A systematic review of present and future pharmaco-structural therapies for hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a common contemporary, treatable, genetic disorder that can be compatible with normal longevity. While current medical therapies are ubiquitous, they are limited by a lack of solid evidence, are often inadequate, poorly tolerated, and do not alter the natural disease course. As such, there has long been a need for effective, evidence-based, and targeted disease-modifying therapies for HCM. In this review, we redefine HCM as a treatable condition, evaluate current strategies for therapeutic intervention, and discuss novel myosin inhibitors. The majority of patients with HCM have elevated left ventricular outflow tract gradients, which predicts worse symptoms and adverse outcomes. Conventional pharmacological therapies for symptomatic HCM can help improve symptoms but are often inadequate and poorly tolerated. Septal reduction therapies (surgical myectomy and alcohol septal ablation) can safely and effectively reduce refractory symptoms and improve outcomes in patients with obstructive HCM. However, they require expertise that is not universally available and are not without risks. Currently, available therapies do not alter the disease course or the progressive cardiac remodeling that ensues, nor subsequent heart failure and arrhythmias. This has been regarded as an unmet need in the care of HCM patients. Novel targeted pharmacotherapies, namely cardiac myosin inhibitors, have emerged to reverse key pathophysiological changes and alter disease course. Their favorable outcomes led to the early Food and Drug Administration approval of mavacamten, a first-in-class myosin modulator, changing the paradigm for the pharmacological treatment of HCM.

SMOC-1 interacts with both BMP and glypican to regulate BMP signaling in C. elegans.

Secreted modular calcium-binding proteins (SMOCs) are conserved matricellular proteins found in organisms from Caenorhabditis elegans to humans. SMOC homologs characteristically contain 1 or 2 extracellular calcium-binding (EC) domain(s) and 1 or 2 thyroglobulin type-1 (TY) domain(s). SMOC proteins in Drosophila and Xenopus have been found to interact with cell surface heparan sulfate proteoglycans (HSPGs) to exert both positive and negative influences on the conserved bone morphogenetic protein (BMP) signaling pathway. In this study, we used a combination of biochemical, structural modeling, and molecular genetic approaches to dissect the functions of the sole SMOC protein in C. elegans. We showed that CeSMOC-1 binds to the heparin sulfate proteoglycan GPC3 homolog LON-2/glypican, as well as the mature domain of the BMP2/4 homolog DBL-1. Moreover, CeSMOC-1 can simultaneously bind LON-2/glypican and DBL-1/BMP. The interaction between CeSMOC-1 and LON-2/glypican is mediated specifically by the EC domain of CeSMOC-1, while the full interaction between CeSMOC-1 and DBL-1/BMP requires full-length CeSMOC-1. We provide both in vitro biochemical and in vivo functional evidence demonstrating that CeSMOC-1 functions both negatively in a LON-2/glypican-dependent manner and positively in a DBL-1/BMP-dependent manner to regulate BMP signaling. We further showed that in silico, Drosophila and vertebrate SMOC proteins can also bind to mature BMP dimers. Our work provides a mechanistic basis for how the evolutionarily conserved SMOC proteins regulate BMP signaling.

Four conservation challenges and a synthesis.

Conservation and management of biological systems involves decision-making over time, with a generic goal of sustaining systems and their capacity to function in the future. We address four persistent and difficult conservation challenges: (1) prediction of future consequences of management, (2) uncertainty about the system's structure, (3) inability to observe ecological systems fully, and (4) nonstationary system dynamics. We describe these challenges in terms of dynamic systems subject to different sources of uncertainty, and we present a basic Markovian framework that can encompass approaches to all four challenges. Finding optimal conservation strategies for each challenge requires issue-specific structural features, including adaptations of state transition models, uncertainty metrics, valuation of accumulated returns, and solution methods. Strategy valuation exhibits not only some remarkable similarities among approaches but also some important operational differences. Technical linkages among the models highlight synergies in solution approaches, as well as possibilities for combining them in particular conservation problems. As methodology and computing software advance, such an integrated conservation framework offers the potential to improve conservation outcomes with strategies to allocate management resources efficiently and avoid negative consequences.

C. elegans SMOC-1 interacts with both BMP and glypican to regulate BMP signaling.

Secreted modular calcium binding (SMOC) proteins are conserved matricellular proteins found in organisms from C. elegans to humans. SMOC homologs characteristically contain one or two extracellular calcium (EC) binding domain(s) and one or two thyroglobulin type-1 (TY) domain(s). SMOC proteins in Drosophila and Xenopus have been found to interact with cell surface heparan sulfate protein glycans (HSPGs) to exert both positive and negative influences on the conserved bone morphogenetic protein (BMP) signaling pathway. In this study, we used a combination of biochemical, structural modeling, and molecular genetic approaches to dissect the functions of the sole SMOC protein in C. elegans . We showed that SMOC-1 binds LON-2/glypican, as well as the mature domain of DBL-1/BMP. Moreover, SMOC-1 can simultaneously bind LON-2/glypican and DBL-1/BMP. The interaction between SMOC-1 and LON-2/glypican is mediated by the EC domain of SMOC-1, while the interaction between SMOC-1 and DBL-1/BMP involves full-length SMOC-1. We further showed that while SMOC-1(EC) is sufficient to promote BMP signaling when overexpressed, both the EC and TY domains are required for SMOC-1 function at the endogenous locus. Finally, when overexpressed, SMOC-1 can promote BMP signaling in the absence of LON-2/glypican. Taken together, our findings led to a model where SMOC-1 functions both negatively in a LON-2-dependent manner and positively in a LON-2-independent manner to regulate BMP signaling. Our work provides a mechanistic basis for how the evolutionarily conserved SMOC proteins regulate BMP signaling.

Partial observability and management of ecological systems.

The actual state of ecological systems is rarely known with certainty, but management actions must often be taken regardless of imperfect measurement (partial observability). Because of the difficulties in accounting for partial observability, it is usually treated in an ad hoc fashion, or simply ignored altogether. Yet incorporating partial observability into decision processes lends a realism that has the potential to improve ecological outcomes significantly. We review frameworks for dealing with partial observability, focusing specifically on dynamic ecological systems with Markovian transitions, i.e., transitions among system states that are influenced by the current system state and management action over time. Fully observable states are represented in an observable Markov decision process (MDP), whereas obscure or hidden states are represented in a partially observable process (POMDP). POMDPs can be seen as a natural extension of observable MDPs. Management under partial observability generalizes the situation for complete observability, by recognizing uncertainty about the system's state and incorporating sequential observations associated with, but not the same as, the states themselves. Decisions that otherwise would depend on the actual state must be based instead on state probability distributions ("belief states"). Partial observability requires adaptation of the entire decision process, including the use of belief states and Bayesian updates, valuation that includes expectations over observations, and optimal strategy that identifies actions for belief states over a continuous belief space. We compare MDPs and POMDPs and highlight POMDP applications to some common ecological problems. We clarify the structure and operations, approaches for finding solutions, and analytic challenges of POMDPs for practicing ecologists. Both observable and partially observable MDPs can use an inductive approach to identify optimal strategies and values, with a considerable increase in mathematical complexity with POMDPs. Better understanding of POMDPs can help decision makers manage imperfectly measured ecological systems more effectively.

Compartmentalization of telomeres through DNA-scaffolded phase separation.

Telomeres form unique nuclear compartments that prevent degradation and fusion of chromosome ends by recruiting shelterin proteins and regulating access of DNA damage repair factors. To understand how these dynamic components protect chromosome ends, we combine in vivo biophysical interrogation and in vitro reconstitution of human shelterin. We show that shelterin components form multicomponent liquid condensates with selective biomolecular partitioning on telomeric DNA. Tethering and anomalous diffusion prevent multiple telomeres from coalescing into a single condensate in mammalian cells. However, telomeres coalesce when brought into contact via an optogenetic approach. TRF1 and TRF2 subunits of shelterin drive phase separation, and their N-terminal domains specify interactions with telomeric DNA in vitro. Telomeric condensates selectively recruit telomere-associated factors and regulate access of DNA damage repair factors. We propose that shelterin mediates phase separation of telomeric chromatin, which underlies the dynamic yet persistent nature of the end-protection mechanism.

Protein polyglutamylation catalyzed by the bacterial calmodulin-dependent pseudokinase SidJ.

