CHARMM: The biomolecular simulation program Brooks, B.R; Brooks, C.L. III; Mackerell, A.D. Jr ...
Journal of computational chemistry,
30 July 2009, Volume:
30, Issue:
10
Journal Article
Peer reviewed
Open access
CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecular simulation program. It has been developed over the last three decades with a primary focus on ...molecules of biological interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. The CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983.
Few studies have examined the relative risks of switching into hypomania or mania associated with second-generation antidepressant drugs in bipolar depression.
To examine the relative acute effects ...of bupropion, sertraline and venlafaxine as adjuncts to mood stabilisers.
In a 10-week trial, participants receiving out-patient treatment for bipolar disorder (stratified for rapid cycling) were randomly treated with a flexible dose of one of the antidepressants, or their respective matching placebos, as adjuncts to mood stabilisers.
A total of 174 adults with bipolar disorder I, II or not otherwise specified, currently in the depressed phase, were included. All three antidepressants were associated with a similar range of acute response (49-53%) and remission (34-41%). There was a significantly increased risk of switches into hypomania or mania in participants treated with venlafaxine compared with bupropion or sertraline.
More caution appears indicated in the use of venlafaxine rather than bupropion or sertraline in the adjunctive treatment of bipolar depression, especially if there is a prior history of rapid cycling.
Objective
We discuss the rationale behind staging systems described specifically for bipolar disorders. Current applications, future directions and research gaps in clinical staging models for ...bipolar disorders are outlined.
Method
We reviewed the literature pertaining to bipolar disorders, focusing on the first episode onwards. We systematically searched data on staging models for bipolar disorders and allied studies that could inform the concept of staging.
Results
We report on several dimensions that are relevant to staging concepts in bipolar disorder. We consider whether staging offers a refinement to current diagnoses by reviewing clinical studies of treatment and functioning and the potential utility of neurocognitive, neuroimaging and peripheral biomarkers.
Conclusion
Most studies to date indicate that globally defined late‐stage patients have a worse overall prognosis and poorer response to standard treatment, consistent with patterns for end‐stage medical disorders. We believe it is possible at this juncture to speak broadly of ‘early’‐ and ‘late’‐stage bipolar disorder. Next steps require further collaborative efforts to consider the details of preillness onset and intermediary stages, and how many additional stages are optimal.
Bipolar spectrum disorders, which include bipolar I, bipolar II, and bipolar disorder not otherwise specified, frequently go unrecognized, undiagnosed, and untreated. This report describes the ...validation of a new brief self-report screening instrument for bipolar spectrum disorders called the Mood Disorder Questionnaire.
A total of 198 patients attending five outpatient clinics that primarily treat patients with mood disorders completed the Mood Disorder Questionnaire. A research professional, blind to the Mood Disorder Questionnaire results, conducted a telephone research diagnostic interview by means of the bipolar module of the Structured Clinical Interview for DSM-IV.
A Mood Disorder Questionnaire screening score of 7 or more items yielded good sensitivity (0.73) and very good specificity (0.90).
The Mood Disorder Questionnaire is a useful screening instrument for bipolar spectrum disorder in a psychiatric outpatient population.
Abstract
The group of enteroviruses contains many important pathogens for humans, including poliovirus, coxsackievirus, rhinovirus, as well as newly emerging global health threats such as EV-A71 and ...EV-D68. Here, we describe an unbiased, system-wide and time-resolved analysis of the proteome and phosphoproteome of human cells infected with coxsackievirus B3. Of the ~3,200 proteins quantified throughout the time course, a large amount (~25%) shows a significant change, with the majority being downregulated. We find ~85% of the detected phosphosites to be significantly regulated, implying that most changes occur at the post-translational level. Kinase-motif analysis reveals temporal activation patterns of certain protein kinases, with several CDKs/MAPKs immediately active upon the infection, and basophilic kinases, ATM, and ATR engaging later. Through bioinformatics analysis and dedicated experiments, we identify mTORC1 signalling as a major regulation network during enterovirus infection. We demonstrate that inhibition of mTORC1 activates TFEB, which increases expression of lysosomal and autophagosomal genes, and that TFEB activation facilitates the release of virions in extracellular vesicles via secretory autophagy. Our study provides a rich framework for a system-level understanding of enterovirus-induced perturbations at the protein and signalling pathway levels, forming a base for the development of pharmacological inhibitors to treat enterovirus infections.
