Synthesis of meeting and recommendations from the Net-Biome round table discussion on "motivated" science on biodiversity management and use in support of overseas sutainable development

Net-Biome Final Meeting (Paris, 15 & 16 February, 2012).This brief report summarizes the deliberations of the Round-Table presentations and discussion held during the Net-Biome Final Meeting (Paris, 15 & 16 February, 2012). The participants identified relevant key issues to support of Biodiversity management and underpinning science in ORs and OCTs. Two major themes emerged: a) Policy context and engagement with stakeholders b) Major scientific opportunities for research in the ORs+OCTs

Prediction of buried mine-like target radar signatures using wideband electromagnetic modeling

ABSTRACT Current ground penetrating radars (GPR) have been tested for land mine detection, but they have generally been costly and have poor performance. Comprehensive modeling and experimentation must be done to predict the electromagnetic (EM) signatures of mines to access the effect of clutter on the EM signature of the mine, and to understand the merit and limitations of using radar for various mine detection scenarios. This modeling can provide a basis for advanced radar design and detection techniques leading to superior performance. Lawrence Livermore National Laboratory (LLNL) has developed a radar technology that when combined with comprehensive modeling and detection methodologies could be the basis of an advanced mine detection system. Micropower Impulse Radar (MIR) technology exhibits a combination of properties, including wideband operation, extremely low power consumption, extremely small size and low cost, array configurability, and noise encoded pulse generation. LLNL is in the process of developing an "optimal" processing algorithm to use with the MIR sensor. In this paper, we use classical numerical models to obtain the signature of mine-like targets and examine the effect of surface roughness on the reconstructed signals. These results are then qualitatively compared to experimental data

Differential transcript profile of inhibitors with potential anti-venom role in the liver of juvenile and adult Bothrops jararaca snake

Background. Snakes belonging to the Bothrops genus are vastly distributed in Central and South America and are responsible for most cases of reported snake bites in Latin America. The clinical manifestations of the envenomation caused by this genus are due to three major activities-proteolytic, hemorrhagic and coagulant-mediated by metalloproteinases, serine proteinases, phospholipases A(2) and other toxic compounds present in snake venom. Interestingly, it was observed that snakes are resistant to the toxic effects of its own and other snake's venoms. This natural immunity may occur due the absence of toxin target or the presence of molecules in the snake plasma able to neutralize such toxins. Methods. In order to identify anti-venom molecules, we construct a cDNA library from the liver of B. jararaca snakes. Moreover, we analyzed the expression profile of four molecules-the already known anti-hemorrhagic factor Bj46a, one gamma-phospholipase A(2) inhibitor, one inter-alpha inhibitor and one C1 plasma protease inhibitor-in the liver of juvenile and adult snakes by qPCR. Results. The results revealed a 30-fold increase of gamma-phospholipase A(2) inhibitor and a minor increase of the inter-alpha inhibitor (5-fold) and of the C1 inhibitor (3-fold) in adults. However, the Bj46a factor seems to be equally transcribed in adults and juveniles. Discussion. The results suggest the up-regulation of different inhibitors observed in the adult snakes might be a physiological adaptation to the recurrent contact with their own and even other snake's venoms throughout its lifespan. This is the first comparative analysis of ontogenetic variation of expression profiles of plasmatic proteins with potential anti-venom activities of the venomous snake B. jararaca. Furthermore, the present data contributes to the understanding of the natural resistance described in these snakes.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Conselho Nacional de Desenvolvimento Tecnologico (CNPq)INCT - Entomologia MolecularInst Butantan, Lab Herpetol, Sao Paulo, BrazilUniv Sao Paulo, Interunidades Biotecnol, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Bioquim, Sao Paulo, BrazilUniv Fed Rio de Janeiro, Dept Bioquim, Rio De Janeiro, BrazilInst Nacl Ciencia & Tecnol Entomol Mol, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Bioquim, Escola Paulista Med, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Bioquim, Sao Paulo, BrazilFAPESP: 2010/10266-5FAPESP: 2012/03657-8FAPESP: 2013/05357-4FAPESP: 2014/11108-0CNPq: 308780/2013-2Web of Scienc

Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis

BackgroundDespite unprecedented efficacy across multiple tumor types, immune checkpoint inhibitor therapy is associated with a unique and wide spectrum of immune‐related adverse events (irAEs), including neurologic events ranging from mild headache to potentially life‐threatening encephalitis. Here, we summarize neurologic irAEs associated with nivolumab and ipilimumab melanoma treatment, present cases of treatment‐related encephalitis, and provide practical guidance on diagnosis and management.MethodsWe searched a Global Pharmacovigilance and Epidemiology database for neurologic irAEs reported over an 8‐year period in patients with advanced melanoma receiving nivolumab with or without ipilimumab from 12 studies sponsored by Bristol‐Myers Squibb. Serious neurologic irAEs were reviewed, and relationship to nivolumab or ipilimumab was assigned.ResultsIn our search of 3,763 patients, 35 patients (0.93%) presented with 43 serious neurologic irAEs, including neuropathy (n = 22), noninfective meningitis (n = 5), encephalitis (n = 6), neuromuscular disorders (n = 3), and nonspecific adverse events (n = 7). Study drug was discontinued (n = 20), interrupted (n = 8), or unchanged (n = 7). Most neurologic irAEs resolved (26/35 patients; 75%). Overall, median time to onset was 45 days (range 1–170) and to resolution was 32 days (2–809+). Median time to onset of encephalitis was 55.5 days (range 18–297); four cases resolved and one was fatal.ConclusionBoth oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors. Prompt diagnosis and management using an established algorithm are critical to minimize serious complications from these neurologic irAEs.Implications for PracticeWith increasing use of checkpoint inhibitors in cancer, practicing oncologists need to be aware of the potential risk of neurologic immune‐related adverse events and be able to provide prompt treatment of this uncommon, but potentially serious, class of adverse events. We summarize neurologic adverse events related to nivolumab alone or in combination with ipilimumab in patients with advanced melanoma from 12 studies and examine in depth 6 cases of encephalitis. We also provide input and guidance on the existing neurologic adverse events management algorithm for nivolumab and ipilimumab.Melanoma is a particularly immunogenic cancer, and immune checkpoint inhibitors have been extensively studied in this tumor type. This review focuses on the incidence of serious neurologic immune‐related adverse events, specifically encephalitis, in patients with advanced melanoma treated with nivolumab alone or in sequence or combination with ipilimumab. Practical guidance is provided for the diagnosis and management of treatment‐related encephalitis associated with nivolumab and ipilimumab.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139998/1/onco12130.pd

Genome-wide signatures of complex introgression and adaptive evolution in the big cats.

The great cats of the genus Panthera comprise a recent radiation whose evolutionary history is poorly understood. Their rapid diversification poses challenges to resolving their phylogeny while offering opportunities to investigate the historical dynamics of adaptive divergence. We report the sequence, de novo assembly, and annotation of the jaguar (Panthera onca) genome, a novel genome sequence for the leopard (Panthera pardus), and comparative analyses encompassing all living Panthera species. Demographic reconstructions indicated that all of these species have experienced variable episodes of population decline during the Pleistocene, ultimately leading to small effective sizes in present-day genomes. We observed pervasive genealogical discordance across Panthera genomes, caused by both incomplete lineage sorting and complex patterns of historical interspecific hybridization. We identified multiple signatures of species-specific positive selection, affecting genes involved in craniofacial and limb development, protein metabolism, hypoxia, reproduction, pigmentation, and sensory perception. There was remarkable concordance in pathways enriched in genomic segments implicated in interspecies introgression and in positive selection, suggesting that these processes were connected. We tested this hypothesis by developing exome capture probes targeting ~19,000 Panthera genes and applying them to 30 wild-caught jaguars. We found at least two genes (DOCK3 and COL4A5, both related to optic nerve development) bearing significant signatures of interspecies introgression and within-species positive selection. These findings indicate that post-speciation admixture has contributed genetic material that facilitated the adaptive evolution of big cat lineages

Probe-dependent negative allosteric modulators of the long-chain free fatty acid receptor FFA4

High-affinity and selective antagonists that are able to block the actions of both endogenous and synthetic agonists of G protein–coupled receptors are integral to analysis of receptor function and to support suggestions of therapeutic potential. Although there is great interest in the potential of free fatty acid receptor 4 (FFA4) as a novel therapeutic target for the treatment of type II diabetes, the broad distribution pattern of this receptor suggests it may play a range of roles beyond glucose homeostasis in different cells and tissues. To date, a single molecule, 4-methyl-N-9H-xanthen-9-yl-benzenesulfonamide (AH-7614), has been described as an FFA4 antagonist; however, its mechanism of antagonism remains unknown. We synthesized AH-7614 and a chemical derivative and demonstrated these to be negative allosteric modulators (NAMs) of FFA4. Although these NAMs did inhibit FFA4 signaling induced by a range of endogenous and synthetic agonists, clear agonist probe dependence in the nature of allosteric modulation was apparent. Although AH-7614 did not antagonize the second long-chain free fatty acid receptor, free fatty acid receptor 1, the simple chemical structure of AH-7614 containing features found in many anticancer drugs suggests that a novel close chemical analog of AH-7614 devoid of FFA4 activity, 4-methyl-N-(9H-xanthen-9-yl)benzamide (TUG-1387), will also provide a useful control compound for future studies assessing FFA4 function. Using TUG-1387 alongside AH-7614, we show that endogenous activation of FFA4 expressed by murine C3H10T1/2 mesenchymal stem cells is required for induced differentiation of these cells toward a more mature, adipocyte-like phenotype

