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Modern wind turbines already represent a tightly optimized confluence of materials science and aerodynamic engineering. Veers et al. review the challenges and opportunities for further expanding this technology, with an emphasis on the need for interdisciplinary collaboration. They highlight the need to better understand atmospheric physics in the regions where taller turbines will operate as well as the materials constraints associated with the scale-up. The mutual interaction of turbine sites with one another and with the evolving features of the overall electricity grid will furthermore necessitate a systems approach to future development. Science , this issue p. eaau2027 Harvested by advanced technical systems honed over decades of research and development, wind energy has become a mainstream energy resource. However, continued innovation is needed to realize the potential of wind to serve the global demand for clean energy. Here, we outline three interdependent, cross-disciplinary grand challenges underpinning this research endeavor. The first is the need for a deeper understanding of the physics of atmospheric flow in the critical zone of plant operation. The second involves science and engineering of the largest dynamic, rotating machines in the world. The third encompasses optimization and control of fleets of wind plants working synergistically within the electricity grid. Addressing these challenges could enable wind power to provide as much as half of our global electricity needs and perhaps beyond.

High-school writing prompts often ask students to provide overly simplified responses to complicated issues, but a person's stance in the real world can rarely, if ever, be reduced to \"agree or disagree.\" Arguments are complex, with more than two points of view and a range of evidence to consider; however, writing classes don't always embrace that.

The fiercely competitive electronic (semiconductor) industry is in constant need of denser and thus faster integrated computer chips, especially for dynamic random access memory (DRAM). This achievement is accomplished by drastically reducing the size of fabricated electronic devices by obtaining extremely higher quality X-ray lithography masks through an optimized mask writing process. Two important considerations in obtaining a feasible mask writing process are in-plane vibration due to mask stepping and in-plane distortion due to sequential stress relief of the resist. The original and wide spread assumption that the mask support ring and mask wafer stiffness act as a fixed boundary for the X-ray mask membrane appears to be incorrect. The inertia of the mask support ring greatly outweighs stiffness considerations and the membrane and mask wafer \"ride along\" as the support ring oscillates in-plane. Thus only the ring needs to be analyzed to determine motion of the membrane. The finite element analyses show that structural damping must be kept below about 1% to prevent unacceptably long wait times between cell patterning. The analysis of in-situ resist stress relief during writing has produced a number of guidelines concerning the maximum resultant distortion. The pattern density of the cells, resist stress, and resist thickness were all directly proportional to the maximum resultant distortion vector while the membrane thickness and membrane Young's modulus were inversely proportional. The analysis of writing styles showed that while the unidirectional method is more accurate than the serpentine approach, both are inferior to the Laird spiral. This new writing approach matches the writing speed of the serpentine writing style and has significantly reduced distortion when compared to either of the existing approaches. Finally, the analysis presented here gives a quantative understanding of how multi-pass writing can reduce pattern placement errors at the expense of feature drift. Such information can now be used by the semiconductor industry to increase the accuracy of the patterning process while maximizing throughput.

Using the results from four separate experiments, a sensitivity analysis of cardiac output, stroke volume, heart rate, and mean arterial pressure to +GZ acceleration, anti-G suit pressure, and positive pressure breathing was conducted. All four hemodynamic parameters showed significant sensitivity to +GZ acceleration with the cardiac output being approximately half as sensitive as the other three parameters. Cardiac output and stroke volume were an order of magnitude more sensitve to anti-G suit pressure than heart rate and mean arterial pressure. Mean arterial pressure was the most sensitive to positive pressure breathing. A review of various controller types was undertaken in order to suggest an appropriate closed-loop protection system which could be used by pilots of high performance aircraft such as jets and space vehicles. An adaptive neural network controller was found to be the most suitable for this application since it allows the physiological parameters to be incorporated into the feedback system as well as the aircraft parameters. This type of controller can also be tuned to meet the needs of individual pilots and maximize Gtolerance. The initial tuning of the controller can be based on the sensitivity analysis conducted in this thesis.

