bluuebunny/crossref_metadata_2025 huggingface dataset:
Conclusion: ‘If Anyone Has Cursed Me…’
Authors: Eidinow Esther
Published: April 2023

This chapter concludes the initial investigation of part 1 into the different possible charges that were brought against women on trial in fourth-century bce Athens. Focusing on the charges that these women were performing illicit ritual practices, in particular accusations linking them and the creation of pharmaka, this chapter asks what kinds of social dynamics might give rise to those kinds of accusations. Returning to the story of Aretaphila (in Plutarch’s treatise on the Virtues of Women) discussed in chapter 1.2, it highlights the role of phthonos. This association between phthonos and magic-making is one that we also find attested in epigraphic evidence. A binding spell dating to the fourth century BCE is one of very few that gives us explicit information about the motivations behind aggressive magical action—and it highlights phthonos.
From Gossip to Action
Authors: Eidinow Esther
Published: April 2023

This chapter examines how the texts analysed in the previous three chapters reveal the role of gossip in expressing and generating interpretations of puzzling events. Such events are usually experiences of misfortune of some kind, and gossip is important in guiding attributions of blame and responsibility. A network analysis of the likely interrelations that shape gossip supports and illuminates these conclusions. This suggests how and why a legal case might develop out of local gossip. However, this process is not automatic, and contextual factors are crucial. The chapter presents a case where gossip failed to develop into a legal case: the case of the murder of Nicodemus. Although it was repeatedly alleged in a number of law-court speeches that Demosthenes was guilty of this murder, he was never charged.
After the War…
Authors: Eidinow Esther
Published: April 2023

This chapter takes a closer look at what is known—and not known—about the socio-economic situation of Athenians in the early to mid-fourth century. It explores changes in the population following the Peloponnesian war, and focuses on the immediate depletion of manpower and experiences of poverty. Despite her extensive foreign policy over the next half-century, the evidence indicates that, at least to begin with, Athens’ revenues were low; the problems of manning and resourcing her navy provides a case study. This chapter examines the ambivalent attitude to metics and foreigners in Athens; the concern with foreignness may reflect the increased mobility of populations. The Aegineticus of Isocrates gives a picture of the kinds of situations that forced families to travel. It reminds us that as well as the men that are the focus of our sources, there were many women caught in similar situations of dependence and survival, whose stories are more difficult to find.
Purification and characterization of a serine protease from the fruit of Ficus carica cultivar Masui Dauphine
Authors: Tokonami Mizuki , Horiguchi Akari , Ueshima Naoki , Takita Teisuke , Takahashi Toru , Nishimura Kosaku , Yasukawa Kiyoshi
Published: April 2023

Ficus carica produces, in addition to the cysteine protease ficin, a serine protease (FSP). Here, we purified FSP to homogeneity from the fruit of F. carica cultivar Masui Dauphine. An 81-fold enrichment in specific activity of FSP with 2.1% recovery was attained. Three protein bands (70, 62, and 60 kDa) were identified on SDS-PAGE. Each band was identified as a subtilisin-like protease (661 amino acids) by trypsin digestion and LC-MS/MS analysis, and the partial N-terminal amino-acid sequence analysis. Gelatin zymography revealed that the active FSP exists as a dimer. The optimum hydrolysis pH of FSP was 7.5, and the pHs at which the enzyme retained its initial activity by 70% in 24 h were 8.0–11.0. The optimum hydrolysis temperature of FSP was 50–60ºC, and the temperature required to reduce the initial activity by 50% in 15 min was 70ºC. These results will inform the industrial use of FSP.
Characterization of phenolic constituents in hazelnut kernels
Authors: Uchikura Takashi , Kitano Tomoe , Yoshimura Morio , Amakura Yoshiaki
Published: April 2023

Hazelnuts contain biologically active phenolic compounds and are widely used for their nutritional value. In this study, the phenolic compounds contained in hazelnuts were isolated from the kernels of Corylus avellana L. and investigated. Spectral analyses revealed 2 new acetophenone glycosides, characterized as 2′,4′,6′-trihydroxyacetophenone-4′-O-(2-O-β-d-apiosyl)-β-d-glucoside and 2′,4′,6′-trihydroxyacetophenone-4′-O-(2-O-β-d-apiosyl-6-O-α-l-arabinosyl)-β-d-glucoside, and 4 known compounds. Four high-molecular-mass condensed tannin fractions were detected in the water-soluble fraction of the extract, characterized as B-type procyanidin consisting of extension and terminal units. Gel permeation chromatography analyses revealed that the average molecular mass, based on the polystyrene standard, was approximately 15 000-113 000. These high-molecular-mass condensed tannin fractions were chemically characterized and exhibited different molecular weights. The fractions of high-molecular-mass condensed tannins were obtained from hazelnuts and tested for 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity. The EC50 values indicated significant activity for all the fractions.
Evaluation of epitranscriptome-wide N6-methyladenosine differential analysis methods
Authors: Duan Daoyu , Tang Wen , Wang Runshu , Guo Zhenxing , Feng Hao
Published: April 2023