Pseudokinases are considered to be the inactive counterparts of conventional protein kinases and comprise approximately 10% of the human and mouse kinomes. Here, we report the crystal structure of the Legionella pneumophila effector protein, SidJ, in complex with the eukaryotic Ca2+-binding regulator, calmodulin (CaM). The structure reveals that SidJ contains a protein kinase-like fold domain, which retains a majority of the characteristic kinase catalytic motifs. However, SidJ fails to demonstrate kinase activity. Instead, mass spectrometry and in vitro biochemical analyses demonstrate that SidJ modifies another Legionella effector SdeA, an unconventional phosphoribosyl ubiquitin ligase, by adding glutamate molecules to a specific residue of SdeA in a CaM-dependent manner. Furthermore, we show that SidJ-mediated polyglutamylation suppresses the ADP-ribosylation activity. Our work further implies that some pseudokinases may possess ATP-dependent activities other than conventional phosphorylation.

The potential for citizen science to produce reliable and useful information in ecology.

We examined features of citizen science that influence data quality, inferential power, and usefulness in ecology. As background context for our examination, we considered topics such as ecological sampling (probability based, purposive, opportunistic), linkage between sampling technique and statistical inference (design based, model based), and scientific paradigms (confirmatory, exploratory). We distinguished several types of citizen science investigations, from intensive research with rigorous protocols targeting clearly articulated questions to mass-participation internet-based projects with opportunistic data collection lacking sampling design, and examined overarching objectives, design, analysis, volunteer training, and performance. We identified key features that influence data quality: project objectives, design and analysis, and volunteer training and performance. Projects with good designs, trained volunteers, and professional oversight can meet statistical criteria to produce high-quality data with strong inferential power and therefore are well suited for ecological research objectives. Projects with opportunistic data collection, little or no sampling design, and minimal volunteer training are better suited for general objectives related to public education or data exploration because reliable statistical estimation can be difficult or impossible. In some cases, statistically robust analytical methods, external data, or both may increase the inferential power of certain opportunistically collected data. Ecological management, especially by government agencies, frequently requires data suitable for reliable inference. With standardized protocols, state-of-the-art analytical methods, and well-supervised programs, citizen science can make valuable contributions to conservation by increasing the scope of species monitoring efforts. Data quality can be improved by adhering to basic principles of data collection and analysis, designing studies to provide the data quality required, and including suitable statistical expertise, thereby strengthening the science aspect of citizen science and enhancing acceptance by the scientific community and decision makers.

Potencial de la Ciencia Ciudadana para Producir Información Útil y Confiable en la Ecología Resumen Examinamos las características de la ciencia ciudadana que influyen sobre la calidad de datos, el poder inferencial, y la utilidad en la ecología. Consideramos temas como el muestreo ecológico (basado en probabilidad, deliberado, oportunista), la conexión entre la técnica de muestreo y la inferencia estadística (basada en diseño, basada en modelo) y los paradigmas científicos (confirmatorio, exploratorio) como trasfondo contextual para nuestra evaluación. Distinguimos varios tipos de investigación de ciencia ciudadana, desde investigación intensiva con protocolos rigurosos enfocados en preguntas claramente articuladas hasta proyectos de participación masiva en plataformas de internet con recolección de datos oportunistas carentes de un diseño de muestreo, y examinamos los objetivos generales, el diseño, el análisis, y la preparación de los voluntarios y el desempeño. Identificamos características clave que influyen sobre la calidad de los datos: los objetivos del proyecto, el diseño y el análisis, y la preparación y el desempeño de los voluntarios. Los proyectos con buenos diseños, voluntarios preparados, y supervisión profesional pueden cumplir con criterios estadísticos para producir datos de alta calidad con un fuerte poder inferencial, y por lo tanto son muy adecuados para los objetivos de investigación ecológica. Los proyectos con una recolección oportunista de datos, un diseño de muestreo ínfimo o nulo, y una preparación mínima de los voluntarios son más adecuados para los objetivos generales relacionados con la educación pública o la exploración de datos ya que la estimación estadística confiable puede ser complicada o imposible. En algunos casos los métodos analíticos estadísticamente sólidos, los datos externos, o ambos, pueden incrementar el poder inferencial de ciertos datos recolectados de manera oportunista. El manejo ecológico, en especial el que realizan las agencias gubernamentales, requiere frecuentemente de datos apropiados para una inferencia confiable. Con protocolos estandarizados, métodos analíticos modernos, y programas supervisados correctamente, la ciencia ciudadana puede contribuir de forma valiosa a la conservación al incrementar el alcance de los esfuerzos de monitoreo para una especie. La calidad de datos puede mejorarse si se adhiere a los principios básicos de la recolección y análisis de datos, se diseñan los estudios para que proporcionen la calidad requerida de datos, y si se incluye una pericia estadística adecuada, fortaleciendo así el aspecto científico de la ciencia ciudadana y aumentando su aceptación dentro de la comunidad científica y con quienes toman las decisiones.

