bluuebunny/crossref_metadata_2025 huggingface dataset:
Pension reforms in Hungary: have they gone too far?
Authors: Dedák István , Fiser Noémi
Published: April 2024

As a result of unfavorable demographic processes, the pension systems in the Central and Eastern European (CEE) EU countries face significant challenges, which has made the implementation of reforms inevitable in the last decade. Relying on economic theory, this paper analyses the effects of the Hungarian pension reforms in comparison with those of other CEE countries, and discusses the consequences from the point of view of social policy and the sustainability of the pension schemes. We explore the reasons why the reforms in Hungary ultimately did not improve sustainability but rather contributed to dismantling the social care system. Therefore, the Hungarian case provides useful lessons for other countries, and at the same time underlines the importance of automatic adjustment mechanisms. The study pays particular attention to the theoretical analysis of pension indexation because its accurate quantitative effects are far from being sufficiently clarified in the literature, although it is vital for a thoughtful evaluation of pension reforms.
Development and validation of the COVID-19 Anxiety Scale for Japanese elite athletes
Authors: Suzuki Kanami , Yamaguchi Tatsuya , Tachiya Yasuhisa , Eda Kaori , Asano Tomoyuki , Senzaki Yoko , Nakajima Kohei
Published: April 2024

Abstract: Introduction: Japanese elite athletes were affected by the spread of COVID-19 infection. Four years after the pandemic, COVID-19 is still spreading and subsiding, and it is expected that some athletes are still concerned about COVID-19. Therefore, we developed the COVID-19 Anxiety Scale for Elite Athletes (CAS-EA) to measure COVID-19 anxiety among Japanese elite athletes and to examine its reliability and validity. Method: This is an observational cross-sectional study. In study 1, a 35-item anxiety questionnaire about COVID-19 was administered to 100 elite athletes on 8/18-9/1/2020. In study 2, 296 elite athletes were asked to respond to the CAS-EA, the Japanese version of State-Trait Anxiety Inventory (STAI), and the Japanese version of the Fear of Coronavirus Virus Scale (FCV-19S) from 8/31-11/8/2022. Results: In study 1, an exploratory factor analysis was conducted to create CAS-EA, which consisted of 19 items with four factors: Restrictions, Sport, Practice and Athlete value. The reliability of the scales was examined, confirming a certain internal consistency. In addition, study 2 showed significant positive correlations with CAS-EA and related scales. In the COVID-19 disaster, psychological stress was more strongly associated with A-trait than physical stress, a result that could be explained by Spielberger’s Trait-state anxiety theory. Furthermore, CAS-EA scores were significantly higher for female than for male, which was consistent with the results of previous studies. Conclusion: An attempt was made to create a scale to measure anxiety about COVID-19 in Japanese elite athletes, and a 4-factor, 19-item CAS-EA was created. The reliability and validity of the scale were tested and confirmed successfully.
The Toba Eruption 74,000 Years ago Strengthened the Indian Winter Monsoon‐Evidence From Coccolithophores
Authors: Guballa Jose Dominick , Bollmann Jörg , Schmidt Katherine , Lückge Andreas
Published: April 2024

