Publications by authors named "Mark Johnson"

1,989 Publications

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Optimizing minirhizotron sample frequency for an evergreen and deciduous tree species.

New Phytol 2003 Jan;157(1):155-161

U.S. Environmental Protection Agency, Western Ecology Division, Corvallis, OR 97333, USA.

•  When using minirhizotrons to study fine dynamics in natural ecosystems, it is important to determine how sample collection frequency influences estimates of fine root production and mortality. Minirhizotron images were collected twice per week from mature Pseudotsuga menziesii and Tilia cordata trees and analyzed to estimate fine root production and mortality. These data were used to create data sets reflecting sample frequencies of 1, 2, 4 or 8 wk. •  When the sampling interval is long, fine roots can appear and disappear between samplings, leading to underestimates of production and mortality. For example, with an 8-wk sample frequency, 24 and 35% of the fine root production in P. menziesii and T. cordata , respectively, is not measured. Fine root mortality displays the same sensitivity to sample frequency. •  Our experimental observations supported the previously published simulation analysis, which provides an estimate of the proportion of fine roots missed at different sample frequencies and is a tool that can be used to select a sample frequency to balance production and mortality accuracy with sampling and analytical effort.
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http://dx.doi.org/10.1046/j.1469-8137.2003.00653.xDOI Listing
January 2003

Transcription factors regulated by cAMP in smooth muscle of the myometrium at human parturition.

Biochem Soc Trans 2021 Apr 16. Epub 2021 Apr 16.

Division of Reproductive and Developmental Biology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW10 9NH, U.K.

Cyclic adenosine monophosphate (cAMP) contributes to maintenance of a quiescent (relaxed) state in the myometrium (i.e. uterine smooth muscle) during pregnancy, which most commonly has been attributed to activation of protein kinase A (PKA). PKA-mediated phosphorylation of cytosolic contractile apparatus components in myometrial smooth muscle cells (mSMCs) are known to promote relaxation. Additionally, PKA also regulates nuclear transcription factor (TF) activity to control expression of genes important to the labour process; these are mostly involved in actin-myosin interactions, cell-to-cell connectivity and inflammation, all of which influence mSMC transition from a quiescent to a contractile (pro-labour) phenotype. This review focuses on the evidence that cAMP modulates the activity of TFs linked to pro-labour gene expression, predominantly cAMP response element (CRE) binding TFs, nuclear factor κB (NF-κB), activator protein 1 (AP-1) family and progesterone receptors (PRs). This review also considers the more recently described exchange protein directly activated by cAMP (EPAC) that may oppose the pro-quiescent effects of PKA, as well as explores findings from other cell types that have the potential to be of novel relevance to cAMP action on TF function in the myometrium.
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http://dx.doi.org/10.1042/BST20201173DOI Listing
April 2021

Spectral Decomposition of the Flow and Characterization of the Sound Signals through Stenoses with Different Levels of Severity.

Bioengineering (Basel) 2021 Mar 19;8(3). Epub 2021 Mar 19.

Infrasonix Inc., 3100 Breckinridge Blvd, Unit 712, Duluth, GA 30096, USA.

Treatments of atherosclerosis depend on the severity of the disease at the diagnosis time. Non-invasive diagnosis techniques, capable of detecting stenosis at early stages, are essential to reduce associated costs and mortality rates. We used computational fluid dynamics and acoustics analysis to extensively investigate the sound sources arising from high-turbulent fluctuating flow through stenosis. The frequency spectral analysis and proper orthogonal decomposition unveiled the frequency contents of the fluctuations for different severities and decomposed the flow into several frequency bandwidths. Results showed that high-intensity turbulent pressure fluctuations appeared inside the stenosis for severities above 70%, concentrated at plaque surface, and immediately in the post-stenotic region. Analysis of these fluctuations with the progression of the stenosis indicated that (a) there was a distinct break frequency for each severity level, ranging from 40 to 230 Hz, (b) acoustic spatial-frequency maps demonstrated the variation of the frequency content with respect to the distance from the stenosis, and (c) high-energy, high-frequency fluctuations existed inside the stenosis only for severe cases. This information can be essential for predicting the severity level of progressive stenosis, comprehending the nature of the sound sources, and determining the location of the stenosis with respect to the point of measurements.
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http://dx.doi.org/10.3390/bioengineering8030041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003520PMC
March 2021

Structural Basis for the Functional Changes by EGFR Exon 20 Insertion Mutations.

Cancers (Basel) 2021 Mar 5;13(5). Epub 2021 Mar 5.

Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, 20520 Turku, Finland.

Activating somatic mutations of the epidermal growth factor receptor (EGFR) are frequently implicated in non-small cell lung cancer (NSCLC). While L858R and exon 19 deletion mutations are most prevalent, exon 20 insertions are often observed in NSCLC. Here, we investigated the structural implications of two common EGFR exon 20 insertions in NSCLC, V769insASV and D770insNPG. The active and inactive conformations of wild-type, D770insNPG and V769insASV EGFRs were probed with molecular dynamics simulations to identify local and global alterations that the mutations exert on the EGFR kinase domain, highlighting mechanisms for increased enzymatic activity. In the active conformation, the mutations increase interactions that stabilize the αC helix that is essential for EGFR activity. Moreover, the key Lys745-Glu762 salt bridge was more conserved in the insertion mutations. The mutants also preserved the state of the structurally critical aspartate-phenylalanine-glycine (DFG)-motif and regulatory spine (R-spine), which were altered in wild-type EGFR. The insertions altered the structure near the ATP-binding pocket, e.g., the P-loop, which may be a factor for the clinically observed tyrosine kinase inhibitor (TKI) insensitivity by the insertion mutants. The inactive state simulations also showed that the insertions disrupt the Ala767-Arg776 interaction that is key for maintaining the "αC-out" inactive conformation, which could consequently fuel the transition from the inactive towards the active EGFR state.
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http://dx.doi.org/10.3390/cancers13051120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961794PMC
March 2021

Spectral Decomposition and Sound Source Localization of Highly Disturbed Flow through a Severe Arterial Stenosis.

