/Syntac (group 2: labial veneer with incisal overlap, group 3: 3/4 veneer with margin in enamel, group 4: 3/4 veneer with margin in dentin, group 5: crown with margin in enamel, group 6: crown with margin in dentin group 7: veneer on worn tooth. After finishing and polishing, specimens were stored in water and thermocycled for 2000 cycles between 5 degrees C and 55 degrees C. The maximal fracture load of the specimens (40-degree inclination) was determined using the universal testing machine (Zwick) at a constant crosshead speed (0.5 mm/min). The statistical analysis was performed using the Kruskal-Wallis test with Bonferroni correction (p < 0.05). Fracture surfaces were qualitatively analyzed by SEM. RESULTS All restored teeth with cervical preparation margins in enamel showed a fracture load not significantly different from the intact teeth (control). Restored teeth with cervical preparation margins in dentin showed a significantly lower fracture load. All restorations showed a fracture load far above 400 N, serving as functional reference for anterior teeth. The failures were predominantly cohesive. CONCLUSION For the restoration of tooth strength, defining the finishing lines of veneers and crowns in enamel is recommended. Restorations with finishing lines in dentin resulted in significant loss of strength. Three-quarter veneers with finishing lines in enamel are functionally equal to crowns with the advantage of conserving tooth structure.
Synthesis, Structure, and Photochemical Behavior of [5]Heli-viologen Isomers

The syntheses of isomeric helical viologens that have potential applications in supramolecular chemistry and catalysis have been developed. The structures of the molecules and their solid-state packing motifs have been determined by X-ray crystallography. Computational studies demonstrate that the magnitude of their racemization barriers is primarily determined by the identity of the helical scaffold and is insensitive to the placement of the viologen functional group. The isomers are similar in their photophysical behavior but very different in their photochemical behavior.
Congestive heart failure with vascular endothelial growth factor receptor tyrosine kinase inhibitors.

e13502 Background: Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are reported to cause congestive heart failure (CHF). However, the risk has not been systema...
Reversing EGFR Mediated Immunoescape by Targeted Monoclonal Antibody Therapy

Uncontrolled growth is a signature of carcinogenesis, in part mediated by overexpression or overstimulation of growth factor receptors. The epidermal growth factor receptor (EGFR) mediates activation of multiple oncogenic signaling pathways and escape from recognition by the host immune system. We discuss how EGFR signaling downregulates tumor antigen presentation, upregulates suppressive checkpoint receptor ligand programmed death ligand (PD-L1), induces secretion of inhibitory molecules such as transforming growth factor beta (TGF) and reprograms the metabolic pathways in cancer cells to upregulate aerobic glycolysis and lactate secretion that ultimately lead to impaired cellular immunity mediated by natural killer (NK) cell and cytotoxic T lymphocytes (CTL). Ultimately, our understanding of EGFR-mediated escape mechanisms has led us to design EGFR-specific monoclonal antibody therapies that not only inhibit tumor cell metabolic changes and intrinsic oncogenic signaling but also activates immune cells that mediate tumor clearance. Importantly, targeted immunotherapy may also benefit from combination with antibodies that target other immunosuppressive pathways such PD-L1 or TGF and ultimately enhance clinical efficacy.
Autophagy gene FIP200 in neural progenitors non–cell autonomously controls differentiation by regulating microglia

Recent studies have shown important roles for autophagy genes in the regulation of different tissue stem cells, including neural stem/progenitor cells (NSCs). However, little is known about whether autophagy can regulate NSCs through cell-extrinsic mechanisms. Here, we show that deletion of an essential autophagy gene, FIP200, in NSCs increased expression of Ccl5 and Cxcl10 in a p53-independent manner, mediating increased infiltration of microglia into the subventricular zone of both FIP200hGFAP conditional knockout (cKO) and FIP200;p53hGFAP 2cKO mice. The microglia exhibited an activated M1 phenotype consistent with their potential to inhibit differentiation of FIP200-null NSCs. Blocking either microglia infiltration or activation rescued the deficient differentiation of FIP200-null NSCs from FIP200;p53hGFAP 2cKO mice. Lastly, we showed that increased chemokine expression in FIP200-null NSCs was induced by abnormal p62 aggregate formation and activation of NF-κB signaling. Our results suggest that autophagy plays a crucial role in regulating neurogenesis and restricting local immune response in postnatal NSCs through non-cell autonomous mechanisms.
An Empirical Study of Technical Debt in Open-Source Software Systems

