bluuebunny/crossref_metadata_2025 huggingface dataset:
The odor of a nontoxic tetrodotoxin analog, 5,6,11-trideoxytetrodotoxin, is detected by specific olfactory sensory neurons of the green spotted puffers
Authors: Suzuki Takehisa , Nakahigashi Ryota , Adachi Masaatsu , Nishikawa Toshio , Abe Hideki
Published: May 2024

Toxic puffers accumulate tetrodotoxin (TTX), a well-known neurotoxin, by feeding on TTX-bearing organisms and using it to defend themselves from predators. Our previous studies have demonstrated that toxic puffers are attracted to 5,6,11-trideoxytetrodotoxin (TDT), a nontoxic TTX analog that is simultaneously accumulated with TTX in toxic puffers and their prey. In addition, activity labeling using immunohistochemistry targeting neuronal activity marker suggests that TDT activates crypt olfactory sensory neurons (OSN) of the green spotted puffer. However, it remains to be determined whether individual crypt OSNs can physiologically respond to TDT. By employing electroporation to express GCaMP6s in OSNs, we successfully identified a distinct group of oval OSNs that exhibited a specific calcium response when exposed to TDT in green spotted puffers. These oval OSNs showed no response to amino acids (AAs), which serve as food odor cues for teleosts. Furthermore, oval morphology and surface positioning of TDT-sensitive OSNs in the olfactory epithelium closely resemble that of crypt OSNs. These findings further substantiate that TDT is specifically detected by crypt OSNs in green spotted puffer. The TDT odor may act as a chemoattractant for finding conspecific toxic puffers and for feeding TTX-bearing organisms for effective toxification.
Cost-effectiveness of population screening for aortic stenosis
Authors: Motazedian Pouya , Prosperi-Porta Graeme , Hibbert Benjamin , Jalal Hawre , Labinaz Marino , Burwash Ian G , Abdel-Razek Omar , Di Santo Pietro , Simard Trevor , Wells George , Coyle Doug
Published: May 2024

Aims

Aortic stenosis (AS) is a progressive disease predominantly affecting elderly patients that carries significant morbidity and mortality without aortic valve replacement, the only proven treatment. Our objective was to determine the cost-effectiveness of AS screening using transthoracic echocardiography (TTE) in a geriatric population from the perspective of the publicly funded healthcare system in Canada.

Methods and results

Markov models estimating the cost-effectiveness ratio (ICER) for AS screening with a one-time TTE were developed. The model included diagnosed and undiagnosed AS health states, hospitalizations, transcatheter aortic valve replacement (TAVR), and post-TAVR health states. Primary analysis included screening at 70 and 80 years of age with intervention at symptom onset, with scenario analysis included for early intervention at the time of severe asymptomatic AS diagnosis. Monte Carlo simulation of 5000 replications was completed with a lifetime horizon and a 1.5% discount for costs and outcomes.Screening for AS at the age of 70 years was associated with an ICER of $156 722, and screening at 80 years of age was associated with an ICER of $28 005, suggesting that screening at 80 years of age is cost-effective when willingness-to-pay per QALY is $50 000. Scenario analysis with early intervention was not cost-effective, with an ICER of $142 157 at 70 years and $124 651 at 80 years.

Conclusion

Screening for AS at 80 years of age with a one-time TTE, in a Canadian population, improves quality of life and is cost-effective in a publicly funded healthcare system providing, TAVR is reserved for symptomatic patients.
What’s in a Name? Tracing the Origins of Alfred’s ‘the Great’
Authors: Firth Matthew
Published: May 2024

King Alfred (r. 871–99) is the only native-born English ruler to have gained the byname ‘the Great’. This was not a contemporary sobriquet, but is often considered to have been bestowed in the Elizabethan era by Reformation scholars who increasingly cast Alfred in the role of the founder of the English nation. The acknowledged exception is a reference to Alfred as Rex Alfredus magnus (King Alfred the Great) in a marginal annotation in Matthew Paris’s early thirteenth-century text, Deeds of the Abbots of St Albans Monastery. This medieval attestation of Alfred’s sobriquet is, however, less isolated than has been previously thought. Drawing on a variety of medieval English and Old Norse-Icelandic texts, this article identifies twenty-five examples of Alfred being called ‘the Great’, twenty-three of which have previously gone unremarked. In so doing, it argues for a widespread tradition of Alfred as ‘the Great’, the first sole ruler of all England, from at least the thirteenth century.
Astyanax mexicanus surface and cavefish chromosome-scale assemblies for trait variation discovery
Authors: Warren Wesley C , Rice Edward S , X Maggs , Roback Emma , Keene Alex , Martin Fergal , Ogeh Denye , Haggerty Leanne , Carroll Rachel A , McGaugh Suzanne , Rohner Nicolas
Published: May 2024

