bluuebunny/crossref_metadata_2025 huggingface dataset:
Advancing Legal Preparedness through the Global Health Security Agenda
Authors: Ayala Ana , Brush Adam , Chai Shuen , Fernandez Jose , Ginsbach Katherine , Gottschalk Katie , Halabi Sam , Hosangadi Divya , Mapatano Dawn , Monahan John , Moretti Carla , Pillinger Mara , Ramirez Gabriela Silvana , Rosenfeld Emily
Published: March 2022

The Global Health Security Agenda (GHSA) is a multilateral, multisectoral partnership comprised of more than 70 countries, international organizations, foundations, and businesses to strengthen global health security.
The Racialized Marketing of Unhealthy Foods and Beverages: Perspectives and Potential Remedies
Authors: Barnhill Anne , Ramírez A. Susana , Ashe Marice , Berhaupt-Glickstein Amanda , Freudenberg Nicholas , Grier Sonya A. , Watson Karen E. , Kumanyika Shiriki
Published: March 2022

We propose that marketing of unhealthy foods and beverages to Black and Latino consumers results from the intersection of a business model in which profits come primarily from marketing an unhealthy mix of products, standard targeted marketing strategies, and societal forces of structural racism, and contributes to health disparities.
Fresh Take: Pitfalls of the FDA’s Proposed Menthol Ban
Authors: Pasha Amirala , Silbert Richard
Published: March 2022

In April 2021, the U.S. Food and Drug Administration announced its intention to ban menthol flavoring in cigarettes and cigars. The Agency’s decision was based in part on the disproportionate impact of menthol flavoring in Black communities.
Distention for Sets of Probabilities
Authors: Stewart Rush T. , Nielsen Michael
Published: March 2022

Bayesians often appeal to “merging of opinions” to rebut charges of excessive subjectivity. But what happens in the short run is often of greater interest than what happens in the limit. Seidenfeld and coauthors use this observation as motivation for investigating the counterintuitive short run phenomenon of dilation, since, they allege, dilation is “the opposite” of asymptotic merging of opinions. The measure of uncertainty relevant for dilation, however, is not the one relevant for merging of opinions. We explicitly investigate the short run behavior of the metric relevant for merging, and show that dilation is independent of the opposite of merging.
RECIPROCAL MONOGENIC QUINTINOMIALS OF DEGREE
Authors: JONES LENNY
Published: March 2022

We prove a new irreducibility result for polynomials over
${\mathbb Q}$
and we use it to construct new infinite families of reciprocal monogenic quintinomials in
${\mathbb Z}[x]$
of degree
$2^n$
.
De Facto Bank Bailouts
Authors: Ngo Phong T. H. , Puente-Moncayo Diego L.
Published: March 2022

The U.S. government uses its voting power to direct IMF loans to countries where U.S. banks are exposed to sovereign default (a de facto bailout). This effect is stronger in years when the costs of direct bailouts are higher and is also found among major European IMF members. We find that de facto bailouts reduce government incentives to default and that U.S. Congressional voting on IMF funding is consistent with a private interest view of government. Overall, we identify an alternative mechanism through which governments can backstop the losses of large multinational banks.
What if it were True? Why Study the New Testament
Authors: Kavin Rowe C.
Published: March 2022

This article argues for a renewal of the discipline of New Testament studies through a focus on the question of truth. To make the argument, the article first engages a recent essay that is highly critical of mainstream NT scholarship and subsequently works with the thought of Søren Kierkegaard, Stanley Cavell, Cora Diamond and Hans-Georg Gadamer to pursue the interpreter's implications in the NT's assertions of truth. The article also briefly exegetes five passages from the NT to illustrate the way the NT makes claims that require judgements about truth. Along the way, the article also engages contemporary NT scholars who argue vociferously against ‘theological’ readings of the NT and others who argue for their inherent necessity.
A New Witness to the Fayyūmic Version of First Corinthians (P.MorganLib. 265). Part II: Notes on its Text-Critical Value, with an Edition of the Coptic Text
Authors: Miroshnikov Ivan
Published: March 2022

This is the second part of a two-part article focused on a fragmentary parchment codex, whose three extant leaves, designated in Leo Depuydt's catalogue as P.MorganLib. 265, are housed at the Morgan Library & Museum in New York. These fragments bear witness to 1 Cor 2.12–3.18; 7.16–30; 15.3–30 in the ‘classical’ variety of Fayyūmic Coptic (dialect F5). The first part of this article was published in NTS 68 (2022) 89–104. In the second part, I discuss the witnesses to the Fayyūmic version (fa) of First Corinthians, the relationship between fa and the Bohairic version (bo), and the text-critical value of the variant readings attested in P.MorganLib. 265. This is followed by the editio princeps of the manuscript, notes on the Coptic text, an English translation and images.
John Chrysostom and Christian Love Magic: A Spellbinding Moment in the History of Interpretation of 1 Cor 7.2–4
Authors: Mitchell Margaret M.
Published: March 2022

This article, originally presented as the presidential address at the 2021 SNTS meeting, held virtually via Leuven due to Covid-19 conditions, investigates the nature of Pauline interpretation, past and present. It brings into the scholarly conversation a neglected ancient source, John Chrysostom's occasional homily on 1 Cor 7.2–4 (Hom. 1 Cor. 7–4 (CPG 4377)), and provides an analysis of key passages showing how the late antique orator-bishop seeks to turn Paul's words from the fifties to Corinth into a magical incantation, and, as inscribed on various materials, a talisman against the evils associated with porneia. The article concludes with defence of the category ‘Christian love magic’ and an argument that New Testament studies constitutes a unified field which should unite (rather than separate out) the work of philology, historical contextualisation, literary criticism, humanistic commitments and hermeneutical sophistication as we trace and analyse the ways human agents construct meanings with New Testament texts, then and now.
Enregistering mask-wearing in the time of a public health crisis
Authors: Lee Sheng-Hsun
Published: March 2022

