bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety of endoscopic ultrasound-guided tissue acquisition with uninterrupted direct oral anticoagulation in a swine model
Authors: Garcia Garcia de Paredes Ana , Hartley Christopher , Hernandez-Lara Ariosto H. , AbiMansour Jad P. , Valls Eric J. Vargas , Pruthi Rajiv K. , Graham Rondell P. , Storm Andrew C. , Gleeson Ferga C. , Levy Michael J. , Rajan Elizabeth
Published: January 2023

Background and study aims The risk of bleeding with endoscopic ultrasound-guided tissue acquisition (EUS-TA) in patients on uninterrupted antithrombotic agents is unknown. This study aimed to assess the safety of EUS-TA without discontinuing direct oral anticoagulants.

Methods Twenty pigs were randomized (1:1) to oral apixaban or placebo. Treatment was administered for 3 days before and 3 days after EUS-TA of the pancreas. Primary endpoint was occurrence of clinically significant bleeding events (CSBEs), defined as a composite outcome of drop in hemoglobin ≥ 2 g/dL and evidence of intraprocedural or post-procedure bleeding. Secondary outcome was cytopathological adequacy of acquired specimens. Endoscopists and pathologists were blinded to the treatment arm.

Results Total of 80 tissue samples were obtained. CSBE occurred in one animal with apixaban levels above the upper limit (P = 1). Intraprocedural bleeding occurred in five animals (25 %), four of which from the apixaban group. Hematoma at necropsy was found in 10 animals (50 %), six of which were on apixaban. Median drop in hemoglobin was similar in both groups. Adequacy of specimens for cytology and pathology evaluation was confirmed in 20 of 20 and 19 of 20 animals, respectively.

Conclusions In this pilot preclinical trial, EUS-TA under apixaban showed a trend toward higher minor bleeding events but did not increase CSBE or prevent adequate cytopathological evaluation.
Evaluating impacts of syntenic block detection strategies on rearrangement phylogeny usingMycobacterium tuberculosisisolates
Authors: Elghraoui Afif , Mirarab Siavash , Swenson Krister M , Valafar Faramarz
Published: January 2023

Motivation

The phylogenetic signal of structural variation informs a more comprehensive understanding of evolution. As (near-)complete genome assembly becomes more commonplace, the next methodological challenge for inferring genome rearrangement trees is the identification of syntenic blocks of orthologous sequences. In this article, we studied 94 reference quality genomes of primarily Mycobacterium tuberculosis (Mtb) isolates as a benchmark to evaluate these methods. The clonal nature of Mtb evolution, the manageable genome sizes, along with substantial levels of structural variation make this an ideal benchmarking dataset.

Results

We tested several methods for detecting homology and obtaining syntenic blocks and two methods for inferring phylogenies from them, then compared the resulting trees to the standard method’s tree, inferred from nucleotide substitutions. We found that, not only the choice of methods, but also their parameters can impact results, and that the tree inference method had less impact than the block determination method. Interestingly, a rearrangement tree based on blocks from the Cactus whole-genome aligner was fully compatible with the highly supported branches of the substitution-based tree, enabling the combination of the two into a high-resolution supertree. Overall, our results indicate that accurate trees can be inferred using genome rearrangements, but the choice of the methods for inferring homology requires care.

Availability and implementation

Analysis scripts and code written for this study are available at https://gitlab.com/LPCDRP/rearrangement-homology.pub and https://gitlab.com/LPCDRP/syntement.

Supplementary information

Supplementary data are available at Bioinformatics online.
3D-equivariant graph neural networks for protein model quality assessment
Authors: Chen Chen , Chen Xiao , Morehead Alex , Wu Tianqi , Cheng Jianlin
Published: January 2023

Motivation

Quality assessment (QA) of predicted protein tertiary structure models plays an important role in ranking and using them. With the recent development of deep learning end-to-end protein structure prediction techniques for generating highly confident tertiary structures for most proteins, it is important to explore corresponding QA strategies to evaluate and select the structural models predicted by them since these models have better quality and different properties than the models predicted by traditional tertiary structure prediction methods.

Results

We develop EnQA, a novel graph-based 3D-equivariant neural network method that is equivariant to rotation and translation of 3D objects to estimate the accuracy of protein structural models by leveraging the structural features acquired from the state-of-the-art tertiary structure prediction method—AlphaFold2. We train and test the method on both traditional model datasets (e.g. the datasets of the Critical Assessment of Techniques for Protein Structure Prediction) and a new dataset of high-quality structural models predicted only by AlphaFold2 for the proteins whose experimental structures were released recently. Our approach achieves state-of-the-art performance on protein structural models predicted by both traditional protein structure prediction methods and the latest end-to-end deep learning method—AlphaFold2. It performs even better than the model QA scores provided by AlphaFold2 itself. The results illustrate that the 3D-equivariant graph neural network is a promising approach to the evaluation of protein structural models. Integrating AlphaFold2 features with other complementary sequence and structural features is important for improving protein model QA.

Availability and implementation

The source code is available at https://github.com/BioinfoMachineLearning/EnQA.