The ability of organisms to adapt to sudden extreme environmental changes produces some of the most drastic examples of rapid phenotypic evolution. The Mexican Tetra, Astyanax mexicanus, is abundant in the surface waters of northeastern Mexico, but repeated colonizations of cave environments have resulted in the independent evolution of troglomorphic phenotypes in several populations. Here, we present three chromosome-scale assemblies of this species, for one surface and two cave populations, enabling the first whole-genome comparisons between independently evolved cave populations to evaluate the genetic basis for the evolution of adaptation to the cave environment. Our assemblies represent the highest quality of sequence completeness with predicted protein-coding and noncoding gene metrics far surpassing prior resources and, to our knowledge, all long-read assembled teleost genomes, including zebrafish. Whole-genome synteny alignments show highly conserved gene order among cave forms in contrast to a higher number of chromosomal rearrangements when compared with other phylogenetically close or distant teleost species. By phylogenetically assessing gene orthology across distant branches of amniotes, we discover gene orthogroups unique to A. mexicanus. When compared with a representative surface fish genome, we find a rich amount of structural sequence diversity, defined here as the number and size of insertions and deletions as well as expanding and contracting repeats across cave forms. These new more complete genomic resources ensure higher trait resolution for comparative, functional, developmental, and genetic studies of drastic trait differences within a species.
QTL analysis of divergent floral morphology traits between Gilia yorkii and G. capitata
Authors: DeTemple Joseph M , Chitwood Daniel H , Mosquera Veronica , Whipple Clinton J
Published: May 2024

Speciation is a complex process typically accompanied by significant genetic and morphological differences between sister populations. In plants, divergent floral morphologies and pollinator differences can result in reproductive isolation between populations. Here, we explore floral trait differences between two recently diverged species, Gilia yorkii and G. capitata. The distributions of floral traits in parental, F1, and F2 populations are compared, and groups of correlated traits are identified. We describe the genetic architecture of floral traits through a quantitative trait locus analysis using an F2 population of 187 individuals. While all identified quantitative trait locus were of moderate (10–25%) effect, interestingly, most quantitative trait locus intervals were non-overlapping, suggesting that, in general, traits do not share a common genetic basis. Our results provide a framework for future identification of genes involved in the evolution of floral morphology.
Nonlinear seismic response analysis of slopes considering the coupled effect of slope geometry and soil stratigraphy
Authors: Li Yiming , Wang Guoxin , Ding Yang
Published: May 2024

To investigate the effects of slope geometric parameters and soil stratigraphic properties on the topographic amplification of ground motions, a large number of 2-D horizontally layered slope models are constructed. First, the linear and nonlinear seismic responses of a slope model are compared, and the result shows that the nonlinear characteristics of soils should be considered when studying the amplifying effect of slope topography on ground motions. Then, the nonlinear seismic responses of these slope models are analysed from four aspects: the maximum shear strain in the slopes, the effects of geometry and stratigraphy on the seismic response, the distance between the maximum topographic amplification indicators and the slope crest, and the influence range of slope topography behind the slope crest. The results indicate that the amplifying effect of slope topography on ground motions increases with increasing slope height or decreasing average shear wave velocity of the overlying soil layers. Besides, the variation of the topographic amplification effect with slope gradient is significantly influenced by soil stratigraphic properties. The distance between the maximum topographic amplification indicators and the slope crest is mainly in the range of 0–60 m, and the influence range of slope topography behind the slope crest is mainly in the range of 0–150 m. Subsequently, approximate relations are derived based on regression analyses of simulation results, which can provide meaningful references for the seismic design and seismic retrofitting of engineering structures behind the slope crest. Finally, the effects of slope geometric parameters and soil stratigraphic properties on ground motion modifications are further evaluated according to the prediction curves provided by the approximate relations.
Men’s peer support for mental health challenges: future directions for research and practice
Authors: Sharp Paul , Zhu Patricia , Ogrodniczuk John S , McKenzie Sarah K , Seidler Zac E , Rice Simon M , Oliffe John L
Published: May 2024

Peer support has a long history of helping people navigate mental health challenges and is increasingly utilized within men’s mental health promotion initiatives. Despite considerable research conceptualizing and evaluating peer support in various contexts, little is known about the gendered dimensions of men’s peer support and mutual help for mental health. This article provides an empirically informed commentary on men’s peer support and informal help-seeking preferences to make recommendations for future directions for research and practice. Research examining men’s peer support is emergent and the available evidence suggests that there is potential to conceptually align with many men’s values and preferences for mental health help-seeking. Peer support offers a non-clinical, strength-based adjunct to professional support that may aid men in navigating a range of mental health challenges. Consideration must be given to the influence of gender socialization and men’s diverse experiences with developing and maintaining peer relationships. It should not be assumed that authentic and supportive relationships will naturally form when men congregate together. As a growing number of interventions and programs emerge targeted at boys and men, there are important opportunities to leverage these health promotion efforts to encourage and coach men to engage in mutual help. Opportunities for research and practice are discussed to better understand and harness the health-promoting potential of peer support for men’s mental health.
An Inflection Point or Business as Usual? Secessionism as State Contestation in Ukraine
Authors: Sanjaume-Calvet Marc , Daniels Lesley-Ann
Published: May 2024

