bluuebunny/crossref_metadata_2025 huggingface dataset:
An Oligopoly-Fringe Model with HARA Preferences
Authors: van der Meijden Gerard , Withagen Cees , Benchekroun Hassan
Published: March 2022

Inspired by empirical evidence from the oil market, we build a model of an oligopoly facing a fringe as well as competition from renewable resources. We explore different subclasses of HARA utility functions (Cobb–Douglas, power and quadratic utility) to check the robustness of results found in the previous literature. For isoelastic demand, we characterize the equilibrium extraction rates of the fringe and the oligopolists. There always exists a phase of simultaneous supply of the oligopolists and the fringe, implying an inefficient order of use of resources since the oligopolists have smaller unit extraction costs and carbon emissions than the fringe. We calibrate our model to the oil market to quantify this sequence effect. In our benchmark calibration, we find for the three HARA subclasses that the sequence effect is responsible for almost all of the welfare loss compared to the first-best. It becomes smaller as market power decreases. Furthermore, we show that climate damage and Green Paradox effects depend non-monotonically on the degree of market power.
Surgical site infections caused by multi-drug resistant organisms: a case–control study in general surgery
Authors: Foschi Diego , Yakushkina Al’ona , Cammarata Francesco , Lamperti Giulia , Colombo Francesco , Rimoldi Sara , Antinori Spinello , Sampietro Gianluca M.
Published: March 2022

Multi-drug resistant organisms (MDR-Os) are emerging as a significant cause of surgical site infections (SSI), but clinical outcomes and risk factors associated to MDR-Os-SSI have been poorly investigated in general surgery. Aims were to investigate risk factors, clinical outcomes and costs of care of multi-drug resistant organisms (MDR-Os-SSI) in general surgery. From January 2018 to December 2019, all the consecutive, unselected patients affected by MDR-O SSI were prospectively evaluated. In the same period, patients with non-MDR-O SSI and without SSI, matched for clinical and surgical data were used as control groups. Risk factors for infection, clinical outcome, and costs of care were compared by univariate and multivariate analysis. Among 3494 patients operated on during the study period, 47 presented an MDR-O SSI. Two control groups of 47 patients with non-MDR-O SSI and without SSI were identified. MDR-Os SSI were caused by poly-microbial etiology, meanly related to Gram negative Enterobacteriales. MDR-Os-SSI were related to major postoperative complications. At univariate analysis, iterative surgery, open abdomen, intensive care, hospital stay, and use of aggressive and expensive therapies were associated to MDR-Os-SSI. At multivariate analysis, only iterative surgery and the need of total parenteral and immune-nutrition were significantly associated to MDR-Os-SSI. The extra-cost of MDR-Os-SSI treatment was 150% in comparison to uncomplicated patients. MDR-Os SSI seems to be associated with major postoperative complications and reoperative surgery, they are demanding in terms of clinical workload and costs of care, they are rare but increasing, and difficult to prevent with current strategies.
Graft weight integration in the early allograft dysfunction formula improves the prediction of early graft loss after liver transplantation
Authors: Manzia Tommaso Maria , Lai Quirino , Hartog Hermien , Aijtink Virginia , Pellicciaro Marco , Angelico Roberta , Gazia Carlo , Polak Wojciech G. , Rossi Massimo , Tisone Giuseppe
Published: March 2022

The role of the graft-to-recipient weight ratio (GRWR) in adult liver transplantation (LT) has been poorly investigated so far. The aim is to evaluate the contribution of the GRWR to the well-recognized early allograft dysfunction (EAD) model (i.e., Olthoff model) for the prediction of 90-day graft loss after LT in adults. Three hundred thirty-one consecutive adult patients undergoing LT between 2009 and 2018 at Tor Vergata and Sapienza University in Rome, Italy, served as the Training-Set. The Validation-Set included 123 LTs performed at the Erasmus Medical Center, Rotterdam, the Netherlands. The mEAD model for 90-day graft loss included the following variables: GRWR $$\le $$
≤
1.57 = 2.5, GRWR $$\ge $$
≥
2.13 = 2.5, total bilirubin ≥ 10.0 mg/dL = 2.0, INR ≥ 1.60 = 2.3, and aminotransferase > 2000 IU/L = 2.2. The mEAD model showed an AUC = 0.74 (95%CI = 0.66–0.82; p < 0.001) and AUC = 0.68 (95%CI = 0.58–0.88; p = 0.01) in the Training-Set and Validation-Set, respectively, outperforming conventional EAD in both cohorts (Training-Set: AUC = 0.64, 95%CI = 0.57–0.72; p = 0.001; Validation-Set: AUC = 0.52, 95%CI = 0.35–0.69, p = 0.87). Incorporation of graft weight in a composite multivariate model allowed for better prediction of patients who presented an aminotransferase peak > 2000 IU/L after LT (OR = 2.39, 95%CI = 1.47–3.93, p = 0.0005). The GRWR is important in determining early graft loss after adult LT, and the mEAD model is a useful predictive tool in this perspective, which may assist in improving the graft allocation process.
Jordan structures of irreducible totally nonnegative matrices with a prescribed sequence of the first p-indices
Authors: Cantó Begoña , Cantó Rafael , Urbano Ana María
Published: March 2022

Let $$A \in {\mathbb {R}}^{n \times n}$$

A
∈

R

n
×
n

be an irreducible totally nonnegative matrix with rank r and principal rank p, that is, A is irreducible with all minors nonnegative, r is the size of the largest invertible square submatrix of A and p is the size of its largest invertible principal submatrix. We consider the sequence $$\{1,i_2,\ldots ,i_p\}$$