This study explores how during the initial outbreak of COVID-19 in Taiwan, mask-wearing emerged as a semiotic register in health communication. Focusing on enregisterment (Agha 2007), I analyze interactional recordings of press conferences by the Taiwanese government, Chinese language lessons offered to international students, and conversations at a convenience store between an Australian student and her Taiwanese friend. The analysis reveals information production and reception on three social scales: public health policies, institutionalized health instruction, and interpersonal-care practices. On each scale, masking is enregistered as a semiotic sign associated with particular social actions, actors, and relations. This enregisterment transpires through an orchestration of verbal and non-verbal resources, conveying ideologies about invisible viruses in everyday life. While inconsistencies exist across scales, masking is consistently overlaid with civic solidarity and moral responsibility. In times of crisis, mask-wearing is an issue of public health and a process of typifying behaviors, identities, and relationships. (COVID-19, enregisterment, scale)*
Principles and Duties: A Critique of Common Morality Theory
Authors: Baker Robert
Published: March 2022

Tom Beauchamp and James Childress‘s revolutionary textbook, Principles of Biomedical Ethics, shaped the field of bioethics in America and around the world. Midway through the Principle’s eight editions, however, the authors jettisoned their attempt to justify the four principles of bioethics —autonomy, beneficence, nonmaleficence, justice—in terms of ethical theory, replacing it with the idea that these principles are part of a common morality shared by all rational persons committed to morality, at all times, and in all places. Other commentators contend that their theory has never been empirically confirmed and is unfalsifiable, since counterexamples can be deemed irrational, or as held by those living lives not committed to morality. The thesis of this paper is that common morality theory is the artifact of a category mistake—conflating common areas regulated by moral norms with common norms regulating moral conduct—that accords mid-twentieth century American liberal morality the status of transcultural, transtemporal, eternal moral truths. Such a conception offers bioethicists no tools for analyzing moral change—moral progress, regress, reform, evolution, devolution, or revolution—no theoretical basis for deconstructing structural classicism, racism, and sexism, or for facilitating international cooperation on ethical issues in the context of culturally based moral differences.
Rethinking the Ethics of Pandemic Rationing: Egalitarianism and Avoiding Wrongs
Authors: Tate Alex James Miller
Published: March 2022

This paper argues that we ought to rethink the harm-reduction prioritization strategy that has shaped early responses to acute resource scarcity (particularly of intensive care unit beds) during the COVID-19 pandemic. Although some authors have claimed that “[t]here are no egalitarians in a pandemic,” it is noted here that many observers and commentators have been deeply concerned about how prioritization policies that proceed on the basis of survival probability may unjustly distribute the burden of mortality and morbidity, even while reducing overall deaths. The paper further argues that there is a general case in favor of an egalitarian approach to medical rationing that has been missed in the ethical commentary so far; egalitarian approaches to resource rationing minimize wrongful harm. This claim is defended against some objections and the paper concludes by explaining why we should consider the possibility that avoiding wrongful harm is more important than avoiding harm simpliciter.
The role of stress position in bilingual auditory word recognition: Cognate processing in Turkish and Dutch
Authors: Muntendam Antje , van Rijswijk Remy , Severijnen Giulio , Dijkstra Ton
Published: March 2022

We examined the effect of word stress position on bilingual auditory cognate processing. Turkish–Dutch early bilinguals who are dominant in their L2 (Dutch) performed an auditory lexical decision task in Turkish or Dutch. While Dutch has variable word stress, with a tendency for penultimate stress, stress in Turkish is mostly predictable and usually falls on the ultimate syllable. Our tasks included two-syllable cognates with penultimate stress in both languages, ultimate stress in both languages, or ultimate stress in Turkish and penultimate stress in Dutch. Some cognate facilitation effects arose in Dutch, while inhibition was found in Turkish. Cognates with ultimate stress were processed faster than cognates with penultimate stress, in both languages. This shows that in Turkish–Dutch early bilinguals, cognate processing depends on Turkish stress position, although Dutch is dominant. Together, the findings support the view that cognates have separate, though linked representations.
A substrate integrated waveguide (SIW) based self-quadruplexing antenna for Ku-band applications
Authors: Agrawal Meha , Kumar Trivesh
Published: March 2022

A substrate integrated waveguide (SIW) based self-quadruplexing antenna and its design approach in Ku-band (12–18 GHz) is presented in this paper. This consists of splitting of TE220 mode of square-shaped SIW cavity by incorporating the two diagonal arrays of metallic vias. Accordingly, four orthogonal dominant mode triangular shape SIW cavity (DMTC) resonators are formed. This methodology ensures enhanced isolation. To achieve the broadside radiation, the cavity structure is fed using microstrip lines and rectangular slots are loaded on the top layer of each DMTC. The length and position of each rectangular slot being chosen such that quad-resonances are achieved at 13, 13.5, 14.3, and 15 GHz for the respective DMTC. The equivalent circuit model of the proposed design is also developed, and the tuning of each frequency band is analyzed without affecting the others. The proposed antenna is producing high isolation (>28 dB) among all four ports and a unidirectional radiation pattern with a high front-to-back ratio (>26.8 dB).
“Safe zones”: A protective alternative to flight or a tool of refugee containment? Clarifying the international legal framework governing access to refugee protection against the backdrop of “safe zones” in conflict-affected contexts
Authors: Macey Harriet
Published: March 2022