Bioengineering (Basel) 2021 Mar 4;8(3). Epub 2021 Mar 4.

Infrasonix Inc., 1665 Lakes Parkway, Suite 102, Lawrenceville, GA 30043, USA.

For the early detection of atherosclerosis, it is imperative to explore the capabilities of new, effective noninvasive diagnosis techniques to significantly reduce the associated treatment costs and mortality rates. In this study, a multifaceted comprehensive approach involving advanced computational fluid dynamics combined with signal processing techniques was exploited to investigate the highly turbulent fluctuating flow through arterial stenosis. The focus was on localizing high-energy mechano-acoustic source potential to transmit to the epidermal surface. The flow analysis results showed the existence of turbulent pressure fluctuations inside the stenosis and in the post-stenotic region. After analyzing the turbulent kinetic energy and pressure fluctuations on the flow centerline and the vessel wall, the point of maximum excitation in the flow was observed around two diameters downstream of the stenosis within the fluctuating zone. It was also found that the concentration of pressure fluctuation closer to the wall was higher inside the stenosis compared to the post-stenotic region. Additionally, the visualization of the most energetic proper orthogonal decomposition (POD) mode and spectral decomposition of the flow indicated that the break frequencies ranged from 80 to 220 Hz and were correlated to the eddies generated within these regions.
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http://dx.doi.org/10.3390/bioengineering8030034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000318PMC
March 2021

The role of breast milk fortifier in the post-discharge nutrition of preterm infants.

Br J Hosp Med (Lond) 2021 Mar 9;82(3):42-48. Epub 2021 Mar 9.

Lead Paediatric Dietitian, Dorset County Hospital, Dorchester, Dorset.

Infants born prematurely are often discharged from hospital before 37 weeks post-menstrual age. While breastfeeding will meet all the nutritional requirements of full-term infants, these preterm infants may need enhanced levels of protein, minerals and possibly energy to ensure optimum growth, bone mineralisation and neurological development. To meet these additional nutrient needs in the neonatal unit, it is currently recommended that multinutrient breast milk fortifier is added to maternal breast milk. There may also be benefits in continuing to provide fortified milk after discharge, potentially including improved growth and preserving breastfeeding, and this is increasingly becoming a recognised practice in some neonatal units. This article presents the discussion and consensus of a multidisciplinary panel of neonatologists, neonatal dietitians, a GP and a neonatal outreach sister. The aim is to develop guidance on providing safe and effective nutritional supplementation for preterm infants after discharge in order to maintain optimal growth. This guidance is aimed at community healthcare staff and is based on the limited evidence available, using shared best practice and expertise.
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http://dx.doi.org/10.12968/hmed.2021.0101DOI Listing
March 2021

Total body water in full-term and preterm newborns: systematic review and meta-analysis.

Arch Dis Child Fetal Neonatal Ed 2021 Mar 31. Epub 2021 Mar 31.

Department of Neonatal Medicine, University Hospital Southampton NHS Foundation Trust, Southampton, UK.

Background: Total body water (TBW) is one component of fat-free mass and changes in TBW are influenced by fluid shifts (especially during transition to postnatal life), electrolyte balance and nutritional status. Normal values for term-born neonates and preterm infants at birth have not been defined in large cohorts, limiting investigation into its monitoring and use in clinical practice.

Objective: To systematically review the evidence base for percentage of TBW in term-born infants, quantify the effect of prematurity on TBW at birth, and describe normal progression of TBW over time in preterm infants.

Methods: Systematic review of Medline, Web of Science Core Collection and EBSCO-CINAHL (January 1946 to January 2020). Included articles used dilutional methods to assess TBW.

Results: Searches identified 2349 articles of which 22 included data suitable for analysis. Mean TBW in term-born newborns was 73.8% (95% CI 72.47% to 75.06%, 15 studies, 433 infants). Meta-regression showed that TBW was higher in preterm infants (up to 90% at 26 weeks gestation, dropping to 75% at 36 weeks corrected gestation) and was negatively correlated with gestation at birth, falling 1.44% per week (95% CI 0.63% to 2.24%, 9 studies, 179 infants). Analysis of TBW over time during the ex utero growth of preterm infants was not possible due to paucity of data.

Conclusion: This review defines the normal TBW percentage in term-born infants and confirms and quantifies previous findings that preterm infants have a higher TBW percentage.
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http://dx.doi.org/10.1136/archdischild-2020-321112DOI Listing
March 2021

Attentive brain states in infants with and without later autism.

Transl Psychiatry 2021 Mar 30;11(1):196. Epub 2021 Mar 30.

Centre for Brain and Cognitive Development, Birkbeck College, University of London, Malet Street, London, WC1E 7HX, UK.