Does the Russian war in Ukraine presage a change in the rules of the game for secessionisms around the globe? In this article, we explore how the Russian war in Ukraine and the contested international order from which it emerges can affect state contestation and secessionist movements through changing opportunities in the international order. International recognition plays a crucial role in state creation. The Great Powers of a given historical moment have the capacity to raise sovereignty expectations since having “friends in high places” has been essential to obtaining statehood, alongside de facto control of the territory. However, the liberal international order in place since 1945 has given way to a more contested landscape that opens new opportunities for different recognition patterns, which change how secessionists evaluate their optimal strategy for state contestation. The effects have already been notable in conflicts such as Transnistria, South Ossetia, Abkhazia, Kosovo, and many other territorial disputes, even “frozen conflicts” over the globe, from Western Sahara to Taiwan. We explore how Russia has created and exploited secessionist claims in eastern Ukraine to justify military aims in the Russian war in Ukraine. Based on a detailed review of the evolution of these claims, we draw different scenarios on the potential effects of a changing world order on state contestation. Our research suggests that the theoretical understanding of secession and secessionists’ optimal strategies need to be reviewed, taking into account the changing contested international order.
A Realist Ethos of Resistance in Global Politics
Authors: Franceschet Antonio
Published: May 2024

Realism is conventionally understood as coldly accepting the powerful dominating the weak. Reversing this image, I argue that Realism contains an implicit ethos of resistance. Drawing on a recent scholarship on the historical complexity and diversity of classical Realism in international relations (IR), this article uncovers this ethos by focusing on three shifts of perspective: (1) from an extreme to moderate view of power politics; (2) from naturalizing the status quo to envisaging progressive change; and (3) from a horizontal view of politics among nations (or other horizontally situated entities) to a global image of power politics. I then explore how these shifts exist in a different scholarship, the emergence of a so-called new Realism in political theory. The article builds a conversation between classical Realism in IR and the new Realist philosopher Bernard Williams’ work, finding that both articulate an ethos of legitimate resistance to domination. The significance of the Realist ethos is that it challenges stereotyped images of the tradition justifying domination and injustices, and it inserts and positions a Realist voice in recent debates over human rights to resist in global politics.
Global Hierarchies and Unequal Pressures in the Report-Making of Truth Commissions
Authors: Menzel Anne , Salehi Mariam
Published: May 2024

In this analytical essay, we situate truth commissions as relevant sites for International Relations (IR) research, in particular on professional communities and knowledge hierarchies. With an empirical focus on report-making, we argue that there is a need to rethink and revise established professional community concepts. While these concepts stress professional communities’ detachment from mundane pressures, we suggest a “pressure lens” to better grasp the key dynamics of expert knowledge production. Based on in-depth interpretive research on three truth commissions—in Sierra Leone, Kenya, and Tunisia—we set out to identify key dynamics in the report-making of truth commissions that contribute to the gap between high expectations and sobering realities regarding truth commissions as “victim-centred” policy instruments. Understanding the dynamics at play requires us to pay attention to unequal pressures—such as time and funding pressures, powerholder interference, and demands voiced by victims and survivors—that bear on the work of experts and professionals who produce truth commission reports. We argue that these pressures and, crucially, the ways in which they tend to play out under conditions of coloniality, are expressions of global hierarchies that shape professional report-making work.
The role of geophysics in geologic hydrogen resources
Authors: Zhang Mengli , Li Yaoguo
Published: May 2024

Transition to cleaner energy sources is crucial for reducing carbon emissions to zero. Among these new clean energy types, there is a growing awareness of the potential for naturally occurring geologic hydrogen (H2) as a primary energy resource that can be readily introduced into the existing energy supply. It is anticipated that geophysics will play a critical role in such endeavors. There are two major different types of geologic H2. One is natural H2 (referred to as gold H2), which is primarily accumulating naturally in reservoirs in certain geological setting; and the other is stimulated H2 (referred to as orange H2), which is produced artificially from source rocks through chemical and physical stimulations. We will first introduce geophysics in geologic H2 in comparison and contrast to the scenarios of blue and green H2. We will then discuss the significance of geophysics in both natural H2 and stimulated H2 in term of both exploration and monitoring tools. Comparing and contrasting the current geophysical tools in hydrocarbon exploration and production, we envision the innovative geophysical technologies and strategies for geologic H2 resources based on our current understanding of both natural and stimulated geologic hydrogen systems. The strategies for H2 exploration will involve a shift from reservoir- to source rock-centered approaches. Last, we believe that the geophysical methods including integration of multi-geophysics, efficient data acquisition, and machine learning in geologic H2 could be potentially provide sufficient new directions and significant opportunities to pursue research for the next one or two decades.
Discourses of ISDS reform: a comparison of UNCITRAL Working Group III and ICSID processes
Authors: Marcoux Jean-Michel , Bjorklund Andrea K , Whitsitt Elizabeth A , Vanhonnaeker Lukas
Published: May 2024