Technical debt (TD) is a term coined by agile software pioneer Ward Cunningham to account for the added software-system effort or cost resulting from taking early software project shortcuts. The debt metaphor reflects that debt accumulates interest: the later it is paid, the more it costs. The TD concept has achieved extensive visibility and usage in the software field, but it applies at least as strongly to cyber-physical systems. In researching the TD phenomena, we have found that open-source software projects are particularly good subjects, as they keep records of the timing, content, and rationale for each update. In this paper, we concentrate on the analysis of open-source software projects to evaluate the relationships between multiple software system characteristics and TD and the relationships between software process factors and TD.
Proceedings of the 2nd International Workshop on Hardware and Architectural Support for Security and Privacy

It is an honor to introduce the technical program for the 2nd International workshop on Hardware and Architectural Support for Security and Privacy (HASP 2013). This year's program includes papers and abstracts on a broad set of topics in hardware security. HASP 2013 received many submissions worldwide. We assigned 3 Program Committee (PC) members to review each submitted paper. The PC members explicitly assigned a grade to each paper they reviewed. The whole review process was double blind. All of the PC members showed a very high degree of professionalism and fairness in their reviews. Some papers received additional reviews to resolve conflicting scores.
2‐fluoro‐5‐maleimidobenzoic acid‐linked albumin drug (MAD) delivery for selective systemic targeting of metastatic prostate cancer

Background The SH-group at Cys-34 of human serum albumin (HSA) is a unique and accessible functional group that can be exploited for efficient linkage of a maleimide containing cytotoxic drug derivative to albumin. The specific maleimide chemistry used for production of the maleimide-linked albumin drug (MAD) is critical, however, to minimize the plasma concentration of "free" cytotoxic drug spontaneously released from albumin carrier thus decreasing dose-limiting host toxicity while enhancing the plasma half-life from minutes to days (ie, pharmacokinetic effect) and tissue concentration of the MAD in the extracellular cellular fluid at sites of cancer (ie, EPR effect). Methods To accomplish this goal, a chemical synthesis was developed using 2-fluoro-5-maleimidobenzoic acid to stably link the potent cytotoxic chemically modified analogue of the naturally occurring sesquiterpene γ-lactone, thapsigargin, 8-O-(12-aminododecanoyl)-8-O-debutanoyl thapsigargin (12ADT), to Cys-34 of albumin to produce 12ADT-MAD. Results Using FITC-labeling, LC/MS analysis, and in vitro growth and clonogenic survival assays on a series of 6 human prostate cancer lines (LNCaP, LAPC-4, VCap, CWR22Rv 1, PC3, and Du145), we documented that 12ADT-MAD is endocytosed by prostate cancer cells where it is degraded into its amino acids liberating cysteinyl-maleimide-12ADT which is both chemically stable at the acidic pH of 5.5 present in the endosome while retaining its high killing ability (IC50 50 nM) via SERCA inhibition. Conclusions Based upon these positive in vitro validation results, the in vivo efficacy versus host toxicity of this 12-ADT-MAD approach is presently being evaluated against a series of patient derived androgen responsive and castration resistant human xenografts in immune-deficient mice.
Possible scheme for observing acceleration (Unruh) radiation

In an FEL the electrons traveling through the undulator are surrounded in their own reference frame by Unruh radiation at a temperature of order 8,000 Kelvin. When these virtual photons scatter from the beam electrons they become real and can be detected. Because of the microbunching of the FEL electron beam this process proceeds coherently for a fraction of the electrons in the microbunch. This enhances the Unruh radiation which is still dominated by the copious spontaneous radiation in the same energy range. We discuss the particular case of the Stanford LCLS, as well as the case of extreme acceleration, when the x-ray beam is brought into collision with the 14 GeV electron beam.
Mechanisms of Environmental Sex Determination in Fish, Amphibians, and Reptiles

