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X-ray free-electron laser (XFEL) is the latest generation of the X-ray source that could become an invaluable technique in structural biology. XFEL has ultrashort pulse duration, extreme peak brilliance, and high spatial coherence, which could enable the observation of the biological molecules in near nature state at room temperature without crystallization. However, for biological systems, due to their low diffraction power and complexity of sample delivery, experiments and data analysis are not straightforward, making it extremely challenging to reconstruct three-dimensional (3D) structures from single particle XFEL data. Given the current limitations to the amount and resolution of the data from such XFEL experiments, we propose a new hybrid approach for characterizing biomolecular conformational transitions by using a single 2D low-resolution XFEL diffraction pattern in combination with another known conformation. In our method, we represent the molecular structure with a coarse-grained model, the Gaussian mixture model, to describe large conformational transitions from low-resolution XFEL data. We obtain plausible 3D structural models that are consistent with the XFEL diffraction pattern by deforming an initial structural model to maximize the similarity between the target pattern and the simulated diffraction patterns from the candidate models. We tested the proposed algorithm on two biomolecules of different sizes with different complexities of conformational transitions, adenylate kinase, and elongation factor 2, using synthetic XFEL data. The results show that, with the proposed algorithm, we can successfully describe the conformational transitions by flexibly fitting the coarse-grained model of one conformation to become consistent with an XFEL diffraction pattern simulated from another conformation. In addition, we showed that the incident beam orientation has some effect on the accuracy of the 3D structure modeling and discussed the reasons for the inaccuracies for certain orientations. The proposed method could serve as an alternative approach for retrieving information on 3D conformational transitions from the XFEL diffraction patterns to interpret experimental data. Since the molecules are represented by Gaussian kernels and no atomic structure is needed in principle, such a method could also be used as a tool to seek initial models for 3D reconstruction algorithms.

Dimensional synthesis refers to design of the dimensions of manipulators by optimising different kinds of performance indices. The motivation of this study is to perform dimensional synthesis for a wide set of spatial manipulators by optimising the manipulability of each manipulator around a pre-defined task point in the workspace and to finally give a prescription of manipulators along with their dimensions optimised for velocity and force transmission. A systematic method to formulate Jacobian matrix of a manipulator is presented. Optimisation of manipulability is performed for manipulation of the end-effector around a chosen task point for 96 1-DOF manipulators, 645 2-DOF manipulators, 8 3-DOF manipulators and 15 4-DOF manipulators taken from the result of enumeration of manipulators that is done in its companion paper devoted to enumeration of possible manipulators up to a number of links. Prescriptions for these sets of manipulators are presented along with their scaled condition numbers and their ordered indices. This gives the designer a prescription of manipulators with their optimised dimensions that reflects the performance of the end-effector around the given task point for velocity and force transmission.

This study is on the enumeration of spatial robotic manipulators, which is an essential basis for a companion study on dimensional synthesis, both of which together present a wider utility in manipulator synthesis. The enumeration of manipulators is done by using adjacency matrix concept. In this paper, a novel way of applying adjacency matrix to spatial manipulators with four types of joints, namely revolute, prismatic, cylindrical and spherical joints, is presented. The limitations of the applicability of the concept to 3D manipulators are discussed. 1-DOF (Degree Of Freedom) manipulators of four links and 2-DOF, 3-DOF and 4-DOF manipulators of three links, four links and five links, are enumerated based on a set of conventions and some assumptions. Finally, 96 1-DOF manipulators of four links, 641 2-DOF manipulators of 5 links, 4 2-DOF manipulators of three links, 8 3-DOF manipulators of four links and 15 4-DOF manipulators of five links are presented.

Efficient management of an epidemic requires identification and isolation of infected individuals from healthy population to curb community spread of the pathogen. Therefore, a faster and efficient diagnostic method for population screening is desirable to flatten the curve of daily raise of cases. This will also help medical professional to treat the epidemic efficiently. The COVID 19 pandemic caused by SARS-CoV-2 coronavirus poses a huge challenge to human being and the countries with high-density population are facing unique challenges. For the SARS-CoV-2 pandemic, Quantitative Real Time Polymerase Chain Reaction (qRT-PCR) emerging as a gold standard for the identification of infection;however, infrastructure requirement for this assay is at a high-demand and therefore, resources are not abundant. We, therefore, propose a Polymerase Chain Reaction (PCR)-based sensitive method for the detection of SARS-CoV-2 coronavirus. The pipeline discussed in the paper will broaden the scope of control and surveillance of COVID 19 in a high-throughput manner without a sophisticated diagnostic infrastructure.