The global impact of the Youngest Toba Tuff (YTT) supereruption is still heavily debated, ranging from having little effects on climate to significantly affecting modern human evolution. Climate models and proxy records show that the eruption may have caused cooling of the Asian landmass, thus impacting regional climate such as the Indian monsoon system. However, the immediate effect of the eruption on the Indian monsoon has not been indisputably demonstrated in any proxy record. Here, we present a paleo‐primary productivity (PP) record in core SO130‐289KL from the northeastern Arabian Sea based on the coccolithophore species Florisphaera profunda transfer function. Florisphaera profunda decreased from ∼30% before the YTT eruption to ∼8% right after the YTT eruption, which translates to an increase in PP by ∼65% from a long‐term average of ∼200 gC/m2/yr for about 8–19 years after the eruption. The duration was estimated using a new error‐weighted mean age of the YTT eruption (73.9 ± 0.1 ka, 2σ uncertainties) based on recent age estimates from ice cores, radiometric dating, and speleothem records. The elevated PP is most likely linked to the deepening of the surface ocean mixed layer driven by strengthened northeasterly Indian winter monsoon winds. This hypothesis is supported by stable oxygen isotope records from speleothem and ice cores, which show indications of a strengthening of the Indian winter monsoon during times of increased PP. Our results support previous modeling studies and provide unequivocal evidence from a marine record for an Indian monsoon response to the supereruption.
Liver stiffness measurements predict Sinusoidal Obstructive Syndrome after hematopoietic stem cell transplantation
Authors: Davidov Yana , Shem-Tov Noga , Yerushalmi Ronit , Hod Tammy , Ben-Ari Ziv , Nagler Arnon , Shimoni Avichai , Danylesko Ivetta
Published: April 2024

Sinusoidal Obstructive Syndrome (SOS) is a life-threatening complication after hematopoietic stem-cell transplantation (HSCT), characterized by post-sinusoidal portal hypertension. FibroScan is used to assess portal hypertension non-invasively. We assessed transient elastography (TE) applicability in diagnosing SOS. The study included 27 adult patients, 11 underwent TE for high SOS risk pre-HSCT, 17 underwent TE post-HSCT due to bilirubin ≥2 mg/dl with no definite diagnosis of SOS. The first group had median Liver Stiffness Measurement (LSM) of 7.4 kPa (range, 3.3–22.5). Based on LSM results, conditioning regimen was modified for six patients and two of them developed SOS. Only one patient who did not have protocol adjustment experienced SOS. No patient with LSM < 7 kPa developed SOS. The second group had median LSM of 7.7 kPa (4.4–31.5). Median LSM after HSCT was significantly higher in patients who subsequently developed established SOS (n = 10) compared to patients who did not (n = 8), with values of 10.7 kPa (5.6–31.5) and 5.9 kPa (4.4–13.8), respectively (p = 0.02). An LSM cut-off of 7.5 kPa had a sensitivity and specificity of 75 and 80% for diagnosing SOS. In conclusion, pre-HSCT LSM can help adjustment of conditioning regimen in patients with high-risk for SOS. Post-HSCT LSM can help in early diagnosis of SOS.
Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells
Authors: Andrianova Maria A. , Seplyarskiy Vladimir B. , Terradas Mariona , Sánchez-Heras Ana Beatriz , Mur Pilar , Soto José Luis , Aiza Gemma , Borràs Emma , Kondrashov Fyodor A. , Kondrashov Alexey S. , Bazykin Georgii A. , Valle Laura
Published: April 2024

Constitutional heterozygous pathogenic variants in the exonuclease domain of POLE and POLD1, which affect the proofreading activity of the corresponding polymerases, cause a cancer predisposition syndrome characterized by increased risk of gastrointestinal polyposis, colorectal cancer, endometrial cancer and other tumor types. The generally accepted explanation for the connection between the disruption of the proofreading activity of polymerases epsilon and delta and cancer development is through an increase in the somatic mutation rate. Here we studied an extended family with multiple members heterozygous for the pathogenic POLD1 variant c.1421T>C p.(Leu474Pro), which segregates with the polyposis and cancer phenotypes. Through the analysis of mutational patterns of patient-derived fibroblasts colonies and de novo mutations obtained by parent-offspring comparisons, we concluded that heterozygous POLD1 L474P just subtly increases the somatic and germline mutation burden. In contrast, tumors developed in individuals with a heterozygous mutation in the exonuclease domain of POLD1, including L474P, have an extremely high mutation rate (>100 mut/Mb) associated with signature SBS10d. We solved this contradiction through the observation that tumorigenesis involves somatic inactivation of the wildtype POLD1 allele. These results imply that exonuclease deficiency of polymerase delta has a recessive effect on mutation rate.
Towards ethical drug pricing: the European Orphan Genomic Therapies Fund
Authors: Risse Johanna , Krzemien Merlin , Schnalke Jan , Heinemann Thomas
Published: April 2024

