Macrocyclic inhibitors of Factor XIa: Discovery of alkyl-substituted macrocyclic amide linkers with improved potency

Optimization of macrocyclic inhibitors of FXIa is described which focused on modifications to both the macrocyclic linker and the P1 group. Increases in potency were discovered through interactions with a key hydrophobic region near the S1 prime pocket by substitution of the macrocyclic linker with small alkyl groups. Both the position of substitution and the absolute stereochemistry of the alkyl groups on the macrocyclic linker which led to improved potency varied depending on the ring size of the macrocycle. Replacement of the chlorophenyltetrazole cinnamide P1 in these optimized macrocycles reduced the polar surface area and improved the oral bioavailability for the series, albeit at the cost of a decrease in potency.     

Giant Cicada Emergence,Protandry and Chorus Centers Formation as Revealed by Studies Using a Sound Trap

The giant cicada, Quesada gigas (Olivier) (Hemiptera: Cicadidae), is an important coffee pest and information about the behavior and reproduction of this species, e.g. emergence, senescence and ovarian maturation status, can be valuable to understand giant cicada ecology and to improve the use of a sound trap as a control method. A great number of Q. gigas adult males and females was captured using a sound trap and a protandrous type of emergence possibly associated with chorus centers formation was observed. All giant cicadas collected until 14–15 days after the beginning of male emergence (DAME) had immature ovaries at two different years of evaluation. On the other hand, the majority of cicadas collected from 20 until 48 DAME had mature ovaries with visible chorionated oocytes. Despite the use of the sound trap to collect insects for ecological studies, we believe that next generations of Q. gigas can be reduced by using this sound trap to hinder the formation of giant cicada chorus centers, to reduce male availability to copulate with females and to reduce the number of females to oviposit in coffee plants.     

Automatic methyl assignment in large proteins by the MAGIC algorithm

Selective methyl labeling is an extremely powerful approach to study the structure, dynamics and function of biomolecules by NMR. Despite spectacular progress in the field, such studies remain rather limited in number. One of the main obstacles remains the assignment of the methyl resonances, which is labor intensive and error prone. Typically, NOESY crosspeak patterns are manually correlated to the available crystal structure or an in silico template model of the protein. Here, we propose methyl assignment by graphing inference construct, an exhaustive search algorithm with no peak network definition requirement. In order to overcome the combinatorial problem, the exhaustive search is performed locally, i.e. for a small number of methyls connected through-space according to experimental 3D methyl NOESY data. The local network approach drastically reduces the search space. Only the best local assignments are combined to provide the final output. Assignments that match the data with comparable scores are made available to the user for cross-validation by additional experiments such as methyl-amide NOEs. Several NMR datasets for proteins in the 25–50 kDa range were used during development and for performance evaluation against the manually assigned data. We show that the algorithm is robust, reliable and greatly speeds up the methyl assignment task.     

Larval identification of two syntopic species <Emphasis Type="Italic">Branchipus schaefferi</Emphasis> and <Emphasis Type="Italic">Tanymastix stagnalis</Emphasis> (Crustacea,Anostraca) sheds light on their pattern of coexistence

In the present study we applied a discriminant function analysis to distinguish two fairy shrimp species, Branchipus schaefferi and Tanymastix stagnalis (Anostraca), co-occurring in Lago dell’Orso in central Italy. Our aim was to obtain information on the pattern of coexistence of these two species to investigate their syntopy since early larval stages. To identify the larvae of the two species we used six discriminant functions, one for each larval stage considered (nauplius, four metanauplius stages and juvenis), and based on morphometric analyses and measurements of different traits (thoracic appendages, body length, length of first antenna, length of head, thorax length and length of furca). The pool was visited at weekly intervals during two time periods for a total of 4 years (1995–1996 and 2000–2001) and physical and chemical variables (water level, water and air temperature, pH and conductivity) were recorded. A total of 1067 specimens were collected, measured and morphometrically identified. B. schaefferi was more abundant and persistent than T. stagnalis. At any stage, T. stagnalis was bigger than B. schaefferi and this difference may justify niche differentiation between coexisting species. Difference in size might be linked to difference in life-span as B. schaefferi reproduced earlier and at a smaller size than T. stagnalis. When the hydroperiod is short, B. schaefferi might be the only species to produce resting eggs in time for reproduction. On the other hand, T. stagnalis may have an advantage in the longest hydroperiods. In an ephemeral seasonal pond such as Lago dell’Orso, coexistence can be fostered and competitive exclusion can be prevented as a result of seasonal environmental changes.     