Computerized Ultrasound Risk Evaluation (CURE) System: Development of Combined Transmission and Reflection Ultrasound with New Reconstruction Algorithms for Breast Imaging

Our Computerized Ultrasound Risk Evaluation (CURE) system has been developed to the engineering prototype stage and generated unique data sets of both transmission and reflection ultrasound (US). This paper will help define the clinical underpinnings of the developmental process and interpret the imaging results from a similar perspective. The CURE project was designed to incorporate numerous diagnostic parameters to improve upon two major areas of early breast cancer detection. CURE may provide improved tissue characterization of breast masses and reliable detection of abnormal microcalcifications found in some breast cancers and ductal carcinoma in situ (DCIS). Current breast US is limited to mass evaluation, whereas mammography also detects and guides biopsy of malignant calcifications. Screening with CURE remains a distant goal, but improved follow-up of mammographic abnormalities may represent a feasible breakthrough. Improved tissue characterization could result in reduction of the estimated one million benign biopsies each year in the United States, costing up to several billion dollars. Most breast calcifications are benign and comprise-80% of stereotactic biopsies guided by mammography. Ultrasound has the capability of finding some groups of calcifications, but further improvements in resolution should also address tissue characterization to define the soft tissue filling of ducts by DCIS. In this manner, CURE may be able to more accurately identify the malignant calcifications associated with progression of DCIS or early cancers. Currently, high-resolution US images of the breast are performed in the reflection mode at higher frequencies, which also limits depth of penetration. Reconstruction of reflection ultrasound images relies upon acoustic impedance differences in the tissue and includes only direct backscatter of the ultrasound signal. Resolution and tissue contrast of current US continues to improve with denser transducer arrays and image processing, but the operator dependent nature of using a moveable transducer head remains a significant problem for thorough coverage of the entire breast. We have therefore undertaken the development of a whole breast (i.e., including auxiliary tail) system, with improved resolution and tissue characterization abilities. The extensive ultrasound physics considerations, engineering, materials process development and subsequent algorithm reconstruction are beyond the scope of this initial paper. The proprietary nature of these processes will be forthcoming as the intellectual property is fully secured. We will focus here on the imaging outcomes as they apply to eventual expansion into clinical use

An intact C-terminal end of albumin is required for its long half-life in humans.

Albumin has an average plasma half-life of three weeks and is thus an attractive carrier to improve the pharmacokinetics of fused therapeutics. The half-life is regulated by FcRn, a cellular receptor that protects against intracellular degradation. To tailor-design the therapeutic use of albumin, it is crucial to understand how structural alterations in albumin affect FcRn binding and transport properties. In the blood, the last C-terminal residue (L585) of albumin may be enzymatically cleaved. Here we demonstrate that removal of the L585 residue causes structural stabilization in regions of the principal FcRn binding domain and reduces receptor binding. In line with this, a short half-life of only 3.5 days was measured for cleaved albumin lacking L585 in a patient with acute pancreatitis. Thus, we reveal the structural requirement of an intact C-terminal end of albumin for a long plasma half-life, which has implications for design of albumin-based therapeutics

‘No memory, no desire’: psychoanalysis in Brazil during repressive times

Until recently, the growth and significance of Brazilian psychoanalysis has been neglected in histories of psychoanalysis. Not only is this history long and rich in its professional and cultural dimensions, but there was an especially important ‘event’ – the so-called ‘Cabernite-Lobo affair’ – that took place during the period of the military dictatorship, which can be seen as dramatising some of the issues concerning the erasure of memory in psychoanalysis, especially in connection with political difficulties. In this paper, we provide an outline of the origins and dissemination of psychoanalysis in Brazil before looking again at the Cabernite-Lobo affair in order to examine in a situated way how psychoanalysis engages with political extremism, and particularly to explore the consequences of an unthinking generalisation of the idea of ‘neutrality’ from the consulting room to the institutional setting. We draw especially on Brazilian papers in Portuguese, which have not been accessible in the English-language psychoanalytic literature