{
1
,

i
2

,
…
,

i
p

}

of the first p-indices of A as the first initial row and column indices of a $$p \times p$$

p
×
p

invertible principal submatrix of A. A triple (n, r, p) is called $$(1,i_2,\ldots ,i_p)$$

(
1
,

i
2

,
…
,

i
p

)

-realizable if there exists an irreducible totally nonnegative matrix $$A \in {\mathbb {R}}^{n \times n}$$

A
∈

R

n
×
n

with rank r, principal rank p, and $$\{1,i_2,\ldots ,i_p\}$$

{
1
,

i
2

,
…
,

i
p

}

is the sequence of its first p-indices. In this work we study the Jordan structures corresponding to the zero eigenvalue of irreducible totally nonnegative matrices associated with a triple (n, r, p) $$(1,i_2,\ldots ,i_p)$$

(
1
,

i
2

,
…
,

i
p

)

-realizable.
GH/IGF-1 axis in a large cohort of ß-thalassemia major adult patients: a cross-sectional study
Authors: Gagliardi I. , Mungari R. , Gamberini M. R. , Fortini M. , Dassie F. , Putti M. C. , Maffei P. , Aliberti L. , Bondanelli M. , Zatelli M. C. , Ambrosio M. R.
Published: March 2022

Purpose

GH deficit (GHD) could represent an endocrine issue in ß-Thalassemia Major (ßTM) patients. GH/IGF-1 axis has not been extensively explored in ßTM adults, so far. We aim to assess GHD and IGF-1 deficiency prevalence in ßTM adult population, focusing on the relationship with liver disease.

Methods

Cross-sectional multi-centre study conducted on 81 adult ßTM patients (44 males, mean age 41 ± 8 years) on transfusion and chelation therapy. GHD was investigated by GHRH + arginine test. IGF-1 levels, routine biochemical exams, Fibroscan, Hepatic Magnetic Resonance Imaging (MRI) and pituitary MRI were collected.

Results

Eighteen patients were affected by GHD and 63 were not (nGHD) according to GHRH + arginine test, while basal GH levels did not differ. GHD was associated with a higher BMI and a worse lipid profile (p < 0.05). No significant differences were observed regarding liver function between the two groups. Pituitary MRI scan was normal except for one case of empty sella. The 94.4% and 93.6% of GHD and nGHD, respectively, presented lower IGF-1 levels than the reference range, and mean IGF-1 SDS was significantly lower in GHD patients.

Conclusion

GHD is frequent in adult ßTM patients and is associated with higher BMI and worse lipid profile. nGHD patients present lower IGF-1 levels as well. There was no relationship between IGF-1 levels and liver disease. Further, multicentric studies with larger cohorts and standardized diagnostic protocols are needed.
Environmentally Tough and Stretchable MXene Organohydrogel with Exceptionally Enhanced Electromagnetic Interference Shielding Performances
Authors: Yu Yuanhang , Yi Peng , Xu Wenbin , Sun Xin , Deng Gao , Liu Xiaofang , Shui Jianglan , Yu Ronghai
Published: March 2022

Conductive hydrogels have potential applications in shielding electromagnetic (EM) radiation interference in deformable and wearable electronic devices, but usually suffer from poor environmental stability and stretching-induced shielding performance degradation. Although organohydrogels can improve the environmental stability of materials, their development is at the expense of reducing electrical conductivity and thus weakening EM interference shielding ability. Here, a MXene organohydrogel is prepared which is composed of MXene network for electron conduction, binary solvent channels for ion conduction, and abundant solvent-polymer-MXene interfaces for EM wave scattering. This organohydrogel possesses excellent anti-drying ability, low-temperature tolerance, stretchability, shape adaptability, adhesion and rapid self-healing ability. Two effective strategies have been proposed to solve the problems of current organohydrogel shielding materials. By reasonably controlling the MXene content and the glycerol-water ratio in the gel, MXene organohydrogel can exhibit exceptionally enhanced EM interference shielding performances compared to MXene hydrogel due to the increased physical cross-linking density of the gel. Moreover, MXene organohydrogel shows attractive stretching-enhanced interference effectiveness, caused by the connection and parallel arrangement of MXene nanosheets. This well-designed MXene organohydrogel has potential applications in shielding EM interference in deformable and wearable electronic devices.
An analysis of the effects of territory properties on population behaviors and evacuation management during disasters using coupled dynamical systems
Authors: Lanza Valentina , Dubos-Paillard Edwige , Charrier Rodolphe , Provitolo Damienne , Berred Alexandre
Published: March 2022

One of the major current challenges in the field of security and safety of populations is to advance further in the understanding and the ability to anticipate their behaviors when faced with threats or disasters. Several factors such as the hazard properties or the culture of risk can influence people behavior during a disaster. In this paper, we assume that the spatial configuration of the site where the disaster takes place has also a significant impact on collective behaviors. For this, we use a mathematical model based on meta-population networks, in order to design realistic evacuation scenarios. This model, called the Alert-Panic-Control model, allows, on the one hand, to take into account the temporal dynamics of collective behaviors in front of disaster and on the other hand, the spatial context considered in terms of site maximum capacity. From the results of a in situ experiment carried out in 2019 with the population of Le Havre (France) concerning an industrial accident hypothesis, and in particular from the different evacuation paths chosen by the respondents, three scenarios of evacuation of the place located below the street level and in front of the Niemeyer Cultural Centre were built. The results are able to quantify how the contagion of panic has a major impact or not on an evacuation forced by specific territorial properties. Too narrow paths can cause panic phenomena due to bottleneck. They also highlight that the function of the refuge places, recreational function in this case, must be taken into account insofar as they can gather many people, impeding the evacuation of the population exposed to the danger.
Ortai, the Yongzheng Emperor, and the Multicolored World of China's Southwestern Frontier
Authors: Bellemare Julie
Published: March 2022

