Independent-Trajectories Thermodynamic-Integration Free-Energy Changes for Biomolecular Systems: Determinants of H5N1 Avian Influenza Virus Neuraminidase Inhibition by Peramivir

Free-energy changes are essential physicochemical quantities for understanding most biochemical processes. Yet, the application of accurate thermodynamic-integration (TI) computation to biological and macromolecular systems is limited by finite-sampling artifacts. In this paper, we employ independent-trajectories thermodynamic-integration (IT-TI) computation to estimate improved free-energy changes and their uncertainties for (bio)molecular systems. IT-TI aids sampling statistics of the thermodynamic macrostates for flexible associating partners by ensemble averaging of multiple, independent simulation trajectories. We study peramivir (PVR) inhibition of the H5N1 avian influenza virus neuraminidase flexible receptor (N1). Binding site loops 150 and 119 are highly mobile, as revealed by N1-PVR 20-ns molecular dynamics. Due to such heterogeneous sampling, standard TI binding free-energy estimates span a rather large free-energy range, from a 19% underestimation to a 29% overestimation of the experimental reference value (−62.2 ± 1.8 kJ mol−1). Remarkably, our IT-TI binding free-energy estimate (−61.1 ± 5.4 kJ mol−1) agrees with a 2% relative difference. In addition, IT-TI runs provide a statistics-based free-energy uncertainty for the process of interest. Using ∼800 ns of overall sampling, we investigate N1-PVR binding determinants by IT-TI alchemical modifications of PVR moieties. These results emphasize the dominant electrostatic contribution, particularly through the N1 E277−PVR guanidinium interaction. Future drug development may be also guided by properly tuning ligand flexibility and hydrophobicity. IT-TI will allow estimation of relative free energies for systems of increasing size, with improved reliability by employing large-scale distributed computing

Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels

Chronic pain is a global problem affecting up to 20% of the world’s population and has a significant economic, social and personal cost to society. Sensory neurons of the dorsal root ganglia (DRG) detect noxious stimuli and transmit this sensory information to regions of the central nervous system (CNS) where activity is perceived as pain. DRG neurons express multiple voltage-gated sodium channels that underlie their excitability. Research over the last 20 years has provided valuable insights into the critical roles that two channels, NaV1.7 and NaV1.9, play in pain signalling in man. Gain of function mutations in NaV1.7 cause painful conditions while loss of function mutations cause complete insensitivity to pain. Only gain of function mutations have been reported for NaV1.9. However, while most NaV1.9 mutations lead to painful conditions, a few are reported to cause insensitivity to pain. The critical roles these channels play in pain along with their low expression in the CNS and heart muscle suggest they are valid targets for novel analgesic drugs

Case report and literature review of popliteal artery entrapment syndrome

Nedaa Skeik,1 Taylor M Thomas,2 Bjorn I Engstrom,3 Jason Q Alexander4 1Vascular Medicine, Minneapolis Heart Institute, 2Research, Minneapolis Heart Institute Foundation, 3Interventional Radiology, Minneapolis Heart Institute, 4Vascular Surgery, Minneapolis Heart Institute, MN, USAAbstract: Popliteal artery entrapment syndrome (PAES) is an uncommon condition resulting from an abnormal anatomic relationship between the popliteal artery and the surrounding musculature. The compression created by this variance in anatomy can lead to ischemia and vascular claudication. The diagnosis of PAES requires a thorough patient history and physical exam, a high index of suspicion, and dedicated imaging techniques. Several treatment options are available, including surgical intervention, thrombolysis, or a combination of these depending on the clinical indication. We present a case of PAES in a 34-year-old man who presented with typical symptoms illustrative of the complicated decision making related to this disorder.Keywords: popliteal artery thrombosis, limb ischemia, revascularizatio

Truncus coeliacus compressios szindróma laparoscopos műtéti megoldása - Esetismertetés.

Case report: The authors report a case of a 34-year-old woman who had postprandial abdominal pain for years. During the course of her examination lactose intolerance and hiatus hernia was diagnosed. After ineffective conservative treatment CT angiography (CTA) and digital substraction angiography (DSA) was performed and showed significant celiac artery stenosis. Percutaneous transluminal angioplasty (PTA) was unsuccessful as extravasal mechanical compression was present, therefore, laparoscopic decompression and surgical division of MAL fibres were carried out. The postoperative period was characterized by a complete relief of previous symptoms and repeated CTA showed normal blood flow. Discussion: The authors emphasize the importance of the measurement of peak velocity of celiac trunk with Colour Duplex abdominal ultrasonography, the examination has 100% sensitivity and 83% specificity. The Duplex ultrasonography is less expensive than the "gold standard" diagnostic methods like CT and DS angiography, and can lead us to early diagnosis. Laparoscopic surgery is safe and low expense method for celiac artery decompression, however, sometimes it is difficult to reveal the exact reason and thus setting up the proper operation plan