Supplementary information

Supplementary data are available at Bioinformatics online.
Associations of mayfly larvae with Corbicula clams
Authors: Bespalaya Yulia V , Palatov Dmitry M , Gofarov Mikhail Yu , Kondakov Alexander V , Kropotin Alexander V , Sousa Ronaldo , Taskinen Jouni , Inkhavilay Khamla , Tanmuangpak Kitti , Tumpeesuwan Sakboworn , Vikhrev Ilya V , Bolotov Ivan N
Published: January 2023

Currently, the parasitic and endosymbiontic fauna of Corbicula clams remain poorly studied throughout their range. Here, using samples from the Mekong basin, we describe two Symbiocloeon species new to science: Symbiocloeon corbiculinus sp. nov. and Symbiocloeon laoensis sp. nov. Our results and a review of available published data indicate that freshwater bivalve-associated mayflies are narrow host specialists, being associated with one or a few closely related species of freshwater bivalves. The bivalve-associated mayfly larvae have several specific morphological traits compared with free-living species, which include a reduction of integument chitinization and a significant reduction of the surface structures on segments. An increase in area of the respiratory surface of larval tergalia was also recorded. The possible positive and negative effects of mayflies on the clam hosts are discussed. This study is an example of the many possible hidden associations between aquatic species that remain to be described.
Big technology and data privacy
Authors: Conyon Martin J
Published: January 2023

This paper discusses big technology and data privacy. First, we show the rapid rise in technology firms since the millennium. Using Facebook as a case study (the most popular social network in 2022), we show its reliance on personally identifiable data collection and advertising. Second, we investigate the Cambridge Analytica data breach. We show that stock prices fall in response to the data breach using event study methods. Cumulative abnormal returns decline by about 9.8% in the event window. Third, we discuss policy options in response to data privacy concerns. The GDPR provides a legislative model for protecting individually identifiable data.
Left atrial reservoir strain as a novel predictor of new-onset atrial fibrillation in light-chain-type cardiac amyloidosis
Authors: Choi You-Jung , Kim Darae , Rhee Tea-Min , Lee Hyun-Jung , Park Jun-Bean , Lee Seung-Pyo , Chang Sung-A , Kim Yong-Jin , Jeon Eun-Seok , Oh Jae K , Choi Jin-Oh , Kim Hyung-Kwan
Published: January 2023

Aims

To investigate whether left arterial reservoir strain (LASr) could predict new-onset atrial fibrillation (NOAF) in patients with light-chain-type cardiac amyloidosis (ALCA).

Methods and results

This study enrolled 427 patients with CA from two tertiary centres between 2005 and 2019. LASr was measured using a vendor-independent analysis programme. The primary outcome was NOAF. A total of 287 patients with ALCA were included [median age 63.0 (56.0–70.0) years, 53.3% male]. The median LASr was 13.9% (10.5–20.8%). During the median follow-up of 0.85 years, AF occurred in 34 patients (11.8%). In the receiver operating characteristics curve analysis, the optimal cut-off of LASr for predicting NOAF was 14.4%. Patients with LASr ≤14.4% had a higher risk of NOAF than those with LASr >14.4% (18.1% vs. 5.1%, P < 0.010). In the multivariate analysis adjusting for confounding factors, including left arterial volume index and left ventricular global longitudinal strain (LV-GLS), higher LASr (%) was independently associated with lower risk for NOAF [adjusted hazard ratio (aHR): 0.936, 95% confidence interval (95% CI): 0.879–0.997, P = 0.039]. Furthermore, LASr ≤14.4% was an independent predictor for NOAF (aHR: 3.370, 95% CI: 1.337–8.492, P = 0.010). This remained true after accounting for all-cause death as a competing risk. Compared with Model 1 (LV-GLS) and Model 2 (LV-GLS plus LAVI), Model 3, including LASr showed a better reclassification ability for predicting NOAF (net reclassification index = 0.735, P < 0.001 compared with Model 1; net reclassification index = 0.514, P = 0.003 compared with Model 2).

Conclusion

LASr was an independent predictor of NOAF in patients with ALCA.
Case report of hidden (yet visible) systolic fascicular potentials in a patient with left bundle branch block during conduction system pacing implantation
Authors: Kaddour Myriam , Kozhuharov Nikola , Burri Haran
Published: January 2023

Background

Left bundle branch pacing (LBBP) is being increasingly adopted as a more physiological alternative to conventional pacing. At implantation, appropriate lead depth can be guided by monitoring a number of parameters, including the presence of a fascicular potential during conducted rhythm. However, in patients with left bundle branch block (LBBB), a presystolic fascicular potential is most often absent, due to upstream conduction block. We present for the first time a case where delayed fascicular potentials were visible within the ventricular electrogram (EGM) of the pacing lead.

Case summary

An 88-year-old patient with decompensated heart failure of ischaemic origin with a left ventricular ejection fraction of 0.30 and LBBB with a QRS of 180 ms was scheduled for LBBP pacemaker implantation. A pacing lead was screwed deep into the interventricular septum in the left bundle branch area. Upon close inspection, fascicular potentials within the ventricular EGM were visible during cycles with LBBB. A presystolic fascicular potential was visible during cycles with a narrow QRS following blocked atrial premature beats with a pause. Threshold testing revealed transition from non-selective to selective LBBP, confirming conduction system capture.