An increasing number of novel genomic therapies are expected to become available for patients with rare or ultra-rare diseases. However, the primary obstacle to equal patient access to these orphan genomic therapies are currently very high prices charged by manufacturers in the context of limited healthcare budgets. Taking into account ethical pricing theories, the paper proposes the implementation of a pricing infrastructure covering all European member states, which has the potential to promote distributive justice while maintaining the attractiveness of genomic therapy development.
Automated in vivo enzyme engineering accelerates biocatalyst optimization
Authors: Orsi Enrico , Schada von Borzyskowski Lennart , Noack Stephan , Nikel Pablo I. , Lindner Steffen N.
Published: April 2024

Achieving cost-competitive bio-based processes requires development of stable and selective biocatalysts. Their realization through in vitro enzyme characterization and engineering is mostly low throughput and labor-intensive. Therefore, strategies for increasing throughput while diminishing manual labor are gaining momentum, such as in vivo screening and evolution campaigns. Computational tools like machine learning further support enzyme engineering efforts by widening the explorable design space. Here, we propose an integrated solution to enzyme engineering challenges whereby ML-guided, automated workflows (including library generation, implementation of hypermutation systems, adapted laboratory evolution, and in vivo growth-coupled selection) could be realized to accelerate pipelines towards superior biocatalysts.
A giant virus infecting the amoeboflagellate Naegleria
Authors: Arthofer Patrick , Panhölzl Florian , Delafont Vincent , Hay Alban , Reipert Siegfried , Cyran Norbert , Wienkoop Stefanie , Willemsen Anouk , Sifaoui Ines , Arberas-Jiménez Iñigo , Schulz Frederik , Lorenzo-Morales Jacob , Horn Matthias
Published: April 2024

Giant viruses (Nucleocytoviricota) are significant lethality agents of various eukaryotic hosts. Although metagenomics indicates their ubiquitous distribution, available giant virus isolates are restricted to a very small number of protist and algal hosts. Here we report on the first viral isolate that replicates in the amoeboflagellate Naegleria. This genus comprises the notorious human pathogen Naegleria fowleri, the causative agent of the rare but fatal primary amoebic meningoencephalitis. We have elucidated the structure and infection cycle of this giant virus, Catovirus naegleriensis (a.k.a. Naegleriavirus, NiV), and show its unique adaptations to its Naegleria host using fluorescence in situ hybridization, electron microscopy, genomics, and proteomics. Naegleriavirus is only the fourth isolate of the highly diverse subfamily Klosneuvirinae, and like its relatives the NiV genome contains a large number of translation genes, but lacks transfer RNAs (tRNAs). NiV has acquired genes from its Naegleria host, which code for heat shock proteins and apoptosis inhibiting factors, presumably for host interactions. Notably, NiV infection was lethal to all Naegleria species tested, including the human pathogen N. fowleri. This study expands our experimental framework for investigating giant viruses and may help to better understand the basic biology of the human pathogen N. fowleri.
Long-term monitoring of SARS-CoV-2 seroprevalence and variants in Ethiopia provides prediction for immunity and cross-immunity
Authors: Merkt Simon , Ali Solomon , Gudina Esayas Kebede , Adissu Wondimagegn , Gize Addisu , Muenchhoff Maximilian , Graf Alexander , Krebs Stefan , Elsbernd Kira , Kisch Rebecca , Betizazu Sisay Sirgu , Fantahun Bereket , Bekele Delayehu , Rubio-Acero Raquel , Gashaw Mulatu , Girma Eyob , Yilma Daniel , Zeynudin Ahmed , Paunovic Ivana , Hoelscher Michael , Blum Helmut , Hasenauer Jan , Kroidl Arne , Wieser Andreas
Published: April 2024