The reform of investor-state dispute settlement (ISDS) has been tackled by the International Centre for Settlement of Investment Disputes (ICSID) and United Nations Commission on International Trade Law (UNCITRAL) Working Group (WG) III. Despite different objectives, both processes have relied on written submissions from various stakeholders. What are the structures and the narratives underlying the discourses of ISDS reform in these organizations? This article explores the content of 172 submissions by using mixed methods. It demonstrates that UNCITRAL WG III has involved less structured submissions whose content has expanded the initial mandate, with narratives encapsulating deeper disagreement among participants. By contrast, ICSID operated through a common pattern across submissions and a stronger focus on procedural issues, with less disagreement revealed in its narratives. The article proceeds in three steps. First, it compares the structure of discourses for each reform process by aggregating the content of submissions through computational analysis. Second, it relies on critical discourse analysis to reveal narratives that have emerged in each process. Lastly, the article explores submissions from actors who have participated in both processes to illustrate how they have navigated the tension between structures and narratives when reforming international investment arbitration.
Cytokinin oxidase/dehydrogenase inhibitors: progress towards agricultural practice
Authors: Nisler Jaroslav , Klimeš Pavel , Končitíková Radka , Kadlecová Alena , Voller Jiří , Chalaki Mahfam , Karampelias Michael , Murvanidze Nino , Werbrouck Stefaan P O , Kopečný David , Havlíček Libor , De Diego Nuria , Briozzo Pierre , Moréra Solange , Zalabák David , Spíchal Lukáš
Published: May 2024

Cytokinin oxidase/dehydrogenase (CKX) inhibitors reduce the degradation of cytokinins in plants and thereby may improve the efficiency of agriculture and plant tissue culture-based practices. Here, we report a synthesis and structure–activity relationship study of novel urea derivatives concerning their CKX inhibitory activity. The most active compounds showed sub-nanomolar IC50 values with maize ZmCKX1, the lowest value yet documented. Other CKX isoforms of maize and Arabidopsis were also inhibited very effectively. The binding mode of four compounds was characterized based on high-resolution crystal complex structures. Using the soil nematode Caenorhabditis elegans, and human skin fibroblasts, key CKX inhibitors with low toxicity were identified. These compounds enhanced the shoot regeneration of Lobelia, Drosera, and Plectranthus, as well as the growth of Arabidopsis and Brassica napus. At the same time, a key compound (identified as 82) activated a cytokinin primary response gene, ARR5:GUS, and a cytokinin sensor, TCSv2:GUS, without activating the Arabidopsis cytokinin receptors AHK3 and AHK4. This strongly implies that the effect of compound 82 is due to the up-regulation of cytokinin signalling. Overall, this study identifies highly effective and easily prepared CKX inhibitors with a low risk of environmental toxicity for further investigation of their potential in agriculture and biotechnology.
Towards determinism in PDL: relations and proof theory
Authors: Benevides Mario , Gomes Leandro , Lopes Bruno
Published: May 2024

Guarded Kleene Algebra with Tests (GKAT) was presented as a fragment of KAT to abstract imperative programming languages, where only if-then-else and while-do statements are allowed in the language. The loss of expressiveness is, nevertheless, compensated by a clear advantage over KAT: it allows almost linear decidability of program equivalence. In this work, we give the first step to optimizing the complexity of dynamic logic equivalence, which is EXPTIME-complete in propositional dynamic logic (PDL). First, and based on strict deterministic PDL, we present guarded propositional dynamic logic (GPDL), a fragment of PDL where programs correspond to GKAT terms. It comes embedded, as expected, with a semantics over relational models and a sound axiomatisation. Then, we present a Natural Deduction system for GPDL, proving its soundness and completeness, concerning the axiomatisation. Based on Smolka et al. (2019, Proceedings of the ACM Programming Language 4), we obtain the main result of this work—the equivalence of GPDL programs can be established in almost linear time.
Usefulness of an Ultrasound-guided Prehospital Care for SCUBA Diving Accidents
Authors: Martinet Camille , Cungi Pierre-Julien , Morin Jean
Published: May 2024

The incidence of diving accidents is increasing. Point-of-care ultrasound is the only imaging tool available in the field for the military physician who practices in isolated conditions. While ultrasound is integrated in the pre-hospital evaluation protocols of severe trauma patients, few applications are described for diving accident victims. Through a clinical case, we propose an algorithm of ultrasound triage for diving accidents with pulmonary symptoms. Point-of-care ultrasound makes it possible to avoid a risky transfer, by supporting a diagnosis and the treatment on the spot, to rule out contraindications to recompression, and to detect and monitor the treatment of high-risk complications such as the capillary leak syndrome.
Irritable Bowel Syndrome in Veterans With Gulf War Illness Evaluated at VA’s War-Related Illness and Injury Study Center
Authors: Nono Djotsa Alice B S , Nguyen Wenker Theresa H , Ahmed Sarah T , Ghosh Saurendro , Malhotra Deeksha , Boyle Stephen H , Gifford Elizabeth J , Sims Kellie J , White Donna L , Steele Lea , Helmer Drew A
Published: May 2024

Introduction

Excess rates of Gulf War illness (GWI) and irritable bowel syndrome (IBS), two chronic multisymptom illnesses, have long been documented among nearly 700,000 veterans who served in the 1990-1991 Persian Gulf War. We sought to report the prevalence, characteristics, and association of GWI and IBS decades after the war in a clinical cohort of deployed Gulf War veterans (GWVs) who were evaluated at the Department of Veterans Affairs’ War Related Illness and Injury Study Center (WRIISC) for unexplained chronic symptoms.