Additional file 1. Study schedule.

Additional file 4. Sonographer pro-forma.

Additional file 3. Probability Score.

Additional file 2. Prednisolone tapering (BSR guidelines).

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.

The topic of this paper is "gerrymandering", namely the curse of deliberate creations of district maps with highly asymmetric electoral outcomes to disenfranchise voters, and it has a long legal history. Measuring and eliminating gerrymandering has enormous implications to sustain the backbone of democratic principles of a society. Although there is no dearth of legal briefs involving gerrymandering over many years, it is only more recently that mathematicians and applied computational researchers have started to investigate this topic. However, it has received relatively little attention so far from the computational complexity researchers dealing with theoretical analysis of computational complexity issues, such as computational hardness, approximability issues, etc. There could be many reasons for this, such as descriptions of these problem non-CS non-math (often legal or political) journals that theoretical CS (TCS) people usually do not follow, or the lack of coverage of these topics in TCS publication venues. One of our modest goals in writing this article is to improve upon this situation by stimulating further interactions between the gerrymandering and TCS researchers. To this effect, our main contributions are twofold: (1) we provide formalization of several models, related concepts, and corresponding problem statements using TCS frameworks from the descriptions of these problems as available in existing non-TCS (perhaps legal) venues, and (2) we also provide computational complexity analysis of some versions of these problems, leaving other versions for future research. The goal of writing this article is not to have the final word on gerrymandering, but to introduce a series of concepts, models and problems to the TCS community and to show that science of gerrymandering involves an intriguing set of partitioning problems involving geometric and combinatorial optimization., Comment: Disclaimer: The authors were not supported, financially or otherwise, by any political party. The research results reported in this paper are purely scientific and reported as they are without any regard to which political party they may be of help (if at all)

Partisan gerrymandering is a major cause for voter disenfranchisement in United States. However, convincing US courts to adopt specific measures to quantify gerrymandering has been of limited success to date. Recently, Stephanopoulos and McGhee introduced a new and precise measure of partisan gerrymandering via the so-called "efficiency gap" that computes the absolutes difference of wasted votes between two political parties in a two-party system. Quite importantly from a legal point of view, this measure was found legally convincing enough in a US appeals court in a case that claims that the legislative map of the state of Wisconsin was gerrymandered; the case is now pending in US Supreme Court. In this article, we show the following: (a) We provide interesting mathematical and computational complexity properties of the problem of minimizing the efficiency gap measure. To the best of our knowledge, these are the first non-trivial theoretical and algorithmic analyses of this measure of gerrymandering. (b) We provide a simple and fast algorithm that can "un-gerrymander" the district maps for the states of Texas, Virginia, Wisconsin and Pennsylvania by bring their efficiency gaps to acceptable levels from the current unacceptable levels. Our work thus shows that, notwithstanding the general worst case approximation hardness of the efficiency gap measure as shown by us,finding district maps with acceptable levels of efficiency gaps is a computationally tractable problem from a practical point of view. Based on these empirical results, we also provide some interesting insights into three practical issues related the efficiency gap measure. We believe that, should the US Supreme Court uphold the decision of lower courts, our research work and software will provide a crucial supporting hand to remove partisan gerrymandering.

With the arrival of modern internet era, large public networks of various types have come to existence to benefit the society as a whole and several research areas such as sociology, economics and geography in particular. However, the societal and research benefits of these networks have also given rise to potentially significant privacy issues in the sense that malicious entities may violate the privacy of the users of such a network by analyzing the network and deliberately using such privacy violations for deleterious purposes. Such considerations have given rise to a new active research area that deals with the quantification of privacy of users in large networks and the corresponding investigation of computational complexity issues of computing such quantified privacy measures. In this paper, we formalize three such privacy measures for large networks and provide non-trivial theoretical computational complexity results for computing these measures. Our results show the first two measures can be computed efficiently, whereas the third measure is provably hard to compute within a logarithmic approximation factor. Furthermore, we also provide computational complexity results for the case when the privacy requirement of the network is severely restricted, including an efficient logarithmic approximation., Comment: 21 pages, 3 figures

