Prioritizing global tall forests toward the 30 × 30 goals.

The Global Deal for Nature sets an ambitious goal to protect 30% of Earth's land and ocean by 2030. The 30 × 30 initiative is a way to allocate conservation resources and extend protection to conserve vulnerable and underprotected ecosystems while reducing carbon emissions to combat climate change. However, most prioritization methods for identifying high-value conservation areas are based on thematic attributes and do not consider vertical habitat structure. Global tall forests represent a rare vertical habitat structure that harbors high species richness in various taxonomic groups and is associated with large amounts of aboveground biomass. Global tall forests should be prioritized when planning global protected areas toward reaching the 30 × 30 goals. We examined the spatial distribution of global tall forests based on the Global Canopy Height 2020 product. We defined global tall forests as areas with the average canopy height above 3 thresholds (20, 25, and 30 m). We quantified the spatial distribution and protection level of global tall forests in high-protection zones, where the 30 × 30 goals are being met or are within reach, and low-protection zones, where there is a low chance of reaching 30 × 30 goals. We quantified the protection level by computing the percentage of global tall forest area protected based on the 2017 World Database on Protected Areas. We also determined the global extent and protection level of undisturbed, mature, tall forests based on the 2020 Global Intact Forest Landscapes mask. In most cases, the percentage of protection decreased as forest height reached the top strata. In the low-protection zones, <30% of forests were protected in almost all tall forest strata. In countries such as Brazil, tall forests had a higher percentage of protection (consistently >30%) compared to forests of lower height, presenting a more effective conservation model than in countries such as the United States, where forest protection was almost uniformly <30% across height strata. Our results show an urgent need to target forest conservation in the greatest height strata, particularly in high-protection areas, where most global tall forests are found. Vegetation vertical structure can inform the decision-making process toward the 30 × 30 goals because it can be used to identify areas of high conservation value for biodiversity protection which also contribute to carbon sequestration.

Priorización de bosques globales altos hacia las metas 30 por 30 Resumen El Tratado Global por la Naturaleza establece una meta ambiciosa de proteger 30% de los continentes y océanos de la Tierra para 2030. La iniciativa 30 por 30 es una forma de asignar recursos para la conservación y extender la protección para conservar ecosistemas vulnerables y sin protección al tiempo que se controlan las emisiones de carbono para combatir el cambio climático. Sin embargo, la mayoría de los métodos de priorización para identificar áreas de elevado valor de conservación se basan en atributos temáticos y no consideran la estructura vertical del hábitat. Los bosques altos globales representan un estructura de hábitat vertical rara que alberga alta riqueza de especies de varios grupos taxonómicos y se asocia con grandes cantidades de biomasa aérea. Los bosques altos globales deberían ser priorizados cuando se planifican áreas protegidas globales en el esfuerzo por alcanzar las metas 30 por 30. Examinamos la distribución espacial de bosques globales con base en el producto Altura de Dosel Global 2020. Definimos a los bosques altos globales como áreas con una altura de dosel promedio por arriba de 3 umbrales (20, 25 y 30 m). Cuantificamos la distribución espacial y el nivel de protección de los bosques altos globales en zonas con gran protección, donde se están alcanzando las metas 30 por 30. Cuantificamos el nivel de protección registrando el porcentaje de bosque alto global protegido con base en la Base de Datos Mundial de Áreas Protegidas 2017. También determinamos la extensión global y el nivel de protección de bosques altos, maduros, no perturbados con base en la mascarilla Paisajes Forestales Globales Intactos 2020. En la mayoría de los casos, el porcentaje de protección decreció a medida que la altura del bosque llegaba al estrato superior. En las zonas poco protegidas, >30% de los bosques estaban protegidos en casi todos los estratos de bosque alto. En países como Brasil, los bosques altos tuvieron un mayor porcentaje de protección (>30% consistentemente) que los bosques de menor altura, presentando un modelo de conservación más efectivo que en países como los Estados Unidos, donde la protección de bosques fue casi uniformemente >30% en los tres estratos de altura. Nuestros resultados muestran una urgente necesidad de enfocar la conservación de bosques en los estratos más altos, particularmente en las áreas muy protegidas, donde se encuentra la mayoría de bosques altos globales. La estructura vertical de la vegetación puede proporcionar información al proceso de toma de decisiones con miras a las metas 30 por 30 debido a que puede ser utilizada para identificar áreas de elevado valor de conservación para la protección de la biodiversidad que también contribuya al secuestro de carbono.

Iminopyrimidinones: a novel pharmacophore for the development of orally active renin inhibitors.

The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.

Modeled distribution shifts of North American birds over four decades based on suitable climate alone do not predict observed shifts.