RNA methylation has emerged recently as an active research domain to study post-transcriptional alteration in gene expression regulation. Various types of RNA methylation, including N6-methyladenosine (m6A), are involved in human disease development. As a newly developed sequencing biotechnology to quantify the m6A level on a transcriptome-wide scale, MeRIP-seq expands RNA epigenetics study in both basic and clinical applications, with an upward trend. One of the fundamental questions in RNA methylation data analysis is to identify the Differentially Methylated Regions (DMRs), by contrasting cases and controls. Multiple statistical approaches have been recently developed for DMR detection, but there is a lack of a comprehensive evaluation for these analytical methods. Here, we thoroughly assess all eight existing methods for DMR calling, using both synthetic and real data. Our simulation adopts a Gamma–Poisson model and logit linear framework, and accommodates various sample sizes and DMR proportions for benchmarking. For all methods, low sensitivities are observed among regions with low input levels, but they can be drastically boosted by an increase in sample size. TRESS and exomePeak2 perform the best using metrics of detection precision, FDR, type I error control and runtime, though hampered by low sensitivity. DRME and exomePeak obtain high sensitivities, at the expense of inflated FDR and type I error. Analyses on three real datasets suggest differential preference on identified DMR length and uniquely discovered regions, between these methods.
Britain and the Future of International Law
Authors: Allott Philip
Published: April 2023

British history shows that Britain has always been internationalist by necessity and by choice, with a belief in the Rule of Law as the basis of all public order, national and international. The human world is facing existential challenges which require new conceptions of international society and the international Rule of Law to which Britain is exceptionally well placed to contribute.
The economic burden of topical corticosteroid use in dermatophytosis: a cost-of-illness analysis of steroid-modified vs. steroid-naive dermatophytosis
Authors: Jagadeesan Soumya , Sreekumar Sarath , Sajini Lekshmi , Binu Aiswarya , Das Anupam
Published: April 2023

Dermatophytosis is one of the leading causes of visits to the dermatology department, especially in India, where the hot and humid climate favours fungal acquisition and perpetuation. Usual modalities of treatment include the use of either oral or topical antifungals or a combination of both, depending on the severity and extent of infection as well as the type of causative organism. But recently, steroid-modified dermatophytosis, an iatrogenically perpetuated dermatophytosis caused by the indiscriminate use of topical corticosteroids has emerged as a troublesome epidemic. We planned a cost-of-illness analysis of superficial dermatophytosis comparing the direct healthcare costs in steroid-naive and steroid-modified dermatophytosis. In our study, the average total cost of treatment for steroid-naive and steroid-modified dermatophytosis was found to be rupees (Rs) 2172.42 and Rs 3770.61 respectively, meaning that the cost for patients who used topical steroids is an additional 40% on average for treatment, when compared with the cost for patients who are steroid naive. The need for more consultations, investigations (relating to atypical presentation) and extended duration of treatment with higher-grade antifungals were found to contribute to the increased financial burden in steroid-modified dermatophytosis.
A simple definition of food resources for the highly polyphagous Lygus lineolaris (Hemiptera: Miridae) enables prediction of adult abundance
Authors: Andow David A
Published: April 2023

Lygus lineolaris (Palisot de Beauvois) is a highly polyphagous herbivore with more than 300 known host plants. The high polyphagy has created logistical challenges for understanding its population dynamics. I hypothesized that the primary food resource of this species can be characterized simply, cutting across the multiple host plant species, and enabling a simpler understanding of its population dynamics. The food resource was defined as the apical buds and meristematic tissue and terminal flowers and young seeds. Adult abundance in a habitat was related to the relative abundance of food in the habitat, abundance on a host plant stem was related to the amount of food resource on the stem, and the rate of emigration was lower from host plant patches with higher amounts of food resources. These results suggest that the population dynamics of L. lineolaris depends less on the identity of the host plants and more on the amount of food resource the various host plant species provide.
Trust intermediary in a cryptomarket for illegal drugs
Authors: Andrei Filippo , Barrera Davide , Krakowski Krzysztof , Sulis Emilio
Published: April 2023

Cooperation without third-party enforcement is particularly puzzling in illicit online markets given the anonymity of online exchanges in the ‘dark web’ and the asymmetry of information between buyers and sellers. Most of the literature investigates the effects of reputation systems on sales. Less is known about the role of (semi)institutionalized solutions to trust problems, such as the escrow service, which deposits payments for online purchases with the market platform and releases them only upon confirmation of the item delivery by a customer. We study the effect of such a trust intermediary on sales in a cryptomarket for illegal drugs. Using a large dataset of illegal online transactions, we estimate two sets of fixed effects models predicting the sellers’ choice to offer the trust intermediary and examine the effects of such a choice on sales. Our results indicate that the trust intermediary reduces online drug sales. We explain this finding by showing suggestive evidence that escrow may crowd out traders’ trust and reciprocity. Our findings have implications for theories of the role of institutions in online markets and offer policy recommendations for law enforcement agencies.
National human rights institutions: independent actors in global human rights governance?
Authors: Lacatus Corina , Carraro Valentina
Published: April 2023

In an increasingly complex global human rights regime, international governmental organizations like the United Nations remain concerned with closing the human rights governance gap. In this context, national human rights institutions (NHRIs) are uniquely equipped regulatory intermediaries—they have the mandated powers to support and monitor national governments' human rights compliance, but require government cooperation to operate effectively. We argue that institutional independence is key for regulatory intermediaries like NHRIs to conduct their work effectively. At the same time, independence should not be solely a formal, de jure feature; it is essential for it to also manifest as de facto independence. We thus investigate the extent to which the de jure independence of NHRIs matches their de facto independence, and explain variation. We measure NHRIs' de jure independence by employing quantitative data on 187 NHRIs. To study their de facto independence, we collect survey data on the participation of Asia–Pacific NHRIs in the Universal Periodic Review (UPR), a peer-review mechanism monitoring states' human rights performance. We show that regulatory intermediaries like NHRIs can be successful even when they lack full de jure independence. De facto independence is key, and is facilitated by both NHRI- and UPR-related factors.
The OSCE and climate security: diplomatic practice in a changing geopolitical context
Authors: Bremberg Niklas
Published: April 2023

