Insulin-Like Growth Factor Binding Proteins: A Structural Perspective

Insulin-like growth factor binding proteins (IGFBP-1 to -6) bind insulin-like growth factors-I and -II (IGF-I and IGF-II) with high affinity. These binding proteins maintain IGFs in the circulation and direct them to target tissues, where they promote cell growth, proliferation, differentiation, and survival via the type 1 IGF receptor. IGFBPs also interact with many other molecules, which not only influence their modulation of IGF action but also mediate IGF-independent activities that regulate processes such as cell migration and apoptosis by modulating gene transcription. IGFBPs-1 to -6 are structurally similar proteins consisting of three distinct domains, N-terminal, linker, and C-terminal. There have been major advances in our understanding of IGFBP structure in the last decade and a half. While there is still no structure of an intact IGFBP, several structures of individual N- and C-domains have been solved. The structure of a complex of N-BP-4:IGF-I:C-BP-4 has also been solved, providing a detailed picture of the structural features of the IGF binding site and the mechanism of binding. Structural studies have also identified features important for interaction with extracellular matrix components and integrins. This review summarizes structural studies reported so far and highlights features important for binding not only IGF but also other partners. We also highlight future directions in which structural studies will add to our knowledge of the role played by the IGFBP family in normal growth and development, as well as in disease

Large-scale prediction of long disordered regions in proteins using random forests

Background: Many proteins contain disordered regions that lack fixed three-dimensional (3D) structure under physiological conditions but have important biological functions. Prediction of disordered regions in protein sequences is important for understanding protein function and in high-throughput determination of protein structures. Machine learning techniques, including neural networks and support vector machines have been widely used in such predictions. Predictors designed for long disordered regions are usually less successful in predicting short disordered regions. Combining prediction of short and long disordered regions will dramatically increase the complexity of the prediction algorithm and make the predictor unsuitable for large-scale applications. Efficient batch prediction of long disordered regions alone is of greater interest in large-scale proteome studies. Results: A new algorithm, IUPforest-L, for predicting long disordered regions using the random forest learning model is proposed in this paper. IUPforest-L is based on the Moreau-Broto auto-correlation function of amino acid indices (AAIs) and other physicochemical features of the primary sequences. In 10-fold cross validation tests, IUPforest-L can achieve an area of 89.5% under the receiver operating characteristic (ROC) curve. Compared with existing disorder predictors, IUPforest-L has high prediction accuracy and is efficient for predicting long disordered regions in large-scale proteomes. Conclusion: The random forest model based on the auto-correlation functions of the AAIs within a protein fragment and other physicochemical features could effectively detect long disordered regions in proteins. A new predictor, IUPforest-L, was developed to batch predict long disordered regions in proteins, and the server can be accessed from http://dmg.cs.rmit.edu.au/IUPforest/IUPforest-L.php

Rethinking Appropriateness of Actions in Environmental Decisions: Connecting Interest and Identity Negotiation with Plural Valuation

Issues of interest, identity and values intertwine in environmental conflicts, creating challenges that cannot generally be overcome using rationalities grounded in generalised argumentation and abstraction. To address the growing need to engage interests and identities along with plural values in the conservation of biodiversity and ecological systems, we introduce the concept of ‘appropriateness of actions’ and ground it in a relational understanding of environmental ethics. A determination of appropriateness for actions comes from combining outputs from value elicitation with those of interest and identity negotiation in ways that are salient to specific people and their relationships to specific places. Drawing on the Blue Mountain Forest Partnership in the Pacific Northwest, we propose factors of success for supporting appropriate actions: 1) understanding context and identifying key stakeholders; 2) surfacing a diversity of interests and building system-level trust; 3) building empathy for different identities grounded in specific places; 4) eliciting diverse values and seeking to understand their links to worldviews and knowledge systems and; 5) seeking out appropriate actions

Lessons learned from 104 years of mobile observatories [poster]

