bluuebunny/crossref_metadata_2025 huggingface dataset:
Production and characterization of radiation-sensitive meiotic mutants of Coprinus cinereus.
Authors: Zolan M E , Tremel C J , Pukkila P J
Published: January 2021

We have isolated four gamma-ray-sensitive mutants of the basidiomycete Coprinus cinereus. When homozygous, two of these (rad 3-1 and rad 9-1) produce fruiting bodies with very few viable basidiospores, the products of meiosis in this organism. A less radiation-sensitive allele of RAD 3, rad 3-2, causes no apparent meiotic defect in homozygous strains. Quantitative measurements of oidial survival of rad 3-1; rad 9-1 double mutants compared to the single mutants indicated that rad 3-1 and rad 9-1 mutants are defective in the same DNA repair pathway. In the few viable basidiospores that are produced by these two strains, essentially normal levels of meiotic recombination can be detected. None of the mutants exhibits increased sensitivity to UV radiation. Cytological examination of meiotic chromosomes from mutant and wild-type fruiting bodies showed that rad 3-1 homozygous strains fail to condense and pair homologous chromosomes during prophase I. Although rad 9-1 strains are successful at chromosome pairing, meiosis is usually not completed in these mutants.
Genetic Analysis of the Heterochromatin of Chromosome 3 in Drosophila Melanogaster. II. Vital Loci Identified through Ems Mutagenesis.
Authors: Marchant G E , Holm D G
Published: January 2021

Chromosome 3 of Drosophila melanogaster contains the last major blocks of heterochromatin in this species to be genetically analyzed. Deficiencies of heterochromatin generated through the detachment of compound-3 chromosomes revealed the presence of vital loci in the heterochromatin of chromosome 3, but an extensive complementation analysis with various combinations of lethal and nonlethal detachment products gave no evidence of tandemly repeated vital genes in this region. These findings indicate that the heterochromatin of chromosome 3 is genetically similar to that of chromosome 2. A more thorough genetic analysis of the heterochromatic regions has been carried out using the chemical mutagen ethyl methanesulfonate (EMS). Seventy-five EMS-induced lethals allelic to loci uncovered by detachment-product deficiencies were recovered and tested for complementation. In total, 12 complementation groups were identified, ten in the heterochromatin to the left of the centromere and two to the right. All but two complementation groups in the left heterochromatic block could be identified as separate loci through deficiency mapping. The interallelic complementation observed between some EMS-induced lethals, as well as the recovery of a temperature-sensitive allele for each of the two loci, provided further evidence that single-copy, transcribed vital genes reside in the heterochromatin of chromosome 3. Cytological analysis of three detachment-product deficiencies provided evidence that at least some of the genes uncovered in this study are located in the most distal segments of the heterochromatin in both arms. This study provides a detailed genetic analysis of chromosome 3 heterochromatin and offers further information on the genetic nature and heterogeneity of Drosophila heterochromatin.
Ceramide contributes to pathogenesis and may be targeted for therapy in VCP inclusion body myopathy
Authors: Weiss Lan , Jung Kwang-Mook , Nalbandian Angele , Llewellyn Katrina , Yu Howard , Ta Lac , Chang Isabela , Migliore Marco , Squire Erica , Ahmed Faizy , Piomelli Daniele , Kimonis Virginia
Published: January 2021

Knock-in homozygote VCPR155H/R155H mutant mice are a lethal model of valosin-containing protein (VCP)-associated inclusion body myopathy associated with Paget disease of bone, frontotemporal dementia and amyotrophic lateral sclerosis. Ceramide (d18:1/16:0) levels are elevated in skeletal muscle of the mutant mice, compared to wild-type controls. Moreover, exposure to a lipid-enriched diet reverses lethality, improves myopathy and normalizes ceramide levels in these mutant mice, suggesting that dysfunctions in lipid-derived signaling are critical to disease pathogenesis. Here, we investigated the potential role of ceramide in VCP disease using pharmacological agents that manipulate the ceramide levels in myoblast cultures from VCP mutant mice and VCP patients. Myoblasts from wild-type, VCPR155H/+ and VCPR155H/R155H mice, as well as patient-induced pluripotent stem cells (iPSCs), were treated with an inhibitor of ceramide degradation to increase ceramide via acid ceramidase (ARN082) for proof of principle. Three chemically distinct inhibitors of ceramide biosynthesis via serine palmitoyl-CoA transferase (L-cycloserine, myriocin or ARN14494) were used as a therapeutic strategy to reduce ceramide in myoblasts. Acid ceramidase inhibitor, ARN082, elevated cellular ceramide levels and concomitantly enhanced pathology. Conversely, inhibitors of ceramide biosynthesis L-cycloserine, myriocin and ARN14494 reduced ceramide production. The results point to ceramide-mediated signaling as a key contributor to pathogenesis in VCP disease and suggest that manipulating this pathway by blocking ceramide biosynthesis might exert beneficial effects in patients with this condition. The ceramide pathway appears to be critical in VCP pathogenesis, and small-molecule inhibitors of ceramide biosynthesis might provide therapeutic benefits in VCP and related neurodegenerative diseases.
Glutathione S-transferase Pi (Gstp) proteins regulate neuritogenesis in the developing cerebral cortex
Authors: Liu Xiaonan , Blazejewski Sara M , Bennison Sarah A , Toyo-oka Kazuhito
Published: January 2021

