Conformational Sampling and Calculation of Molecular Free Energy Using Superposition Approximations

The superposition approximations (SAs), first proposed in the distribution function theories of liquids, are a family of approximations to a multivariate probability distribution function (pdf) in terms of its lower order marginal pdfs. In this talk, we first present the relationship between various forms of SA, the measurement of correlation via mutual information, and approximations to the entropy of the full pdf via truncations of the Mutual Information Expansion. Next, based on the SAs, a novel framework to construct computationally tractable approximations to the N-dimensional Boltzmann conformational distribution of molecule in terms of its low order marginal pdfs is presented. The marginal pdfs are obtained as normalized histograms of internal coordinates of a set of Boltzmann distributed conformations obtained by molecular dynamics (MD) simulation. We evaluate the accuracy of these approximate distributions constructed from marginal pdfs of order L <=3 for small molecules (<= 52 atoms) by using a novel conformational sampling algorithm to sample from them and comparing the samples with the original MD conformations used to populate the pdfs. We find that the triplet (L=3) level approximation has high conformational overlap with the physical Boltzmann distribution, and significantly better than that for the singlet (L=1) or doublet (L=2) level approximations. The results shed light on the relative importance of correlations of different orders. The singlet (L=1) and doublet (L=2) level approximate distributions are then used to define reference systems with known free energies, and then to compute the physical free energy of molecules using the reference system approach. Free energies are computed for small peptides as test molecules, and it is found that the convergence of the free energy estimate using a doublet reference is dramatically faster than with the singlet reference, consistent with greater overlap of the doublet reference system with the physical system. Potential further developments and practical applications are discussed

Achieving Starvation-Freedom with Greater Concurrency in Multi-Version Object-based Transactional Memory Systems

To utilize the multi-core processors properly concurrent programming is needed. Concurrency control is the main challenge while designing a correct and efficient concurrent program. Software Transactional Memory Systems (STMs) provides ease of multithreading to the programmer without worrying about concurrency issues such as deadlock, livelock, priority inversion, etc. Most of the STMs works on read-write operations known as RWSTMs. Some STMs work at high-level operations and ensure greater concurrency than RWSTMs. Such STMs are known as Object-Based STMs (OSTMs). The transactions of OSTMs can return commit or abort. Aborted OSTMs transactions retry. But in the current setting of OSTMs, transactions may starve. So, we proposed a Starvation-Free OSTM (SF-OSTM) which ensures starvation-freedom in object based STM systems while satisfying the correctness criteria as co-opacity. Databases, RWSTMs and OSTMs say that maintaining multiple versions corresponding to each key of transaction reduces the number of aborts and improves the throughput. So, to achieve greater concurrency, we proposed Starvation-Free Multi-Version OSTM (SF-MVOSTM) which ensures starvation-freedom while storing multiple versions corresponding to each key and satisfies the correctness criteria such as local opacity. To show the performance benefits, We implemented three variants of SF-MVOSTM (SF-MVOSTM, SF-MVOSTM-GC and SF-KOSTM) and compared it with state-of-the-art STMs.Comment: 68 pages, 24 figures. arXiv admin note: text overlap with arXiv:1709.0103

Evaluating the effect of dexmedetomidine premedication on the quality of subarachnoid block, haemodynamics and sedation in patients undergoing lower limb surgeries: a prospective randomized controlled trial