Under-reporting of COVID-19 and the limited information about circulating SARS-CoV-2 variants remain major challenges for many African countries. We analyzed SARS-CoV-2 infection dynamics in Addis Ababa and Jimma, Ethiopia, focusing on reinfection, immunity, and vaccination effects. We conducted an antibody serology study spanning August 2020 to July 2022 with five rounds of data collection across a population of 4723, sequenced PCR-test positive samples, used available test positivity rates, and constructed two mathematical models integrating this data. A multivariant model explores variant dynamics identifying wildtype, alpha, delta, and omicron BA.4/5 as key variants in the study population, and cross-immunity between variants, revealing risk reductions between 24% and 69%. An antibody-level model predicts slow decay leading to sustained high antibody levels. Retrospectively, increased early vaccination might have substantially reduced infections during the delta and omicron waves in the considered group of individuals, though further vaccination now seems less impactful.
F-actin architecture determines the conversion of chemical energy into mechanical work
Authors: Sakamoto Ryota , Murrell Michael P.
Published: April 2024

Mechanical work serves as the foundation for dynamic cellular processes, ranging from cell division to migration. A fundamental driver of cellular mechanical work is the actin cytoskeleton, composed of filamentous actin (F-actin) and myosin motors, where force generation relies on adenosine triphosphate (ATP) hydrolysis. F-actin architectures, whether bundled by crosslinkers or branched via nucleators, have emerged as pivotal regulators of myosin II force generation. However, it remains unclear how distinct F-actin architectures impact the conversion of chemical energy to mechanical work. Here, we employ in vitro reconstitution of distinct F-actin architectures with purified components to investigate their influence on myosin ATP hydrolysis (consumption). We find that F-actin bundles composed of mixed polarity F-actin hinder network contraction compared to non-crosslinked network and dramatically decelerate ATP consumption rates. Conversely, linear-nucleated networks allow network contraction despite reducing ATP consumption rates. Surprisingly, branched-nucleated networks facilitate high ATP consumption without significant network contraction, suggesting that the branched network dissipates energy without performing work. This study establishes a link between F-actin architecture and myosin energy consumption, elucidating the energetic principles underlying F-actin structure formation and the performance of mechanical work.
Patrilineal segmentary systems provide a peaceful explanation for the post-Neolithic Y-chromosome bottleneck
Authors: Guyon Léa , Guez Jérémy , Toupance Bruno , Heyer Evelyne , Chaix Raphaëlle
Published: April 2024

Studies have found a pronounced decline in male effective population sizes worldwide around 3000–5000 years ago. This bottleneck was not observed for female effective population sizes, which continued to increase over time. Until now, this remarkable genetic pattern was interpreted as the result of an ancient structuring of human populations into patrilineal groups (gathering closely related males) violently competing with each other. In this scenario, violence is responsible for the repeated extinctions of patrilineal groups, leading to a significant reduction in male effective population size. Here, we propose an alternative hypothesis by modelling a segmentary patrilineal system based on anthropological literature. We show that variance in reproductive success between patrilineal groups, combined with lineal fission (i.e., the splitting of a group into two new groups of patrilineally related individuals), can lead to a substantial reduction in the male effective population size without resorting to the violence hypothesis. Thus, a peaceful explanation involving ancient changes in social structures, linked to global changes in subsistence systems, may be sufficient to explain the reported decline in Y-chromosome diversity.
Correlation between two distant quasiparticles in separate superconducting islands mediated by a single spin
Authors: Estrada Saldaña Juan Carlos , Vekris Alexandros , Pavešič Luka , Žitko Rok , Grove-Rasmussen Kasper , Nygård Jesper
Published: April 2024