GSTP proteins are metabolic enzymes involved in the removal of oxidative stress and intracellular signaling and also have inhibitory effects on JNK activity. However, the functions of Gstp proteins in the developing brain are unknown. In mice, there are three Gstp proteins, Gstp1, 2 and 3, whereas there is only one GSTP in humans. By reverse transcription-polymerase chain reaction (RT-PCR) analysis, we found that Gstp1 was expressed beginning at E15.5 in the cortex, but Gstp2 and 3 started expressing at E18.5. Gstp 1 and 2 knockdown (KD) caused decreased neurite number in cortical neurons, implicating them in neurite initiation. Using in utero electroporation (IUE) to knock down Gstp1 and 2 in layer 2/3 pyramidal neurons in vivo, we found abnormal swelling of the apical dendrite at P3 and reduced neurite number at P15. Using time-lapse live imaging, we found that the apical dendrite orientation was skewed compared with the control. We explored the molecular mechanism and found that JNK inhibition rescued reduced neurite number caused by Gstp knockdown, indicating that Gstp regulates neurite formation through JNK signaling. Thus, we found novel functions of Gstp proteins in neurite initiation during cortical development. These findings not only provide novel functions of Gstp proteins in neuritogenesis during cortical development but also help us to understand the complexity of neurite formation.
Biogeographical patterns of meso- and bathypelagic fish along a Northeastern Atlantic transect
Authors: García-Seoane Eva , Wienerroither Rupert , Mork Kjell Arne , Underwood Melanie J , Melle Webjørn
Published: January 2021

The influence of oceanographic variables on assemblages of meso- and bathypelagic fish was investigated along a Northeastern Atlantic Ocean transect (Cape Verde to the Bay of Biscay) during May 2019. Fish were collected using a macrozooplankton trawl during daylight hours at ten stations. Along the transect, 17 hydrographic stations were also performed with a CTD (Conductivity, Temperature, and Depth). A total of 130 fish taxa were identified. The dominant family was Gonostomatidae, with four species (Cyclothone braueri, Cyclothone microdon, Cyclothone pseudopallida, and Cyclothone pallida) being responsible of more than 78% of the total density. The most frequent species that appeared to be ubiquitous were C. braueri and C. pseudopallida, while Myctophidae was the most diverse family. Multivariate analyses revealed two clusters related with the latitudinal gradient. The fish community in the southern stations (25–37°N) was more diverse than in the northern stations (42–48°N). Temperature from 300 to 700 m depth explained 65% of variation in terms of density and 58% in terms of biomass, both statistically significant. The investigated variation in the deep-pelagic ecosystems on a large spatial scale gives essential information to ecosystem management approaches and marine spatial planning.
Sovereignty’s rationale: Afterword to the Foreword by Neil Walker
Authors: Duke George
Published: January 2021

In this response to Neil Walker’s rich and insightful Foreword essay “The Sovereignty Surplus,” I examine some of the motivational and practical reasons which explain the persistence of the sovereign state form. An insufficient attentiveness to these reasons, I argue, leads Walker to attribute an exaggerated causal significance to his “five Rs” or phenomena of surplus and accrual.
On the algebraic structure of the Moore–Penrose inverse of a polynomial matrix
Authors: Kafetzis Ioannis S , Karampetakis Nicholas P
Published: January 2021

This work establishes the connection between the finite and infinite algebraic structure of singular polynomial matrices and their Moore–Penrose (MP) inverse. The uniqueness of the MP inverse leads to the assumption that such a relation must exist. It is proved that the MP inverse of a singular polynomial matrix has no finite zeros and its finite poles are fully determined. Furthermore, the existence of a correspondence between the infinite pole/zero structure of any singular polynomial matrix and its MP inverse is proved to exist. Finally, it is shown that the minimal indices of the two aforementioned matrices are connected as well.
Equivalence of local- and global-best approximations, a simple stable local commuting projector, and optimal hp approximation estimates in
H
(div)
Authors: Ern Alexandre , Gudi Thirupathi , Smears Iain , Vohralík Martin
Published: January 2021

Given an arbitrary function in $\boldsymbol{H}({\operatorname{div}})$, we show that the error attained by the global-best approximation by $\boldsymbol{H}({\operatorname{div}})$-conforming piecewise polynomial Raviart–Thomas–Nédélec elements under additional constraints on the divergence and normal flux on the boundary is, up to a generic constant, equivalent to the sum of independent local-best approximation errors over individual mesh elements, without constraints on the divergence or normal fluxes. The generic constant only depends on the shape-regularity of the underlying simplicial mesh, the space dimension, and the polynomial degree of the approximations. The analysis also gives rise to a stable, local, commuting projector in $\boldsymbol{H}({\operatorname{div}})$, delivering an approximation error that is equivalent to the local-best approximation. We next present a variant of the equivalence result, where robustness of the constant with respect to the polynomial degree is attained for unbalanced approximations. These two results together further enable us to derive rates of convergence of global-best approximations that are fully optimal in both the mesh size $h$ and the polynomial degree $p$, for vector fields that only feature elementwise the minimal necessary Sobolev regularity. We finally show how to apply our findings to derive optimal a priori$hp$-error estimates for mixed and least-squares finite element methods applied to a model diffusion problem.
Patient-reported outcome measures in mental health clinical research: a descriptive review in comparison with clinician-rated outcome measures
Authors: Baandrup Lone , Rasmussen Jesper Østrup , Mainz Jan , Videbech Poul , Kristensen Solvejg
Published: January 2021

Purpose

To review how patient-reported outcome (PRO) measures in mental health clinical research complement traditional clinician-rated outcome (CRO) measures.

Data sources

Medline, Embase, PsycInfo and Scopus.

Study selection

Latest update of the literature search was conducted in August 2019, using a specified set of search terms to identify controlled and uncontrolled studies (published since 1996) of pharmacological or non-pharmacological interventions in adults (≥18 years) in hospital-based mental health care.