Early difficulties in engaging attentive brain states in social settings could affect learning and have cascading effects on social development. We investigated this possibility using multichannel electroencephalography during a face/non-face paradigm in 8-month-old infants with (FH, n = 91) and without (noFH, n = 40) a family history of autism spectrum disorder (ASD). An event-related potential component reflecting attention engagement, the Nc, was compared between FH infants who received a diagnosis of ASD at 3 years of age (FH-ASD; n = 19), FH infants who did not (FH-noASD; n = 72) and noFH infants (who also did not, hereafter noFH-noASD; n = 40). 'Prototypical' microstates during social attention were extracted from the noFH-noASD group and examined in relation to later categorical and dimensional outcome. Machine-learning was used to identify the microstate features that best predicted ASD and social adaptive skills at three years. Results suggested that whilst measures of brain state timing were related to categorical ASD outcome, brain state strength was related to dimensional measures of social functioning. Specifically, the FH-ASD group showed shorter Nc latency relative to other groups, and duration of the attentive microstate responses to faces was informative for categorical outcome prediction. Reduced Nc amplitude difference between faces with direct gaze and a non-social control stimulus and strength of the attentive microstate to faces contributed to the prediction of dimensional variation in social skills. Taken together, this provides consistent evidence that atypical attention engagement precedes the emergence of difficulties in socialization and indicates that using the spatio-temporal characteristics of whole-brain activation to define brain states in infancy provides an important new approach to understanding of the neurodevelopmental mechanisms that lead to ASD.
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http://dx.doi.org/10.1038/s41398-021-01315-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009890PMC
March 2021

Size-Dependent Onset of Nitric Acid Dissociation in Cs·(HNO)(HO) Clusters at 20 K.

J Phys Chem Lett 2021 Apr 29;12(13):3335-3342. Epub 2021 Mar 29.

Sterling Chemistry Laboratory, Yale University, New Haven, Connecticut 06511, United States.

We report the water-mediated charge separation of nitric acid upon incorporation into size-selected Cs·(HNO)(HO) clusters at 20 K. Dramatic spectral changes are observed in the = 7-9 range that are traced to the formation of many isomeric structures associated with intermediate transfer of the acidic proton to the water network. This transfer is complete by = 10, which exhibits much simpler vibrational band patterns consistent with those expected for a tricoordinated hydronium ion (the Eigen motif) along with the NO stretching bands predicted for a hydrated NO anion that is directly complexed to the Cs cation. Theoretical analysis of the = 10 spectrum indicates that the dissociated ions adopt a solvent-separated ion-pair configuration such that the Cs and HO cations flank the NO anion in a microhydrated salt bridge. This charge separation motif is evidently assisted by the electrostatic stabilization of the product NO/HO ion pair by the proximal metal ion.
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http://dx.doi.org/10.1021/acs.jpclett.1c00235DOI Listing
April 2021

A Phase I Evaluation of the Pharmacokinetics and Tolerability of the HIV-1 Maturation Inhibitor GSK3640254 and Tenofovir Alafenamide/Emtricitabine in Healthy Participants.

Antimicrob Agents Chemother 2021 Mar 22. Epub 2021 Mar 22.

ViiV Healthcare, Research Triangle Park, NC, USA.

GSK3640254 is a next-generation maturation inhibitor that would likely be combined with standard antiretroviral agents to form a regimen of ≥2 fully active classes. This phase I, open-label, 2-period, 1-way study assessed potential pharmacokinetic (PK) interactions between GSK3640254 and tenofovir alafenamide/emtricitabine (TAF/FTC; including the metabolite tenofovir [TFV]) in healthy volunteers. Eligible participants received TAF/FTC 25/200 mg once daily (QD) on Days 1 through 21 with a moderate-fat meal; GSK3640254 200 mg QD was added on Days 15 through 21. Geometric least squares mean ratios (GMRs) and 90% CIs were derived using linear mixed-effect models. Adverse events (AEs) and laboratory, electrocardiogram, and vital sign parameters were monitored. Sixteen participants, all male, received treatment; one withdrew because of treatment-related grade 1 urticaria. After TAF/FTC + GSK3640254 coadministration, TAF steady-state area under the plasma concentration-time curve from time 0 to the end of the dosing interval and maximum observed concentration were 11% and 13% lower than when TAF/FTC was administered alone, with GMR (90% CI) of 0.886 (0.75-1.04) and 0.874 (0.68-1.12), respectively. Steady-state PK of TFV and FTC was similar when TAF/FTC was administered alone or with GSK3640254. No clinically significant trends in tolerability or safety were observed. GSK3640254 200 mg QD did not meaningfully affect the steady-state PK of TAF, TFV, or FTC in healthy participants under fed conditions and was not associated with major tolerability or safety findings. These data support the further investigation of GSK3640254 for coadministration with TAF/FTC for the treatment of HIV (ClinicalTrials.gov, NCT03836729).
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http://dx.doi.org/10.1128/AAC.02173-20DOI Listing
March 2021

Routine abdominal magnetic resonance imaging can determine psoas muscle area in paediatric Crohn's disease and correlates with bioelectrical impedance spectroscopy measures of lean mass.

Clin Nutr ESPEN 2021 04 13;42:233-238. Epub 2021 Feb 13.

Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK. Electronic address:

Background: Paediatric Crohn's disease (CD) has been associated with undernutrition. Accurate and accessible measures of body composition would provide data to personalise nutritional therapy. We assessed feasibility of MRI-derived measures of psoas cross-sectional area (PCSA) in paediatric CD and correlated with anthropometric and bioelectrical impedance spectroscopy (BIS) measures.