Materials and Methods

We analyzed data gathered from clinical intake questionnaires of deployed GWVs who were evaluated at WRIISC clinics between 2008 and 2020. We applied Centers for Disease Control (CDC) criteria to determine the prevalence of severe GWI. IBS was identified using Rome IV diagnostic criteria (current IBS) and veterans’ self-reported “history of physician-diagnosed IBS.” We examined associations between IBS and GWI using bivariate analyses and multivariable logistic regression.

Results

Among the N = 578 GWVs evaluated by the WRIISC, severe GWI (71.8%), history of physician-diagnosed IBS (50.3%) and current IBS (42.2%) were all highly prevalent. Nearly half of GWVs with severe GWI met Rome criteria for IBS (45.8%), and over half reported a history of physician-diagnosed IBS (56.1%). In multivariable models, severe GWI was significantly associated both with current IBS (adjusted odds ratio (aOR): 1.68, 95% CI: 1.11, 2.54) and with veteran-reported history of physician-diagnosed IBS (aOR: 2.15, 95% CI: 1.43, 2.23). IBS with diarrhea (IBS-D) was the most common subtype among GWVs with current IBS (61.1%). However, IBS-mixed affected a significantly greater proportion of veterans with severe GWI, compared to veterans who did not have severe GWI (P = .03).

Conclusions

More than 20 years after the Persian Gulf War, our findings indicate a high degree of comorbidity between severe GWI and IBS among deployed GWVs seeking care for unexplained illnesses. Our results suggest GWVs with GWI should be screened for IBS for which evidence-based treatments are available and could potentially reduce symptom burden. Conversely, symptoms of IBS should trigger additional evaluation for non-gastrointestinal symptoms in deployed Gulf War veterans to identify possible GWI and ensure a comprehensive approach to care.
Candidates for downstream jets at interplanetary shocks
Authors: Hietala H , Trotta D , Fedeli A , Wilson L B , Vuorinen L , Coburn J T
Published: May 2024

Localized dynamic pressure enhancements arising from kinetic processes are frequently observed downstream of the Earth’s bow shock. These structures, called jets, modify their plasma surroundings and participate in particle energization. Here, we report the first observations of jet-like structures in a non-planetary shock environment: downstream of interplanetary shocks. We introduce an analysis approach suitable for such conditions and apply it to Wind spacecraft data. We present one event with a Mach number similar to the Earth’s bow shock as a benchmark, as well as two low Mach number, low beta shocks: a parameter range that is difficult to access at planets. The jet-like structures we find are tens of ion inertial lengths in size, and some are observed further away from the shock than in a limited magnetosheath. We find that their properties are similar to those of magnetosheath jets: in the frame of the shock these structures are fast, cold, and most have no strong magnetic field variations. All three interplanetary shocks feature foreshock activity, but no strongly compressive waves. We discuss the implications, these findings have for the proposed jet formation mechanisms.
Orbit determination of asteroid (469219) Kamo‘oalewa using a combination of historical and new observations
Authors: Huang Hao , Liu Shanhong , Ge Liang , Cao Jianfeng , Li Xie , Gao Jian
Published: May 2024

The orbit solution of near-Earth asteroids heavily relies on ground-based optical observations. The orbit uncertainty is limited by the insufficient observation quantity and quality. The Chinese Tianwen-2 mission targets a near-Earth asteroid (469219) Kamo‘oalewa and a main-belt comet, 311P/PANSTARRS. To accurately determine the orbit of Kamo‘oalewa, more optical observations are needed. Autonomous observation experiments focusing on Kamo‘oalewa were carried out using the 2.16-m telescope at the Xinglong Observatory of the National Astronomical Observatory of China. We found that this telescope could observe near-Earth asteroids as faint as a magnitude of 22.8. Based on the stacking method and trailed star extraction algorithm, 14 optical observations were obtained from 2022 to 2024. The orbit for Kamo‘oalewa was determined by combining our observations with historical observations between 2004 and 2024. The inclusion of our observations results in improved orbital uncertainties of Kamo‘oalewa by 18.67, 7.93, and 11.12 km (1σ) in the X, Y, and Z directions, respectively. Furthermore, by combining all existing and simulated observations, the uncertainty of the orbital determination of Kamo‘oalewa was analysed. When using an additional 180 group observations from 3 Chinese observatories over 2 yr, the orbital uncertainties of Kamo‘oalewa in the 3 directions could be reduced to 30 km (1σ).
New Drosophila promoter-associated architectural protein Mzfp1 interacts with CP190 and is required for housekeeping gene expression and insulator activity
Authors: Sokolov Vladimir , Kyrchanova Olga , Klimenko Natalia , Fedotova Anna , Ibragimov Airat , Maksimenko Oksana , Georgiev Pavel
Published: May 2024