Data extraction

Two authors extracted data independently using a pre-designed extraction form.

Results of data synthesis

Among the 2962 publications identified, 257 were assessed by full text reading. A total of 24 studies reported in 26 publications were included in this descriptive review. We identified subjective and objective outcome measures, classified these according to the pharmacopsychometric triangle and compared them qualitatively in terms of incremental information added to the clinical study question. The data reviewed here from primarily depression and schizophrenia intervention studies show that results from PRO measures and CRO measures generally point in the same direction. There was a relative lack of PRO measures on functioning and medication side effects compared with PRO measures on symptom burden and health-related quality of life.

Conclusion

PROs and CROs supplement each other and at most times support identical study conclusions. Future studies would benefit from a more systematic approach toward use of PROs and a clearer rationale of how to weigh and report the results in comparison with CROs.
Combination of vancomycin plus piperacillin and risk of acute kidney injury: a worldwide pharmacovigilance database analysis
Authors: Contejean Adrien , Tisseyre Mylène , Canouï Etienne , Treluyer Jean-Marc , Kerneis Solen , Chouchana Laurent
Published: January 2021

Background

Excess of acute kidney injury (AKI) secondary to the association of vancomycin plus piperacillin is debated.

Objectives

To detect a signal for an increased risk of AKI with the vancomycin and piperacillin combination compared with other vancomycin-based regimens.

Methods

Using VigiBase, the WHO global database of individual case safety reports (ICSR) from 1997 to 2019, we conducted a disproportionality analysis comparing the reporting of AKI cases between different vancomycin-based regimens (vancomycin plus piperacillin, cefepime or meropenem). To take into account a possible notoriety bias, we secondarily restricted the study period to before 2014, the date of the first publication of AKI in patients receiving vancomycin plus piperacillin. Results are expressed using the reporting OR (ROR) and its 95% CI.

Results

From 1997 to 2019, 53 701 ICSR concerning vancomycin have been registered in the database, including 6016 reports of AKI (11.2%), among which 925 (15.4%) were reported with vancomycin/piperacillin, 339 (5.6%) with vancomycin/cefepime and 197 (3.7%) with vancomycin/meropenem. ROR (95% CI) for AKI was 2.6 (2.4–2.8) for vancomycin/piperacillin, 2.5 (2.2–2.9) for vancomycin/cefepime and 0.5 (0.4–0.6) for vancomycin/meropenem versus other vancomycin-containing regimens. After restriction of the study period to 1997–2013, the ROR for AKI remains significant only for vancomycin/piperacillin [ROR (95% CI) = 2.1 (1.8–2.4)].

Conclusions

We found a disproportionality in reports of AKI in patients receiving vancomycin plus piperacillin compared with vancomycin in other regimens. This suggests a drug–drug interaction between these two antibiotics resulting in an increased risk of AKI.
Impact of a problem-oriented view on clinical data retrieval
Authors: Semanik Michael G , Kleinschmidt Peter C , Wright Adam , Willett Duwayne L , Dean Shannon M , Saleh Sameh N , Co Zoe , Sampene Emmanuel , Buchanan Joel R
Published: January 2021

Objective

The electronic health record (EHR) data deluge makes data retrieval more difficult, escalating cognitive load and exacerbating clinician burnout. New auto-summarization techniques are needed. The study goal was to determine if problem-oriented view (POV) auto-summaries improve data retrieval workflows. We hypothesized that POV users would perform tasks faster, make fewer errors, be more satisfied with EHR use, and experience less cognitive load as compared with users of the standard view (SV).

Methods

Simple data retrieval tasks were performed in an EHR simulation environment. A randomized block design was used. In the control group (SV), subjects retrieved lab results and medications by navigating to corresponding sections of the electronic record. In the intervention group (POV), subjects clicked on the name of the problem and immediately saw lab results and medications relevant to that problem.

Results

With POV, mean completion time was faster (173 seconds for POV vs 205 seconds for SV; P < .0001), the error rate was lower (3.4% for POV vs 7.7% for SV; P = .0010), user satisfaction was greater (System Usability Scale score 58.5 for POV vs 41.3 for SV; P < .0001), and cognitive task load was less (NASA Task Load Index score 0.72 for POV vs 0.99 for SV; P < .0001).

Discussion

The study demonstrates that using a problem-based auto-summary has a positive impact on 4 aspects of EHR data retrieval, including cognitive load.

Conclusion

EHRs have brought on a data deluge, with increased cognitive load and physician burnout. To mitigate these increases, further development and implementation of auto-summarization functionality and the requisite knowledge base are needed.
Language and Consumer Dishonesty: A Self-Diagnosticity Theory
Authors: Gai Phyliss Jia , Puntoni Stefano
Published: January 2021

How does foreign language influence consumer dishonesty? We propose a self-diagnosticity theory arguing that compared to one’s native language, using a foreign language makes lying appear less self-diagnostic, thereby increasing or decreasing lying depending on which aspect of the self is salient. In situations where lying reflects an undesirable, dishonest self, using a foreign language increases lying. In contrast, in situations where lying primarily reflects a desirable (e.g., competent or compassionate) self, using a foreign language decreases lying. Ten studies, spanning various languages, consumer contexts, and experimental paradigms, support the theory. The studies establish that the effect of language on lying jointly depends on the self-diagnosticity of lying and on whether lying is diagnostic of a positive or a negative aspect of the self. The findings highlight self-diagnosticity as a valuable lens to understand the behavior of bilingual consumers and offer practical guidance for addressing dishonesty in the marketplace.
Radiation signatures from striped blazar jet
Authors: Zhang Haocheng , Giannios Dimitrios
Published: January 2021

