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This book examines deterrence theory, using a multidisciplinary approach to look for evidence of its validity. The contributors aim to understand the conditions under which a strong threat of punishment produces either restraint in an adversary or leads to undesired military escalation, as it seems to have done in some international crises in the past. It looks at qualitative and quantitative studies of international military crises and game theoretical models. It also considers indirect evidence from the study of international trade conflicts, revolutions, interpersonal conflict and small market competition. It concludes that deterrence theory is neither valid nor invalid and that it is more productive to look for conditional statements about when the theory holds true.

There is growing understanding that life evolution on Earth is intimately related to and shaped by the global tectono-magmatic style that evolved through geological time until modern plate tectonics was established in the Neoproterozoic, between 1000 and 541 million years ago. The co-evolution of life and tectonics on Earth is the subject of Biogeodynamics—an emerging field at the interface between the disciplines of geodynamics, geomorphology, climate, ocean and atmosphere sciences, geobiology, and ecology. Biogeodynamics focuses on how evolution of the planetary interiors, surface, atmosphere, ocean, climate, and life interact and interrelate. Here, we review the state of the art for our understanding of co-evolution of modern plate tectonics and complex life. We start by explaining what Biogeodynamics is, then explain what are the modern plate tectonics and single-lid tectonics and how these differ, and then discuss how plate tectonics controls global terrestrial biodiversity today. We summarize first biodiversity in the Mesoproterozoic and Neoproterozoic, including how evolution accelerated remarkably in the Neoproterozoic and then summarize geological evidence for a protracted Mesoproterozoic single lid that was slowly transformed in Neoproterozoic time into the modern global plate tectonic mosaic. We next explore how the Neoproterozoic tectonic revolution enhanced five factors that accelerated biological evolution: (1) increased nutrient supply; (2) increased free oxygen in the atmosphere and ocean; (3) climate amelioration; (4) accelerated habitat formation; and (5) moderate sustained environmental pressure. Finally, we suggest some avenues for future biogeodynamic research into the co-evolution of Earth's tectonics and Biosphere. A 5-min video overview can be seen at https://www.youtube.com/watch?v=4jaMCz71ejc&t=5s.

Additional file 1. Supplementary Materials. This file includes a detailed description of the immunostaining methods and the search queries for the literature search.

Additional file 1: Supplemental Table 1. Self- and Informant-Reported Symptomatic Status of Participants at Time of Study Screening. Supplemental Table 2. Baseline Neuropsychological Test Performance of the Asymptomatic Unexposed Men. Supplemental Table 3. T-Score Distributions of Baseline Neuropsychological Test Performance of the Asymptomatic Unexposed Men. Supplemental Table 4. Baseline Neuropsychological Test Performance of the Former College and Professional Football Players. Supplemental Table 5. T-Score Distributions of Baseline Neuropsychological Test Performance for Former College and Professional Football Players.

Background Gender inequity is widespread in academic medicine, including in the promotion, academic recognition, and compensation of female faculty. Objective To assess whether these inequities extend to the GME intern selection process, this study examines differences in the interview scores assigned to male and female applicants at one large internal medicine residency program. Methods Subjects include 1399 applicants who completed 3099 interviews for internship positions for the Brigham and Women's Hospital internal medicine residency in Electronic Residency Application Service (ERAS) cycles 2015–2016, 2017–2018, 2018–2019, and 2019–2020. Unadjusted and multivariable linear regressions were used to assess the simultaneous effect of applicant gender, interviewer gender, and applicant academic characteristics on pre-interview, post-interview, and change in interview scores. Results Our analysis included 3027 interviews (97.7%) of 1359 applicants (97.1%). There were no statistically significant differences in the interview scores assigned to female versus male applicants. This was true across pre-interview scores (difference = 0.03, P = .61), post-interview scores (difference = 0.00, P = .98), and change in interview scores (difference = 0.01, P = .24) as well as when adjusting for the baseline academic characteristics of both male and female applicants. This was also true when analyzing individual application years, individual residency tracks, and accounting for the gender of the faculty interviewers. Conclusions The findings do not support the presence of gender inequity in the interview scores assigned to male and female applicants included in this study.