In Drosophila, a group of zinc finger architectural proteins recruits the CP190 protein to the chromatin, an interaction that is essential for the functional activity of promoters and insulators. In this study, we describe a new architectural C2H2 protein called Madf and Zinc-Finger Protein 1 (Mzfp1) that interacts with CP190. Mzfp1 has an unusual structure that includes six C2H2 domains organized in a C-terminal cluster and two tandem MADF domains. Mzfp1 predominantly binds to housekeeping gene promoters located in both euchromatin and heterochromatin genome regions. In vivo mutagenesis studies showed that Mzfp1 is an essential protein, and both MADF domains and the CP190 interaction region are required for its functional activity. The C2H2 cluster is sufficient for the specific binding of Mzfp1 to regulatory elements, while the second MADF domain is required for Mzfp1 recruitment to heterochromatin. Mzfp1 binds to the proximal part of the Fub boundary that separates regulatory domains of the Ubx and abd-A genes in the Bithorax complex. Mzfp1 participates in Fub functions in cooperation with the architectural proteins Pita and Su(Hw). Thus, Mzfp1 is a new architectural C2H2 protein involved in the organization of active promoters and insulators in Drosophila.
ProtVar: mapping and contextualizing human missense variation
Authors: Stephenson James D , Totoo Prabhat , Burke David F , Jänes Jürgen , Beltrao Pedro , Martin Maria J
Published: May 2024

Genomic variation can impact normal biological function in complex ways and so understanding variant effects requires a broad range of data to be coherently assimilated. Whilst the volume of human variant data and relevant annotations has increased, the corresponding increase in the breadth of participating fields, standards and versioning mean that moving between genomic, coding, protein and structure positions is increasingly complex. In turn this makes investigating variants in diverse formats and assimilating annotations from different resources challenging. ProtVar addresses these issues to facilitate the contextualization and interpretation of human missense variation with unparalleled flexibility and ease of accessibility for use by the broadest range of researchers. By precalculating all possible variants in the human proteome it offers near instantaneous mapping between all relevant data types. It also combines data and analyses from a plethora of resources to bring together genomic, protein sequence and function annotations as well as structural insights and predictions to better understand the likely effect of missense variation in humans. It is offered as an intuitive web server https://www.ebi.ac.uk/protvar where data can be explored and downloaded, and can be accessed programmatically via an API.
Global kidney health priorities—perspectives from the ISN-GKHA
Authors: Okpechi Ikechi G , Luyckx Valerie A , Tungsanga Somkanya , Ghimire Anukul , Jha Vivekanand , Johnson David W , Bello Aminu K
Published: May 2024

Kidney diseases have become a global epidemic with significant public health impact. Chronic kidney disease (CKD) is set to become the fifth largest cause of death by 2040, with major impacts on low-resource countries. This review is based on a recent report of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) which uncovered gaps in key vehicles of kidney care delivery assessed using World Health Organization building blocks for health systems (financing, services delivery, workforce, access to essential medicines, health information systems and leadership/governance). High-income countries had more centres for kidney replacement therapies (KRT), higher KRT access, higher allocation of public funds to KRT, larger workforces, more health information systems, and higher government recognition of CKD and KRT as health priorities than low-income nations. Evidence identified from the current ISN-GKHA initiative should serve as template for generating and advancing policies and partnerships to address the global burden of kidney disease. The results provide opportunities for kidney health policymakers, nephrology leaders and organizations to initiate consultations to identify strategies for improving care delivery and access in equitable, resource-sensitive manners. Policies to increase use of public funding for kidney care, lower the cost of KRT and increase workforces should be a high priority in low-resource nations, while strategies that expand access to kidney care and maintain current status of care should be prioritized in high-income countries. In all countries, the perspectives of people with CKD should be exhaustively explored to identify core kidney care priorities.
Calcineurin inhibitor effects on kidney electrolyte handling and blood pressure: tacrolimus versus voclosporin
Authors: Wei Kuang-Yu , van Heugten Martijn H , van Megen Wouter H , van Veghel Richard , Rehaume Linda M , Cross Jennifer L , Viel John J , van Willigenburg Hester , Silva Pedro Henrique Imenez , Danser A H Jan , de Baaij Jeroen H F , Hoorn Ewout J
Published: May 2024

Background

Calcineurin inhibitors (CNIs) affect kidney electrolyte handling and blood pressure (BP) through an effect on the distal tubule. The second-generation CNI voclosporin causes hypomagnesaemia and hypercalciuria less often than tacrolimus. This suggests different effects on the distal tubule, but this has not yet been investigated experimentally.

Methods

Rats were treated with voclosporin, tacrolimus or vehicle for 28 days. Dosing was based on a pilot experiment to achieve clinically therapeutic concentrations. Drug effects were assessed by electrolyte handling at day 18 and 28, thiazide testing at day 20, telemetric BP recordings and analysis of messenger RNA (mRNA) and protein levels of distal tubular transporters at day 28.

