A novel potent metal-binding NDM-1 inhibitor was identified by fragment virtual,SPR and NMR screening

NDM-1 can hydrolyze nearly all available β-lactam antibiotics, including carbapenems. NDM-1 producing bacterial strains are worldwide threats. It is still very challenging to find a potent NDM-1 inhibitor for clinical use. In our study, we used a metal-binding pharmacophore (MBP) enriched virtual fragment library to screen NDM-1 hits. SPR screening helped to verify the MBP virtual hits and identified a new NDM-1 binder and weak inhibitor A1. A solution NMR study of ¹⁵N-labeled NDM-1 showed that A1 disturbed all three residues coordinating the second zinc ion (Zn2) in the active pocket of NDM-1. The perturbation only happened in the presence of zinc ion, indicating that A1 bound to Zn2. Based on the scaffold of A1, we designed and synthesized a series of NDM-1 inhibitors. Several compounds showed synergistic antibacterial activity with meropenem against NDM-1 producing K. pneumoniae.     

The structure of 180° supernumerary limbs and a hypothesis of their formation

The results of a detailed analysis of 100 supernumerary limbs generated by 180° ipsilateral rotation (on the same limb stump) of regeneration blastemas is presented. The limbs were analyzed in terms of their position of origin, frequency, cartilage structure by Victoria blue staining, and muscle structure by serial sections. Single, double, or triple supernumeraries can be produced at no unique position of origin, although the posterodorsal quadrant was preferred. Four classes of supernumerary limbs were generated by such operations—normal; double dorsal or double ventral; part normal/part mirror imaged; part normal/part inverted in approximately equal frequencies. After amputation of these supernumeraries the same muscle patterns are faithfully regenerated. A hypothesis to explain the production of these abnormal limbs is proposed based on the observed phenomenon of fusion of supernumerary blastemata, but their regenerative behaviour presents problems for current models of pattern formation. Similar results have been obtained with developing limb buds and the relation between development and regeneration is discussed.     

Biosynthesis of bacterial glycogen: purification and characterization of ADPglucose pyrophosphorylase with modified regulatory properties from Escherichia coli B mutant CL1136-504

The l-thyroxine binding site in human serum thyroxine-binding globulin was investigated by affinity labeling with N-bromoacetyl-l-thyroxine (BrAcT₄). Competitive binding studies showed that, in the presence of 100 molar excess of BrAcT₄, binding of thyroxine to thyroxine-binding globulin was nearly totally abolished. The reaction of BrAcT₄ to form covalent binding was inhibited in the presence of thyroxine and the affinity-labeled thyroxinebinding globulin lost its ability to bind thyroxine. These results indicate BrAcT₄ and thyroxine competed for the same binding site. Affinity labeling with 2 mol of BrAcT₄/mol of thyroxine-binding globulin resulted in the covalent attachment of 0.7 mol of ligand. By amino acid analysis and high voltage paper electrophoresis, methionine was identified as the major residue labeled (75%). Lysine, tyrosine, and histidine were also found to be labeled to the extent of 8, 8, and 5%, respectively.     

Rainfall and parasitic wasp (Hymenoptera: Ichneumonoidea) activity in successional forest stages at Barro Colorado Nature Monument, Panama, and La Selva Biological Station, Costa Rica

1 In 1997, we ran two Malaise insect traps in each of four stands of wet forest in Costa Rica (two old‐growth and two 20‐year‐old stands) and four stands of moist forest in Panama (old‐growth, 20, 40 and 120‐year‐old stands). 2 Wet forest traps caught 2.32 times as many ichneumonoids as moist forest traps. The average catch per old‐growth trap was 1.89 times greater than the average catch per second‐growth trap. 3 Parasitoids of lepidopteran larvae were caught in higher proportions in the wet forest, while pupal parasitoids were relatively more active in the moist forest. 4 We hypothesize that moisture availability is of key importance in determining parasitoid activity, community composition and trophic interactions.     

Harassment of Mature Female Chimpanzees by Young Males in the Mahale Mountains

Juvenile and adolescent male chimpanzees sometimes threaten older, apparently stronger individuals such as mature females. I label the behavior harassment. Harassment comprises 25 behaviors, 14 of which are accompanied by the use of objects such as branches: Clubbing, flailing and throwing are the most common. Females respond to harassment with 10 behaviors, including scream, avoid, ignore, and retaliate. Females tend to respond to harassment by juvenile males by ignoring them. However, they are more likely to retaliate, scream or avoid in response to harassment by adolescent males. I propose the rank improvement hypothesis that harassment initiates the process of male domination of females, and compare the predictions derived from it with those of the exploratory aggression hypothesis. Males stopped harassing females significantly earlier when females ignored them versus when they did not ignore them. This is not consistent with the exploratory aggression hypothesis. Males harassed adult females significantly longer when females retaliated than when they did not, which is consistent with the rank improvement hypothesis. Although the observations are congruent with my hypothesis, we need more data to test it.     