In many reptiles, amphibians, and fishes, the environment plays a key role in determining the sexes of individuals. Temperature, in particular, appears to be a potent modulator of sex allocation in all three vertebrate classes, yet we do not yet know how temperature interacts with physiology in these systems to influence sexual development. In this chapter, I discuss the gene targets that may be key mediators of temperature sex determination in reptiles, fish, and amphibians, discuss the potential role of hormones in the process of sex determination for all three groups, and highlight the need for comparative studies to explore the potential of a conserved mediator that facilitates sex allocation in response to a variety of environmental and social cues.
Regulation of the activins-follistatins-inhibins axis by energy status: Impact on reproductive function

Abstract Background We have previously demonstrated that the adipose tissue derived hormone leptin controls reproductive function by regulating the hypothalamic-pituitary-gonadal axis in response to energy deficiency. Here, we evaluate the activins-follistatins-inhibins (AFI) axis during acute (short-term fasting in healthy people) and chronic energy deficiency (women with hypothalamic amenorrhea due to strenuous exercise [HA]) and investigate their relation to leptin and reproductive function in healthy subjects and subjects with HA. Methods The AFI axis was investigated in: a) A double-blinded study in healthy subjects having three randomly assigned admissions, each time for four days: in the isocaloric fed state, complete fasting with placebo treatment, complete fasting with leptin replacement, b) A case-control study comparing women with HA vs healthy controls, c) An open-label interventional study investigating leptin treatment in women with HA over a period of up to three months, d) A randomized interventional trial investigating leptin treatment vs placebo in women with HA for nine months. Results The circulating levels of activin A, activin B, follistatin and follistatin-like 3 change robustly in response to acute and chronic energy deficiency. Leptin replacement in acute energy deprivation does not affect the levels of these hormones suggesting an independent regulation by these two hormonal pathways. In chronic energy deficiency, leptin replacement restores only activin B levels, which are in turn associated with an increase in the number of dominant follicles. Conclusions We demonstrate for the first time that the AFI axis is affected both by acute and chronic energy deficiency. Partial restoration of a component of the axis, i.e. activin B only, through leptin replacement is associated with improved reproductive function in women with HA.
HIV/AIDS and the African-American Community 2018: a Decade Call to Action

HIV/AIDS disproportionately affects African-Americans more than any other racial or ethnic group in the USA. Currently representing only 12% of the US population, African-Americans now comprise close to half of the total reported HIV/AIDS cases in the USA according to the Centers for Disease Control and Prevention since the initial reporting of HIV/AIDS. In this paper, we examined the prevalence and current direction of the HIV/AIDS epidemic in the African-American community especially in comparison to our first call to action in 2008. The situation remains dire and broader attention is necessary from the public health and medical sectors who serve the majority of African-American populations and the community at-large to work towards closing this health disparity gap. This paper thus recommends an action plan for community leaders (i.e., the public health sector, policy makers, public health practitioners, and other stakeholders) to reduce the disparity.
RFLP facilitated analysis of tiller and leaf angles in rice ( Oryza sativa L.)

Plant type is an important composite trait associated with the yield potential in rice and other cereal crops. Several characters associated with the plant type of modern rice cultivars including tiller angle, leaf and flag leaf angle, were investigated using a complete linkage map with 115 well distributed RFLP markers and progeny testing of 2418 F2 derived F4 lines from a cross between O. sativa ssp. japonica cv. ‘Lemont’ and spp. indica cv. ‘Teqing’. One major gene (Ta) and 11 QTLs were largely responsible for the tremendous variation of the three plant type characters in the Lemont/Teqing F2 population. The major gene, Ta, located between RZ228 and RG667 on chromosome 9, accounted for 47.5% of the phenotypic variation in tiller angle and had large pleiotropic effects on both leaf and flag leaf angles. This gene plus four QTLs accounted for 69.1% of the genotypic variation in tiller angle. Eight additional QTLs for leaf and flag leaf angles were also identified, which collectively explained 52.0 and 66.4% of the genotypic variation of these traits. Ta and three QTLs ( QFla2, QFla5 and QFla7) apparently affected the related plant type characters differently, suggesting their possible differential expression in different developmental stages of rice plants or possibly clustering of different genes affecting these traits. Plant type, and consequently grain yield of rice, may be improved by deliberately manipulating these QTLs in a marker-assisted selection program.
Narrow hybrid zone between two subspecies of big sagebrush (Artemisia tridentata: Asteraceae) : XII. Galls on sagebrush in a reciprocal transplant garden.