This article analyses the role of the Organization for Security and Co-operation in Europe (OSCE) in the field of climate security. In 2021, the OSCE unanimously adopted a ministerial decision on climate change despite rising geopolitical tensions between Russia and the US. Why and how was this possible? The article answers these questions, drawing on a unique set of qualitative data collected from interviews with diplomats and officials conducted during Sweden's OSCE chairpersonship. The analytical framework draws on the concept of communities of practice to analyse how Swedish and like-minded diplomats built on the OSCE's approach to security to informally expand the domain of knowledge on climate-related security risks in the organization. The article suggests that the current political impasse in the OSCE does not necessarily mean that initiatives advanced by groups of like-minded states, in collaboration with the OSCE secretariat, need to be paralyzed. The findings reveal important features of multilateral diplomacy on climate security as well as how the OSCE works in practice.
Associations of periconceptional oral contraceptive use with pregnancy complications and adverse birth outcomes
Authors: Schreuder Anton , Mokadem Ibtissam , Smeets Nori J L , Spaanderman Marc E A , Roeleveld Nel , Lupattelli Angela , van Gelder Marleen M H J
Published: April 2023

Background

Periconceptional use of oral contraceptives (OCs) has been reported to increase risks of pregnancy complications and adverse birth outcomes, but risks are suggested to differ depending on the timing of discontinuation, amount of oestrogen and progestin content.

Methods

Prospective cohort study among 6470 pregnancies included in the PRegnancy and Infant DEvelopment (PRIDE) Study in 2012–19. Exposure was defined as any reported use of OCs within 12 months pre-pregnancy or after conception. Outcomes of interest were gestational diabetes, gestational hypertension, pre-eclampsia, pre-term birth, low birthweight and small for gestational age (SGA). Multivariable Poisson regression using stabilized inverse probability weighting estimated relative risks (RRs) with 95% CIs.

Results

Any periconceptional OC use was associated with increased risks of pre-eclampsia (RR 1.38, 95% CI 0.99–1.93), pre-term birth (RR 1.38, 95% CI 1.09–1.75) and low birthweight (RR 1.45, 95% CI 1.10–1.92), but not with gestational hypertension (RR 1.09, 95% CI 0.91–1.31), gestational diabetes (RR 1.02, 95% CI 0.77–1.36) and SGA (RR 0.96, 95% CI 0.75–1.21). Associations with pre-eclampsia were strongest for discontinuation 0–3 months pre-pregnancy, for OCs containing ≥30 µg oestrogen and for first- or second-generation OCs. Pre-term birth and low birthweight were more likely to occur when OCs were discontinued 0–3 months pre-pregnancy, when using OCs containing <30 µg oestrogen and when using third-generation OCs. Associations with SGA were observed for OCs containing <30 µg oestrogen and for third- or fourth-generation OCs.

Conclusions

Periconceptional OC use, particularly those containing oestrogen, was associated with increased risks of pre-eclampsia, pre-term birth, low birthweight and SGA.
On Multiplicative Functions with Small Partial Sums
Authors: Sachpazis Stelios
Published: April 2023

In analytic number theory, several results make use of information regarding the prime values of a multiplicative function in order to extract information about its averages. Examples of such results include Wirsing’s theorem and the Landau–Selberg–Delange method. In this paper, we are interested in the opposite direction. In particular, we prove that when $f$ is a suitable divisor-bounded multiplicative function with small partial sums, then $f(p)\approx -p^{i\gamma _1}-\ldots -p^{i\gamma _m}$ on average, where the $\gamma _j$s are the imaginary parts of the zeros of the Dirichet series of $f$ on the line $\textrm {Re}(s)=1$. This extends a result of Koukoulopoulos and Soundararajan and it builds upon ideas coming from previous work of Koukoulopoulos for the case where $|f|\leqslant 1$.
European Regional International Society and the Political Economy of the Global Sugar Regime
Authors: Andrieu Kieran , Lubbock Rowan
Published: April 2023

This paper seeks to contribute to the English School's (ES) understanding of the European Regional International Society (ERIS) through the work of Karl Polanyi. While ES theory has long been interested in regional international societies, its general approach remains limited to a methodologically internationalist frame that fails to capture the dynamism and historical change of regional formations. We therefore aim to better ground the ES account of the ERIS within a more robust political economy framework that incorporates domestic dynamics with international processes. The article first examines the making of the nineteenth-century liberal order and its eventual breakdown during the turn of the century—the “great transformation”, which ultimately informed the rationale for the European Community (EC). We then focus our analysis on the EC's Common Agricultural Policy. With specific examination of sugar production, we explore the tensions and contradictions bound up with the formation of a protected domestic and regional sugar market, the pressures it exerted on the wider international society, and the ways in which European officials skillfully exploited the post-Cold War liberalization of international society as a means of (partially) “disembedding” European sugar. Lastly, we hope that this article begins a new conversation on how the tenets of political economy (Polanyian or otherwise) might, at long last, make an impact on ES theory.
Genetic and biochemical characterization of BIM-1, a novel acquired subgroup B1 MBL found in a Pseudomonas sp. strain from the Brazilian Amazon region
Authors: Souza Cintya O , Cayô Rodrigo , Lima Karla Valéria B , Brasiliense Danielle M , Streling Ana Paula , Siqueira André V , Alberto-Lei Felipe , Leal Josiane T , Nodari Carolina S , Pérez-Chaparro Paula Juliana , Lima Luana N G C , Lima Marcelo O , Costa Brenda Natasha S , De Queiroz Thais Karolina L , Silva Paola J S N , Mamizuka Elza M , Marcondes Marcelo F , Mcculloch John Anthony , Gales Ana Cristina
Published: April 2023