Methods: MRI small bowel/pelvis images of patients with CD, aged <18 years, were retrieved. Patients with concurrent anthropometric and BIS measurements were eligible for inclusion. The PCSA at L3 was calculated by two assessors and combined. To assess reproducibility of measures we calculated the coefficient of variation (CoV). Age, height-Z-scores, weight-Z-scores and BIS measures were correlated with PCSA. Using normal paediatric data from CT-scans we derived psoas area Z-scores for our cohort.

Results: 10 patients were included. Mean age at MRI scan was 14.6 years (11.7-16.3). PCSA was calculated for all MRI scans. There was high reproducibility between measurers, mean CoV 0.099. There was a significant positive correlation between PCSA and BIA-derived fat free mass, Pearson correlation coefficient (PCC) 0.831, p = 0.003. Correlation coefficients for PCSA and Height-for-age Z-score, weight-for-age -Z-score and age were PCC 0.343- p = 0.33, PCC = 0.222- p = 0.54, and PCC 0.6034- p = 0.065, respectively. The mean PCSA Z-score was -1.81, with 70% of the patients having a Z-score < -2.0.

Conclusions: These data demonstrate the feasibility of deriving measures of body composition from routine MRI imagine. There was significant positive correlation between PCSA and BIS-derived lean mass. Further studies are required to confirm applicability of normal ranges prior to routine clinical implementation.
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http://dx.doi.org/10.1016/j.clnesp.2021.01.031DOI Listing
April 2021

The undetected loss of aged carbon from boreal mineral soils.

Sci Rep 2021 Mar 18;11(1):6202. Epub 2021 Mar 18.

Department of Physical Geography and Ecosystem Science, Lund University, Lund, Sweden.

The boreal forest is among the largest terrestrial biomes on earth, storing more carbon (C) than the atmosphere. Due to rapid climatic warming and enhanced human development, the boreal region may have begun transitioning from a net C sink to a net source. This raises serious concern that old biogenic soil C can be re-introduced into the modern C cycle in near future. Combining bio-decay experiments, mixing models and the Keeling plot method, we discovered a distinct old pre-bomb organic carbon fraction with high biodegradation rate. In total, 34 ± 12% of water-extractable organic carbon (WEOC) in podzols, one of the dominating boreal soil types, consisted of aged (~ 1000 year) labile C. The omission of this aged (i.e., ΔC depleted) WEOC fraction in earlier studies is due to the co-occurrence with ΔC enriched modern C formed following 1950s nuclear bomb testing masking its existence. High lability of aged soil WEOC and masking effects of modern ΔC enriched C suggests that the risk for mobilization and re-introduction of this ancient C pool into the modern C cycle has gone undetected. Our findings have important implications for earth systems models in terms of climate-carbon feedbacks and the future C balance of the boreal forest.
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http://dx.doi.org/10.1038/s41598-021-85506-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973788PMC
March 2021

Surgical repair of primary non-complex rhegmatogenous retinal detachment in the modern era of small-gauge vitrectomy.

BMJ Open Ophthalmol 2021 25;6(1):e000651. Epub 2021 Feb 25.

Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Objective: To report anatomic and visual outcomes of pars plana vitrectomy (PPV), as well as scleral buckling (SB) and PPV/SB as surgical treatments for the management of primary, non-complex rhegmatogenous retinal detachment (RRD).

Methods And Analysis: Data from 751 eyes that underwent PPV, SB or combined PPV/SB as a surgical treatment for primary non-complex RRD with at least 3 months of follow-up were analysed to determine rates of single surgery anatomic success (SSAS) and final anatomic success (FAS). Patients or the public were not involved in the design, conduct or reporting of this research.

Results: PPV accounted for 89.0% (n=668), PPV/SB for 6.8% (n=51) and SB for 4.2% (n=32) cases. Overall SSAS (91.2% PPV, 84.3% PPV/SB, 93.8% SB; p=0.267) and FAS (96.7% PPV, 94.1% PPV/SB and 100.0% SB; p=0.221) were reported for the three surgical groups. SSAS and FAS were similar for lens status, macular detachment status and the presence or absence of inferior retinal breaks for each of the PPV, PPV/SB and SB groups.

Conclusions: In this large, single institution, retrospective case series, we report surgical outcomes for patients with primary non-complex RRD managed with PPV, SB or PPV/SB in the modern era of small-gauge vitrectomy. We demonstrate that primary PPV without adjunct SB provides excellent anatomic and visual outcomes irrespective of lens status, macular involvement or pathology location.
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http://dx.doi.org/10.1136/bmjophth-2020-000651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908907PMC
February 2021

Structural leitmotif and functional variations of the structural catalytic core in (chymo)trypsin-like serine/cysteine fold proteinases.

Int J Biol Macromol 2021 Mar 10;179:601-609. Epub 2021 Mar 10.

Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland.