Atmospheric aerosol deposition is an important source of nutrients and trace metals to the open ocean that can enhance ocean productivity and carbon sequestration and thus influence atmospheric ...carbon dioxide concentrations and climate. Using aerosol samples from different back trajectories in incubation experiments with natural communities, we demonstrate that the response of phytoplankton growth to aerosol additions depends on specific components in aerosols and differs across phytoplankton species. Aerosol additions enhanced growth by releasing nitrogen and phosphorus, but not all aerosols stimulated growth. Toxic effects were observed with some aerosols, where the toxicity affected picoeukaryotes and Synechococcus but not Prochlorococcus. We suggest that the toxicity could be due to high copper concentrations in these aerosols and support this by laboratory copper toxicity tests preformed with Synechococcus cultures. However, it is possible that other elements present in the aerosols or unknown synergistic effects between these elements could have also contributed to the toxic effect. Anthropogenic emissions are increasing atmospheric copper deposition sharply, and based on coupled atmosphere-ocean calculations, we show that this deposition can potentially alter patterns of marine primary production and community structure in high aerosol, low chlorophyll areas, particularly in the Bay of Bengal and downwind of South and East Asia.
Recurrent bleeding is one of the major causes of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). Antifibrinolytic therapy is known to reduce recurrent bleeding, ...however, its beneficial effect on outcome remains unclear. The effect of treatment with tranexamic acid (TXA) until aneurysm treatment on clinical outcome is evaluated.
Patients with an aSAH from two high-volume tertiary referral treatment centers in the Netherlands, Academic Medical Center (AMC) and Radboud University Medical Center (RUMC), between January 2012 and December 2015 were included. Patients were classified into one of two groups; standard treatment or TXA treatment. Demographic and clinical characteristics, in-hospital complications and clinical outcome were compared between the two groups. Multivariate logistic regression was used to adjust for the influence of treatment center and baseline differences.
Standard treatment was given in 509 patients, and 119 patients received additional TXA therapy before aneurysm occlusion. Patients treated with TXA did not experience less recurrent bleeding adjusted or unadjusted for treatment center (adjusted odds ratio aOR 0.80, 95% confidence interval 95% CI: 0.37-1.73). In-hospital mortality, was significantly lower in the TXA group than the standard care group (adjusted OR aOR 0.42, 95% CI: 0.20-0.85). Poor outcome (mRS 4-6) assessed after six months was not different between treatment groups (aOR 1.05, 95% CI: 0.64-1.74).
Pooled data from two high-volume treatment centers did not show improved clinical outcome after additional TXA treatment in aSAH patients. However, TXA treatment was associated with a decrease in mortality.
Abstract
The plasma-induced charge of non-spherical microparticles is a crucial parameter in complex plasma physics, aerosol science and astrophysics. Yet, the literature describes this charge by two ...competing models, neither of which has been experimentally verified or refuted. Here we offer experimental proof that the charge on a two-particle cluster (doublet) in the spatial afterglow of a low-pressure plasma equals the charge that would be obtained by the smallest enclosing sphere and that it should therefore not be based on its geometrical capacitance but rather on the capacitance of its smallest enclosing sphere. To support this conclusion, the size, mass and charge of single particles (singlets) and doublets are measured with high precision. The measured ratio between the plasma-afterglow-induced charges on doublets and singlets is compared to both models and shows perfect agreement with the predicted ratio using the capacitance of the smallest enclosing sphere, while being significantly dissimilar to the predicted ratio based on the particle’s geometrical capacitance.
Therapeutic angiogenesis, a new experimental strategy for the treatment of vascular insufficiency, uses the administration of mediators known to induce vascular development in embryogenesis to induce ...neovascularization of ischemic adult tissues. This report summarizes a phase I clinical experience with a gene-therapy strategy that used an E1(-)E3(-) adenovirus (Ad) gene-transfer vector expressing human vascular endothelial growth factor (VEGF) 121 cDNA (Ad(GV)VEGF121.10) to induce therapeutic angiogenesis in the myocardium of individuals with clinically significant coronary artery disease.
Ad(GV)VEGF121.10 was administered to 21 individuals by direct myocardial injection into an area of reversible ischemia either as an adjunct to conventional coronary artery bypass grafting (group A, n=15) or as sole therapy via a minithoracotomy (group B, n=6). There was no evidence of systemic or cardiac-related adverse events related to vector administration. In both groups, coronary angiography and stress sestamibi scan assessment of wall motion 30 days after therapy suggested improvement in the area of vector administration. All patients reported improvement in angina class after therapy. In group B, in which gene transfer was the only therapy, treadmill exercise assessment suggested improvement in most individuals.
The data are consistent with the concept that direct myocardial administration of Ad(GV)VEGF121.10 to individuals with clinically significant coronary artery disease appears to be well tolerated, and initiation of phase II evaluation of this therapy is warranted.
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