Relativistic jets from supermassive black holes are among the most powerful and luminous astrophysical systems in Universe. We propose that the open magnetic field lines through the black hole, which drive a strongly magnetized jet, may have their polarity reversing over time scales related to the growth of the magnetorotational dynamo in the disc, resulting in dissipative structures in the jet characterized by reversing toroidal field polarities, referred to as ‘stripes’. The magnetic reconnection between the stripes dissipates the magnetic energy and powers jet acceleration. The striped jet model can explain the jet acceleration, large-scale jet emission, and blazar emission signatures consistently in a unified physical picture. Specifically, we find that the jet accelerates to the bulk Lorentz factor Γ ≳ 10 within 1-parsec distance from the central engine. The acceleration slows down but continues at larger distances, with intrinsic acceleration rate $\dot{\Gamma }/\Gamma$ between $0.0005$ and $0.005~\rm {yr^{-1}}$ at tens of parsecs, which is in very good agreement with recent radio observations. Magnetic reconnection continuously accelerates non-thermal particles over large distances from the central engine, resulting in the core-shift effect and overall flat-to-inverted synchrotron spectrum. The large-scale spectral luminosity peak νpeak is antiproportional to the location of the peak of the dissipation, which is set by the minimal stripe width lmin. The blazar zone is approximately at the same location. At this distance, the jet is moderately magnetized, with the comoving magnetic field strength and dissipation power consistent with typical leptonic blazar model parameters.
Nucleosynthesis in magneto-rotational supernovae
Authors: Reichert M , Obergaulinger M , Eichler M , Aloy M Á , Arcones A
Published: January 2021

We present the nucleosynthesis of magneto-rotational supernovae (MR-SNe) including neutrino-driven and magneto-rotational-driven ejecta based, for the first time, on two-dimensional simulations with accurate neutrino transport. The models analysed here have different rotation and magnetic fields, allowing us to explore the impact of these two key ingredients. The accurate neutrino transport of the simulations is critical to analyse the slightly neutron rich and proton rich ejecta that are similar to the, also neutrino-driven, ejecta in standard supernovae. In the model with strong magnetic field, the r-process produces heavy elements up to the third r-process peak (A ∼ 195), in agreement with previous works. This model presents a jet-like explosion with proton-rich jets surrounded by neutron rich material where the r-process occurs. We have estimated a lower limit for 56Ni of 2.5 × 10−2M⊙, which is still well below the expected hypernova value. Longer simulations including the accretion disk evolution are required to get a final prediction. In addition, we have found that the late evolution is critical in a model with weak magnetic field in which lately ejected neutron rich matter produces elements up to the second r-process peak. Even if we cannot yet provide conclusions for hypernova nucleosynthesis, our results agree with observations of old stars and radioactive isotopes in supernova remnants. This makes MR-SNe a good additional scenario to neutron star mergers for the synthesis of heavy elements and brings us closer to understand their origin and the role of MR-SNe in the early galaxy nucleosynthesis.
Tracing the simulated high-redshift circum-galactic medium with Lyman α emission
Authors: Mitchell Peter D , Blaizot Jérémy , Cadiou Corentin , Dubois Yohan , Garel Thibault , Rosdahl Joakim
Published: January 2021

With the Multi Unit Spectroscopic Explorer (MUSE), it is now possible to detect spatially extended Lyman α (Lyα) emission from individual faint (MUV ∼ −18) galaxies at redshifts, 3 < z < 6, tracing gas out to circum-galactic scales. To explore the implications of such observations, we present a cosmological radiation hydrodynamics simulation of a single galaxy, chosen to be typical of the Lyα-emitting galaxies detected by MUSE in deep fields. We use this simulation to study the origin and dynamics of the high-redshift circum-galactic medium (CGM). We find that the majority of the mass in the diffuse CGM is comprised of material infalling for the first time towards the halo center, but with the inner CGM also containing a comparable amount of mass that has moved past first-pericentric passage, and is in the process of settling into a rotationally supported configuration. Making the connection to Lyα emission, we find that the observed extended surface brightness profile is due to a combination of three components: scattering of galactic Lyα emission in the CGM, in-situ emission of CGM gas (mostly infalling), and Lyα emission from small satellite galaxies. The weight of these contributions vary with distance from the galaxy such that (1) scattering dominates the inner regions (r < 7 kpc), at surface brightness larger than a few 10−19 cgs, (2) all components contribute equally around r ∼ 10 kpc (or SB∼10−19), and (3) the contribution of small satellite galaxies takes over at large distances (or SB∼10−20).
Measurements of pulse jitter and single-pulse variability in millisecond pulsars using MeerKAT
Authors: Parthasarathy A , Bailes M , Shannon R M , van Straten W , Osłowski S , Johnston S , Spiewak R , Reardon D J , Kramer M , Venkatraman Krishnan V , Pennucci T T , Abbate F , Buchner S , Camilo F , Champion D J , Geyer M , Hugo B , Jameson A , Karastergiou A , Keith M J , Serylak M
Published: January 2021

Using the state-of-the-art SKA precursor, the MeerKAT radio telescope, we explore the limits to precision pulsar timing of millisecond pulsars achievable due to pulse stochasticity (jitter). We report new jitter measurements in 15 of the 29 pulsars in our sample and find that the levels of jitter can vary dramatically between them. For some, like the 2.2 ms pulsar PSR J2241−5236, we measure an implied jitter of just ∼4 ns h−1, while others, like the 3.9 ms PSR J0636−3044, are limited to ∼100 ns h−1. While it is well known that jitter plays a central role to limiting the precision measurements of arrival times for high signal-to-noise ratio observations, its role in the measurement of dispersion measure (DM) has not been reported, particularly in broad-band observations. Using the exceptional sensitivity of MeerKAT, we explored this on the bright millisecond pulsar PSR J0437−4715 by exploring the DM of literally every pulse. We found that the derived single-pulse DMs vary by typically 0.0085 cm−3 pc from the mean, and that the best DM estimate is limited by the differential pulse jitter across the band. We postulate that all millisecond pulsars will have their own limit on DM precision which can only be overcome with longer integrations. Using high-time resolution filterbank data of 9 μs, we also present a statistical analysis of single-pulse phenomenology. Finally, we discuss optimization strategies for the MeerKAT pulsar timing program and its role in the context of the International Pulsar Timing Array.
The rapid transition from star formation to AGN-dominated rest-frame ultraviolet light at z ≃ 4
Authors: Bowler R A A , Adams N J , Jarvis M J , Häußler B
Published: January 2021

With the advent of deep optical-to-near-infrared extragalactic imaging on the degree scale, samples of high-redshift sources are being selected that contain both bright star-forming (SF) galaxies and faint active galactic nuclei (AGN). In this study, we investigate the transition between SF- and AGN-dominated systems at z ≃ 4 in the rest-frame ultraviolet (UV). We find a rapid transition to AGN-dominated sources brightward of MUV ≃ −23.2. The effect is observed in the rest-frame UV morphology and size–luminosity relation, where extended clumpy systems become point-source-dominated, and also in the available spectra for the sample. These results allow us to derive the rest-frame UV luminosity function (LF) for the SF- and AGN-dominated subsamples. We find the SF-dominated LF is best fit with a double power law, with a lensed Schechter function being unable to explain the existence of extremely luminous SF galaxies at MUV ≃ −23.5. If we identify AGN-dominated sources according to a point-source morphology criterion, we recover the relatively flat faint-end slope of the AGN LF determined in previous studies. If we instead separate the LF according to the current spectroscopic AGN fraction, we find a steeper faint-end slope of α = −1.83 ± 0.11. Using a simple model to predict the rest-frame AGN LF from the z = 4 galaxy LF, we find that the increasing impact of host galaxy light on the measured morphology of faint AGN can explain our observations.
Pentapeptide repeat protein QnrB1 requires ATP hydrolysis to rejuvenate poisoned gyrase complexes
Authors: Mazurek Łukasz , Ghilarov Dmitry , Michalczyk Elizabeth , Pakosz Zuzanna , Metelev Mikhail , Czyszczoń Wojciech , Wawro Karolina , Behroz Iraj , Dubiley Svetlana , Süssmuth Roderich D , Heddle Jonathan G
Published: January 2021

DNA gyrase, a type II topoisomerase found predominantly in bacteria, is the target for a variety of ‘poisons’, namely natural product toxins (e.g. albicidin, microcin B17) and clinically important synthetic molecules (e.g. fluoroquinolones). Resistance to both groups can be mediated by pentapeptide repeat proteins (PRPs). Despite long-term studies, the mechanism of action of these protective PRPs is not known. We show that a PRP, QnrB1 provides specific protection against fluoroquinolones, which strictly requires ATP hydrolysis by gyrase. QnrB1 binds to the GyrB protein and stimulates ATPase activity of the isolated N-terminal ATPase domain of GyrB (GyrB43). We probed the QnrB1 binding site using site-specific incorporation of a photoreactive amino acid and mapped the crosslinks to the GyrB43 protein. We propose a model in which QnrB1 binding allosterically promotes dissociation of the fluoroquinolone molecule from the cleavage complex.
In vivo phage display: identification of organ-specific peptides using deep sequencing and differential profiling across tissues
Authors: Pleiko Karlis , Põšnograjeva Kristina , Haugas Maarja , Paiste Päärn , Tobi Allan , Kurm Kaarel , Riekstina Una , Teesalu Tambet
Published: January 2021

In vivo phage display is widely used for identification of organ- or disease-specific homing peptides. However, the current in vivo phage biopanning approaches fail to assess biodistribution of specific peptide phages across tissues during the screen, thus necessitating laborious and time-consuming post-screening validation studies on individual peptide phages. Here, we adopted bioinformatics tools used for RNA sequencing for analysis of high-throughput sequencing (HTS) data to estimate the representation of individual peptides during biopanning in vivo. The data from in vivo phage screen were analyzed using differential binding—relative representation of each peptide in the target organ versus in a panel of control organs. Application of this approach in a model study using low-diversity peptide T7 phage library with spiked-in brain homing phage demonstrated brain-specific differential binding of brain homing phage and resulted in identification of novel lung- and brain-specific homing peptides. Our study provides a broadly applicable approach to streamline in vivo peptide phage biopanning and to increase its reproducibility and success rate.
Mobile element warfare via CRISPR and anti-CRISPR in Pseudomonas aeruginosa
Authors: León Lina M , Park Allyson E , Borges Adair L , Zhang Jenny Y , Bondy-Denomy Joseph
Published: January 2021