In [1] Zawadoski introduces a banking network model in which the asset and counter-party risks are treated separately and the banks hedge their assets risks by appropriate OTC contracts. In his model, each bank has only two counter-party neighbors, a bank fails due to the counter-party risk only if at least one of its two neighbors default, and such a counter-party risk is a low probability event. Informally, the author shows that the banks will hedge their asset risks by appropriate OTC contracts, and, though it may be socially optimal to insure against counter-party risk, in equilibrium banks will {\em not} choose to insure this low probability event. In this paper, we consider the above model for more general network topologies, namely when each node has exactly 2r counter-party neighbors for some integer r>0. We extend the analysis of [1] to show that as the number of counter-party neighbors increase the probability of counter-party risk also increases, and in particular the socially optimal solution becomes privately sustainable when each bank hedges its risk to at least n/2 banks, where n is the number of banks in the network, i.e., when 2r is at least n/2, banks not only hedge their asset risk but also hedge its counter-party risk., to appear in Network Models in Economics and Finance, V. Kalyagin, P. M. Pardalos and T. M. Rassias (editors), Springer Optimization and Its Applications series, Springer, 2014

Background: Various modalities of treatment have been used and recommended in the treatment of acute gout. These include drugs such as colchicine, NSAIDs and oral prednisolone. Intramuscular depot methylprednisolone (im MP) is currently used in the treatment of rheumatoid arthritis as well as polymyalgia. However the response to im MP in acute gouty arthritis in an inpatient setting (where there are usually contraindications to NSAIDs) has not been previously described in literature. Methods: Eighteen case records of patients presenting with acute gouty arthritis and referred to Rheumatology, between October 2008 and October 2009, were reviewed. Results: Fourteen men and four women, with a mean age of 60 years (range 55-88 years) were seen. Of the 18, 14 patients had a previous history of chronic gout and 4 patients were newly diagnosed. Sixteen patients had polyarticular gout (mainly bilateral wrists and knees) and the remaining 2 had monoarticular gout (1 knee, 1 wrist). Seventeen patients had synovial fluid analysis, which revealed negatively birefringent urate crystals, and 1 patient refused joint aspiration. All patients had predisposing co-morbidities such as diabetes (10), hypertension (15), CCF (5), chronic kidney disease (8) and 2 patients had a history of chronic alcohol excess. Five patients initially received NSAIDs and 3 had concomitant colchicine with all 5 showing a delayed response. All patients were given im MP 120 mg in the gluteal region as a deep injection. All responded completely to im yMP within 2 days with resolution of pain and swelling of inflamed joints. All patients felt much improved and rated the treatment highly. Conclusions: The latest BSR guidelines recommends the use of steroids in the management of refractory cases of gout, i.e. patients intolerant of or having contraindications to NSAIDS or colchicine. This restricted indication is based mainly on the side effects to oral steroids or lack of expertise with intra-articular injections. We have shown that a single intramuscular methyl prednisolone injection is highly effective, very convenient, patient acceptable and safe treatment for gout particularly in elderly patients with multiple co-morbidities. As most cases of inpatient gout have comorbidities such as in our series with contraindications to NSAIDs, we recommend the use of im methyl prednisolone as the first-line treatment in such patients. It may be a less painful alternative to intra-articular steroid injections and safer than bigger doses of oral steroids (especially in diabetes). Disclosure statement: All authors have declared no conflicts of interest

Although the results are correct, it was pointed out that the results follow from some previously known results. Accordingly, this version of the paper is withdrawn by the authors., Comment: Although the results are correct, it was pointed out that the results follow from some previously known results. Accordingly, this version of the paper is withdrawn by the authors