Results

Compared with vehicle, tacrolimus but not voclosporin significantly increased the fractional excretions of calcium (>4-fold), magnesium and chloride (both 1.5-fold) and caused hypomagnesaemia. Tacrolimus but not voclosporin significantly reduced distal tubular transporters at the mRNA and/or protein level, including the sodium–chloride cotransporter, transient receptor melastatin 6, transient receptor potential vanilloid 5, cyclin M2, sodium–calcium exchanger and calbindin-D28K. Tacrolimus but not voclosporin reduced the mRNA level and urinary excretion of epidermal growth factor. The saluretic response to hydrochlorothiazide at day 20 was similar in the voclosporin and vehicle groups, whereas it was lower in the tacrolimus group. The phosphorylated form of the sodium–chloride cotransporter was significantly higher at day 28 in rats treated with voclosporin than in those treated with tacrolimus. Tacrolimus transiently increased BP, whereas voclosporin caused a gradual but persistent increase in BP that was further characterized by high renin, normal aldosterone and low endothelin-1.

Conclusions

In contrast to tacrolimus, voclosporin does not cause hypercalciuria and hypomagnesaemia, but similarly causes hypertension. Our data reveal differences between the distal tubular effects of tacrolimus and voclosporin and provide a pathophysiological basis for the clinically observed differences between the two CNIs.
Empirical and simulation data reveal a lack of avoidance of wind turbines by Gyps fulvus (Griffon Vulture)
Authors: Sassi Yohan , Ziletti Noémie , Duriez Olivier , Robira Benjamin
Published: May 2024

The increase of wind turbine installations to limit climate change may affect bird populations because of collisions with rotor blades. Birds may respond to wind turbine presence along a gradient of behavioral changes: avoiding the wind farm (macro-scale) or the wind turbines either by anticipating wind turbine locations (meso-scale) or engaging in last-minute flee attempts (micro-scale). We investigated flight responses of 25 adult Gyps fulvus (Griffon Vulture) equipped with GPS tags over 3 years in an area that included 10 wind farms in Causses, France. At the macro-scale, foraging range and habitat use revealed that G. fulvus did not avoid wind farms. To investigate avoidance at meso- and micro-scales, we focused on the 4 most visited wind farms. We compared vulture flights to null movement models, which allowed us to keep the correlation between flights and topography while creating movement independent of wind turbine locations. At most sites, G. fulvus did not show avoidance behavior. Overall, our results suggest wind farm-specific responses by soaring birds as a function of landscape topography. Thus, to reduce collision risks, stakeholders should first avoid constructing wind farms close to vulture nesting colonies. When siting, developers should investigate G. fulvus use of local topography to avoid areas in which birds are likely to travel. Finally, managers must prioritize the detection of species not able to avoid turbines when designing preventive measures, such as switching off on-demand technologies.
SEPALLATA-driven MADS transcription factor tetramerization is required for inner whorl floral organ development
Authors: Hugouvieux Veronique , Blanc-Mathieu Romain , Janeau Aline , Paul Michel , Lucas Jeremy , Xu Xiaocai , Ye Hailong , Lai Xuelei , Le Hir Sarah , Guillotin Audrey , Galien Antonin , Yan Wenhao , Nanao Max , Kaufmann Kerstin , Parcy François , Zubieta Chloe
Published: May 2024

MADS transcription factors are master regulators of plant reproduction and flower development. The SEPALLATA (SEP) subfamily of MADS transcription factors is required for the development of floral organs and plays roles in inflorescence architecture and development of the floral meristem. SEPALLATAs act as organizers of MADS complexes, forming both heterodimers and heterotetramers in vitro. To date, the MADS complexes characterized in angiosperm floral organ development contain at least 1 SEPALLATA protein. Whether DNA binding by SEPALLATA-containing dimeric MADS complexes is sufficient for launching floral organ identity programs, however, is not clear as only defects in floral meristem determinacy were observed in tetramerization-impaired SEPALLATA mutant proteins. Here, we used a combination of genome-wide-binding studies, high-resolution structural studies of the SEP3/AGAMOUS (AG) tetramerization domain, structure-based mutagenesis and complementation experiments in Arabidopsis (Arabidopsis thaliana) sep1 sep2 sep3 and sep1 sep2 sep3 ag-4 plants transformed with versions of SEP3 encoding tetramerization mutants. We demonstrate that while SEP3 heterodimers can bind DNA both in vitro and in vivo and recognize the majority of SEP3 wild-type-binding sites genome-wide, tetramerization is required not only for floral meristem determinacy but also for floral organ identity in the second, third, and fourth whorls.
Mussel inspired 3D elastomer enabled rapid calvarial bone regeneration through recruiting more osteoprogenitors from the dura mater
Authors: Wang Xuqiao , Ma Chaoqun , Zhang Xinchi , Yuan Pingping , Wang Yujiao , Fu Mingdi , Zhang Zheqian , Shi Ruiying , Wei Na , Wang Juncheng , Wu Wei
Published: May 2024