Double-Loop Learning in Adaptive Management: The Need, the Challenge, and the Opportunity.

Adaptive management addresses uncertainty about the processes influencing resource dynamics, as well as the elements of decision making itself. The use of management to reduce both kinds of uncertainty is known as double-loop learning. Though much work has been done on the theory and procedures to address structural uncertainty, there has been less progress in developing an explicit approach for institutional learning about decision elements. Our objective is to describe evidence-based learning about the decision elements, as a complement to the formal "learning by doing" framework for reducing structural uncertainties. Adaptive management is described as a multi-phase approach to management and learning, with a set-up phase of identifying stakeholders, objectives, and other decision elements; an iterative phase that uses these elements in an ongoing cycle of technical learning about system structure and management impacts; and an institutional learning phase involving the periodic reconsideration of the decision elements. We describe a framework for institutional learning that is complementary to that of technical learning, including uncertainty metrics, propagation of change, and mechanisms and consequences of change over time. Operational issues include ways to recognize when the decision elements should be revisited, which elements should be adjusted, and how alternatives can be identified and incorporated based on experience and management performance. We discuss the application of this framework in decision making for renewable natural resources. As important as it is to learn about the processes driving resource dynamics, learning about the elements of the decision architecture is equally, if not more, important.

Phenotypic characterization of diamond (dind), a Drosophila gene required for multiple aspects of cell division.

Many genes are required for the assembly of the mitotic apparatus and for proper chromosome behavior during mitosis and meiosis. A fruitful approach to elucidate the mechanisms underlying cell division is the accurate phenotypic characterization of mutations in these genes. Here, we report the identification and characterization of diamond (dind), an essential Drosophila gene required both for mitosis of larval brain cells and for male meiosis. Larvae homozygous for any of the five EMS-induced mutations die in the third-instar stage and exhibit multiple mitotic defects. Mutant brain cells exhibit poorly condensed chromosomes and frequent chromosome breaks and rearrangements; they also show centriole fragmentation, disorganized mitotic spindles, defective chromosome segregation, endoreduplicated metaphases, and hyperploid and polyploid cells. Comparable phenotypes occur in mutant spermatogonia and spermatocytes. The dind gene encodes a non-conserved protein with no known functional motifs. Although the Dind protein exhibits a rather diffuse localization in both interphase and mitotic cells, fractionation experiments indicate that some Dind is tightly associated with the chromatin. Collectively, these results suggest that loss of Dind affects chromatin organization leading to defects in chromosome condensation and integrity, which in turn affect centriole stability and spindle assembly. However, our results do not exclude the possibility that Dind directly affects some behaviors of the spindle and centrosomes.

Value of sample information in dynamic, structurally uncertain resource systems.

Few if any natural resource systems are completely understood and fully observed. Instead, there almost always is uncertainty about the way a system works and its status at any given time, which can limit effective management. A natural approach to uncertainty is to allocate time and effort to the collection of additional data, on the reasonable assumption that more information will facilitate better understanding and lead to better management. But the collection of more data, either through observation or investigation, requires time and effort that often can be put to other conservation activities. An important question is whether the use of limited resources to improve understanding is justified by the resulting potential for improved management. In this paper we address directly a change in value from new information collected through investigation. We frame the value of information in terms of learning through the management process itself, as well as learning through investigations that are external to the management process but add to our base of understanding. We provide a conceptual framework and metrics for this issue, and illustrate them with examples involving Florida scrub-jays (Aphelocoma coerulescens).

Frequencies of decision making and monitoring in adaptive resource management.

Adaptive management involves learning-oriented decision making in the presence of uncertainty about the responses of a resource system to management. It is implemented through an iterative sequence of decision making, monitoring and assessment of system responses, and incorporating what is learned into future decision making. Decision making at each point is informed by a value or objective function, for example total harvest anticipated over some time frame. The value function expresses the value associated with decisions, and it is influenced by system status as updated through monitoring. Often, decision making follows shortly after a monitoring event. However, it is certainly possible for the cadence of decision making to differ from that of monitoring. In this paper we consider different combinations of annual and biennial decision making, along with annual and biennial monitoring. With biennial decision making decisions are changed only every other year; with biennial monitoring field data are collected only every other year. Different cadences of decision making combine with annual and biennial monitoring to define 4 scenarios. Under each scenario we describe optimal valuations for active and passive adaptive decision making. We highlight patterns in valuation among scenarios, depending on the occurrence of monitoring and decision making events. Differences between years are tied to the fact that every other year a new decision can be made no matter what the scenario, and state information is available to inform that decision. In the subsequent year, however, in 3 of the 4 scenarios either a decision is repeated or monitoring does not occur (or both). There are substantive differences in optimal values among the scenarios, as well as the optimal policies producing those values. Especially noteworthy is the influence of monitoring cadence on valuation in some years. We highlight patterns in policy and valuation among the scenarios, and discuss management implications and extensions.