Objectives

To characterize a novel acquired MBL, BIM-1, in a Pseudomonas #2 (subgroup P. guariconensis) strain isolated from the Aurá river located in the Brazilian Amazon hydrographic basin.

Methods

WGS using an Illumina® MiSeq System was used to characterize the genome of Pseudomonas sp. IEC33019 strain. Southern blotting/hybridization assays were performed to confirm the location of the MBL-encoding gene, blaBIM-1 (Belém Imipenemase). Antimicrobial susceptibility testing, cloning, and biochemical and phenotypic characterization were performed to determine BIM-1 kinetics.

Results

The IEC33019 strain showed high resistance rates to β-lactams, ciprofloxacin and aminoglycosides, being susceptible only to polymyxins and susceptible, increased exposure to aztreonam. WGS analysis revealed a novel acquired MBL-encoding gene, blaBIM-1, found as a gene cassette inserted into a class 1 integron (In1326) that also carried qnrVC1 and aadA11e. In1326 was located in a complex transposon, Tn7122, carried by a 52.7 kb conjugative plasmid (pIEC33019) with a toxin/antitoxin system (vapB/vapC). BIM-1 belongs to the molecular subgroup B1 and shares 70.2% and 64.9% similarity with SIM-1 and IMP-1, respectively. Kinetics analysis of BIM-1 showed hydrolytic activity against all β-lactams tested.

Conclusions

BIM-1 is a novel acquired MBL encoded by a gene carried by mobile genetic elements, which can be transferred to other Gram-negative bacilli (GNB). Because the IEC33019 strain was recovered from a river impacted by a populous metropolitan region with poor basic sanitation and served by limited potable freshwater, it would be important to establish the role of the BIM-1-producing GNB as nosocomial pathogens and/or as colonizers of the riverside population in this geographical region.
Drug–drug interaction: decreased posaconazole trough concentrations during concomitant flucloxacillin treatment
Authors: Wortman Julia M , Leegwater Emiel , Van Lammeren-Venema Daniëlle , Van Nieuwkoop Cees , Sobels Annemieke , Wilms Erik B
Published: April 2023

Background and objectives

Posaconazole is used as prophylaxis of invasive fungal disease in immune-compromised haematological patients with prolonged neutropenia after intensive chemotherapy. During routine therapeutic drug monitoring of posaconazole, we repeatedly observed low posaconazole serum concentrations in patients that were concomitantly treated with flucloxacillin. A possible interaction between flucloxacillin and posaconazole was explored in this case series.

Patients and methods

Posaconazole trough serum concentrations during and before/after flucloxacillin treatment were collected from 10 patients.

Results

With a median concentration of 0.5 mg/L (IQR 0.3–0.6), the posaconazole trough serum concentration decreased by 47% during flucloxacillin treatment compared with the concentration before/after flucloxacillin treatment (0.9 mg/L, IQR 0.6–1.3). As a result, the posaconazole target trough concentration of ≥0.7 mg/L was only achieved in five out of nine patients during flucloxacillin treatment.

Conclusions

Careful monitoring of posaconazole serum trough concentrations is recommended when concomitant use of flucloxacillin cannot be avoided.
3,5-bis(styryl)pyrazole inhibits mitosis and induces cell death independent of BubR1 and p53 levels by depolymerizing microtubules
Authors: Batra Pooja J , Kumari Anuradha , Liao Vivian W Y , Hibbs David E , Groundwater Paul W , Panda Dulal
Published: April 2023

Here, we show that 3,5-bis[(1E)-2-(2,6-dichlorophenyl)ethenyl]-1H-pyrazole 2l depolymerizes microtubules and reduces the number of growing tips of microtubules. The fluorescence recovery after photobleaching experiment in live MCF-7 cells showed that pyrazole 2l suppresses spindle microtubule dynamics. Further, the compound inhibits chromosome movements, activates the spindle assembly checkpoint and blocks mitosis in MCF-7 cells. Pyrazole 2l treatment induced cell death in a variety of pathways. Pyrazole 2l induces cell death independent of BubR1 and p53 levels of MCF-7 cells upon microtubule depolymerization. Further, pyrazole 2l increases the interaction between NF-κB and microtubules and enhances the nuclear localization of NF-κB at its half-maximal proliferation inhibitory concentration while a high concentration of the compound reduced the nuclear localization of NF-κB. Interestingly, the compound exerted significantly stronger antiproliferative effects in cancerous cells than in non-cancerous cells. The results indicated that pyrazole 2l inhibits mitosis by targeting microtubules, induces several types of cell death stimuli and suggests its potential as a lead in developing anticancer agent.
Clinical practice of UroVysion® urine test in patients with bladder carcinoma in situ treated with intravesical Bacillus Calmette–Guerin
Authors: Miyake Makito , Hori Shunta , Fujii Tomomi , Nishimura Nobutaka , Oda Yuki , Miyamoto Tatsuki , Tomizawa Mitsuru , Shimizu Takuto , Ohnishi Kenta , Morizawa Yosuke , Gotoh Daisuke , Nakai Yasushi , Torimoto Kazumasa , Tanaka Nobumichi , Fujimoto Kiyohide
Published: April 2023