Based on ethnographic field research in Bethlehem, West Bank, in 1995-1996, I examine the shared discursive space inhabited by Islamic, Christian and secular nationalist symbols and narratives in contemporary Palestinian society. I argue that the Israeli occupation of Bethlehem provides the context that shapes the normal processes of selective appropriation of religious tradition among Palestinian Christians and Muslims, particularly the selective emphasis on symbolic persons. Further, I speculate on the ways in which Palestinian Muslims and Christians employ the symbolic narratives of martyrs, heroes and saints in the construction of multiple identities and group boundaries on the national, communal and personal levels of discourse. The thesis is organized around four central chapters, which present case studies of symbolic persons in contemporary Palestinian discourse and practice: (1) Jesus as a Palestinian revolutionary martyr; (2) the Christian saint Mar Jiryis (St. George), conflated in popular discourse and practice with the Muslim saint Khadr (Khidr); (3) the conqueror-heroes 'Umar ibn al-Khattab and Salah al-Din al-Ayyubi, symbols of national liberation and interfaith tolerance; and (4) martyrs of the Palestinian intifadah as the embodiment of the Palestinian collective experience. I examine the variety of ways in which traditional Christian and Islamic narratives of these figures are filtered through local and national political events and ideologies as well as the everyday experiences and religious practices of individuals. These case studies drawn from a local Palestinian context shed light on academic discussions of religion and nationalism, religion and politics, myth and historical memory, contextual theology and interfaith relations, and the syncretic use of symbols in popular theological and political discourse.

Bioregionalism is an innovative way of thinking about place and planet from an ecological perspective. Although bioregional ideas occur regularly in ecocritical writing, until now no systematic effort has been made to outline the principles of bioregional literary criticism and to use it as a way to read, write, understand, and teach literature. The twenty-four original essays here are written by an outstanding selection of international scholars. The range of bioregions covered is global and includes such diverse places as British Columbia's Meldrum Creek and Italy's Po River Valley, the Arctic and the Outback. There are even forays into cyberspace and outer space. In their comprehensive introduction, the editors map the terrain of the bioregional movement, including its history and potential to inspire and invigorate place-based and environmental literary criticism. Responding to bioregional tenets, this volume is divided into four sections. The essays in the \"Reinhabiting\" section narrate experiments in living-in-place and restoring damaged environments. The \"Rereading\" essays practice bioregional literary criticism, both by examining texts with strong ties to bioregional paradigms and by opening other, less-obvious texts to bioregional analysis. In \"Reimagining,\" the essays push bioregionalism to evolve-by expanding its corpus of texts, coupling its perspectives with other approaches, or challenging its core constructs. Essays in the \"Renewal\" section address bioregional pedagogy, beginning with local habitat studies and concluding with musings about the Internet. In response to the environmental crisis, we must reimagine our relationship to the places we inhabit. This volume shows how literature and literary studies are fundamental tools to such a reimagining.

DNA methylation loss occurs frequently in cancer genomes, primarily within lamina-associated, late-replicating regions termed partially methylated domains (PMDs). We profiled 39 diverse primary tumors and 8 matched adjacent tissues using whole-genome bisulfite sequencing (WGBS) and analyzed them alongside 343 additional human and 206 mouse WGBS datasets. We identified a local CpG sequence context associated with preferential hypomethylation in PMDs. Analysis of CpGs in this context (‘solo-WCGWs’) identified previously undetected PMD hypomethylation in almost all healthy tissue types. PMD hypomethylation increased with age, beginning during fetal development, and appeared to track the accumulation of cell divisions. In cancer, PMD hypomethylation depth correlated with somatic mutation density and cell cycle gene expression, consistent with its reflection of mitotic history and suggesting its application as a mitotic clock. We propose that late replication leads to lifelong progressive methylation loss, which acts as a biomarker for cellular aging and which may contribute to oncogenesis. Whole-genome DNA methylation profiling and analysis of normal tissues from both human and mouse reveal that hypomethylation within partially methylated, late-replicating domains depends on sequence context, starts early in development, accumulates with cell divisions and progresses with organismal aging.

