Lower-rim ferrocenyl substituted calixarenes: new electrochemical sensors for anions

New ferrocene substituted calix[4 and 5]arenes have been prepared and the crystal structure of a lower-rim substituted bis ferrocene calix[4]arene (7) has been elucidated. The respective ferrocene/ferrocenium redox-couples of compounds 6 (a calix[4]arene tetra ferrocene amide) and 8 (a calix[5]arene pentaferrocene amide) are shown to be significantly cathodically perturbed in the presence of anions by up to 160 mV in the presence of dihydrogen phosphate

The Alzheimer’s Disease Drug Development Landscape

Background: Alzheimer’s disease (AD) is a devastating neurodegenerative disease leading to dementia. The field has made significant progress over the last 15 years. AD diagnosis has shifted from syndromal, based on signs and symptoms, to a biomarker construct based on the pathological hallmarks of the disease: amyloid β deposition, pathologic tau, and neurodegeneration. Numerous genetic risk factors for sporadic AD have been identified, providing further insight into the molecular underpinnings of the disease. For the last two decades, however, drug development for AD has been proven to be particularly challenging. Here, we provide a unique overview of the drug development landscape for AD. By comparing preclinical and clinical drug development pipelines, we aim to describe trends and differences regarding target classes and therapeutic modalities in preclinical and clinical development. Methods: We analyzed proprietary and public databases and company websites for drugs in preclinical development for AD by the pharmaceutical industry and major clinical trial registries for drugs in clinical development for AD. Drugs were categorized by target class and treatment modality. Results: We found a higher proportion of preclinical interventions targeting molecular pathways associated with sporadic AD genetic risk variants, compared to clinical stage interventions. These include apolipoprotein E (ApoE) and lipids, lysosomal/endosomal targets, and proteostasis. Further, we observed a trend suggesting that more traditional therapeutic modalities are developed for these novel targets, while more novel treatment modalities such as gene therapies and enzyme treatments are in development for more traditional targets such as amyloid β and tau. Interestingly, the percentage of amyloid β targeting therapies in preclinical development (19.2%) is even higher than the percentage in clinical development (10.7%), indicating that diversification away from interventions targeting amyloid-beta has not materialized. Inflammation is the second most popular target class in both preclinical and clinical development. Conclusions: Our observations show that the AD drug development pipeline is diversifying in terms of targets and treatment modalities, while amyloid-targeting therapies remain a prominent avenue of development as well. To further advance AD drug development, novel companion diagnostics are needed that are directed at disease mechanisms related to genetic risk factors of AD, both for patient stratification and assessment of therapeutic efficacy in clinical trials

Interaction between the NS4B amphipathic helix, AH2, and charged lipid headgroups alters membrane morphology and AH2 oligomeric state — Implications for the Hepatitis C virus life cycle

AbstractThe non-structural protein 4B (NS4B) from Hepatitis C virus (HCV) plays a pivotal role in the remodelling of the host cell's membranes, required for the formation of the viral replication complex where genome synthesis occurs. NS4B is an integral membrane protein that possesses a number of domains vital for viral replication. Structural and biophysical studies have revealed that one of these, the second amphipathic N-terminal helix (AH2), plays a key role in these remodelling events. However, there is still limited understanding of the mechanism through which AH2 promotes these changes. Here we report on solid-state NMR and molecular dynamics studies that demonstrate that AH2 promotes the clustering of negatively charged lipids within the bilayer, a process that reduces the strain within the bilayer facilitating the remodelling of the lipid bilayer. Furthermore, the presence of negatively charged lipids within the bilayer appears to promote the disassociation of AH2 oligomers, highlighting a potential role for lipid recruitment in regulating NS protein interactions

Tree scattering amplitudes of the spin-4/3 fractional superstring I: the untwisted sectors

Scattering amplitudes of the spin-4/3 fractional superstring are shown to satisfy spurious state decoupling and cyclic symmetry (duality) at tree-level in the string perturbation expansion. This fractional superstring is characterized by the spin-4/3 fractional superconformal algebra---a parafermionic algebra studied by Zamolodchikov and Fateev involving chiral spin-4/3 currents on the world-sheet in addition to the stress-energy tensor. Examples of tree scattering amplitudes are calculated in an explicit c=5 representation of this fractional superconformal algebra realized in terms of free bosons on the string world-sheet. The target space of this model is three-dimensional flat Minkowski space-time with a level-2 Kac-Moody so(2,1) internal symmetry, and has bosons and fermions in its spectrum. Its closed string version contains a graviton in its spectrum. Tree-level unitarity (i.e., the no-ghost theorem for space-time bosonic physical states) can be shown for this model. Since the critical central charge of the spin-4/3 fractional superstring theory is 10, this c=5 representation cannot be consistent at the string loop level. The existence of a critical fractional superstring containing a four-dimensional space-time remains an open question.Comment: 42 pages, 4 figures, latex, IASSNS-HEP-93/57, CLNS-92/117

The extracellular surface of the GLP-1 receptor is a molecular trigger for biased agonism