Discussion

The present case illustrates that fascicular potentials, which are most probably retrograde (or alternatively anterograde with very slow conduction), may be visualized within the ventricular EGM during LBBP implantation in patients with LBBB. Implanting physicians should scrutinize the EGM for these potentials, as they provide valuable information that adequate lead depth has been reached. The prevalence of these findings needs to be further evaluated.
Antithrombotic therapy and cardiovascular outcomes after transcatheter aortic valve implantation in patients without indications for chronic oral anticoagulation: a systematic review and network meta-analysis of randomized controlled trials
Authors: Guedeney Paul , Roule Vincent , Mesnier Jules , Chapelle Celine , Portal Jean-Jacques , Laporte Silvy , Ollier Edouard , Zeitouni Michel , Kerneis Mathieu , Procopi Niki , Barthelemy Olivier , Sorrentino Sabato , Mihalovic Michal , Silvain Johanne , Vicaut Eric , Montalescot Gilles , Collet Jean-Philippe
Published: January 2023

Aims

As the antithrombotic regimen that may best prevent ischaemic complications along with the lowest bleeding risk offset following transcatheter aortic valve implantation (TAVI) remains unclear, we aimed to compare the safety and efficacy of antithrombotic regimens in patients without having an indication for chronic oral anticoagulation.

Methods and results

We conducted a PROSPERO-registered (CRD42021247924) systematic review and network meta-analysis of randomized controlled trials evaluating post-TAVI antithrombotic regimens up to April 2022. We estimated the relative risk (RR) and 95% confidence intervals (95% CIs) using a random-effects model in a frequentist pairwise and network metanalytic approach. We included seven studies comprising 4006 patients with a mean weighted follow-up of 12.9 months. Risk of all-cause death was significantly reduced with dual antiplatelet therapy (DAPT) compared with low-dose rivaroxaban + 3-month single antiplatelet therapy (SAPT) (RR 0.60, 95% CI 0.41–0.88), while no significant reduction was observed with SAPT vs. DAPT (RR 1.02, 95% CI 0.67–1.58) and SAPT and DAPT compared with apixaban or edoxaban (RR 0.60, 95% CI 0.32–1.14 and RR 0.59, 95% CI 0.34–1.02, respectively). SAPT was associated with a significant reduction of life-threatening, disabling, or major bleeding compared with DAPT (RR 0.45, 95% CI 0.29–0.70), apixaban or edoxaban alone (RR 0.45, 95% CI 0.25–0.79), and low-dose rivaroxaban + 3-month SAPT (RR 0.30, 95% CI 0.16–0.57). There were no differences between the various regimens with respect to myocardial infarction, stroke, or systemic embolism.

Conclusion

Following TAVI in patients without an indication for chronic oral anticoagulant, SAPT more than halved the risk of bleeding compared with DAPT and direct oral anticoagulant-based regimens without significant ischaemic offset.
Cardiovascular, renal, and lower limb outcomes in patients with type 2 diabetes after percutaneous coronary intervention and treated with sodium–glucose cotransporter 2 inhibitors vs. dipeptidyl peptidase-4 inhibitors
Authors: Lee Hsin-Fu , Chan Yi-Hsin , Chuang Chi , Li Pei-Ru , Yeh Yung-Hsin , Hsiao Fu-Chih , Peng Jian-Rong , See Lai-Chu
Published: January 2023

Aims

Patients with type 2 diabetes (T2D) who undergo percutaneous coronary intervention (PCI) are at higher risk of adverse cardiovascular and renal events than non-diabetic patients. However, limited evidence is available regarding the cardiovascular, renal, and limb outcomes of patients with T2D after PCI and who were treated with sodium–glucose cotransporter-2 inhibitors (SGLT2i). We compare the specified outcomes in patients with T2D after PCI who were treated with SGLT2i vs. dipeptidyl peptidase-4 inhibitors (DPP4i).

Methods and results

In this nationwide retrospective cohort study, we identified 4248 and 37 037 consecutive patients with T2D who underwent PCI with SGLT2i and DPP4i, respectively, for 1 May 2016–31 December 2019. We used propensity score matching (PSM) to balance the covariates between study groups. After PSM, SGLT2i, and DPP4i were associated with comparable risks of ischaemic stroke, acute myocardial infarction, and lower limb amputation. However, SGLT2i was associated with significantly lower risks of heart failure hospitalization [HFH; 1.35% per year vs. 2.28% per year; hazard ratio (HR): 0.60; P = 0.0001], coronary revascularization (2.33% per year vs. 3.36% per year; HR: 0.69; P = 0.0003), composite renal outcomes (0.10% per year vs. 1.05% per year; HR: 0.17; P < 0.0001), and all-cause mortality (2.27% per year vs. 3.80% per year, HR: 0.60; P < 0.0001) than were DPP4i.

Conclusion

Our data indicated that SGLT2i, compared with DPP4i, were associated with lower risks of HFH, coronary revascularization, composite renal outcomes, and all-cause mortality for patients with T2D after PCI. Further randomized or prospective studies can investigate the effects of SGLT2i in patients with T2D after PCI.
A high-quality chromosome-level genome assembly of rohu carp, Labeo rohita, and its utilization in SNP-based exploration of gene flow and sex determination
Authors: Arick Mark A , Grover Corrinne E , Hsu Chuan-Yu , Magbanua Zenaida , Pechanova Olga , Miller Emma R , Thrash Adam , Youngblood Ramey C , Ezzell Lauren , Alam Md Samsul , Benzie John A H , Hamilton Matthew G , Karsi Attila , Lawrence Mark L , Peterson Daniel G
Published: January 2023