By examining a series of events involving sightings of multicolored clouds and discoveries of colorful minerals in China's southwestern provinces, this article considers the political implications of natural manifestations of polychromy in the Yongzheng period. Through previously unexamined written and material correspondence between governor-general Ortai (1680–1745) and the Yongzheng emperor (r. 1723–35), I argue that physical occurrences of color, both above and below ground, were understood as signs of Heavenly approval of the emperor's governance at a time of questionable military expansion into the Southwest. I also consider how celestial phenomena and colorful stones were translated into design motifs and carved into exclusive items at the Qing court, positing that these objects were understood as signs of the Yongzheng emperor's political legitimacy and concrete evidence of Qing control over the remote reaches of the empire.
Absolute Paleointensity Experiments on Aged Thermoremanent Magnetization: Assessment of Reliability of the Tsunakawa‐Shaw and Other Methods With Implications for “Fragile” Curvature
Authors: Yamamoto Y. , Tauxe L. , Ahn H. , Santos C.
Published: March 2022

Absolute paleointensity (API) of the geomagnetic field can be estimated from volcanic rocks by comparing the natural remanent magnetization (NRM) to a laboratory‐induced thermoremanent magnetization (Lab‐TRM). Plots of NRM unblocking versus Lab‐TRM blocking from API experiments often exhibit nonideal curvature, which can result in biased estimates. Previous work showed that curvature can increase with age; however, selection criteria designed to eliminate such behavior yielded accurate estimates for two‐year‐aged specimens (70.3 ± 3.8 μT;N = 96 specimens out of 120 experiments). API can also be estimated in coercivity space. Here, we use the Tsunakawa‐Shaw (TS) method applied to 20 specimens aged in the laboratory field of 70.0 μT for 4 years, after acquisition of zero‐age (fresh) Lab‐TRM in the same field. Selection criteria for the TS experiment also yielded accurate results (68.5 ± 4.5 μT;N = 17 specimens). In thermal API experiments, curvature is related to internal structure with more single domain‐like behavior having the least curvature. Here we show that the fraction of anhysteretic remanent magnetization demagnetized by low‐temperature treatment was larger for samples with larger thermal curvatures suggesting a magnetocrystalline anisotropy source. We also tested experimental remedies that have been proposed to improve the accuracy of paleointensity estimates. In particular, we test the efficacy of the multi‐specimen approach and a strategy pretreating specimens with low field alternating field demagnetization prior to the paleointensity experiment. Neither yielded accurate results.
Phenotypic and genetic analysis of a wellbeing factor score in the UK Biobank and the impact of childhood maltreatment and psychiatric illness
Authors: Jamshidi Javad , Schofield Peter R. , Gatt Justine M. , Fullerton Janice M.
Published: March 2022

Wellbeing is an important aspect of mental health that is moderately heritable. Specific wellbeing-related variants have been identified via GWAS meta-analysis of individual questionnaire items. However, a multi-item within-subject index score has potential to capture greater heritability, enabling improved delineation of genetic and phenotypic relationships across traits and exposures that are not possible on aggregate-data. This research employed data from the UK Biobank resource, and a wellbeing index score was derived from indices of happiness and satisfaction with family/friendship/finances/health, using principal component analysis. GWAS was performed in Caucasian participants (N = 129,237) using the derived wellbeing index, followed by polygenic profiling (independent sample; N = 23,703). The wellbeing index, its subcomponents, and negative indicators of mental health were compared via phenotypic and genetic correlations, and relationships with psychiatric disorders examined. Lastly, the impact of childhood maltreatment on wellbeing was investigated. Five independent genome-wide significant loci for wellbeing were identified. The wellbeing index had SNP-heritability of ~8.6%, and stronger phenotypic and genetic correlations with its subcomponents (0.55–0.77) than mental health phenotypes (−0.21 to −0.39). The wellbeing score was lower in participants reporting various psychiatric disorders compared to the total sample. Childhood maltreatment exposure was also associated with reduced wellbeing, and a moderate genetic correlation (rg = ~−0.56) suggests an overlap in heritability of maltreatment with wellbeing. Thus, wellbeing is negatively associated with both psychiatric disorders and childhood maltreatment. Although notable limitations, biases and assumptions are discussed, this within-cohort study aids the delineation of relationships between a quantitative wellbeing index and indices of mental health and early maltreatment.
Genetic alteration of human MYH6 is mimicked by SARS-CoV-2 polyprotein: mapping viral variants of cardiac interest
Authors: Anand Praveen , Lenehan Patrick J. , Niesen Michiel , Yoo Unice , Patwardhan Dhruti , Montorzi Marcelo , Venkatakrishnan A. J. , Soundararajan Venky
Published: March 2022