Background: Present study was designed to evaluate the effect of intravenous dexmedetomidine on haemodynamics, sedation and quality of spinal anaesthesia with 0.5% hyperbaric bupivacaine.Methods: Sixty ASA grade 1 and 2, 18-60 years aged patients scheduled for elective lower limb surgeries were randomly divided into two groups: Group C (Control) and Group D (Study), received intravenous normal saline 10ml and intravenous dexmedetomidine 1μg/kg in dilution of 10ml respectively over 10minutes duration, 10minutes before subarachnoid block with 2.5ml of 0.5% hyperbaric bupivacaine. The heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), quality of sensory and motor block and level of sedation were monitored intraoperatively and postoperatively.Results: The heart rate was statistically significantly decreased in group D both intraoperatively and postoperatively. Intraoperative and postoperative SBP and DBP were lower in dexmedetomidine group but clinically that was insignificant. Intraoperative Ramsay sedation scores were significantly higher in dexmedetomidine group (3.49±0.240) as compared to control group (2.51±0.249) (p<0.001) but the patients were easily arousable. The duration of sensory blockade (208.83±9.53 min vs 162.83±9.62 min), duration for 2 dermatomal regression of sensory blockade (146.5±10.013min vs 98±8.57min) and the duration for motor block regression to Modified Bromage scale 0 (167.33±10.5min vs 137.83±11.94min) were significantly prolonged in dexmedetomidine group as compared to control group. The highest level of sensory blockade was also significantly higher in dexmedetomidine group (T6.90±0.759 vs T7.60±0.621). There was no difference in the time for attaining highest level of sensory blockade, time taken for motor blockade to reach Modified Bromage Scale 3 between both the groups. Average 24hr mean VAS score was significantly lower in dexmedetomidine group (1.37±0.15 vs1.72±0.17, p<0.001). Time to first request for rescue analgesic was also significantly longer in dexmedetomidine group (mean 174.33min vs 143.5min). Average 24hour consumption of tramadol analgesic was significantly higher in control group as compared to dexmedetomidine group (391.86±111.62mg vs 279.86±80.55mg, p<0.001).Conclusions: Intravenous dexmedetomidine significantly prolongs the duration of sensory and motor block of bupivacaine spinal anaesthesia. It provides excellent sedation and analgesia. Dexmedetomidine induced decrease in heart rate, systolic/diastolic blood pressure are not clinically significant.

Obtaining Progress Guarantee and GreaterConcurrency in Multi-Version Object Semantics

Software Transactional Memory Systems (STMs) provides ease of multithreading to the programmer withoutworrying about concurrency issues such as deadlock, livelock, priority inversion, etc. Most of the STMs workson read-write operations known as RWSTMs. Some STMs work at high-level operations and ensure greaterconcurrency than RWSTMs. Such STMs are known as Object-Based STMs (OSTMs). The transactions of OSTMscan return commit or abort. Aborted OSTMs transactions retry. But in the current setting of OSTMs, transactionsmay starve. So, we proposed a Starvation-Free OSTM (SF-OSTM) which ensures starvation-freedom whilesatisfying the correctness criteria as opacity.Databases, RWSTMs and OSTMs say that maintaining multiple versions corresponding to each key reduces thenumber of aborts and improves the throughput. So, to achieve the greater concurrency, we proposed Starvation-Free Multi-Version OSTM (SF-MVOSTM) which ensures starvation-freedom while storing multiple versioncorresponding to each key and satisfies the correctness criteria as local opacity. To show the performance benefits,We implemented three variants of SF-MVOSTM and compare its performance with state-of-the-art STM

An Efficient Approach to Achieve Compositionality using Optimized Multi-Version Object Based Transactional Systems

In the modern era of multi-core systems, the main aim is to utilize the cores properly. This utilization can be done by concurrent programming. But developing a flawless and well-organized concurrent program is difficult. Software Transactional Memory Systems (STMs) are a convenient programming interface which assist the programmer to access the shared memory concurrently without worrying about consistency issues such as priority-inversion, deadlock, livelock, etc. Another important feature that STMs facilitate is compositionality of concurrent programs with great ease. It composes different concurrent operations in a single atomic unit by encapsulating them in a transaction. Many STMs available in the literature execute read/write primitive operations on memory buffers. We represent them as Read-Write STMs or RWSTMs. Whereas, there exist some STMs (transactional boosting and its variants) which work on higher level operations such as insert, delete, lookup, etc. on a hash-table. We refer these STMs as Object Based STMs or OSTMs. The literature of databases and RWSTMs say that maintaining multiple versions ensures greater concurrency. This motivates us to maintain multiple version at higher level with object semantics and achieves greater concurrency. So, this paper pro-poses the notion of Optimized Multi-version Object Based STMs or OPT-MVOSTMs which encapsulates the idea of multiple versions in OSTMs to harness the greater concurrency efficiently

Equilibrium molecular thermodynamics from Kirkwood sampling.