Labeo rohita (rohu) is a carp important to aquaculture in South Asia, with a production volume close to Atlantic salmon. While genetic improvements to rohu are ongoing, the genomic methods commonly used in other aquaculture improvement programs have historically been precluded in rohu, partially due to the lack of a high-quality reference genome. Here we present a high-quality de novo genome produced using a combination of next-generation sequencing technologies, resulting in a 946 Mb genome consisting of 25 chromosomes and 2,844 unplaced scaffolds. Notably, while approximately half the size of the existing genome sequence, our genome represents 97.9% of the genome size newly estimated here using flow cytometry. Sequencing from 120 individuals was used in conjunction with this genome to predict the population structure, diversity, and divergence in three major rivers (Jamuna, Padma, and Halda), in addition to infer a likely sex determination mechism in rohu. These results demonstrate the utility of the new rohu genome in modernizing some aspects of rohu genetic improvement programs.
Joint estimation ofS-wave velocity and damping ratio of the near-surface from active Rayleigh wave surveys processed with a wavefield decomposition approach
Authors: Bergamo Paolo , Maranò Stefano , Fäh Donat
Published: January 2023

The use of surface wave measurements to derive an S-wave velocity profile of the subsurface has become a widely applied procedure; however, their potential use to reconstruct the S-wave material damping properties of the subsoil is generally overlooked, due to the difficulties in obtaining consistent surface wave amplitude information from field data and translating them into robust estimates of the dissipative properties of the near-surface. In this work, we adapt a wavefield decomposition technique for the processing of elastic surface wave data to the extraction of the complete set of properties of Rayleigh waves generated by a controlled source and propagating in dissipative geomaterials. Retrieved information includes multimodal phase velocity and ellipticity as well as the frequency-dependent attenuation coefficient. We exploit the key advantages of wavefield decomposition processing (joint interpretation of multicomponent recordings, coupled estimation of wave propagation parameters, modelling of multiple superimposing modes) to maximize the robustness of the retrieval of Rayleigh wave properties, especially of the dissipative ones. For the subsequent interpretation of Rayleigh wave dispersion, ellipticity and attenuation data we implement a joint Monte Carlo inversion yielding a coupled estimate of S-wave velocity and damping ratio profile for the subsurface; we incorporate a series of geophysical constraints to narrow down the searched parameter space to realistic soil models. We apply this processing and inversion scheme to a bespoke synthetic data set and to a field survey for the characterization of a strong motion station; in both cases, we succeed in retrieving Rayleigh wave multimodal dispersion, ellipticity and attenuation curves. From the inversion of data from the simulated seismogram we are able to reconstruct the properties of the synthetic model. As for the real case, we determine an S-wave velocity and damping ratio model for the soil column below the station, through which we are able to model the inelastic earthquake local response observed at the site. Basing on the results obtained for the real case, we argue that one of the advantages brought by our processing method—the possibility to process active Rayleigh wave data acquired by a 2-D array illuminated by different source positions—may play a key role in allowing to retrieve dissipative properties of the near-surface closer to the material damping of the soil materials, and less influenced by scattering determined by possible discontinuities in the subsurface.
The Trinidad and Tobago microzonation project: San Fernando
Authors: Papadopoulos Ilias , Manzano Jevan , Reddock Kafele , Latchman Joan L
Published: January 2023

The city of San Fernando is the industrial capital of the twin island nation of Trinidad and Tobago in the West Indies. Situated at the west coast, is in close proximity with the Central Range Fault, a major fault crossing the whole island and continuing offshore. Due to this proximity, but also because of the complex tectonics in the area with deep and shallow earthquakes, a detailed seismic hazard map deemed important. A microzonation study was carried throughout the boundaries of the city, using ambient noise techniques. 1200 single-site records of ambient noise, along with 16 microtremor array measurements were obtained. The results indicate that the alluvium deposits in the river basins along with a small part of reclaimed land appear to have velocities in the range 220–500 m s–1 and thickness from shallow to about 60 m. The marls, which cover the majority of the study area, exhibit shear wave velocities in the range of 700–1600 m s–1, depending on the level of compaction, with thickness that can reach almost 100 m. The hardest formations, Naparima Hill and San Fernando formations, in weathered state they appear with velocities above 1000 m s–1, while their unweathered state reaches 3000 m s–1. A parametric investigation which was conducted as an independent investigation to validate the experimental results, is in good agreement. An empirical susceptibility method to calculate the most vulnerable areas, reveals that areas close to coast and the river banks might experience much higher shaking values.
N-glycosylation on Asn-57 is required for the correct HAI-2 protein folding and protease inhibitory activity
Authors: Huang Nanxi , Wang Qiaochu , Chen Chao-Yang , Hu Je-Ming , Wang Jehng-Kang , Chang Ping-Ying , Johnson Michael D , Lin Chen-Yong
Published: January 2023

Hepatocyte growth factor activator inhibitor (HAI)-2 is an integral membrane Kunitz-type serine protease inhibitor that regulates the proteolysis of matriptase and prostasin in a cell-type selective manner. The cell-type selective nature of HAI-2 function depends largely on whether the inhibitor and potential target enzymes are targeted to locations in close proximity. The N-glycan moiety of HAI-2 can function as a subcellular targeting signal. HAI-2 is synthesized with 1 of 2 different N-glycan modifications: one of oligomannose-type, which largely remains in the endoplasmic reticulum/GA, and another of complex-type, which is targeted toward the apical surface in vesicle-like structures, and could function as an inhibitor of matriptase and prostasin. HAI-2 contains 2 putative N-glycosylation sites, Asn-57 and Asn-94, point mutations of which were generated and characterized in this study. The protein expression profile of the HAI-2 mutants indicates that Asn-57, and not Asn-94, is responsible for the N-glycosylation of both HAI-2 species, suggesting that the form with oligomannose-type N-glycan is the precursor of the form with complex-type N-glycan. Unexpectedly, the vast majority of non-glycosylated HAI-2 is synthesized into multiple disulfide-linked oligomers, which lack protease inhibitory function, likely due to distorted conformations caused by the disarrayed disulfide linkages. Although forced expression of HAI-2 in HAI-2 knockout cells artificially enhances HAI-2 oligomerization, disulfide-linked HAI-2 oligomers can also be observed in unmodified cells. These results suggest that N-glycosylation on Asn-57 is required for folding into a functional HAI-2 with full protease suppressive activity and correct subcellular targeting signal.
Methylenetetrahydrofolate reductase deficiency and high-dose FA supplementation disrupt embryonic development of energy balance and metabolic homeostasis in zebrafish
Authors: Simonian Rebecca , Pannia Emanuela , Hammoud Rola , Noche Ramil R , Cui Xiucheng , Kranenburg Eva , Kubant Ruslan , Ashcraft Paula , Wasek Brandi , Bottiglieri Teodoro , Dowling James J , Anderson G Harvey
Published: January 2023

Folic acid (synthetic folate, FA) is consumed in excess in North America and may interact with common pathogenic variants in methylenetetrahydrofolate reductase (MTHFR); the most prevalent inborn error of folate metabolism with wide-ranging obesity-related comorbidities. While preclinical murine models have been valuable to inform on diet–gene interactions, a recent Folate Expert panel has encouraged validation of new animal models. In this study, we characterized a novel zebrafish model of mthfr deficiency and evaluated the effects of genetic loss of mthfr function and FA supplementation during embryonic development on energy homeostasis and metabolism. mthfr-deficient zebrafish were generated using CRISPR mutagenesis and supplemented with no FA (control, 0FA) or 100 μm FA (100FA) throughout embryonic development (0–5 days postfertilization). We show that the genetic loss of mthfr function in zebrafish recapitulates key biochemical hallmarks reported in MTHFR deficiency in humans and leads to greater lipid accumulation and aberrant cholesterol metabolism as reported in the Mthfr murine model. In mthfr-deficient zebrafish, energy homeostasis was also impaired as indicated by altered food intake, reduced metabolic rate and lower expression of central energy-regulatory genes. Microglia abundance, involved in healthy neuronal development, was also reduced. FA supplementation to control zebrafish mimicked many of the adverse effects of mthfr deficiency, some of which were also exacerbated in mthfr-deficient zebrafish. Together, these findings support the translatability of the mthfr-deficient zebrafish as a preclinical model in folate research.
Identification of potential causal metabolites associated with atopic dermatitis
Authors: Jia Yiming , Wang Rong , Sun Lulu , Guo Daoxia , Shi Mengyao , Zhang Kaixin , Yang Pinni , Wang Yu , Liu Fanghua , Chen Guo-Chong , Zhang Yonghong , Zhu Zhengbao
Published: January 2023

Atopic dermatitis is a chronically recurrent dermatologic disease affected by complex pathophysiology with limited therapeutic options. To identify promising biomarkers for atopic dermatitis, we conducted a Mendelian randomization (MR) study to systematically screen blood metabolome for potential causal mediators of atopic dermatitis and further predict target-mediated side effects. We selected 128 unique blood metabolites from three European-descent metabolome genome-wide association studies (GWASs) with a total of 147 827 participants. Atopic dermatitis dataset originated from a large-scale GWAS including 10 788 cases and 30 047 controls of European ancestry. MR analyses were performed to estimate the associations of blood metabolites with atopic dermatitis. We then applied a phenome-wide MR analysis to ascertain potential on-target side effects of metabolite intervention. Three metabolites were identified as potential causal mediators for atopic dermatitis, including docosahexaenoic acid (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.81–0.94; P = 3.45 × 10−4), arachidonate (OR, 0.30; 95% CI, 0.17–0.53; P = 4.09 × 10−5) and 1-arachidonoylglycerophosphoethanolamine (1-arachidonoyl-GPE) (OR, 0.25; 95% CI, 0.12–0.53; P = 2.58 × 10−4). In the phenome-wide MR analysis, docosahexaenoic acid and arachidonate were also identified to have beneficial or detrimental effects on multiple diseases beyond atopic dermatitis, respectively. No adverse side effects were found for 1-arachidonoyl-GPE. In this systematic MR study, docosahexaenoic acid, arachidonate and 1-arachidonoyl-GPE were identified as potential causal and beneficial mediators in the development of atopic dermatitis. Side-effect profiles were characterized to help inform drug target prioritization, and 1-arachidonoyl-GPE was a promising target for prevention and treatment of atopic dermatitis with no predicted adverse side effects.
Tracking integrated ecosystem assessments in the ICES network: a social network analysis of the ICES expert groups
Authors: Fuller Jessica L , Strehlow Harry V , Schmidt Jörn O , Bodin Örjan , Dankel Dorothy J
Published: January 2023

The advice the International Council for the Exploration of the Sea (ICES) provides to its member countries is crucial for the sustainable management of shared marine resources, and the conservation of relevant marine ecosystems. In 2014, ICES made a strategic decision to integrate marine and social sciences in a new type of assessment framework called “integrated ecosystem assessments” (IEA) to deliver advice on societal trade-offs between different policy options. The IEA-focused expert groups formed before and after this period now cover all major ecoregions. To track the progression of IEAs in the ICES network over time, we conducted a social network analysis (SNA) on expert group attendance for the years 2015–2019. The IEA-focused expert groups generally ranked lower in the overall ICES network. Our study shows that some IEA-groups become more connected over time, while others decline. We also evaluated the role of workshops in the ICES network, particularly their role in the development of IEA knowledge. Our study shows that workshops play an important role in ICES network connectivity. The study demonstrates how social network analysis can be used to study an organization such as ICES and determine the effectiveness, or impact, of that organizational function.
Names from Nowhere? Fictitious Country Names in Survey Vignettes Affect Experimental Results
Authors: Majnemer Jacklyn , Meibauer Gustav
Published: January 2023

Using fictitious country names in hypothetical scenarios is widespread in experimental international relations research. We survey sixty-four peer-reviewed articles to find that it is justified by reference to necessary “neutralization” compared to real-world scenarios. However, this neutralization effect has not been independently tested. Indeed, psychology and toponymy scholarship suggest that names entail implicit cues that can inadvertently bias survey results. We use a survey experiment to test neutralization and naming effects. We find not only limited evidence for neutralization, but also little evidence for systematic naming effects. Instead, we find that respondents were often more willing to support using force against fictitious countries than even adversarial real-world countries. Real-world associations may provide a “deterrent” effect not captured by hypothetical scenarios with fictitious country names. In turn, fictionalization may decrease the stakes as experienced by respondents. Researchers should therefore carefully explain rationales for and expected effects of fictitious country names, and test their fictitious names independently.
In vivopharmacokinetic/pharmacodynamic evaluation of cefepime/taniborbactam combination against cefepime-non-susceptible Enterobacterales andPseudomonas aeruginosain a murine pneumonia model
Authors: Abdelraouf Kamilia , Nicolau David P
Published: January 2023

Background

Cefepime/taniborbactam is a cephalosporin/bicyclic boronate β-lactamase inhibitor combination in clinical development for nosocomial pneumonia due to MDR Gram-negative bacteria. A murine pneumonia model was used to characterize cefepime/taniborbactam in vivo pharmacodynamics against Enterobacterales and Pseudomonas aeruginosa strains.

Methods

Clinical cefepime-non-susceptible Enterobacterales and P. aeruginosa strains expressing serine carbapenemases and/or other cefepime-hydrolysing β-lactamases with cefepime/taniborbactam combination MICs of 0.12–16 mg/L were used. Cefepime and taniborbactam human-simulated regimens equivalent to clinical doses (i.e. 2/0.5 g q8h) were established in the pneumonia model. The in vivo activity of the cefepime human-simulated regimen given alone or concomitantly with escalating taniborbactam exposures against eight Enterobacterales and four P. aeruginosa strains was assessed. Taniborbactam pharmacokinetics were evaluated to determine systemic exposures of regimens used; taniborbactam fAUC0–24/MIC values required for efficacy were estimated using the Hill equation. In addition, the in vivo activity of the cefepime/taniborbactam combination human-simulated regimen was assessed against 18 strains.

Results

Among Enterobacterales, median taniborbactam fAUC0–24/MIC values associated with stasis and 1 log kill were 0.96 and 4.03, respectively, while for P. aeruginosa, requirements were 1.35 and 3.02 for stasis and 1 log kill, respectively. The cefepime/taniborbactam human-simulated regimen produced >2 log kill in 14/18 strains and >1 log kill in 18/18 strains.

Conclusions

Cefepime/taniborbactam produced marked in vivo bactericidal activity against cefepime-non-susceptible Enterobacterales and P. aeruginosa isolates with cefepime/taniborbactam MICs up to and including 16 mg/L in the pneumonia model. Assessments of the probability of clinical attainment of the identified targets should be undertaken to support the selected cefepime/taniborbactam dose for treatment of nosocomial pneumonia.
Molecular features and transmission of NDM-producing Enterobacterales in Israeli hospitals
Authors: Adler Amos , Ghosh Hiren , Gross Andrea , Rechavi Amit , Lasnoy Michal , Assous Marc V , Geffen Yuval , Darawshe Basel , Wiener-Well Yonit , Grundmann Hajo , Reuter Sandra
Published: January 2023

Objectives

NDM-producing Enterobacterales (NDME) account for 34.9% of new carbapenemase-producing Enterobacterales cases in Israeli hospitals. The goals of this study were to characterize the genomic composition of NDME isolates and mobile genetic elements (MGEs) and to identify NDME transmission events (TEs).

Methods

The study was conducted at the Tel-Aviv Sourasky, Rambam and Sha’are-Zedek Medical Centers (TASMC, RMC and SZMC, respectively). All NDME isolates detected between January 2018 and July 2019 were included.

Phylogenetic analysis was based on core-genome SNP distances. Core-genome distance of ≤5 SNPs between isolates from patients with overlapping hospitalization periods was suggestive of a potential TE. MGEs were classified by comparison of the blaNDM gene flanking regions.

Results

The study included 212 NDME isolates from 203 patients, including 104 isolates from TASMC, 30 isolates from RMC and 78 isolates from SZMC. The majority of isolates (n = 157; 74%) harboured the blaNDM-1 gene, followed by the blaNDM-5 (n = 48) and blaNDM-15 genes (n = 7). The most common NDME species were Klebsiella pneumoniae (n = 67), Escherichia coli (n = 65) and Enterobacter cloacae (n = 45), all showing a highly diverse clonal structure. Most blaNDM-1-harbouring isolates (134/157; 85%) were divided into nine different MGE modules, variably distributed across species and hospitals.

The numbers of post-admission acquisition cases (n = 118) that could be linked to other cases by both molecular and epidemiological criteria were 13/58 (24.2%), 3/48 (6.3%) and 4/12 (33.3%) in TASMC, SZMC and RMC, respectively.

