bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal Epidermal Growth Factor Promotes Neonatal Claudin-2 Dependent Increases in Small Intestinal Calcium Permeability
Authors: Beggs Megan R , Young Kennedi , Plain Allen , O'Neill Debbie D , Raza Ahsan , Flockerzi Veit , Dimke Henrik , Alexander R Todd
Published: June 2023

A higher concentration of calcium in breast milk than blood favors paracellular calcium absorption enabling growth during postnatal development. We aimed to determine whether suckling animals have greater intestinal calcium permeability to maximize absorption and to identify the underlying molecular mechanism. We examined intestinal claudin expression at different ages in mice and in human intestinal epithelial (Caco-2) cells in response to hormones or human milk. We also measured intestinal calcium permeability in wildtype, Cldn2 and Cldn12 KO mice and Caco-2 cells in response to hormones or human milk. Bone mineralization in mice was assessed by μCT. Calcium permeability across the jejunum and ileum of mice were 2-fold greater at 2 wk than 2 mo postnatal age. At 2 wk, Cldn2 and Cldn12 expression were greater, but only Cldn2 KO mice had decreased calcium permeability compared to wildtype. This translated to decreased bone volume, cross-sectional thickness, and tissue mineral density of femurs. Weaning from breast milk led to a 50% decrease in Cldn2 expression in the jejunum and ileum. Epidermal growth factor (EGF) in breast milk specifically increased only CLDN2 expression and calcium permeability in Caco-2 cells. These data support intestinal permeability to calcium, conferred by claudin-2, being greater in suckling mice and being driven by EGF in breast milk. Loss of the CLDN2 pathway leads to suboptimal bone mineralization at 2 wk of life. Overall, EGF-mediated control of intestinal claudin-2 expression contributes to maximal intestinal calcium absorption in suckling animals.
New mutant alleles for Spargel/dPGC-1 highlights the function of Spargel RRM domain in oogenesis and expands the role of Spargel in embryogenesis and intracellular transport
Authors: Roy Swagota D , Nagarajan Sabarish , Jalal Md Shah , Basar Md Abul , Duttaroy Atanu
Published: June 2023

Energy metabolism in vertebrates is controlled by three members of the PGC-1 (PPAR γ− coactivator 1) family, transcriptional coactivators that shape responses to physiological stimuli by interacting with the nuclear receptors and other transcription factors. Multiple evidence now supports that Spargel protein found in insects and ascidians is the ancestral form of vertebrate PGC-1's. Here, we undertook functional analysis of srl gene in Drosophila, asking about the requirement of Spargel per se during embryogenesis and its RNA binding domains. CRISPR- engineered srl gene deletion turned out to be an amorphic allele that is late embryonic/early larval lethal and Spargel protein missing its RNA binding domain (SrlΔRRM) negatively affects female fertility. Overexpression of wild-type Spargel in transgenic flies expedited the growth of egg chambers. On the other hand, oogenesis is blocked in a dominant-negative fashion in the presence of excess Spargel lacking its RRM domains. Finally, we observed aggregation of Notch proteins in egg chambers of srl mutant flies, suggesting that Spargel is involved in intracellular transport of Notch proteins. Taken together, we claim that these new mutant alleles of spargel are emerging powerful tools for revealing new biological functions for Spargel, an essential transcription coactivator in both Drosophila and mammals.
Recombination and sterility in inversion homo- and heterokaryotypes under a general counting model of chiasma interference
Authors: Kapperud Øystein
Published: June 2023

It has long been known that the chiasmata are not independently distributed in most organisms, a phenomenon known as chiasma interference. In this paper, I suggest a model of chiasma interference that generalizes the Poisson model, the counting model, the Poisson-skip model, and the two-pathway counting model into a single framework, and use it to derive infinite series expressions for the sterility and recombination pattern probabilities in inversion homo- and heterokaryotypes, and a closed-form expression for the special case of the two-pathway counting model in homokaryotypes. I then use these expressions to perform maximum likelihood parameter estimations for recombination and tetrad data from various species. The results imply that the simpler counting models perform well compared to more complex ones, that interference works in a similar way in homo- and heterokaryotypes, and that the model fits well with data for the latter as well as the former. I also find evidence that the interference signal is broken by the centromere in some species, but not others, suggestions of negative interference in Aspergillus nidulans, and no consistent support for the theory that a second noninterfering chiasma pathway exists only in organisms that require double-strand break for synapsis. I suggest that the latter finding is at least partly due to issues involved in analyzing aggregate data from different experiments and individuals.
Irreducible ambiguity? The line between custom and statute in the law-making of thirteenth-century Poland
Authors: Górecki Piotr
Published: June 2023

A resurging subject today is medieval customary law and its boundary with statute. Regarding Poland, the inquiry is complicated by a historiographical consensus that here the law essentially was customary, supplemented by statute only in the later fourteenth century. This certainty has reduced legal reality to unwarranted uniformity. In response, I survey the terminology related to custom and statute, examine one document bridging that terminology and an enactment resembling a statute, and place that enactment in a long earlier legacy of written rule-making. This is not a sharp transition from custom to statute, but an evolving sequence of written expression.
Collecting–Gathering Biophysics of the BlackwormLumbriculus variegatus
Authors: Tuazon Harry , Nguyen Chantal , Kaufman Emily , Tiwari Ishant , Bermudez Jessica , Chudasama Darshan , Peleg Orit , Bhamla M Saad
Published: June 2023