So-called “safe zones” pose an increasingly pressing threat to genuine and robust international legal protection for persons fleeing conflict. This paper aims to address the key challenges and risks of safe zones under international law and to provide some clarifications on the legal framework which must be respected by refugee-receiving States. Through assessing the intentions of preventing migration flows which underlie their creation, this paper will demonstrate that the existence of safe zones cannot be used to circumvent the obligations of refugee-receiving States under international law, specifically the right to leave and seek asylum and the prohibition of non-refoulement. This paper concludes that safe zones should only be created as an urgent response to humanitarian crises in order to ensure the immediate safety of civilians in conflict zones, and only under very strict conditions. In this respect, this paper will demonstrate that even if safe zones comply with certain minimum protective standards, because of the volatility and complexities of the conflict environment they should not and cannot act as a substitute for genuine refugee protection under international law.
Linear Modeling of Spectra of Fine Particulate Materials: Implications for Compositional Analyses of Primitive Asteroids
Authors: Lowry Vanessa C. , Donaldson Hanna Kerri L. , Campins Humberto , Bowles Neil , Hamilton Victoria E. , Brown Eloïse C.
Published: March 2022

In this study, we applied a sum to one constraint weighted least squares (STO WLS) model to thermal infrared (TIR) spectra of a suite of primitive asteroid analogs spectrally and volumetrically dominated by fine particulates (<38 μm). Since coarse particulate emissivity spectra combine linearly, deriving compositions from these are fairly straightforward. Across the TIR it is not as straightforward for fine particulate emissivity spectra due to the nonlinear behavior that arises from volumetric scattering between particles when the particle size becomes comparable to the wavelength of light. Using a WLS model, mixed spectra may be deconvolved into areal percentages of each end member which we assume corresponds to their volume percentages. We used a spectral library of pure mineral spectra to model TIR spectra of a suite of physical mixtures and meteorites obtained under ambient (Earth‐like) and simulated asteroid environment (SAE) conditions collected for the OSIRIS‐REx team (Donaldson Hanna et al., 2021, https://doi.org/10.1029/2020JE006624). The STO WLS model underestimated the modal abundances of the dominant mineral phases by ∼25.0 ± 0.1% on average over the full spectral range and ∼22.0 ± 0.4% over a limited spectral range in all of the ambient and SAE physical mixture and meteorite spectra. Minor phases present in the mixtures and meteorites (abundances ≤5%) were typically not modeled. Also, phases not present in the mixtures were commonly selected (∼2 phases on average with an average abundance of ∼25.2 ± 1.9%) to get the best mathematical fit.
Block Kinematics in North China From GPS Measurements
Authors: Wang Wei , Zhao Bin , Qiao Xuejun , Ding Kaihua
Published: March 2022

The North China Craton (NCC) is an important tectonic element in China, which is characterized by intense seismic activity and complex tectonic setting. Thus quantifying its deformation is essential for studying the tectonic processes and deformation mechanisms in this region. Here we use a combination of dense GPS data sets to analyze the crustal movement and present updated estimates of fault motions based on elastic block models. We uncover spatial variations in deformation patterns, indicating that different mechanisms may dominate the tectonic processes for different parts of the NCC. In the western part, the rifts around the Ordos block manifest strike‐slip and extensional deformation, and the strike‐slip motion is more significant than the extensional component; whereas in the east, the Tanlu fault experiences right‐lateral and shortening slips, consistent with the features from historical seismic activity and regional tectonics. Our analysis indicates that the deformation in the eastern NCC is principally influenced by the Pacific subduction, whereas the deformation in the western NCC is mainly related to the India‐Eurasia collision. Moreover, our estimate of motion along the Tanlu fault supports a relatively long seismic interval of ∼10 ka, comparable to those inferred from recent paleoseismic research on this fault and other slow‐slip faults in the NCC. Our study indicates that the faults in the NCC even with very slow motions may still have the potential to produce strong earthquakes. Thus seismic risks across these slow‐slip faults cannot be ignored and should not be determined solely based on the rate of fault motions.
Hydrothermal Exploration of the Southern Chile Rise: Sediment‐Hosted Venting at the Chile Triple Junction
Authors: German C. R. , Baumberger T. , Lilley M. D. , Lupton J. E. , Noble A. E. , Saito M. , Thurber A. R. , Blackman D. K.
Published: March 2022

We report results from a hydrothermal plume survey along the southernmost Chile Rise from the Guamblin Fracture Zone to the Chile Triple Junction (CTJ) encompassing two segments (93 km cumulative length) of intermediate spreading‐rate mid‐ocean ridge axis. Our approach used in situ water column sensing (CTD, optical clarity, redox disequilibrium) coupled with sampling for shipboard and shore based geochemical analyses (δ3He, CH4, total dissolvable iron (TDFe) and manganese, (TDMn)) to explore for evidence of seafloor hydrothermal venting. Across the entire survey, the only location at which evidence for submarine venting was detected was at the southernmost limit to the survey. There, the source of a dispersing hydrothermal plume was located at 46°16.5’S, 75°47.9’W, coincident with the CTJ itself. The plume exhibits anomalies in both δ3He and dissolved CH4 but no enrichments in TDFe or TDMn beyond what can be attributed to resuspension of sediments covering the seafloor where the ridge intersects the Chile margin. These results are indicative of sediment‐hosted venting at the CTJ.
Southern China Winter Rainfall Modulated by South China Sea Warming
Authors: Wang Qiang , Zhong Wenxiu , Yang Song , Wang Junbin , Zeng Lili , Chen Ju , He Yunkai
Published: March 2022