Acute cardiac injury has been observed in a subset of COVID-19 patients, but the molecular basis for this clinical phenotype is unknown. It has been hypothesized that molecular mimicry may play a role in triggering an autoimmune inflammatory reaction in some individuals after SARS-CoV-2 infection. Here we investigate if linear peptides contained in proteins that are primarily expressed in the heart also occur in the SARS-CoV-2 proteome. Specifically, we compared the library of 136,704 8-mer peptides from 144 human proteins (including splicing variants) to 9926 8-mers from all the viral proteins in the reference SARS-CoV-2 proteome. No 8-mers were exactly identical between the reference human proteome and the reference SARS-CoV-2 proteome. However, there were 45 8-mers that differed by only one amino acid when compared to the reference SARS-CoV-2 proteome. Interestingly, analysis of protein-coding mutations from 141,456 individuals showed that one of these 8-mers from the SARS-CoV-2 Replicase polyprotein 1a/1ab (KIALKGGK) is identical to anMYH6peptide encoded by the c.5410 C > A (Q1804K) genetic variation, which has been observed at low prevalence in Africans/African Americans (0.08%), East Asians (0.3%), South Asians (0.06%), and Latino/Admixed Americans (0.003%). Furthermore, analysis of 4.85 million SARS-CoV-2 genomes from over 200 countries shows that viral evolution has already resulted in 20 additional 8-mer peptides that are identical to human heart-enriched proteins encoded by reference sequences or genetic variants. Whether such mimicry contributes to cardiac inflammation during or after COVID-19 illness warrants further experimental evaluation. We suggest that SARS-CoV-2 variants harboring peptides identical to human cardiac proteins should be investigated as “viral variants of cardiac interest”.
UBAP2L promotes gastric cancer metastasis by activating NF-κB through PI3K/AKT pathway
Authors: Li Ou , Zhao Cheng , Zhang Jian , Li Feng-Nan , Yang Zi-Yi , Liu Shi-Lei , Cai Chen , Jia Zi-Yao , Gong Wei , Shu Yi-Jun , Dong Ping
Published: March 2022

Ubiquitin-associated protein 2-like (UBAP2L) is highly expressed in various types of tumors and has been shown to participate in tumor growth and metastasis; however, its role in gastric cancer (GC) remains unknown. In this study, we observed that UBAP2L expression was markedly elevated in GC tissues and five GC cell lines. Higher expression of UBAP2L was associated with poor prognosis as revealed by bioinformatics analysis on online websites and laboratory experiments. Knockdown of UBAP2L impeded the migration and invasion abilities of GC cell lines. In contrast, its overexpression enhanced the migration and invasion abilities of GC cell lines. Overexpression of UBAP2L also increased the number and size of lung metastatic nodules in vivo. According to the results of mass spectrometry and pathway annotation of the identified proteins, the PI3K/AKT pathway was found to be related to UBAP2L regulation. Further exploration and rescue experiments revealed that UBAP2L stimulates the expression and nuclear aggregation of p65 and promotes the expression of SP1 by activating the PI3K/AKT pathway. In summary, our findings indicate that UBAP2L regulates GC metastasis through the PI3K/AKT/SP1/NF-κB axis. Thus, targeting UBAP2L may be a potential therapeutic strategy for GC.
Rapid age-grading and species identification of natural mosquitoes for malaria surveillance
Authors: Siria Doreen J. , Sanou Roger , Mitton Joshua , Mwanga Emmanuel P. , Niang Abdoulaye , Sare Issiaka , Johnson Paul C. D. , Foster Geraldine M. , Belem Adrien M. G. , Wynne Klaas , Murray-Smith Roderick , Ferguson Heather M. , González-Jiménez Mario , Babayan Simon A. , Diabaté Abdoulaye , Okumu Fredros O. , Baldini Francesco
Published: March 2022

The malaria parasite, which is transmitted by several Anopheles mosquito species, requires more time to reach its human-transmissible stage than the average lifespan of mosquito vectors. Monitoring the species-specific age structure of mosquito populations is critical to evaluating the impact of vector control interventions on malaria risk. We present a rapid, cost-effective surveillance method based on deep learning of mid-infrared spectra of mosquito cuticle that simultaneously identifies the species and age class of three main malaria vectors in natural populations. Using spectra from over 40, 000 ecologically and genetically diverse An. gambiae, An. arabiensis, and An. coluzzii females, we develop a deep transfer learning model that learns and predicts the age of new wild populations in Tanzania and Burkina Faso with minimal sampling effort. Additionally, the model is able to detect the impact of simulated control interventions on mosquito populations, measured as a shift in their age structures. In the future, we anticipate our method can be applied to other arthropod vector-borne diseases.
ADARs act as potent regulators of circular transcriptome in cancer
Authors: Shen Haoqing , An Omer , Ren Xi , Song Yangyang , Tang Sze Jing , Ke Xin-Yu , Han Jian , Tay Daryl Jin Tai , Ng Vanessa Hui En , Molias Fernando Bellido , Pitcheshwar Priyankaa , Leong Ka Wai , Tan Ker-Kan , Yang Henry , Chen Leilei
Published: March 2022

Circular RNAs (circRNAs) are produced by head-to-tail back-splicing which is mainly facilitated by base-pairing of reverse complementary matches (RCMs) in circRNA flanking introns. Adenosine deaminases acting on RNA (ADARs) are known to bind double-stranded RNAs for adenosine to inosine (A-to-I) RNA editing. Here we characterize ADARs as potent regulators of circular transcriptome by identifying over a thousand of circRNAs regulated by ADARs in a bidirectional manner through and beyond their editing function. We find that editing can stabilize or destabilize secondary structures formed between RCMs via correcting A:C mismatches to I(G)-C pairs or creating I(G).U wobble pairs, respectively. We provide experimental evidence that editing also favors the binding of RNA-binding proteins such as PTBP1 to regulate back-splicing. These ADARs-regulated circRNAs which are ubiquitously expressed in multiple types of cancers, demonstrate high functional relevance to cancer. Our findings support a hitherto unappreciated bidirectional regulation of circular transcriptome by ADARs and highlight the complexity of cross-talk in RNA processing and its contributions to tumorigenesis.
Microbiomes in the Challenger Deep slope and bottom-axis sediments
Authors: Zhou Ying-Li , Mara Paraskevi , Cui Guo-Jie , Edgcomb Virginia P. , Wang Yong
Published: March 2022