Proteinases with the (chymo)trypsin-like serine/cysteine fold comprise a large superfamily performing their function through the Acid - Base - Nucleophile catalytic triad. In our previous work (Denesyuk AI, Johnson MS, Salo-Ahen OMH, Uversky VN, Denessiouk K. Int J Biol Macromol. 2020;153:399-411), we described a universal three-dimensional (3D) structural motif, NBCZone, that contains eleven amino acids: dipeptide 42 T-43 T, pentapeptide 54 T-55 T-56 T-57 T(base)-58 T, tripeptide 195 T(nucleophile)-196 T-197 T and residue 213 T (T - numeration of amino acids in trypsin). The comparison of the NBCZones among the members of the (chymo)trypsin-like protease family suggested the existence of 15 distinct groups. Within each group, the NBCZones incorporate an identical set of conserved interactions and bonds. In the present work, the structural environment of the catalytic acid at the position 102 T and the fourth member of the "catalytic tetrad" at the position 214 T was analyzed in 169 3D structures of proteinases with the (chymo)trypsin-like serine/cysteine fold. We have identified a complete Structural Catalytic Core (SCC) consisting of two classes and four groups. The proteinases belonging to different classes and groups differ from each other by the nature of the interaction between their N- and C-terminal β-barrels. Comparative analysis of the 3CLpro(s) from SARS-CoV-2 and SARS-CoV, used as an example, showed that the amino acids at positions 103 T and 179 T affect the nature of the interaction of the "catalytic acid" core (102 T-Core, N-terminal β-barrel) with the "supplementary" core (S-Core, C-terminal β-barrel), which ultimately results in the modulation of the enzymatic activity. The reported analysis represents an important standalone contribution to the analysis and systematization of the 3D structures of (chymo)trypsin-like serine/cysteine fold proteinases. The use of the developed approach for the comparison of 3D structures will allow, in the event of the appearance of new representatives of a given fold in the PDB, to quickly determine their structural homologues with the identification of possible differences.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.03.042DOI Listing
March 2021

Hunting bats adjust their echolocation to receive weak prey echoes for clutter reduction.

Sci Adv 2021 Mar 3;7(10). Epub 2021 Mar 3.

Zoophysiology, Department of Biology, Aarhus University, Aarhus, Denmark.

How animals extract information from their surroundings to guide motor patterns is central to their survival. Here, we use echo-recording tags to show how wild hunting bats adjust their sensory strategies to their prey and natural environment. When searching, bats maximize the chances of detecting small prey by using large sensory volumes. During prey pursuit, they trade spatial for temporal information by reducing sensory volumes while increasing update rate and redundancy of their sensory scenes. These adjustments lead to very weak prey echoes that bats protect from interference by segregating prey sensory streams from the background using a combination of fast-acting sensory and motor strategies. Counterintuitively, these weak sensory scenes allow bats to be efficient hunters close to background clutter broadening the niches available to hunt for insects.
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http://dx.doi.org/10.1126/sciadv.abf1367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929515PMC
March 2021

PAS domains in bacterial signal transduction.

Curr Opin Microbiol 2021 Feb 26;61:8-15. Epub 2021 Feb 26.

Division of Microbiology and Molecular Genetics, Alumni Hall for Basic Sciences, Loma Linda University, Loma Linda, CA, 92350, USA. Electronic address:

PAS domains are widespread, versatile domains found in proteins from all kingdoms of life. The PAS fold is composed of an antiparallel β-sheet with several flanking α-helices, and contains a conserved cleft for cofactor or ligand binding. The last few years have seen a prodigious increase in identified PAS domains and resolved PAS structures, including structures with effector and other domains. New bacterial PAS ligands have been discovered, and structure-function studies have improved our understanding of PAS signaling mechanisms. The list of bacterial PAS functions has now expanded to include roles in signal sensing, modulation, transduction, dimerization, protein interaction, and cellular localization.
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http://dx.doi.org/10.1016/j.mib.2021.01.004DOI Listing
February 2021

Demystifying the Diffuse Vibrational Spectrum of Aqueous Protons Through Cold Cluster Spectroscopy.

Annu Rev Phys Chem 2021 Mar 1. Epub 2021 Mar 1.

Sterling Chemistry Laboratory, Yale University, New Haven, Connecticut 06520, USA; email:

The ease with which the pH is routinely determined for aqueous solutions masks the fact that the cationic product of Arrhenius acid dissolution, the hydrated proton, or H(aq), is a remarkably complex species. Here, we review how results obtained over the past 30 years in the study of H⋅(HO) cluster ions isolated in the gas phase shed light on the chemical nature of H(aq). This effort has also revealed molecular-level aspects of the Grotthuss relay mechanism for positive-charge translocation in water. Recently developed methods involving cryogenic cooling in radiofrequency ion traps and the application of two-color, infrared-infrared (IR-IR) double-resonance spectroscopy have established a clear picture of how local hydrogen-bond topology drives the diverse spectral signatures of the excess proton. This information now enables a new generation of cluster studies designed to unravel the microscopic mechanics underlying the ultrafast relaxation dynamics displayed by H(aq). Expected final online publication date for the , Volume 72 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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http://dx.doi.org/10.1146/annurev-physchem-061020-053456DOI Listing
March 2021

Risk stratification and management of women with cardiomyopathy/heart failure planning pregnancy or presenting during/after pregnancy: a position statement from the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy.

Eur J Heart Fail 2021 Feb 20. Epub 2021 Feb 20.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

This position paper focusses on the pathophysiology, diagnosis and management of women diagnosed with a cardiomyopathy, or at risk of heart failure (HF), who are planning to conceive or present with (de novo or previously unknown) HF during or after pregnancy. This includes the heterogeneous group of heart muscle diseases such as hypertrophic, dilated, arrhythmogenic right ventricular and non-classified cardiomyopathies, left ventricular non-compaction, peripartum cardiomyopathy, Takotsubo syndrome, adult congenital heart disease with HF, and patients with right HF. Also, patients with a history of chemo-/radiotherapy for cancer or haematological malignancies need specific pre-, during and post-pregnancy assessment and counselling. We summarize the current knowledge about pathophysiological mechanisms, including gene mutations, clinical presentation, diagnosis, and medical and device management, as well as risk stratification. Women with a known diagnosis of a cardiomyopathy will often require continuation of drug therapy, which has the potential to exert negative effects on the foetus. This position paper assists in balancing benefits and detrimental effects.
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http://dx.doi.org/10.1002/ejhf.2133DOI Listing
February 2021

EEG signatures of cognitive and social development of preschool children-a systematic review.