New insight into the contribution of anomalous South China Sea (SCS) warming is proposed to understand strong southern China (SC) winter rainfall. El Niño events, which weaken the East Asian winter monsoon (EAWM), favor SC winter rainfall. However, the changes in SC winter rainfall are not always in phase with the El Niño‐Southern Oscillation, making the prediction of East Asian climate challenging. Here, we show that the increased moisture associated with the warming SCS induced by the weakening western boundary current leads to increased meridional moisture transport to SC. Particularly, during the El Niño mature winter phase, this effect works jointly with a weakened EAWM to determine an increased rainfall over SC. Therefore, we suggest that the thermal state of the SCS should be considered when large‐scale tropical ocean‐atmosphere variability is utilized to predict SC winter rainfall.
The Seasonality of Oceanic Carbon Cycling
Authors: Derouin Sarah
Published: March 2022

Scientists uncovered how seasonal changes affect the amount and rate of carbon as it moves from the ocean’s surface to its depths.
Dopamine transporter silencing in the rat: systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits
Authors: Reinwald Jonathan R. , Gass Natalia , Mallien Anne S. , Sartorius Alexander , Becker Robert , Sack Markus , Falfan-Melgoza Claudia , Clemm von Hohenberg Christian , Leo Damiana , Pfeiffer Natascha , Middelman Anthonieke , Meyer-Lindenberg Andreas , Homberg Judith R. , Weber-Fahr Wolfgang , Gass Peter
Published: March 2022

Silencing of dopamine transporter (DAT), a main controlling factor of dopaminergic signaling, results in biochemical and behavioral features characteristic for neuropsychiatric diseases with presumed hyperdopaminergia including schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar disorder, and obsessive-compulsive disorder (OCD). Investigation of DAT silencing thus provides a transdiagnostic approach towards a systems-level understanding of common underlying pathways. Using a high-field multimodal imaging approach and a highly sensitive cryogenic coil, we integrated structural, functional and metabolic investigations in tandem with behavioral assessments on a newly developed preclinical rat model, comparing DAT homozygous knockout (DAT-KO, N = 14), heterozygous knockout (N = 8) and wild-type male rats (N = 14). We identified spatially distributed structural and functional brain alterations encompassing motor, limbic and associative loops that demonstrated strong behavioral relevance and were highly consistent across imaging modalities. DAT-KO rats manifested pronounced volume loss in the dorsal striatum, negatively correlating with cerebellar volume increase. These alterations were associated with hyperlocomotion, repetitive behavior and loss of efficient functional small-world organization. Further, prefrontal and midbrain regions manifested opposite changes in functional connectivity and local network topology. These prefrontal disturbances were corroborated by elevated myo-inositol levels and increased volume. To conclude, our imaging genetics approach provides multimodal evidence for prefrontal-midbrain decoupling and striato-cerebellar neuroplastic compensation as two key features of constitutive DAT blockade, proposing them as transdiagnostic mechanisms of hyperdopaminergia. Thus, our study connects developmental DAT blockade to systems-level brain changes, underlying impaired action inhibition control and resulting in motor hyperactivity and compulsive-like features relevant for ADHD, schizophrenia and OCD.
miR-146a impedes the anti-aging effect of AMPK via NAMPT suppression and NAD+/SIRT inactivation
Authors: Gong Hui , Chen Honghan , Xiao Peng , Huang Ning , Han Xiaojuan , Zhang Jian , Yang Yu , Li Tiepeng , Zhao Tingting , Tai Haoran , Xu Weitong , Zhang Gongchang , Gong Chuhui , Yang Ming , Tang Xiaoqiang , Xiao Hengyi
Published: March 2022

Nicotinamide adenine dinucleotide (NAD+) is indispensable for the anti-aging activity of the sirtuin (SIRT) family enzymes. AMP-activated protein kinase (AMPK) upregulates NAD+ synthesis and SIRT activity in a nicotinamide phosphoribosyltransferase (NAMPT)-dependent manner. However, the molecular mechanisms that affect AMPK-driven NAMPT expression and NAD+/SIRT activation remain unclear. In this study, we tried to identify senescence-associated microRNAs (miRNAs) that negatively regulate the cascade linking AMPK and NAMPT expression. miRNA-screening experiments showed that the expression of miR-146a increased in senescent cells but decreased following AMPK activation. Additionally, miR-146a overexpression weakened the metformin-mediated upregulation of NAMPT expression, NAD+ synthesis, SIRT activity, and senescence protection, whereas treatment with the miR-146a inhibitor reversed this effect. Importantly, these findings were observed both in vitro and in vivo. Mechanistically, miR-146a directly targeted the 3′-UTR of Nampt mRNA to reduce the expression of NAMPT. AMPK activators metformin and 5-aminoimidazole-4-carboxamide (AICAR) hindered miR-146a expression at the transcriptional level by promoting IκB kinase (IKK) phosphorylation to attenuate nuclear factor-kappaB (NF-κB) activity. These findings identified a novel cascade that negatively regulates the NAD+/SIRT pathway by suppressing miR-146a-mediated NAMPT downregulation. Furthermore, our results showed that miR-146a impedes the anti-aging effect of AMPK. This mutual inhibitory relationship between miR-146a and AMPK enriches our understanding of the molecular connections between AMPK and SIRT and provides new insight into miRNA-mediated NAD+/SIRT regulation and an intervention point for the prevention of aging and age-related diseases.
Stress vulnerability shapes disruption of motor cortical neuroplasticity
Authors: Gellner Anne-Kathrin , Sitter Aileen , Rackiewicz Michal , Sylvester Marc , Philipsen Alexandra , Zimmer Andreas , Stein Valentin
Published: March 2022