Glasdegib is a Hedgehog pathway inhibitor. This phase II, randomized, open-label, multicenter study (ClinicalTrials.gov, NCT01546038) evaluated the efficacy of glasdegib plus low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome unsuitable for intensive chemotherapy. Glasdegib 100 mg (oral, QD) was administered continuously in 28-day cycles; LDAC 20 mg (subcutaneous, BID) was administered for 10 per 28 days. Patients (stratified by cytogenetic risk) were randomized (2:1) to receive glasdegib/LDAC or LDAC. The primary endpoint was overall survival. Eighty-eight and 44 patients were randomized to glasdegib/LDAC and LDAC, respectively. Median (80% confidence interval [CI]) overall survival was 8.8 (6.9–9.9) months with glasdegib/LDAC and 4.9 (3.5–6.0) months with LDAC (hazard ratio, 0.51; 80% CI, 0.39–0.67, P  = 0.0004). Fifteen (17.0%) and 1 (2.3%) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission ( P  < 0.05). Nonhematologic grade 3/4 all-causality adverse events included pneumonia (16.7%) and fatigue (14.3%) with glasdegib/LDAC and pneumonia (14.6%) with LDAC. Clinical efficacy was evident across patients with diverse mutational profiles. Glasdegib plus LDAC has a favorable benefit–risk profile and may be a promising option for AML patients unsuitable for intensive chemotherapy.

The role of DNA cytosine methylation, an epigenetic regulator of chromatin structure and function, during normal and pathological brain development and aging remains unclear. Here, we examined by MethyLight PCR the DNA methylation status at 50 loci, encompassing primarily 5' CpG islands of genes related to CNS growth and development, in temporal neocortex of 125 subjects ranging in age from 17 weeks of gestation to 104 years old. Two psychiatric disease cohorts--defined by chronic neurodegeneration (Alzheimer's) or lack thereof (schizophrenia)--were included. A robust and progressive rise in DNA methylation levels across the lifespan was observed for 8/50 loci (GABRA2, GAD1, HOXA1, NEUROD1, NEUROD2, PGR, STK11, SYK) typically in conjunction with declining levels of the corresponding mRNAs. Another 16 loci were defined by a sharp rise in DNA methylation levels within the first few months or years after birth. Disease-associated changes were limited to 2/50 loci in the Alzheimer's cohort, which appeared to reflect an acceleration of the age-related change in normal brain. Additionally, methylation studies on sorted nuclei provided evidence for bidirectional methylation events in cortical neurons during the transition from childhood to advanced age, as reflected by significant increases at 3, and a decrease at 1 of 10 loci. Furthermore, the DNMT3a de novo DNA methyl-transferase was expressed across all ages, including a subset of neurons residing in layers III and V of the mature cortex. Therefore, DNA methylation is dynamically regulated in the human cerebral cortex throughout the lifespan, involves differentiated neurons, and affects a substantial portion of genes predominantly by an age-related increase.

Reversal of HIV-1 latency by small molecules is a potential cure strategy. This approach will likely require effective drug combinations to achieve high levels of latency reversal. Using resting CD4+ T cells (rCD4s) from infected individuals, we developed an experimental and theoretical framework to identify effective latency-reversing agent (LRA) combinations. Utilizing ex vivo assays for intracellular HIV-1 mRNA and virion production, we compared 2-drug combinations of leading candidate LRAs and identified multiple combinations that effectively reverse latency. We showed that protein kinase C agonists in combination with bromodomain inhibitor JQ1 or histone deacetylase inhibitors robustly induce HIV-1 transcription and virus production when directly compared with maximum reactivation by T cell activation. Using the Bliss independence model to quantitate combined drug effects, we demonstrated that these combinations synergize to induce HIV-1 transcription. This robust latency reversal occurred without release of proinflammatory cytokines by rCD4s. To extend the clinical utility of our findings, we applied a mathematical model that estimates in vivo changes in plasma HIV-1 RNA from ex vivo measurements of virus production. Our study reconciles diverse findings from previous studies, establishes a quantitative experimental approach to evaluate combinatorial LRA efficacy, and presents a model to predict in vivo responses to LRAs.