Conclusions

The study depicted a complex and diverse population structure, suggesting that NDME had not spread via clonal expansion.
What is fair and efficient in the face of climate change?
Authors: Snoep Martijn
Published: January 2023

Competition law shouldn’t stand in the way of genuine colloboration between competitors to reduce negative externalities, like the emission of greenhouse gases. Competition authorities around the world can play a role by giving guidance. in doing so, they should neither stick to orthodoxy not become naïve.
Multiobjective optimization of frozen and freeze-driedLactobacillus delbrueckiisubsp.bulgaricusCFL1 production via the modification of fermentation conditions
Authors: Tovilla Coutiño Maria de L , Passot Stéphanie , Trelea Ioan-Cristian , Ropers Marie-Hélène , Gohon Yann , Fonseca Fernanda
Published: January 2023

Aim

This study investigates the individual and combined effects of fermentation parameters for improving cell biomass productivity and the resistance to freezing, freeze-drying, and freeze-dried storage of Lactobacillus delbrueckii subsp. bulgaricus CFL1.

Methods and Results

Cells were cultivated at different temperatures (42°C and 37°C) and pH values (5.8 and 4.8) and harvested at various growth phases (mid-exponential, deceleration, and stationary growth phases). Specific acidifying activity was determined after fermentation, freezing, freeze-drying, and freeze-dried storage. Multiple regression analyses were performed to identify the effects of fermentation parameters on the specific acidifying activity losses and to generate the corresponding 3D response surfaces. A multiobjective decision approach was applied to optimize biomass productivity and specific acidifying activity. The temperature positively influenced biomass productivity, whereas low pH during growth reduced the loss of specific acidifying activity after freezing and freeze-drying. Furthermore, freeze-drying resistance was favored by increased harvest time.

Conclusions

Productivity, and freezing and freeze-drying resistances of L. delbrueckii subsp. bulgaricus CFL1 were differentially affected by the fermentation parameters studied. There was no single fermentation condition that improved both productivity and resistance to freezing and freeze-drying. Thus, Pareto fronts were helpful to optimize productivity and resistance, when cells were grown at 42°C, pH 4.8, and harvested at the deceleration phase.
Integrative proteomics and metabolomics profiling to understand the biochemical basis of beef muscle darkening at a slightly elevated pH
Authors: Kiyimba Frank , Cassens Drew , Hartson Steven D , Rogers Janet , Habiger Joshua , Mafi Gretchen G , Ramanathan Ranjith
Published: January 2023

Previous studies investigated the biochemical basis of dark-cutting conditions at elevated muscle pH (above 6), but the molecular basis at slightly above normal pH (between 5.6 and 5.8) is still unclear. The objective was to determine protein and metabolite profiles to elucidate postmortem muscle darkening at slightly elevated pH. Loins were selected based on the criteria established in our laboratory before sample collections, such as pH less than 5.8, L* values (muscle lightness) less than 38, and not discounted by the grader (high-pH beef with dark color are discounted and not sold in retail stores). Six bright red loins (longissimus lumborum) at normal-pH (average pH = 5.57) and six dark-colored strip loins at slightly elevated pH (average pH = 5.70) from A maturity carcasses were obtained within 72-h postmortem from a commercial beef purveyor. Surface color, oxygen consumption, metmyoglobin reducing activity, protein, and metabolite profiles were determined on normal-pH and dark-colored steaks at slightly elevated pH. Enzymes related to glycogen metabolism and glycolytic pathways were more differently abundant than metabolites associated with these pathways. The results indicated that oxygen consumption and metmyoglobin reducing activity were greater (P < 0.05) in darker steaks than normal-pH steaks. Enzymes involved with glycogen catabolic pathways and glycogen storage disease showed lower abundance in dark beef. The tricarboxylic acid metabolite, aconitic acid, was overabundant in darker-colored beef than normal-pH beef, but glucose derivative metabolites were less abundant. The majority of glycogenolytic proteins and metabolites reported as overabundant in the previous dark-cutting studies at high pH (>6.4) also did not show significant differences in the current study. Therefore, our data suggest enzymes involved in glycogen metabolism, in part, create a threshold for muscle darkening than metabolites.
An Assay Method for Characterizing Bacteriophage T7 RNA Polymerase Activity by Transcription–Translation (TX-TL) System
Authors: Cui Mingxin , Wong Okei , Li Qiang , Wang Wenya
Published: January 2023

T7 system is a commonly used in protein expression and the highest transcription activity of T7 RNAP usually caused the instability of T7 system. In order to apply T7 system extensively, it is essential to characterize T7 RNAP activity. In the present paper, an assay method for T7 RNAP activity was developed with a transcription–translation (TX-TL) system. After the optimization of TX-TL system, the operating parameters were determined as 34°C, 60 min with 20 ng/μl of plasmid DNA template. The standard curve of TX-TL assay method indicated an excellent correlation (r = 0.998), and the sensitivity was better than that of western blotting method. The precision investigation indicated a mean-relative error of 2.58% and a standard-relative error of 7.01%. Moreover, the cell lysate could be added directly to the optimized TX-TL system without affecting T7 RNAP activity assay. The feasibility of present method was further confirmed by characterizing T7 RNAP activity in cell lysate of five strains of Escherichia coli (E. coli) DH5α with different T7 RNAP activities and seven commercial strains of E. coli (DE3). The present assay method for T7 RNAP activity would have a great application in synthetic biology, metabolic engineering, enzyme engineering and biomedicine.
State and Future Science of Opioids and Potential of Biased-ligand Technology in the Management of Acute Pain After Burn Injury
Authors: Hill David M , DeBoer Erik
Published: January 2023