Chronic stress is a major cause of neuropsychiatric conditions such as depression. Stress vulnerability varies individually in mice and humans, measured by behavioral changes. In contrast to affective symptoms, motor retardation as a consequence of stress is not well understood. We repeatedly imaged dendritic spines of the motor cortex in Thy1-GFP M mice before and after chronic social defeat stress. Susceptible and resilient phenotypes were discriminated by symptom load and their motor learning abilities were assessed by a gross and fine motor task. Stress phenotypes presented individual short- and long-term changes in the hypothalamic–pituitary–adrenal axis as well as distinct patterns of altered motor learning. Importantly, stress was generally accompanied by a marked reduction of spine density in the motor cortex and spine dynamics depended on the stress phenotype. We found astrogliosis and altered microglia morphology along with increased microglia-neuron interaction in the motor cortex of susceptible mice. In cerebrospinal fluid, proteomic fingerprints link the behavioral changes and structural alterations in the brain to neurodegenerative disorders and dysregulated synaptic homeostasis. Our work emphasizes the importance of synaptic integrity and the risk of neurodegeneration within depression as a threat to brain health.
Edonerpic maleate regulates glutamate receptors through CRMP2- and Arc-mediated mechanisms in response to brain trauma
Authors: Chen Tao , Yang Li-Kun , Ai Pu , Zhu Jie , Hang Chun-Hua , Wang Yu-Hai
Published: March 2022

Dysfunction of ionotropic glutamate receptors (iGluRs) is a key molecular mechanism of excitotoxic neuronal injury following traumatic brain injury (TBI). Edonerpic maleate is a low molecular-weight compound that was screened as a candidate neuroprotective agent. In this study, we investigated its effects on TBI and GluRs signaling. Traumatic neuronal injury (TNI) induced by scratch followed by glutamate treatment was performed to mimic TBI in vitro. Edonerpic maleate at 1 and 10 μM exerted protective activity when it was added within 2 h following injury. The protective activities were also confirmed by the reduction of lipid peroxidation and oxidative stress. In addition, edonerpic maleate inhibited the expression of surface NR2B, total GluR1, and surface GluR1, and mitigated the intracellular Ca2+ responses following injury in vitro. Western blot analysis showed that edonerpic maleate reduced the cleavage of collapsing response mediator protein 2 (CRMP2), but increased the expression of postsynaptic protein Arc. By using gene overexpression and silencing technologies, CRMP2 was overexpressed and Arc was knockdown in cortical neurons. The results showed that the effect of edonerpic maleate on NMDA receptor expression was mediated by CRMP2, whereas the edonerpic maleate-induced AMPA receptor regulation was dependent on Arc activation. In in vivo TBI model, 30 mg/kg edonerpic maleate alleviated the TBI-induced brain edema, neuronal loss, and microglial activation, with no effect on locomotor function at 24 h. However, edonerpic maleate improves long-term neurological function after TBI. Furthermore, edonerpic maleate inhibited CRMP2 cleavage but increased Arc activation in vivo. In summary, our results identify edonerpic maleate as a clinically potent small compound with which to attenuate TBI-related brain damage through regulating GluRs signaling.
In vitro maturation of Toxoplasma gondii bradyzoites in human myotubes and their metabolomic characterization
Authors: Christiansen Céline , Maus Deborah , Hoppenz Ellen , Murillo-León Mateo , Hoffmann Tobias , Scholz Jana , Melerowicz Florian , Steinfeldt Tobias , Seeber Frank , Blume Martin
Published: March 2022

The apicomplexan parasiteToxoplasma gondiiforms bradyzoite-containing tissue cysts that cause chronic and drug-tolerant infections. However, current in vitro models do not allow long-term culture of these cysts to maturity. Here, we developed a human myotube-based in vitro culture model of functionally mature tissue cysts that are orally infectious to mice and tolerate exposure to a range of antibiotics and temperature stresses. Metabolomic characterization of purified cysts reveals global changes that comprise increased levels of amino acids and decreased abundance of nucleobase- and tricarboxylic acid cycle-associated metabolites. In contrast to fast replicating tachyzoite forms ofT. gondiithese tissue cysts tolerate exposure to the aconitase inhibitor sodium fluoroacetate. Direct access to persistent stages ofT. gondiiunder defined cell culture conditions will be essential for the dissection of functionally important host-parasite interactions and drug evasion mechanisms. It will also facilitate the identification of new strategies for therapeutic intervention.
Structural insight into Marburg virus nucleoprotein–RNA complex formation
Authors: Fujita-Fujiharu Yoko , Sugita Yukihiko , Takamatsu Yuki , Houri Kazuya , Igarashi Manabu , Muramoto Yukiko , Nakano Masahiro , Tsunoda Yugo , Taniguchi Ichiro , Becker Stephan , Noda Takeshi
Published: March 2022