Poster session IN13B-1211 presented 10 December 2007 at the AGU Fall Meeting, 10–14 December 2007, San Francisco, CA, USAAs the oceanographic community ventures into a new era of integrated observatories, it may be helpful to look back on the era of "mobile observatories" to see what Cyberinfrastructure lessons might be learned. For example, SIO has been operating research vessels for 104 years, supporting a wide range of disciplines: marine geology and geophysics, physical oceanography, geochemistry, biology, seismology, ecology, fisheries, and acoustics. In the last 6 years progress has been made with diverse data types, formats and media, resulting in a fully-searchable online SIOExplorer Digital Library of more than 800 cruises (http://SIOExplorer.ucsd.edu). Public access to SIOExplorer is considerable, with 795,351 files (206 GB) downloaded last year. During the last 3 years the efforts have been extended to WHOI, with a "Multi-Institution Testbed for Scalable Digital Archiving" funded by the Library of Congress and NSF (IIS 0455998). The project has created a prototype digital library of data from both institutions, including cruises, Alvin submersible dives, and ROVs. In the process, the team encountered technical and cultural issues that will be facing the observatory community in the near future. Technological Lessons Learned: Shipboard data from multiple institutions are extraordinarily diverse, and provide a good training ground for observatories. Data are gathered from a wide range of authorities, laboratories, servers and media, with little documentation. Conflicting versions exist, generated by alternative processes. Domain- and institution-specific issues were addressed during initial staging. Data files were categorized and metadata harvested with automated procedures. With our second-generation approach to staging, we achieve higher levels of automation with greater use of controlled vocabularies. Database and XML- based procedures deal with the diversity of raw metadata values and map them to agreed-upon standard values, in collaboration with the Marine Metadata Interoperability (MMI) community. All objects are tagged with an expert level, thus serving an educational audience, as well as research users. After staging, publication into the digital library is completely automated. The technical challenges have been largely overcome, thanks to a scalable, federated digital library architecture from the San Diego Supercomputer Center, implemented at SIO, WHOI and other sites. The metadata design is flexible, supporting modular blocks of metadata tailored to the needs of instruments, samples, documents, derived products, cruises or dives, as appropriate. Controlled metadata vocabularies, with content and definitions negotiated by all parties, are critical. Metadata may be mapped to required external standards and formats, as needed. Cultural Lessons Learned: The cultural challenges have been more formidable than expected. They became most apparent during attempts to categorize and stage digital data objects across two institutions, each with their own naming conventions and practices, generally undocumented, and evolving across decades. Whether the questions concerned data ownership, collection techniques, data diversity or institutional practices, the solution involved a joint discussion with scientists, data managers, technicians and archivists, working together. Because metadata discussions go on endlessly, significant benefit comes from dictionaries with definitions of all community-authorized metadata values.Funding provided by the Library of Congress and NSF (IIS 0455998

Bis[methyl 3-(propyl­amino)­but-2-eno­ato]zinc

The title compound, [Zn(C8H14NO2)2], represents a zinc complex with the Zn2+ cation coordinated by two O and two N atoms in a distorted tetrahedral geometry

Die Ballon-Okklusionsangiographie der Pulmonalarterien bei chronischer pulmonaler Hypertonie

