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Replication Protein A (RPA) is a broadly conserved complex comprised of the RPA1, 2 and 3 subunits. RPA protects the exposed single-stranded DNA (ssDNA) during DNA replication and repair. Using structural modeling, we discover an inhibitor, JC-229, that targets RPA1 in Trypanosoma brucei , the causative parasite of African trypanosomiasis. The inhibitor is highly toxic to T. brucei cells, while mildly toxic to human cells. JC-229 treatment mimics the effects of Tb RPA1 depletion, including DNA replication inhibition and DNA damage accumulation. In-vitro ssDNA-binding assays demonstrate that JC-229 inhibits the activity of Tb RPA1, but not the human ortholog. Indeed, despite the high sequence identity with T. cruzi and Leishmania RPA1, JC-229 only impacts the ssDNA-binding activity of Tb RPA1. Site-directed mutagenesis confirms that the DNA-Binding Domain A (DBD-A) in Tb RPA1 contains a JC-229 binding pocket. Residue Serine 105 determines specific binding and inhibition of Tb RPA1 but not T. cruzi and Leishmania RPA1. Our data suggest a path toward developing and testing highly specific inhibitors for the treatment of African trypanosomiasis. The authors identify a small molecule inhibitor targeting the ssDNA-binding function of T. brucei Replication Protein A1 without affecting the host ortholog. They confirm the key residue in Tb RPA1 involved in the species-specific selectivity of the chemical probe.

The anthrax lethal toxin (LT) enters host cells and enzymatically cleaves MAPKKs or MEKs. How these molecular events lead to death from anthrax remains poorly understood, but published reports suggest a direct effect of LT on vascular permeability. We have found that LT challenge in mice disrupts signaling through Tie-2, a tonically activated receptor tyrosine kinase in the endothelium. Genetic manipulations favoring Tie-2 activation enhanced interendothelial junctional contacts, prevented vascular leakage, and promoted survival following a lethal dose of LT. Cleavage of MEK1/2 was necessary for LT to induce endothelial barrier dysfunction, and activated Tie-2 signaled through the uncleaved fraction of MEKs to prevent LT’s effects on the endothelium. Finally, primates infected with toxin-secreting Bacillus anthracis bacilli developed a rapid and marked imbalance in the endogenous ligands that signal Tie-2, similar to that seen in LT-challenged mice. Our results show that B. anthracis LT blunts signaling through Tie-2, thereby weakening the vascular barrier and contributing to lethality of the disease. Measurement of circulating Tie-2 ligands and manipulation of Tie-2 activity may represent future prognostic and therapeutic avenues for humans exposed to B. anthracis .

Reactive oxygen species (ROS) are largely considered to be pathogenic to normal endothelial function in disease states such as sepsis. We hypothesized that Angiopoietin-1 (Angpt-1), an endogenous agonist of the endothelial-specific receptor, Tie-2, promotes barrier defense by activating NADPH oxidase (NOX) signaling. Using primary human microvascular endothelial cells (HMVECs), we found that Angpt-1 stimulation induces phosphorylation of p47phox and a brief oxidative burst that is lost when chemical inhibitors of NOX activity or siRNA against the NOX component p47phox were applied. As a result, there was attenuated ROS activity, disrupted junctional contacts, enhanced actin stress fiber accumulation, and induced gap formation between confluent HMVECs. All of these changes were associated with weakened barrier function. The ability of Angpt-1 to prevent identical changes induced by inflammatory permeability mediators, thrombin and lipopolysaccharides (LPS), was abrogated by p47phox knockdown. P47phox was required for Angpt-1 to activate Rac1 and inhibit mediator-induced activation of the small GTPase RhoA. Finally, Angpt-1 gene transfer prevented vascular leakage in wildtype mice exposed to systemically administered LPS, but not in p47phox knock out (p47-/-) littermates. These results suggest an essential role for NOX signaling in Angpt-1-mediated endothelial barrier defense against mediators of systemic inflammation. More broadly, oxidants generated for signal transduction may have a barrier-promoting role in vascular endothelium.

Skeletal integrity is dependent on the coordinated actions of bone-forming osteoblasts and bone-resorbing osteoclasts, which recognize and respond to multiple environmental inputs. Here we have studied the roles in bone development and growth of Akt1 and Akt2, two closely related signaling proteins, by evaluating mice lacking either of these enzymes. Global deficiency of Akt1 but not Akt2 caused a reduction in whole body and femoral bone mineral density, in femoral cortical thickness and volume, and in trabecular thickness in both males and females when measured at 20-weeks of age, which was reflected in diminished femoral resistance to fracture. Haplo-deficiency of Akt1 in male mice also decreased femoral cortical and trabecular skeletal parameters, and reduced bone strength. Cell-based studies showed that genetic Akt1 deficiency diminished the rate of proliferation of osteoblast progenitors and impaired osteoclast differentiation in primary culture but that loss of Akt2 did not. Our results demonstrate differential effects of Akt1 and Akt2 on skeletal maturation and architecture through actions on both osteoblast and osteoclast precursors.