PurposeFlourine-18-flortaucipir tau positron emission tomography (PET) was developed for the detection for Alzheimer's disease. Human imaging studies have begun to investigate its use in chronic traumatic encephalopathy (CTE). Flortaucipir-PET to autopsy correlation studies in CTE are needed for diagnostic validation. We examined the association between end-of-life flortaucipir PET and postmortem neuropathological measurements of CTE-related tau in six former American football players.MethodsThree former National Football League players and three former college football players who were part of the DIAGNOSE CTE Research Project died and agreed to have their brains donated. The six players had flortaucipir (tau) and florbetapir (amyloid) PET prior to death. All brains from the deceased participants were neuropathologically evaluated for the presence of CTE. On average, the participants were 59.0 (SD = 9.32) years of age at time of PET. PET scans were acquired 20.33 (SD = 13.08) months before their death. Using Spearman correlation analyses, we compared flortaucipir standard uptake value ratios (SUVRs) to digital slide-based AT8 phosphorylated tau (p-tau) density in a priori selected composite cortical, composite limbic, and thalamic regions-of-interest (ROIs).ResultsFour brain donors had autopsy-confirmed CTE, all with high stage disease (n = 3 stage III, n = 1 stage IV). Three of these four met criteria for the clinical syndrome of CTE, known as traumatic encephalopathy syndrome (TES). Two did not have CTE at autopsy and one of these met criteria for TES. Concomitant pathology was only present in one of the non-CTE cases (Lewy body) and one of the CTE cases (motor neuron disease). There was a strong association between flortaucipir SUVRs and p-tau density in the composite cortical (ρ = 0.71) and limbic (ρ = 0.77) ROIs. Although there was a strong association in the thalamic ROI (ρ = 0.83), this is a region with known off-target binding. SUVRs were modest and CTE and non-CTE cases had overlapping SUVRs and discordant p-tau density for some regions.ConclusionsFlortaucipir-PET could be useful for detecting high stage CTE neuropathology, but specificity to CTE p-tau is uncertain. Off-target flortaucipir binding in the hippocampus and thalamus complicates interpretation of these associations. In vivo biomarkers that can detect the specific p-tau of CTE across the disease continuum are needed.

Additional file 4: Table e-1. Estimated Marginal Means and SEM in parentheses for rank normalized CSF analyte measurements from No CTE/no AD (control) group; showing ANCOVA adjusted for age, p

Additional file 1. Supplemental results

Additional file 1.

Supplementary Table 5: Whole rock isotopic compositions of Sr, Nd, and Pb.

Supplementary Document 1: Analytical Techniques.

Appendix A. Detailed analytical procedure

Supplementary Figure 1: Cathodluminescence (CL) images of zircons from samples of the Atud igneous complex.

IntroductionRecent research with neuropathologic or biomarker evidence of Alzheimer's disease (AD) casts doubt on traumatic brain injury (TBI) as a risk factor for AD. We leveraged the National Alzheimer's Coordinating Center to examine the association between self-reported TBI with loss of consciousness and AD neuropathologic changes, and with baseline and longitudinal clinical status.MethodsThe sample included 4761 autopsy participants (453 with remote TBI with loss of consciousness; 2822 with AD neuropathologic changes) from National Alzheimer's Coordinating Center.ResultsSelf-reported TBI did not predict AD neuropathologic changes (P>.10). Reported TBI was not associated with baseline or change in dementia severity or cognitive function in participants with or without autopsy-confirmed AD.DiscussionSelf-reported TBI with loss of consciousness may not be an independent risk factor for clinical or pathological AD. Research that evaluates number and severity of TBIs is needed to clarify the neuropathological links between TBI and dementia documented in other large clinical databases.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Figure S1. Aβ, TDP-43 and PrP immunoreactivity in CTE Cases 1–3. a: Widespread Aβ deposits in the subpial surface (arrow) and core dense Aβ plaques (arrowhead) in the frontal cortex. b: TDP-43 cytoplasmic inclusions (arrow) and “dot-like” structures (arrowhead) in the hippocampus. c and d: Plaque-like PrP deposits (arrow in c) and intense PrP immunoreactivity in the subcortical white matter of the temporal lobe. e and f: Granular Aβ deposits (e) and diffuse Aβ plaques (f) in the parietal (e) and frontal (f) cortices; e, inset: a rare core dense Aβ plaque. Abs: 4G8 (a, e, f), TDP-43 in (b), 3F4 (c and d). Scalebar inset in e: 20 μm. (PDF 3628 kb)

Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)–based tests ( P −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE e4 allele with NFIC SNP. We also obtained GWS evidence ( P −6 ) for gene-based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

PurposeTo determine if older patients with breast cancer have cognitive impairment before systemic therapy.Patients and methodsParticipants were patients with newly diagnosed nonmetastatic breast cancer and matched friend or community controls age > 60 years without prior systemic treatment, dementia, or neurologic disease. Participants completed surveys and a 55-minute battery of 17 neuropsychological tests. Biospecimens were obtained for APOE genotyping, and clinical data were abstracted. Neuropsychological test scores were standardized using control means and standard deviations (SDs) and grouped into five domain z scores. Cognitive impairment was defined as any domain z score two SDs below or ≥ two z scores 1.5 SDs below the control mean. Multivariable analyses evaluated pretreatment differences considering age, race, education, and site; comparisons between patient cases also controlled for surgery.ResultsThe 164 patient cases and 182 controls had similar neuropsychological domain scores. However, among patient cases, those with stage II to III cancers had lower executive function compared with those with stage 0 to I disease, after adjustment (P = .05). The odds of impairment were significantly higher among older, nonwhite, less educated women and those with greater comorbidity, after adjustment. Patient case or control status, anxiety, depression, fatigue, and surgery were not associated with impairment. However, there was an interaction between comorbidity and patient case or control status; comorbidity was strongly associated with impairment among patient cases (adjusted odds ratio, 8.77; 95% CI, 2.06 to 37.4; P = .003) but not among controls (P = .97). Only diabetes and cardiovascular disease were associated with impairment among patient cases.ConclusionThere were no overall differences between patients with breast cancer and controls before systemic treatment, but there may be pretreatment cognitive impairment within subgroups of patient cases with greater tumor or comorbidity burden.

Careful selection of statistical analysis is crucial in concussion research utilizing retrospective self-report. Spurious associations are lost after adjusting for reporting bias.

ヒアルロニダーゼは最近まで説明することなど必要ないと考えられていた酵素群である。これらの酵素の基質であるヒアルロナンは、徐々に重要性が増し、今や細胞の運動性、傷害治癒、発生のような基本的な過程において主要な役割を果たしており、また癌の進展にも関与していることが認められている。ヒトを悩ます下等生物においてもヒアルロニダーゼは、下等生物が侵入する際や体の中に広がっていく時に関与している、即ち細菌の有毒因子として、ガス壊その組織切開に対する病毒因子として、梅毒においてトレポネーマの広がる手段として、寄生生物ネマトーダが皮膚や内蔵へ潜り込む方法としてヒアルロニダーゼは使われている。またヒアルロニダーゼはハチ、スズメバチ、クモ、サンショウオ、ヘビ、トカゲ等多くの生物の毒液の成分でもある。これらの毒液のヒアルロニダーゼのあるものとほ乳類の精子の細胞膜に見出される酵素との間に相同性のあることは特に興味深く、酵素タンパク質の300アミノ酸の36%が保持されていることから古いタンパク質であることが分かる。明らかにヒアルロニダーゼは、多くの重要なヒトの病気の病態に関与した生物学的に興味深い酵素である。最近までなおざりにされてきたこれらの一群の酵素についてさらに研究を進めていかなくてはならない。