The nucleoprotein (NP) of Marburg virus (MARV), a close relative of Ebola virus (EBOV), encapsidates the single-stranded, negative-sense viral genomic RNA (vRNA) to form the helical NP–RNA complex. The NP–RNA complex constitutes the core structure for the assembly of the nucleocapsid that is responsible for viral RNA synthesis. Although appropriate interactions among NPs and RNA are required for the formation of nucleocapsid, the structural basis of the helical assembly remains largely elusive. Here, we show the structure of the MARV NP–RNA complex determined using cryo-electron microscopy at a resolution of 3.1 Å. The structures of the asymmetric unit, a complex of an NP and six RNA nucleotides, was very similar to that of EBOV, suggesting that both viruses share common mechanisms for the nucleocapsid formation. Structure-based mutational analysis of both MARV and EBOV NPs identified key residues for helical assembly and subsequent viral RNA synthesis. Importantly, most of the residues identified were conserved in both viruses. These findings provide a structural basis for understanding the nucleocapsid formation and contribute to the development of novel antivirals against MARV and EBOV.
The control of transcriptional memory by stable mitotic bookmarking
Authors: Bellec Maëlle , Dufourt Jérémy , Hunt George , Lenden-Hasse Hélène , Trullo Antonio , Zine El Aabidine Amal , Lamarque Marie , Gaskill Marissa M. , Faure-Gautron Heloïse , Mannervik Mattias , Harrison Melissa M. , Andrau Jean-Christophe , Favard Cyril , Radulescu Ovidiu , Lagha Mounia
Published: March 2022

To maintain cellular identities during development, gene expression profiles must be faithfully propagated through cell generations. The reestablishment of gene expression patterns upon mitotic exit is mediated, in part, by transcription factors (TF) mitotic bookmarking. However, the mechanisms and functions of TF mitotic bookmarking during early embryogenesis remain poorly understood. In this study, taking advantage of the naturally synchronized mitoses ofDrosophilaearly embryos, we provide evidence that GAGA pioneer factor (GAF) acts as a stable mitotic bookmarker during zygotic genome activation. We show that, during mitosis, GAF remains associated to a large fraction of its interphase targets, including atcis-regulatory sequences of key developmental genes with both active and repressive chromatin signatures. GAF mitotic targets are globally accessible during mitosis and are bookmarked via histone acetylation (H4K8ac). By monitoring the kinetics of transcriptional activation in living embryos, we report that GAF binding establishes competence for rapid activation upon mitotic exit.
A comprehensive WGS-based pipeline for the identification of new candidate genes in inherited retinal dystrophies
Authors: González-del Pozo María , Fernández-Suárez Elena , Bravo-Gil Nereida , Méndez-Vidal Cristina , Martín-Sánchez Marta , Rodríguez-de la Rúa Enrique , Ramos-Jiménez Manuel , Morillo-Sánchez María José , Borrego Salud , Antiñolo Guillermo
Published: March 2022

To enhance the use of Whole Genome Sequencing (WGS) in clinical practice, it is still necessary to standardize data analysis pipelines. Herein, we aimed to define a WGS-based algorithm for the accurate interpretation of variants in inherited retinal dystrophies (IRD). This study comprised 429 phenotyped individuals divided into three cohorts. A comparison of 14 pathogenicity predictors, and the re-definition of its cutoffs, were performed using panel-sequencing curated data from 209 genetically diagnosed individuals with IRD (training cohort). The optimal tool combinations, previously validated in 50 additional IRD individuals, were also tested in patients with hereditary cancer (n = 109), and with neurological diseases (n = 47) to evaluate the translational value of this approach (validation cohort). Then, our workflow was applied for the WGS-data analysis of 14 individuals from genetically undiagnosed IRD families (discovery cohort). The statistical analysis showed that the optimal filtering combination included CADDv1.6, MAPP, Grantham, and SIFT tools. Our pipeline allowed the identification of one homozygous variant in the candidate gene CFAP20 (c.337 C > T; p.Arg113Trp), a conserved ciliary gene, which was abundantly expressed in human retina and was located in the photoreceptors layer. Although further studies are needed, we propose CFAP20 as a candidate gene for autosomal recessive retinitis pigmentosa. Moreover, we offer a translational strategy for accurate WGS-data prioritization, which is essential for the advancement of personalized medicine.
Generation of nonlinearity in the electrical response of yeast suspensions
Authors: Tamura K. , Muraji M. , Tanaka K. , Shirafuji T.
Published: March 2022

The mechanism through which nonlinearity is generated in the response waveform of the electric current obtained by applying alternating current voltage to yeast suspension has not yet been elucidated. In this paper, we showed that the response waveform depends on the applied voltage and frequency. The results showed that distortion (nonlinearity) in the waveform increases as the applied voltage increases and/or the frequency decreases. We suggest a model for the generation of nonlinearity based on the influx of potassium ions into the cell via potassium ion channels and transporters in the membrane due to the applied voltage. Furthermore, we validated this model by simulating an electrical circuit.
Modular polymer platform as a novel approach to head and neck cancer therapy
Authors: Alhiyari Yazeed , Shao Jundong , Han Albert Y. , Miller Amanda , Krane Jeffrey F. , Luff Marie , Momcilovic Milica , Shackelford David , Gu Zhen , John Maie A. St.
Published: March 2022