Bacteria deploy multiple defenses to prevent mobile genetic element (MGEs) invasion. CRISPR–Cas immune systems use RNA-guided nucleases to target MGEs, which counter with anti-CRISPR (Acr) proteins. Our understanding of the biology and co-evolutionary dynamics of the common Type I-C CRISPR–Cas subtype has lagged because it lacks an in vivo phage-host model system. Here, we show the anti-phage function of a Pseudomonas aeruginosa Type I-C CRISPR–Cas system encoded on a conjugative pKLC102 island, and its Acr-mediated inhibition by distinct MGEs. Seven genes with anti-Type I-C function (acrIC genes) were identified, many with highly acidic amino acid content, including previously described DNA mimic AcrIF2. Four of the acr genes were broad spectrum, also inhibiting I-E or I-F P. aeruginosa CRISPR–Cas subtypes. Dual inhibition comes at a cost, however, as simultaneous expression of Type I-C and I-F systems renders phages expressing the dual inhibitor AcrIF2 more sensitive to targeting. Mutagenesis of numerous acidic residues in AcrIF2 did not impair anti-I-C or anti-I-F function per se but did exacerbate inhibition defects during competition, suggesting that excess negative charge may buffer DNA mimics against competition. Like AcrIF2, five of the Acr proteins block Cascade from binding DNA, while two function downstream, likely preventing Cas3 recruitment or activity. One such inhibitor, AcrIC3, is found in an ‘anti-Cas3’ cluster within conjugative elements, encoded alongside bona fide Cas3 inhibitors AcrIF3 and AcrIE1. Our findings demonstrate an active battle between an MGE-encoded CRISPR–Cas system and its diverse MGE targets.
Impact of Tobacco Smoking on the Risk of COVID-19: A Large Scale Retrospective Cohort Study
Authors: Paleiron Nicolas , Mayet Aurélie , Marbac Vanessa , Perisse Anne , Barazzutti Hélène , Brocq François-Xavier , Janvier Frédéric , Dautzenberg Bertrand , Bylicki Olivier
Published: January 2021

Introduction

Preliminary reports indicated that smokers could be less susceptible to coronavirus SARS-CoV-2, which causes Covid-19. However, once infected an increased risk of severe disease is reported. We investigated the association between smoking and COVID-19 during an outbreak of the disease on a naval vessel.

Methods

We conducted a cross-sectional, observational study on the 1769 sailors of the same navy aircraft carrier at sea exposed at the same time to SARS-CoV2 to investigate the link between tobacco consumption and Covid-19.

Results

Among the 1688 crewmembers (87% men; median age = 28 [interquartile range 23–35]) included, 1279 (76%) developed Covid-19 (1038 [62%] reverse-transcriptase- polymerase chain reaction testing–positive and 241 [14%] with only clinical signs). One hundred and seven patients were hospitalized. The univariable analysis odds ratio (OR) for Covid-19 infection was 0.59 (95% confidence interval [CI], 0.45–0.78; p < .001) for current smokers versus former and nonsmokers; sex, body mass index or blood group had no significant impact. Crewmembers >50 years old had an increased risk of contracting Covid-19 (OR, 2.84 [95% CI, 1.30–7.5]; p = .01). Multivariable analysis retained the lower risk of current smokers becoming infected (OR, 0.64 [0.49–0.84]; p < .001) and age >50 years was significatively associated with Covid-19 (OR, 2.6 [1.17–6.9]; p = .03).

Conclusions

Current smoking status was associated with a lower risk of developing Covid-19 but cannot be considered as efficient protection against infection. The mechanism of the lower susceptibility of smokers to SARS-CoV-2 requires further research.

Trial Registration

IRB no.: 0011873-2020-09

Implications

(1) Recent epidemiologic data suggest a paradoxical link between smoking and COVID-19. (2) Among the 1688 crewmembers (with an attack rate of 76% and exposed at the same time in the same place to SARS-CoV2), we found a significantly lower risk for developing COVID-19 in current smokers (71%) versus former and nonsmokers (80%). This finding strongly supports the need for further research on nicotine physiological pathway and its impact on COVID-19 infection whilst emphasizing that tobacco smoking should not be considered as efficient protection against COVID-19.
Mass mobilization for police accountability: The case of Nigeria’s #EndSARS protest
Authors: Ojedokun Usman A , Ogunleye Yetunde O , Aderinto Adeyinka A
Published: January 2021

Organized public protests against police organization are a rare occurrence in Nigeria. However, between November 2017 and October 2020, a series of online and offline protests organized under the umbrella of #EndSARS campaign was staged against the operation of the Special Anti-Robbery Squad (SARS) unit of the Nigeria Police Force. Thus, this article X-rayed the circumstances that led to the emergence of the #EndSARS protest as a strategic means for seeking police accountability, and the impact of the mass action on policing and law enforcement in Nigeria. Although the #EndSARS protest constitutes a major turning point in the yearnings of Nigerian citizens for police accountability, the campaign has some far-reaching consequences on policing and law enforcement in Nigeria. It is imperative for the Nigeria Police Force to make more efforts towards developing the protest policing skills and approach of its personnel.
Matrix Metalloproteinase 9 Blood Alterations in Patients With Schizophrenia Spectrum Disorders: A Systematic Review and Meta-Analysis
Authors: Schoretsanitis Georgios , de Filippis Renato , Ntogka Maria , Leucht Stefan , Correll Christoph U , Kane John M
Published: January 2021

Background

Matrix metalloproteinase 9 (MMP-9), an extracellular network protease implicated in glutamatergic signaling, may be part of the pathophysiology of schizophrenia spectrum disorders (SSD).

Methods

We performed a systematic review in PubMed/Embase until July 15, 2020, conducting a random-effects meta-analysis of studies comparing MMP-9 blood levels in SSD vs healthy controls (HCs) and psychiatric controls (PCs), calculating between-group differences in standardized mean differences (SMDs) ± 95% confidence intervals (CIs). Meta-regression analyses included sex, age, illness duration, antipsychotic dose, and Positive and Negative Syndrome Scale (PANSS) total/subscales. Subgroup analyses included first-episode patients (FEP) vs non-FEP, each vs HCs and vs PCs, and blood sample type. Study quality was assessed using the Newcastle-Ottawa scale.