Ligand-directed signal bias offers opportunities for sculpting molecular events, with the promise of better, safer therapeutics. Critical to the exploitation of signal bias is an understanding of the molecular events coupling ligand binding to intracellular signaling. Activation of class B G protein-coupled receptors is driven by interaction of the peptide N terminus with the receptor core. To understand how this drives signaling, we have used advanced analytical methods that enable separation of effects on pathway-specific signaling from those that modify agonist affinity and mapped the functional consequence of receptor modification onto three-dimensional models of a receptor-ligand complex. This yields molecular insights into the initiation of receptor activation and the mechanistic basis for biased agonism. Our data reveal that peptide agonists can engage different elements of the receptor extracellular face to achieve effector coupling and biased signaling providing a foundation for rational design of biased agonists

Densidade da madeira de árvores em savanas do norte da Amazônia brasileira

Densidade da madeira (DM) é uma variável importante para estimativas de estoques de carbono arbóreo em ecossistemas terrestres. Este tema é pobremente investigado em áreas de savana da Amazônia brasileira. O objetivo deste estudo foi investigar a DM das oito principais espécies arbóreas que ocorrem na savana aberta de Roraima, a maior área de savana do norte do bioma Amazônia. Foram verificadas as variações na DM em função da espécie e dos diferentes diâmetros observados ao longo da dimensão vertical de 75 indivíduos amostrados em seis sítios de coleta. Foi utilizado o método direto para obtenção de peças de madeira do fuste e da copa. Os resultados indicaram discrepância significativa interespecífica, sendo Roupala montana Aubl. a espécie de maior DM média (0,674 g cm-3). Foi detectado que existe variação significativa da DM entre as peças do fuste e da copa, independente da espécie e do sítio de coleta. A densidade da madeira de peças da copa com diâmetro entre 5 e 10 cm pode ser utilizada como preditora da DM média do indivíduo arbóreo. Nós concluimos que a DM das oito espécies arbóreas investigadas possui variabilidade interespecífica, com discrepâncias entre a DM do fuste e das partes lenhosas da copa. As distinções aqui detectadas devem ser considerados como uma importante ferramenta para melhorar as estimativas de estoque de carbono em áreas de savanas na Amazônia

Early above- and below-ground responses of subboreal conifer seedlings to various levels of deciduous canopy removal

We examined the growth of understory conifers, following partial or complete deciduous canopy removal, in a field study established in two regions in Canada. In central British Columbia, we studied the responses of three species (Pseudotsuga menziesii var. glauca (Beissn.) Franco, Picea glauca (Moench) Voss x Picea engelmannii Parry ex Engelm., and Abies lasiocarpa (Hook.) Nutt.), and in northwestern Quebec, we studied one species (Abies balsamea (L.) Mill.). Stem and root diameter and height growth were measured 5 years before and 3 years after harvesting. Both root and stem diameter growth increased sharply following release but seedlings showed greater root growth, suggesting that in the short term, improvement in soil resource capture and transport, and presumably stability, may be more important than an increase in stem diameter and height growth. Response was strongly size dependent, which appears to reflect greater demand for soil resources as well as higher light levels and greater tree vigour before release for taller individuals. Growth ratios could not explain the faster response generally attributed to true fir species or the unusual swift response of spruces. Good prerelease vigour of spruces, presumably favoured by deciduous canopies, could explain their rapid response to release

Toward a 21st-century health care system: Recommendations for health care reform

The coverage, cost, and quality problems of the U.S. health care system are evident. Sustainable health care reform must go beyond financing expanded access to care to substantially changing the organization and delivery of care. The FRESH-Thinking Project (www.fresh-thinking.org) held a series of workshops during which physicians, health policy experts, health insurance executives, business leaders, hospital administrators, economists, and others who represent diverse perspectives came together. This group agreed that the following 8 recommendations are fundamental to successful reform: 1. Replace the current fee-for-service payment system with a payment system that encourages and rewards innovation in the efficient delivery of quality care. The new payment system should invest in the development of outcome measures to guide payment. 2. Establish a securely funded, independent agency to sponsor and evaluate research on the comparative effectiveness of drugs, devices, and other medical interventions. 3. Simplify and rationalize federal and state laws and regulations to facilitate organizational innovation, support care coordination, and streamline financial and administrative functions. 4. Develop a health information technology infrastructure with national standards of interoperability to promote data exchange. 5. Create a national health database with the participation of all payers, delivery systems, and others who own health care data. Agree on methods to make de-identified information from this database on clinical interventions, patient outcomes, and costs available to researchers. 6. Identify revenue sources, including a cap on the tax exclusion of employer-based health insurance, to subsidize health care coverage with the goal of insuring all Americans. 7. Create state or regional insurance exchanges to pool risk, so that Americans without access to employer-based or other group insurance could obtain a standard benefits package through these exchanges. Employers should also be allowed to participate in these exchanges for their employees' coverage. 8. Create a health coverage board with broad stakeholder representation to determine and periodically update the affordable standard benefit package available through state or regional insurance exchanges