PLoS One 2021 19;16(2):e0247223. Epub 2021 Feb 19.

Centre for Brain and Cognitive Development, Birkbeck, University of London, London, United Kingdom.

Background: Early identification of preschool children who are at risk of faltering in their development is essential to ensuring that all children attain their full potential. Electroencephalography (EEG) has been used to measure neural correlates of cognitive and social development in children for decades. Effective portable and low-cost EEG devices increase the potential of its use to assess neurodevelopment in children at scale and particularly in low-resource settings. We conducted a systematic review aimed to synthesise EEG measures of cognitive and social development in 2-5-year old children. Our secondary aim was to identify how these measures differ across a) the course of development within this age range, b) gender and c) socioeconomic status (SES).

Methods And Findings: A systematic literature search identified 51 studies for inclusion in this review. Data relevant to the primary and secondary aims was extracted from these studies and an assessment for risk of bias was done, which highlighted the need for harmonisation of EEG data collection and analysis methods across research groups and more detailed reporting of participant characteristics. Studies reported on the domains of executive function (n = 22 papers), selective auditory attention (n = 9), learning and memory (n = 5), processing of faces (n = 7) and emotional stimuli (n = 8). For papers investigating executive function and selective auditory attention, the most commonly reported measures were alpha power and the amplitude and latency of positive (P1, P2, P3) and negative (N1, N2) deflections of event related potential (ERPs) components. The N170 and P1 ERP components were the most commonly reported neural responses to face and emotional faces stimuli. A mid-latency negative component and positive slow wave were used to index learning and memory, and late positive potential in response to emotional non-face stimuli. While almost half the studies described changes in EEG measures across age, only eight studies disaggregated results based on gender, and six included children from low income households to assess the impact of SES on neurodevelopment. No studies were conducted in low- and middle-income countries.

Conclusion: This review has identified power across the EEG spectrum and ERP components to be the measures most commonly reported in studies in which preschool children engage in tasks indexing cognitive and social development. It has also highlighted the need for additional research into their changes across age and based on gender and SES.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247223PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895403PMC
February 2021

Scaling advantage over path-integral Monte Carlo in quantum simulation of geometrically frustrated magnets.

Nat Commun 2021 Feb 18;12(1):1113. Epub 2021 Feb 18.

D-Wave Systems, Burnaby, BC, Canada.

The promise of quantum computing lies in harnessing programmable quantum devices for practical applications such as efficient simulation of quantum materials and condensed matter systems. One important task is the simulation of geometrically frustrated magnets in which topological phenomena can emerge from competition between quantum and thermal fluctuations. Here we report on experimental observations of equilibration in such simulations, measured on up to 1440 qubits with microsecond resolution. By initializing the system in a state with topological obstruction, we observe quantum annealing (QA) equilibration timescales in excess of one microsecond. Measurements indicate a dynamical advantage in the quantum simulation compared with spatially local update dynamics of path-integral Monte Carlo (PIMC). The advantage increases with both system size and inverse temperature, exceeding a million-fold speedup over an efficient CPU implementation. PIMC is a leading classical method for such simulations, and a scaling advantage of this type was recently shown to be impossible in certain restricted settings. This is therefore an important piece of experimental evidence that PIMC does not simulate QA dynamics even for sign-problem-free Hamiltonians, and that near-term quantum devices can be used to accelerate computational tasks of practical relevance.
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http://dx.doi.org/10.1038/s41467-021-20901-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892843PMC
February 2021

Validation of Real-Time Kinematic (RTK) Devices on Sheep to Detect Grazing Movement Leaders and Social Networks in Merino Ewes.

Sensors (Basel) 2021 Jan 30;21(3). Epub 2021 Jan 30.

Agriculture and Food, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Armidale, NSW 2350, Australia.

Understanding social behaviour in livestock groups requires accurate geo-spatial localisation data over time which is difficult to obtain in the field. Automated on-animal devices may provide a solution. This study introduced an Real-Time-Kinematic Global Navigation Satellite System (RTK-GNSS) localisation device (RTK rover) based on an RTK module manufactured by the company u-blox (Thalwil, Switzerland) that was assembled in a box and harnessed to sheep backs. Testing with 7 sheep across 4 days confirmed RTK rover tracking of sheep movement continuously with accuracy of approximately 20 cm. Individual sheep geo-spatial data were used to observe the sheep that first moved during a grazing period (movement leaders) in the one-hectare test paddock as well as construct social networks. Analysis of the optimum location update rate, with a threshold distance of 20 cm or 30 cm, showed that location sampling at a rate of 1 sample per second for 1 min followed by no samples for 4 min or 9 min, detected social networks as accurately as continuous location measurements at 1 sample every 5 s. The RTK rover acquired precise data on social networks in one sheep flock in an outdoor field environment with sampling strategies identified to extend battery life.
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http://dx.doi.org/10.3390/s21030924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866524PMC
January 2021

Impact of storage conditions on peripheral leukocytes transcriptome.