Hadal trenches are the deepest and most remote regions of the ocean. The 11-kilometer deep Challenger Deep is the least explored due to the technical challenges of sampling hadal depths. It receives organic matter and heavy metals from the overlying water column that accumulate differently across its V-shaped topography. Here, we collected sediments across the slope and bottom-axis of the Challenger Deep that enable insights into its in situ microbial communities. Analyses of 586 metagenome-assembled genomes retrieved from 37 metagenomes show distinct diversity and metabolic capacities between bottom-axis and slope sites. 26% of prokaryotic 16S rDNA reads in metagenomes were novel, with novelty increasing with water and sediment depths. These predominantly heterotrophic microbes can recycle macromolecules and utilize simple and complex hydrocarbons as carbon sources. Metagenome and metatranscriptome data support reduction and biotransformation of arsenate for energy gain in sediments that present a two-fold greater accumulation of arsenic compared to non-hadal sites. Complete pathways for anaerobic ammonia oxidation are predominantly identified in genomes recovered from bottom-axis sediments compared to slope sites. Our results expand knowledge of microbially-mediated elemental cycling in hadal sediments, and reveal differences in distribution of processes involved in nitrogen loss across the trench.
Comparative effectiveness of the BNT162b2 and ChAdOx1 vaccines against Covid-19 in people over 50
Authors: Xie Junqing , Feng Shuo , Li Xintong , Gea-Mallorquí Ester , Prats-Uribe Albert , Prieto-Alhambra Dani
Published: March 2022

Although pivotal trials with varying populations and study methods suggest higher efficacy for mRNA than adenoviral Covid-19 vaccines, not many studies have directly compared vaccine effectiveness in the population. Here, we conduct a head-to-head comparison of BNT162b2 versus ChAdOx1 against Covid-19. We analyse 235,181 UK Biobank participants aged 50 years or older and vaccinated with one or two doses of BNT162b2 or ChAdOx1. People are followed from the vaccination date until 18/10/2021. Inverse probability weighting is used to minimise confounding and the Cox models to derive hazard ratio. We find that, compared with one dose of ChAdOx1, vaccination with BNT162b2 is associated with a 28% (95% CI, 12-42) decreased risk of SARS-CoV-2 infection. Also, two doses of BNT162b2 vs ChAdOx1 confers 30% (95% CI, 25-35) and 29% (95% CI, 10-45) lower risks of both infection and hospitalisation during the study period when the Delta variant is dominant. Furthermore, the comparative protection against the infection persists for at least six months among the fully vaccinated, suggesting no differential waning between the two vaccines. These findings can inform evidence-based Covid-19 vaccination campaigns and booster strategies.
A pharmacogenetic interaction analysis of bevacizumab with paclitaxel in advanced breast cancer patients
Authors: Coltelli Luigi , Allegrini Giacomo , Orlandi Paola , Finale Chiara , Fontana Andrea , Masini Luna Chiara , Scalese Marco , Arrighi Giada , Barletta Maria Teresa , De Maio Ermelinda , Banchi Marta , Fini Elisabetta , Guidi Patrizia , Frenzilli Giada , Donati Sara , Giovannelli Simona , Tanganelli Lucia , Salvadori Barbara , Livi Lorenzo , Meattini Icro , Pazzagli Ilaria , Di Lieto Marco , Pistelli Mirco , Casadei Virginia , Ferro Antonella , Cupini Samanta , Orlandi Francesca , Francesca Damiana , Lorenzini Giulia , Barellini Leonardo , Falcone Alfredo , Cosimi Alessandro , Bocci Guido
Published: March 2022

To investigate pharmacogenetic interactions among VEGF-A, VEGFR-2, IL-8, HIF-1α, EPAS-1, and TSP-1 SNPs and their role on progression-free survival (PFS) in metastatic breast cancer (MBC) patients treated with bevacizumab plus first-line paclitaxel or with paclitaxel alone. Analyses were performed on germline DNA, and SNPs were investigated by real-time PCR technique. The multifactor dimensionality reduction (MDR) methodology was applied to investigate the interaction between SNPs. The present study was an explorative, ambidirectional cohort study: 307 patients from 11 Oncology Units were evaluated retrospectively from 2009 to 2016, then followed prospectively (NCT01935102). Two hundred and fifteen patients were treated with paclitaxel and bevacizumab, whereas 92 patients with paclitaxel alone. In the bevacizumab plus paclitaxel group, the MDR software provided two pharmacogenetic interaction profiles consisting of the combination between specific VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes. Median PFS for favorable genetic profile was 16.8 vs. the 10.6 months of unfavorable genetic profile (p = 0.0011). Cox proportional hazards model showed an adjusted hazard ratio of 0.64 (95% CI, 0.5–0.9; p = 0.004). Median OS for the favorable genetic profile was 39.6 vs. 28 months of unfavorable genetic profile (p = 0.0103). Cox proportional hazards model revealed an adjusted hazard ratio of 0.71 (95% CI, 0.5–1.01; p = 0.058). In the 92 patients treated with paclitaxel alone, the results showed no effect of the favorable genetic profile, as compared to the unfavorable genetic profile, either on the PFS (p = 0.509) and on the OS (p = 0.732). The pharmacogenetic statistical interaction between VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes may identify a population of bevacizumab-treated patients with a better PFS.
Synthesis of new series of quinoline derivatives with insecticidal effects on larval vectors of malaria and dengue diseases
Authors: Murugan Kadarkarai , Panneerselvam Chellasamy , Subramaniam Jayapal , Paulpandi Manickam , Rajaganesh Rajapandian , Vasanthakumaran Murugan , Madhavan Jagannathan , Shafi S. Syed , Roni Mathath , Portilla-Pulido Johan S. , Mendez Stelia C. , Duque Jonny E. , Wang Lan , Aziz Al Thabiani , Chandramohan Balamurugan , Dinesh Devakumar , Piramanayagam Shanmughavel , Hwang Jiang-Shiou
Published: March 2022