In January 2019, the use of the UroVysion® urine test for surveillance of non-muscle invasive bladder cancer with carcinoma in situ (CIS) was approved in Japan. Clinical evidence of its use remains limited. Herein, we report the real-world clinical practice of the UroVysion test. Of 29 patients underwent at least one UroVysion test at our hospital from 2019 to 2022, only two (6.9%) tested positive without any visible tumor on the cystoscopy after the initial transurethral resection: a 77-year-old man with T1 high-grade tumor and concomitant CIS and a 76-year-old woman with CIS. The remaining 27 patients (93.1%) tested negative post-transurethral resection. This study was the first to report the Japanese real-world practice of the UroVysion test, demonstrating relatively low positive rate as compared to the previous reports from other countries. Further clinical evidence from other Japanese institutes needs to be accumulated to update the true value of this test.
Settlement Around the World: Settlement Rates in the Largest Economies
Authors: Chang Yun-chien , Klerman Daniel
Published: April 2023

This article presents the first rigorous, multi-country analysis of settlement rates. Data on settlement were collected for twenty-three of the twenty-five largest economies. Settlement rates vary greatly, from below 15% in France, Belgium, and Russia, to over two-thirds in Australia. Settlement rates also vary by subject matter, with settlement rates generally highest in tort, especially in the U.S. There are also dramatic differences in settlement rates by legal origin, with common law countries generally having the highest settlement rates. Because settlement rates in civil law countries are so low, selection effects may not be a significant problem for empirical work involving them. Higher settlement rates are correlated with early disclosure and shorter court delays, but more research is needed to explain the large differences in settlement rates.
In vitro simulation of the acute lymphoblastic leukemia niche: a critical view on the optimal approximation for drug testing
Authors: Pottosin Igor , Olivas-Aguirre Miguel , Dobrovinskaya Oxana
Published: April 2023

Acute lymphoblastic leukemia with the worst prognosis is related to minimal residual disease. Minimal residual disease not only depends on the individual peculiarities of leukemic clones but also reflects the protective role of the acute lymphoblastic leukemia microenvironment. In this review, we discuss in detail cell-to-cell interactions in the 2 leukemic niches, more explored bone marrow and less studied extramedullary adipose tissue. A special emphasis is given to multiple ways of interactions of acute lymphoblastic leukemia cells with the bone marrow or extramedullary adipose tissue microenvironment, indicating observed differences in B- and T-cell–derived acute lymphoblastic leukemia behavior. This analysis argued for the usage of coculture systems for drug testing. Starting with a review of available sources and characteristics of acute lymphoblastic leukemia cells, mesenchymal stromal cells, endothelial cells, and adipocytes, we have then made an update of the available 2-dimensional and 3-dimensional systems, which bring together cellular elements, components of the extracellular matrix, or its imitation. We discussed the most complex available 3-dimensional systems like “leukemia-on-a-chip,” which include either a prefabricated microfluidics platform or, alternatively, the microarchitecture, designed by using the 3-dimensional bioprinting technologies. From our analysis, it follows that for preclinical antileukemic drug testing, in most cases, intermediately complex in vitro cell systems are optimal, such as a “2.5-dimensional” coculture of acute lymphoblastic leukemia cells with niche cells (mesenchymal stromal cells, endothelial cells) plus matrix components or scaffold-free mesenchymal stromal cell organoids, populated by acute lymphoblastic leukemia cells. Due to emerging evidence for the correlation of obesity and poor prognosis, a coculture of adipocytes with acute lymphoblastic leukemia cells as a drug testing system is gaining shape.
G protein-coupled receptor–mediated membrane targeting of PLCγ2 is essential for neutrophil chemotaxis
Authors: Xu Xuehua , Wen Xi , Bhimani Smit , Moosa Amer , Parsons Dustin , Ha HyunGee , Jin Tian
Published: April 2023

The current dogma is that chemoattractants G protein-coupled receptors activate β phospholipase C while receptor tyrosine kinases activate γ phospholipase C. Here, we show that chemoattractant/G protein-coupled receptor-mediated membrane recruitment of γ2 phospholipase C constitutes G protein-coupled receptor-mediated phospholipase C signaling and is essential for neutrophil polarization and migration during chemotaxis. In response to a chemoattractant stimulation, cells lacking γ2 phospholipase C (plcg2kd) displayed altered dynamics of diacylglycerol production and calcium response, increased Ras/PI3K/Akt activation, elevated GSK3 phosphorylation and cofilin activation, impaired dynamics of actin polymerization, and, consequently, defects in cell polarization and migration during chemotaxis. The study reveals a molecular mechanism of membrane targeting of γ2 phospholipase C and the signaling pathways by which γ2 phospholipase C plays an essential role in neutrophil chemotaxis.
Inverse agonists of retinoic acid receptor/retinoid X receptor signaling as lineage-specific antitumor agents against human adenoid cystic carcinoma
Authors: Viragova Sara , Aparicio Luis , Palmerini Pierangela , Zhao Junfei , Valencia Salazar Luis E , Schurer Alexandra , Dhuri Anika , Sahoo Debashis , Moskaluk Christopher A , Rabadan Raul , Dalerba Piero
Published: April 2023

Background

Adenoid cystic carcinoma (ACC) is a lethal malignancy of exocrine glands, characterized by the coexistence within tumor tissues of 2 distinct populations of cancer cells, phenotypically similar to the myoepithelial and ductal lineages of normal salivary epithelia. The developmental relationship linking these 2 cell types, and their differential vulnerability to antitumor treatments, remains unknown.

