Design and synthesis of potent inhibitors of the mono(ADP-ribosyl)transferase,PARP14

A series of (Z)-4-(3-carbamoylphenylamino)-4-oxobut-2-enyl amides were synthesized and tested for their ability to inhibit the mono-(ADP-ribosyl)transferase, PARP14 (a.k.a. BAL-2; ARTD-8). Two synthetic routes were established for this series and several compounds were identified as sub-micromolar inhibitors of PARP14, the most potent of which was compound 4t, IC₅₀ = 160 nM. Furthermore, profiling other members of this series identified compounds with >20-fold selectivity over PARP5a/TNKS1, and modest selectivity over PARP10, a closely related mono-(ADP-ribosyl)transferase.     

Nonlinear scaling of foraging contacts with rodent population density

Density‐dependent shifts in population processes like territoriality, reproduction, dispersal, and parasite transmission are driven by changes in contacts between individuals. Despite this, surprisingly little is known about how contacts change with density, and thus the mechanisms driving density‐dependent processes. A simple linear contact–density function is often assumed, but this is not based on a sound basis of empirical data. We addressed this question using a replicated, semi‐natural experiment in which we measured contacts at feeding stations between multimammate mice, Mastomys natalensis, across ten distinct, linearly increasing densities between 10 and 272 animals/ha. Unexpectedly, unique contacts increased not linearly but sigmoidally with density, which we attribute to the species’ scramble competition mating system, small‐scale dominance/avoidance and absence of territoriality. These results provide new insights into how species’ characteristics can relate to density‐dependent changes in contacts, and the unexpected shape of the contact–density function warrants that density‐dependence in ecological models, such as parasite transmission models, must be parameterized with care.     

Arenavirus Dynamics in Experimentally and Naturally Infected Rodents

Infectious diseases of wildlife are typically studied using data on antibody and pathogen levels. In order to interpret these data, it is necessary to know the course of antibodies and pathogen levels after infection. Such data are typically collected using experimental infection studies in which host individuals are inoculated in the laboratory and sampled over an extended period, but because laboratory conditions are controlled and much less variable than natural conditions, the immune response and pathogen dynamics may differ. Here, we compared Morogoro arenavirus infection patterns between naturally and experimentally infected multimammate mice (Mastomys natalensis). Longitudinal samples were collected during three months of bi-weekly trapping in Morogoro, Tanzania, and antibody titer and viral RNA presence were determined. The time of infection was estimated from these data using a recently developed Bayesian approach, which allowed us to assess whether the natural temporal patterns match the previously observed patterns in the laboratory. A good match was found for 52% of naturally infected individuals, while most of the mismatches can be explained by the presence of chronically infected individuals (35%), maternal antibodies (10%), and an antibody detection limit (25%). These results suggest that while laboratory data are useful for interpreting field samples, there can still be differences due to conditions that were not tested in the laboratory.     

Automated cerebrospinal fluid cytology

OBJECTIVE: To evaluate the Abbott CELL-DYN Sapphire cytometer for cerebrospinal fluid (CSF) cell count and differentiation. METHODS: One hundred three analyses of CSF cells by the CELL-DYN Sapphire were compared with routine cell count and microscopic differentiation and correlation coefficients calculated. RESULTS: The total cell count of both methods correlated well. The detection of erythrocytes was good (0.898), and a higher content of erythrocytes >100/microL had little effect on total leukocyte count. The correlation between both methods was best with higher leukocyte counts >25/microL (r=0.987), whereas at cell counts <25/microL, the correlation was considerably less precise (r=0.613). For the differentiation of cells, lymphocytes and neutrophils showed moderate correlation. The results for monocytes and eosinophils did not correlate. CONCLUSION: The results for the total cell count in this study are comparable with those achieved with the Bayer Advia 120. While the Abbott CELL-DYN Sapphire yielded slightly better results for erythrocytes and total cell count with a higher erythrocyte content, the Advia 120 achieved slightly better results of lymphocyte and neutrophil count in a previous study.     

Time- and space-resolved Monte Carlo study of water radiolysis for photon,electron and ion irradiation

Time-dependent yields of the most important products of water radiolysis , ^•OH, H^•, H₃O⁺, H₂, OH⁻ and H₂O₂ have been calculated for ⁶⁰Co-photons, electrons, protons, helium- and carbon-ions incident onto water. G values have been evaluated for the interval from 1 ps to 1 μs after initial energy deposition as a function of time, as well as after 1 ns and at the end of the chemical stage as a function of linear energy transfer (LET), covering an interval from approximately 0.2 up to 750 keV/μm by means of different particle types. In this work, the modules of the biophysical Monte Carlo track structure code PARTRAC dealing with the simulation of prechemical and chemical stages have been improved to extend interaction data sets for heavier ions. Among other newly selected parameter values, the thermalisation distance between the point of generation and hydration of subexcitation electrons has been adopted from recent data in the literature. As far as data from the literature are available, good agreement has been found with the calculated time- and LET-dependent yields in this work, supporting the selection of the revised parameter values.     

Are local plague endemicity and ecological characteristics of vectors and reservoirs related? A case study in north-east Tanzania

The pattern of plague endemicity in Tanzania is characterized by continuous re-appearance of the disease in some locations,while in other neighbouring villages the disease has never or seldom been observed.To understand the reasons for this pattern,we studied small mammal and flea species composition,diversity and relative abundances in two plague-endemic and two plague-free locations.We asked(a)whether fleas more abundant in plague-endemic locations differ in their characteristic abundance and the degree o...     

Crystal Structure of the ATPase Domain of the Human AAA+ Protein Paraplegin/SPG7

Paraplegin is an m-AAA protease of the mitochondrial inner membrane that is linked to hereditary spastic paraplegias. The gene encodes an FtsH-homology protease domain in tandem with an AAA+ homology ATPase domain. The protein is believed to form a hexamer that uses ATPase-driven conformational changes in its AAA-domain to deliver substrate peptides to its protease domain. We present the crystal structure of the AAA-domain of human paraplegin bound to ADP at 2.2 Å. This enables assignment of the roles of specific side chains within the catalytic cycle, and provides the structural basis for understanding the mechanism of disease mutations.

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