51 research outputs found
Contracting edges to destroy a pattern: A complexity study
Given a graph G and an integer k, the objective of the -Contraction
problem is to check whether there exists at most k edges in G such that
contracting them in G results in a graph satisfying the property . We
investigate the problem where is `H-free' (without any induced copies of
H). It is trivial that H-free Contraction is polynomial-time solvable if H is a
complete graph of at most two vertices. We prove that, in all other cases, the
problem is NP-complete. We then investigate the fixed-parameter tractability of
these problems. We prove that whenever H is a tree, except for seven trees,
H-free Contraction is W[2]-hard. This result along with the known results
leaves behind three unknown cases among trees.Comment: 30 pages, 10 figures, a short version is accepted to FCT 202
Elementary Mechanisms Producing Facilitation of Cav2.1 (P/Q-type) Channels
The regulation of CaV2.1 (P/Q-type) channels by calmodulin (CaM) showcases the powerful Ca2+ decoding capabilities of CaM in complex with the family of CaV1-2 Ca2+ channels. Throughout this family, CaM does not simply exert a binary on/off regulatory effect; rather, Ca2+ binding to either the C- or N-terminal lobe of CaM alone can selectively trigger a distinct form of channel modulation. Additionally, Ca2+ binding to the C-terminal lobe triggers regulation that appears preferentially responsive to local Ca2+ influx through the channel to which CaM is attached (local Ca2+ preference), whereas Ca2+ binding to the N-terminal lobe triggers modulation that favors activation via Ca2+ entry through channels at a distance (global Ca2+ preference). CaV2.1 channels fully exemplify these features; Ca2+ binding to the C-terminal lobe induces Ca2+-dependent facilitation of opening (CDF), whereas the N-terminal lobe yields Ca2+-dependent inactivation of opening (CDI). In mitigation of these interesting indications, support for this local/global Ca2+ selectivity has been based upon indirect inferences from macroscopic recordings of numerous channels. Nagging uncertainty has also remained as to whether CDF represents a relief of basal inhibition of channel open probability (Po) in the presence of external Ca2+, or an actual enhancement of Po over a normal baseline seen with Ba2+ as the charge carrier. To address these issues, we undertake the first extensive single-channel analysis of CaV2.1 channels with Ca2+ as charge carrier. A key outcome is that CDF persists at this level, while CDI is entirely lacking. This result directly upholds the local/global Ca2+ preference of the lobes of CaM, because only a local (but not global) Ca2+ signal is here present. Furthermore, direct single-channel determinations of Po and kinetic simulations demonstrate that CDF represents a genuine enhancement of open probability, without appreciable change of activation kinetics. This enhanced-opening mechanism suggests that the CDF evoked during action-potential trains would produce not only larger, but longer-lasting Ca2+ responses, an outcome with potential ramifications for short-term synaptic plasticity
Complement factor I deficiency: a potentially treatable cause of fulminant cerebral inflammation
Objective To raise awareness of complement factor I (CFI) deficiency as a potentially treatable cause of severe cerebral inflammation.
Methods Case report with neuroradiology, neuropathology, and functional data describing the mutation with review of literature.
Results We present a case of acute, fulminant, destructive cerebral edema in a previously well 11-year-old, demonstrating massive activation of complement pathways on neuropathology and compound heterozygote status for 2 pathogenic mutations in CFI which result in normal levels but completely abrogate function.
