Analysis of grain-boundary structure in Al–Cu interconnects

The role of crystallographic texture in electromigration resistance of interconnect lines is well documented. The presence of a strong (111) fiber texture results in a more reliable interconnect structure. It is also generally accepted that grain-boundary diffusion is the primary mechanism by which electromigration failures occur. It has been difficult to this point, however, to obtain statistically reliable information of grain-boundary structure in these materials as transmission electron microscopy investigations are limited by tedious specimen preparation and small, nonrepresentative, imaging regions. The present work focuses upon characterization of texture and grain-boundary structure of interconnect lines using orientation imaging microscopy, and particularly, upon the linewidth dependence of these measures. Conventionally processed Al–1%Cu lines were investigated to determine the affects of a postpatterning anneal on boundary structure as a function of linewidth. It was observed that texture tended to strengthen slightly with decreasing linewidth subsequent to the anneal procedure. Grain morphology changed substantially as the narrow lines became near bamboo in character and the crystallographic character of the boundary plane changed as a function of linewidth. These results are contrasted with those obtained from Al–1%Cu lines, which were fabricated using the damascene process. The damascene lines show a marked weakening in texture as the linewidth decreases, accompanied by a more random misorientation distribution. A description of the competing energetics, which result in the observed microstructures, is included. © 1997 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71133/2/JAPIAU-82-5-2383-1.pd

Epidemic growth rates and host movement patterns shape management performance for pathogen spillover at the wildlife–livestock interface

Managing pathogen spillover at the wildlife–livestock interface is a key step towards improving global animal health, food security and wildlife conservation. However, predicting the effectiveness of management actions across host–pathogen systems with different life histories is an on-going challenge since data on intervention effectiveness are expensive to collect and results are system-specific.We developed a simulation model to explore how the efficacies of different management strategies vary according to host movement patterns and epidemic growth rates. The model suggested that fast-growing, fast-moving epidemics like avian influenza were best-managed with actions like biosecurity or containment, which limited and localized overall spillover risk. For fast-growing, slower-moving diseases like foot-and-mouth disease, depopulation or prophylactic vaccination were competitive management options. Many actions performed competitively when epidemics grew slowly and host movements were limited, and how management efficacy related to epidemic growth rate or host movement propensity depended on what objectivewas used to evaluatemanagement performance. This framework offers one means of classifying and prioritizing responses to novel pathogen spillover threats, and evaluating current management actions for pathogens emerging at the wildlife–livestock interface. This article is part of the theme issue ‘Dynamic and integrative approaches to understanding pathogen spillover’

Pneumonia in Bighorn Sheep: Testing the Super-Spreader Hypothesis

Following introduction of pneumonia, disease can persist in bighorn sheep (Ovis canadensis) populations for decades as annual or sporadic pneumonia epidemics in lambs.  Recurring years of depressed recruitment due to high rates of pneumonia-induced mortality in juveniles is a major obstacle to population recovery.  Management strategies for resolving this problem have so far been elusive. We are investigating the feasibility of removing individual “super-spreaders” to improve lamb survival.  Individual variation in infection and transmission is well documented in human diseases (e.g. “Typhoid Mary”).  We are testing the hypothesis that pneumonia epidemics in lambs are initiated by transmission of pathogens from a few “chronic-shedder” ewes. We have completed the first year of a 5-year project in the Hells Canyon region of Idaho, Oregon, and Washington, and in a captive population at South Dakota State University. Through repeated testing of free-ranging individuals in Hells Canyon, we have identified individual differences in shedding of Mycoplasma ovipneumoniae, a primary pathogen in the bighorn sheep respiratory disease complex.  We also found that when penned separately in captivity, lambs of ewes that consistently tested positive (chronic shedders) were infected and died of pneumonia, whereas lambs born to ewes from an infected population that tested negative (non-shedders), were not infected and survived.  Over the next 4 years we plan to 1) continue and expand testing of free-ranging and captive animals, 2) determine whether removal of chronic-shedder ewes improves lamb survival in free-ranging populations, 3) expand and replicate chronic-shedder commingling experiments in captivity, and 4) establish and monitor a new population founded with non-shedders from an infected population

An ancient family of lytic polysaccharide monooxygenases with roles in arthropod development and biomass digestion.

Thermobia domestica belongs to an ancient group of insects and has a remarkable ability to digest crystalline cellulose without microbial assistance. By investigating the digestive proteome of Thermobia, we have identified over 20 members of an uncharacterized family of lytic polysaccharide monooxygenases (LPMOs). We show that this LPMO family spans across several clades of the Tree of Life, is of ancient origin, and was recruited by early arthropods with possible roles in remodeling endogenous chitin scaffolds during development and metamorphosis. Based on our in-depth characterization of Thermobia's LPMOs, we propose that diversification of these enzymes toward cellulose digestion might have endowed ancestral insects with an effective biochemical apparatus for biomass degradation, allowing the early colonization of land during the Paleozoic Era. The vital role of LPMOs in modern agricultural pests and disease vectors offers new opportunities to help tackle global challenges in food security and the control of infectious diseases

One-piece, composite crucible with integral withdrawal/discharge section

A one-piece, composite open-bottom casting mold with integral withdrawal section is fabricated by thermal spraying of materials compatible with and used for the continuous casting of shaped products of reactive metals and alloys such as, for example, titanium and its alloys or for the gas atomization thereof

Consumer Attitudes and Use of Antibiotics

Recent antibiotic use is a risk factor for infection or colonization with resistant bacterial pathogens. Demand for antibiotics can be affected by consumers’ knowledge, attitudes, and practices. In 1998–1999, the Foodborne Diseases Active Surveillance Network (FoodNet) conducted a population-based, random-digit dialing telephone survey, including questions regarding respondents’ knowledge, attitudes, and practices of antibiotic use. Twelve percent had recently taken antibiotics; 27% believed that taking antibiotics when they had a cold made them better more quickly, 32% believed that taking antibiotics when they had a cold prevented more serious illness, and 48% expected a prescription for antibiotics when they were ill enough from a cold to seek medical attention. These misguided beliefs and expectations were associated with a lack of awareness of the dangers of antibiotic use; 58% of patients were not aware of the possible health dangers. National educational efforts are needed to address these issues if patient demand for antibiotics is to be reduced

Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist

"Background Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days. Methods Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis. Findings Mean serum IGF-1 concentrations fell by at least 50%: 467 μg/L (SE 24), 526 μg/L (29), and 523 μg/L (40) in patients treated for 6, 12 and 18 months, respectively (p less than 0·001), whereas growth hormone increased by 12·5 μg/L (2·1), 12·5 μg/L (3·0), and 14·2 μg/L (5·7) (p less than 0·001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8·0 μg/L (2·5) at baseline, rose to 15·2 μg/L (2·4) on drug, and fell back within 30 days of withdrawal to 8·3 μg/L (2·7). Antibodies to growth hormone were detected in 27 (16·9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p less than 0·05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11·46 months (0·70) decreased by 0·033 cm3(0·057; p=0·353). Interpretation Pegvisomant is an effective medical treatment for acromegaly.

Future perspectives in melanoma research: meeting report from the "Melanoma Bridge";: Napoli, December 3rd-6th 2014.

The fourth "Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma