bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACE-2-like enzymatic activity is associated with immunoglobulin in COVID-19 patients
Authors: Song Yufeng , Myers Regan , Mehl Frances , Murphy Lila , Brooks Bailey , Wilson Jeffrey M. , Kadl Alexandra , Woodfolk Judith , Zeichner Steven L. 
Published: March 2024

ABSTRACT

Many mechanisms responsible for COVID-19 pathogenesis are well-established, but COVID-19 includes features with unclear pathogenesis, such as autonomic dysregulation, coagulopathies, and high levels of inflammation. The receptor for the SARS-CoV-2 spike protein receptor-binding domain (RBD) is angiotensin-converting enzyme 2 (ACE2). We hypothesized that some COVID-19 patients may develop antibodies that have a negative molecular image of RBD sufficiently similar to ACE2 to yield ACE2-like catalytic activity—ACE2-like abzymes. To explore this hypothesis, we studied patients hospitalized with COVID-19 who had plasma samples available obtained about 7 days after admission. ACE2 is a metalloprotease that requires Zn
2+
for activity. However, we found that the plasma from some patients studied could specifically cleave a synthetic ACE2 peptide substrate, even though the plasma samples were collected using disodium EDTA anticoagulant. When we spiked plasma with synthetic ACE2, no ACE2 substrate cleavage activity was observed unless Zn
2+
was added or the plasma was diluted to decrease EDTA concentration. After processing samples by 100 kDa size exclusion columns and protein A/G adsorption, which depleted immunoglobulin by >99.99%, the plasma samples did not cleave the ACE2 substrate peptide. The data suggest that some patients with COVID-19 develop antibodies with abzyme-like activity capable of cleaving synthetic ACE2 substrate. Since abzymes can exhibit promiscuous substrate specificities compared to the enzyme whose active site image they resemble, and since proteolytic cascades regulate many physiologic processes, anti-RBD abzymes may contribute to some otherwise obscure COVID-19 pathogenesis.

IMPORTANCE
We provide what we believe to be the first description of angiotensin-converting enzyme 2 (ACE2)-like enzymatic activity associated with immunoglobulin in COVID-19 patients. COVID-19 includes many puzzling clinical features that have unclear pathogenesis, including a hyperinflammatory state, abnormalities of the clotting cascade, and blood pressure instability. We hypothesized that some patients with COVID-19 patients may produce antibodies against SARS-CoV-2 with enzymatic activity, or abzymes, that target important proteolytic regulatory cascades. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein binds ACE2 on the surface of the future host cell. This means that the RBD has a negative molecular image of ACE2. We hypothesized that some antibodies produced against the RBD would have, in turn, a negative molecular image of the RBD sufficiently similar to ACE2 to have ACE2-like catalytic activity. In other words, some anti-RBD antibodies would be ACE2-like abzymes. Abzymes elicited by SARS-CoV-2 infection have the potential to affect host physiology.
Alternate typhoid toxin assembly evolved independently in the two
Salmonella
species
Authors: Chemello Antonio J. , Fowler Casey C. 
Published: March 2024

ABSTRACT

AB
5
-type toxins are a diverse family of protein toxins composed of an enzymatic active (A) subunit and a pentameric delivery (B) subunit.
Salmonella enterica
serovar Typhi’s typhoid toxin features two A subunits, CdtB and PltA, in complex with the B subunit PltB. Recently, it was shown that
S
. Typhi encodes a horizontally acquired B subunit, PltC, that also assembles with PltA/CdtB to produce a second form of typhoid toxin.
S
. Typhi therefore produces two AB
5
toxins with the same A subunits but distinct B subunits, an evolutionary twist that is unique to typhoid toxin. Here, we show that, remarkably, the
Salmonella bongori
species independently evolved an analogous capacity to produce two typhoid toxins with distinct B subunits.
S. bongori
’s alternate B subunit, PltD, is evolutionarily distant from both PltB and PltC and outcompetes PltB to form the predominant toxin. We show that, surprisingly,
S. bongori
elicits similar levels of CdtB-mediated intoxication as
S
. Typhi during infection of cultured human epithelial cells. This toxicity is exclusively due to the PltB toxin, and strains lacking
pltD
produce increased amounts of PltB toxin and exhibit increased toxicity compared to the wild type, suggesting that the acquisition of the PltD subunit potentially made
S. bongori
less virulent toward humans. Collectively, this study unveils a striking example of convergent evolution that highlights the importance of the poorly understood “two-toxin” paradigm for typhoid toxin biology and, more broadly, illustrates how the flexibility of A-B interactions has fueled the evolutionary diversification and expansion of AB
5
-type toxins.

IMPORTANCE

Typhoid toxin is an important
Salmonella
Typhi virulence factor and an attractive target for therapeutic interventions to combat typhoid fever. The recent discovery of a second version of this toxin has substantial implications for understanding
S
. Typhi pathogenesis and combating typhoid fever. In this study, we discover that a remarkably similar two-toxin paradigm evolved independently in
Salmonella bongori
, which strongly suggests that this is a critical aspect of typhoid toxin biology. We observe significant parallels between how the two toxins assemble and their capacity to intoxicate host cells during infection in
S
. Typhi and
S. bongori
, which provides clues to the biological significance of this unusual toxin arrangement. More broadly, AB5 toxins with diverse activities and mechanisms are essential virulence factors for numerous important bacterial pathogens. This study illustrates the capacity for novel A-B interactions to evolve and thus provides insight into how such a diverse arsenal of toxins might have emerged.
Phylogenetic lineage dynamics of global parainfluenza virus type 3 post-COVID-19 pandemic
Authors: Lee Kihyun , Park Kuenyoul , Sung Heungsup , Kim Mi-Na 
Published: March 2024

ABSTRACT

During the coronavirus disease 2019 (COVID-19) pandemic, outbreaks of parainfluenza virus type 3 (PIV-3) decreased due to infection control measures. However, a post-pandemic resurgence of PIV-3 has recently been observed. Nonetheless, the role of viral genetic epidemiology, possibly influenced by a genetic bottleneck effect, remains unexplored. We investigated the phylogenetic structure of the publicly available PIV-3 whole-genome and hemagglutinin-neuraminidase (HN) gene sequences spanning the last 65 years, including the COVID-19 pandemic. Sequences were retrieved from the nucleotide database of the National Center for Biotechnology Information using the search term “Human respirovirus 3.” Sequence subsets covering all six genes of PIV-3 or the HN gene were designated as the whole-genome and HN surveillance data sets, respectively. Using these data sets, we constructed maximum-likelihood phylogenetic trees and performed a time-scaled analysis using a Bayesian SkyGrid coalescent prior. A total of 455 whole-genome and 1,139 HN gene sequences were extracted, revealing 10 and 11 distinct lineages, respectively, with >98% concurrence in lineage assignments. During the 2020 COVID-19 pandemic, only three single-lineage clusters were identified in Japan, Korea, and the USA. The inferred year of origin for PIV-3 was 1938 (1903–1963) for the whole-genome data set and 1955 (1930–1963) for the HN gene data set. Our study suggests that PIV-3 epidemics in the post-COVID era are likely influenced by a pandemic-driven bottleneck phenomenon and supports previous hypotheses suggesting s that PIV-3 originated during the early half of the 20th century.

IMPORTANCE
Using publicly available parainfluenza virus type 3 (PIV-3) whole-genome sequences, we estimated that PIV-3 originated during the 1930s, consistent with previous hypotheses. Lineage typing and time-scaled phylogenetic analysis revealed that PIV-3 experienced a bottleneck phenomenon in Korea and the USA during the coronavirus disease 2019 pandemic. We identified the conservative hemagglutinin-neuraminidase gene as a viable alternative marker in long-term epidemiological studies of PIV-3 when whole-genome analysis is limited.
Cultivating efficiency: high-throughput growth analysis of anaerobic bacteria in compact microplate readers
Authors: Snoeyenbos-West Oona L. O. , Guerrero Christina R. , Valencia Makaela , Carini Paul 
Published: March 2024

ABSTRACT

Anaerobic microbes play crucial roles in environmental processes, industry, and human health. Traditional methods for monitoring the growth of anaerobes, including plate counts or subsampling broth cultures for optical density measurements, are time and resource-intensive. The advent of microplate readers revolutionized bacterial growth studies by enabling high-throughput and real-time monitoring of microbial growth kinetics. Yet, their use in anaerobic microbiology has remained limited. Here, we present a workflow for using small-footprint microplate readers and the Growthcurver R package to analyze the kinetic growth metrics of anaerobic bacteria. We benchmarked the small-footprint Cerillo Stratus microplate reader against a BioTek Synergy HTX microplate reader in aerobic conditions using
Escherichia coli
DSM 28618 cultures. The growth rates and carrying capacities obtained from the two readers were statistically indistinguishable. However, the area under the logistic curve was significantly higher in cultures monitored by the Stratus reader. We used the Stratus to quantify the growth responses of anaerobically grown
E. coli
and
Clostridium bolteae
DSM 29485 to different doses of the toxin sodium arsenite. The growth of
E. coli
and
C. bolteae
was sensitive to arsenite doses of 1.3 µM and 0.4 µM, respectively. Complete inhibition of growth was achieved at 38 µM arsenite for
C. bolteae
and 338 µM in
E. coli
. These results show that the Stratus performs similarly to a leading brand of microplate reader and can be reliably used in anaerobic conditions. We discuss the advantages of the small format microplate readers and our experiences with the Stratus.

IMPORTANCE
We present a workflow that facilitates the production and analysis of growth curves for anaerobic microbes using small-footprint microplate readers and an R script. This workflow is a cost and space-effective solution to most high-throughput solutions for collecting growth data from anaerobic microbes. This technology can be used for applications where high throughput would advance discovery, including microbial isolation, bioprospecting, co-culturing, host-microbe interactions, and drug/toxin-microbial interactions.
Evaluation and model to achieve sex parity in cataract surgical coverage in Theni district, India
Authors: Gupta Sachin , Ravindran Ravilla D , Vardhan Ashok , Ravilla Thulasiraj D 
Published: March 2024

Background/aims
To propose an approach to determine the target ratio of cataract surgical rates (CSRs) of female to male subpopulations to increase sex parity in cataract surgical coverage (CSC), based on the sex gap in cataract burden and incidence, and demonstrate its application to Theni district, India.

Methods
A population-based longitudinal study between January 2016 and April 2018. We recruited 24 327 participants using random cluster sampling. We conducted detailed eye examinations of 7087 participants aged ≥40 years (4098 females, 2989 males). We fit exponential models to the age-specific and sex-specific cataract burden and estimated annual incidence rates. We developed a spreadsheet-based planning tool to compute the target CSR ratio of female to male subpopulations.

Results
Among those aged ≥40 years, cataract burden was 21.4% for females and 17.5% for males (p<0.05). CSC was 73.9% for females versus 78.6% for males (p<0.05), with an effective CSC of 52.6% for females versus 57.6% for males (p<0.05). Treating only incident cataracts each year requires a target CSR ratio of female to male subpopulations of 1.30, while addressing in addition 10% of the coverage backlog for females and 5% for males requires a target CSR ratio of 1.48.

Conclusions
The female population in Theni district, as in many low-income and middle-income countries, bears a higher cataract burden and lower CSC. To enhance sex parity in coverage, both the higher number of annual incident cataracts and the larger backlog in females will need to be addressed.
Using drones to measure the status of cavity-nesting raptors
Authors: Bird David M. , Petalas Christina , Pace Paul , Elliott Kyle H. 
Published: March 2024

Many wildlife species, including hole-nesting raptors, occupy cavities that are challenging or unsafe for observers to examine. We conducted field tests using an inexpensive, off-the-shelf camera attached to an affordable commercial drone to assess the reproductive success of American kestrels ( Falco sparverius), a small, cavity-nesting raptor. Specifically, we developed a system that consisted of (1) a wireless mini camera transmitting images to an observer’s phone and (2) a Mini-Mavic 2 drone controlled through direct line-of-sight piloting. Following successful preliminary flights involving chicken eggs and other inanimate objects, we field-tested the system in two kestrel nest boxes in the wild. The system accurately recorded the contents of all nest boxes during the trials, provided the wind speed remained below approximately 2.5 m/s (5 knots). However, wind speeds at this level were observed only 40% of the days in our study area during kestrel breeding, which limited the surveying opportunities. Our system offers a promising method for surveying wildlife inhabiting inaccessible cavities.
Cosmology of f(Q) gravity in non-flat Universe
Authors: Shabani Hamid , De Avik , Loo Tee-How , Saridakis Emmanuel N. 
Published: March 2024

AbstractWe investigate the cosmological implications of f(Q) gravity, which is a modified theory of gravity based on non-metricity, in non-flat geometry. We perform a detailed dynamical-system analysis keeping the f(Q) function completely arbitrary. As we show, the cosmological scenario admits a dark-matter dominated point, as well as a dark-energy dominated de Sitter solution which can attract the Universe at late times. However, the main result of the present work is that there are additional critical points which exist solely due to curvature. In particular, we find that there are curvature-dominated accelerating points which are unstable and thus can describe the inflationary epoch. Additionally, there is a point in which the dark-matter and dark-energy density parameters are both between zero and one, and thus it can alleviate the coincidence problem. Finally, there is a saddle point which is completely dominated by curvature. In order to provide a specific example, we apply our general analysis to the power-law case, showing that we can obtain the thermal history of the Universe, in which the curvature density parameter may exhibit a peak at intermediate times. These features, alongside possible indications that non-zero curvature could alleviate the cosmological tensions, may serve as advantages for f(Q) gravity in non-flat geometry.
Xevinapant Combined with Pembrolizumab in Patients with Advanced, Pretreated, Colorectal and Pancreatic Cancer: Results of the Phase Ib/II CATRIPCA Trial
Authors: Voisin Allison , Terret Catherine , Schiffler Camille , Bidaux Anne-Sophie , Vanacker Hélène , Perrin-Niquet Marlène , Barbery Maud , Vinceneux Armelle , Eberst Lauriane , Stéphan Pierre , Garin Gwenaële , Spaggiari Dany , Pérol David , Grinberg-Bleyer Yenkel , Cassier Philippe A. 
Published: March 2024

Abstract

Purpose:
Xevinapant is an orally available inhibitor of apoptosis proteins (IAP) inhibitor. Preclinical data suggest that IAP antagonism may synergize with immune checkpoint blockers by modulating the NFκB pathway in immune cells.

Patients and Methods:
Adult patients with non–high microsatellite instability advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) or colorectal cancer were enrolled in this phase Ib/II study and received pembrolizumab 200 mg every 3 weeks intravenously, and ascending doses of oral xevinapant (100, 150, and 200 mg daily for 14 days on/7 days off). Dose escalation followed a 3+3 design with a 21-day dose-limiting toxicity (DLT) evaluation period. Following the determination of the recommended phase II dose (RP2D), 14 patients with PDAC and 14 patients with colorectal cancer were enrolled in expansion cohorts to assess preliminary efficacy.

Results:
Forty-one patients (26 males) with a median age of 64 years were enrolled: 13 in the dose escalation and 28 in the two expansion cohorts. No DLT was observed during dose escalation. The RP2D was identified as xevinapant 200 mg/day + pembrolizumab 200 mg every 3 weeks. The most common adverse events (AE) were fatigue (37%), gastrointestinal AE (decreased appetite in 37%, nausea in 24%, stomatitis in 12%, and diarrhea and vomiting in 10% each), and cutaneous AE (pruritus, dry skin, and rash seen in 20%, 15%, and 15% of patients, respectively). The best overall response according to RECIST1.1 was partial response (confirmed) in 1 (3%), stable disease in 4 (10%), and progressive disease in 35 (88%).

Conclusions:
Xevinapant combined with pembrolizumab was well tolerated with no unexpected AEs. However, antitumor activity was low.
Diagnostic Performance of Angiography-Derived Quantitative Flow Ratio in Complex Coronary Lesions
Authors: Wu Xianpeng , Wang Kan , Li Guohua , Wu Jie , Jiang Jun , Gao Feng , Zhu Lingjun , Xu Qiyuan , Wang Xinhong , Xu Mengxi , Chen Hui , Ma Longhui , Han Xianjun , Luo Nan , Tu Shengxian , Wang Jian’an , Hu Xinyang 
Published: March 2024

BACKGROUND:
Quantitative flow ratio derived from computed tomography angiography (CT-QFR) and invasive coronary angiography (Murray law–based quantitative flow ratio [μQFR]) are novel approaches enabling rapid computation of fractional flow reserve without the use of pressure guidewires and vasodilators. However, the feasibility and diagnostic performance of both CT-QFR and μQFR in evaluating complex coronary lesions remain unclear.

