bluuebunny/crossref_metadata_2025 huggingface dataset:
Repetitive catamenial myocardial infarction due to coronary artery spasm: a case report
Authors: Talmor Nina , Gurin Michael , Smilowitz Nathaniel , Gossett Dana , Eisner Bruria , Pleasure Mitchell , Reynolds Harmony R
Published: January 2023

Background

Coronary artery spasm is an established mechanism of myocardial infarction with non-obstructive coronary arteries (MINOCA). Various mechanisms have been proposed, ranging from vascular smooth muscle hyperreactivity to endothelial dysfunction, to autonomic nervous system dysregulation.

Case summary

We report a case of a 37-year-old woman who presented with recurrent non-ST elevation myocardial infarction (NSTEMI), coinciding with her menstrual periods. Intracoronary acetylcholine provocation testing resulted in coronary spasm in the left anterior descending artery (LAD) that was relieved with nitroglycerine. Initiating calcium channel blockade and suppressing cyclical variation in sex hormones resulted in improvement of her symptoms and cessation of monthly NSTEMI events due to coronary spasm.

Discussion

Initiating calcium channel blockade and suppressing cyclical variation in sex hormones resulted in improvement of her symptoms and cessation of monthly NSTEMI events due to coronary spasm. Catamenial coronary artery spasm is a rare, but clinically important, presentation of myocardial infarction with non-obstructive coronary arteries (MINOCA).
Leisure-time and competitive sport participation: a changing paradigm for HCM patients
Authors: Pelliccia Antonio , Day Sharlene , Olivotto Iacopo
Published: January 2023

HCM has long been considered the most frequent cause of death in athletes, and reason for disqualification from sport. However, our perception of the impact of sports on HCM is largely based on anecdotal evidence. In this review, we provide a reappraisal of current knowledge relative to (1) the impact of sport on LV remodelling, and (2) on the clinical outcome of HCM in athletes. (1) The limited available evidence argues against the hypothesis that intensive exercise conditioning may trigger and/or worsen the development of LV hypertrophy or cause changes in LV function in adult HCM athletes. (2) Recent observations challenge the concept of a detrimental effect of sport on HCM clinical course. The Reset-HCM study showed that 16-week moderate-intensity exercise resulted in a small, significant increase in exercise capacity and no adverse events. In a cohort of 88 low-risk HCM athletes followed for a 7-year period, survival analyses showed no difference in mortality between HCM who discontinued or pursued vigorous exercise programmes.

Further reassurance was provided by the ICD Sports Safety Registry. Clinical implications: At present, patients’ attitude to sport participation is highly variable, based on social and legal backgrounds surrounding medical practice in different countries. The shared-decision-making as suggested by current US and European guidelines allows the physician to deliver a tailored and more liberal advice. Physicians should be aware of the changing paradigm relative to exercise and sport prescription for HCM and promote active lifestyle as an integral component of modern management of HCM patients.
Slingshot homolog-1 amplifies mitochondrial abnormalities by distinctly impairing health and clearance of mitochondria
Authors: Cazzaro Sara , Zhao Xingyu , Zhao Victoria K , Kim Yenna K , Woo Jung-A A
Published: January 2023

Accumulating toxic protein assemblies, including Aβ and tau, and dysfunctional mitochondria are associated with synaptic and neuronal loss in Alzheimer’s disease (AD). Such accumulations are thought to be owing to clearance defects in the autophagy-lysosome pathway. Mitochondrial dysfunction is evident in AD brains and animal models at multiple levels, such as mitochondrial genomic mutations, disrupted bioenergetics, deregulated mitochondrial dynamics and impaired clearance of damaged mitochondria (mitophagy). Slingshot homolog-1 (SSH1) is a phosphatase activated by oxidative stress, high intracellular levels of Ca2+ and Aβ42 oligomers (Aβ42O), known for its function to dephosphorylate/activate cofilin through the N-terminal region. SSH1-mediated cofilin dephosphorylation results in Ab42O-induced severing of F-actin and translocation of cofilin to mitochondria, which promotes mitochondria-mediated apoptosis, synaptic loss and synaptic deficits. On the other hand, SSH1-mediated dephosphorylation/deactivation of the autophagy-cargo receptor p62 (SQSTM1), through its C-terminal region, inhibits p62 autophagy flux. However, the interplay between these two different activities of SSH1 in Aβ42O-induced mitochondrial toxicity remains unclear. In this study, we assessed the role of endogenous SSH1 and different regions of SSH1 in regulating mitochondrial health, mitochondrial respiration, clearance of damaged mitochondria and synaptic integrity in vitro and in vivo. Our results indicate that SSH1 suppresses mitochondrial health and respiration through the cofilin-binding N-terminal region, whereas SSH1 impairs mitophagy through a newly identified ~ 100 residue p62-binding domain in the C-terminal region. These results indicate that both N-terminal and C-terminal regions negatively impact mitochondria by distinct and independent modalities to amplify mitochondrial abnormalities, making SSH1 an excellent target to mitigate AD pathogenesis.
Staphylococcus aureus bacteriuria: implications and management
Authors: Mason C Y , Sobti A , Goodman A L
Published: January 2023

Background

Staphylococcus aureus is isolated in around 0.2%–4% of positive urinary cultures, more commonly in the contexts of long-term care, urological abnormalities and procedures, male sex, older age and comorbidities. Isolation may represent contamination, colonization, urinary tract infection or bacteraemic seeding from another site, and may be linked to S. aureus bacteraemia. However, there is little guidance on investigation and management of S. aureus bacteriuria. We performed a retrospective analysis of cases in our service, including clinical characteristics, investigations and treatment.