Synopsis

Many organisms exhibit collecting and gathering behaviors as a foraging and survival method. Benthic macroinvertebrates are classified as collector–gatherers due to their collection of particulate matter. Among these, the aquatic oligochaete Lumbriculus variegatus (California blackworms) demonstrates the ability to ingest both organic and inorganic materials, including microplastics. However, earlier studies have only qualitatively described their collecting behaviors for such materials. The mechanism by which blackworms consolidate discrete particles into a larger clump remains unexplored quantitatively. In this study, we analyze a group of blackworms in a large arena with an aqueous algae solution (organic particles) and find that their relative collecting efficiency is proportional to population size. We found that doubling the population size (N = 25–N = 50) results in a decrease in time to reach consolidation by more than half. Microscopic examination of individual blackworms reveals that both algae and microplastics physically adhere to the worm’s body and form clumps due to external mucus secretions by the worms. Our observations also indicate that this clumping behavior reduces the worm’s exploration of its environment, possibly due to thigmotaxis. To validate these observed biophysical mechanisms, we create an active polymer model of a worm moving in a field of particulate debris. We simulate its adhesive nature by implementing a short-range attraction between the worm and the nearest surrounding particles. Our findings indicate an increase in gathering efficiency when we add an attractive force between particles, simulating the worm’s mucosal secretions. Our work provides a detailed understanding of the complex mechanisms underlying the collecting–gathering behavior in L. variegatus, informing the design of bioinspired synthetic collector systems, and advances our understanding of the ecological impacts of microplastics on benthic invertebrates.
Beliefs About Collective Responsibility for Educational Equity and Attitudes Toward Public Assistance to Students Experiencing Socioeconomic Disadvantage
Authors: Lee Jung-Sook , Lee Jihyun
Published: June 2023

Neoliberal educational reforms that emphasize market-based competition and individual responsibility have exacerbated socioeconomic segregation in the Australian school system, thereby putting underprivileged students at a greater disadvantage. This necessitates a renewed focus on educational equity. As the public’s policy preferences are important in policymaking, it is essential to understand the factors that contribute to the public’s attitudes toward equity-oriented educational policies. In this study, we investigated beliefs about collective responsibility as a contributing factor. An online survey of adults (N = 1,999) conducted in the most populous state in Australia revealed that people’s beliefs about collective responsibility for socioeconomic achievement gaps positively predicted their support for public assistance to students and schools in need. Furthermore, people’s appraisals of educational equity positively predicted their support for public assistance, partly due to its positive effects on those beliefs about collective responsibility. These results provide insight into ways to shape the public’s attitudes toward equity-oriented educational policies.
The good, the bad, and the ugly of US antitrust
Authors: Stucke Maurice E
Published: June 2023

This article examines the bad and ugly as the US federal agencies seek to rejuvenate competition. The bad is legislative hiatus to update the antitrust laws for the digital economy. The ugly is when courts push their own economic beliefs, without regard for the congressional intent and aims of the antitrust laws. Regardless of who wins, the rule of law (and those most dependent on the antitrust law) suffer. To correct America's market power problem, the article proposes restoring the constitutional balance, where the courts adjudicate, the legislature legislates, and enforcers enforce.
The water flea Moina macrocopa () (Cladocera: Daphniidae) withstands 100,000 × g in a centrifuge for 10 minutes
Authors: Ito Takafumi
Published: June 2023

The water flea Moina macrocopa (Straus, 1820) survived and did not become pelleted when centrifuged at 21,500 × g for 10 minutes. Five out of six individuals tested swam in the microtube after being centrifuged at 100,000 × g for 10 minutes. It was confirmed that M. macrocopa occurred near the bottom of a 15 ml centrifuge tube on the spoke of a bicycle wheel due to the centrifugal force of 5 × g. This results suggests that M. macrocopa would have withstood conditions of 100,000 × g at the bottom of the tube. This is the first report that a crustacean can withstand extremely high gravitational forces, which prompts the potential use of M. macrocopa as a new model for extreme hypergravity.
HBWO-JS: jellyfish search boosted hybrid beluga whale optimization algorithm for engineering applications
Authors: Yuan Xinguang , Hu Gang , Zhong Jingyu , Wei Guo
Published: June 2023

Beluga whale optimization (BWO) algorithm is a recently proposed population intelligence algorithm. Inspired by the swimming, foraging, and whale falling behaviors of beluga whale populations, it shows good competitive performance compared to other state-of-the-art algorithms. However, the original BWO faces the challenges of unbalanced exploration and exploitation, premature stagnation of iterations, and low convergence accuracy in high-dimensional complex applications. Aiming at these challenges, a hybrid BWO based on the jellyfish search optimizer (HBWO-JS), which combines the vertical crossover operator and Gaussian variation strategy with a fusion of jellyfish search (JS) optimizer, is developed for solving global optimization in this paper. First, the BWO algorithm is fused with the JS optimizer to improve the problem that BWO tends to fall into the best local solution and low convergence accuracy in the exploitation stage through multi-stage exploration and collaborative exploitation. Then, the introduced vertical cross operator solves the problem of unbalanced exploration and exploitation processes by normalizing the upper and lower bounds of two stochastic dimensions of the search agent, thus further improving the overall optimization capability. In addition, the introduced Gaussian variation strategy forces the agent to explore the minimum neighborhood, extending the entire iterative search process and thus alleviating the problem of premature stagnation of the algorithm. Finally, the superiority of the proposed HBWO-JS is verified in detail by comparing it with basic BWO and eight state-of-the-art algorithms on the CEC2019 and CEC2020 test suites, respectively. Also, the scalability of HBWO-JS is evaluated in three dimensions (10D, 30D, 50D), and the results show the stable performance of the proposed algorithm in terms of dimensional scalability. In addition, three practical engineering designs and two Truss topology optimization problems demonstrate the practicality of HBWO-JS. The optimization results show that HBWO-JS has a strong competitive ability and broad application prospects.
Abortion, Impairment, and Well-Being
Authors: Gillham Alex R
Published: June 2023