Controlled coupling between distant particles is a key requirement for the implementation of quantum information technologies. A promising platform are hybrid systems of semiconducting quantum dots coupled to superconducting islands, where the tunability of the dots is combined with the macroscopic coherence of the islands to produce states with non-local correlations, e.g. in Cooper pair splitters. Electrons in hybrid quantum dots are typically not amenable to long-distance spin alignment as they tend to be screened into a localized singlet state by bound superconducting quasiparticles. However, two quasiparticles coming from different superconductors can overscreen the quantum dot into a doublet state, leading to ferromagnetic correlations between the superconducting islands. We present experimental evidence of a stabilized overscreened state, implying correlated quasiparticles over a micrometer distance. We propose alternating chains of quantum dots and superconducting islands as a novel platform for controllable large-scale spin coupling.
IFT cargo and motors associate sequentially with IFT trains to enter cilia of C. elegans
Authors: Mitra Aniruddha , Loseva Elizaveta , Peterman Erwin J. G.
Published: April 2024

Intraflagellar transport (IFT) orchestrates entry of proteins into primary cilia. At the ciliary base, assembled IFT trains, driven by kinesin-2 motors, can transport cargo proteins into the cilium, across the crowded transition zone. How trains assemble at the base and how proteins associate with them is far from understood. Here, we use single-molecule imaging in the cilia of C. elegans chemosensory neurons to directly visualize the entry of kinesin-2 motors, kinesin-II and OSM-3, as well as anterograde cargo proteins, IFT dynein and tubulin. Single-particle tracking shows that IFT components associate with trains sequentially, both in time and space. Super-resolution maps of IFT components in wild-type and mutant worms reveal ciliary ultrastructure and show that kinesin-II is essential for axonemal organization. Finally, imaging cilia lacking kinesin-II and/or transition zone function uncovers the interplay of kinesin-II and OSM-3 in driving efficient transport of IFT trains across the transition zone.
Goal-directed and flexible modulation of syllable sequence within birdsong
Authors: Kawaji Takuto , Fujibayashi Mizuki , Abe Kentaro
Published: April 2024

Songs constitute a complex system of vocal signals for inter-individual communication in songbirds. Here, we elucidate the flexibility which songbirds exhibit in the organizing and sequencing of syllables within their songs. Utilizing a newly devised song decoder for quasi-real-time annotation, we execute an operant conditioning paradigm, with rewards contingent upon specific syllable syntax. Our analysis reveals that birds possess the capacity to modify the contents of their songs, adjust the repetition length of particular syllables and employing specific motifs. Notably, birds altered their syllable sequence in a goal-directed manner to obtain rewards. We demonstrate that such modulation occurs within a distinct song segment, with adjustments made within 10 minutes after cue presentation. Additionally, we identify the involvement of the parietal-basal ganglia pathway in orchestrating these flexible modulations of syllable sequences. Our findings unveil an unappreciated aspect of songbird communication, drawing parallels with human speech.
Flower-shaped 2D crystals grown in curved fluid vesicle membranes
Authors: Wan Hao , Jeon Geunwoong , Xin Weiyue , Grason Gregory M. , Santore Maria M.
Published: April 2024

The morphologies of two-dimensional (2D) crystals, nucleated, grown, and integrated within 2D elastic fluids, for instance in giant vesicle membranes, are dictated by an interplay of mechanics, permeability, and thermal contraction. Mitigation of solid strain drives the formation of crystals with vanishing Gaussian curvature (i.e., developable domain shapes) and, correspondingly, enhanced Gaussian curvature in the surrounding 2D fluid. However, upon cooling to grow the crystals, large vesicles sustain greater inflation and tension because their small area-to-volume ratio slows water permeation. As a result, more elaborate shapes, for instance, flowers with bendable but inextensible petals, form on large vesicles despite their more gradual curvature, while small vesicles harbor compact planar crystals. This size dependence runs counter to the known cumulative growth of strain energy of 2D colloidal crystals on rigid spherical templates. This interplay of intra-membrane mechanics and processing points to the scalable production of flexible molecular crystals of controllable complex shape.
Public perceptions on carbon removal from focus groups in 22 countries
Authors: Low Sean , Fritz Livia , Baum Chad M. , Sovacool Benjamin K.
Published: April 2024