Methods

Data were collected on all urine samples taken from adult patients over a 5-year period from which S. aureus was isolated. Detailed analysis including investigations and management was conducted in those collected over a 1-year period.

Results

From 511 patients, 668 urine cultures positive for S. aureus were identified; 6.5% of cases were positive for MRSA. Of 93 patients who had blood cultures taken, there were 6 cases of S. aureus bacteraemia, 4 of which were associated with urological instrumentation. Of 94 cases analysed in detail, 57% were treated with antibiotics, and 49% had repeat urine cultures. Factors associated with recurrence were urinary catheterization, urological abnormality, diabetes and inpatient status.

Conclusions

Our experience does not support the routine taking of blood cultures or treatment of asymptomatic bacteriuria in well patients with S. aureus bacteriuria in this setting. However, repeat urine culture, and investigation and treatment of higher risk patients, for example, prior to bladder instrumentation, may be warranted. We propose a simple algorithm to guide clinicians.
The role of hospital antimicrobial and infectious diseases pharmacists in the UK: a theoretically underpinned exploration
Authors: Micallef C , Enoch D A , Kamranpour P , Santos R , Tyler N , Scott S
Published: January 2023

Objectives

We sought to characterise the role of hospital infection pharmacists in the UK and to understand the core challenges being faced, future role development desires and the required support to address these.

Methods

We developed a questionnaire underpinned by the theoretical domains framework exploring the barriers and enablers to pharmacists fulfilling their perceived roles and responsibilities. Any pharmacist whose role included ‘specialist antimicrobial’ or ‘infectious diseases’ was invited to complete a questionnaire sent via national infection and pharmacy groups/networks. Descriptive statistics were used to report responses to each item, and a content analysis was undertaken to summarize the key messages from an extended response option.

Results

Of the 102 respondents, 91 (89.2%) were from English hospitals. Fifty-three (52%) were from district general hospitals and 45 (45.1%) from teaching hospitals. Most (97, 95%) respondents were of a senior grade. The need for a comprehensive educational programme, recognition of research as core to the role and integration with infection/microbiology departments were key requirements along with protected time to engage with the activities. Highlights of the role were opportunities to teach, making a significant contribution to patient care and scope to contribute to strategy and vision. The COVID-19 pandemic negatively impacted on respondents’ capacity to undertake their perceived roles and responsibilities.

Conclusions

Our study delineates the need for UK infection and pharmacy policy makers to review hospital infection pharmacist developmental pathways and roles. Joint learning, and closer working, with infection/microbiology departments may be an efficient strategy to address the issues raised.
A Turn of the Tables: Psychological Contracts and Word of Mouth about Sharing Economy Platforms When Consumers Get Reviewed
Authors: Rifkin Laura Schrier , Kirk Colleen P , Corus Canan
Published: January 2023

The Peer-to-Peer sector of the sharing economy relies on reputation systems through which consumers and providers review each other. Whereas prior research has examined the effects of reviews by consumers on providers and firms, this research examines, for the first time, a turn of the tables in which consumers are evaluated. Across a pilot and seven studies (five preregistered), using multiple actual behaviors and sharing contexts, results reveal that a negative review of the consumer from the peer provider leads to negative word of mouth (NWOM) about the platform. Drawing from psychological contract theory, the research demonstrates that this effect is mediated by consumers' perceived betrayal by the platform. Two sets of moderators are identified. The first set establishes that a breach of consumers' psychological contract with the platform underlies the effect. In the second set, platform policies that may render a breach more or less consequential can intensify or mitigate consumer reactions. Specifically, making the review private (vs. public) and providing opportunities for justice restoration (response, revenge, and dispute) attenuate the effect of review valence on betrayal and NWOM. Implications for sharing economy platform managers and consumers are discussed.
Corporate Power and Accountability in International Economic Law
Authors: Low Lucinda A
Published: January 2023

Over the past twenty-five years, States, international institutions, and private entities have attempted to rein in corruption and promote corporate social responsibility. Such efforts have produced mixed results but have led to greater international cooperation and the establishment of clear norms. Increasing the accountability of multinational corporate actors remains a challenge but depends upon cooperation among boards of directors, national governments, nongovernmental organizations, and international institutions. This paper analyzes the relationship among municipal statutes, nonbinding ‘soft law’, and private standards. None on their own can effectively solve the problem of irresponsible corporate behavior but together have made meaningful steps in creating a more fair and accountable business environment.
Taking Stakeholder Engagement in International Policy-Making Seriously: Is the WTO Finally Opening Up?
Authors: Pauwelyn Joost
Published: January 2023

In the face of multiple global challenges, major policy-making initiatives are under way at various international fora. In many of these talks and discussions, a central question is how to fairly and effectively engage external stakeholders. While lagging behind for decades, the World Trade Organization has woken up to the potential of more actively engaging stakeholders in international trade policy-making, both to make better policies and mitigate implementation challenges. This contribution describes the groundbreaking steps taken in a number of Member-led informal discussions and dialogues: the Trade and Environmental Sustainability Structured Discussions and the Informal Dialogue on Plastics Pollution and Environmentally Sustainable Plastics Trade. The objective of this contribution is to describe and applaud recent developments and initiate a discussion on how the process can be made more inclusive and robust and, potentially, also be extended to formal World Trade Organization activities. In this context, the World Health Organization’s ongoing negotiations on a new pandemic treaty are used to offer an interesting point of comparison.
A new Pipistrelle bat from the oceanic Island of Príncipe (Western Central Africa)
Authors: Juste Javier , Torrent Laura , Méndez-Rodríguez Aline , Howard Kelli , García-Mudarra Juan Luis , Nogueras Jesús , Ibáñez Carlos
Published: January 2023

We describe a population of pipistrelle-like bats from Príncipe Island (Gulf of Guinea, Western Central Africa) as a new species based on the molecular and morphological characteristics of six specimens collected more than 30 years ago. The description of this new species was not possible until the traditionally entangled systematics of the whole pipistrelle group was clarified in recent years with the inclusion of molecular techniques and adequate species sampling. In this new taxonomic framework, the new species was clearly included within the dark-winged group of the recently described genus Pseudoromicia. The pipistrelles from Príncipe Island present a moderately inflated skull in lateral view with inner upper incisors that are moderately bicuspids and a baculum distinctly long with expanded tips. Besides these morphological characters, the new bat species is distinguished by its dwarfism, being the smallest species recognized within the genus. The ecology and conservation status of this endemic island species are unknown and field studies are urgently needed to evaluate the situation and conservation threats to this new species in its natural habitat.
Glyphosate exposure and urinary oxidative stress biomarkers in the Agricultural Health Study
Authors: Chang Vicky C , Andreotti Gabriella , Ospina Maria , Parks Christine G , Liu Danping , Shearer Joseph J , Rothman Nathaniel , Silverman Debra T , Sandler Dale P , Calafat Antonia M , Beane Freeman Laura E , Hofmann Jonathan N
Published: January 2023

Background

Glyphosate is the most widely applied herbicide worldwide, and its use has been associated with increased risks of certain hematopoietic cancers in epidemiologic studies. Animal and in vitro experiments suggest that glyphosate may induce oxidative stress, a key characteristic of carcinogens; however, evidence in human populations remains scarce. We investigated associations between glyphosate exposure and urinary oxidative stress biomarkers in the Biomarkers of Exposure and Effect in Agriculture study, a molecular epidemiologic subcohort in the Agricultural Health Study.

Methods

This analysis included 268 male farmers selected based on self-reported recent and lifetime occupational glyphosate use and 100 age- and geography-matched male nonfarmers. Concentrations of glyphosate and oxidative stress biomarkers (8-hydroxy-2′-deoxyguanosine [8-OHdG], 8-iso-prostaglandin-F2α, and malondialdehyde [MDA]) were quantified in first-morning-void urine. We performed multivariable linear regression to evaluate associations of urinary glyphosate and self-reported glyphosate use with each oxidative stress biomarker.

Results

Urinary glyphosate concentrations were positively associated with levels of 8-OHdG (highest vs lowest glyphosate quartile; geometric mean ratio = 1.15, 95% confidence interval = 1.03 to 1.28; Ptrend = .02) and MDA (geometric mean ratio = 1.20, 95% confidence interval = 1.03 to 1.40; Ptrend = .06) overall. Among farmers reporting recent glyphosate use (last 7 days), use in the previous day was also associated with statistically significantly increased 8-OHdG and MDA levels. Compared with nonfarmers, we observed elevated 8-iso-prostaglandin-F2α levels among farmers with recent, high past 12-month, or high lifetime glyphosate use.

Conclusions

Our findings contribute to the weight of evidence supporting an association between glyphosate exposure and oxidative stress in humans and may inform evaluations of the carcinogenic potential of this herbicide.
Exploring the antibacterial potential of Lactococcus lactis subsp. lactis bv. diacetylactis BGBU1-4 by genome mining, bacteriocin gene overexpression, and chemical protein synthesis of lactolisterin BU variants
Authors: Malesevic Milka , Gardijan Lazar , Miljkovic Marija , O'Connor Paula M , Mirkovic Nemanja , Jovcic Branko , Cotter Paul D , Jovanovic Goran , Kojic Milan
Published: January 2023

Lactic acid bacterium Lactococcus lactis BGBU1-4 produces 43 amino acids (aa) long bacteriocin, lactolisterin BU (LBU), a 5.161 kDa peptide with potent antibacterial activity against many Gram-positive pathogens. In addition, BGBU1-4 produces an additional unknown product of 3.642 kDa with antibacterial activity. Here, we determined that the significant amount of naturally produced LBU breaks down to create a 3.642 kDa truncated form of LBU bacteriocin consisting of 31 N-terminal aa (LBU1-31) that exhibits 12.5% the antibacterial activity of the full-length LBU. We showed that chemically synthesized LBU is stable and 50% less active than native LBU, and so we used the synthetic peptides of LBU and its variants to further study their activities and antibacterial potential. Deletion analysis of LBU revealed that the 24 N-terminal aa of LBU (LBU1-24) are responsible for antibacterial activity, while downstream aa (25–43) determine the species-specific effectiveness of LBU. Although LBU1-31 contains aa 1–24, the truncation at position 31 is predicted to change the structure within aa 15–31 and might impact on antibacterial activity. Intriguingly, whole genome sequencing and genome mining established that BGBU1-4 is abundant in genes that encode potential antibacterials, but produces LBU and its breakdown product LBU1-31 exclusively.
The ultraviolet continuum slopes (β) of galaxies at z ≃ 8-16 from JWST and ground-based near-infrared imaging
Authors: Cullen Fergus , McLure R J , McLeod D J , Dunlop J S , Donnan C T , Carnall A C , Bowler R A A , Begley R , Hamadouche M L , Stanton T M
Published: January 2023

We study the rest-frame ultraviolet (UV) continuum slopes (β) of galaxies at redshifts 8 < z < 16 (〈z〉 = 10), using a combination of JWST ERO and ERS NIRCam imaging and ground-based near-infrared imaging of the COSMOS field. The combination of JWST and ground-based imaging provides a wide baseline in both redshift and absolute UV magnitude (−22.6 < MUV < −17.9), sufficient to allow a meaningful comparison to previous results at lower redshift. Using a power-law fitting technique, we find that our full sample (median MUV = −19.3 ± 1.3) returns an inverse-variance weighted mean value of 〈β〉 = −2.10 ± 0.05, with a corresponding median value of β = −2.29 ± 0.09. These values imply that the UV colours of galaxies at z > 8 are, on average, no bluer than the bluest galaxies in the local universe (e.g. NGC 1705; β = −2.46). We find evidence for a β − MUV relation, such that brighter UV galaxies display redder UV slopes ($\rm {d}\beta / \rm {d} M_{\rm UV} = -0.17 \pm 0.05$). Comparing to results at lower redshift, we find that the slope of our β − MUV relation is consistent with the slope observed at z ≃ 5 and that, at a given MUV, our 8 < z < 16 galaxies are bluer than their z ≃ 5 counterparts, with an inverse-variance weighted mean offset of 〈Δβ〉 = −0.38 ± 0.09. We do not find strong evidence that any objects in our sample display ultra-blue UV continuum slopes (i.e. β ≲ −3) that would require their UV emission to be dominated by ultra-young, dust-free stellar populations with high Lyman-continuum escape fractions. Comparing our results to the predictions of theoretical galaxy formation models, we find that the galaxies in our sample are consistent with the young, metal-poor, and moderately dust-reddened galaxies expected at z > 8.
Close encounters of tight binary stars with stellar-mass black holes
Authors: Ryu Taeho , Perna Rosalba , Pakmor Ruediger , Ma Jing-Ze , Farmer Rob , de Mink Selma E
Published: January 2023

Strong dynamical interactions among stars and compact objects are expected in a variety of astrophysical settings, such as star clusters and the disks of active galactic nuclei. Via a suite of three-dimensional hydrodynamics simulations using the moving-mesh code arepo, we investigate the formation of transient phenomena and their properties in close encounters between an $2\, {\rm M}_{\odot }$ or $20\, {\rm M}_{\odot }$ equal-mass circular binary star and single $20\, {\rm M}_{\odot }$ black hole (BH). Stars can be disrupted by the BH during dynamical interactions, naturally producing electromagnetic transient phenomena. Encounters with impact parameters smaller than the semimajor axis of the initial binary frequently lead to a variety of transients whose electromagnetic signatures are qualitatively different from those of ordinary disruption events involving just two bodies. These include the simultaneous or successive disruptions of both stars and one full disruption of one star accompanied by successive partial disruptions of the other star. On the contrary, when the impact parameter is larger than the semimajor axis of the initial binary, the binary is either simply tidally perturbed or dissociated into bound and unbound single stars (‘micro-Hills’ mechanism). The dissociation of $20\, {\rm M}_{\odot }$ binaries can produce a runaway star and an active BH moving away from one another. Also, the binary dissociation can either produce an interacting binary with the BH, or a non-interacting, hard binary; both could be candidates of BH high- and low-mass X-ray binaries. Hence, our simulations especially confirm that strong encounters can lead to the formation of the (generally difficult to form) BH low-mass X-ray binaries.
Self-consistent models of our Galaxy
Authors: Binney James , Vasiliev Eugene
Published: January 2023

A new class of models of stellar discs is introduced and used to build a self-consistent model of our Galaxy. The model is defined by the parameters that specify the action-based distribution functions (DFs) f(J) of four stellar discs (three thin-disc age cohorts and a thick disc), spheroidal bulge and spheroidal stellar and dark haloes. From these DFs plus a specified distribution of gas, we solve for the densities of stars and dark matter and the potential they generate. The principal observational constraints are the kinematics of stars with Gaia Radial Velocity Spectrometer (RVS) data and the density of stars in the column above the Sun. The model predicts the density and kinematics of stars and dark matter throughout the Galaxy, and suggests the structure of the dark halo prior to the infall of baryons. The code used to create the model is available on github.
Atomic data on inelastic processes in boron–hydrogen collisions with accounting for fine structure
Authors: Voronov Yaroslav V , Yakovleva Svetlana A , Belyaev Andrey K
Published: January 2023

This paper reports the results of investigations of inelastic processes in B + H and B+ + H− collisions with accounting for the fine structure. The calculations of the cross-sections and rate coefficients for excitation, de-excitation, ion-pair formation, and mutual neutralization processes (240 in total) are performed by using the quantum asymptotic method, which is modified in this paper for accounting of the fine structure, and by the multichannel approach within the framework of the Born–Oppenheimer formalism. It is found that accounting for the fine structure may change the rate coefficients significantly, and the rates calculated with accounting for the fine structure cannot be obtained by a simple redistribution of the non-relativistic rates. The processes important for non-local thermodynamic equilibrium modelling of stellar atmospheres are designated.
Consistent and simultaneous modelling of galaxy clustering and galaxy–galaxy lensing with subhalo abundance matching
Authors: Contreras Sergio , Angulo Raul E , Chaves-Montero Jonás , White Simon D M , Aricò Giovanni
Published: January 2023

The spatial distribution of galaxies and their gravitational lensing signal offer complementary tests of galaxy formation physics and cosmology. However, their synergy can only be fully exploited if both probes are modelled accurately and consistently. In this paper, we demonstrate that this can be achieved using an extension of Sub-Halo Abundance Matching extended model (SHAMe), dubbed SHAMe. Specifically, we use mock catalogues built from the TNG300 hydrodynamical simulation to show that SHAMe can simultaneously model the multipoles of the redshift–space galaxy correlation function and galaxy–galaxy lensing, without noticeable bias within the statistical sampling uncertainties of a SDSS volume and on scales r ∈ [0.6 − 30]h−1 Mpc. Modelling the baryonic processes in galaxy–galaxy lensing with a baryonification scheme allows SHAMe’s range of validity to be extended to r ∈ [0.1 − 30] h−1 Mpc. Remarkably, our model achieves this level of precision with just five free parameters beyond those describing the baryonification model. At fixed cosmology, we find that galaxy–galaxy lensing provides a general consistency test but little additional information on galaxy modelling parameters beyond that encoded in the redshift-space multipoles. It does, however, improve constraints if only the projected correlation function is available, as in surveys with only photometric redshifts. We expect SHAMe to have a higher fidelity across a wider range of scales than more traditional methods such as Halo Occupation Distribution modelling. Thus it should provide a significantly more powerful and more robust tool for analysing next-generation large-scale surveys.
Catching a Milky Way open cluster in its last breath
Authors: Piatti Andrés E
Published: January 2023

Theoretical models have suggested peculiar velocity dispersion profiles of star clusters facing dissolution. They predicted that, besides bound stars that still belong to the star cluster, and unbound ones already stripped off, there is an intermediate population of stars that having acquired the enough energy to escape the cluster are still within the cluster Jacobi radius. Both, potential escapers and unbound stars, show hot kinematics, not observed along tidal tails of star clusters. We report on the first evidence of an open cluster with stars crossing such a transitional scenario, namely: ASCC 92. The open cluster gathers nearly 10 per cent of its initial total mass, and is moving towards Galactic regions affected by higher interstellar absorption. Precisely, the obscured appearance of the cluster could have hampered disentangling its true internal dynamical evolutionary stage, previously.
The comptonizing medium of the black hole X-ray binary MAXI J1535−571 through type-C quasi-periodic oscillations
Authors: Rawat Divya , Méndez Mariano , García Federico , Altamirano Diego , Karpouzas Konstantinos , Zhang Liang , Alabarta Kevin , Belloni Tomaso M , Jain Pankaj , Bellavita Candela
Published: January 2023

We present a detailed spectral and temporal analysis of the black hole candidate MAXI J1535−571 using NICER observations in 2017 September and October. We focus specifically on observations in the hard-intermediate state when the source shows type-C quasi-periodic oscillations (QPOs). We fitted the time-averaged spectrum of the source and the rms and phase-lag spectra of the QPO with a one-component time-dependent Comptonization model. We found that the corona contracts from ∼104–3× 10 3 km as the QPO frequency increases from ∼ 1.8–9.0 Hz. The fits suggest that the system would consist of two coronas, a small one that dominates the time-averaged spectrum and a larger one, possibly the jet, that dominates the rms and lag spectra of the QPO. We found a significant break in the relation between the spectral parameters of the source and the properties of the QPO, including its lag spectra, with QPO frequency. The change in the relations happens when the QPO frequency crosses a critical frequency ν c ≈ 3.0 Hz. Interestingly, the QPO reaches this critical frequency simultaneously as the radio emission from the jet in this source is quenched.
Single-cell gene regulatory network prediction by explainable AI
Authors: Keyl Philipp , Bischoff Philip , Dernbach Gabriel , Bockmayr Michael , Fritz Rebecca , Horst David , Blüthgen Nils , Montavon Grégoire , Müller Klaus-Robert , Klauschen Frederick
Published: January 2023

The molecular heterogeneity of cancer cells contributes to the often partial response to targeted therapies and relapse of disease due to the escape of resistant cell populations. While single-cell sequencing has started to improve our understanding of this heterogeneity, it offers a mostly descriptive view on cellular types and states. To obtain more functional insights, we propose scGeneRAI, an explainable deep learning approach that uses layer-wise relevance propagation (LRP) to infer gene regulatory networks from static single-cell RNA sequencing data for individual cells. We benchmark our method with synthetic data and apply it to single-cell RNA sequencing data of a cohort of human lung cancers. From the predicted single-cell networks our approach reveals characteristic network patterns for tumor cells and normal epithelial cells and identifies subnetworks that are observed only in (subgroups of) tumor cells of certain patients. While current state-of-the-art methods are limited by their ability to only predict average networks for cell populations, our approach facilitates the reconstruction of networks down to the level of single cells which can be utilized to characterize the heterogeneity of gene regulation within and across tumors.
The formation of HuR/YB1 complex is required for the stabilization of target mRNA to promote myogenesis
Authors: Sánchez Brenda Janice , Mubaid Souad , Busque Sandrine , de los Santos Yossef Lopez , Ashour Kholoud , Sadek Jason , Lian Xian Jin , Khattak Shahryar , Di Marco Sergio , Gallouzi Imed-Eddine
Published: January 2023

mRNA stability is the mechanism by which cells protect transcripts allowing their expression to execute various functions that affect cell metabolism and fate. It is well-established that RNA binding proteins (RBPs) such as HuR use their ability to stabilize mRNA targets to modulate vital processes such as muscle fiber formation (myogenesis). However, the machinery and the mechanisms regulating mRNA stabilization are still elusive. Here, we identified Y-Box binding protein 1 (YB1) as an indispensable HuR binding partner for mRNA stabilization and promotion of myogenesis. Both HuR and YB1 bind to 409 common mRNA targets, 147 of which contain a U-rich consensus motif in their 3′ untranslated region (3′UTR) that can also be found in mRNA targets in other cell systems. YB1 and HuR form a heterodimer that associates with the U-rich consensus motif to stabilize key promyogenic mRNAs. The formation of this complex involves a small domain in HuR (227–234) that if mutated prevents HuR from reestablishing myogenesis in siHuR-treated muscle cells. Together our data uncover that YB1 is a key player in HuR-mediated stabilization of pro-myogenic mRNAs and provide the first indication that the mRNA stability mechanism is as complex as other key cellular processes such as mRNA decay and translation.
Metabolically-targeted dCas9 expression in bacteria
Authors: Pellegrino Gregory M , Browne Tyler S , Sharath Keerthana , Bari Khaleda A , Vancuren Sarah J , Allen-Vercoe Emma , Gloor Gregory B , Edgell David R
Published: January 2023

The ability to restrict gene expression to a relevant bacterial species in a complex microbiome is an unsolved problem. In the context of the human microbiome, one desirable target metabolic activity are glucuronide-utilization enzymes (GUS) that are implicated in the toxic re-activation of glucuronidated compounds in the human gastrointestinal (GI) tract, including the chemotherapeutic drug irinotecan. Here, we take advantage of the variable distribution of GUS enzymes in bacteria as a means to distinguish between bacteria with GUS activity, and re-purpose the glucuronide-responsive GusR transcription factor as a biosensor to regulate dCas9 expression in response to glucuronide inducers. We fused the Escherichia coli gusA regulatory region to the dCas9 gene to create pGreg-dCas9, and showed that dCas9 expression is induced by glucuronides, but not other carbon sources. When conjugated from E. coli to Gammaproteobacteria derived from human stool, dCas9 expression from pGreg-dCas9 was restricted to GUS-positive bacteria. dCas9-sgRNAs targeted to gusA specifically down-regulated gus operon transcription in Gammaproteobacteria, with a resulting ∼100-fold decrease in GusA activity. Our data outline a general strategy to re-purpose bacterial transcription factors responsive to exogenous metabolites for precise ligand-dependent expression of genetic tools such as dCas9 in diverse bacterial species.
Molecular architecture and oligomerization of Candida glabrata Cdc13 underpin its telomeric DNA-binding and unfolding activity
Authors: Coloma Javier , Gonzalez-Rodriguez Nayim , Balaguer Francisco A , Gmurczyk Karolina , Aicart-Ramos Clara , Nuero Óscar M , Luque-Ortega Juan Román , Calugaru Kimberly , Lue Neal F , Moreno-Herrero Fernando , Llorca Oscar
Published: January 2023

The CST complex is a key player in telomere replication and stability, which in yeast comprises Cdc13, Stn1 and Ten1. While Stn1 and Ten1 are very well conserved across species, Cdc13 does not resemble its mammalian counterpart CTC1 either in sequence or domain organization, and Cdc13 but not CTC1 displays functions independently of the rest of CST. Whereas the structures of human CTC1 and CST have been determined, the molecular organization of Cdc13 remains poorly understood. Here, we dissect the molecular architecture of Candida glabrata Cdc13 and show how it regulates binding to telomeric sequences. Cdc13 forms dimers through the interaction between OB-fold 2 (OB2) domains. Dimerization stimulates binding of OB3 to telomeric sequences, resulting in the unfolding of ssDNA secondary structure. Once bound to DNA, Cdc13 prevents the refolding of ssDNA by mechanisms involving all domains. OB1 also oligomerizes, inducing higher-order complexes of Cdc13 in vitro. OB1 truncation disrupts these complexes, affects ssDNA unfolding and reduces telomere length in C. glabrata. Together, our results reveal the molecular organization of C. glabrata Cdc13 and how this regulates the binding and the structure of DNA, and suggest that yeast species evolved distinct architectures of Cdc13 that share some common principles.
Multi-layered chromatin proteomics identifies cell vulnerabilities in DNA repair
Authors: Sigismondo Gianluca , Arseni Lavinia , Palacio-Escat Nicolàs , Hofmann Thomas G , Seiffert Martina , Krijgsveld Jeroen
Published: January 2023