Mosquito borne diseases are on the rise because of their fast spread worldwide and the lack of effective treatments. Here we are focusing on the development of a novel anti-malarial and virucidal agent with biocidal effects also on its vectors. We have synthesized a new quinoline (4,7-dichloroquinoline) derivative which showed significant larvicidal and pupicidal properties against a malarial and a dengue vector and a lethal toxicity ranging from 4.408 µM/mL (first instar larvae) to 7.958 µM/mL (pupal populations) for Anopheles stephensi and 5.016 µM/mL (larva 1) to 10.669 µM/mL (pupae) for Aedes aegypti. In-vitro antiplasmodial efficacy of 4,7-dichloroquinoline revealed a significant growth inhibition of both sensitive strains of Plasmodium falciparum with IC50 values of 6.7 nM (CQ-s) and 8.5 nM (CQ-r). Chloroquine IC50 values, as control, were 23 nM (CQ-s), and 27.5 nM (CQ-r). In vivo antiplasmodial studies with P. falciparum infected mice showed an effect of 4,7-dichloroquinoline compared to chloroquine. The quinoline compound showed significant activity against the viral pathogen serotype 2 (DENV-2). In vitro conditions and the purified quinoline exhibited insignificant toxicity on the host system up to 100 µM/mL. Overall, 4,7-dichloroquinoline could provide a good anti-vectorial and anti-malarial agent.
Smartphone app reveals that lynx avoid human recreationists on local scale, but not home range scale
Authors: Thorsen Neri H. , Bischof Richard , Mattisson Jenny , Hofmeester Tim R. , Linnell John D. C. , Odden John
Published: March 2022

Outdoor recreation is increasing and affects habitat use and selection by wildlife. These effects are challenging to study, especially for elusive species with large spatial requirements, as it is hard to obtain reliable proxies of recreational intensity over extensive areas. Commonly used proxies, such as the density of, or distance to, hiking paths, ignore outdoor recreation occurring on other linear feature types. Here we utilized crowdsourced data from the Strava training app to obtain a large-scale proxy for pedestrian outdoor recreation intensity in southeast Norway. We used the proxy and GPS-tracking data from collared Eurasian lynx (Lynx lynx) to investigate how recreation affects habitat selection at the home range scale and local scale by lynx during summer. We fitted resource selection functions at the two scales using conditional logistic regression. Our analysis revealed that lynx avoided areas of recreational activity at the local scale, but not at home range scale. Nonetheless, lynx frequently used areas associated with recreation, and to a greater degree at night than during the day. Our results suggest that local-scale avoidance of recreation and temporal adjustments of habitat use by lynx mitigate the need for a home range-scale response towards recreation. Scale-dependent responses and temporal adjustments in habitat use may facilitate coexistence between humans and large carnivores.
Beta-blocker/ACE inhibitor therapy differentially impacts the steady state signaling landscape of failing and non-failing hearts
Authors: Sorrentino Andrea , Bagwan Navratan , Linscheid Nora , Poulsen Pi C. , Kahnert Konstantin , Thomsen Morten B. , Delmar Mario , Lundby Alicia
Published: March 2022

Heart failure is a multifactorial disease that affects an estimated 38 million people worldwide. Current pharmacotherapy of heart failure with reduced ejection fraction (HFrEF) includes combination therapy with angiotensin-converting enzyme inhibitors (ACEi) and β-adrenergic receptor blockers (β-AR blockers), a therapy also used as treatment for non-cardiac conditions. Our knowledge of the molecular changes accompanying treatment with ACEi and β-AR blockers is limited. Here, we applied proteomics and phosphoproteomics approaches to profile the global changes in protein abundance and phosphorylation state in cardiac left ventricles consequent to combination therapy of β-AR blocker and ACE inhibitor in HFrEF and control hearts. The phosphorylation changes induced by treatment were profoundly different for failing than for non-failing hearts. HFrEF was characterized by profound downregulation of mitochondrial proteins coupled with derangement of β-adrenergic and pyruvate dehydrogenase signaling. Upon treatment, phosphorylation changes consequent to HFrEF were reversed. In control hearts, treatment mainly led to downregulation of canonical PKA signaling. The observation of divergent signaling outcomes depending on disease state underscores the importance of evaluating drug effects within the context of the specific conditions present in the recipient heart.
Relevance of cortisol and copeptin blood concentration changes in an experimental pain model
Authors: Blum Claudine A. , Velly Laëtitia , Brochet Christine , Ziegler Frédéric , Tavolacci Marie-Pierre , Hausfater Pierre , Lvovschi Virginie Eve
Published: March 2022

The effect of pain and analgesics on stress biomarkers is not well studied. We evaluated the effect of acute pain and analgesics on serum cortisol and copeptin in an experimental pain model in healthy volunteers. Healthy volunteers presented at 8 a.m. for an experimental pain stimulation. Cortisol and copeptin levels were measured before, during and after electrophysiological stimulation, first before and then during opioid delivery. Difference in biomarker levels compared to baseline levels was calculated, and potential influencing factors were evaluated by linear regression analysis. Cortisol decreased by 13% during the 10 min of rest at baseline, but copeptin did not change significantly. Cortisol had a median decrease of −24% or −83 nmol/l (−44 to −124 nmol/l, p = 0.0002) during the electrophysiological stimulation training session, while the median difference for copeptin was −22% or −1.01 pmol/l (−2.35 to 0.08 pmol/l, p = 0.0003). After administration of opioids, cortisol did not decrease but increased by 3% (p = 0.043), indicating an increasing opioids effect on cortisol. This effect was not visible for copeptin (median change −0.003 pmol/l (−0.50 to 0.24), p = 0.45). In this experimental pain model performed in the morning, moderate pain did not have a relevant effect on cortisol or copeptin levels, whereas opioids led to a discrete peak of cortisol.