Methods

Using single-cell RNA sequencing, we identified cell-surface markers (CD49f, KIT) that enabled the differential purification of myoepithelial-like (CD49fhigh/KITneg) and ductal-like (CD49flow/KIT+) cells from patient-derived xenografts (PDXs) of human ACCs. Using prospective xenotransplantation experiments, we compared the tumor-initiating capacity of the 2 cell types and tested whether one could differentiate into the other. Finally, we searched for signaling pathways with differential activation between the 2 cell types and tested their role as lineage-specific therapeutic targets.

Results

Myoepithelial-like cells displayed higher tumorigenicity than ductal-like cells and acted as their progenitors. Myoepithelial-like and ductal-like cells displayed differential expression of genes encoding for suppressors and activators of retinoic acid signaling, respectively. Agonists of retinoic acid receptor (RAR) or retinoid X receptor (RXR) signaling (all-trans retinoic acid, bexarotene) promoted myoepithelial-to-ductal differentiation, whereas suppression of RAR/RXR signaling with a dominant-negative RAR construct abrogated it. Inverse agonists of RAR/RXR signaling (BMS493, AGN193109) displayed selective toxicity against ductal-like cells and in vivo antitumor activity against PDX models of human ACC.

Conclusions

In human ACCs, myoepithelial-like cells act as progenitors of ductal-like cells, and myoepithelial-to-ductal differentiation is promoted by RAR/RXR signaling. Suppression of RAR/RXR signaling is lethal to ductal-like cells and represents a new therapeutic approach against human ACCs.
Women’s disordered eating and sexual function: the role of interoception
Authors: Poovey Kendall , de Jong David , Rancourt Diana
Published: April 2023

Background

Among women, disordered eating and sexual difficulties commonly co-occur.

Aim

We investigated whether interoceptive dysfunction (ie, altered processing of body cues) may be a common cause (ie, third variable) contributing to these concomitant outcomes above and beyond body mass index (BMI) and body image concerns.

Methods

Women (n = 1201; mean age = 25.92 years; mean BMI = 25.46 kg/m2; 61.6% heterosexual, 27.5% bisexual) were recruited from sexual education courses at a midsize southeastern university and Reddit communities related to women’s health, sex, and disordered eating. Participants completed online measures of self-reported interoception (Multidimensional Assessment of Interoceptive Awareness Version 2), disordered eating attitudes and behaviors (Eating Disorder Examination Questionnaire), sexual function (Female Sexual Function Index), and demographic information, including height and weight. Regression, commonality, and dominance analyses were completed in R.

Outcomes

Sexual function was assessed via the Female Sexual Function Index.

Results

Both general interoception and body trust (a facet of interoception concerned with trust of internal sensations) predicted dietary restraint and sexual function (Ps < .001). After accounting for both general interoception (β = 0.27, P < .001) and body trust (β = 0.32, P < .001) in hierarchal regression models predicting sexual function, dietary restraint either evidenced a reduction in its standardized beta or was no longer associated with sexual function. Body image concerns also emerged as a robust predictor of women’s sexual function. Body trust accounted for the most unique variance (4.45%) in women’s sexual function and commonly accounted for another 3.70% of variance with body image concerns.

Clinical Implications

Interoceptive exposure interventions may contribute to better outcomes for women with disordered eating, sexual difficulties, or co-occurring concerns, a notion worthy of future investigation.

Strengths and Limitations

Strengths include a large diverse sample in terms of sexual orientation (>35% sexual minority) and body size (BMIs from underweight to class 3 obesity). The cross-sectional nature of this study precludes any conclusions regarding temporal precedence or causality. Future studies should use different measures of dietary restraint for nonclinical populations (eg, objective measures of caloric intake).

Conclusion

Findings suggest that both interoception and body image concerns contribute to the co-occurrence of disordered eating behaviors and sexual difficulties, and that both may be important risk/maintaining factors to consider in future work. Interoception should be integrated into models of women’s sexual function, as it may be just as important to women’s sexual well-being as body image concerns.
Development and properties evaluation of multi-strain probiotic with cholesterol-lowering potentialin vitro
Authors: Zhao Peng , Li Mingxing , Mo Xiang , Yang Junwei , Liu Lifeng , Huang Yuanxia , Qiu Zhongping
Published: April 2023