The understanding of molecular cell biology requires insight into the structure and dynamics of networks that are made up of thousands of interacting molecules of DNA, RNA, proteins, metabolites, and other components. One of the central goals of systems biology is the unraveling of the as yet poorly characterized complex web of interactions among these components. This work is made harder by the fact that new species and interactions are continuously discovered in experimental work, necessitating the development of adaptive and fast algorithms for network construction and updating. Thus, the "reverse-engineering" of networks from data has emerged as one of the central concern of systems biology research. A variety of reverse-engineering methods have been developed, based on tools from statistics, machine learning, and other mathematical domains. In order to effectively use these methods, it is essential to develop an understanding of the fundamental characteristics of these algorithms. With that in mind, this chapter is dedicated to the reverse-engineering of biological systems. Specifically, we focus our attention on a particular class of methods for reverse-engineering, namely those that rely algorithmically upon the so-called "hitting-set" problem, which is a classical combinatorial and computer science problem, Each of these methods utilizes a different algorithm in order to obtain an exact or an approximate solution of the hitting set problem. We will explore the ultimate impact that the alternative algorithms have on the inference of published in silico biological networks., Comment: 15 pages; in Algorithms in Computational Molecular Biology: Techniques, Approaches and Applications, M. Elloumi and A. Zomaya (editors), John Wiley & Sons, Inc., January 2011

Two general algorithms based on opportunity costs are given for approximating a revenue-maximizing set of bids an auctioneer should accept, in a combinatorial auction in which each bidder offers a price for some subset of the available goods and the auctioneer can only accept non-intersecting bids. Since this problem is difficult even to approximate in general, the algorithms are most useful when the bids are restricted to be connected node subsets of an underlying object graph that represents which objects are relevant to each other. The approximation ratios of the algorithms depend on structural properties of this graph and are small constants for many interesting families of object graphs. The running times of the algorithms are linear in the size of the bid graph, which describes the conflicts between bids. Extensions of the algorithms allow for efficient processing of additional constraints, such as budget constraints that associate bids with particular bidders and limit how many bids from a particular bidder can be accepted.

Objective.To prospectively evaluate the disease course and the performance of clinical, patient-reported outcome (PRO) and musculoskeletal ultrasound measures in patients with polymyalgia rheumatica (PMR).Methods.The study population included 85 patients with new-onset PMR who were initially treated with prednisone equivalent dose of 15 mg daily tapered gradually, and followed for 26 weeks. Data collection included physical examination findings, laboratory measures of acute-phase reactants, and PRO measures. Ultrasound evaluation was performed at baseline and Week 26 to assess for features previously reported to be associated with PMR. Response to corticosteroid treatment was defined as 70% improvement in PMR on visual analog scale (VAS).Results.At baseline, 77% had hip pain in addition to shoulder pain and 100% had abnormal C-reactive protein or erythrocyte sedimentation rate. On ultrasound, 84% had shoulder findings and 32% had both shoulder and hip findings. Response to corticosteroid treatment occurred in 73% of patients by Week 4 and was highly correlated with percentage improvement in other VAS measures. Presence of ultrasound findings at baseline predicted response to corticosteroids at 4 weeks. Factor analysis revealed 6 domains that sufficiently represented all the outcome measures: PMR-related pain and physical function, an elevated inflammatory marker, hip pain, global pain, mental function, and morning stiffness.Conclusion.PRO measures and inflammatory markers performed well in assessing disease activity in patients with PMR. A minimum set of outcome measures consisting of PRO measures of pain and function and an inflammatory marker should be used in practice and in clinical trials in PMR.

The objective of this study was to develop European League Against Rheumatism/American College of Rheumatology classification criteria for polymyalgia rheumatica (PMR). Candidate criteria were evaluated in a 6-month prospective cohort study of 125 patients with new-onset PMR and 169 non-PMR comparison subjects with conditions mimicking PMR. A scoring algorithm was developed based on morning stiffness > 45 minutes (2 points), hip pain/limited range of motion (1 point), absence of rheumatoid factor and/or anti-citrullinated protein antibody (2 points), and absence of peripheral joint pain (1 point). A score >= 4 had 68% sensitivity and 78% specificity for discriminating all comparison subjects from PMR. The specificity was higher (88%) for discriminating shoulder conditions from PMR and lower (65%) for discriminating RA from PMR. Adding ultrasound, a score >= 5 had increased sensitivity to 66% and specificity to 81%. According to these provisional classification criteria, patients >= 50 years old presenting with bilateral shoulder pain, not better explained by an alternative pathology, can be classified as having PMR in the presence of morning stiffness > 45 minutes, elevated C-reactive protein and/or erythrocyte sedimentation rate, and new hip pain. These criteria are not meant for diagnostic purposes.