As climate change alters the global environment, it is critical to understand the relationship between shifting climate suitability and species distributions. Key questions include whether observed changes in population abundance are aligned with the velocity and direction of shifts predicted by climate suitability models and if the responses are consistent among species with similar ecological traits. We examined the direction and velocity of the observed abundance-based distribution centroids compared with the model-predicted bioclimatic distribution centroids of 250 bird species across the United States from 1969 to 2011. We hypothesized that there is a significant positive correlation in both direction and velocity between the observed and the modeled shifts. We then tested five additional hypotheses that predicted differential shifting velocity based on ecological adaptability and climate change exposure. Contrary to our hypotheses, we found large differences between the observed and modeled shifts among all studied bird species and within specific ecological guilds. However, temperate migrants and habitat generalist species tended to have higher velocity of observed shifts than other species. Neotropical migratory and wetland birds also had significantly different observed velocities than their counterparts, which may be due to their climate change exposure. The velocity based on modeled bioclimatic suitability did not exhibit significant differences among most guilds. Boreal forest birds were the only guild with significantly faster modeled-shifts than the other groups, suggesting an elevated conservation risk for high latitude and altitude species. The highly idiosyncratic species responses to climate and the mismatch between shifts in modeled and observed distribution centroids highlight the challenge of predicting species distribution change based solely on climate suitability and the importance of non-climatic factors traits in shaping species distributions.

A global dataset of inland fisheries expert knowledge.

Inland fisheries and their freshwater habitats face intensifying effects from multiple natural and anthropogenic pressures. Fish harvest and biodiversity data remain largely disparate and severely deficient in many areas, which makes assessing and managing inland fisheries difficult. Expert knowledge is increasingly used to improve and inform biological or vulnerability assessments, especially in data-poor areas. Integrating expert knowledge on the distribution, intensity, and relative influence of human activities can guide natural resource management strategies and institutional resource allocation and prioritization. This paper introduces a dataset summarizing the expert-perceived state of inland fisheries at the basin (fishery) level. An electronic survey distributed to professional networks (June-September 2020) captured expert perceptions (n = 536) of threats, successes, and adaptive capacity to fisheries across 93 hydrological basins, 79 countries, and all major freshwater habitat types. This dataset can be used to address research questions with conservation relevance, including: demographic influences on perceptions of threat, adaptive capacities for climate change, external factors driving multi-stressor interactions, and geospatial threat assessments.

A facile and efficient synthesis of 3,3-dimethyl isopropylidene proline from (+)-3-carene.

A highly efficient and practical route to 3,4-isopropylidene proline I, starting from (+)-3-carene, was developed. The three continuous stereocenters were constructed using the inherent chirality of the starting natural product 2. The overall yield for the 12-step synthesis is 34%. The optimized sequence leading to 1 has been successfully applied on a multigram scale, thereby establishing the practicality of this route.

Discovery of a vorapaxar analog with increased aqueous solubility.

An analog of the thrombin receptor antagonist vorapaxar (SCH 530348) with increased aqueous solubility, compound 9c (SCH 602539), was discovered through incorporation of polar substituents on the pyridine ring of the himbacine-derived lead series. This analog retained the excellent potency, pharmacokinetic and safety properties of vorapaxar while increasing the aqueous solubility by 20-fold. Also presented are in vivo evaluations of this compound in a cynomolgus monkey platelet aggregation assay and in a Folts model of thrombosis in anesthetized monkeys.

FiCli, the Fish and Climate Change Database, informs climate adaptation and management for freshwater fishes.

Inland fishes provide important ecosystem services to communities worldwide and are especially vulnerable to the impacts of climate change. Fish respond to climate change in diverse and nuanced ways, which creates challenges for practitioners of fish conservation, climate change adaptation, and management. Although climate change is known to affect fish globally, a comprehensive online, public database of how climate change has impacted inland fishes worldwide and adaptation or management practices that may address these impacts does not exist. We conducted an extensive, systematic primary literature review to identify peer-reviewed journal publications describing projected and documented examples of climate change impacts on inland fishes. From this standardized Fish and Climate Change database, FiCli (pronounced fick-lee), researchers and managers can query fish families, species, response types, or geographic locations to obtain summary information on inland fish responses to climate change and recommended management actions. The FiCli database is updatable and provides access to comprehensive published information to inform inland fish conservation and adaptation planning in a changing climate.

Crystal structures of MEK1 binary and ternary complexes with nucleotides and inhibitors.

MEK1 is a member of the MAPK signal transduction pathway that responds to growth factors and cytokines. We have determined that the kinase domain spans residues 35-382 by proteolytic cleavage. The complete kinase domain has been crystallized and its X-ray crystal structure as a complex with magnesium and ATP-gammaS determined at 2.1 A. Unlike crystals of a truncated kinase domain previously published, the crystals of the intact domain can be grown either as a binary complex with a nucleotide or as a ternary complex with a nucleotide and one of a multitude of allosteric inhibitors. Further, the crystals allow for the determination of costructures with ATP competitive inhibitors. We describe the structures of nonphosphorylated MEK1 (npMEK1) binary complexes with ADP and K252a, an ATP-competitive inhibitor (see Table 1), at 1.9 and 2.7 A resolution, respectively. Ternary complexes have also been solved between npMEK1, a nucleotide, and an allosteric non-ATP competitive inhibitor: ATP-gammaS with compound 1 and ADP with either U0126 or the MEK1 clinical candidate PD325089 at 1.8, 2.0, and 2.5 A, respectively. Compound 1 is structurally similar to PD325901. These structures illustrate fundamental differences among various mechanisms of inhibition at the molecular level. Residues 44-51 have previously been shown to play a negative regulatory role in MEK1 activity. The crystal structure of the integral kinase domain provides a structural rationale for the role of these residues. They form helix A and repress enzymatic activity by stabilizing an inactive conformation in which helix C is displaced from its active state position. Finally, the structure provides for the first time a molecular rationale that explains how mutations in MEK may lead to the cardio-facio-cutaneous syndrome.