The DNA damage response (DDR) is essential to maintain genome stability, and its deregulation predisposes to carcinogenesis while encompassing attractive targets for cancer therapy. Chromatin governs the DDR via the concerted interplay among different layers, including DNA, histone post-translational modifications (hPTMs) and chromatin-associated proteins. Here, we employ multi-layered proteomics to characterize chromatin-mediated functional interactions of repair proteins, signatures of hPTMs and the DNA-bound proteome during DNA double-strand break (DSB) repair at high temporal resolution. Our data illuminate the dynamics of known and novel DDR-associated factors both at chromatin and at DSBs. We functionally attribute novel chromatin-associated proteins to repair by non-homologous end-joining (NHEJ), homologous recombination (HR) and DSB repair pathway choice. We reveal histone reader ATAD2, microtubule organizer TPX2 and histone methyltransferase G9A as regulators of HR and involved in poly-ADP-ribose polymerase-inhibitor sensitivity. Furthermore, we distinguish hPTMs that are globally induced by DNA damage from those specifically acquired at sites flanking DSBs (γH2AX foci-specific) and profiled their dynamics during the DDR. Integration of complementary chromatin layers implicates G9A-mediated monomethylation of H3K56 in DSBs repair via HR. Our data provide a dynamic chromatin-centered view of the DDR that can be further mined to identify novel mechanistic links and cell vulnerabilities in DSB repair.
A threefold approach to rescue the 2030 Agenda from failing
Authors: Pradhan Prajal
Published: January 2023

Rescuing the 2030 Agenda for Sustainable Development from failing requires prioritizing Sustainable Development Goals (SDGs), understanding the impacts of underachieving SDGs, and building a post-2030 Agenda based on scientific evidence.
Hinduism in Karnataka
Authors: Devadevan Manu
Published: January 2023

This is a bibliography of a wide assortment of religious traditions that are characterized today as representing Hinduism. The geographical extent is limited to the areas that are included in the administrative province of Karnataka, formed in 1956 on the recommendations of the States Reorganisation Committee, a body set up by the Government of India. The bibliography enumerates works produced in English after this date, as the older works are mostly dated now. It must be borne in mind that this province is not coterminous with the region of Karnataka that has existed with porous and shifting boundaries for more than a thousand years. The checkered history of administrative divisions in the last two centuries has left its impression on historical research too, including research on the history of religious traditions. The transformation of diversely organized religious groups into monolithic communities—such as Hinduism and Vīraśaivism—was a product of historical developments over these two centuries, a fact which is increasingly recognized in academia today. Research on “Hinduism” in “Karnataka” must then acknowledge the prochronism in the former and the parachronism in the latter. Research on the history of religion in Karnataka has not been extensive or exhaustive. Much has been written on the 12th-century saint Basava and his Śaiva contemporaries, identified today as pioneers of Vīraśaivism. The historical fallouts of their work and the diverse traditions that they gave birth to in the following centuries have also been extensively commented upon, although much of it is in Kannada. From the 1980s, the Kannada academia has evinced interest in the siddha traditions of the region, including Nātha, Datta, and the Śākta traditions. The Vaiṣṇavite haridāsa tradition has received little attention. The dvaita tradition of Uḍupi, which commenced with Ānandatīrtha (Madhvācārya) in the thirteenth century, has drawn the interest of a few Anglophone researchers. There are a few interesting works on state festivals, especially of the Vijayanagara and Woḍeyar rulers. The most extensive research in English has been on temple architecture, which can form the subject of a veritable bibliographical essay in its own right. Unfortunately, there are no works that make a critical assessment or descriptive survey of the status of research. In what follows, I will describe the extant research thematically, which for want of space is not an exhaustive survey but limited to the most significant works.
Japanese Foreign Policy
Authors: McCarthy Mary
Published: January 2023

Japanese foreign policy is a dynamic field of study undergoing profound changes in two main ways. First, there are the actual shifts in the foreign policies being constructed in Tokyo. Second, there is an evolution of the scholarly tools that are being used to analyze those policies. Both provide opportunities for researchers and students alike to discover deeper insights into Japan and the international system. Japan has often been painted as an outlier in applications of theories of foreign policy and international relations (IR). Hence, we have the long-standing “normal” debates permeating the scholarship on Japanese foreign policy (in other words, explorations of the degree to which Japanese foreign policy is “normal” or is becoming more “normal”). Yet, as a perceived outlier, the Japan case may actually be pointing out weaknesses in many of our theories in IR and highlighting how theories created in a “Western” context may be limited. Therefore, it is a case study that can enrich our ontological and epistemological perceptions by complicating them. When Japan became an economic superpower in the postwar era, it did not develop the comparable military capabilities that many IR theorists, particularly in the realist school of thought, predicted as the natural next step. Some theorists tried to explain this apparent puzzle using constructivist frameworks, such as norms and identity. They talked about Japan’s pacifism, antimilitarism, or nuclear allergy. Still others argued that this was a rational strategic choice by Japan in keeping with defensive realism or a realist/liberalist combo. With Japan’s enhanced focus in the post–Cold War era on security and building military capabilities, scholars used this development as evidence to support that they were always correct in their frameworks or to argue that external and/or internal circumstances have altered so that new frameworks need to be used to explain these changes. Some began to talk of the malleability of identity and to reject any notion of static norms. This bibliography seeks to take into account both the scholarly heritage upon which current research rests and the new directions in incorporating a diversity of actors, institutions, and interpretations into our understanding of Japanese foreign policy. In doing so, several broad themes emerge across the sections of this bibliography. One is how, although history can constrain one’s foreign policy, it can also create opportunities for the development of distinctive policymaking tools.
Ambulatory Assessment in Behavioral Science
Authors: Ebner-Priemer Ulrich , Trull Timothy
Published: January 2023