Hendricks’ The Impairment Argument (TIA) claims that it is immoral to impair a fetus by causing it to have fetal alcohol syndrome (FAS). Since aborting a fetus impairs it to a greater degree than causing it to have FAS, then abortion is also immoral. In this article, I argue that TIA ought to be rejected. This is because TIA can only succeed if it explains why causing an organism to have FAS impairs it to a morally objectionable degree, entails that abortion impairs an organism to a morally objectionable and greater degree than causing FAS, and satisfies The Impairment Principle’s ceteris paribus clause. In order to do all three things, TIA must presuppose some theory of well-being. Even then, no theory of well-being accomplishes all three tasks that TIA must in order to succeed. However, even if this is false and TIA can meet all three objectives by presupposing some theory of well-being, it would not do very much to advance the debate about the morality of abortion. As I argue, TIA would essentially restate well-established arguments against abortion based on whatever theory of well-being it must presuppose in order to be successful.
Geraniol suppresses tumour growth and enhances chemosensitivity of 5-fluorouracil on breast carcinoma in mice: involvement of miR-21/PTEN signalling
Authors: El-Ganainy Samar O , Shehata Asmaa M , El-Mallah Ahmed , Abdallah Dina , Mohy El-Din Mahmoud M
Published: June 2023

Objectives

Breast cancer is the most diagnosed cancer in females worldwide. Phytochemicals are among the recent compelling approaches showing anticancer activity. Geraniol is a monoterpenoid showing anti-tumoral potential in cell lines. However, its exact mechanism in breast cancer has not been elucidated. In addition, the possible chemosenstizing effect of geraniol when combined with chemotherapeutic drugs in breast carcinoma has not been previously addressed.

Methods

Therefore, the aim of the current work is to investigate the potential therapeutic as well as chemosensitizing effects of geraniol on breast carcinoma induced in mice through examination of tumour biomarkers and histopathology profile.

Key findings

Results showed a prominent suppression of tumour growth following geraniol treatment. This was accompanied with miR-21 downregulation that subsequently upregulated PTEN and suppressed mTOR levels. Geraniol was also able to activate apoptosis and inhibit autophagy. Histopathological examination revealed high necrosis areas separating malignant cells in the geraniol-treated group. Combined geraniol and 5-fluorouracil treatment induced more than 82% inhibition of tumour rate, surpassing the effect of each drug alone.

Conclusions

It can be concluded that geraniol could represent a promising avenue for breast cancer treatment as well as a potential sensitizing agent when combined with chemotherapeutic drugs.
Intraosseous extension of supraspinatus calcific tendonitis in a young patient with severe shoulder pain: a rare case report
Authors: Albishi Waleed , Alaseem Abdulrahman , Aljasser Sarah , Almohideb Faten , Almalki Mamdouh , AlFaleh Ahmed F
Published: June 2023

Calcific tendinopathy is one of the causes of shoulder pain and limited range of motion when it affects the rotator cuff tendons. Complications of such a condition are rare and include intraosseous and intramuscular migration. Calcific tendonitis can be classified as acute, subacute or chronic based on the onset of symptoms. The incidence of calcific tendonitis affects females more than males, with the median age of onset being between 40 and 60 years old. Diagnostic modalities include radiographs and computed tomography (CT); however, these are suboptimal when compared to the sensitivity of magnetic resonance imaging. Ninety percent of these cases are treated non-surgically. We present a rare case of a young female patient with right shoulder pain and limited range of motion secondary to the intraosseous migration of calcific tendonitis. The patient’s symptoms were resolved after a CT-guided percutaneous bone biopsy of the lesion. Clinical correlation with the aid of imaging and histopathology is a multimodal approach to help diagnose and treat such conditions.
Metabolic reprogramming in inflammaging and aging in T cells
Authors: Bevilacqua Alessio , Ho Ping-Chih , Franco Fabien
Published: June 2023

Aging represents an emerging challenge for public health due to the declined immune responses against pathogens, weakened vaccination efficacy, and disturbed tissue homeostasis. Metabolic alterations in cellular and systemic levels are also known to be cardinal features of aging. Moreover, cellular metabolism has emerged to provide regulations to guide immune cell behavior via modulations on signaling cascades and epigenetic landscape, and the aberrant aging process in immune cells can lead to inflammaging, a chronic and low-grade inflammation that facilitates aging by perturbing homeostasis in tissues and organs. Here, we review how the metabolic program in T cells is influenced by the aging process and how aged T cells modulate inflammaging. In addition, we discuss the potential approaches to reverse or ameliorate aging by rewiring the metabolic programming of immune cells.
Observational signatures of carbon–oxygen white dwarf merger remnants
Authors: Yao Philippe Z , Quataert Eliot , Goulding Andy
Published: June 2023

