Quantum computation with trapped polar molecules

We propose a novel physical realization of a quantum computer. The qubits are electric dipole moments of ultracold diatomic molecules, oriented along or against an external electric field. Individual molecules are held in a 1-D trap array, with an electric field gradient allowing spectroscopic addressing of each site. Bits are coupled via the electric dipole-dipole interaction. Using technologies similar to those already demonstrated, this design can plausibly lead to a quantum computer with $\gtrsim 10^4$ qubits, which can perform $\sim 10^5$ CNOT gates in the anticipated decoherence time of $\sim 5$ s.Comment: 4 pages, RevTeX 4, 2 figures. Edited for length and converted to RevTeX, but no substantial changes from earlier pdf versio

High-precision determination of transition amplitudes of principal transitions in Cs from van der Waals coefficient C_6

A method for determination of atomic dipole matrix elements of principal transitions from the value of dispersion coefficient C_6 of molecular potentials correlating to two ground-state atoms is proposed. The method is illustrated on atomic Cs using C_6 deduced from high-resolution Feshbach spectroscopy. The following reduced matrix elements are determined < 6S_{1/2} || D || 6P_{1/2} > =4.5028(60) |e| a0 and =6.3373(84) |e| a0 (a0= 0.529177 \times 10^{-8} cm.) These matrix elements are consistent with the results of the most accurate direct lifetime measurements and have a similar uncertainty. It is argued that the uncertainty can be considerably reduced as the coefficient C_6 is constrained further.Comment: 4 pages; 3 fig

Streamlining screening of emotional function in Veterans with traumatic brain injury

ObjectivesThis study examined how depression, anxiety, and sleep items from the Neurobehavioral Symptom Inventory (NSI) predict results from longer inventories.MethodThis was a retrospective review from 484, predominantly male (96.1%) Veterans, mean age 29.7 years, who underwent brief neuropsychological screening during a comprehensive, multidisciplinary evaluation for mild traumatic brain injury (TBI). Participants completed the NSI, insomnia severity index (ISI), and hospital anxiety and depression scale (HADS).Results: Overall,97.1% who endorsed “severe”/“very severe” anxiety on the NSI had significant anxiety on the HADS; 85% reporting “severe”/“very severe” depression on the NSI, had significant depression on the HADS; and 97.7% reporting “severe”/“very severe” sleep problems on the NSI, had significant sleep difficulties on the ISI.ConclusionClose correspondence between “severe”/“very severe” symptoms on the NSI and lengthier checklists suggests additional checklists may be eliminated and individuals can be referred for mental health treatment. NSI reports of “mild”/“moderate” require further screening.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144598/1/jclp22595_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144598/2/jclp22595.pd

Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors

Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics

Hematology and serum biochemistry values of free-ranging Iberian wolves (Canis lupus) trapped by leg-hold snares

Hematology and serum biochemistry are important tools in assessing the health and physiological status of wildlife populations. Nevertheless, studies on free-ranging wolves (Canis lupus) are scarce, and no reference values are available neither for Iberian wolves nor for wolves captured with leghold snares. We report 37 hematology and serum biochemistry variables obtained from 26 free-ranging Iberian wolves captured with leg-hold snares between 2007 and 2014, including variables previously not reported in the literature. The values obtained are similar to the published reference intervals for Scandinavian wolves captured by darting from a helicopter, except for higher values for mean corpuscular hemoglobin concentration (MCHC), red blood cell distribution width (RDW), leukocyte count, creatinine kinase (CK), ?-globulins, and total bilirubin (TBIL) and lower values for alkaline phosphatase (ALP). We propose that differences in leukocyte count, CK, and TBIL are related to the method of capture, while differences in RDW, MCHC, ALP, and ?-globulins could reflect physiological adaptations to environmental conditions, sampling, or pre-analytical artifacts. Lymphocyte count was lower and neutrophil/lymphocyte ratio was significantly higher in older, reproductive females, while ALP and phosphorus were higher in juvenile wolves. For the first time, we describe hematology and serum biochemistry values of free-ranging Iberian wolves captured with leg-hold snares. The data reported here is the first published reference for wolves captured with similar methods and for monitoring Iberian wolves populations’ physiological and health status.We thank Nuria Fandos and Carla Ferreira, rangers from Xunta de Galicia and Parque Nacional de los Picos de Europa, and volunteers who helped during the trapping sessions. The wolves were captured under projects financed by Associacao de Conservacao do Habitat do Lobo Iberico (ACHLI) in Portugal and by Picos de Europa National Park, Ministerio de Agricultura, Alimentacion y Medio Ambiente, and Xunta de Galicia in Spain. Sara Roque benefited from grant SFRH/BD/12291/2003 from Fundacao para a Ciencia e a Tecnologia. Jose V. Lopez-Bao was supported by a postdoctoral contract from the Spanish Ministry of Economy and Competitiveness. This is the paper no. 5 from the Iberian Wolf Research Team

Anticholinergic drug burden tools/scales and adverse outcomes in different clinical settings: a systematic review of reviews