Cell cycle-dependent regulation of Greatwall kinase by protein phosphatase 1 and regulatory subunit 3B.

Greatwall (Gwl) kinase plays an essential role in the regulation of mitotic entry and progression. Mitotic activation of Gwl requires both cyclin-dependent kinase 1 (CDK1)-dependent phosphorylation and its autophosphorylation at an evolutionarily conserved serine residue near the carboxyl terminus (Ser-883 in Xenopus). In this study we show that Gwl associates with protein phosphatase 1 (PP1), particularly PP1γ, which mediates the dephosphorylation of Gwl Ser-883. Consistent with the mitotic activation of Gwl, its association with PP1 is disrupted in mitotic cells and egg extracts. During mitotic exit, PP1-dependent dephosphorylation of Gwl Ser-883 occurs prior to dephosphorylation of other mitotic substrates; replacing endogenous Gwl with a phosphomimetic S883E mutant blocks mitotic exit. Moreover, we identified PP1 regulatory subunit 3B (PPP1R3B) as a targeting subunit that can direct PP1 activity toward Gwl. PPP1R3B bridges PP1 and Gwl association and promotes Gwl Ser-883 dephosphorylation. Consistent with the cell cycle-dependent association of Gwl and PP1, Gwl and PPP1R3B dissociate in M phase. Interestingly, up-regulation of PPP1R3B facilitates mitotic exit and blocks mitotic entry. Thus, our study suggests PPP1R3B as a new cell cycle regulator that functions by governing Gwl dephosphorylation.

Unfair competition governs the interaction of pCPI-17 with myosin phosphatase (PP1-MYPT1).

The small phosphoprotein pCPI-17 inhibits myosin light-chain phosphatase (MLCP). Current models postulate that during muscle relaxation, phosphatases other than MLCP dephosphorylate and inactivate pCPI-17 to restore MLCP activity. We show here that such hypotheses are insufficient to account for the observed rapidity of pCPI-17 inactivation in mammalian smooth muscles. Instead, MLCP itself is the critical enzyme for pCPI-17 dephosphorylation. We call the mutual sequestration mechanism through which pCPI-17 and MLCP interact inhibition by unfair competition: MLCP protects pCPI-17 from other phosphatases, while pCPI-17 blocks other substrates from MLCP's active site. MLCP dephosphorylates pCPI-17 at a slow rate that is, nonetheless, both sufficient and necessary to explain the speed of pCPI-17 dephosphorylation and the consequent MLCP activation during muscle relaxation.

State-Dependent Resource Harvesting with Lagged Information about System States.

Markov decision processes (MDPs), which involve a temporal sequence of actions conditioned on the state of the managed system, are increasingly being applied in natural resource management. This study focuses on the modification of a traditional MDP to account for those cases in which an action must be chosen after a significant time lag in observing system state, but just prior to a new observation. In order to calculate an optimal decision policy under these conditions, possible actions must be conditioned on the previous observed system state and action taken. We show how to solve these problems when the state transition structure is known and when it is uncertain. Our focus is on the latter case, and we show how actions must be conditioned not only on the previous system state and action, but on the probabilities associated with alternative models of system dynamics. To demonstrate this framework, we calculated and simulated optimal, adaptive policies for MDPs with lagged states for the problem of deciding annual harvest regulations for mallards (Anas platyrhynchos) in the United States. In this particular example, changes in harvest policy induced by the use of lagged information about system state were sufficient to maintain expected management performance (e.g. population size, harvest) even in the face of an uncertain system state at the time of a decision.

Resilience and Resource Management.