Many double white dwarf (WD) mergers likely do not lead to a prompt thermonuclear explosion. We investigate the prospects for observationally detecting the surviving remnants of such mergers, focusing on the case of mergers of double Carbon–Oxygen WDs. For ∼104 yr, the merger remnant is observationally similar to an extreme AGB star evolving to become a massive WD. Identifying merger remnants is thus easiest in galaxies with high-stellar masses (high WD merger rate) and low star formation rates (low birth rate of ∼6–10 M⊙ stars). Photometrically identifying merger remnants is challenging even in these cases because the merger remnants appear similar to He stars and post-outburst classical novae. We propose that the most promising technique for discovering WD merger remnants is through their unusual surrounding photoionized nebulae. We use CLOUDY photoionization calculations to investigate their unique spectral features. Merger remnants should produce weak hydrogen lines, strong carbon and oxygen recombination, and fine-structure lines in the UV, optical and IR. With narrow-band imaging or integral field spectrographs, we predict that multiple candidates are detectable in the bulge of M31, the outskirts of M87 and other nearby massive galaxies, and the Milky Way. Our models roughly reproduce the WISE nebula surrounding the Galactic WD merger candidate IRAS 00500+6713; we predict detectable [Ne vi] and [Mg vii] lines with JWST but that the mid-IR WISE emission is dominated by dust not fine-structure lines.
Parameters of 220 million stars from Gaia BP/RP spectra
Authors: Zhang Xiangyu , Green Gregory M , Rix Hans-Walter
Published: June 2023

We develop, validate and apply a forward model to estimate stellar atmospheric parameters (Teff, log g, and [Fe/H]), revised distances and extinctions for 220 million stars with XP spectra from Gaia DR3. Instead of using ab initio stellar models, we develop a data-driven model of Gaia XP spectra as a function of the stellar parameters, with a few straightforward built-in physical assumptions. We train our model on stellar atmospheric parameters from the LAMOST survey, which provides broad coverage of different spectral types. We model the Gaia XP spectra with all of their covariances, augmented by 2MASS and WISE photometry that greatly reduces degeneracies between stellar parameters, yielding more precise determinations of temperature and dust reddening. Taken together, our approach overcomes a number of important limitations that the astrophysical parameters released in Gaia DR3 faced, and exploits the full information content of the data. We provide the resulting catalogue of stellar atmospheric parameters, revised parallaxes, and extinction estimates, with all their uncertainties. The modelling procedure also produces an estimate of the optical extinction curve at the spectral resolution of the XP spectra (R ∼ 20–100), which agrees reasonably well with the R(V) = 3.1 CCM model. Remaining limitations that will be addressed in future work are that the model assumes a universal extinction law, ignores binary stars and does not cover all parts of the Hertzsprung–Russell Diagram (e.g. white dwarfs).
Modelling simultaneous CoRoT and Spitzer light curves: the impact of bending waves in the inner disc
Authors: Nagel E , Bouvier J
Published: June 2023

We present a physical interpretation of the amplitude of light curves of young stellar objects (YSOs) simultaneously observed in the infrared with the Spitzer Space Telescope and in the optical with the CoRoT satellite. The modelled objects come from a sample of YSOs in the star forming region NGC 2264, and we focus on a subsample showing periodic dips in their CoRoT light curves. The model includes emission and stellar occultation caused by a warp at the inner edge of the disc. In order to fit the observed fluxes, we add a contribution coming from the inner disc. We find that the disc flux signal has the same periodicity as the stellar rotation, with a phase offset between the stellar and the disc signal of half the period, that is, the peak of the former coincides with the minimum of the latter. This behaviour is consistent with MHD simulations where a bending wave appears opposite to the warp formed at the base of the magnetospheric stream, which is rotating with the stellar rotation period. This evidence highlights the importance of infrared observations to complement the information extracted from optical light curves to be able to characterize structures at the inner disc.
ATM–ESCO2–SMC3 axis promotes 53BP1 recruitment in response to DNA damage and safeguards genome integrity by stabilizing cohesin complex
Authors: Fu Jianfeng , Zhou Siru , Xu Huilin , Liao Liming , Shen Hui , Du Peng , Zheng Xiaofeng
Published: June 2023

53BP1 is primarily known as a key regulator in DNA double-strand break (DSB) repair. However, the mechanism of DSB-triggered cohesin modification-modulated chromatin structure on the recruitment of 53BP1 remains largely elusive. Here, we identified acetyltransferase ESCO2 as a regulator for DSB-induced cohesin-dependent chromatin structure dynamics, which promotes 53BP1 recruitment. Mechanistically, in response to DNA damage, ATM phosphorylates ESCO2 S196 and T233. MDC1 recognizes phosphorylated ESCO2 and recruits ESCO2 to DSB sites. ESCO2-mediated acetylation of SMC3 stabilizes cohesin complex conformation and regulates the chromatin structure at DSB breaks, which is essential for the recruitment of 53BP1 and the formation of 53BP1 microdomains. Furthermore, depletion of ESCO2 in both colorectal cancer cells and xenografted nude mice sensitizes cancer cells to chemotherapeutic drugs. Collectively, our results reveal a molecular mechanism for the ATM–ESCO2–SMC3 axis in DSB repair and genome integrity maintenance with a vital role in chemotherapy response in colorectal cancer.
Simultaneous measurement of nascent transcriptome and translatome using 4-thiouridine metabolic RNA labeling and translating ribosome affinity purification
Authors: Imai Hirotatsu , Utsumi Daisuke , Torihara Hidetsugu , Takahashi Kenzo , Kuroyanagi Hidehito , Yamashita Akio
Published: June 2023

