Effect of the integration method on the accuracy and computational efficiency of free energy calculations using thermodynamic integration

Although calculations of free energy using molecular dynamics simulations have gained significant importance in the chemical and biochemical fields, they still remain quite computationally intensive. Furthermore, when using thermodynamic integration, numerical evaluation of the integral of the Hamiltonian with respect to the coupling parameter may introduce unwanted errors in the free energy. In this paper, we compare the performance of two numerical integration techniques-the trapezoidal and Simpson's rules and propose a new method, based on the analytic integration of physically based fitting functions that are able to accurately describe the behavior of the data. We develop and test our methodology by performing detailed studies on two prototype systems, hydrated methane and hydrated methanol, and treat Lennard-Jones and electrostatic contributions separately. We conclude that the widely used trapezoidal rule may introduce systematic errors in the calculation, but these errors are reduced if Simpson's rule is employed, at least for the electrostatic component. Furthermore, by fitting thermodynamic integration data, we are able to obtain precise free energy estimates using significantly fewer data points (5 intermediate states for the electrostatic component and 11 for the Lennard-Jones term), thus significantly decreasing the associated computational cost. Our method and improved protocol were successfully validated by computing the free energy of more complex systems hydration of 2-methylbutanol and of 4-nitrophenol-thus paving the way for widespread use in solvation free energy calculations of drug molecules

Metastable liquid-liquid phase transition in a single-component system with only one crystal phase and no density anomaly

We investigate the phase behavior of a single-component system in 3 dimensions with spherically-symmetric, pairwise-additive, soft-core interactions with an attractive well at a long distance, a repulsive soft-core shoulder at an intermediate distance, and a hard-core repulsion at a short distance, similar to potentials used to describe liquid systems such as colloids, protein solutions, or liquid metals. We showed [Nature {\bf 409}, 692 (2001)] that, even with no evidences of the density anomaly, the phase diagram has two first-order fluid-fluid phase transitions, one ending in a gas--low-density liquid (LDL) critical point, and the other in a gas--high-density liquid (HDL) critical point, with a LDL-HDL phase transition at low temperatures. Here we use integral equation calculations to explore the 3-parameter space of the soft-core potential and we perform molecular dynamics simulations in the interesting region of parameters. For the equilibrium phase diagram we analyze the structure of the crystal phase and find that, within the considered range of densities, the structure is independent of the density. Then, we analyze in detail the fluid metastable phases and, by explicit thermodynamic calculation in the supercooled phase, we show the absence of the density anomaly. We suggest that this absence is related to the presence of only one stable crystal structure.Comment: 15 pages, 21 figure

Low-energy electronic states of carbon nanocones in an electric field

«Non v’è salvezza al di fuori del mostruoso»; «la diserzione, intrinseca alla letteratura, diventa nel fantastico sfida blasfema, obiezione, tradimento»: in questi passi, lo scrittore italiano Giorgio Manganelli (1922-1990) riafferma la portata trasgressiva della sua opera, indicando nel superamento dei limiti razionali, del verosimile, dell’accettabile o, in altre parole, del narrabile la via per sottrarre la letteratura ad una funzione strumentale. Così, nel privilegiarla come atto di linguaggio e nel disimpegnarla da mansioni mimetico-realistiche, Manganelli la popola di esseri informi e metamorfici. Ad esempio, in opere quali Hilarotragoedia (1964) e Dall’inferno (1985) il mostruoso non si presenta come qualcosa di aberrante, ma piuttosto come il risultato di una sorta di teologia paradossale, in grado di sovvertire o burlare le grandi convenzioni umane. Partendo da tali questioni, l’articolo affronterà il tema del mostro quale infrazione e sovversione essenziali allo scardinamento di un orizzonte ermeneutico antropocentrico, come voleva, tra gli altri, Foucault. «There is no salvation beyond the monstrous»; «desertion, intrinsic to literature, becomes in the Fantastic a blasphemous challenge, objection and betrayal»: with these words, the Italian writer Giorgio Manganelli (1922-1990) reaffirms the transgression of his work. With the overcoming of rational limits, of the plausible, of the acceptable or, in other words, of the tellable, the writer illustrates the way to prevent the use of literature as an instrumental function. Therefore, by using literature as an act of speech and by disengaging it from its mimetic-realistic responsibilities, Manganelli populates it with shapeless and metamorphic beings. In works such as Hilarotragoedia (1964) and From Hell (1985), for example, the monstrous does not resemble something aberrant, but rather it represents a kind of paradoxical theology, capable of subverting or mocking the great human convictions. Starting from these questions, this paper will approach the subject of the monster as infringement and subversion essential for the disruption of a hermeneutic and anthropocentric horizon, as Foucault, among others, wished

Expression of nuclear retinoid receptors in normal, premalignant and malignant gastric tissues determined by in situ hybridization