Several species of gall-forming insects specialize on big sagebrush (Artemisia tridentata), a species that shows much clinal and subspecific variation throughout its geographic range. Two of those subspecies, basin big sagebrush (A. t. ssp. tridentata) and mountain big sagebrush (A. t. ssp. vaseyana), form a narrow hybrid zone at Salt Creek, Utah. Reciprocal transplant experiments have shown that the hybrid big sagebrush at Salt Creek are more fit than either parental subspecies, but only in the hybrid zone. Do genotype and environment influence the density and distribution of galls on big sagebrush? We counted galls on parental and hybrid big sagebrush in three reciprocal transplant gardens at Salt Creek. Gardens were in each of the two parental zones and in the hybrid zone. Transplanted seedlings came from five source populations: two parental and three hybrid populations. We identified seven kinds of gall-forming flies (Rhopalomyia midges and Eutreta fruitflies) that produced identifiable galls. Densities of galls varied among the three gardens and five source populations, and there was also a significant garden by source interaction in gall density. In general, variation in gall density among gardens (i.e., environments) was much greater than the variation among source populations (i.e., genotypes). Nevertheless, significant genotype-environment interactions were observed for five of the seven kinds of galls. Overall density of galls, mostly due to Rhopalomyia ampullaria, was greatest in the high-elevation (mountain) garden and least in the low-elevation (basin) garden. To the best of our knowledge, this is the first reciprocal transplant experiment addressing herbivore richness in a hybrid zone.
Human Cytomegalovirus Modulation of Signal Transduction

An upregulation of cellular signaling pathways is observed in multiple cell types upon human cytomegalovirus (HCMV) infection, suggesting that a global feature of HCMV infection is the activation of the host cell. HCMV initiates and maintains cellular signaling through a multitiered process that is dependent on a series of events: (1) the viral glycoprotein ligand interacts with its cognate receptor, (2) cellular enzymes and viral tegument proteins present in the incoming virion are released and (3) a variety of viral gene products are expressed. Viral-mediated cellular modification has differential outcomes depending on the cell type infected. In permissive cell types, such as diploid fibroblasts, the upregulation of cellular signaling pathways following infection can initiate the viral gene cascade and promote the efficient transcription of multiple viral gene classes. In other cell types, such as endothelial cells and monocytes/macrophages, the upregulation of cellular pathways initiates functional host changes that allow viral spread to multiple organ systems. Together, the modification of signaling processes appears to be part of a thematic strategy deployed by the virus to direct the required functional changes in target cells that ultimately promote viral survival and persistence in the host.
Dynamic Mechanical Response of T800/F3900 Composite Under Tensile and Compressive Loading

The effect of strain rate on the mechanical response of T800/F3900, a strengthened epoxy carbon-fiber reinforced polymer, is studied by conducting compression and tensile tests at different strain rates. Low strain rate tests (0.001 s−1 and 1 s−1) are done using a hydraulic frame and high strain rate tests (300 s−1–600 s−1) are done with the SHB technique. Digital Image Correlation is used in all tests to obtain full-field strain measurements. Tension tests have been done on unidirectional laminates in the 90 ° direction. Compression tests have been done on unidirectional laminates in the 90 ° and through the thickness directions. No or small strain rate effect is observed between the low strain rate tests. The results from the high strain rate tests show significant strain rate effects.
Stromal prorenin receptor is critical for normal kidney development

Formation of the metanephric kidney requires coordinated interaction among the stroma, ureteric bud, and cap mesenchyme. The transcription factor Foxd1, a specific marker of renal stromal cells, is...
Abstract 4998: Molecular profiling reveals heterogeneity of active self-renewal pathways in bladder cancer stem cells

The objective of the current study is to investigate the functional involvement of self-renewal related genes in patient bladder cancer stem cells. First, by fractionating primary patient bladder transitional cell carcinomas (TCCs) into subpopulations with flow cytometry, a unique tumor-initiating subpopulation expressing CD44 was identified in 5 independent TCCs, based on their enriched potential (10-200 folds) to induce xenograft tumors in immunocompromised mice. To extend this finding to a larger sample set, we analyzed a tissue array containing more than 300 bladder TCCs by immunohistochemistry. Approximately 40.4% of TCCs contain CD44+ cells; these cells usually express cytokeratin 5 (CK5) (P
Past the Anthropocentric: Sociocognitive Perspectives for Tech-Mediated Language Learning