Regulation of gene expression in response to various biological processes, including extracellular stimulation and environmental adaptation requires nascent RNA synthesis and translation. Analysis of the coordinated regulation of dynamic RNA synthesis and translation is required to determine functional protein production. However, reliable methods for the simultaneous measurement of nascent RNA synthesis and translation at the gene level are limited. Here, we developed a novel method for the simultaneous assessment of nascent RNA synthesis and translation by combining 4-thiouridine (4sU) metabolic RNA labeling and translating ribosome affinity purification (TRAP) using a monoclonal antibody against evolutionarily conserved ribosomal P-stalk proteins. The P-stalk-mediated TRAP (P-TRAP) technique recovered endogenous translating ribosomes, allowing easy translatome analysis of various eukaryotes. We validated this method in mammalian cells by demonstrating that acute unfolded protein response (UPR) in the endoplasmic reticulum (ER) induces dynamic reprogramming of nascent RNA synthesis and translation. Our nascent P-TRAP (nP-TRAP) method may serve as a simple and powerful tool for analyzing the coordinated regulation of transcription and translation of individual genes in various eukaryotes.
Structural insights into the DNA recognition mechanism by the bacterial transcription factor PdxR
Authors: Freda Ida , Exertier Cécile , Barile Anna , Chaves-Sanjuan Antonio , Vega Mirella Vivoli , Isupov Michail N , Harmer Nicholas J , Gugole Elena , Swuec Paolo , Bolognesi Martino , Scipioni Anita , Savino Carmelinda , Di Salvo Martino Luigi , Contestabile Roberto , Vallone Beatrice , Tramonti Angela , Montemiglio Linda Celeste
Published: June 2023

Specificity in protein–DNA recognition arises from the synergy of several factors that stem from the structural and chemical signatures encoded within the targeted DNA molecule. Here, we deciphered the nature of the interactions driving DNA recognition and binding by the bacterial transcription factor PdxR, a member of the MocR family responsible for the regulation of pyridoxal 5′-phosphate (PLP) biosynthesis. Single particle cryo-EM performed on the PLP-PdxR bound to its target DNA enabled the isolation of three conformers of the complex, which may be considered as snapshots of the binding process. Moreover, the resolution of an apo-PdxR crystallographic structure provided a detailed description of the transition of the effector domain to the holo-PdxR form triggered by the binding of the PLP effector molecule. Binding analyses of mutated DNA sequences using both wild type and PdxR variants revealed a central role of electrostatic interactions and of the intrinsic asymmetric bending of the DNA in allosterically guiding the holo-PdxR–DNA recognition process, from the first encounter through the fully bound state. Our results detail the structure and dynamics of the PdxR–DNA complex, clarifying the mechanism governing the DNA-binding mode of the holo-PdxR and the regulation features of the MocR family of transcription factors.
Cardiovascular disease biomarkers derived from circulating cell-free DNA methylation
Authors: Cuadrat Rafael R C , Kratzer Adelheid , Arnal Hector Giral , Rathgeber Anja C , Wreczycka Katarzyna , Blume Alexander , Gündüz Irem B , Ebenal Veronika , Mauno Tiina , Osberg Brendan , Moobed Minoo , Hartung Johannes , Jakobs Kai , Seppelt Claudio , Meteva Denitsa , Haghikia Arash , Leistner David M , Landmesser Ulf , Akalin Altuna
Published: June 2023

Acute coronary syndrome (ACS) remains a major cause of worldwide mortality. The syndrome occurs when blood flow to the heart muscle is decreased or blocked, causing muscle tissues to die or malfunction. There are three main types of ACS: Non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, and unstable angina. The treatment depends on the type of ACS, and this is decided by a combination of clinical findings, such as electrocardiogram and plasma biomarkers. Circulating cell-free DNA (ccfDNA) is proposed as an additional marker for ACS since the damaged tissues can release DNA to the bloodstream. We used ccfDNA methylation profiles for differentiating between the ACS types and provided computational tools to repeat similar analysis for other diseases. We leveraged cell type specificity of DNA methylation to deconvolute the ccfDNA cell types of origin and to find methylation-based biomarkers that stratify patients. We identified hundreds of methylation markers associated with ACS types and validated them in an independent cohort. Many such markers were associated with genes involved in cardiovascular conditions and inflammation. ccfDNA methylation showed promise as a non-invasive diagnostic for acute coronary events. These methods are not limited to acute events, and may be used for chronic cardiovascular diseases as well.
BAK1 protects the receptor-like kinase BIR2 from SNIPER2a/b-mediated degradation to promote pattern-triggered immunity in Nicotiana benthamiana
Authors: Liu Fan , Zeng Mengzhu , Sun Yujing , Chen Zhiyuan , Chen Zhaodan , Wang Lei , Cui Jia-Rong , Zhang Fushuang , Lv Di , Chen Xue , Xu Yuanpeng , Duan Kai-Xuan , Wang Yan , Wang Yuanchao
Published: June 2023