Dynamics of Newly Established Elk Populations

Abstract: The dynamics of newly established elk (Cervus elaphus) populations can provide insights about maximum sustainable rates of reproduction, survival, and increase. However, data used to estimate rates of increase typically have been limited to counts and rarely have included complementary estimates of vital rates. Complexities of population dynamics cannot be understood without considering population processes as well as population states. We estimated pregnancy rates, survival rates, age ratios, and sex ratios for reintroduced elk at Theodore Roosevelt National Park, North Dakota, USA; combined vital rates in a population projection model; and compared model projections with observed elk numbers and population ratios. Pregnancy rates in January (early in the second trimester of pregnancy) averaged 54.1% (SE = 5.4%) for subadults and 91.0% (SE = 1.7%) for adults, and 91.6% of pregnancies resulted in recruitment at 8 months. Annual survival rates of adult females averaged 0.96 (95% CI = 0.94-0.98) with hunting included and 0.99 (95% CI = 0.97-0.99) with hunting excluded from calculations. Our fitted model explained 99.8% of past variation in population estimates and represents a useful new tool for short-term management planning. Although we found no evidence of temporal variation in vital rates, variation in population composition caused substantial variation in projected rates of increase (Λ = 1.20-1.36). Restoring documented hunter harvests and removals of elk by the National Park Service led to a potential rate of Λ = 1.26. Greater rates of increase substantiated elsewhere were within the expected range of chance variation, given our model and estimates of vital rates. Rates of increase realized by small elk populations are too variable to support inferences about habitat quality or density dependence.     

Can we rely on forest reserves for primate conservation?

Tropical forests contain much of the world's biodiversity, yet their rate of decline is increasing. The strategy most frequently used to protect this biodiversity is to make parks and reserves. While there is a great deal of research on the effectiveness of parks for protecting biodiversity, there is little research on how well extractive reserves conserve biodiversity. Here, we evaluate the effectiveness of four forest reserves in western Uganda at maintaining populations of primates and compare census data from the reserves to data from the neighbouring well‐protected Kibale National Park. The relative abundance of the five most common primates in the park was approximately four times that of the forest reserves. In the forest reserves, evidence of new human encroachment was seen every 500 m, while in the park it was seen every 100,000 m. Two recommendations emerge from our research: (i) for forest reserves, such as those studied here, to have conservation value for primates, extraction must be reduced and (ii) until the long‐term viability of the populations in forest reserves can be ascertained, they should not be considered in estimates of the sizes of endangered species protected ranges.     

Cord-factor analogs: synthesis of 6,6'-di-O-mycoloyl- and -corynomycoloyl-(alpha-D-galactopyranosyl alpha-D-galactopyranoside)

Appropriate solvolysis of 2,3,2',3'-tetra-O-benzyl-4,6,4', 6'-tetra-O-mesyl-alpha,alpha-trehalose gave 2,3,2',3' -tetra-O-benzyl-(alpha-D-galactopyranosyl alpha-D-galactopyranoside) (2). Selective tosylation or mesylation of 2 respectively gave the 6, 6'-ditosylate (3) and 6,6'-dimesylate (4), the structures of which were confirmed by the 1H-n.m.r. spectra of the corresponding 4,4'-di-O-acetyl derivatives. Treatment of 3 with potassium mycolate in toluene, and subsequent hydrogenolysis, gave the 6'-mycolate 6-tosylate derivative. Treatment of 3 with potassium mycolate or potassium corynomycolate in hexamethylphosphoric triamide, followed by catalytic hydrogenolysis, yielded the respective cord-factor analogs 6,6'-di-O-mycoloyl-(alpha-D-galactopyranosyl alpha-D-galactopyranoside) and 6,6'-di-O-corynomycoloyl-(alpha-D-galactopyranosyl alpha-D-galactopyranoside). The same 6,6'-diesters were obtained from the 6,6'-dimesylate 4. Putative 4,6-anhydro-6'-monomycolates are also described.