Binding mode of conformations and structure-based pharmacophore development for farnesyltransferase inhibitors

Farnesyltransferase (FTase) is one of the prenyltransferase family enzymes that catalyse the transfer of 15-membered isoprenoid (farnesyl) moiety to the cysteine of CAAX motif-containing proteins including Rho and Ras family of G proteins. Inhibitors of FTase act as drugs for cancer, malaria, progeria and other diseases. In the present investigation, we have developed two structure-based pharmacophore models from protein–ligand complex (3E33 and 3E37) obtained from the protein data bank. Molecular dynamics (MD) simulations were performed on the complexes, and different conformers of the same complex were generated. These conformers were undergone protein–ligand interaction fingerprint (PLIF) analysis, and the fingerprint bits have been used for structure-based pharmacophore model development. The PLIF results showed that Lys164, Tyr166, TrpB106 and TyrB361 are the major interacting residues in both the complexes. The RMSD and RMSF analyses on the MD-simulated systems showed that the absence of FPP in the complex 3E37 has significant effect in the conformational changes of the ligands. During this conformational change, some interactions between the protein and the ligands are lost, but regained after some simulations (after 2 ns). The structure-based pharmacophore models showed that the hydrophobic and acceptor contours are predominantly present in the models. The pharmacophore models were validated using reference compounds, which significantly identified as HITs with smaller RMSD values. The developed structure-based pharmacophore models are significant, and the methodology used in this study is novel from the existing methods (the original X-ray crystallographic coordination of the ligands is used for the model building). In our study, along with the original coordination of the ligand, different conformers of the same complex (protein–ligand) are used. It concluded that the developed methodology is significant for the virtual screening of novel molecules on different targets.     

Erratum to: Specific stressors in endonasal skull base surgery with and without navigation

European Archives of Oto-Rhino-Laryngology -     

Lower body mass index and higher height are correlated with increased varicocele risk

To evaluate the anthropometric indexes in subjects with varicocele compared to controls and the incidence of varicocele in different body mass index (BMI) groups for the purpose of exploring the association between varicocele and anthropometric indexes. A comprehensive literature search was conducted by using PubMed, MEDLINE, EMBASE databases and Cochrane Library up to February 2019. A systematic review and meta‐analysis was conducted by STATA, and Newcastle–Ottawa Scale was utilised for assessing risk of bias. Ultimately, 13 articles containing seven case–control studies and six cross‐sectional studies with 1,385,630 subjects were involved in our study. Pooled results demonstrated that varicocele patients had a lower BMI (WMD = ?0.77, 95% CI = ?1.03 to ?0.51) and a higher height than nonvaricocele participants, especially in grade 3 varicocele patients. Subgroup analyses showed that normal BMI individuals had a higher risk of varicocele than obese or overweight individuals and a lower risk than underweight individuals. In conclusion, this study indicates that varicocele patients have a lower BMI and a higher height than nonvaricocele participants. Moreover, men with excess bodyweight have a lower incidence of varicocele compared to normal weight or underweight people. That is to say, high BMI and adiposity protect against varicocele and high BMI is associated with a decreased risk of varicocele.     

In Vivo Kinematics of Functional Ankle Instability Patients and Lateral Ankle Sprain Copers During Stair Descent

Patients with mechanic ankle instability experience increased tibiotalar and subtalar joint laxity. However, in vivo joint kinematics in functional ankle instability (FAI) patients and lateral ankle sprain (LAS) copers, especially during dynamic activities, are poorly understood. Ten FAI patients, 10 LAS copers, and 10 healthy controls were included in this study. A dual fluoroscopic imaging system was used to analyze the tibiotalar and subtalar joint kinematics during stair descent. Five key poses of stair descent were analyzed. Kinematic data from six degrees of freedom were calculated utilizing a solid modeling software. The range of motion and joint positions in each degree of freedom were compared among the three groups. The tibiotalar joints of FAI patients and LAS copers were significantly more inverted than those of healthy controls during the foot strike (p = 0.016, = 0.264). The subtalar joints of FAI patients were significantly more anteriorly translated (pose 2, p = 0.003, = 0.352; pose 3, p < 0.001, = 0.454; pose 4, p = 0.004, = 0.334), inverted (pose 4, p = 0.027, = 0.234; pose 5,p = 0.034, = 0.221), and externally rotated (pose 4, p = 0.037, = 0.217; pose 5; p = 0.004, = 0.331) than those of healthy controls during the mid‐stance and the heel off. The FAI patients showed excessive tibiotalar inversion and subtalar joint hypermobility during stair descent. Meanwhile, the LAS copers maintained subtalar joint stability, and only showed excessive tibiotalar inversion in foot strike. These data provide insight into the mechanisms behind the development of FAI after initial LAS. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1860–1867, 2019     

Demodex: a skin resident in man and his best friend

Demodex mites are microscopic arachnids found in the normal skin of many mammals. In humans, it is well established that Demodex mite density is higher in patients with the skin condition rosacea, and treatment with acaricidal agents is effective in resolving symptoms. However, pathophysiology of rosacea is complex and multifactorial. In dogs, demodicosis is a significant veterinary issue, particularly the generalized form of the disease which can be fatal if untreated. In each species, clinical and molecular studies have shown that the host’s immunological interactions with Demodex mites are an important, but not fully understood, aspect of how Demodex can live in the skin either as a harmless commensal organism or as a pathogenic agent. This review outlines the role of Demodex mites in humans and dogs, considering morphology, prevalence, symptoms, diagnosis, histology treatment and pathogenesis.