Clinicaltrials.gov identifier: NCT01975753 (registered on November 5, 2013, before start of recruitment).
Gossip promotes cooperation only when it is pro-socially motivated
Authors: Testori Martina , Hemelrijk Charlotte K. , Beersma Bianca
Published: March 2022

Humans are often shown to cooperate with one another. Most of the mechanisms that foster cooperation among humans rely on reputation, which itself relies on the acquisition of information about other people’s behaviors. Gossip has been proposed as a cheap yet efficient tool to acquire information, and it has largely been proved to be an effective means to foster and maintain cooperation. However, empirical studies supporting this claim have ignored two aspects: (1) they often compared gossip to treatments in which no reputation was available, impeding a direct assessment of whether it is gossip that promotes cooperation or rather the introduction of a reputation system; and (2) they focused on pro-social gossip (e.g., gossip aimed at helping the receiver), neglecting the impact of other types of gossip. We show here that, in contrast with the widespread notion that gossip promotes cooperation, gossip mostly depletes cooperation compared to first-hand information. If lying is fruitful for individuals or if a group’s behavior is largely uncooperative, gossip leads to negative reputational information and decreased cooperation.
Affinity2Vec: drug-target binding affinity prediction through representation learning, graph mining, and machine learning
Authors: Thafar Maha A. , Alshahrani Mona , Albaradei Somayah , Gojobori Takashi , Essack Magbubah , Gao Xin
Published: March 2022

Drug-target interaction (DTI) prediction plays a crucial role in drug repositioning and virtual drug screening. Most DTI prediction methods cast the problem as a binary classification task to predict if interactions exist or as a regression task to predict continuous values that indicate a drug's ability to bind to a specific target. The regression-based methods provide insight beyond the binary relationship. However, most of these methods require the three-dimensional (3D) structural information of targets which are still not generally available to the targets. Despite this bottleneck, only a few methods address the drug-target binding affinity (DTBA) problem from a non-structure-based approach to avoid the 3D structure limitations. Here we propose Affinity2Vec, as a novel regression-based method that formulates the entire task as a graph-based problem. To develop this method, we constructed a weighted heterogeneous graph that integrates data from several sources, including drug-drug similarity, target-target similarity, and drug-target binding affinities. Affinity2Vec further combines several computational techniques from feature representation learning, graph mining, and machine learning to generate or extract features, build the model, and predict the binding affinity between the drug and the target with no 3D structural data. We conducted extensive experiments to evaluate and demonstrate the robustness and efficiency of the proposed method on benchmark datasets used in state-of-the-art non-structured-based drug-target binding affinity studies. Affinity2Vec showed superior and competitive results compared to the state-of-the-art methods based on several evaluation metrics, including mean squared error, rm2, concordance index, and area under the precision-recall curve.
Thioredoxin interacting protein protects mice from fasting induced liver steatosis by activating ER stress and its downstream signaling pathways
Authors: Miyahara Hiroyuki , Hasegawa Kosei , Yashiro Masato , Ohara Toshiaki , Fujisawa Masayoshi , Yoshimura Teizo , Matsukawa Akihiro , Tsukahara Hirokazu
Published: March 2022

Under normal conditions, fasting results in decreased protein disulfide isomerase (PDI) activity and accumulation of unfolded proteins, leading to the subsequent activation of the unfolded protein response (UPR)/autophagy signaling pathway to eliminate damaged mitochondria. Fasting also induces upregulation of thioredoxin-interacting protein (TXNIP) expression and mice deficient of this protein (TXNIP-KO mice) was shown to develop severe hypoglycemia, hyperlipidemia and liver steatosis (LS). In the present study, we aimed to determine the role of TXNIP in fasting-induced LS by using male TXNIP-KO mice that developed LS without severe hypoglycemia. In TXNIP-KO mice, fasting induced severe microvesicular LS. Examinations by transmission electron microscopy revealed mitochondria with smaller size and deformities and the presence of few autophagosomes. The expression of β-oxidation-associated genes remained at the same level and the level of LC3-II was low. PDI activity level stayed at the original level and the levels of p-IRE1 and X-box binding protein 1 spliced form (sXBP1) were lower. Interestingly, treatment of TXNIP-KO mice with bacitracin, a PDI inhibitor, restored the level of LC3-II after fasting. These results suggest that TXNIP regulates PDI activity and subsequent activation of the UPR/autophagy pathway and plays a protective role in fasting-induced LS.
Detection and characterization of simvastatin and its metabolites in rat tissues and biological fluids using MALDI high resolution mass spectrometry approach
Authors: Yin Wencui , Al-Wabli Reem I. , Attwa Mohamed W. , Rahman A. F. M. Motiur , Kadi Adnan A.
Published: March 2022

Simvastatin (SV) is a hypolipidemic agent, and it is the 2nd most widely prescribed lipid-lowering drug. Here, the detection and characterization of SV and its metabolites was studied in selected organs/tissues (lung, liver, brain, heart and kidney) and biological samples (blood, urine and feces) of rats. MALDI Orbitrap MS was used as a high-resolution mass analyzer. 2,5-Dihydroxybenzoic acid (DHB) and 1,5-diaminonaphthalene (DAN) were used as matrices. Several sample loading methods onto the MALDI plate were attempted and dried droplet method was found to be superior. Two different cell disruption methods, pulverization and homogenization, were also evaluated for the optimum sensitivity in MALDI. Pulverization allowed the detection of more metabolites in all organs except the liver, where homogenization led to the detection of more metabolites. Altogether, 13 metabolites were detected, and one metabolite tentatively identified as a reduced product is being reported for the first time. SV and its metabolites were distributed to all the tissues studied except the brain. Overall, the results implied that the pulverized samples were more uniform and larger in surface area, resulting in their more efficient and complete extraction during sample preparation. As shown in the present study, MALDI Orbitrap MS is a useful tool to study drug and metabolite detection and characterization.
European-wide forest monitoring substantiate the neccessity for a joint conservation strategy to rescue European ash species (Fraxinus spp.)
Authors: George Jan-Peter , Sanders Tanja G. M. , Timmermann Volkmar , Potočić Nenad , Lang Mait
Published: March 2022