Results

Four, five, and two trials were rated as high, fair, and low quality. In 11 studies (n = 1443), 643 patients (age = 36.7 ± 14.1 years, females = 42.9%) were compared with HCs (n = 631), with 4 studies including also 169 PCs. MMP-9 levels were higher in SSD vs HCs (SMD = 0.52, 95%CI = 0.20–0.85, P = .002), but not in PCs vs HCs (n = 132, after removing one implausible outlier [SMD = 0.33, 95%CI = −0.16 to 0.85, P = .082]). MMP-9 differences between SSD and HCs were associated with higher PANSS total (coefficient = 0.02, 95%CI = 0.01–0.02, P < .001), PANSS positive (coefficient = 0.08, 95%CI = 0.02–0.13, P = .006), and PANSS general scores (coefficient = 0.02, 95%CI = 0.01–0.03, P < .001). MMP-9 level differences vs HCs did not vary significantly between FEP (n = 103, SMD = 0.44, 95%CI = 0.15–0.72, P = .71) and non-FEP patients (n = 466, SMD = 0.59, 95%CI = 0.38–0.80; P = .34) (FEP vs non-FEP: P = .39). In four high-quality studies, MMP-9 levels remained significantly higher in SSD vs HCs (SMD = 0.82, 95%CI = 0.03–1.61).

Conclusions

Findings suggest MMP-9 upregulation in SSD, requiring further validation and understanding of related pathways.
Beat-to-beat blood pressure variability: an early predictor of disease and cardiovascular risk
Authors: Bakkar Nour-Mounira Z. , El-Yazbi Ahmed F. , Zouein Fouad A. , Fares Souha A.
Published: January 2021

Blood pressure (BP) varies on the long, short and very-short term. Owing to the hidden physiological and pathological information present in BP time-series, increasing interest has been given to the study of continuous, beat-to-beat BP variability (BPV) using invasive and noninvasive methods. Different linear and nonlinear parameters of variability are employed in the characterization of BP signals in health and disease. Although linear parameters of beat-to-beat BPV are mainly measures of dispersion, such as standard deviation (SD), nonlinear parameters of BPV quantify the degree of complexity/irregularity- using measures of entropy or self-similarity/correlation. In this review, we summarize the value of linear and nonlinear parameters in reflecting different information about the pathophysiology of changes in beat-to-beat BPV independent of or superior to mean BP. We then provide a comparison of the relative power of linear and nonlinear parameters of beat-to-beat BPV in detecting early and subtle differences in various states. The practical advantage and utility of beat-to-beat BPV monitoring support its incorporation into routine clinical practices.
Elevated heart rate and cardiovascular risk in hypertension
Authors: Mancia Giuseppe , Masi Stefano , Palatini Paolo , Tsioufis Costas , Grassi Guido
Published: January 2021

Epidemiological studies have shown that chronically elevated resting heart rate (HR) is significantly associated with organ damage, morbidity and mortality in a wide range of patients including hypertensive patients. Evidence is also available that an increased HR reflects sympathetic nervous system overdrive which is also known to adversely affect organ structure and function and to increase the risk of unfavourable outcomes in several diseases. The causal relationship between elevated HR, organ damage, and cardiovascular outcomes can thus be explained by its relationship with sympathetic cardiovascular influences although evidence of sympathetically-independent adverse effect of HR increases per se makes it more complex. Interventions that target HR by modulating the sympathetic nervous system have therefore a strong pathophysiological and clinical rationale. As most clinical guidelines now recommend the use of combination therapies in patients with hypertension, it might be desirable to consider as combination components drugs which lower HR, if HR is elevated such as, according to guideliines, when it is above 80 b/min.
Mucosal and Histologic Healing in Children With Inflammatory Bowel Disease Treated With Antitumor Necrosis Factor-Alpha
Authors: Scarallo Luca , Alvisi Patrizia , Bolasco Giulia , Di Toma Michele , Lanari Marcello , Cangiari Alice , Paci Monica , Naldini Sara , Renzo Sara , Barp Jacopo , De Masi Salvatore , Lionetti Paolo
Published: January 2021

Objectives:

Mucosal healing (MH) and histological healing (HH) have been recently proposed as a novel treatment target for inflammatory bowel disease (IBD). The aim of the present study was to evaluate real-life achievement of such outcomes in a cohort of pediatric patients with IBD treated with anti-TNF-alpha (ATA) agents.

Methods:

A retrospective analysis was performed on patients affected by IBD who received ATA and were followed up at two referral centers. Incidence and cumulative rates for MH and HH for each group were calculated.

Results:

Of 170 (105 Crohn's disease [CD] and 65 ulcerative colitis [UC]) patients, 78 with CD and 56 with UC underwent endoscopic re-assessment during the study period. MH was achieved by 32 CD (41%) and 30 UC (53.6%) patients; 26 CD (33.3%) and 22 UC (39.3%) patients achieved HH. MH incidence rate was 19.1/1000 and 47/1000 person-months, whereas HH incidence rate was 15.5/1000 and 34.7/1000 person-months for CD and UC, respectively. Remission at the end of induction was associated with higher MH and HH rates (HR: 2.43, P = 0.049 and HR: 2.94, P = 0.046, respectively) in CD. In UC, adalimumab was associated with lower MH and HH rates (HR: 0.16, P = 0.004 and HR: 0.07, P = 0.003).