Head and neck cancer is the sixth most common cancer in the world, with more than 300,000 deaths attributed to the disease annually. Aggressive surgical resection often with adjuvant chemoradiation is the cornerstone of treatment. However, the necessary chemoradiation treatment can result in collateral damage to adjacent vital structures causing a profound impact on quality of life. Here, we present a novel polymer of poly(lactic-co-glycolic) acid and polyvinyl alcohol that can serve as a versatile multidrug delivery platform as well as for detection on cross-sectional imaging while functioning as a fiduciary marker for postoperative radiotherapy and radiotherapeutic dosing. In a mouse xenograft model, the dual-layered polymer composed of calcium carbonate/thymoquinone was used for both polymer localization and narrow-field infusion of a natural therapeutic compound. A similar approach can be applied in the treatment of head and neck cancer patients, where immunotherapy and traditional chemotherapy can be delivered simultaneously with independent release kinetics.
Factors controlling the transfer of biogenic organic species from seawater to sea spray aerosol
Authors: Santander Mitchell V. , Schiffer Jamie M. , Lee Christopher , Axson Jessica L. , Tauber Michael J. , Prather Kimberly A.
Published: March 2022

Ocean waves transfer sea spray aerosol (SSA) to the atmosphere, and these SSA particles can be enriched in organic matter relative to salts compared to seawater ratios. A fundamental understanding of the factors controlling the transfer of biogenic organic matter from the ocean to the atmosphere remains elusive. Field studies that focus on understanding the connection between organic species in seawater and SSA are complicated by the numerous processes and sources affecting the composition of aerosols in the marine environment. Here, an isolated ocean–atmosphere system enables direct measurements of the sea–air transfer of different classes of biogenic organic matter over the course of two phytoplankton blooms. By measuring excitation–emission matrices of bulk seawater, the sea surface microlayer, and SSA, we investigate time series of the transfer of fluorescent species including chlorophyll-a, protein-like substances, and humic-like substances. Herein, we show the emergence of different molecular classes in SSA at specific times over the course of a phytoplankton bloom, suggesting that SSA chemical composition changes over time in response to changing ocean biological conditions. We compare the temporal behaviors for the transfer of each component, and discuss the factors contributing to differences in transfer between phases.
Neural stem cell therapy in conjunction with curcumin loaded in niosomal nanoparticles enhanced recovery from traumatic brain injury
Authors: Narouiepour Abdolreza , Ebrahimzadeh-bideskan Alireza , Rajabzadeh Ghadir , Gorji Ali , Negah Sajad Sahab
Published: March 2022

Despite a great amount of effort, there is still a need for reliable treatments of traumatic brain injury (TBI). Recently, stem cell therapy has emerged as a new avenue to address neuronal regeneration after TBI. However, the environment of TBI lesions exerts negative effects on the stem cells efficacy. Therefore, to maximize the beneficial effects of stem cells in the course of TBI, we evaluated the effect of human neural stem/progenitor cells (hNS/PCs) and curcumin-loaded niosome nanoparticles (CM-NPs) on behavioral changes, brain edema, gliosis, and inflammatory responses in a rat model of TBI. After TBI, hNS/PCs were transplanted within the injury site and CM-NPs were orally administered for 10 days. Finally, the effect of combination therapy was compared to several control groups. Our results indicated a significant improvement of general locomotor activity in the hNS/PCs + CM-NPs treatment group compared to the control groups. We also observed a significant improvement in brain edema in the hNS/PCs + CM-NPs treatment group compared to the other groups. Furthermore, a significant decrease in astrogliosis was seen in the combined treatment group. Moreover, TLR4-, NF-κB-, and TNF-α- positive cells were significantly decreased in hNS/PCs + CM-NPs group compared to the control groups. Taken together, this study indicated that combination therapy of stem cells with CM-NPs can be an effective therapy for TBI.
The sGC stimulator BAY-747 and activator runcaciguat can enhance memory in vivo via differential hippocampal plasticity mechanisms
Authors: Nelissen Ellis , Possemis Nina , Van Goethem Nick P. , Schepers Melissa , Mulder-Jongen Danielle A. J. , Dietz Lisa , Janssen Wiebke , Gerisch Michael , Hüser Jörg , Sandner Peter , Vanmierlo Tim , Prickaerts Jos
Published: March 2022

Soluble guanylate cyclase (sGC) requires a heme-group bound in order to produce cGMP, a second messenger involved in memory formation, while heme-free sGC is inactive. Two compound classes can increase sGC activity: sGC stimulators acting on heme-bound sGC, and sGC activators acting on heme-free sGC. In this rodent study, we investigated the potential of the novel brain-penetrant sGC stimulator BAY-747 and sGC activator runcaciguat to enhance long-term memory and attenuate short-term memory deficits induced by the NOS-inhibitor L-NAME. Furthermore, hippocampal plasticity mechanisms were investigated. In vivo, oral administration of BAY-747 and runcaciguat to male Wistar rats enhanced memory acquisition in the object location task (OLT), while only BAY-747 reversed L-NAME induced memory impairments in the OLT. Ex vivo, both BAY-747 and runcaciguat enhanced hippocampal GluA1-containing AMPA receptor (AMPAR) trafficking in a chemical LTP model for memory acquisition using acute mouse hippocampal slices. In vivo only runcaciguat acted on the glutamatergic AMPAR system in hippocampal memory acquisition processes, while for BAY-747 the effects on the neurotrophic system were more pronounced as measured in male mice using western blot. Altogether this study shows that sGC stimulators and activators have potential as cognition enhancers, while the underlying plasticity mechanisms may determine disease-specific effectiveness.
The impact of healthcare reform on the dynamic changes in health service utilization and equity: a 10-year follow-up study
Authors: Guo Wenqin , Liu Gangjun , Ma Li , Gao Baokai , Wang Wenlong , Hu Zhaoyan , Tian Yanmei , Xiao Wenwen , Qiao Hui
Published: March 2022

