Changing and unchanging values in the world of the future, November 8, 9, and 10, 2001

This repository item contains a single issue of the Pardee Conference Series, a publication series that began publishing in 2006 by the Boston University Frederick S. Pardee Center for the Study of the Longer-Range Future. This was the Center's Inaugural Conference that took place during November 8, 9, and 10, 2001. Organized by David Fromkin, Director Frederick S. Pardee Center for the Study of the Longer-Range Future. Co-Sponsored by Boston University and Carnegie Council on Ethics and International Affairs.This conference brought together a discussion of different perspectives on what future paradigm shifts will look like – in government, in foreign policy, in what constitutes “classics,” in economic and religious modes, and changes in the interaction between these values. The conference agreed that today’s Western society values democracy, constitutionalism, liberalism, rule of law, open society, and market economy. These are not contingent upon one another and may change. But the “needs and aspirations” of humanity will at their most essential core remain the same. The amount and type of power given to governments is not a fixed thing, and developments in the meaning of democracy and how it is achieved may illustrate this

Civil conflict, federalism and strategic delegation of leadership

This article analyzes negative externalities that policymakers in one region or group may impose upon the citizens of neighboring regions or groups. These externalities may be material, but they may also be psychological (in the form of envy). The latter form of externality may arise from the production of 'conspicuous' public goods. As a result, decentralized provision of conspicuous public goods may be too high. Potentially, a centralized legislature may internalize negative externalities. However, in a model with strategic delegation, we argue that the median voter in each jurisdiction may anticipate a reduction in local public goods supply and delegate to a policymaker who cares more for public goods than she does herself. This last effect mitigates the expected benefits of policy centralization. The authors' theory is then applied to the setting of civil conflict, where they discuss electoral outcomes in Northern Ireland and Yugoslavia before and after significant institutional changes that affected the degree of centralization. These case studies provide support for the authors' theoretical predictions

Respiratory function in patients with lumbar stenosis: a comparative analysis

Degenerative diseases of the spine are conditions that involve loss of structure and normal function of the spine and may lead to worsening functional capacity, decreased exercise tolerance, and reduced quality of life due to neurogenic lameness and chronic low back pain. The choice of arthrodesis is due to the presence of evolutionary neurological injury or intractable pain. Objective: To analyze and compare spirometric values ​​and respiratory muscle strength in patients with lumbar stenosis. Method: Cross-sectional study with 38 patients of both sexes, divided into a group of 19 operated patients and another group of 19 patients awaiting surgery, aged between 50 and 80 years, who were evaluated by spirometry and manovacuometry. Results: In our study, it was observed that pulmonary function was within the reference values, considering that the group of operated patients presented better performance in spirometry and manovacuometry. Conclusion: operated patients showed improvement in lung function compared to non-operated patients.As doenças degenerativas da coluna vertebral são condições que envolvem a perda de estrutura e a função normal da coluna e podem levar à piora da capacidade funcional, a diminuição da tolerância ao exercício e a redução da qualidade de vida por claudicação neurogênica e dor lombar crônica. A escolha da artrodese ocorre devido a presença de lesão neurológica evolutiva ou dor intratável. Objetivo: Analisar e comparar valores espirométricos e força muscular respiratória em pacientes com estenose lombar. Método: Estudo transversal com 38 pacientes de ambos os sexos, dividido em um grupo de 19 pacientes operados e outro grupo de 19 pacientes que aguardavam cirurgia, com idade entre 50 e 80 anos, que foram avaliados por espirometria e manovacuometria. Resultados: Em nosso estudo, observou-se que a função pulmonar estavam dentro dos valores de referências, considerando que o grupo de pacientes operados apresentou melhor desempenho em espirometria e manovacuometria. Conclusão: pacientes operados apresentaram melhora na função pulmonar em comparação com pacientes não operados

Dark Energy Spectroscopic Instrument (DESI) Fiber Positioner Production

The Dark Energy Spectroscopic Instrument (DESI) is under construction to measure the expansion history of the Universe using the Baryon Acoustic Oscillation technique. The spectra of 35 million galaxies and quasars over 14000 sq deg will be measured during the life of the experiment. A new prime focus corrector for the KPNO Mayall telescope will deliver light to 5000 fiber optic positioners. The fibers in turn feed ten broad-band spectrographs. We will describe the production and manufacturing processes developed for the 5000 fiber positioner robots mounted on the focal plane of the Mayall telescope.Comment: SPIE 201

Isodicentric Y Chromosomes and Sex Disorders as Byproducts of Homologous Recombination that Maintains Palindromes