Researchers in second language acquisition (SLA) have long debated the nature of human cognition and how it affects second language learning (L2L). On the one hand, and largely dominating the field of SLA, is the cognitive approach, which focuses on the brain as the unit for cognitive analysis. On the other hand, sociocultural theory holds that human cognition is mediated by cultural artifacts. These perspectives present significantly different views on interaction, understanding it as either auxiliary or instrumental in the learning process, or “fundamentally constitutive” of learning (Mondada & Pekarek Doehler, 2004, p. 502). Increasingly concerned with the role of technology in language learning, current computer-assisted language learning (CALL) research demands theoretical frameworks that account for the ecological relationship between learners, the tools they use, and the environments they inhabit. This article raises the issue of how anthropocentric perspectives on technology have permeated the field of CALL until now, inhibiting its development. I suggest the need for CALL to adopt a less instrumental, more determinist (Carr, 2010) view of the role that technology plays in language learning, by engaging in sociocognitive research (Atkinson, 2010) that embraces the transformative power that technology has over cognition.
Aberrant Wnt/β-catenin signaling in TGF-β pathway elf+/-, and elf+/-/smad3+/- mutant mouse models of human Beckwith- Wiedemann Syndrome

3457 Background: We have shown that adaptor protein ELF, a β-spectrin is a key mediator of TGF-β signaling (Science, 2003 Jan 24; 299). Disruption of TGF-β signaling through ELF and SMAD4 leads to gastrointestinal tumors with aberrant E-Cadherin and β-catenin interaction (Science, 2005, Oct 7; 310, Oncogene, 2006 Mar 23; 25). Interestingly, heterozygous deletion of elf+/-and smad3+/- leads to spontaneous multi-organ tumor growth with a compelling phenotype of human Beckwith-Wiedemann syndrome (BWS). Elf and elf+/-/smad3+/- mutant mice develop a high frequency of tumors in organs of endodermal lineage including liver, pancreas, stomach, small intestine, lung, thymus, and, kidney. This mouse model provides an excellent opportunity to study the tumorigenecity due to disruptions in the TGF-β pathway as well as provide insight into human BWS, a human hereditary cancer syndrome. The Beckwith-Wiedemann syndrome (BWS) has no clear causal mutation, with loss of imprinting at chromosome 11 and amplification of insulin-like growth factor 2 (IGF2), which is also increased (10-20% of cases) in elf+/-and elf+/-/smad3+/- mouse model of BWS. Aims 1. Identify oncogenic pathways that are activated in the elf+/-and elf+/-/smad3+/- tumors 2. Study the molecular mechanism by which loss of TGF-β signaling leads to tumorigenesis in this mouse model of BWS. Methods and Results: 1. Broad micro array analysis revealed a marked increase in gene expression in the Wnt pathway i.e. Wnt11/16, Frizzled4/5 and LRP6. 2. Endogenous ELF interacts with β-catenin which is in the center of Wnt signaling. ELF is also required for localization of β-catenin associated molecule E-cadherin at the adherence junctions. 3. Tumors from elf+/- and elf+/-/smad3+/- mice show a marked abnormal accumulation of nuclear β-catenin and its target gene c-Myc at RNA and protein levels. 4. Tumors from elf+/- and elf+/-/smad3+/- mice also show 10 fold higher protein expression of IGF2 protein. Transcript levels of one of the IGF2 regulators, HIFα is also increased as seen by micro array analysis. Conclusions: 1. Wnt/β-catenin pathway is activated in these mouse models of BWS, and potentially provides a strong therapeutic target in BWS tumors. In human BWS elevated levels of β-catenin has been reported (Pediatr Dev Pathol, 2003 Jul-Aug; 6) 2. ELF could regulate Wnt signaling most likely by direct interaction with β-catenin. 3. Regulation of Wnt/β-catenin signaling by ELF could be mediated by high IGF2. IGF2 has been shown to increase Frizzled mediated Wnt/β-catenin signaling (4). IGF2 is associated with human BWS. The mechanism of IGF2 regulation by ELF is under investigation. 4. Elf+/-and elf+/-/smad3+/- mice present as powerful models for analyzing the pathophysiology of BWS and generating new therapeutics for these cancers.
An agent-based model of insect resistance management and mitigation for Bt maize: a social science perspective.