Background: Cumulative anticholinergic exposure (anticholinergic burden) has been linked to a number of adverse outcomes. To conduct research in this area, an agreed approach to describing anticholinergic burden is needed. Objective: This review set out to identify anticholinergic burden scales, to describe their rationale, the settings in which they have been used and the outcomes associated with them. Methods: A search was performed using the Healthcare Databases Advanced Search of MEDLINE, EMBASE, Cochrane, CINAHL and PsycINFO from inception to October 2016 to identify systematic reviews describing anticholinergic burden scales or tools. Abstracts and titles were reviewed to determine eligibility for review with eligible articles read in full. The final selection of reviews was critically appraised using the ROBIS tool and pre-defined data were extracted; the primary data of interest were the anticholinergic burden scales or tools used. Results: Five reviews were identified for analysis containing a total of 62 original articles. Eighteen anticholinergic burden scales or tools were identified with variation in their derivation, content and how they quantified the anticholinergic activity of medications. The Drug Burden Index was the most commonly used scale or tool in community and database studies, while the Anticholinergic Risk Scale was used more frequently in care homes and hospital settings. The association between anticholinergic burden and clinical outcomes varied by index and study. Falls and hospitalisation were consistently found to be associated with anticholinergic burden. Mortality, delirium, physical function and cognition were not consistently associated. Conclusions: Anticholinergic burden scales vary in their rationale, use and association with outcomes. This review showed that the concept of anticholinergic burden has been variably defined and inconsistently described using a number of indices with different content and scoring. The association between adverse outcomes and anticholinergic burden varies between scores and has not been conclusively established

StrokeCog-15 Is an Efficient Neuropsychological Battery to Screen for Cognitive Impairment in Chronic Stroke

BACKGROUND:Poststroke cognitive impairment can significantly impact functional outcomes and quality of life. While comprehensive neuropsychological evaluations are valuable in characterizing this impairment, their time-intensive nature is not always feasible. Thus, we set out to develop a brief cognitive battery that is sensitive to poststroke cognitive impairment.METHODS:Neuropsychological testing was completed in a validation sample of 126 participants with chronic ischemic stroke (median days since stroke, 337 [interquartile range, 235–1057]) as part of StrokeCog, a prospective observational cohort study. This comprehensive 60-minute cognitive battery contained 9 tests covering 5 cognitive domains. A partial least square regression analysis informed the selection of a brief, 15-minute battery of 4 tests (StrokeCog-15) covering 4 cognitive domains: language, memory, working memory, and processing speed/executive functioning. We then compared StrokeCog-15 with Montreal Cognitive Assessment and an established 30-minute battery in its ability to detect cognitive impairment as identified by the comprehensive battery. Finally, we assessed the utility of StrokeCog-15 in an external validation sample of 61 participants (median days since stroke, 210 [interquartile range, 193–230]) enrolled in the parallel Stroke-IMPaCT study.RESULTS:Cognitive impairment was common, occurring in 50% (n=61) and 66% (n=40) of the 2 cohorts. Deficits occurred most frequently in the memory and processing speed/executive functioning domains. In the derivation sample, StrokeCog-15 demonstrated high sensitivity (0.97) and adequate specificity (0.78) in detecting cognitive impairment on the comprehensive battery, outperforming both Montreal Cognitive Assessment (sensitivity, 0.77; specificity, 0.73) and the 30-minute battery (sensitivity, 0.97; specificity, 0.35). StrokeCog-15 similarly demonstrated high sensitivity (0.93) and adequate specificity (0.67) in the validation sample.CONCLUSIONS:A brief 15-minute battery of tests has high sensitivity to detect cognitive impairment as identified on a longer neuropsychological test battery. StrokeCog-15 assesses multiple cognitive domains commonly impacted by stroke and represents an efficient yet effective means to identify chronic poststroke cognitive impairment

A constitutively active and uninhibitable caspase-3 zymogen efficiently induces apoptosis

The caspase-3 zymogen has essentially zero activity until it is cleaved by initiator caspases during apoptosis. However, a mutation of V266E in the dimer interface activates the protease in the absence of chain cleavage. We show that low concentrations of the pseudo-activated procaspase-3 kill mammalian cells rapidly and, importantly, this protein is not cleaved nor is it inhibited efficiently by the endogenous regulator XIAP (X-linked inhibitor of apoptosis). The 1.63 Å (1 Å = 0.1 nm) structure of the variant demonstrates that the mutation is accommodated at the dimer interface to generate an enzyme with substantially the same activity and specificity as wild-type caspase-3. Structural modelling predicts that the interface mutation prevents the intersubunit linker from binding in the dimer interface, allowing the active sites to form in the procaspase in the absence of cleavage. The direct activation of procaspase-3 through a conformational switch rather than by chain cleavage may lead to novel therapeutic strategies for inducing cell death

Fingerprinting the Substrate Specificity of M1 and M17 Aminopeptidases of Human Malaria, Plasmodium falciparum

Plasmodium falciparum, the causative agent of human malaria, expresses two aminopeptidases, PfM1AAP and PfM17LAP, critical to generating a free amino acid pool used by the intraerythrocytic stage of the parasite for proteins synthesis, growth and development. These exopeptidases are potential targets for the development of a new class of anti-malaria drugs.To define the substrate specificity of recombinant forms of these two malaria aminopeptidases we used a new library consisting of 61 fluorogenic substrates derived both from natural and unnatural amino acids. We obtained a detailed substrate fingerprint for recombinant forms of the enzymes revealing that PfM1AAP exhibits a very broad substrate tolerance, capable of efficiently hydrolyzing neutral and basic amino acids, while PfM17LAP has narrower substrate specificity and preferentially cleaves bulky, hydrophobic amino acids. The substrate library was also exploited to profile the activity of the native aminopeptidases in soluble cell lysates of P. falciparum malaria.This data showed that PfM1AAP and PfM17LAP are responsible for majority of the aminopeptidase activity in these extracts. These studies provide specific substrate and mechanistic information important for understanding the function of these aminopeptidases and could be exploited in the design of new inhibitors to specifically target these for anti-malaria treatment