Excellent correlation between substituent constants and pyridinium N-methyl chemical shifts.

Substituents on the pyridinium ring of N-methylpyridinium derivatives, especially those on the 2- or 4-positions, have a large effect on the (1)H and (13)C NMR chemical shifts of the N-methyl group. Reasonable correlations between the chemical shift changes and the resonance substituent constants are observed. The dual substituent parameter approach provides an excellent correlation when a combination of polar and resonance substituent constants is employed.

Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: a potential therapeutic agent for the treatment of hepatitis C infection.

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or polyethylene glycol (PEG)-interferon-alpha alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.

Total Synthesis of (+)-Himbacine and (+)-Himbeline.

Himbacine (1), a complex piperidine alkaloid isolated from the bark of Australian magnolias, is a promising lead in Alzheimer's disease research due to its potent muscarinic receptor antagonist property. We have described here a highly efficient synthetic strategy that resulted in the total synthesis of himbacine (1) in about 10% overall yield and isohimbacine (1a), an unnatural isomer of himbacine, in 18% overall yield. The total synthesis of himbacine was initially approached using an intramolecular Diels-Alder reaction as the key step to generate intermediate 5 followed by a [3 + 2] cycloaddition with nitrone 4 to produce the isoxazolidine derivative 3. Methylation followed by catalytic reduction of 3 gave 12'-hydroxyhimbacine (20), which, upon dehydration, gave isohimbacine (1a) as the sole product. In an alternative approach, an all-encompassing intramolecular Diels-Alder reaction of an appropriately substituted tetraene derivative 31, which bears the entire latent carbon framework and functional group substitution of himbacine, gave the desired advanced tricyclic intermediate 33, which was readily converted to (+)-himbeline (2) and (+)-himbacine (1).

The discovery of N-((2H-tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822): a potent and selective glucagon receptor antagonist.

A novel series of spiroimidazolone-based antagonists of the human glucagon receptor (hGCGR) has been developed. Our efforts have led to compound 1, N-((2H-tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822), a potent hGCGR antagonist with exceptional selectivity over the human glucagon-like peptide-1 receptor. Oral administration of 1 lowered 24 h nonfasting glucose levels in imprinting control region mice on a high fat diet with diet-induced obesity following single oral doses of 3 and 10 mg/kg. Furthermore, compound 1, when dosed orally, was found to decrease fasting blood glucose at 30 mg/kg in a streptozotocin-treated, diet-induced obesity mouse pharmacodynamic assay and blunt exogenous glucagon-stimulated glucose excursion in prediabetic mice.

Discovery of cyclic acylguanidines as highly potent and selective beta-site amyloid cleaving enzyme (BACE) inhibitors: Part I--inhibitor design and validation.

A number of novel amidine containing heterocycles were designed to reproduce the unique interaction pattern, revealed by X-ray crystallography, between the BACE-1 catalytic diad and a weak NMR screening hit (3), with special attention paid to maintaining the appropriate basicity and limiting the number of H-bonding donors of these scaffolds. The iminohydantoin cores (10 and 23) were examined first and found to interact with the catalytic diad in one of two binding modes (A and B), each with the iminohydantoin core flipped 180 degrees in relation to the other. The amidine structural motif within each core forms a bidentate interaction with a different aspartic acid of the catalytic diad. Both modes reproduced a highly conserved interaction pattern between the inhibitors and the catalytic aspartates, as revealed by 3. Potent iminohydantoin BACE-1 inhibitors have been obtained, validating the molecular design as aspartyl protease catalytic site inhibitors. Brain penetrant small molecule BACE inhibitors with high ligand efficiencies have been discovered, enabling multiple strategies for further development of these inhibitors into highly potent, selective and in vivo efficacious BACE inhibitors.

Discovery of Narlaprevir (SCH 900518): A Potent, Second Generation HCV NS3 Serine Protease Inhibitor.

Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laboratories, is currently undergoing phase III clinical trials. Detailed investigations toward a second generation protease inhibitor culminated in the discovery of narlaprevir (SCH 900518), 37, with improved potency (∼10-fold over 1), pharmacokinetic profile and physicochemical characteristics, currently in phase II human trials. Exploration of synthetic sequence for preparation of 37 resulted in a route that required no silica gel purification for the entire synthesis.