Geohydrology and model analysis for water-supply management in a small area of west-central Kansas /

Mode of access: Internet.

Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial

Background The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. Findings Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3–33·9). Progression-free survival (median 11·0 months [95% CI 10·6–12·9] with afatinib vs 10·9 months [9·1–11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57–0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9–15·0] with afatinib vs 11·5 months [10·1–13·1] with gefitinib; HR 0·73 [95% CI 0·58–0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population.

Small Indigenous Freshwater Fish Species: their Role in Poverty Alleviation, Food Security and Conservation of Biodiversity, 23-25 February 2010, Central Inland Fisheries Research Institute, Barrackpore, Kolkata, West Bengal. Workshop report

This is the report on the workshop on “Small Indigenous Freshwater Fish Species: Their Role in Poverty Alleviation, Food Security and Conservation of Biodiversity”, organized by the International Collective in Support of Fishworkers(ICSF) in collaboration with the Inland Fisheries Society of India (IFSI). The workshop was a forum for exchange of views on the role of small indigenous freshwater fish species (SIFFS) in enhancing rural food supply and livelihood security, and in conserving biodiversity. The workshop also discussed the socioeconomic and cultural contexts for the culture and capture of SIFFS, and how to enhance access—especially for women—to better incomes, livelihoods and nutritional security, through appropriate policy spaces. This report provides a fresh focus on SIFFS, usually regarded as ‘trash’ fish. It urges scientists, researchers and decisionmakers to develop policy and legislative measures to ensure the conservation and promotion of SIFFS, both in capture- and culture-fisheries systems. This report will be useful for fishworker organizations, researchers, policymakers, fish farmers, members of civil society and anyone interested in fisheries and livelihoods. (PDF contains 86 pages)

Viral metagenomic analysis of feces of wild small carnivores

Background: Recent studies have clearly demonstrated the enormous virus diversity that exists among wild animals. This exemplifies the required expansion of our knowledge of the virus diversity present in wildlife, as well as the potential transmission of these viruses to domestic animals or humans. Methods: In the present study we evaluated the viral diversity of fecal samples (n = 42) collected from 10 different species of wild small carnivores inhabiting the northern part of Spain using random PCR in combination with next-generation sequencing. Samples were collected from American mink (Neovison vison), European mink (Mustela lutreola), European polecat (Mustela putorius), European pine marten (Martes martes), stone marten (Martes foina), Eurasian otter (Lutra lutra) and Eurasian badger (Meles meles) of the family of Mustelidae; common genet (Genetta genetta) of the family of Viverridae; red fox (Vulpes vulpes) of the family of Canidae and European wild cat (Felis silvestris) of the family of Felidae. Results: A number of sequences of possible novel viruses or virus variants were detected, including a theilovirus, phleboviruses, an amdovirus, a kobuvirus and picobirnaviruses. Conclusions: Using random PCR in combination with next generation sequencing, sequences of various novel viruses or virus variants were detected in fecal samples collected from Spanish carnivores. Detected novel viruses highlight the viral diversity that is present in fecal material of wild carnivores.

Central representation of dynamics when manipulating handheld objects.

To explore the neural mechanisms related to representation of the manipulation dynamics of objects, we performed whole-brain fMRI while subjects balanced an object in stable and highly unstable states and while they balanced a rigid object and a flexible object in the same unstable state, in all cases without vision. In this way, we varied the extent to which an internal model of the manipulation dynamics was required in the moment-to-moment control of the object's orientation. We hypothesized that activity in primary motor cortex would reflect the amount of muscle activation under each condition. In contrast, we hypothesized that cerebellar activity would be more strongly related to the stability and complexity of the manipulation dynamics because the cerebellum has been implicated in internal model-based control. As hypothesized, the dynamics-related activation of the cerebellum was quite different from that of the primary motor cortex. Changes in cerebellar activity were much greater than would have been predicted from differences in muscle activation when the stability and complexity of the manipulation dynamics were contrasted. On the other hand, the activity of the primary motor cortex more closely resembled the mean motor output necessary to execute the task. We also discovered a small region near the anterior edge of the ipsilateral (right) inferior parietal lobule where activity was modulated with the complexity of the manipulation dynamics. We suggest that this is related to imagining the location and motion of an object with complex manipulation dynamics.