The detection of microbial infections by plants induces the rapid formation of immune receptor complexes at the plasma membrane. However, how this process is controlled to ensure proper immune signaling remains largely unknown. Here, we found that the Nicotiana benthamiana membrane-localized leucine-rich repeat receptor-like kinase BAK1-INTERACTING RLK 2 (NbBIR2) constitutively associates with BRI1-ASSOCIATED RECEPTOR KINASE 1 (NbBAK1) in vivo and in vitro and promotes complex formation with pattern recognition receptors. In addition, NbBIR2 is targeted by 2 RING-type ubiquitin E3 ligases, SNC1-INFLUENCING PLANT E3 LIGASE REVERSE 2a (NbSNIPER2a) and NbSNIPER2b, for ubiquitination and subsequent degradation in planta. NbSNIPER2a and NbSNIPER2b interact with NbBIR2 in vivo and in vitro and are released from NbBIR2 upon treatment with different microbial patterns. Furthermore, accumulation of NbBIR2 in response to microbial patterns is tightly associated with NbBAK1 abundance in N. benthamiana. NbBAK1 acts as a modular protein that stabilizes NbBIR2 by competing with NbSNIPER2a or NbSNIPER2b for association with NbBIR2. Similar to NbBAK1, NbBIR2 positively regulates pattern-triggered immunity and resistance to bacterial and oomycete pathogens in N. benthamiana, whereas NbSNIPER2a and NbSNIPER2b have the opposite effect. Together, these results reveal a feedback regulatory mechanism employed by plants to tailor pattern-triggered immune signaling.
Network Interventions: Applying Network Science for Pragmatic Action in Public Administration and Policy
Authors: Siciliano Michael D , Whetsell Travis
Published: June 2023

Public management and policy scholars have engaged in extensive development of theory and empirical study of networks and collaborative systems of governance. This scholarship has focused on understanding the mechanisms of network formation and the implications of network properties on individual and collective outcomes. Despite rich descriptive work and inferential analyses, little work has attempted to intervene in these systems. In this article, we develop the foundation for a new body of research in our field focused on network interventions. Network interventions are defined as the purposeful use of network data to identify strategies for accelerating behavior change, improving performance, and producing desirable outcomes (Valente, 2012). We extend network intervention strategies from the field of public health to public sector interorganizational and governance networks. Public sector actors have an interest in network interventions based on the fundamental pursuit of efficiency, effectiveness, and equity. Network interventions can increase the uptake of an organizational change among employees, improve the performance of a governance system, or promote the spread of a successful policy across jurisdictions. We provide scholars and practitioners with a useful way to conceptualize where, why, and how network interventions might be deployed in the pursuit of public value.
Antiprotozoal activity of auranofin on Trypanosoma cruzi, Leishmania tropica and Toxoplasma gondii: in vitro and ex vivo study
Authors: Yıldırım Ahmet , Özbilgin Ahmet , Yereli Kor
Published: June 2023

Background

Three obligate intracellular protozoan parasite species, which are responsible for significant morbidity and mortality and settle in macrophage cells, affect more than one-half of the world's population, namely, Trypanosoma cruzi, Leishmania tropica and Toxoplasma gondii, which are causative agents of Chagas disease, leishmaniasis and toxoplasmosis, respectively. In the current study, it was aimed to investigate the in vitro and ex vivo antiprotozoal activity of auranofin on T. cruzi, L. tropica and T. gondii.

Methods

The in vitro drug efficacy (IC50) of auranofin was investigated by haemocytometry and the CellTiter-Glo assay methods and the ex vivo drug efficacy (IC50) by light microscopic examination of Giemsa-stained slides. Also, the cytotoxic activity (CC50) of auranofin was examined by the CellTiter-Glo assay. The selectivity index (SI) was calculated for auranofin.

Results

According to IC50, CC50 and SI data, auranofin did not exhibit cytotoxic activity on Vero cells, but exhibited antiprotozoal activity on epimastigotes and intracellular amastigotes of T. cruzi, promastigotes and intracellular amastigotes of L. tropica and intracellular tachyzoites of T. gondii (p<0.05).

Conclusions

The detection antiprotozoal activity of auranofin on T. cruzi, L. tropica and T. gondii according to the IC50, CC50 and SI values is considered an important and promising development. This is significant because auranofin may be an effective alternative treatment for Chagas disease, leishmaniasis and toxoplasmosis in the future.
Editors as Gatekeepers: One Medical Education Journal’s Efforts to Resist Racism in Scholarly Publishing
Authors: Wyatt Tasha R. , Bullock Justin L. , Andon Anabelle , Odukoya Erica J. , Torres Carlos G. , Gingell Gareth , Han Heeyoung , Zaidi Zareen , Mylona Elza , Torre Dario , Cianciolo Anna T.
Published: June 2023

Purpose

Journals have begun to expand the racial diversity of editors as a first step to countering institutional racism. Given the power editors hold as gatekeepers, a diverse team helps ensure that minoritized scholars have equal opportunity to contribute. In 2021, Teaching and Learning in Medicine (TLM) created an editorial internship for racially minoritized individuals. This study examines the first 6 months of this program to better understand its creation and initial successes.

Method

The authors employed critical collaborative autoethnography, a qualitative methodology, focusing on the underlying assumptions around power and hierarchy that are implicit in the design and implementation of the TLM internship. Participants included 13 TLM editorial board members (10 internship selection committee members, 3 mentors, 2 independent researchers), 3 external selection committee members, and 3 interns, with some holding multiple roles. Ten participants served as authors of this report. Data included archival emails, planning documents, and focus groups. The initial analysis explored what happened and how and was followed by a thematic analysis in which participants reflected on their responsibility for implementing an antiracist program.