Resilience is an umbrella concept with many different shades of meaning. The use of the term has grown over the past several decades to the point that by now, many disciplines have their own definitions and metrics. In this paper, we aim to provide a context and focus for linkages of resilience to natural resources management. We consider differences and similarities in resilience as presented in several disciplines relevant to resource management. We present a conceptual framework that includes environmental drivers, management interventions, and system responses cast in terms of system resilience, as well as a process for decision making that allows learning about system resilience through experience and incorporation of that learning into management. We discuss the current state of operational management for resilience, and suggest ways to improve it. Finally, we describe the challenges in managing for resilience and offer some recommendations about the scientific information needs and scientific issues relevant to making resilience a more meaningful component of natural resources management.

Three Cases of West Nile Encephalitis over an Eight-Day Period at a Downtown Los Angeles Community Hospital.

Since its introduction in New York City in 1999, the virus has spread throughout the entire North American continent and continues to spread into Central and Latin America. Our report discusses the signs and symptoms, diagnostics, and treatment of West Nile disease. It is important to recognize the disease quickly and initiate appropriate treatment. We present three cases of West Nile encephalitis at White Memorial Medical Center in East Los Angeles that occurred over the span of eight days. All three patients live within four to six miles from the hospital and do not live or work in an environment favorable to mosquitoes including shallow bodies of standing water, abandoned tires, or mud ruts. All the patients were Hispanic. Physicians and other health care providers should consider West Nile infection in the differential diagnosis of causes of aseptic meningitis and encephalitis, obtain appropriate laboratory studies, and promptly report cases to public health authorities. State governments should establish abatement programs that will eliminate sources that allow for mosquito reproduction and harboring. The public needs to be given resources that educate them on what entails the disease caused by the West Nile virus, what the symptoms are, and, most importantly, what they can do to prevent themselves from becoming infected.

RZZ and Mad1 dynamics in Drosophila mitosis.

The presence or absence of Mad1 at kinetochores is a major determinant of spindle assembly checkpoint (SAC) activity, the surveillance mechanism that delays anaphase onset if one or more kinetochores remain unattached to spindle fibers. Among the factors regulating the levels of Mad1 at kinetochores is the Rod, Zw10, and Zwilch (RZZ) complex, which is required for Mad1 recruitment through a mechanism that remains unknown. The relative dynamics and interactions of Mad1 and RZZ at kinetochores have not been extensively investigated, although Mad1 has been reported to be stably recruited to unattached kinetochores. In this study, we directly compare Mad1-green fluorescent protein (GFP) turnover dynamics on unattached Drosophila kinetochores with that of RZZ, tagged either with GFP-Rod or GFP-Zw10. We find that nearly 40 % of kinetochore-bound Mad1 has a significant dynamic component, turning over with a half-life of 12 s. RZZ in contrast is essentially stable on unattached kinetochores. In addition, we report that a fraction of RZZ and Mad1 can co-immunoprecipitate, indicating that the genetically determined recruitment hierarchy (in which Mad1 depends on RZZ) may reflect a physical association of the two complexes.

Value of information in natural resource management: technical developments and application to pink-footed geese.

The "value of information" (VOI) is a generic term for the increase in value resulting from better information to guide management, or alternatively, the value foregone under uncertainty about the impacts of management (Yokota and Thompson, Medical Decision Making 2004; 24: 287). The value of information can be characterized in terms of several metrics, including the expected value of perfect information and the expected value of partial information. We extend the technical framework for the value of information by further developing the relationship between value metrics for partial and perfect information and describing patterns of their performance. We use two different expressions for the expected value of partial information to highlight its relationship to the expected value of perfect information. We also develop the expected value of partial information for hierarchical uncertainties. We highlight patterns in the value of information for the Svalbard population of the pink-footed goose (Anser brachyrhynchus), a population that is subject to uncertainty in both reproduction and survival functions. The framework for valuing information is seen as having widespread potential in resource decision making, and serves as a motivation for resource monitoring, assessment, and collaboration.

Tandem deprotection-dimerization-macrocyclization route to C(2) symmetric cyclo-tetrapeptides.

Dimerization-macrocyclization has been a long-standing problem in the cyclization of peptides since, together with the desired cyclic product, many cyclic oligomers and linear polymers may also be formed during the reaction. Therefore, the development of a process that affords the cyclic dimer predominantly is difficult. A novel and versatile strategy for the synthesis of symmetric cyclo-tetrapeptides by palladium-promoted tandem deprotection/cyclo-dimerization from readily available Cbz-dipeptidoyl benzotriazolides is reported (Cbz=carboxybenzyl).