Genomics:GTL Bioenergy Research Centers White Paper

In his Advanced Energy Initiative announced in January 2006, President George W. Bush committed the nation to new efforts to develop alternative sources of energy to replace imported oil and fossil fuels. Developing cost-effective and energy-efficient methods of producing renewable alternative fuels such as cellulosic ethanol from biomass and solar-derived biofuels will require transformational breakthroughs in science and technology. Incremental improvements in current bioenergy production methods will not suffice. The Genomics:GTL Bioenergy Research Centers will be dedicated to fundamental research on microbe and plant systems with the goal of developing knowledge that will advance biotechnology-based strategies for biofuels production. The aim is to spur substantial progress toward cost-effective production of biologically based renewable energy sources. This document describes the rationale for the establishment of the centers and their objectives in light of the U.S. Department of Energy's mission and goals. Developing energy-efficient and cost-effective methods of producing alternative fuels such as cellulosic ethanol from biomass will require transformational breakthroughs in science and technology. Incremental improvements in current bioenergy-production methods will not suffice. The focus on microbes (for cellular mechanisms) and plants (for source biomass) fundamentally exploits capabilities well known to exist in the microbial world. Thus 'proof of concept' is not required, but considerable basic research into these capabilities remains an urgent priority. Several developments have converged in recent years to suggest that systems biology research into microbes and plants promises solutions that will overcome critical roadblocks on the path to cost-effective, large-scale production of cellulosic ethanol and other renewable energy from biomass. The ability to rapidly sequence the DNA of any organism is a critical part of these new capabilities, but it is only a first step. Other advances include the growing number of high-throughput techniques for protein production and characterization; a range of new instrumentation for observing proteins and other cell constituents; the rapid growth of commercially available reagents for protein production; a new generation of high-intensity light sources that provide precision imaging on the nanoscale and allow observation of molecular interactions in ultrafast time intervals; major advances in computational capability; and the continually increasing numbers of these instruments and technologies within the national laboratory infrastructure, at universities, and in private industry. All these developments expand our ability to elucidate mechanisms present in living cells, but much more remains to be done. The Centers are designed to accomplish GTL program objectives more rapidly, more effectively, and at reduced cost by concentrating appropriate technologies and scientific expertise, from genome sequence to an integrated systems understanding of the pathways and internal structures of microbes and plants most relevant to developing bioenergy compounds. The Centers will seek to understand the principles underlying the structural and functional design of selected microbial, plant, and molecular systems. This will be accomplished by building technological pathways linking the genome-determined components in an organism with bioenergy-relevant cellular systems that can be characterized sufficiently to generate realistic options for biofuel development. In addition, especially in addressing what are believed to be nearer-term approaches to renewable energy (e.g., producing cellulosic ethanol cost-effectively and energy-efficiently), the Center research team must understand in depth the current industrial-level roadblocks and bottlenecks (see section, GTL's Vision for Biological Energy Alternatives, below). For the Centers, and indeed the entire BER effort, to be successful, Center research must be integrated with individual investigator research, and coordination of activities, from DNA sequencing to high-throughput protein development and characterization

Post-postfeminism? New feminist visibilities in postfeminist times

This article contributes to debates about the value and utility of the notion of postfeminism for a seemingly “new” moment marked by a resurgence of interest in feminism in the media and among young women. The paper reviews current understandings of postfeminism and criticisms of the term’s failure to speak to or connect with contemporary feminism. It offers a defence of the continued importance of a critical notion of postfeminism, used as an analytical category to capture a distinctive contradictory-but-patterned sensibility intimately connected to neoliberalism. The paper raises questions about the meaning of the apparent new visibility of feminism and highlights the multiplicity of different feminisms currently circulating in mainstream media culture – which exist in tension with each other. I argue for the importance of being able to “think together” the rise of popular feminism alongside and in tandem with intensified misogyny. I further show how a postfeminist sensibility informs even those media productions that ostensibly celebrate the new feminism. Ultimately, the paper argues that claims that we have moved “beyond” postfeminism are (sadly) premature, and the notion still has much to offer feminist cultural critics

When Is a Preannounced New Product Likely to Be Delayed?

Consider that a firm announces a deadline for a new product introduction. Conditional on such a preannouncement, how must an external observer evaluate whether the product will be delayed beyond that deadline? Using data collected from managers in the computer hardware, software, and telecommunications industries, the authors present an analysis that demonstrates that delays in new product introductions beyond preannounced deadlines can be jointly explained by factors related to (1) the firm's motivations to delay the product, (2) the presence of constraints that prevent delay (or the availability of opportunities to delay the product), and (3) the firm's abilities pertaining to product development

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Controversy and consensus on the management of elevated sperm DNA fragmentation in male infertility: A global survey, current guidelines, and expert recommendations