European ash (Fraxinus excelsior) and narrow-leafed ash (F. angustifolia) are keystone forest tree species with a broad ecological amplitude and significant economic importance. Besides global warming both species are currently under significant threat by an invasive fungal pathogen that has been spreading progressively throughout the continent for almost three decades. Ash dieback caused by the ascomyceteHymenoscyphus fraxineusis capable of damaging ash trees of all age classes and often ultimately leads to the death of a tree after years of progressively developing crown defoliation. While studies at national and regional level already suggested rapid decline of ash populations as a result of ash dieback, a comprehensive survey at European level with harmonized crown assessment data across countries could shed more light into the population decline from a pan-European perspective and could also pave the way for a new conservation strategy beyond national boarders. Here we present data from the ICP Forests Level I crown condition monitoring from 27 countries resulting in > 36,000 observations. We found a substantial increase in defoliation and mortality over time indicating that crown defoliation has almost doubled during the last three decades. Hotspots of mortality are currently situated in southern Scandinavia and north-eastern Europe. Overall survival probability after nearly 30 years of infection has already reached a critical value of 0.51, but with large differences among regions (0.20–0.86). Both a Cox proportional hazard model as well as an Aalen additive regression model strongly suggest that survival of ash is significantly lower in locations with excessive water regime and which experienced more extreme precipitation events during the last two decades. Our results underpin the necessity for fast governmental action and joint rescue efforts beyond national borders since overall mean defoliation will likely reach 50% as early as 2030 as suggested by time series forecasting.
Effect of plasma exchange on COVID-19 associated excess of von Willebrand factor and inflammation in critically ill patients
Authors: Seibert Felix S. , Blazquez-Navarro Arturo , Hölzer Bodo , Doevelaar Adrian A. N. , Nusshag Christian , Merle Uta , Morath Christian , Zgoura Panagiota , Dittmer Rita , Schneppenheim Sonja , Wilhelm Jochen , Babel Nina , Budde Ulrich , Westhoff Timm H.
Published: March 2022

Ubiquitous microthromboses in the pulmonary vasculature play a crucial role in the pathogenesis of COVID-19 associated acute respiratory distress syndrome (ARDS). Excess of Willebrand factor (vWf) with intravascular multimer formation was identified as a key driver of this finding. Plasma exchange (PLEX) might be a therapeutic option to restore the disbalance between vWf and ADAMTS13. We report the effects of PLEX on vWf, ADAMTS13, inflammatory cytokines and parameters of ventilation. We investigated 25 patients, who were on mechanical ventilation for COVID-19 pneumonia with ARDS at two German university hospitals. All patients received PLEX as an ultima ratio measure for refractory ARDS. VWf antigen (vWf:Ag), ADAMTS13 activity, a cytokine panel mirroring the inflammatory situation and clinical parameters were assessed before and after three to six PLEX therapies with fresh frozen plasma. Before the PLEX sequence there was an excessive release of vWf:Ag (425.4 ± 167.5%) and mildly reduced ADAMTS13 activity (49.7 ± 23.3%). After the PLEX series, there was a significant increase of ADAMTS13 activity to 62.4 ± 17.7% (p = 0.029) and a significant decrease of vWf:Ag to 336.1 ± 138.2% (p = 0.041) resulting in a 63% improvement of the ADAMT13/vWf:Ag ratio from 14.5 ± 10.0 to 23.7 ± 14.6, p = 0.024. Comparison of parameters before and after individual PLEX sessions (n = 35) revealed a mean reduction of vWf from 387.8 ± 165.1 to 213.2 ± 62.3% (p = 0.001) and an increase of ADAMTS13 activity from 60.4 ± 20.1 to 70.5 ± 14.0% (p = 0.001). Parallelly, monocyte chemotactic protein-1 and interleukin-18 decreased significantly (p = 0.034 each). Along the PLEX sequence lactate dehydrogenase (p = 0.001), C-reactive protein (p = 0.001), and positive end expiratory pressure (p = 0.01) significantly decreased accompanied by an improvement of Horovitz index (p = 0.001). PLEX restores the disbalance between ADAMTS13 and vWf:Ag, a driver of immunothrombosis. Moreover, it reduces the inflammatory state and is associated with a benefit of ventilation parameters. These findings render a further rationale to regard PLEX as a therapeutic option in severe COVID-19.
Simulation of the RAFT polymerization in 3D: steric restrictions and incompatibility between species
Authors: Gavrilov Alexey A. , Chertovich Alexander V.
Published: March 2022

RAFT polymerization model for dissipative particle dynamics is developed. The question of how to choose parameters for the model is discussed. The incompatibility between the species is shown to have a dramatic effect on the polymerization results.
Cucurbiturils mimicked by low polarizability solvents with pre-formed cavities: an empirical model to predict hydrocarbon selectivity
Authors: Nazimuddin Md , Barbero Héctor , Rabbani Ramin , Masson Eric
Published: March 2022

Mimicking cucurbiturils with low polarizability solvents and pre-formed cavities allows the in silico prediction of their selectivities towards hydrocarbons and noble gases in aqueous solution.