[[abstract]]Retinoids exhibit multiple functions through interaction with nuclear retinoid receptors and have growth-suppressive activity on gastric cancer cells. To better understand the roles of nuclear retinoid receptors during gastric carcinogenesis, we have used in situ hybridization to investigate expression of retinoic acid receptors (RARs) and retinoid x receptors (RXRs) in premalignant and malignant formalin-fixed paraffin-embedded gastric tissues. Histological sections of eight normal, 17 distal normal and nine gastric cancer tissues were hybridized with non-radioactive RNA probes for subtypes of RAR and RXR. Expression of RARα, RARβ, RARγ, RXRα and RXRβ was found in most cell types in gastric mucosa tissues from normal individuals as well as in distal normal tissues from cancer patients. Expression of RARα and RARβ were found in three and seven cancer tissues, respectively, and levels of RXRα mRNA were significantly decreased in poorly differentiated cancer tissues. Among the five investigated nuclear retinoid receptors, only expression of RARα mRNA was significantly decreased in intestinal metaplasia, dysplasia and cancer tissues when compared to adjacent normal tissues. In conclusion, normal gastric mucosa expressed both RARs and RXRs, which supports the physiological role of retinoic acid on normal gastric mucosa. The decrease in RARα expression in premalignant and malignant gastric tissues suggests a significant role of RARα during gastric carcinogenesis.[[notice]]補正完畢[[incitationindex]]SC

Chiang Kai-shek’s “secret deal” at Xian and the start of the Sino-Japanese War

Using newly available archives, particularly the diary and the presidential papers of Chiang Kai-shek, this article challenges the conventional interpretations of the Xian Incident (1936), in particular the widely held belief that the kidnapping of China’s leader Chiang by two rebellious generals forced him to form a united front with the Communist Party to confront Japanese aggression, and of the outbreak of the Sino-Japanese War 7 months later. It puts forth the interpretation that full-scale war between China and Japan was started not by Japan but by Chiang after a Japanese provocation, and the united front was only formed after Chiang ordered his best army units to attack Japanese forces in Shanghai in August 1937 turning it into the largest land battle after the First World War. It must be noted, however, that Japan acted provocatively and aggressively in a local incident outside Beijing a month earlier. Chiang decided on war not because he reached an agreement with the Chinese Communists to form a united front whilst a captive in Xian but because in Xian he received a signal from Josef Stalin that the Soviet Union would support him in a war with Japan. Chiang read Stalin right and the Soviet Union became the largest supplier of weapons to China in the first 4 years of China’s 8-year war with Japan. The hitherto unknown or “secret deal” Chiang made in Xian was an implicit one with Stalin, not with the Chinese Communist Party or its man on the spot Zhou Enlai

MicroRNA-122 Modulates the Rhythmic Expression Profile of the Circadian Deadenylase Nocturnin in Mouse Liver

Nocturnin is a circadian clock-regulated deadenylase thought to control mRNA expression post-transcriptionally through poly(A) tail removal. The expression of Nocturnin is robustly rhythmic in liver at both the mRNA and protein levels, and mice lacking Nocturnin are resistant to diet-induced obesity and hepatic steatosis. Here we report that Nocturnin expression is regulated by microRNA-122 (miR-122), a liver specific miRNA. We found that the 3′-untranslated region (3′-UTR) of Nocturnin mRNA harbors one putative recognition site for miR-122, and this site is conserved among mammals. Using a luciferase reporter construct with wild-type or mutant Nocturnin 3′-UTR sequence, we demonstrated that overexpression of miR-122 can down-regulate luciferase activity levels and that this effect is dependent on the presence of the putative miR-122 recognition site. Additionally, the use of an antisense oligonucleotide to knock down miR-122 in vivo resulted in significant up-regulation of both Nocturnin mRNA and protein expression in mouse liver during the night, resulting in Nocturnin rhythms with increased amplitude. Together, these data demonstrate that the normal rhythmic profile of Nocturnin expression in liver is shaped in part by miR-122. Previous studies have implicated Nocturnin and miR-122 as important post-transcriptional regulators of both lipid metabolism and circadian clock controlled gene expression in the liver. Therefore, the demonstration that miR-122 plays a role in regulating Nocturnin expression suggests that this may be an important intersection between hepatic metabolic and circadian control

Granulocyte-Colony Stimulating Factor (G-CSF) in Stroke Patients with Concomitant Vascular Disease—A Randomized Controlled Trial

G-CSF has been shown in animal models of stroke to promote functional and structural regeneration of the central nervous system. It thus might present a therapy to promote recovery in the chronic stage after stroke.Here, we assessed the safety and tolerability of G-CSF in chronic stroke patients with concomitant vascular disease, and explored efficacy data. 41 patients were studied in a double-blind, randomized approach to either receive 10 days of G-CSF (10 µg/kg body weight/day), or placebo. Main inclusion criteria were an ischemic infarct >4 months prior to inclusion, and white matter hyperintensities on MRI. Primary endpoint was number of adverse events. We also explored changes in hand motor function for activities of daily living, motor and verbal learning, and finger tapping speed, over the course of the study.Adverse events (AEs) were more frequent in the G-CSF group, but were generally graded mild or moderate and from the known side-effect spectrum of G-CSF. Leukocyte count rose after day 2 of G-CSF dosing, reached a maximum on day 8 (mean 42/nl), and returned to baseline 1 week after treatment cessation. No significant effect of treatment was detected for the primary efficacy endpoint, the test of hand motor function.These results demonstrate the feasibility, safety and reasonable tolerability of subcutaneous G-CSF in chronic stroke patients. This study thus provides the basis to explore the efficacy of G-CSF in improving chronic stroke-related deficits.ClinicalTrials.gov NCT00298597