BACKGROUND Farmers around the world have used Bt maize for more than two decades, delaying resistance using a high-dose/refuge strategy. Nevertheless, field-evolved resistance to Bacillus thuringiensis (Bt) toxins has been documented. This paper describes a spatially explicit population genetics model of resistance to Bt toxins by the insect Ostrinia nubilalis and an agent-based model of farmer adoption of Bt maize incorporating social networks. The model was used to evaluate multiple resistance mitigation policies, including combinations of increased refuges for all farms, localized bans on Bt maize where resistance develops, area-wide sprays of insecticides on fields with resistance and taxes on Bt maize seed for all farms. Evaluation metrics included resistance allele frequency, pest population density, farmer adoption of Bt maize and economic surplus. RESULTS The most effective mitigation policies for maintaining a low resistance allele frequency were 50% refuge and localized bans. Area-wide sprays were the most effective for maintaining low pest populations. Based on economic surplus, refuge requirements were the recommended policy for mitigating resistance to high-dose Bt maize. Social networks further enhanced the benefits of refuges relative to other mitigation policies but accelerated the emergence of resistance. CONCLUSION These results support using refuges as the foundation of resistance mitigation for high-dose Bt maize, just as for resistance management. Other mitigation policies examined were more effective but more costly. Social factors had substantial effects on the recommended management and mitigation of insect resistance, suggesting that agent-based models can make useful contributions for policy analysis.
Perspectives on the Impact of the COVID-19 Pandemic on the Sports Medicine Surgeon – Implications for Current and Future Care

As the COVID-19 (Coronavirus disease 2019) pandemic continues, the paradigm of treatment continues to rapidly evolve, especially for sports medicine surgeons, because treatment before the pandemic was considered predominantly elective. This article provides subjective and objective data on the changes implicated by the COVID-19 pandemic with regard to the interactions and practices of sports medicine surgeons. This perspective also considers the potential impact on the patients and athletes treated by sports medicine surgeons. This article discusses the impact of the COVID-19 pandemic on sports medicine and provides thoughts on how the landscape of the field may continue to change.
Sparse adaptive channel identification method using the cross-relation

Abstract Cross-relation methods can be used for blind channel identification. The conventional algorithm based on the singular value composition is complex, so variations involving adaptive methods have been developed. These have been extended to algorithms that encourage sparsity in the estimated filter response. In this paper, these methods are applied to complex signals and the method is further extended to tie one of the signals to a particular lag as an anchor constraint, enabling it to be used for source localization in multipath environments. Results demonstrate the performance of these modified cross-relation techniques to source localization.
rigrag: high-resolution mapping of genic targeting preferences during HIV-1 integration in vitro and in vivo.

HIV-1 integration favors recurrent integration gene (RIG) targets and genic proviruses can confer cell survival in vivo. However, the relationship between initial RIG integrants and how these evolve in patients over time are unknown. To address these shortcomings, we built phenomenological models of random integration in silico, which were used to identify 3718 RIGs as well as 2150 recurrent avoided genes from 1.7 million integration sites across 10 in vitro datasets. Despite RIGs comprising only 13% of human genes, they harbored 70% of genic HIV-1 integrations across in vitro and patient-derived datasets. Although previously reported to associate with super-enhancers, RIGs tracked more strongly with speckle-associated domains. While depletion of the integrase cofactor LEDGF/p75 significantly reduced recurrent HIV-1 integration in vitro, LEDGF/p75 primarily occupied non-speckle-associated regions of chromatin, suggesting a previously unappreciated dynamic aspect of LEDGF/p75 functionality in HIV-1 integration targeting. Finally, we identified only six genes from patient samples-BACH2, STAT5B, MKL1, MKL2, IL2RB and MDC1-that displayed enriched integration targeting frequencies and harbored proviruses that likely contributed to cell survival. Thus, despite the known preference of HIV-1 to target cancer-related genes for integration, we conclude that genic proviruses play a limited role to directly affect cell proliferation in vivo.
An Uncommonly Difficult Business: Reviewing Women’s Writing in Eighteenth‑Century London’s Subscription Publishing, 1749–1774