Conclusions:

We reported a real-life experience arising from a large cohort of pediatric IBD who received ATA scheduled treatment. Less than half of patients with CD and only a little >50% of UC patients achieved MH. Microscopical inflammation was observed in 18.8% CD and 26.7% UC patients who achieved MH. Overall, MH and HH rates appear lower compared to previously published data.
Lunatibacter salilacus gen. nov., sp. nov., a member of the family Cyclobacteriaceae, isolated from a saline and alkaline lake sediment
Authors: Han Ming-Xian , Huang Jian-Rong , Jiang Hong-Chen , Fang Bao-Zhu , Xie Yuan-Guo , Li Wen-Jun
Published: January 2021

A non-motile, Gram-staining negative, catalase- and oxidase-positive, crescent-rod shaped bacterium, designated strain CUG 91308T, was isolated from a sediment sample of Qinghai Lake, Qinghai Province, China. Colonies on OSM agar were round, smooth, flat and pinkish-orange in colour. Strain CUG 91308Tcould grow at 15–37 °C, pH 6–12 and in the presence of up to 7.0 % NaCl (w/v). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain CUG 91308Tbelonged to the familyCyclobacteriaceaeand formed a clade with the genusLunatimonasin the phylogenetic tree, but separated from any species of the known genera within the family. The genomic DNA G+C content is about 42.1 %. The predominant fatty acids (>10 %) were iso-C15 : 0(21.1 %), summed feature 3 (C16 : 1 ω7c / C16 : 1 ω6c / iso-C15 : 02OH) (14.3 %), iso-C17 : 03OH (12.3 %) and summed feature 9 (iso-C17 : 1 ω9c / C16 : 010-methyl) (10.6 %). The polar lipids of strain CUG 91308Twere phosphatidylethanolamine (PE) and four unidentified polar lipids. Strain CUG 91308Tcontained MK-7 as the major respiratory quinone. On the basis of phenotypic, genotypic and phylogenetic data, strain CUG 91308Trepresents a novel species of a novel genus in the familyCyclobacteriaceae, for which the nameLunatibacter salilacusgen. nov., sp. nov. is proposed. The type strain of the proposed new isolate is CUG 91308T(=KCTC 62636T=CGMCC 1.13593T).
Syncope and COVID-19 disease – a systematic review
Authors: de Freitas Raquel Falcão , Torres Sofia Cardoso , L. Nunes José Pedro
Published: January 2021

Background

Syncope is not a common manifestation of COVID-19, but it may occur in this context and it can be the presenting symptom in some cases. Although several mechanisms may explain the pathophysiology behind COVID-19 related syncope, a valid relationship has not been established yet. In this systematic review, we aimed to examine the current incidence of syncope in COVID-19 patients and to explore different patterns observed in this setting.

Methods

A systematic review across PubMed, ISI Web of Knowledge and SCOPUS was performed, according to PRISMA guidelines, in order to identify all relevant articles regarding both COVID-19 and syncope.

Results

We identified 81 publications, of which 62 were excluded. The cumulative incidence of syncope and pre-syncope across the selected studies was 7.1% (256/3584 patients). Unspecified syncope was the most common type (76.2% of the reported episodes), followed by reflex syncope (18.1% of the cases). Orthostatic hypotension was responsible for 3.6% of the cases and syncope of presumable cardiac cause accounted for 2.0%. Arterial hypertension was present in 64.7% of the patients and either angiotensin receptor blockers or angiotensin converting enzyme inhibitors were used by 39.5% of hypertensive patients with syncope.

Conclusion

Syncope, although not considered a typical symptom of the COVID-19 disease, can be associated with it, particularly in early stages. Different types of syncope were seen in this context, each with different implications requiring distinct approaches. A careful reevaluation of blood pressure whenever a patient develops COVID-19 is suggested, including reassessment of antihypertensive therapy.
Outbreak or pseudo-outbreak? Integrating SARS-CoV-2 sequencing to validate infection control practices in an end stage renal disease facility
Authors: Pfaff Bridget L. , Richmond Craig S. , Sabin Arick P. , Athas Deena M. , Adams Jessica C. , Meller Megan E. , Usha Kumari , Schmitz Sarah A. , Simmons Brian J. , Borgert Andrew J. , Kenny Paraic A.
Published: January 2021

Background

The COVID-19 pandemic of 2020 poses a particularly high risk for End Stage Renal Disease (ESRD) patients and led to a need for facility-wide control plans to prevent introduction and spread of infection within ESRD facilities. Rapid identification of clusters of contemporaneous cases is essential, as these may be indicative of within-facility spread. Nevertheless, in a setting of high community COVID-19 prevalence, a series of ESRD patients may test positive at around the same time without their shared ESRD facility being the nexus for disease spread. Here we describe a series of five cases occurring within an eleven-day period in November 2020 in a hospital-based 32-station ESRD facility in southwest Wisconsin, the subsequent facility-wide testing, and the use of genetic sequence analysis of positive specimens to evaluate whether these cases were linked.

Methods

Four patient cases and one staff case were identified in symptomatic individuals by RT-PCR. Facility-wide screening was initiated at the request of local public health and conducted using Abbot BinaxNOW antigen tests. SARS-CoV-2 genome sequences were obtained from residual diagnostic test specimens using an amplicon-based approach on an Ion Torrent S5 sequencer.

Results

Residual specimens from 4 of 5 cases were available for sequence analysis. Each sequence was very clearly genetically distinct from the others, indicating that these contemporaneous cases were not linked. Facility-wide screening of 47 staff and 107 patients did not identify any additional cases.

Conclusions

These data indicate that despite the outward appearance of a case cluster, the facility did not experience within-facility spread nor serve as the epicenter of a new outbreak, suggesting that the enacted rigorous infection control procedures (screening, masking, distancing) practiced stringently by patients and staff were sufficient to permit dialysis to proceed safely in a very high-risk population under pressure from increasing community spread. These data also demonstrate the utility of rapid turnaround SARS-CoV-2 sequencing in outbreak investigations in settings like ESRD facilities.