Distribution, feeding and body condition of four small fish species in the near-shore and central areas of Liangzi Lake, China

Small fish abundance is usually high in heavily vegetated habitats in Yangtze lakes, China. Visual and swimming barriers created by dense macrophytes beds could reduce feeding efficiency and growth of small fishes. We tested the hypothesis that small fishes in habitats with dense macrophytes would show decreased feeding efficiency and reduced growth rates by comparing feeding efficiency (measured as the relative weight of fore-gut contents), total length, and condition factor of four small young-of-the-year fishes collected in the near-shore (heavily vegetated) and central (less vegetated) areas of Liangzi Lake. Feeding efficiency, total length, or condition factor were each significantly reduced in the near-shore area compared with the central area for Ctenogobius giurinus, Pseudorasbora parva and Carassius auratus auratus. This supports our hypothesis that vegetation abundance may mediate feeding efficiency and growth of small fishes. Although Hypseleotris swinhonis did not show significant decreases in feeding efficiency or growth in the near-shore area, there was not any reversed tendency, i.e. increased feeding rate or growth in the near-shore area compared to the central area.

Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease.

Neurodegenerative diseases such as Huntington disease are devastating disorders with no therapeutic approaches to ameliorate the underlying protein misfolding defect inherent to poly-glutamine (polyQ) proteins. Given the mounting evidence that elevated levels of protein chaperones suppress polyQ protein misfolding, the master regulator of protein chaperone gene transcription, HSF1, is an attractive target for small molecule intervention. We describe a humanized yeast-based high-throughput screen to identify small molecule activators of human HSF1. This screen is insensitive to previously characterized activators of the heat shock response that have undesirable proteotoxic activity or that inhibit Hsp90, the central chaperone for cellular signaling and proliferation. A molecule identified in this screen, HSF1A, is structurally distinct from other characterized small molecule human HSF1 activators, activates HSF1 in mammalian and fly cells, elevates protein chaperone expression, ameliorates protein misfolding and cell death in polyQ-expressing neuronal precursor cells and protects against cytotoxicity in a fly model of polyQ-mediated neurodegeneration. In addition, we show that HSF1A interacts with components of the TRiC/CCT complex, suggesting a potentially novel regulatory role for this complex in modulating HSF1 activity. These studies describe a novel approach for the identification of new classes of pharmacological interventions for protein misfolding that underlies devastating neurodegenerative disease.

Live Imaging of Host-Parasite Interactions in a Zebrafish Infection Model Reveals Cryptococcal Determinants of Virulence and Central Nervous System Invasion.

UNLABELLED: The human fungal pathogen Cryptococcus neoformans is capable of infecting a broad range of hosts, from invertebrates like amoebas and nematodes to standard vertebrate models such as mice and rabbits. Here we have taken advantage of a zebrafish model to investigate host-pathogen interactions of Cryptococcus with the zebrafish innate immune system, which shares a highly conserved framework with that of mammals. Through live-imaging observations and genetic knockdown, we establish that macrophages are the primary immune cells responsible for responding to and containing acute cryptococcal infections. By interrogating survival and cryptococcal burden following infection with a panel of Cryptococcus mutants, we find that virulence factors initially identified as important in causing disease in mice are also necessary for pathogenesis in zebrafish larvae. Live imaging of the cranial blood vessels of infected larvae reveals that C. neoformans is able to penetrate the zebrafish brain following intravenous infection. By studying a C. neoformans FNX1 gene mutant, we find that blood-brain barrier invasion is dependent on a known cryptococcal invasion-promoting pathway previously identified in a murine model of central nervous system invasion. The zebrafish-C. neoformans platform provides a visually and genetically accessible vertebrate model system for cryptococcal pathogenesis with many of the advantages of small invertebrates. This model is well suited for higher-throughput screening of mutants, mechanistic dissection of cryptococcal pathogenesis in live animals, and use in the evaluation of therapeutic agents. IMPORTANCE: Cryptococcus neoformans is an important opportunistic pathogen that is estimated to be responsible for more than 600,000 deaths worldwide annually. Existing mammalian models of cryptococcal pathogenesis are costly, and the analysis of important pathogenic processes such as meningitis is laborious and remains a challenge to visualize. Conversely, although invertebrate models of cryptococcal infection allow high-throughput assays, they fail to replicate the anatomical complexity found in vertebrates and, specifically, cryptococcal stages of disease. Here we have utilized larval zebrafish as a platform that overcomes many of these limitations. We demonstrate that the pathogenesis of C. neoformans infection in zebrafish involves factors identical to those in mammalian and invertebrate infections. We then utilize the live-imaging capacity of zebrafish larvae to follow the progression of cryptococcal infection in real time and establish a relevant model of the critical central nervous system infection phase of disease in a nonmammalian model.

