Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors

Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics

Synthesis Paper: Targeted Livestock Grazing: Prescription for Healthy Rangelands

Targeted livestock grazing is a proven tool for manipulating rangeland vegetation, and current knowledge about targeted livestock grazing is extensive and expanding rapidly. Targeted grazing prescriptions optimize the timing, frequency, intensity, and selectivity of grazing (or browsing) in combinations that purposely exert grazing/browsing pressure on specific plant species or portions of the landscape. Targeted grazing differs from traditional grazing management in that the goal of targeted grazing is to apply defoliation or trampling to achieve specific vegetation management objectives, whereas the goal of traditional livestock grazing management is generally the production of livestock commodities. A shared aim of targeted livestock grazing and traditional grazing management is to sustain healthy soils, flora, fauna, and water resources that, in turn, can sustain natural ecological processes (e.g., nutrient cycle, water cycle, energy flow). Targeted grazing prescriptions integrate knowledge of plant ecology, livestock nutrition, and livestock foraging behavior. Livestock can be focused on target areas through fencing, herding, or supplement placement. Although practices can be developed to minimize the impact of toxins contained in target plants, the welfare of the animals used in targeted grazing must be a priority. Monitoring is needed to determine if targeted grazing is successful and to refine techniques to improve efficacy and efficiency. Examples of previous research studies and approaches are presented to highlight the ecological benefits that can be achieved when targeted grazing is applied properly. These cases include ways to suppress invasive plants and ways to enhance wildlife habitat and biodiversity. Future research should address the potential to select more adapted and effective livestock for targeted grazing and the associated animal welfare concerns with this practice. Targeted livestock grazing provides land managers a viable alternative to mechanical, chemical, and prescribed fire treatments to manipulate rangeland vegetation

Potential impact of tomosynthesis on the detection and diagnosis of breast lesi

Objective: The aim of this study was to evaluate the clinical performance of 3D tomosynthesis in comparison with Full Field Digital Mammography (FFDM) in the detection and diagnosis of breast lesions. Material and methods: 132 patients underwent standard digital mammography and tomosynthesis and the likelihood of malignancy was categorized according to (ACR) BI-RADS. Results: Tomosynthesis images had significantly increased the number of cases with BI-RAD 1 or 2 (normal/benign) to 62 (42.7%) compared to 39 (26.8%) at mammogram (p < 0.005). Tomosynthesis helped also in more clarification of benign characters. Tomosynthesis images had significantly decreased the number of indeterminate/suspicious lesions (BI-RADS 3 and 4) from 90 (62%) cases to 39 (26.8%) (p < 0.005). In a total of 40 lesions (27.5%) assigned to BI-RADS 5 at tomosynthesis, the tomosynthesis showed better performance in assessment of tumor extension and higher level in detection of clusters of micro-calcifications. The accuracy, specificity, sensitivity and positive and negative predictive values (%) of mammography alone versus when combined with the tomosynthesis were as follows: 59.3, 62.8, 55.2, 56 and 62 versus 91.7, 92.3, 91, 91, and 92.3 respectively (Table 4). Tomosynthesis significantly improved the detection of the breast lesions on mammography images especially in the dense breast with significantly higher accurate BI-RADS scoring (P value <0.005). Conclusion: Breast tomosynthesis is a promising technology that offers improved diagnostic and screening accuracy, fewer recalls as well as 3D lesion localization. Lesion conspicuity is improved using DBT compared with FFDM with a more confidence in making clinical decisions

The clinical value of ultrasound elastography in predicting malignant thyroid nodules

Objective: This study aims to evaluate the clinical value of ultrasound elastography (USE) in providing information on the nature of the thyroid nodules. This was performed using the elastography score and strain ratio in differentiating thyroid benign and malignant nodules and the histopathological examination was used as the diagnostic standard of reference. Methods: We examined 84 thyroid nodules in 62 patients with ultrasound elastography. Elastography score was assigned based on a four-point scale according to the classification proposed by Itoh et al. with a score of 1 (low stiffness over the entire nodule) to a score of 4 (high stiffness over the entire nodule). Thyroid strain ratio (normal tissue to lesion strain ratio) was calculated. Histopathological results were the standard reference. The area under the curve (AUC) and the best cut-off point were both obtained using receiver-operating characteristic (ROC) curve analysis. The sensitivity, specificity, and accuracy of both techniques were calculated. Results: Fifty-four of the 84 nodules had scores of 1 and 2, and 50 of these nodules were diagnosed histopathologically as benign. Thirty of the 84 nodules had a score of 3 and 4, and 21 of these nodules were diagnosed histopathologically as malignant. The scores of 1 and 2 with Itoh criteria were significantly seen in benign nodules, whereas, scores of 3 and 4 were significantly seen in malignant nodules (p < 0.05) with sensitivity 84%, specificity 84.7%, PPV 70%, NPV 92.6% and accuracy 84.5%. The mean SR for the benign nodules and malignant ones was significantly different (2.92 ± 0.96 vs. 4.53 ± 0.82, p < 0.001). With ROC analysis, the best cut-off strain ratio point was 3.5 for differentiating benign and malignant nodules with area under the curve (AUC) = 0.87 (0.8–0.95). The sensitivity of the strain ratio was 88%, while the specificity was 86.4%, PPV = 73.3%, NPV = 94.4% and accuracy = 86.9%. Conclusions: Both the elastographic score and strain ratio are higher in malignant nodules than those in benign ones. Ultrasound elastography can provide quantitative information on thyroid nodule helping in differentiating benign and malignant ones

Incorporation field crop residues in rabbit rations

Abstract Background In Egypt, the area of Berseem was decreased and wheat area increased which lead to high price of rabbit rations. Using non-traditional feed led to decrease the cost of feeding. The main objective of this study is to replace 50% of Berseem hay (BH) of rabbit rations by agriculture by-products such as Mung bean husks (MBH), soybean vein hay (SBVH), or peanut vein hay (PVH). Method Twenty-four New Zealand White (NZW) rabbits aged 5–6 weeks (584 ± 25 g) were randomly divided into four equal experimental groups. Feeding trial lasted 70 days. Results Except for organic matter (OM) digestibility, treatments had no effect on all other nutrient digestibilites that includes dry matter (DM), crude protein (CP), crude fiber (CF), ether extract (EE), and nitrogen free extract (NFE) and nutritive values {total digestible nutrient (TDN) and digestible crude protein (DCP)}. Instead, 50% of BH by the other alternative source of agriculture by-products had no effect on all carcass parameters measured. However, dressing percentages was improved. Treatments had no effect on albumin, total lipids, triglycerides, total cholesterol, low-density lipoprotein (LDL), glutamic oxaloacetic transaminase (GOT), creatinine, and alkaline phosphatase. Conclusion It can be instead 50% of hay used in rabbit rations with alternative sources of roughage, such as Mung bean husks, soybean vein hay, or peanut vein hay, without any adverse effect on their performance, digestion, carcass characteristics, and blood constituents