Mol Biol Rep 2021 Feb 9;48(2):1151-1159. Epub 2021 Feb 9.

BGI-Shenzhen, Shenzhen, 518083, China.

Leukocytes reflect the physiological and pathological states of each individual, and transcriptomic data of leukocytes have been used to reflect health conditions. Since the overall impact of ex vivo conditions on the leukocyte transcriptome before RNA stabilization remains unclear, we evaluated the influence of temporary storage conditions on the leukocyte transcriptome through RNA sequencing. We collected peripheral blood with EDTA tubes, which were processed immediately or stored either at 4 °C or room temperature (RT, 18-22 °C) for 2 h, 6 h and 24 h. Total cellular RNA was extracted from 42 leukocyte samples after red blood cells lysis for subsequent RNA sequencing. We applied weighted gene co-expression network analysis to construct co-expression networks of mRNA and lncRNA among the samples, and then performed gene ontology (GO) term enrichment to explore possible biological processes affected by storage conditions. Storage conditions change the gene expression of peripheral leukocytes. Comparing with fresh leukocytes, storage for 24 h at 4 °C and RT affected 1515 (1.51%) and 10,823 (10.82%) genes, respectively. Pathway enrichment analysis identified nucleosome assembly enriched in up-regulated genes at both conditions. When blood was stored at RT for 24 h, genes involved in apoptotic signaling pathway, negative regulation of cell cycle and lymphocyte activation were upregulated, while the relative proportion of neutrophils was significantly decreased. Temporary storage conditions profoundly affect the gene expression profiles of leukocytes and might further change cell viability and state. Storage of blood samples at 4 °C within 6 h largely maintains their original transcriptome.
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http://dx.doi.org/10.1007/s11033-021-06194-3DOI Listing
February 2021

Ocular Toxoplasmosis after Exposure to Wild Game.

Ocul Immunol Inflamm 2021 Feb 9:1-6. Epub 2021 Feb 9.

Department of Ophthalmology and Visual Sciences, University of Michigan , Ann Arbor, Michigan, USA.

: To describe eight patients with toxoplasma retinochoroiditis following exposure to wild game. : Retrospective, multicenter case series : Eight men, aged 29 to 71 (mean, 56 years), developed toxoplasmic retinochoroiditis after hunting and/or consuming wild game in the United States, including seven deer and one bear. Five patients developed the disease after eating undercooked game meat, while three developed ocular findings after cleaning hunted animals. Seven patients were healthy prior to exposure. LogMAR visual acuity at presentation was 0.697 ± 0.745, improving to 0.256 ± 0.335 by last follow-up. Disease complications developed in five (62.5%) patients, of which recurrence of retinochoroiditis was the most common. : Contact with wild game is a potential source of primary ocular toxoplasmosis in immunocompetent adults. Hunters and consumers of rare game are at risk of serious ocular disease and appropriate contact precautions and cooking may reduce this complication.
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http://dx.doi.org/10.1080/09273948.2020.1854316DOI Listing
February 2021

Cannabis and crash risk among older drivers.

Accid Anal Prev 2021 Mar 4;152:105987. Epub 2021 Feb 4.

AAA Foundation for Traffic Safety, 607 14th Street, NW, Suite 201, Washington, DC 20005-2000, USA.

The purpose of this research was to reanalyze data collected from the National Highway Traffic Safety Administration's Drug and Alcohol Crash Risk Study to investigate whether driving under the influence of cannabis (THC-positive) was associated with elevated crash risk for younger and older drivers. The data came from a case-control relative risk study collected from Virginia Beach, VA, over a 20-month period. Data collectors gathered driver information from the scene of vehicle crashes and, in some cases, from hospitals. Non-crash controls were sampled from the same locations, days, and times as crashes. Key data items included driver demographics and oral fluid and blood samples, which were assayed for licit and illicit drugs. We found no overall association between cannabis use and risk of crash involvement. However, when age and age were allowed to interact with THC, significant interaction effects emerged. THC was associated with increased risk of crash involvement for older drivers. Difference between THC-positive and sober drivers emerged as significant at age 64. The research underscores the value of examining drugged driving in the context of driver age. Age-related declines in neurocognitive and psychomotor functioning were not measured but might be important in explaining the results.
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http://dx.doi.org/10.1016/j.aap.2021.105987DOI Listing
March 2021

Regression of drusen or vitelliform material heralding geographic atrophy: correlation between clinical observations and basic science.

Graefes Arch Clin Exp Ophthalmol 2021 Feb 6. Epub 2021 Feb 6.

Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, MI, 48105, USA.

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http://dx.doi.org/10.1007/s00417-021-05101-7DOI Listing
February 2021

Phase I evaluation of pharmacokinetics and tolerability of the HIV-1 maturation inhibitor GSK3640254 and dolutegravir in healthy adults.

Br J Clin Pharmacol 2021 Feb 3. Epub 2021 Feb 3.

ViiV Healthcare, Research Triangle Park, NC, USA.

Aims: GSK3640254, a novel, next-generation maturation inhibitor effective against a range of HIV polymorphisms with no cross-resistance to current antiretroviral therapy, could potentially be coadministered with dolutegravir as a 2-drug regimen. In this phase I study, pharmacokinetics and tolerability of GSK3640254 plus dolutegravir were assessed.