Die chronische pulmonale Hypertonie ist eine seltene Erkrankung, die heute noch als unheilbar gilt. Die therapeutischen Möglichkeiten haben sich in den letzten Jahren rasant weiterentwickelt und orientieren sich an der Pathogenese und an den Befunden aus der bildgebenden Diagnostik. Diese muss in ihren Möglichkeiten der differentialdiagnostischen Eingrenzung zugrundeliegender Ursachen der pulmonalen Hypertonie Schritt halten. Insbesondere die Ergebnisse der intraarteriellen Pulmonalisangiographie als Referenzmethode in der Bildgebung der Lungen-strombahn haben meist unmittelbare therapeutische Konsequenz, z.B. ob ein Patient für eine pulmonale Thrombendarteriektomie gegeignet ist oder nicht. Wir haben überprüft, ob die selektive pulmonale Ballon-Okklusionsangiographie als Erweiterung der standardisierten Übersichtsangiographie die Differentialdiagnose z.B. der embolischen (CTEPH) gegenüber der nichtembolischen (NoCTEPH) Erkrankung verbessert. Zu diesem Zweck wurden Untersuchungen von 50 Patienten bestehend aus jeweils einer konventionellen Übersichtsangiographie und der ergänzenden Ballon-Okklusionsangiographie retrospektiv nach einem standardisierten Studienprotokoll ausgewertet. Zunächst wurde eine digitale Subtraktionsangiographie der Pulmonalarterien angefertigt. Anschließend führten wir einen weichen Latex-Ballonkatheter in Segment- oder Subsegmentarterien ein. Dann entfalteten wir den Ballon, um die sondierte Arterie zu verschließen und injizierten jeweils 10 bis 15 ml Kontrastmittel, um die kleinen peripheren Gefäße sichtbar zu machen. 13 Patienten litten an einer nichtthrombembolischen Form der chronischen pulmonalen Hypertonie. Bei 36 von 37 Patienten mit CTEPH fanden wir organisiertes embolisches Material als irreguläre Stenosen, Verschlüsse oder Strickleitersysteme (Webs und Bands). In der Darstellung dieser pathologischen Befunde war die Ballon-Okklusionsangiographie der Übersichtsangiographie sowohl qualitativ als auch quantitativ überlegen. Nach unseren Daten entdeckt die Ballon-Okklusionsangiographie in etwa bei jedem fünften Patienten mit negativer Übersichtsangiographie wenigstens ein thrombembolisches Residuum, sie steigert somit als Verfeinerung der Methode die Sensitivität der Pulmonalisangiographie. Generell stellte sie 2,7 bis 3,6 Aufteilungsgenerationen der peripheren Gefäße mehr dar als die konventionelle selektive DSA. Außerdem fanden wir bei 17 Patienten Kollateralgefäße zu den peripheren Segmenten von zentral verschlossenen Pulmonal-arterien. Dieses Phänomen war nur in der Ballon-Okklusionsangiographie zu beobachten und erwies sich als spezifisch für Patienten mit thrombembolischer pulmonaler Hypertonie. Der Befund ist insofern erstaunlich, als dass Pulmonalarterien eigentlich als funktionelle Endarterien ohne Anastomosen zu Nachbararterien beschrieben werden. Bei 11 Patienten fanden sich Anastomosen zu subpleuralen Bronchialarterien. Dieses bereits bekannte Phänomen steht nach unseren Daten in keinem Zusammenhang mit einer bestimmten Erkrankung und ist somit als unspezifisches Merkmal der chronischen pulmonalen Hypertonie zu deuten. In drei Fällen konnten histologisch postkapilläre Formen der pulmonalen Hypertonie (zweimal pulmonale veno-okklusive Erkrankung (PVOD), einmal primäre kapilläre Hämangiomatose) gesichert werden. Bei diesen Patienten zeigte die Ballon-Okklusionsangiographie eine Füllung der Lungenvenen ohne angiographisch sichtbare Anfärbung des Kapillarbettes (fehlende Parenchymanfärbung). Die geschilderten Erkenntnisse aus unserer Studie lassen sich für die Praxis wie folgt zusammenfassen: 1. Die Ballon-Okklusionsangiographie verbessert die Visualisierung der peripheren Pulmonalarterien. 2. Sie erleichtert die Detektion und Lokalisation thrombembolischer Residuen 3. Sie hilft bei der Differentialdiagnose zwischen thrombembolischer und nicht-thrombembolischer chronischer pulmonaler Hypertonie. 4. Vorher unsichtbare Anastomosen und Kollateralgefäße werden sichtbar. 5. Venöse Füllung ohne Parenchymanfärbung ist offensichtlich ein Zeichen der Parenchymerkrankung; diese Konstellation ist bei Patienten mit chronischer pulmonaler Hypertonie möglicherweise ein Hinweis auf das Vorliegen der pulmonalen venookklusiven Erkrankung (PVOD) oder der primären kapillären Hämangiomatose (PCH). 6. Die selektive Ballon-Okklusionsangiographie segmentaler Pulmonalarterien verbessert in Zusammenschau mit der Computertomographie die Zuverlässigkeit in der Selektion von Kandidaten für eine pulmonale Thrombendarteriektomie oder eine Prostazyklintherapie.Purpose: Test the ability of selective balloon occlusion angiography of pulmonary segmental arteries in the differential diagnosis of chronic pulmonary hypertension: embolic vs. non-embolic disease, pulmonary capillary hemangiomatosis, and venoocclusive disease. Methods and Materials: In 50 patients with pulmonary hypertension, digital subtraction angiography (DSA) of pulmonary arteries were used to assist in the selection of candidates appropriate for thrombo-endarterectomy. In addition to these standard methods, we introduced a soft latex balloon catheter into segmental arteries, inflated the balloon to occlude the artery, and injected 10 to 15 ml contrast medium to visualize small peripheral vessels as completely as possible. Results: 13 patients suffered from non-embolic pulmonary hypertension. In 36 of 37 patients with embolic pulmonary hypertension organizing embolic material was depicted as irregular narrowing or occlusion of pulmonary arteries, and weblike strictures. In all of these patients occlusion technique revealed more tiny webs or organized micro emboli in small peripheral arteries. According to our data balloon occlusion angiography discovers in every fifth patient showing a negative conventional pulmonary angiography at least one thromboembolic residuum and thus increases as a sophisticated method the sensitivity of the pulmonary angiography. Generally, occlusion technique revealed additional 2,7 to 3,6 ramifications of peripheral vessels in comparison to conventional selective DSA. Unexpectedly, we found in 11 patients anastomoses to bronchial arteries and in 17 patients collateral vessels to the peripheral segments of centrally occluded pulmonary arteries. These findings are astonishing, because pulmonary arteries are believed ramifying dichotomically without anastomoses. Obviously, there are alterations of pulmonary perfusion, which overcome normal anatomy. 3 patients with characteristic CT signs of interstitial disease (poorly defined nodular opacities and septal lines) underwent lung biopsy: 2 cases of venoocclusive disease, 1 case of pulmonary capillary hemangiomatosis. Occlusion angiography in these 3 patients revealed filling of veins without opacification of capillaries (failing parenchymal phase). Conclusion: Balloon occlusion technique improves the visualization of peripheral pulmonary arteries. Differential diagnosis of embolic and non-embolic pulmonary hypertension is facilitated. Previously invisible anastomoses and collateral vessels become visible. Venous filling without capillary opacification is apparently a sign of parenchymal disease; in patients with chronic pulmonary hypertension it might be a hint at venoocclusive disease or pulmonary capillary hemangiomatosi

