A New Approach for Estimating the Free Energy Differences among Multiple Thermodynamic States in Statistical Simulations.

In this letter, a new approach to compute free energy differences (FEDs) between multiple thermodynamics states is introduced. The method directly uses energy probability densities, which can be extracted with high accuracy from equilibrium simulations to obtain FEDs. Methods in current use, such as Bennett acceptance ratio (BAR), its multistate generalization (MBAR), or the weighted histogram analysis method (WHAM), require iterative solution of nonlinear equations which are known to be slowly convergent. The equations providing MBAR FEDs are identical to those derived earlier by Souaille and Roux in a method that has become known informally as "binless WHAM". In contrast, we obtain FEDs by solution of linear equations. For the classic two-state problem, the statistical error of our method, solving linear equations, is shown analytically to match that of BAR under common conditions.

Factors Affecting Success of New Drug Clinical Trials.

Clinical trials are an essential process in the development of new drugs. In spite of time-consuming processes and high costs, the overall success rate of clinical trials is only 7.9%, which is a high risk for biopharmaceutical companies. However, despite these huge risks, research on finding factors affecting clinical trials to overcome and manage to risks has been insufficient. Considering these characteristics of the pharmaceutical industry, this study investigated the factors affecting the success of sponsor-initiated clinical trials. The success factors investigated were categorized into four factors: quality of clinical trials, speed of clinical trials, relationship type, and communication. Logistic regression was performed to measure each factor by analyzing 24,295 cases of Phase 1 to 4 trials from ClinicalTrials.gov. Because of the analysis, the factors affecting the success of the clinical trials were varied according to each clinical phase and the drug types: New Molecular Entity (NME)/Biologics, and the success ratio in the quality variable affected the overall clinical trial phases. Additionally, the experience, speed, relationship type, and communication variables were also found to be statistically significant for the success of each phase and drug type.

A theoretical study of polymorphism in VQIVYK fibrils.

The VQIVYK fragment from the Tau protein, also known as PHF6, is essential for aggregation of Tau into neurofibrillary lesions associated with neurodegenerative diseases. VQIVYK itself forms amyloid fibrils composed of paired ß-sheets. Therefore, the full Tau protein and VQIVYK fibrils have been intensively investigated. A central issue in these studies is polymorphism, the ability of a protein to fold into more than one structure. Using all-atom molecular simulations, we generate five stable polymorphs of VQIVYK fibrils, establish their relative free energy with umbrella sampling methods, and identify the side chain interactions that provide stability. The two most stable polymorphs, which have nearly equal free energy, are formed by interdigitation of the mostly hydrophobic VIY "face" sides of the ß-sheets. Another stable polymorph is formed by interdigitation of the QVK "back" sides. When we turn to examine structures from cryo-electron microscopy experiments on Tau filaments taken from diseased patients or generated in vitro, we find that the pattern of side chain interactions found in the two most stable face-to-face as well as the back-to-back polymorphs are recapitulated in amyloid structures of the full protein. Thus, our studies suggest that the interactions stabilizing PHF6 fibrils explain the amyloidogenicity of the VQIVYK motif within the full Tau protein and provide justification for the use of VQIVYK fibrils as a test bed for the design of molecules that identify or inhibit amyloid structures.

Blood Supply by the Superior Cerebellar Artery and Posterior Inferior Cerebellar Artery to the Motor and Nonmotor Domains of the Human Dentate Nucleus.

BACKGROUND: The human cerebellum plays an important role in motor and nonmotor coordination. Any functional loss of the dentate nucleus can result in interruption of the cerebellar efferent pathway based on its somatotopy. However, understanding of the vascular supply to the dentate nucleus remains inadequate. METHODS: The origin of the perforators to the dentate nucleus was investigated by microscopic anatomic dissection of 14 human cerebellar hemispheres. The dentate nuclei were divided dorsoventrally, rostrocaudally, and mediolaterally to identify which cerebellar artery dominated which part of the dentate nucleus. RESULTS: The average number of perforators from the superior cerebellar artery (SCA) to the dentate nucleus was 2.2 ± 0.9. The average number of perforators from the posterior inferior cerebellar artery (PICA) was 1.8 ± 0.7. The anterior inferior cerebellar artery did not provide perforators to the dentate nucleus. The dorsal, rostral, and lateral halves of the dentate nucleus were more frequently dominated by the SCA than by the PICA. The ventral and medial halves of the dentate nucleus were more frequently dominated by the PICA than by the SCA. The dorsal rostrolateral and the ventral caudomedial sections were mainly supplied by the SCA and PICA, respectively. CONCLUSIONS: These findings in combination with findings of previous imaging studies suggest that the SCA is mainly associated with the motor activity and the PICA is mainly associated with the nonmotor activity of the dentate nucleus.

Percutaneous temporal wiring method for minimally invasive plate osteosynthesis of a distal tibial fracture.

Reduction of distal tibial fractures-especially fractures that include an oblique or spiral fracture component-during operative treatment with minimally invasive plate osteosynthesis is not always easy. Unexpected and unacceptable displacement can sometimes be seen after plate fixation. We designed an effective fracture reduction method involving a percutaneous temporal wiring technique for the reduction of distal tibial fractures, including fractures that contain oblique or spiral fracture components, during the minimally invasive plate osteosynthesis procedure. Our method can consistently accomplish satisfactory reduction of these fractures and easily maintain reduced fractures, fix the plate, reduce the level of radiation exposure during the operation.

The patellar inferior pole: a new landmark of the anteromedial working portal for arthroscopic surgery of the posterior horn of the medial meniscus.

We assessed the patellar inferior pole (PIP) as a new landmark of the anteromedial (AM) instrumental portal for arthroscopic surgery of the posterior horn of the medial meniscus (PHMM). Fifty normal right knees in young adults (group 1) and 50 knees from adults of various ages undergoing arthroscopic surgery for relatively simple intra-articular pathologies or diagnosis (group 2) were included. In both groups, on 30 degrees flexion true lateral plain radiographs, the line passing through the PIP and the distalmost femoral condyle; (Kim's AM portal line) was drawn, then the length from the anterior end of the medial tibial plateau (MTP) to the meeting point of Kim's AM portal line with the MTP (length C) and the anteroposterior length of the MTP (length D) was measured. The length C was then taken as a percentage of length D (C-D percentage), and the distance between the PIP and the anterior joint line (length E) was measured. The average C-D percentages and lengths E were 110+/-33.6% and 14.8+/-3.8 mm in group 1, and 114+/-38.4% and 16.3+/-4.7 mm in group 2. There were no significant differences in the C-D percentages or the lengths E between the two groups. Also, in group 2, the AM portal was made at the PIP level, and we assessed the relative ease of instrument insertion to reach the PHMM and the body of the lateral meniscus (LM) using a scoring system of our own design. Fort-nine and 48 knees were classified as good for the PHMM and for the body of the LM, respectively. We concluded that the PIP can be used as a skin landmark for arthroscopic surgery of the PHMM.