Reductive Dissolution of Jarosite by Acidiphilium cryptum in Presence of Chelating Agents and Dissolved Iron

The mutual effects of Acidiphilium cryptum, nine ligands and dissolved iron on jarosite dissolution were studied in a 2³ full factorial experiment. Ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA) and oxalic acid were able to dissolve jarosite chemically, but bacterial action enhanced this dissolution; from 88 ± 1, 46 ± 0 and 36 ± 0 µmol/L d to 129 ± 3, 177 ± 5 and 106 ± 14 µmol/L d, respectively. Oxalate and NTA exhibited a synergistic effect with dissolved iron and bacteria that may be explained by a model in which iron complexes behave as redox mediators in the microbial respiration in which jarosite, a solid substrate, serves as terminal electron acceptor.     

Evolution of Volatile Emission in Rhus coriaria Organs During Different Stages of Growth and Evaluation of the Essential Oil Composition

Rhus coriaria, also known as Sumac, has been traditionally used in many countries as spice, condiment, dying agent, and medicinal herb. The chemical composition of essential oils (EOs) and the volatile emissions from different organs of this species collected in Sicily (Italy) were analyzed by gas chromatography‐flame ionization detection and gas chromatography/mass spectrometry. Monoterpene and sesquiterpene hydrocarbons were the most abundant class in the volatile emissions with β‐caryophyllene and α‐pinene were the main constituents in the majority of the examined samples. The EO composition was characterized by high amount of monoterpene and sesquiterpene hydrocarbons together with diterpenes. The main compounds in the EO obtained from the leaves and both stages of fruit maturation were cembrene and β‐caryophyllene, while α‐pinene and tridecanoic acid were the key compounds in the flower EO. All the data were submitted to multivariate statistical analysis showing many differences among the different plant parts and their ontogenetic stages.     

Kinetics of carbendazim degradation in a horizontal tubular biofilm reactor

Bioprocess and Biosystems Engineering - The fungicide carbendazim is an ecotoxic agent affecting aquatic biota. Due to its suspected hormone-disrupting effects, it is considered a “priority...     

Impact of drought stress on growth and quality of miscanthus for biofuel production

Miscanthus has a high potential as a biomass feedstock for biofuel production. Drought tolerance is an important breeding goal in miscanthus as water deficit is a common abiotic stress and crop irrigation is in most cases uneconomical. Drought may not only severely reduce biomass yields, but also affect biomass quality for biofuel production as cell wall remodeling is a common plant response to abiotic stresses. The quality and plant weight of 50 diverse miscanthus genotypes were evaluated under control and drought conditions (28 days no water) in a glasshouse experiment. Overall, drought treatment decreased plant weight by 45%. Drought tolerance – as defined by maintenance of plant weight – varied extensively among the tested miscanthus genotypes and ranged from 30% to 110%. Biomass composition was drastically altered due to drought stress, with large reductions in cell wall and cellulose content and a substantial increase in hemicellulosic polysaccharides. Stress had only a small effect on lignin content. Cell wall structural rigidity was also affected by drought conditions; substantially higher cellulose conversion rates were observed upon enzymatic saccharification of drought‐treated samples with respect to controls. Both cell wall composition and the extent of cell wall plasticity under drought varied extensively among all genotypes, but only weak correlations were found with the level of drought tolerance, suggesting their independent genetic control. High drought tolerance and biomass quality can thus potentially be advanced simultaneously. The extensive genotypic variation found for most traits in the evaluated miscanthus germplasm provides ample scope for breeding of drought‐tolerant varieties that are able to produce substantial yields of high‐quality biomass under water deficit conditions. The higher degradability of drought‐treated samples makes miscanthus an interesting crop for the production of second‐generation biofuels in marginal soils.