MYBL1 rearrangements and MYB amplification in breast adenoid cystic carcinomas lacking the MYB–NFIB fusion gene

Breast adenoid cystic carcinoma (AdCC), a rare type of triple-negative breast cancer, has been shown to be driven by MYB pathway activation, most often underpinned by the MYB–NFIB fusion gene. Alternative genetic mechanisms, such as MYBL1 rearrangements, have been reported in MYB–NFIB-negative salivary gland AdCCs. Here we report on the molecular characterization by massively parallel sequencing of four breast AdCCs lacking the MYB–NFIB fusion gene. In two cases, we identified MYBL1 rearrangements (MYBL1–ACTN1 and MYBL1–NFIB), which were associated with MYBL1 overexpression. A third AdCC harboured a high-level MYB amplification, which resulted in MYB overexpression at the mRNA and protein levels. RNA-sequencing and whole-genome sequencing revealed no definite alternative driver in the fourth AdCC studied, despite high levels of MYB expression and the activation of pathways similar to those activated in MYB–NFIB-positive AdCCs. In this case, a deletion encompassing the last intron and part of exon 15 of MYB, including the binding site of ERG-1, a transcription factor that may downregulate MYB, and the exon 15 splice site, was detected. In conclusion, we demonstrate that MYBL1 rearrangements and MYB amplification probably constitute alternative genetic drivers of breast AdCCs, functioning through MYBL1 or MYB overexpression. These observations emphasize that breast AdCCs probably constitute a convergent phenotype, whereby activation of MYB and MYBL1 and their downstream targets can be driven by the MYB–NFIB fusion gene, MYBL1 rearrangements, MYB amplification, or other yet to be identified mechanisms. Copyright © 2017 Pathological Society of Great Britain and Ireland

Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification

Background HER2 is overexpressed and amplified in approximately 15% of invasive breast cancers, and is the molecular target and predictive marker of response to anti-HER2 agents. In a subset of these cases, heterogeneous distribution of HER2 gene amplification can be found, which creates clinically challenging scenarios. Currently, breast cancers with HER2 amplification/overexpression in just over 10% of cancer cells are considered HER2-positive for clinical purposes; however, it is unclear as to whether the HER2-negative components of such tumors would be driven by distinct genetic alterations. Here we sought to characterize the pathologic and genetic features of the HER2-positive and HER2-negative components of breast cancers with heterogeneous HER2 gene amplification and to define the repertoire of potential driver genetic alterations in the HER2-negative components of these cases.Results We separately analyzed the HER2-negative and HER2-positive components of 12 HER2 heterogeneous breast cancers using gene copy number profiling and massively parallel sequencing, and identified potential driver genetic alterations restricted to the HER2-negative cells in each case. In vitro experiments provided functional evidence to suggest that BRF2 and DSN1 overexpression/amplification, and the HER2 I767M mutation may be alterations that compensate for the lack of HER2 amplification in the HER2-negative components of HER2 heterogeneous breast cancers.Conclusions Our results indicate that even driver genetic alterations, such as HER2 gene amplification, can be heterogeneously distributed within a cancer, and that the HER2-negative components are likely driven by genetic alterations not present in the HER2-positive components, including BRF2 and DSN1 amplification and HER2 somatic mutations

A qualitative study of carers' experiences of dementia cafes : a place to feel supported and be yourself

Abstract Background Unpaid, informal carers or caregivers play an important role in supporting people living with dementia but the role can be challenging and carers themselves may benefit from support. Alzheimer’s, dementia or memory cafés are one such form of support . These cafés are usually provided in the voluntary sector and are a place where people with dementia and those supporting them, usually family carers, can meet with others in similar situations. Methods Using semi-structured interviews, this qualitative study explored the experiences of 11 carers from five dementia cafés in and around London, England. Results Thematic analysis resulted in the identification of four key themes. Cafés provide a relaxed, welcoming atmosphere where carers can go where they feel supported and accepted. Café attendance often brought a sense of normality to these carers’ lives. Carers and those they care for look forward to going and often enjoy both the activities provided and socialising with others. Other highlighted benefits included peer support from other carers, information provision and support from the volunteer café coordinators. Despite diversity in how the cafés were run and in the activities offered, there were many reported similarities amongst carers in the value ascribed to attending the cafés. Conclusions Dementia cafés appear to be a valuable, perhaps unique form of support for carers giving them brief respite from their caring role. Future research incorporating mixed methods is needed to understand the perspectives of those living with dementia