Small volume laboratory on a chip measurements incorporating the quartz crystal microbalance to measure the viscosity-density product of room temperature ionic liquids

A microfluidic glass chip system incorporating a quartz crystal microbalance (QCM) to measure the square root of the viscosity-density product of room temperature ionic liquids (RTILs) is presented. The QCM covers a central recess on a glass chip, with a seal formed by tightly clamping from above outside the sensing region. The change in resonant frequency of the QCM allows for the determination of the square root viscosity-density product of RTILs to a limit of similar to 10 kg m(-2) s(-0.5). This method has reduced the sample size needed for characterization from 1.5 ml to only 30 mu l and allows the measurement to be made in an enclosed system.

ULTRASTRUCTURAL-LOCALIZATION OF FMRFAMIDE-IMMUNOREACTIVITY AND PANCREATIC POLYPEPTIDE-IMMUNOREACTIVITY WITHIN THE CENTRAL-NERVOUS-SYSTEM OF THE LIVER FLUKE, FASCIOLA-HEPATICA (TREMATODA, DIGENEA)

A post-embedding immunogold technique was used to examine the subcellular distribution of immunoreactivities to the invertebrate peptide, FMRFamide, and to vertebrate pancreatic polypeptide (PP) within the central nervous system of the trematode, Fasciola hepatica. Gold labeling of peptide was localised exclusively over both dense-cored and ellipsoidal electron-dense vesicles (with a homogeneous matrix) present within nerve cell bodies, small and 'giant' nerve processes of the neuropile in the cerebral ganglia and transverse commissure, as well as in the main longitudinal nerve cords. Double labeling demonstrated an apparent co-localisation of FMRFamide and PP immunoreactivities in the same dense-cored vesicles, although populations of ellipsoidal electron-dense vesicles that labeled solely for FMRFamide were also evident. Antigen pre-absorption studies indicated little, if any, cross-reactivity of the two antisera.

Isolation basin records of late Quaternary sea-level change, central mainland British Columbia, Canada.

Isolation basin records from the Seymour-Belize Inlet Complex, a remote area of central mainland British Columbia, Canada are used to constrain post-glacial sea-level changes and provide a preliminary basis for testing geophysical model predictions of relative sea-level (RSL) change. Sedimentological and diatom data from three low-lying (<4 m elevation) basins record falling RSLs in late-glacial times and isolation from the sea by ~11,800–11,200 14C BP. A subsequent RSL rise during the early Holocene (~8000 14C BP) breached the 2.13 m sill of the lowest basin (Woods Lake), but the two more elevated basins (sill elevations of ~3.6 m) remained isolated. At ~2400 14C BP, RSL stood at 1.49 ± 0.34 m above present MTL. Falling RSLs in the late Holocene led to the final emergence of the Woods Lake basin by 1604 ± 36 14C BP. Model predictions generated using the ICE-5G model partnered with a small number of different Earth viscosity models generally show poor agreement with the observational data, indicating that the ice model and/or Earth models considered can be improved upon. The best data-model fits were achieved with relatively low values of upper mantle viscosity (5 × 1019 Pa s), which is consistent with previous modelling results from the region. The RSL data align more closely with observational records from the southeast of the region (eastern Vancouver Island, central Strait of Georgia), than the immediate north (Bella Bella–Bella Coola and Prince Rupert-Kitimat) and areas to the north-west (Queen Charlotte Sound, Hecate Strait), underlining the complexity of the regional response to glacio-isostatic recovery.

Orally bioavailable small molecule drug protects memory in Alzheimer's disease models

Oligomers of beta-amyloid (Aß) are implicated in the early memory impairment seen in Alzheimer's disease before to the onset of discernable neurodegeneration. Here, the capacity of a novel orally bioavailable, central nervous system-penetrating small molecule 5-aryloxypyrimidine, SEN1500, to prevent cell-derived (7PA2 [conditioned medium] CM) Aß-induced deficits in synaptic plasticity and learned behavior was assessed. Biochemically, SEN1500 bound to Aß monomer and oligomers, produced a reduction in thioflavin-T fluorescence, and protected a neuronal cell line and primary cortical neurons exposed to synthetic soluble oligomeric Aß1-42. Electrophysiologically, SEN1500 alleviated the in vitro depression of long-term potentiation induced by both synthetic Aß1-42 and 7PA2 CM, and alleviated the in vivo depression of long-term potentiation induced by 7PA2 CM, after systemic administration. Behaviorally, oral administration of SEN1500 significantly reduced memory-related deficits in operant responding induced after intracerebroventricular injection of 7PA2 CM. SEN1500 reduced cytotoxicity, acute synaptotoxicity, and behavioral deterioration after in vitro and in vivo exposure to synthetic Aß and 7PA2 CM, and shows promise for development as a clinically viable disease-modifying Alzheimer's disease treatment. © 2013 Elsevier Inc.