Carbon removal is emerging as a pillar of governmental and industry commitments toward achieving Net Zero targets. Drawing from 44 focus groups in 22 countries, we map technical and societal issues that a representative sample of publics raise on five major types of carbon removal (forests, soils, direct air capture, enhanced weathering, and bioenergy with carbon capture and storage), and how these translate to preferences for governance actors, mechanisms, and rationales. We assess gaps and overlaps between a global range of public perceptions and how carbon removal is currently emerging in assessment, innovation, and decision-making. In conclusion, we outline key societal expectations for informing assessment and policy: prioritize public engagement as more than acceptance research; scrutiny and regulation of industry beyond incentivizing innovation; systemic coordination across sectors, levels, and borders; and prioritize underlying causes of climate change and interrelated governance issues.
Kataegis in clinical and molecular subgroups of primary breast cancer
Authors: Veerla Srinivas , Staaf Johan
Published: April 2024

Kataegis is a hypermutation phenomenon characterized by localized clusters of single base pair substitution (SBS) reported in multiple cancer types. Despite a high frequency in breast cancer, large-scale analyses of kataegis patterns and associations with clinicopathological and molecular variables in established breast cancer subgroups are lacking. Therefore, WGS profiled primary breast cancers (n = 791) with associated clinical and molecular data layers, like RNA-sequencing data, were analyzed for kataegis frequency, recurrence, and associations with genomic contexts and functional elements, transcriptional patterns, driver alterations, homologous recombination deficiency (HRD), and prognosis in tumor subgroups defined by ER, PR, and HER2/ERBB2 status. Kataegis frequency was highest in the HER2-positive(p) subgroups, including both ER-negative(n)/positive(p) tumors (ERnHER2p/ERpHER2p). In TNBC, kataegis was neither associated with PAM50 nor TNBC mRNA subtypes nor with distant relapse in chemotherapy-treated patients. In ERpHER2n tumors, kataegis was associated with aggressive characteristics, including PR-negativity, molecular Luminal B subtype, higher mutational burden, higher grade, and expression of proliferation-associated genes. Recurrent kataegis loci frequently targeted regions commonly amplified in ER-positive tumors, while few recurrent loci were observed in TNBC. SBSs in kataegis loci appeared enriched in regions of open chromatin. Kataegis status was not associated with HRD in any subgroup or with distinct transcriptional patterns in unsupervised or supervised analysis. In summary, kataegis is a common hypermutation phenomenon in established breast cancer subgroups, particularly in HER2p subgroups, coinciding with an aggressive tumor phenotype in ERpHER2n disease. In TNBC, the molecular implications and associations of kataegis are less clear, including its prognostic value.
Multi-project wafers for flexible thin-film electronics by independent foundries
Authors: Çeliker Hikmet , Dehaene Wim , Myny Kris
Published: April 2024

Flexible and large-area electronics rely on thin-film transistors (TFTs) to make displays1–3, large-area image sensors4–6, microprocessors7–11, wearable healthcare patches12–15, digital microfluidics16,17and more. Although silicon-based complementary metal–oxide–semiconductor (CMOS) chips are manufactured using several dies on a single wafer and the multi-project wafer concept enables the aggregation of various CMOS chip designs within the same die, TFT fabrication is currently lacking a fully verified, universal design approach. This increases the cost and complexity of manufacturing TFT-based flexible electronics, slowing down their integration into more mature applications and limiting the design complexity achievable by foundries. Here we show a stable and high-yield TFT platform for the fabless manufacturing of two mainstream TFT technologies, wafer-based amorphous indium–gallium–zinc oxide and panel-based low-temperature polycrystalline silicon, two key TFT technologies applicable to flexible substrates. We have designed the iconic 6502 microprocessor in both technologies as a use case to demonstrate and expand the multi-project wafer approach. Enabling the foundry model for TFTs, as an analogy of silicon CMOS technologies, can accelerate the growth and development of applications and technologies based on these devices.
Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers
Authors: Ferretti Stephane , Hamon Jacques , de Kanter Ruben , Scheufler Clemens , Andraos-Rey Rita , Barbe Stephanie , Bechter Elisabeth , Blank Jutta , Bordas Vincent , Dammassa Ernesta , Decker Andrea , Di Nanni Noemi , Dourdoigne Marion , Gavioli Elena , Hattenberger Marc , Heuser Alisa , Hemmerlin Christelle , Hinrichs Jürgen , Kerr Grainne , Laborde Laurent , Jaco Isabel , Núñez Eloísa Jiménez , Martus Hans-Joerg , Quadt Cornelia , Reschke Markus , Romanet Vincent , Schaeffer Fanny , Schoepfer Joseph , Schrapp Maxime , Strang Ross , Voshol Hans , Wartmann Markus , Welly Sarah , Zécri Frédéric , Hofmann Francesco , Möbitz Henrik , Cortés-Cros Marta
Published: April 2024