Pain associated with severe burn injury is one of the most intense and clinically challenging to manage, as the metabolic imbalances associated with the inflammation caused by the injury and treatment interventions (e.g., dressing changes and debridement, excision, and grafting) can further worsen the pain. In the pharmacologic management of a complex, hospitalized patient with burn injuries, opioid therapy remains an efficacious mainstay of treatment. However, the complex nature of pain, injury characteristics, and common demographics after burn injury place patients at high risk of opioid-related adverse events. Thus, guidelines recommend that decisions about choice of opioid be based on physiology, pharmacology, and physician experience, in addition to individualizing initial treatment with subsequent continual adjustments throughout care. Although substantial progress has been made in pain management strategies with utilization of nonopioid medications and nonpharmacologic adjuncts to opioid pharmacotherapy, there is still a need to evaluate new therapies, as an optimal regimen still lacks significant evidential support. Herein, we review the actions of opioids at the cellular level, contributing to both nociception and opioid-related adverse events. We also discuss the most recently approved intravenously administered opioid, oliceridine, developed utilizing biased ligand technology, including a summary of its clinical efficacy and safety in the management of severe acute pain. While oliceridine has been evaluated for the management of moderate-to-severe acute pain, the large phase 3 studies did not include patients with burn injuries. However, potential implications and future study direction for pain associated with burn injury are discussed.
Walled cosmopolitanization: how China’s Great Firewall mediates young urban gay men’s lives
Authors: Song Lin , Wu Shangwei
Published: January 2023

This article explores the role of censorship as a communication technology in shaping experiences of cosmopolitanization. Drawing on interviews with urban Chinese gay men who circumvent the country’s Great Firewall, the article studies how censorship shapes people’s media choices, practices, and social outlooks. It presents three findings. First, censorship produces a domesticated media ecology characterized by controlled exchanges with the outside world, constructing the perceived “localness” and “foreignness” of media artifacts. Second, censorship creates an exclusive “cosmopolitan digital class” that establishes a hierarchy of desirability based on people’s media practices. Third, censorship promotes a paradoxical intertwining of cosmopolitanization and encapsulation, popularizing a mindset that is at once open—willing to move across the Wall and access alternative information—and closed: subscribing to territorial understandings of selfhood. Based on these findings, the article proposes the concept of “walled cosmopolitanization” to describe the vulnerability of the cosmopolitan self in censored environments.
Recent Developments in U.S. Climate Law: Judicial Retrenchment and Congressional Action
Authors: Farber Daniel A
Published: January 2023

The United States signed the United Nations Framework Convention on Climate Change in June of 1992. For nearly 30 years thereafter, Congress remained gridlocked and unable to pass significant climate change legislation. During that time, the executive branch was the main forum for the development of federal climate policy, forcing the Environmental Protection Agency (EPA) to creatively reinterpret 1970s legislation to deal with climate change. The situation changed in two crucial ways in 2022: The Supreme Court’s decision in West Virginia v. EPA reined in EPA’s authority, and Congress finally enacted major climate legislation in the form of a multi-billion dollar tax and spending bill. These two events will shape the future of US climate efforts.
State Capitalism in the GATT/WTO Legal Order
Authors: Mavroidis Petros C , Sapir André
Published: January 2023

Originally, the multilateral trading regime did not address state capitalism in a comprehensive manner, since none of the General Agreement on Tariffs and Trade founders had espoused this form of economic governance. The General Agreement on Tariffs and Trade did contain specific provisions dealing with state trading and with subsidies, but nothing more. This situation has remained unchanged over the years, except for tightening the screws in areas already regulated (like subsidies), even though the General Agreement on Tariffs and Trade/World Trade Organization membership has become more and more heterogenous, with some members being overtly state capitalists. This was the case because these new members were either too small to really matter (e.g. Hungary) or because it was hoped that bigger players would transform into market economies (e.g. China). In hindsight, this has proved to be a grave error, since many of the difficulties that the world trading system currently faces originate in the unsatisfactory disciplining of state intervention in the workings of the economy of World Trade Organization members.
Review of the Mimeticus Subgroup ofCulex(Culex) (Diptera: Culicidae), With an Assessment of the Specific Status of Three Nominal Species Described From India
Authors: Somboon Pradya , Phanitchakun Thanari , Namgay Rinzin , Harbach Ralph E
Published: January 2023

The Mimeticus Subgroup of the subgenus Culex, genus Culex Linnaeus, is reviewed and revised. Mitochondrial COI sequences of species of the subgroup available in GenBank were analysed to verify the identity of voucher specimens. The specific status of three species described from India, Cx. gaugleri Suman, Cx. katezari Karlekar, Andrew & Deshpande, and Cx. kodaikanalensis Suman, Veer & Chandra, was examined and found to be unsupportable. Culex gaugleri and Cx. kodaikanalensis are synonyms of Cx. jacksoni based on the similarity of DNA sequences and dubious evidence of morphological differentiation. Culex katezari is recognized as a nomen dubium because the morphological description and molecular information provided by the authors are insufficient for its identification. A number of specimens registered in GenBank were found to be misidentified. In addition, available data indicate that the Mimeticus Subgroup may include at least three unrecognized species, referred to informally as Cx. mimeticus form B, Cx. mimulus form X, and Cx. mimulus form Y.