Purpose: India is one of the countries which has maximum number of livestock with rules the rural economy, which are eventually dealt by veterinarians to overcome different crisis. Veterinarians are entrusted with combating various disastrous situations whichever come in the way of this natural resource. This article deals with information needs and seeking behaviour of veterinary users who are aspiring to be future experts in the field and faculty personnel of two Veterinary Council of India accredited colleges situated in North East India, namely College of Veterinary Science, Assam and College of Veterinary Science, Mizoram. Methodology: The authors visited the above mentioned colleges to elicit data from respondents. A questionnaire was propounded for the purpose. Later the data were analysed, tabulated and hypothesis were drawn and checked. Scope and Coverage: The article encompasses veterinary college students; faculty personnel of two Veterinary Councils of India (VCI) accredited veterinary colleges of Assam and Mizoram. Findings: Sixty percent female respondents had graduation degree followed by 58.06% male respondents having the same. Overwhelming majority of both the male and female respondents claimed that they visited library for books while, 71.43% female respondents visited library for borrowing books. Chi square test proved that there is a significant relationship between the gender of the respondents and the purpose to visit the library. Originality: This article is entirely original in nature. No other research works have been performed in this region so far.

Stapled α−helical peptides have emerged as a promising new modality for a wide range of therapeutic targets. Here, we report a potent and selective dual inhibitor of MDM2 and MDMX, ATSP-7041, which effectively activates the p53 pathway in tumors in vitro and in vivo. Specifically, ATSP-7041 binds both MDM2 and MDMX with nanomolar affinities, shows submicromolar cellular activities in cancer cell lines in the presence of serum, and demonstrates highly specific, on-target mechanism of action. A high resolution (1.7-Å) X-ray crystal structure reveals its molecular interactions with the target protein MDMX, including multiple contacts with key amino acids as well as a role for the hydrocarbon staple itself in target engagement. Most importantly, ATSP-7041 demonstrates robust p53-dependent tumor growth suppression in MDM2/MDMX-overexpressing xenograft cancer models, with a high correlation to on-target pharmacodynamic activity, and possesses favorable pharmacokinetic and tissue distribution properties. Overall, ATSP-7041 demonstrates in vitro and in vivo proof-of-concept that stapled peptides can be developed as therapeutically relevant inhibitors of protein–protein interaction and may offer a viable modality for cancer therapy.

A biodiversity assessment of any region is a fundamental necessity towards implementing an efficient conservation action plan. The alteration of habitat and vegetation composition through the successful invasion of non-indigenous species can be a serious management issue. The most prominent threat resulting in a rapid decline of native plant communities is the competition and indirect effects of alien plant species. In this study, we aim to assess the spread of invasive Prosopis juliflora and its consequences on the native flora over a span of three decades in Keoladeo National Park, India. The community structure was assessed by gridding the entire park with quadrates laid systematically. We recorded a total of 7179 individual plants, of which 3667 individuals were woody trees representing 26 species and 3512 individuals were shrubs belonging to 25 species. The invasive P. juliflora represented a maximum number of individuals among both trees (n = 957) and shrubs (n = 1560), and appears to be the dominant shrub species (IVI-74.96; SDI-0.14). The spatial comparison of species dominance (1985–2015) showed a significant increase in the dominance of P. juliflora ( Z  = 5.14, p < 0.00), replacing the dominant native species, including Acacia nilotica , Mitragyna parvifolia , Prosopis cineraria , Salvadora oleoides, Salvadora persica and Ziziphus mauritiana . The classified images also confirm an increase in spatial extent of both pure stands of invasive P. juliflora (from 4.02 to 16.46%) and open scrub dominant with P. juliflora thickets (from 2.16 to 50.94%). The article also discusses possible reasons of the high invasibility of P. juliflora, particularly its high allelopathic (inhibition) effect and highlights conservation management issues in the region. These issues deserve careful consideration to help safeguard the entire ecosystem of this world heritage site.

We examined factors responsible for spatial occupancy and burrow site selection for permanent occupancy by Indian crested porcupine in Keoladeo National Park, Bharatpur, Rajasthan, India. We employed occupancy framework to examine a priori hypotheses and to obtain detection histories of faecal droppings and burrow occurrence. The detection probability (0.19 ± 0.05SE) and occupancy (0.28 ± 0.05SE) of burrow sites were lower than those of faecal deposits (0.33 ± 0.029SE and 0.71 ± 0.06SE) respectively. The rodents avoided areas with water cover and selected those closer to the boundary of nearby agricultural fields at higher elevation as burrow sites. None of the considered covariates influenced their spatial occupancy. This study infers the strategic placement of burrows by these apex ecosystem engineers, also providing crucial ecological niche for various other co-occupants.

A calcifying epithelial odontogenic tumour (CEOT) is a rare benign odontogenic tumour of epithelial origin accounting for approximately 1% of all odontogenic tumours. The intraosseous form occurs more commonly in the posterior mandible whereas the extraosseous form is common in the anterior maxilla. CEOT is often asymptomatic and presents with a painless swelling of the mandible. Various histopathological variants of CEOT have been reported in the literature such as clear cell, Langerhans cell and CEOT with cementum-like areas with a 10–20% local recurrence. We report a case of a clear cell variant of CEOT in the left posterior mandible associated with an impacted third molar exhibiting its characteristic driven snow radiographic appearance. In addition, a few areas showed soap bubble multilocular presentation, change in trabeculae pattern and pathological fracture with the cupping type of root resorption in the mandibular second molar. Histopathologically, Liesegang rings were seen in the epithelium.