In eighteenth-century London, publishing began to transition from a patronage system to a commercial business. An increase in literary reviews accompanied the shift. Publishing by subscription emerged as an evolving form of patronage where authors received monetary support from readers before publication. Women authors found subscription publishing welcoming as a means to avoid the commercial marketplace. Some authors used this publishing method in the name of seeking charitable support. Reviewers linked subscription publishing to female authors and acts of charity as reviewers attempted to circumvent the problem of potentially alienating their own readership, who could be subscribers. Through rhetorical analysis of 171 digitized bound volumes of 11 of London’s literary review periodicals, this paper argues that reviewers’ treatment of women authors and the associated use of subscription publications led to a disparaging perception of both by London’s growing reading public.
Temporal change in chromatin accessibility predicts regulators of nodulation in Medicago truncatula

Rhizobia can establish associations with legumes to provide plants with nitrogen, in a critical symbiosis for agricultural systems. Symbiosis triggers extensive genome and transcriptome remodeling in the plant, yet the extent of chromatin changes and impact on gene expression is unknown. We combined gene regulatory features and their chromatin accessibility (ATAC-seq) profile to predict the temporal transcriptome (RNA-seq) dynamics of roots treated with rhizobia lipo-chitooligosaccharides. Using a novel approach, Dynamic Regulatory Module Networks, we predicted gene expression as a function of regulatory feature chromatin accessibility. This approach uses regularized regression and identifies the cis-regulatory elements and associated transcription factors that most significantly contribute to transcriptomic changes triggered by lipo-chitooligosaccharides. Regulators involved in auxin (SHY2), ethylene (EIN3), and abscisic acid (ABI5) hormone response, as well as histone and DNA methylation (IBM1), emerged among those most predictive of transcriptome dynamics.
Surpassing our genes: The subversive post-human message of 'Gattaca'

Se sol esmentar la pel·licula Gattaca en els debats publics sobre els perills socials de l’edicio genetica humana. En l’imaginari public, el missatge es clar: el seu futur distopic es un avis dels perills que comporta l’acceptacio social del perfeccionisme i la discriminacio genetics. Aquest article defensa que si realitzem aquest tipus de lectures, se’ns escapa un missatge mes profund. Mes que donar una llico de bioetica en contra de l’us de la genetica per a crear millors nadons, el que la pel·licula defensa en realitat, al nostre parer, es que aquesta intromissio genetica dificilment pot tenir exit, pero que crear un individu posthuma superior mitjancant enginyeria genetica es possible i desitjable.
Ultrastructural response of rat lung to 90 days' exposure to oxygen at 450 mm Hg

Young Sprague-Dawley rats were exposed to 100% oxygen at 450 mm Hg in constant environment capsules for 90 days. Lung tissue examined by electron microscopy revealed a number of changes, many similar to those observed after exposure to oxygen at 760 mm Hg for shorter periods of time. Alterations in vesicle size and number and in mitochondrial matrix and cristae appear in both the endothelial and epithelial cells. Blebbing and rarefication of cytoplasm occur in both cell layers of the alveolo-capillary wall. Also seen are fluid in the basement membrane, platelets in the capillaries, and alveolar fluid and debris. All of these alterations occur at 1 atm exposure. However, after exposure to 450 mm Hg the changes are not as widespread nor as destructive as they are at the higher pressure.
A History of the Chinese Language

Preface. List of tables List of figures 1. A Walk Through Time: General Introduction 2. A Tale of Two Tribes: Prehistory 3. Thus Spake Confucius: Sounds of Old Chinese 4. Poetically they dwelt: Sounds of Middle Chinese 5. Marco Polo's Phrasebook: Sounds of Early Modern Chinese 6. Philosophy and History: Classical Chinese 7. Literature and Religion: Vernacular Writing 8. In Other Words: vocabulary change 9. One for all: Modern Standard Chinese 10. Celebration of Diversity: Modern Chinese Dialects 11. The Legend of Cangjie: Chinese characters References Appendices I-V Index
INCENTIVES FOR WELLNESS: TACKLING ISSUES OF EFFECTIVENESS, BIOLOGY, SCOPE, AND COST SHIFTING

Morgan Downey raises several interesting issues in his essay. We agree on several points, for example, that current regulations are "really quite porous," with the result that enrollees will be able to get the rewards even if they do not alter their health behaviors. There are also several areas of disagreement that merit further discussion, and I focus on those in this essay. To provide context, my position is that financial incentives for healthy behavior can improve social welfare by internalizing the external costs of risky behaviors and help people with time-inconsistent preferences to adhere to a healthier lifestyle. To achieve the goal of increasing social welfare, the penalties for risky health behaviors should be set equal to the external costs. The design of the rewards (in terms of their frequency, salience, and the amount of loss aversion they invoke) may be critical in determining their effectiveness.
Cross-gyre transport by North Brazil Current rings.