Conclusions Our case adds to a very small number of extant reports of this phenomenon associated with a spectrum of inflammatory histopathologies including hemorrhagic leukoencephalopathy and clinical presentations resembling severe acute disseminated encephalomyelitis. CFI deficiency can result in uncontrolled activation of the complement pathways in the brain resulting in devastating cerebral inflammation. The deficit is latent, but the catastrophic dysregulation of the complement system may be the result of a C3 acute phase response. Diagnoses to date have been retrospective. Diagnosis requires a high index of suspicion and clinician awareness of the limitations of first-line clinical tests of complement activity and activation. Simple measurement of circulating CFI levels, as here, may fail to diagnose functional deficiency with absent CFI activity. These diagnostic challenges may mean that the CFI deficiency is being systematically under-recognized as a cause of fulminant cerebral inflammation. Complement inhibitory therapies (such as eculizumab) offer new potential treatment, underlining the importance of prompt recognition, and real-time whole exome sequencing may play an important future role
Evaluation of a field-deployable Nafion (TM)-based air-drying system for collecting whole air samples and its application to stable isotope measurements of CO2
Atmospheric flask samples are either collected at atmospheric pressure by opening a valve of a pre-evacuated flask or pressurized with the help of a pump to a few bar above ambient pressure. Under humid conditions, there is a risk that water vapor in the sample leads to condensation on the walls of the flask, notably at higher than ambient sampling pressures. Liquid water in sample flasks is known to affect the CO2 mixing ratios and also alters the isotopic composition of oxygen (17O and 18O) in CO2 via isotopic equilibration. Hence, for accurate determination of CO2 mole fractions and its stable isotopic composition, it is vital to dry the air samples to a sufficiently low dew point before they are pressurized in flasks to avoid condensation. Moreover, the drying system itself should not influence the mixing ratio and the isotopic composition of CO2 or that of the other constituents under study. For the Airborne Stable Isotopes of Carbon from the Amazon (ASICA) project focusing on accurate measurements of CO2 and its singly substituted stable isotopologues over the Amazon, an air-drying system capable of removing water vapor from air sampled at a dew point lower than -2 °C, flow rates up to 12 L min-1 and without the need for electrical power was needed. Since to date no commercial air-drying device that meets these requirements has been available, we designed and built our own consumable-free, power-free and portable drying system based on multitube Nafion™ gas sample driers (Perma Pure, Lakewood, USA). The required dry purge air is provided by feeding the exhaust flow of the flask sampling system through a dry molecular sieve (type 3A) cartridge. In this study we describe the systematic evaluation of our Nafion™-based air sample dryer with emphasis on its performance concerning the measurements of atmospheric CO2 mole fractions and the three singly substituted isotopologues of CO2 (16O13C16O, 16O12C17O and 16O12C18O), as well as the trace gas species CH4, CO, N2O and SF6. Experimental results simulating extreme tropical conditions (saturated air at 33 °C) indicated that the response of the air dryer is almost instantaneous and that approximately 85 L of air, containing up to 4 % water vapor, can be processed staying below a -2 °C dew point temperature (at 275 kPa). We estimated that at least eight flasks can be sampled (at an overpressure of 275 kPa) with a water vapor content below -2 °C dew point temperature during a typical flight sampling up to 5 km altitude over the Amazon, whereas the remaining samples would stay well below 5 °C dew point temperature (at 275 kPa). The performance of the air dryer on measurements of CO2, CH4, CO, N2O, and SF6 and the CO2 isotopologues 16O13C16O and 16O12C18O was tested in the laboratory simulating real sampling conditions by compressing humidified air from a calibrated cylinder, after being dried by the air dryer, into sample flasks. We found that the mole fraction and the isotopic composition difference between the different test conditions (including the dryer) and the base condition (dry air, without dryer) remained well within or very close to, in the case of N2O, the World Meteorological Organization recommended compatibility goals for independent measurement programs, proving that the test condition induced no significant bias on the sample measurements
A monomeric StayGold fluorescent protein
StayGold is an exceptionally bright and stable fluorescent protein that is highly resistant to photobleaching. Despite favorable fluorescence properties, use of StayGold as a fluorescent tag is limited because it forms a natural dimer. Here we report the 1.6 Å structure of StayGold and generate a derivative, mStayGold, that retains the brightness and photostability of the original protein while being fully monomeric
Dynamic susceptibility-contrast magnetic resonance imaging with contrast agent leakage correction aids in predicting grade in pediatric brain tumours: a multicenter study
Background: Relative cerebral blood volume (rCBV) measured using dynamic susceptibility-contrast MRI can differentiate between low- and high-grade pediatric brain tumors. Multicenter studies are required for translation into clinical practice. Objective: We compared leakage-corrected dynamic susceptibility-contrast MRI perfusion parameters acquired at multiple centers in low- and high-grade pediatric brain tumors. Materials and methods: Eighty-five pediatric patients underwent pre-treatment dynamic susceptibility-contrast MRI scans at four centers. MRI protocols were variable. We analyzed data using the Boxerman leakage-correction method producing pixel-by-pixel estimates of leakage-uncorrected (rCBV uncorr) and corrected (rCBV corr) relative cerebral blood volume, and the leakage parameter, K 2. Histological diagnoses were obtained. Tumors were classified by high-grade tumor. We compared whole-tumor median perfusion parameters between