We present two methods for barrierless equilibrium sampling of molecular systems based on the recently proposed Kirkwood method (J. Chem. Phys. 2009, 130, 134102). Kirkwood sampling employs low-order correlations among internal coordinates of a molecule for random (or non-Markovian) sampling of the high dimensional conformational space. This is a geometrical sampling method independent of the potential energy surface. The first method is a variant of biased Monte Carlo, where Kirkwood sampling is used for generating trial Monte Carlo moves. Using this method, equilibrium distributions corresponding to different temperatures and potential energy functions can be generated from a given set of low-order correlations. Since Kirkwood samples are generated independently, this method is ideally suited for massively parallel distributed computing. The second approach is a variant of reservoir replica exchange, where Kirkwood sampling is used to construct a reservoir of conformations, which exchanges conformations with the replicas performing equilibrium sampling corresponding to different thermodynamic states. Coupling with the Kirkwood reservoir enhances sampling by facilitating global jumps in the conformational space. The efficiency of both methods depends on the overlap of the Kirkwood distribution with the target equilibrium distribution. We present proof-of-concept results for a model nine-atom linear molecule and alanine dipeptide.This research was funded by the European Research Council and EPSRC grant EP/I001352/1. Y.O. was supported, in part, by the JSPS Grant-in-Aid for Scientific Research on Innovative Areas (“Dynamical Ordering and Integrated Functions”).This is the final published version. It first appeared at http://pubs.acs.org/doi/abs/10.1021/acs.jpcb.5b01800

Etiologies and risk factors for dementia

Dementia is understood as a clinical syndrome characterized by impairment in memory impairment along with cognitive deficits in other domains. Over the years, understanding about the causes of dementias has improved. Broadly, dementias can be classified as irreversible degenerative dementias and reversible dementias. Alzheimer′s disease is the prototype of degenerative dementias and is characterized by the accumulation of beta-amyloid protein (called as amyloid plaques) outside the neurons and accumulation of tau protein (called tau tangles) inside the neurons. Vascular dementias are characterized by cerebrovascular insults which lead to pathological brain changes that impair cognition. The pathological hallmark of Lewy body dementia is the presence of α-synuclein neuronal inclusions, also known as Lewy bodies, accompanied by neuronal loss. Frontotemporal dementias are characterized by abnormal deposits of the microtubule-associated protein tau, the trans-activation response TAR DNA-binding protein with molecular weight 43 kDa (TDP-43), and the fused in sarcoma protein. Reversible dementias are characterized by the primary illness and may not present with characteristic brain deposits as seen with many degenerative dementias

An efficient approach to achieve compositionality using optimized multi-version object based transactional systems

In the modern era of multi-core systems, the main aim is to utilize the cores properly. This utilization can be done by concurrent programming. But developing a flawless and well-organized concurrent program is difficult. Software Transactional Memory Systems (STMs) are a convenient programming interface which assist the programmer to access the shared memory concurrently without worrying about consistency issues. Many STMs available in the literature execute read/write primitive operations on memory buffers. We represent them as Read-Write STMs or RWSTMs. Whereas, there exists some STMs which work on higher level operations. We refer these STMs as Object Based STMs or OSTMs. The literature of databases and RWSTMs say that maintaining multiple versions ensures greater concurrency. So, this paper proposes the notion of Optimized Multi-version Object Based STMs or OPT-MVOSTMs which encapsulates the idea of multiple versions in OSTMs to harness the greater concurrency efficiently