Probiotics have a cholesterol-lowering effect. Multi-strain probiotics (MSPs) outperformed single-strain probiotics due to the interaction of strains. Hence, we expect to develop a high-efficiency MSP for lowering cholesterol. Three strains, including Lactobacillus caseiS1, Enterococcus faeciumS4, and L. harbinensisS6, were used to develop the MSPs. To evaluate their effect, gastrointestinal tolerance, bile salt hydrolase (BSH) activity, cholesterol-lowering rate, antioxidant ability, gamma-aminobutyric acid (GABA) production, and antibiotic sensitivity were determined. The triple lactic acid bacteria probiotic (TLP) was the most efficient one. After 24 h treatment with artificial gastric fluid, 47.88% of TLP survived. TLP exhibited the highest BSH activity (149.40 U·ml−1) and cholesterol-lowering rate (75.05%) in vitro, with co-precipitation reducing the majority of cholesterol. The reducing power and superoxide radical scavenging rate of the cell-free supernatant and the hydroxyl radical scavenging rate in viable cells were 1.52, 85.03%, and 89.66%, respectively, and the GABA production was 0.67 mg·ml−1, which enhanced the health benefit effects. By fuzzy mathematical analysis, TLP was the optimal probiotic and was competitive with commercial probiotics. The three strains were susceptible to 13 antibiotics. Therefore, TLP has the potential to develop into a cholesterol-lowering probiotic preparation.
The correlation between denaturation of glyceraldehyde-3-phosphate dehydrogenase and inactivation ofSaccharomyces pastorianuscells by pressurized carbon dioxide microbubbles
Authors: Takahashi Konomi , Kobayashi Fumiyuki , Narai-Kanayama Asako , Odake Sachiko
Published: April 2023

For the purpose of clarifying the relationship between pasteurization and inactivation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in Saccharomyces pastorianus cells induced by pressurized carbon dioxide microbubbles (CO2MB) treatment, a storage test of S. pastorianus cells after CO2MB treatment was conducted to ascertain their recovery, and the treatment condition in the inactivation of GAPDH in S. pastorianus cells by CO2MB was investigated. Each population of S. pastorianus for 48, 96, and 144 h at 25°C was decreased significantly by CO2MB treatment at 35°C for 3 min (MB35-3 and MB35-5) or at 40°C and 45°C for 1 and 3 min (MB40-1, MB40-3, and MB45-1). In the storage test, recovery of treated cells was not observed after storage for 144 h at 25°C. The denaturation of GAPDH in the S. pastorianus cells caused by the same treatment as the storage test was detected by using sodium dodecyl sulphate polyacrylamide gel electrophoresis. While the activities at MB35-1, MB35-3, and MB40-1 were significantly higher than those at non-treatment, and those at MB35-5, MB40-3, and MB45-1 were lower. Therefore, GAPDH denaturation, but not the activity, was associated with the inactivation of S. pastorianus cells.
Unravelling optical and X-ray properties of the disc-dominated intermediate polar IGR J15094-6649
Authors: Joshi Arti , Rawat Nikita , Schwope Axel , Pandey J C , Scaringi Simone , Sahu D K , Rao Srinivas M , Singh Mridweeka
Published: April 2023

We present analyses of an Intermediate Polar, IGR J15094-6649, based on the archival optical data obtained from the Transiting Exoplanet Survey Satellite (TESS) and X-ray data obtained from the Suzaku, NuSTAR, and Neil Gehrels Swift Observatory (Swift). Present analysis confirms and refines the previously reported spin period of IGR J15094-6649 as 809.49584 ± 0.00075 s. Clear evidence of a beat period of 841.67376 ± 0.00082 s is found during the long-term TESS optical observations, which was not evident in the earlier studies. The dominance of X-ray and optical spin pulse unveils the disc-fed dominance accretion, however, the presence of an additional beat frequency indicates that part of the accreting material also flows along the magnetic field lines. The energy-dependent spin pulsations in the low (<10 keV) energy band are due to the photoelectric absorption in the accretion flow. However, the complex absorbers may be responsible to produce low amplitude spin modulations via Compton scattering in the hard (>10 keV) energy band and indicate that the height of the X-ray emitting region may be negligible. The observed double-humped X-ray profiles with a pronounced dip are indicative of the photoelectric absorption in the intervening accretion stream. Analysis of the X-ray spectra reveals the complexity of the X-ray emission, being composed of multitemperature plasma components with a soft excess, reflection, and suffers from strong absorption.
Evolution of the SARS-CoV-2 Mutational Spectrum
Authors: Bloom Jesse D , Beichman Annabel C , Neher Richard A , Harris Kelley
Published: April 2023

SARS-CoV-2 evolves rapidly in part because of its high mutation rate. Here, we examine whether this mutational process itself has changed during viral evolution. To do this, we quantify the relative rates of different types of single-nucleotide mutations at 4-fold degenerate sites in the viral genome across millions of human SARS-CoV-2 sequences. We find clear shifts in the relative rates of several types of mutations during SARS-CoV-2 evolution. The most striking trend is a roughly 2-fold decrease in the relative rate of G→T mutations in Omicron versus early clades, as was recently noted by Ruis et al. (2022. Mutational spectra distinguish SARS-CoV-2 replication niches. bioRxiv, doi:10.1101/2022.09.27.509649). There is also a decrease in the relative rate of C→T mutations in Delta, and other subtle changes in the mutation spectrum along the phylogeny. We speculate that these changes in the mutation spectrum could arise from viral mutations that affect genome replication, packaging, and antagonization of host innate-immune factors, although environmental factors could also play a role. Interestingly, the mutation spectrum of Omicron is more similar than that of earlier SARS-CoV-2 clades to the spectrum that shaped the long-term evolution of sarbecoviruses. Overall, our work shows that the mutation process is itself a dynamic variable during SARS-CoV-2 evolution and suggests that human SARS-CoV-2 may be trending toward a mutation spectrum more similar to that of other animal sarbecoviruses.
Differential impact of COVID-19 on mental health and burnout
Authors: Maniero C , Ng S M , Collett G , Godec T , Siddiqui I , Antoniou S , Kumar A , Janmohamed A , Nair S , Kotecha A , Khan R , Khanji M Y , Kapil V , Gupta J , Gupta A K
Published: April 2023

Background

There may be differential impact of the COVID-19 pandemic on mental health and burnout rates of healthcare professionals (HCPs) performing different roles.