low- and high-grade tumors and across tumor types. Results: Forty tumors were classified as low grade, 45 as high grade. Mean whole-tumor median rCBV uncorr was higher in high-grade tumors than low-grade tumors (mean ± standard deviation [SD] = 2.37±2.61 vs. –0.14±5.55; P<0.01). Average median rCBV increased following leakage correction (2.54±1.63 vs. 1.68±1.36; P=0.010), remaining higher in high-grade tumors than low grade-tumors. Low-grade tumors, particularly pilocytic astrocytomas, showed T1-dominant leakage effects; high-grade tumors showed T2*-dominance (mean K 2=0.017±0.049 vs. 0.002±0.017). Parameters varied with tumor type but not center. Median rCBV uncorr was higher (mean = 1.49 vs. 0.49; P=0.015) and K 2 lower (mean = 0.005 vs. 0.016; P=0.013) in children who received a pre-bolus of contrast agent compared to those who did not. Leakage correction removed the difference. Conclusion: Dynamic susceptibility-contrast MRI acquired at multiple centers helped distinguish between children’s brain tumors. Relative cerebral blood volume was significantly higher in high-grade compared to low-grade tumors and differed among common tumor types. Vessel leakage correction is required to provide accurate rCBV, particularly in low-grade enhancing tumors
Recent Developments in the General Atomic and Molecular Electronic Structure System
A discussion of many of the recently implemented features of GAMESS (General Atomic and Molecular Electronic Structure System) and LibCChem (the C++ CPU/GPU library associated with GAMESS) is presented. These features include fragmentation methods such as the fragment molecular orbital, effective fragment potential and effective fragment molecular orbital methods, hybrid MPI/OpenMP approaches to Hartree-Fock, and resolution of the identity second order perturbation theory. Many new coupled cluster theory methods have been implemented in GAMESS, as have multiple levels of density functional/tight binding theory. The role of accelerators, especially graphical processing units, is discussed in the context of the new features of LibCChem, as it is the associated problem of power consumption as the power of computers increases dramatically. The process by which a complex program suite such as GAMESS is maintained and developed is considered. Future developments are briefly summarized
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Evaluation of a field-deployable Nafion (TM)-based air-drying system for collecting whole air samples and its application to stable isotope measurements of CO2
Atmospheric flask samples are either collected at atmospheric pressure by opening a valve of a pre-evacuated flask or pressurized with the help of a pump to a few bar above ambient pressure. Under humid conditions, there is a risk that water vapor in the sample leads to condensation on the walls of the flask, notably at higher than ambient sampling pressures. Liquid water in sample flasks is known to affect the CO2 mixing ratios and also alters the isotopic composition of oxygen (17O and 18O) in CO2 via isotopic equilibration. Hence, for accurate determination of CO2 mole fractions and its stable isotopic composition, it is vital to dry the air samples to a sufficiently low dew point before they are pressurized in flasks to avoid condensation. Moreover, the drying system itself should not influence the mixing ratio and the isotopic composition of CO2 or that of the other constituents under study. For the Airborne Stable Isotopes of Carbon from the Amazon (ASICA) project focusing on accurate measurements of CO2 and its singly substituted stable isotopologues over the Amazon, an air-drying system capable of removing water vapor from air sampled at a dew point lower than −2 ∘C, flow rates up to 12 L min−1 and without the need for electrical power was needed. Since to date no commercial air-drying device that meets these requirements has been available, we designed and built our own consumable-free, power-free and portable drying system based on multitube Nafion™ gas sample driers (Perma Pure, Lakewood, USA). The required dry purge air is provided by feeding the exhaust flow of the flask sampling system through a dry molecular sieve (type 3A) cartridge. In this study we describe the systematic evaluation of our Nafion™-based air sample dryer with emphasis on its performance concerning the measurements of atmospheric CO2 mole fractions and the three singly substituted isotopologues of CO2 (16O13C16O, 16O12C17O and 16O12C18O), as well as the trace gas species CH4, CO, N2O and SF6. Experimental results simulating extreme tropical conditions (saturated air at 33 ∘C) indicated that the response of the air dryer is almost instantaneous and that approximately 85 L of air, containing up to 4 % water vapor, can be processed staying below a −2 ∘C dew point temperature (at 275 kPa). We estimated that at least eight flasks can be sampled (at an overpressure of 275 kPa) with a water vapor content below −2 ∘C dew point temperature during a typical flight sampling up to 5 km altitude over the Amazon, whereas the remaining samples would stay well below 5 ∘C dew point temperature (at 275 kPa). The performance of the air dryer on measurements of CO2, CH4, CO, N2O, and SF6 and the CO2 isotopologues 16O13C16O and 16O12C18O was tested in the laboratory simulating real sampling conditions by compressing humidified air from a calibrated cylinder, after being dried by the air dryer, into sample flasks. We found that the mole fraction and the isotopic composition difference between the different test conditions (including the dryer) and the base condition (dry air, without dryer) remained well within or very close to, in the case of N2O, the World Meteorological Organization recommended compatibility goals for independent measurement programs, proving that the test condition induced no significant bias on the sample measurements.
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GA4GH: International policies and standards for data sharing across genomic research and healthcare.
The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits
AI is a viable alternative to high throughput screening: a 318-target study
: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery
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