Massive palindromes in the human Y chromosome harbor mirror-image gene pairs essential for spermatogenesis. During evolution, these gene pairs have been maintained by intrapalindrome, arm-to-arm recombination. The mechanism of intrapalindrome recombination and risk of harmful effects are unknown. We report 51 patients with isodicentric Y (idicY) chromosomes formed by homologous crossing over between opposing arms of palindromes on sister chromatids. These ectopic recombination events occur at nearly all Y-linked palindromes. Based on our findings, we propose that intrapalindrome sequence identity is maintained via noncrossover pathways of homologous recombination. DNA double-strand breaks that initiate these pathways can be alternatively resolved by crossing over between sister chromatids to form idicY chromosomes, with clinical consequences ranging from spermatogenic failure to sex reversal and Turner syndrome. Our observations imply that crossover and noncrossover pathways are active in nearly all Y-linked palindromes, exposing an Achilles' heel in the mechanism that preserves palindrome-borne genes.National Institutes of Health (U.S.)Howard Hughes Medical InstituteNetherlands Organization for Scientific ResearchUniversity of Amsterdam. Academic Medical CenterBoehringer Ingelheim (Fellowship

Trial of SAGE-217 in Patients with Major Depressive Disorder

BACKGROUND: Altered neurotransmission of gamma-aminobutyric acid (GABA) has been implicated in the pathogenesis of depression. Whether SAGE-217, an oral, positive allosteric modulator of GABA type A receptors, is effective and safe for the treatment of major depressive disorder is unknown. METHODS: In this double-blind, phase 2 trial, we enrolled patients with major depression and randomly assigned them in a 1:1 ratio to receive 30 mg of SAGE-217 or placebo once daily. The primary end point was the change from baseline to day 15 in the score on the 17-item Hamilton Depression Rating Scale (HAM-D; scores range from 0 to 52, with higher scores indicating more severe depression). Secondary efficacy end points, which were assessed on days 2 through 8 and on days 15, 21, 28, 35, and 42, included changes from baseline in scores on additional depression and anxiety scales, a reduction from baseline of more than 50% in the HAM-D score, a HAM-D score of 7 or lower, and a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) (on a scale of 1 to 7, with a score of 7 indicating that symptoms are very much worse). RESULTS: A total of 89 patients underwent randomization: 45 patients were assigned to the SAGE-217 group, and 44 to the placebo group. The mean baseline HAM-D score was 25.2 in the SAGE-217 group and 25.7 in the placebo group. The least-squares mean (+/-SE) change in the HAM-D score from baseline to day 15 was -17.4+/-1.3 points in the SAGE-217 group and -10.3+/-1.3 points in the placebo group (least-squares mean difference in change, -7.0 points; 95% confidence interval, -10.2 to -3.9; P \u3c 0.001). The differences in secondary end points were generally in the same direction as those of the primary end point. There were no serious adverse events. The most common adverse events in the SAGE-217 group were headache, dizziness, nausea, and somnolence. CONCLUSIONS: Administration of SAGE-217 daily for 14 days resulted in a reduction in depressive symptoms at day 15. Adverse events were more common in the SAGE-217 group than in the placebo group. Further trials are needed to determine the durability and safety of SAGE-217 in major depressive disorder and to compare SAGE-217 with available treatments. (Funded by Sage Therapeutics; ClinicalTrials.gov number, NCT03000530.)

TWIST1 promotes invasion through mesenchymal change in human glioblastoma

Background: Tumor cell invasion into adjacent normal brain is a mesenchymal feature of GBM and a major factor contributing to their dismal outcomes. Therefore, better understandings of mechanisms that promote mesenchymal change in GBM are of great clinical importance to address invasion. We previously showed that the bHLH transcription factor TWIST1 which orchestrates carcinoma metastasis through an epithelial mesenchymal transition (EMT) is upregulated in GBM and promotes invasion of the SF767 GBM cell line in vitro. Results: To further define TWIST1 functions in GBM we tested the impact of TWIST1 over-expression on invasion in vivo and its impact on gene expression. We found that TWIST1 significantly increased SNB19 and T98G cell line invasion in orthotopic xenotransplants and increased expression of genes in functional categories associated with adhesion, extracellular matrix proteins, cell motility and locomotion, cell migration and actin cytoskeleton organization. Consistent with this TWIST1 reduced cell aggregation, promoted actin cytoskeletal re-organization and enhanced migration and adhesion to fibronectin substrates. Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. Distinct from carcinoma EMT, TWIST1 did not generate an E- to N-cadherin "switch" in GBM cell lines. The clinical relevance of putative TWIST target genes SNAI2 and fibroblast activation protein alpha (FAP) identified in vitro was confirmed by their highly correlated expression with TWIST1 in 39 human tumors. The potential therapeutic importance of inhibiting TWIST1 was also shown through a decrease in cell invasion in vitro and growth of GBM stem cells. Conclusions: Together these studies demonstrated that TWIST1 enhances GBM invasion in concert with mesenchymal change not involving the canonical cadherin switch of carcinoma EMT. Given the recent recognition that mesenchymal change in GBMs is associated with increased malignancy, these findings support the potential therapeutic importance of strategies to subvert TWIST1-mediated mesenchymal change