To describe the diverse methodologies for researching daily life a variety of terms have been coined: ecological momentary assessment (EMA), ambulatory assessment, experience sampling method (ESM), real-time data capture, or digital phenotyping, just to name a few. In line with the definition of the international society devoted to researching daily life Society for Ambulatory Assessment (SAA), these various terms serve to highlight the different origins and ancestors. Researchers in the Netherlands, Germany, and the United States started developing cutting-edge methods to assess dynamics of behavior and experience in everyday life in the 1970s and 1980s. Although the diverse backgrounds can be clearly differentiated, with Ambulatory Assessment having a focus on combining e-diaries with physiological and behavioral monitoring—ESM, by using paper-pencil diaries and pagers, and EMA, by utilizing e-diaries early on—these research groups coined their terms to describe a broad set of tools to assess affective experiences, cognition, behavior, and physiological processes in daily life. Accordingly, the Society for Ambulatory Assessment introduced “ambulatory assessment” as the umbrella term, covering a range of real-time data capture methodologies that originate from different scientific disciplines (psychology, medicine, computer science, etc.), and it focuses on the common goal, namely, to assess the ongoing behavior, physiology, experience, and environmental aspects of people in naturalistic settings. Distinct features of ambulatory assessment, which differentiates it from traditional assessment approaches like retrospective questionnaires or laboratory-based techniques, include: (1) assessment of data in the real world, increasing the ecological validity and generalizability of the method, (2) focus on individuals’ momentary or very recent states to minimize retrospective biases, (3) ability to study within-subject processes and dynamics, (4) possibility for multimodal and context-specific assessments, and (5) use of real-time analyses to trigger situational assessments and interventions.
Mingei
Authors: Jones Meghen
Published: January 2023

Amid the rapid changes brought on by Japan’s modernization and urbanization in the late nineteenth and early twentieth centuries arose a discourse of the appreciation of folk culture. From the 1920s onward, writer, educator, and aesthete Yanagi Sōetsu (Muneyoshi, 柳宗悦, b. 1889–d. 1961) spearheaded the Mingei movement, centered on the recognition and preservation of Japanese folk craft objects and their creation. The term mingei, usually translated into English as “folk craft” or “folk art,” is a shortened form of minshūteki kōgei民衆的工芸, or “people’s craft.” Coined in the mid-1920s, the two characters of mingei combine “of the people” (民min) with “art” or “craft” (藝, 芸gei). Yanagi defined mingei as functional, ordinary, healthy objects of daily life for the common classes created by anonymous makers in quantity. Unlike folk studies specialists relying on ethnographic or empirical values, Yanagi and his followers determined what constitutes mingei according to aesthetic and moral precepts of goodness and truth, with Pure Land Buddhism a particular influence in post–World War II discourse. Through the activities of the Japan Mingei Association (Nihon Mingei Kyōkai 日本民藝協, 1931–), the Japan Folk Crafts Museum (Nihon Mingeikan 日本民藝館, 1936–) and several journals, the Mingei movement has aimed to advance the research, collecting, promotion, and sale of mingei objects. Mingei exhibitions and various forms of outreach have positioned Mingei aesthetic values as Japanese national cultural identity, and special attention has been given to the preservation of craft making in remote areas. By the end of World War II, mingei had become a household word in Japan, and in the 1950s the Japanese government used the term in official documents to categorize one genre of Japanese craft (kōgei). Today, there are dozens of museums throughout Japan with ties to the Japan Mingei Association as well as a Mingei museum in San Diego, California, founded in 1978 by Martha Longenecker. In some respects, the Mingei movement’s ethos parallels the utopianism of the late-19th-century British Arts and Crafts movement and its offshoot in Germany, the Deutscher Werkbund. But the Mingei movement did not focus heavily on economic issues or promote collaborations between artists and designers within industrial production and architecture like its forebears in Europe. Mingei precepts have greatly influenced modern craft ideology in the English-reading world, particularly for ceramists in the post–World War II era. Publications on Mingei mainly comprise primary sources by Yanagi and his followers, museum catalogues, and scholarly analyses from anthropological, art-historical, and postcolonialist historical points of view. Over the last few decades, critical studies of Mingei have probed the contradictions, complexities, and problems of Yanagi’s theories in light of their political and economic contexts. Several recent publications in Japanese explore Mingei’s relevance to contemporary society. This bibliography’s focus is English-language sources, with select Japanese-language primary sources and recent scholarship.