The Motion Sickness Assessment Questionnaire (MSAQ) was developed in order to assess the multiple dimensions of the motion sickness syndrome (gastrointestinal, central nervous system, peripheral, and sopite-related symptoms). The aim of this study was to evaluate the psychometric properties of the Greek version of the MSAQ.The MSAQ was translated into Greek and then translated back into English. Minor differences between the two texts were corrected. The Greek version was then administered to male subjects before and after nauseogenic motion stimulation. With the use of a motor driven rotating chair, the subjects were exposed to Coriolis cross-coupling stimulation. A battery of statistical tests was used to evaluate the psychometric properties of the MSAQ.There were 112 subjects who participated. Internal consistency, measured with Cronbach's alpha coefficient, was excellent for the total scale and subscales. The test-retest evaluation was done with Pearson's coefficient and Bland-Altman's plot for the total score and subscales and showed statistically significant results. Mean total MSAQ score was 19.04 before the exposure and 33.46 after the exposure, which was statistically significant.Results suggest the Greek-MSAQ is a valid instrument with satisfactory internal consistency, reliability, reproducibility, validity, and responsiveness and can be used in future studies of motion sickness in Greek speaking populations. Kousoulis P, Pantes A, Alevetsovitis G, Fydanaki O. Psychometric properties of the Greek version of the Gianaros Motion Sickness Assessment Questionaire. Aerosp Med Hum Perform. 2016; 87(11):954-957.

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Table S1. Molecular classification of sCJD subtypes [8, 15]. Table S2 showing sex, sCJD subtype, age at onset and death, disease duration in study cases and respective controls. (DOCX 17 kb)

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Table S1. Molecular classification of sCJD subtypes [8, 15]. Table S2 showing sex, sCJD subtype, age at onset and death, disease duration in study cases and respective controls. (DOCX 17 kb)

This chapter construes Kant’s contention that a categorical imperative is a synthetic a priori principle as equivalent to Gewirth’s claim that such an imperative is a dialectically necessary principle (a strict requirement of agential self-understanding). It is not concerned to defend either Kant’s or Gewirth’s argument for a categorical imperative, but to elucidate the “dialectically necessary method” (which rests on the dialectical necessity of a principle making it categorically binding) and to defend this method against David Enoch’s critique of “constitutivism” (taken as trying to show that transcendental arguments for morality, construed as dialectically necessary ones, are futile, even if they can be successful, because normativity cannot be constituted in dialectical necessity). In the process, it relates the dialectically necessary method to internalism, naturalism, foundationalism, coherentism, and realism.

The geochemical and Sr–Nd–Pb isotope properties, as well as the Laser Ablation Inductively Coupled Plasma and Mass Spectrometry (LA-ICP-MS) U–Pb zircon age, of Eğrikar Monzogranite in the eastern Pontides, are primarily investigated in this study with the aim of determining its magma source and geodynamic evolution. The U–Pb zircon age obtained from Eğrikar Monzogranite is 78 ± 1.5 Ma, thereby reflecting the age of monzogranite. The I-type Eğrikar Monzogranite comprises quartz, plagioclase (An35–45), orthoclase, muscovite, and biotite. The geochemical analyses of the Eğrikar Monzogranite indicate being medium K calc-alkaline, peraluminous, and resembling magmatic arc granite. The Eğrikar Monzogranite is enriched in large ion lithophile elements and light rare earth elements relative to high field strength elements. Chondrite-normalized rare earth element patterns have concave upward shapes (LaN/YbN 2.47–8.58) with pronounced negative Eu anomalies (EuN/Eu* = 0.29–0.65). Initial εNd(i) values vary between 1.85 and 2.18 and initial 87Sr/86Sr values between 0.7048 and 0.7067. Fractionation of plagioclase, hornblende, and apatite played an important role in the evolution of Eğrikar Monzogranite. The crystallization temperatures of the melts ranged from 770°C to 919°C based on zircon and apatite saturation temperatures. The geochemical and isotopic data suggest being generated by the partial melting of mafic lower crustal sources.

Livros resenhado:NEUMANN, Dietrich; STERN, Robert A. M. The structure of light: Richard Kelly and the illumination of modern architecture. New York: Yale University Press, 2010, 214 p. ISBN: 978-0-300-16370-4

is missing (Short communication).

We investigate the link between productivity of firms and their sourcing behavior. Following Antràs and Helpman (2004) we distinguish between domestic and foreign sourcing, as well as between outsourcing and vertical integration. A firm's choice is driven by a hold-up problem caused by lack of enforceable contracts. We use Spanish firm-level data to examine the productivity premia associated with the different sourcing strategies.

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