TEX11 is mutated in infertile men with azoospermia and regulates genome-wide recombination rates in mouse

Genome‐wide recombination is essential for genome stability, evolution, and speciation. Mouse Tex11, an X‐linked meiosis‐specific gene, promotes meiotic recombination and chromosomal synapsis. Here, we report that TEX11 is mutated in infertile men with non‐obstructive azoospermia and that an analogous mutation in the mouse impairs meiosis. Genetic screening of a large cohort of idiopathic infertile men reveals that TEX11 mutations, including frameshift and splicing acceptor site mutations, cause infertility in 1% of azoospermic men. Functional evaluation of three analogous human TEX11 missense mutations in transgenic mouse models identified one mutation (V748A) as a potential infertility allele and found two mutations non‐causative. In the mouse model, an intronless autosomal Tex11 transgene functionally substitutes for the X‐linked Tex11 gene, providing genetic evidence for the X‐to‐autosomal retrotransposition evolution phenomenon. Furthermore, we find that TEX11 protein levels modulate genome‐wide recombination rates in both sexes. These studies indicate that TEX11 alleles affecting expression level or substituting single amino acids may contribute to variations in recombination rates between sexes and among individuals in humans.Howard Hughes Medical Institute (Award)National Institutes of Health (U.S.) (NIH/NIGMS grant R01GM076327

Tissue coverage of a hydrophilic polymer-coated zotarolimus-eluting stent vs. a fluoropolymer-coated everolimus-eluting stent at 13-month follow-up: an optical coherence tomography substudy from the RESOLUTE All Comers trial

Aims To compare the tissue coverage of a hydrophilic polymer-coated zotarolimus-eluting stent (ZES) vs. a fluoropolymer-coated everolimus-eluting stent (EES) at 13 months, using optical coherence tomography (OCT) in an ‘all-comers' population of patients, in order to clarify the mechanism of eventual differences in the biocompatibility and thrombogenicity of the devices. Methods and results Patients randomized to angiographic follow-up in the RESOLUTE All Comers trial (NCT00617084) at pre-specified OCT sites underwent OCT follow-up at 13 months. Tissue coverage and apposition were assessed strut by strut, and the results in both treatment groups were compared using multilevel logistic or linear regression, as appropriate, with clustering at three different levels: patient, lesion, and stent. Fifty-eight patients (30 ZES and 28 EES), 72 lesions, 107 stents, and 23 197 struts were analysed. Eight hundred and eighty-seven and 654 uncovered struts (7.4 and 5.8%, P= 0.378), and 216 and 161 malapposed struts (1.8 and 1.4%, P= 0.569) were found in the ZES and EES groups, respectively. The mean thickness of coverage was 116 ± 99 µm in ZES and 142 ± 113 µm in EES (P= 0.466). No differences in per cent neointimal volume obstruction (12.5 ± 7.9 vs. 15.0 ± 10.7%) or other areas-volumetric parameters were found between ZES and EES, respectively. Conclusion No significant differences in tissue coverage, malapposition, or lumen/stent areas and volumes were detected by OCT between the hydrophilic polymer-coated ZES and the fluoropolymer-coated EES at 13-month follow-u

Overview of the Dark Energy Spectroscopic Instrument

The Dark Energy Spectroscopic Instrument (DESI) is under construction to measure the expansion history of the Universe using the Baryon Acoustic Oscillation technique. The spectra of 35 million galaxies and quasars over 14000 square degrees will be measured during the life of the experiment. A new prime focus corrector for the KPNO Mayall telescope will deliver light to 5000 fiber optic positioners. The fibers in turn feed ten broad-band spectrographs. We present an overview of the instrumentation, the main technical requirements and challenges, and the current status of the project.Comment: 11 pages, 4 figure