Abstract Recent observations collected as part of the North Brazil Current Rings Experiment are used to assess the role played by NBC rings in tropical to subtropical cross-gyre transport in the Atlantic Ocean. During the course of the 20 month experiment, four different NBC Rings were surveyed by ships and twelve additional rings were identified by moored current meters and temperature/salinity recorders. Of the total of 16 rings observed, four were subsurface-intensified rings with little or no surface signal. Except for these subsurface rings, generally good agreement was found in the identification of NBC rings during the experiment by various techniques including satellite altimetry, ocean color, and inverted echo sounders. The observations of water properties in the ring cores provided by the in-situ temperature and salinity measurements are used to estimate the trapped core volumes of South Atlantic water in the rings. Based on these new measurements we estimate a ring formation rate of 8-9 rings per year, with no apparent seasonal variation in the formation rate. However, the surface rings show a seasonal cycle in their vertical penetration and associated trapped core volumes. Deeper rings tend to occur in fall and early winter, while shallower rings occur in spring and summer. The subsurface rings are usually smaller in diameter than the surface rings (average radius of maximum velocity 100 km versus 130 km), but have a thicker layer of trapped South Atlantic water and consequently a larger transport per ring. The average ring-induced transport including all ring types is about 1.1 Sv per ring, leading to an estimate of 9.3 Sv for the total annualized ring transport. This value is nearly twice that of most previous estimates, and suggests that NBC rings could account for more than half of the northward transport in the warm limb of the Atlantic meridional overturning cell.
Characterization of the Carbohydrate Fragments Obtained from Saccharomyces cerevisiae Mannan by Alkaline Degradation

Abstract Mild alkaline degradation of Saccharomyces cerevisiae X2180 wild type mannan, under conditions that effect β elimination of the substituted serine and threonine residues, releases mannose, mannobiose, mannotriose, and mannotetraose. Methylation analysis demonstrated that these fragments have the same structures as those that are obtained by acetolysis of the polysaccharide component of the yeast mannan. Similar treatment of a mutant mannan that lacks the mannotetraose unit in the polysaccharide component produced only mannose, mannobiose, and mannotriose. Thus, the single mutation alters both the tetrasaccharide units in the polysaccharide component of the mannan and those that are attached to serine and threonine. Because these studies were carried out on the total cell wall mannan, rather than a single molecular species, we cannot say that both the polysaccharide chains and the shorter oligosaccharides linked to serine and threonine are present in the same molecule. Strong alkaline degradation in the presence of sodium borotritide of the mannan residue recovered from the β elimination reaction yielded a protein-free polysaccharide that gave radioactive N-acetylglucosaminitol on acetolysis. Thus, the mannose-containing polysaccharide of the mannan is attached to glucosamine, and it is probable that the linkage to protein is through a di-N-acetylchitobiose to asparagine as in many other glycoproteins. The mannan isolated from the wild type and mutant strains of S. cerevisiae by procedures that avoid exposure to alkali had a molecular weight of 133,000. On treatment with 0.1 n sodium hydroxide at room temperature, the molecular weight was reduced to about 40,000. These conditions could saponify acyl ester bonds but are unlikely to break phosphodiester linkages or any other linkages except those of the oligosaccharides attached to serine and threonine.
Zero-IF VGA with novel offset cancellation

Reliable offset control is a vital feature of a zero-IF variable gain amplifier (VGA). Many traditional methods sacrifice speed (settling time) to achieve offset control by realizing a high pass feature in the signal path. This paper introduces a novel VGA architecture that is capable of controlling offset for all gain settings with a single offline calibration cycle. The VGA realizes very fast gain/startup settling time with only a slight increase in power and area requirements by eliminating the need for a high pass filter. The VGA circuit draws 3mA and has a gain range of 0/spl sim/42dB with 1dB steps. It has a 10MHz bandwidth at 42dB, has a gain settling time of 140nsec, and controls output offset within 2.2mV.