Currently, the successful healing of critical-sized calvarial bone defects remains a considerable challenge. The immune response plays a key role in regulating bone regeneration after material grafting. Previous studies mainly focused on the relationship between macrophages and bone marrow mesenchymal stem cells (BMSCs), while dural cells were recently found to play a vital role in the calvarial bone healing. In this study, a series of 3D elastomers with different proportions of polycaprolactone (PCL) and poly(glycerol sebacate) (PGS) were fabricated, which were further supplemented with polydopamine (PDA) coating. The physicochemical properties of the PCL/PGS and PCL/PGS/PDA grafts were measured, and then they were implanted as filling materials for 8 mm calvarial bone defects. The results showed that a matched and effective PDA interface formed on a well-proportioned elastomer, which effectively modulated the polarization of M2 macrophages and promoted the recruitment of dural cells to achieve full-thickness bone repair through both intramembranous and endochondral ossification. Single-cell RNA sequencing analysis revealed the predominance of dural cells during bone healing and their close relationship with macrophages. The findings illustrated that the crosstalk between dural cells and macrophages determined the vertical full-thickness bone repair for the first time, which may be the new target for designing bone grafts for calvarial bone healing.
Exploratory study to document large-scale sulfur purification in Ayurveda pharmaceutics
Authors: Chandhiruthil Sathyan Anjana , Dasan Harisankar , Sasikumar Anand , Ruknuddin Galib
Published: May 2024

Background

Ayurvedic manuscripts describe five distinct techniques to purify sulfur, each designed to improve its purity, quality, and effectiveness. The complexity of these methods emphasizes the importance of being meticulous in ensuring the purification of sulfur, which is a crucial step in maintaining the high standards of quality and safety that are integral to the herbo mineral formulations in Ayurveda medicine.

Objectives

The study was conducted to document the technological modifications implemented by Ayurvedic pharmaceutics to purify sulfur.

Methods

A convenient sampling methodology was utilized for the selection of study sites. The study included pharmaceutical companies that employ mechanized processes. An in-depth interview was conducted with the production manager at each site, using a semi-structured questionnaire consisting of three domains.

Results

Four pharmaceutical companies that use mechanized processes were selected for the survey. These companies have innovatively modified the traditional melting and pouring (Dhalana) process to purify significant amounts of sulfur. The quantity of sulfur being purified is varied among the selected companies, ranging from 5 kg to 150 kg.

Conclusions

Implementing appropriate optimization techniques can enhance the efficiency of mechanized manufacturing processes. Collaborating with interdisciplinary sectors is crucial in devising more effective mechanization solutions.
Medical Voluntarism and Orthopaedic Advancements: Lancashire and the Disabled Ex-Servicemen of the First World War
Authors: Smith Nicola
Published: May 2024

This article explores the fundamental role of Lancashire’s medical voluntarism in providing restorative orthopaedic treatments to the region’s First World War, disabled ex-servicemen and assisting in their return to society. It offers a case study of orthopaedic treatments and schemes of rehabilitation provided at Grangethorpe Hospital, Rusholme, between 1914 and 1918. Forming a regional comparison to existing histories of First World War disabled ex-servicemen, which focus primarily on the interwar period, this article traces continuities in pioneering medicine and examples of Lancashire-based medical individuals and institutions. In doing so, this article demonstrates how the region’s response to disablement during the Industrial Revolution underpinned the construction of charities and the advancement of orthopaedic treatments required to provide rehabilitative care during the First World War. Moreover, this paper situates Lancashire and its commitment to medical voluntarism and the reconstruction of disabled ex-servicemen as a key site in the UK’s history of voluntarism.
Sequential Bayesian Phylogenetic Inference
Authors: Höhna Sebastian , Hsiang Allison Y
Published: May 2024

The ideal approach to Bayesian phylogenetic inference is to estimate all parameters of interest jointly in a single hierarchical model. However, this is often not feasible in practice due to the high computational cost. Instead, phylogenetic pipelines generally consist of sequential analyses, whereby a single point estimate from a given analysis is used as input for the next analysis (e.g., a single multiple sequence alignment is used to estimate a gene tree). In this framework, uncertainty is not propagated from step to step, which can lead to inaccurate or spuriously confident results. Here, we formally develop and test a sequential inference approach for Bayesian phylogenetic inference, which uses importance sampling to generate observations for the next step of an analysis pipeline from the posterior distribution produced in the previous step. Our sequential inference approach presented here not only accounts for uncertainty between analysis steps but also allows for greater flexibility in software choice (and hence model availability) and can be computationally more efficient than the traditional joint inference approach when multiple models are being tested. We show that our sequential inference approach is identical in practice to the joint inference approach only if sufficient information in the data is present (a narrow posterior distribution) and/or sufficiently many important samples are used. Conversely, we show that the common practice of using a single point estimate can be biased, for example, a single phylogeny estimate can transform an unrooted phylogeny into a time-calibrated phylogeny. We demonstrate the theory of sequential Bayesian inference using both a toy example and an empirical case study of divergence-time estimation in insects using a relaxed clock model from transcriptome data. In the empirical example, we estimate 3 posterior distributions of branch lengths from the same data (DNA character matrix with a GTR+Γ+I substitution model, an amino acid data matrix with empirical substitution models, and an amino acid data matrix with the PhyloBayes CAT-GTR model). Finally, we apply 3 different node-calibration strategies and show that divergence time estimates are affected by both the data source and underlying substitution process to estimate branch lengths as well as the node-calibration strategies. Thus, our new sequential Bayesian phylogenetic inference provides the opportunity to efficiently test different approaches for divergence time estimation, including branch-length estimation from other software.