Aims

To examine mental health and burnout rates, and possible drivers for any disparities between professional roles.

Methods

In this cohort study, online surveys were distributed to HCPs in July–September 2020 (baseline) and re-sent 4 months later (follow-up; December 2020) assessing for probable major depressive disorder (MDD), generalized anxiety disorder (GAD), insomnia, mental well-being and burnout (emotional exhaustion and depersonalization). Separate logistic regression models (at both phases) compared the risk of outcomes between roles: healthcare assistants (HCAs), nurses and midwives (nurses), allied health professionals (AHPs) and doctors (reference group). Separate linear regression models were also developed relating the change in scores to professional role.

Results

At baseline (n = 1537), nurses had a 1.9-fold and 2.5-fold increased risk of MDD and insomnia, respectively. AHPs had a 1.7-fold and 1.4-fold increased risk of MDD and emotional exhaustion, respectively. At follow-up (n = 736), the disproportionate risk between doctors and others worsened: nurses and HCAs were at 3.7-fold and 3.6-fold increased risk of insomnia, respectively. Nurses also had a significantly increased risk of MDD, GAD, poor mental well-being and burnout. Nurses also had significantly worsened anxiety, mental well-being and burnout scores over time, relative to doctors.

Conclusions

Nurses and AHPs had excess risk of adverse mental health and burnout during the pandemic, and this difference worsened over time (in nurses especially). Our findings support adoption of targeted strategies accounting for different HCP roles.
The impossibility of the impossible trinity? The case of Indonesia
Authors: Basri M Chatib , Sumartono Luqman
Published: April 2023

The impossible trinity suggests that an economy cannot simultaneously achieve a fixed exchange rate, high capital mobility, and independent monetary policy without abandoning one of these. However, This paper looks at Indonesia’s experiences from the 2009 QE and the 2013 taper tantrum, considering why Indonesian policy-makers were unable to use policies as per the trilemma, and the policy implications of this. There are three possible reasons why Indonesia found it difficult to implement this trilemma policy choice: differing monetary policy objectives, volatile floating exchange rates, and balance sheet effects. The commodity supercycle also plays an exogenous role, unable to be overcome by monetary or exchange rate policy while at the same time impacting fiscal policy, income redistribution, trade balance, and the exchange rate. Overall, this paper argues that monetary policy on its own is likely to be insufficient to manage the economy adequately. Other levers and factors, such as macroprudential policy, fiscal policy, capital flow management, and institutional quality, are critical to make the policy choices more effective.
How will digital technologies influence the international monetary system?
Authors: Prasad Eswar
Published: April 2023

New and evolving financial technologies, including the advent of cryptocurrencies and central bank digital currencies (CBDCs), will make cross-border payments cheaper and quicker. However, reduced frictions in global capital flows could also result in more capital flow and exchange rate volatility, which is of particular concern for emerging market economies. There will be greater competition among fiat currencies and certain private currencies such as stablecoins in their roles as mediums of exchange for payment and settlement of domestic as well as cross-border transactions. However, neither the advent of CBDCs nor the lowering of barriers to international financial flows will do much on their own to reorder the international monetary system or the balance of power among major currencies. Currencies such as the US dollar that are dominant stores of value will remain so because that dominance rests not just on the issuing country’s economic size and financial market depth, but also on a strong institutional foundation that is essential for maintaining investors’ trust in a currency.
Large root cortical cells and reduced cortical cell files improve growth under suboptimal nitrogen in silico
Authors: Lopez-Valdivia Ivan , Yang Xiyu , Lynch Jonathan P
Published: April 2023

Suboptimal nitrogen availability is a primary constraint to plant growth. We used OpenSimRoot, a functional-structural plant/soil model, to test the hypothesis that larger root cortical cell size (CCS), reduced cortical cell file number (CCFN), and their interactions with root cortical aerenchyma (RCA) and lateral root branching density (LRBD) are useful adaptations to suboptimal soil nitrogen availability in maize (Zea mays). Reduced CCFN increased shoot dry weight over 80%. Reduced respiration, reduced nitrogen content, and reduced root diameter accounted for 23%, 20%, and 33% of increased shoot biomass, respectively. Large CCS increased shoot biomass by 24% compared with small CCS. When simulated independently, reduced respiration and reduced nutrient content increased the shoot biomass by 14% and 3%, respectively. However, increased root diameter resulting from large CCS decreased shoot biomass by 4% due to an increase in root metabolic cost. Under moderate N stress, integrated phenotypes with reduced CCFN, large CCS, and high RCA improved shoot biomass in silt loam and loamy sand soils. In contrast, integrated phenotypes composed of reduced CCFN, large CCS, and reduced LRBD had the greatest growth in silt loam, while phenotypes with reduced CCFN, large CCS, and high LRBD were the best performers in loamy sands. Our results support the hypothesis that larger CCS, reduced CCFN, and their interactions with RCA and LRBD could increase nitrogen acquisition by reducing root respiration and root nutrient demand. Phene synergisms may exist between CCS, CCFN, and LRBD. CCS and CCFN merit consideration for breeding cereal crops with improved nitrogen acquisition, which is critical for global food security.