In the past decade, the government of China has implemented healthcare reforms to provide universal access to healthcare by 2020. We aimed to systematically analyse the dynamic changes in health services and equity during the past 10 years to understand the correlation between health services and social-economic status. We performed a longitudinal study in which we extracted aggregated data mainly from a project (2009, 2011, 2012, 2015, 2019). A multi-stage stratified cluster randomized design was used to obtain a representative sample in each county. Concentration indexes were used to analyse the equity of the changes in utilization. We built multivariate random-effects generalized least squares regression models with the panel data to test whether the rate of receiving a medical consultation in the last 2 weeks or the rate of hospital admission or the prevalence of chronic illness was associated with social-economic status including education level and rural disposable income per capita. We found declines in both the rate of not receiving a medical consultation during the last 2 weeks (P < 0.05 intervention group) and the rate of hospital avoidance (P < 0.05) from 2009 to 2019. The equity in residents' health service utilization has improved constantly. We additionally found that rural disposable income per capita is a protective factor for the rate of a receiving a medical consultation during the last 2 weeks and the rate of hospital admission. China’s 2009 healthcare reform have positively influenced utilization rates and equity in health service utilization in the past decade, a range of health service-targeted strategies are needed including strengthen the prevention and treatment of chronic diseases, focus attention on the health status of elderly residents and improve social-economic status, especially the level of education.
Effect of low-level light therapy in patients with dry eye: a prospective, randomized, observer-masked trial
Authors: Park Yuli , Kim Hoon , Kim Sehwan , Cho Kyong Jin
Published: March 2022

To evaluate the efficacy of low-level light therapy (LLLT) with near-infrared light-emitting diodes (LED-LLLT) for the treatment of dry eye. 40 patients were randomly assigned with a 1:1 allocation ratio to receive LED-LLLT (LLLT group, n = 20) or placebo treatment (placebo group, n = 20). Patients in the LLLT group received LLLT twice a week for 3 weeks, for a total of 6 treatment sessions. The primary endpoint was the changes in the fluorescein corneal staining (FCS) score. The secondary endpoints were the changes in the ocular surface disease index (OSDI) score, lissamine green conjunctival staining (LGCS) scores, tear film break-up time (TBUT), Schirmer test, and the meibomian gland dysfunction (MGD) index. These were evaluated before treatment and 4 weeks after start of treatment. The mean difference of score change in primary endpoint revealed significant improvement in the LLLT group, compared to the placebo. Among secondary endpoints, LGCS, Schirmer's test, upper meibography scores showed significant improvements, while TBUT, lid debris, lid swelling, lid telangiectasia, meibomian gland secretion and expressibility scores had slight improvement without significant differences. No serious adverse events were observed. The use of LED-LLLT for the treatment of dry eye and MGD appears to be safe and beneficial.
The genome trilogy of Anopheles stephensi, an urban malaria vector, reveals structure of a locus associated with adaptation to environmental heterogeneity
Authors: Thakare Aditi , Ghosh Chaitali , Alalamath Tejashwini , Kumar Naveen , Narang Himani , Whadgar Saurabh , Paul Kiran , Shrotri Shweta , Kumar Sampath , Soumya M. , Rao Raksha , Chakraborty Mahul , Choudhary Bibha , Ghosh Susanta K. , Subramani Suresh , Swain Sunita , Srinivasan Subhashini
Published: March 2022

Anopheles stephensiis the most menacing malaria vector to watch for in newly urbanising parts of the world. Its fitness is reported to be a direct consequence of the vector adapting to laying eggs in over-head water tanks with street-side water puddles polluted by oil and sewage. Large frequent inversions in the genome of malaria vectors are implicated in adaptation. We report the genome assembly of a strain ofAn. stephensiof the type-form, collected from a construction site from Chennai (IndCh) in 2016. The genome reported here with a L50 of 4, completes the trilogy of high-resolution genomes of strains with respect to a 16.5 Mbp 2Rbgenotype inAn. stephensiknown to be associated with adaptation to environmental heterogeneity. Unlike the reported genomes of two other strains, STE2 (2R+b/2Rb) and UCI (2Rb/2Rb), IndCh is found to be homozygous for the standard form (2R+b/2R+b). Comparative genome analysis revealed base-level details of the breakpoints and allowed extraction of 22,650 segregating SNPs for typing this inversion in populations. Whole genome sequencing of 82 individual mosquitoes from diverse geographical locations reveal that one third of both wild and laboratory populations maintain the heterozygous genotype of 2Rb. The large number of SNPs can be tailored to 1740 exonic SNPs enabling genotyping directly from transcriptome sequencing. The genome trilogy approach accelerated the study of fine structure and typing of an important inversion inAn. stephensi, putting the genome resources for this understudied species on par with the extensively studied malaria vector,Anopheles gambiae. We argue that the IndCh genome is relevant for field translation work compared to those reported earlier by showing that individuals from diverse geographical locations cluster with IndCh, pointing to significant convergence resulting from travel and commerce between cities, perhaps, contributing to the survival of the fittest strain.