Results

While the program developed interns’ editorial skills, which they greatly valued, and diversified the TLM editorial board, it did not achieve the goal of fostering antiracism. Mentors focused on conducting joint peer reviews with interns, assuming that racial experiences can and should be separate from the editorial process, thus working within, rather than trying to change, the existing racist system.

Conclusions

Given these findings, greater structural change is needed to disrupt the existing racist system. These experiences underscore the importance of recognizing the harmful impact a race-neutral lens can have on antiracist efforts. Moving forward, TLM will implement lessons learned ahead of offering the internship again with the goal of creating the transformative change intended with the creation of the program.
A Novel Fusion Partner, SP100, Drives Nuclear Dot Localization of ALK in Epithelioid Fibrous Histiocytoma
Authors: Russell-Goldman Eleanor , Dong Fei , Laga Alvaro , Hanna John
Published: June 2023

Epithelioid fibrous histiocytoma (EFH) is a distinctive benign cutaneous neoplasm composed of uniform epithelioid cells, often with binucleated cells. EFH are characterized by the presence of anaplastic lymphoma kinase (ALK) gene rearrangements with a variety of binding partners. These rearrangements result in the overexpression of ALK, which can be detected using immunohistochemistry. Cytoplasmic ALK expression is by far the most common pattern encountered. Here, we describe a case of EFH with a distinctive intranuclear dot-like ALK expression pattern. Subsequent next-generation DNA sequencing revealed a novel SP100::ALK gene fusion. Speckled protein-100 (SP100) is a constituent of nuclear dots, also known as promyelocytic leukemia bodies, which are still poorly understood membraneless subnuclear structures. Thus, this novel ALK fusion partner seems to explain this distinctive pattern of ALK localization. We examined ALK expression patterns in 11 other cases of EFH, but all showed typical cytoplasmic localization. This study expands the morphologic and molecular spectrum of EFH, provides a dramatic illustration of the ability of fusion partners to control protein localization, and implies that tumorigenic ALK signaling may occur at a variety of subcellular locations.
A Rare Case of a Basomelanocytic Tumor
Authors: Wen Daniel , Chen Tony , Martin Richard C. W.
Published: June 2023

Basal cell carcinomas and melanoma are common cutaneous malignancies. However, the development of a basomelanocytic tumor that simultaneously includes elements of melanoma and basal cell carcinoma is extremely rare. We present the case of an 84-year-old man who presented with a nonpigmented, nonulcerated pink nodule of his left upper back and discuss the current management recommendations for basomelanocytic tumors.
Histopathologic Spectrum of Alopecias Seen in a Jamaican Setting
Authors: Ho Jonathan D. , Collie Chico J. , Spencer Sherri-Ann
Published: June 2023

Alopecia is common in Jamaican, primarily Afro-Caribbean patients. We performed a retrospective review examining the histopathologic alopecia diagnoses over ∼5 years. Requisition forms and pathology reports were assessed. Demographic/clinical/technical/diagnostic and pathologic findings of chronicity/severity data were recorded. Three hundred thirty-eight biopsies were included. The majority were 4 mm punches, grossed horizontally. The F:M ratio was 4.8:1, mean age = 42.7 years, and mean duration of alopecia = 5.1 years. Cicatricial alopecias (CAs) predominated over non-CAs (NCAs). The top 10 diagnoses were central centrifugal CA (21.9%), folliculitis decalvans (10.9%), multifactorial alopecias (10.1%), pattern hair loss (8%), lichen planopilaris (7.1%), alopecia areata (6.2%), discoid lupus erythematosus (6.2%), nonclassifiable lymphocytic scarring alopecias (5.6%), frontal fibrosing alopecia (5.3%), and nonspecific NCAs (5%). This contrasted with other richly pigmented populations where discoid lupus erythematosus predominates. Other interesting findings included relatively frequent folliculitis decalvans and lichen planus pigmentosus in 40.9% of frontal fibrosing alopecia cases. Scarring/nonscarring clinicopathologic congruence occurred in 83.4%.

Regarding histopathologic features of severity/chronicity, CAs had markedly decreased hair counts. Perifollicular fibrosis affecting retained hairs occurred in 75% of CAs, moderate to severe in >50% of these. Approximately 50% of NCA samples demonstrated advanced miniaturization (T:V ratio <2:1). In our study, relatively young women with chronic hair loss and CA are most frequently biopsied. Central centrifugal CA is the most common diagnosis. Local features of chronic/severe disease are seen microscopically. Clinical impression of scarring/nonscarring correlates well with histopathology.
Community-level social vulnerability and individual socioeconomic status on liver transplant referral outcome
Authors: Yilma Mignote , Cogan Raymond , Shui Amy M. , Neuhaus John M. , Light Carolyn , Braun Hillary , Mehta Neil , Hirose Ryutaro
Published: June 2023

Background:

Recent endeavors emphasize the importance of understanding early barriers to liver transplantation (LT) by consistently collecting data on patient demographics, socioeconomic factors, and geographic social deprivation indices.