METHODS:
Between September 2014 and September 2021, 240 patients with 30% to 90% coronary diameter stenosis who underwent both coronary computed tomography angiography and invasive coronary angiography with fractional flow reserve within 60 days were retrospectively enrolled. The diagnostic performance of CT-QFR and μQFR in detecting functional ischemia among all lesions, especially complex coronary lesions, was analyzed using fractional flow reserve as the reference standard.

RESULTS:
CT-QFR and μQFR analyses were performed on 309 and 289 vessels, respectively. The diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for CT-QFR in all lesions at the per-vessel level were 91% (with a 95% CI of 84%–96%), 92% (95% CI, 88%–95%), 83% (95% CI, 75%–90%), 96% (95% CI, 93%–98%), and 92% (95% CI, 88%–95%), with values for μQFR of 90% (95% CI, 81%–95%), 97% (95% CI, 93%–99%), 92% (95% CI, 84%–97%), 96% (95% CI, 92%–98%), and 94% (95% CI, 91%–97%), respectively. Among bifurcation, tandem, and moderate-to-severe calcified lesions, the diagnostic values of CT-QFR and μQFR showed great correlation and agreement with those of invasive fractional flow reserve, achieving an area under the receiver operating characteristic curve exceeding 0.9 for each complex lesion at the vessel level. Furthermore, the accuracies of CT-QFR and μQFR in the gray zone were 85% and 84%, respectively.

CONCLUSIONS:
Angiography-derived quantitative flow ratio (CT-QFR and μQFR) demonstrated remarkable diagnostic performance in complex coronary lesions, indicating its pivotal role in the management of patients with coronary artery disease.
Cardiac Magnetic Resonance to Predict Cardiac Mass Malignancy: The CMR Mass Score
Authors: Paolisso Pasquale , Bergamaschi Luca , Angeli Francesco , Belmonte Marta , Foà Alberto , Canton Lisa , Fedele Damiano , Armillotta Matteo , Sansonetti Angelo , Bodega Francesca , Amicone Sara , Suma Nicole , Gallinoro Emanuele , Attinà Domenico , Niro Fabio , Rucci Paola , Gherbesi Elisa , Carugo Stefano , Mushtaq Saima , Baggiano Andrea , Pavon Anna Giulia , Guglielmo Marco , Conte Edoardo , Andreini Daniele , Pontone Gianluca , Lovato Luigi , Pizzi Carmine 
Published: March 2024

BACKGROUND:
Multimodality imaging is currently suggested for the noninvasive diagnosis of cardiac masses. The identification of cardiac masses’ malignant nature is essential to guide proper treatment. We aimed to develop a cardiac magnetic resonance (CMR)-derived model including mass localization, morphology, and tissue characterization to predict malignancy (with histology as gold standard), to compare its accuracy versus the diagnostic echocardiographic mass score, and to evaluate its prognostic ability.

METHODS:
Observational cohort study of 167 consecutive patients undergoing comprehensive echocardiogram and CMR within 1-month time interval for suspected cardiac mass. A definitive diagnosis was achieved by histological examination or, in the case of cardiac thrombi, by histology or radiological resolution after adequate anticoagulation treatment. Logistic regression was performed to assess CMR-derived independent predictors of malignancy, which were included in a predictive model to derive the CMR mass score. Kaplan-Meier curves and Cox regression were used to investigate the prognostic ability of predictors.

RESULTS:

In CMR, mass morphological features (non-left localization, sessile, polylobate, inhomogeneity, infiltration, and pericardial effusion) and mass tissue characterization features (first-pass perfusion and heterogeneity enhancement) were independent predictors of malignancy. The CMR mass score (range, 0–8 and cutoff, ≥5), including sessile appearance, polylobate shape, infiltration, pericardial effusion, first-pass contrast perfusion, and heterogeneity enhancement, showed excellent accuracy in predicting malignancy (areas under the curve, 0.976 [95% CI, 0.96–0.99]), significantly higher than diagnostic echocardiographic mass score (areas under the curve, 0.932;
P
=0.040). The agreement between the diagnostic echocardiographic mass and CMR mass scores was good (κ=0.66). A CMR mass score of ≥5 predicted a higher risk of all-cause death (
P
<0.001; hazard ratio, 5.70) at follow-up.

CONCLUSIONS:
A CMR-derived model, including mass morphology and tissue characterization, showed excellent accuracy, superior to echocardiography, in predicting cardiac masses malignancy, with prognostic implications.