Purpose Sperm DNA fragmentation (SDF) has been associated with male infertility and poor outcomes of assisted reproductive technology (ART). The purpose of this study was to investigate global practices related to the management of elevated SDF in infertile men, summarize the relevant professional society recommendations, and provide expert recommendations for managing this condition. Materials and Methods An online global survey on clinical practices related to SDF was disseminated to reproductive clinicians, according to the CHERRIES checklist criteria. Management protocols for various conditions associated with SDF were captured and compared to the relevant recommendations in professional society guidelines and the appropriate available evidence. Expert recommendations and consensus on the management of infertile men with elevated SDF were then formulated and adapted using the Delphi method. Results A total of 436 experts from 55 different countries submitted responses. As an initial approach, 79.1% of reproductive experts recommend lifestyle modifications for infertile men with elevated SDF, and 76.9% prescribe empiric antioxidants. Regarding antioxidant duration, 39.3% recommend 4–6 months and 38.1% recommend 3 months. For men with unexplained or idiopathic infertility, and couples experiencing recurrent miscarriages associated with elevated SDF, most respondents refer to ART 6 months after failure of conservative and empiric medical management. Infertile men with clinical varicocele, normal conventional semen parameters, and elevated SDF are offered varicocele repair immediately after diagnosis by 31.4%, and after failure of antioxidants and conservative measures by 40.9%. Sperm selection techniques and testicular sperm extraction are also management options for couples undergoing ART. For most questions, heterogenous practices were demonstrated. Conclusions This paper presents the results of a large global survey on the management of infertile men with elevated SDF and reveals a lack of consensus among clinicians. Furthermore, it demonstrates the scarcity of professional society guidelines in this regard and attempts to highlight the relevant evidence. Expert recommendations are proposed to help guide clinicians

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The subsistence economy of the Locarno Beach culture (3300-2400 B.P.)

This thesis is concerned with analysing vertebrate fauna (mammals, birds, and fish) from the Locarno Beach culture (3300-2400 B.P.) of the Fraser River Delta area in southern British Columbia. The principal objective is to reconstruct site level vertebrate exploitative patterns for the Locarno Beach culture components at the Locarno Beach (DhRt 6), Whalen Farm (DfRs 3), and Musqueam NE (DhRt 4) sites. Qualitative and quantitative faunal analytic methods are employed to evaluate faunal data from each component. Data are also evaluated by seasonal availability and preferred habitat categories. The results of the faunal analysis indicate that Locarno Beach culture populations exploited mainly riverine and foreshore resources. Salmon is the major vertebrate resource, followed by land mammals (deer and elk) and waterfowl (mainly diving species). Intensive herring, flatfish, and waterfowl exploitation took place at two sites (DhRt 6 and DfRs 3), probably in conjunction with shellfish harvesting during the late winter through early spring (February to April). DhRt 6 was also occupied during the spring to early summer (April to June) for surf smelt procurement. The third site (DhRt 4) was occupied from late winter through the summer and may have been a major encampment for Fraser River salmon procurement. DhRt 4 also shares many attributes associated with Marpole and Late Prehistoric culture village sites. It is concluded that the Locarno Beach culture vertebrate subsistence economy is part of the Northwest Coast pattern. The Locarno Beach culture is a development from the St. Mungo culture (4300 - 3300 B.P.) with greater emphasis on riverine resources, especially salmon. Locarno Beach culture vertebrate fauna data indicate a range of site types, including seasonal resource extraction sites, salmon fishing sites, and possibly a winter village site. Similar to Marpole (2400-1600 B.P.) and Late Prehistoric (1600-1100 B.P.) cultures, Locarno Beach culture populations of the Fraser Delta exploited aggregated resources (e.g. herring, flatfish, waterfowl, and shellfish) at seasonally occupied camps during the late winter to early spring. The primary summer subsistence activity was salmon procurement. Preliminary evidence suggests that Fraser River sockeye salmon runs (late summer to fall) were intensively exploited with fishing nets near DhRt 4. Prolonged occupation at DhRt 4 during the winter may indicate that this site was a winter village, as well as a fishing site.Arts, Faculty ofAnthropology, Department ofGraduat

Typing of human papillomavirus in Western Cape women with cervical intraepithelial neoplasia

Thesis (MTech (Biomedical Technology))--Cape Technikon, Cape Town, 2002Infection \\'ith specific high risk human papilloma"iruses (HPV) has been shown to play a causal role in the development of ceJVical intraepithelial neoplasia (CIN) and cenical cancer in women. The development of a prophylactic vaccine to immull.ize women against HPV infection would play a \'ita! role in protecting women against HPV infection and ultimately ceMcal cancer. Despite cancer of the cer\'ix being the second most common cancer in South African women, a literature search reveals that few studies have been performed in South Africa on the types of HPV prevalent in women with CIN or cancer ofthe ceMx. HPVs that infect the anogenital tract have also been shown to infect the oral ca\'ity. However, the HPV prevalence rates vary greatly between studies and the significance of the presence ofHPV in the oral ca\'ity is still not understood. The primary objectives of this study were to establish the HPV prevalence rate infecting women with CIN lesions using a sensitive nested polymerase chain reaction (PCR) and to develop a novel restriction fragment length polymorphism (RFLP) method to type the high risk mucosal HPVs detected in these women. The secondary objective of this study was to establish the prevalence rate and HPV types infecting the oral mucosa of women with CIN lesions and to compare these HPV types with those detected in the ceMx. Cemcal punch biopsies were taken from 163 women with CIN lesions and buccal cells were collected from 33 of these participants. DNAwas extracted from the biopsies and buccal samples and PCR using CCRS primers performed to ensure sample adequacy. Nested PCR usmg consensus degenerate primers for HPV was performed on all samples sho\\'wg sufficient amplifiable DNA A novel restriction fragment length pol)morphism (RFLP) method was developed to identify the 10 high risk mucosal HPVs considered human carcinogens of group 1 by the International Agency for Research on Cancer (lARC) as well as HPV 11 which is commonly found in the oral cavity