Methods:

In this retrospective single-center cohort study of 1657 adults referred for LT evaluation, we assessed the association between community-level vulnerability and individual socioeconomic status measures on the rate of waitlisting and transplantation. Patients’ addresses were linked to Social Vulnerability Index (SVI) at the census tract–level to characterize community-level vulnerability. Descriptive statistics were used to describe patient characteristics. Multivariable cause-specific HRs were used to assess the association between community-level vulnerability, individual measures of the socioeconomic status, and LT evaluation outcomes (waitlist and transplantation).

Results:

Among the 1657 patients referred for LT during the study period, 54% were waitlisted and 26% underwent LT. A 0.1 increase in overall SVI correlated with an 8% lower rate of waitlisting (HR 0.92, 95% CI 0.87–0.96, p < 0.001), with socioeconomic status, household characteristics, housing type and transportation, and racial and ethnic minority status domains contributing significantly to this association. Patients residing in more vulnerable communities experienced a 6% lower rate of transplantation (HR 0.94, 95% CI 0.91– 0.98, p = 0.007), with socioeconomic status and household characteristic domain of SVI significantly contributing to this association. At the individual level, both government insurance and employment status were associated with lower rates of waitlisting and transplantation. There was no association with mortality prior to waitlisting or mortality while on the waitlist.

Conclusion:

Our findings indicate that both individual and community measures of the socioeconomic status (overall SVI) are associated with LT evaluation outcomes. Furthermore, we identified individual measures of neighborhood deprivation associated with both waitlisting and transplantation.
The prevalence and risk factors for cognitive impairment in obesity and NAFLD
Authors: Wernberg Charlotte W. , Grønkjær Lea L. , Gade Jacobsen Birgitte , Indira Chandran Vineesh , Krag Aleksander , Graversen Jonas H. , Weissenborn Karin , Vilstrup Hendrik , Lauridsen Mette M.
Published: June 2023

Background:

Severe obesity may be accompanied by cognitive dysfunction and NAFLD, but the associations remain unclear. We describe the prevalence and features of cognitive dysfunction and examine the associations between cognitive dysfunction and the presence and severity of NAFLD, and the associations between cognitive dysfunction and signs of other obesity-related comorbidities and neuronal damage.

Methods:

A cross-sectional study of patients with a body mass index of 35 kg/m2 underwent evaluation for bariatric surgery. They were screened for adiposity-related comorbidity and underwent a liver biopsy and basic cognitive testing with the Continuous Reaction Time test, the Portosystemic Encephalopathy Syndrome test, and the Stroop Test. A representative subgroup also underwent the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The primary study outcome was “cognitive impairment,” defined as ≥2 abnormal basic cognitive tests and/or an abnormal RBANS. The Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) served as a biomarker for neuronal damage.

Results:

We included 180 patients; 72% were women, age 46 ± 12 years, 78% had NAFLD, and 30% with NASH without cirrhosis. 8% were cognitively impaired by the basic tests and 41% by RBANS results. Most impaired were executive and short-time memory functions. There were no associations between cognitive impairment and BMI, NAFLD presence or severity, or metabolic comorbidities. Male sex (OR: 3.67, 95% CI, 1.32–10.27) and using 2 or more psychoactive medications (5.24, 95% CI, 1.34–20.4) were associated with impairment. TREM2 was not associated with cognitive impairment.

Conclusions:

Nearly half of this severely obese study cohort exhibited measurable multidomain cognitive impairment. This was not dependent on NAFLD or another adiposity comorbidity.
Relationship between postoperative residual refractive error and preoperative corneal stiffness in small-incision lenticule extraction
Authors: Cao Huazheng , Jhanji Vishal , Wang Yan
Published: June 2023

Purpose:

To explore the relationship between postoperative residual refractive error and preoperative corneal stiffness after small-incision lenticule extraction (SMILE).

Setting:

Hospital clinic.

Design:

Retrospective cohort study.

Methods:

Corneal stiffness was evaluated using the stress–strain index (SSI). Associations between postoperative spherical equivalent (SE) and corneal stiffness were determined using longitudinal regression analysis after adjustment for sex, age, preoperative SE, and other variables. The cohort was divided into halves to compare risk ratios for residual refraction in corneas with different SSI values. Low SSI values were defined as having less-stiff corneas and others as having stiffer corneas.

Results:

287 patients (287 eyes) were included. Greater undercorrection was found in less-stiff corneas across all follow-up timepoints (less-stiff corneas: 1 day: −0.36 ± 0.45 diopters [D], 1 month: −0.22 ± 0.36 D, and 3 months: −0.13 ± 0.15 D; stiffer corneas: −0.22 ± 0.37 D, −0.14 ± 0.35 D, and −0.05 ± 0.11 D, respectively). Postoperative refraction exhibited a mean 0.05 D undercorrection for every 0.1-unit decrease in the SSI after adjustment for variables. The SSI accounted for nearly 10% of the variance in refractive outcomes. Less-stiff corneas increased the risk ratio of postoperative absolute SE >0 D and ≥0.25 D by 2.242 (95% CI, 1.334-3.768) and 3.023 (95% CI, 1.466-6.233), respectively, compared with stiffer corneas.

Conclusions:

Postoperative residual refractive error was associated with preoperative corneal stiffness. Patients with less-stiff corneas had a 2- to 3-fold increased risk of residual refractive error after SMILE. Preoperative analysis of corneal stiffness can help modify nomogram algorithms of surgery and improve the predictability of refractive outcomes.