Methods: Healthy participants received dolutegravir 50 mg once daily (QD) on Days 1-5 in period 1, GSK3640254 200 mg QD on Days 1-7 in period 2, and dolutegravir 50 mg plus GSK3640254 200 mg QD on Days 1-7 in period 3. All treatments were administered with a moderate-fat meal 30 minutes prior to dosing. Pharmacokinetics parameters were derived by noncompartmental methods, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed effects models. Adverse events, laboratory measurements, electrocardiography and vital signs were monitored.

Results: Sixteen participants completed the study. GMRs (90% CIs) for dolutegravir area under the plasma concentration-time curve from time 0 to the end of the dosing interval at steady state, maximum observed concentration and plasma concentration at the end of the dosing interval were 1.17 (1.118-1.233), 1.09 (1.044-1.138) and 1.24 (1.160-1.315), respectively. The GMRs (90% CIs) for GSK3640254 were 1.04 (0.992-1.094), 0.99 (0.923-1.065) and 0.10 (0.939-1.056), respectively. Dolutegravir plus GSK3640254 coadministration did not meaningfully alter steady-state exposure to dolutegravir or GSK3640254. No clinically significant trends in tolerability or safety were observed.

Conclusion: Coadministration of GSK3640254 with dolutegravir did not result in clinically significant drug interaction and was well tolerated.
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http://dx.doi.org/10.1111/bcp.14759DOI Listing
February 2021

Pregnancy outcome in thoracic aortic disease data from the Registry Of Pregnancy And Cardiac disease.

Heart 2021 Jan 19. Epub 2021 Jan 19.

Cardiology Department, Erasmus Medical Center, Rotterdam, Netherlands

Background: Cardiovascular disease is the leading cause of death during pregnancy with thoracic aortic dissection being one of the main causes. Thoracic aortic disease is commonly related to hereditary disorders and congenital heart malformations such as bicuspid aortic valve (BAV). Pregnancy is considered a high risk period in women with underlying aortopathy.

Methods: The ESC EORP Registry Of Pregnancy And Cardiac disease (ROPAC) is a prospective global registry that enrolled 5739 women with pre-existing cardiac disease. With this analysis, we aim to study the maternal and fetal outcome of pregnancy in women with thoracic aortic disease.

Results: Thoracic aortic disease was reported in 189 women (3.3%). Half of them were patients with Marfan syndrome (MFS), 26% had a BAV, 8% Turner syndrome, 2% vascular Ehlers-Danlos syndrome and 11% had no underlying genetic defect or associated congenital heart defect. Aortic dilatation was reported in 58% of patients and 6% had a history of aortic dissection. Four patients, of whom three were patients with MFS, had an acute aortic dissection (three type A and one type B aortic dissection) without maternal or fetal mortality. No complications occurred in women with a history of aortic dissection. There was no significant difference in median fetal birth weight if treated with a beta-blocker or not (2960 g (2358-3390 g) vs 3270 g (2750-3570 g), p value 0.25).

Conclusion: This ancillary analysis provides the largest prospective data review on pregnancy risk for patients with thoracic aortic disease. Overall pregnancy outcomes in women with thoracic aortic disease followed according to current guidelines are good.
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http://dx.doi.org/10.1136/heartjnl-2020-318183DOI Listing
January 2021

Deletions in CWH43 cause idiopathic normal pressure hydrocephalus.

EMBO Mol Med 2021 Mar 18;13(3):e13249. Epub 2021 Jan 18.

University of Massachusetts Medical School, Worcester, MA, USA.

Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder that occurs in about 1% of individuals over age 60 and is characterized by enlarged cerebral ventricles, gait difficulty, incontinence, and cognitive decline. The cause and pathophysiology of iNPH are largely unknown. We performed whole exome sequencing of DNA obtained from 53 unrelated iNPH patients. Two recurrent heterozygous loss of function deletions in CWH43 were observed in 15% of iNPH patients and were significantly enriched 6.6-fold and 2.7-fold, respectively, when compared to the general population. Cwh43 modifies the lipid anchor of glycosylphosphatidylinositol-anchored proteins. Mice heterozygous for CWH43 deletion appeared grossly normal but displayed hydrocephalus, gait and balance abnormalities, decreased numbers of ependymal cilia, and decreased localization of glycosylphosphatidylinositol-anchored proteins to the apical surfaces of choroid plexus and ependymal cells. Our findings provide novel mechanistic insights into the origins of iNPH and demonstrate that it represents a distinct disease entity.
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http://dx.doi.org/10.15252/emmm.202013249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933959PMC
March 2021

Annual Research Review: Anterior Modifiers in the Emergence of Neurodevelopmental Disorders (AMEND)-a systems neuroscience approach to common developmental disorders.

J Child Psychol Psychiatry 2021 Jan 11. Epub 2021 Jan 11.

Centre for Brain and Cognitive Development, Department of Psychological Sciences, Birkbeck, University of London, London, UK.

We present the Anterior Modifiers in the Emergence of Neurodevelopmental Disorders (AMEND) framework, designed to reframe the field of prospective studies of neurodevelopmental disorders. In AMEND we propose conceptual, statistical and methodological approaches to separating markers of early-stage perturbations from later developmental modifiers. We describe the evidence for, and features of, these interacting components before outlining analytical approaches to studying how different profiles of early perturbations and later modifiers interact to produce phenotypic outcomes. We suggest this approach could both advance our theoretical understanding and clinical approach to the emergence of developmental psychopathology in early childhood.
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http://dx.doi.org/10.1111/jcpp.13372DOI Listing
January 2021