The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens1–6. Despite advances in treatment with immune checkpoint inhibitors7–10, there is an unmet need in the treatment of MSI cancers11–14. Here we report the structural, biochemical, cellular and pharmacological characterization of the clinical-stage WRN helicase inhibitor HRO761, which was identified through an innovative hit-finding and lead-optimization strategy. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation. Pharmacological inhibition by HRO761 recapitulated the phenotype observed by WRN genetic suppression, leading to DNA damage and inhibition of tumour cell growth selectively in MSI cells in a p53-independent manner. Moreover, HRO761 led to WRN degradation in MSI cells but not in microsatellite-stable cells. Oral treatment with HRO761 resulted in dose-dependent in vivo DNA damage induction and tumour growth inhibition in MSI cell- and patient-derived xenograft models. These findings represent preclinical pharmacological validation of WRN as a therapeutic target in MSI cancers. A clinical trial with HRO761 (NCT05838768) is ongoing to assess the safety, tolerability and preliminary anti-tumour activity in patients with MSI colorectal cancer and other MSI solid tumours.
PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function
Authors: Morotti Matteo , Grimm Alizee J. , Hope Helen Carrasco , Arnaud Marion , Desbuisson Mathieu , Rayroux Nicolas , Barras David , Masid Maria , Murgues Baptiste , Chap Bovannak S. , Ongaro Marco , Rota Ioanna A. , Ronet Catherine , Minasyan Aspram , Chiffelle Johanna , Lacher Sebastian B. , Bobisse Sara , Murgues Clément , Ghisoni Eleonora , Ouchen Khaoula , Bou Mjahed Ribal , Benedetti Fabrizio , Abdellaoui Naoill , Turrini Riccardo , Gannon Philippe O. , Zaman Khalil , Mathevet Patrice , Lelievre Loic , Crespo Isaac , Conrad Marcus , Verdeil Gregory , Kandalaft Lana E. , Dagher Julien , Corria-Osorio Jesus , Doucey Marie-Agnes , Ho Ping-Chih , Harari Alexandre , Vannini Nicola , Böttcher Jan P. , Dangaj Laniti Denarda , Coukos George
Published: April 2024

Expansion of antigen-experienced CD8+ T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer1. Interleukin-2 (IL-2) acts as a key regulator of CD8+ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability2,3. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE2), a known negative regulator of immune response in the tumour microenvironment4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8+ TILs via the PGE2 receptors EP2 and EP4. Mechanistically, PGE2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγc chain, resulting in defective assembly of IL-2Rβ–IL2Rγc membrane dimers. This results in impaired IL-2–mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE2 signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.
Alternative splicing of CARM1 regulated by LincGET-guided paraspeckles biases the first cell fate in mammalian early embryos
Authors: Wang Jiaqiang , Zhang Yiwei , Gao Jiaze , Feng Guihai , Liu Chao , Li Xueke , Li Pengcheng , Liu Zhonghua , Lu Falong , Wang Leyun , Li Wei , Zhou Qi , Liu Yusheng
Published: April 2024

The heterogeneity of CARM1 controls first cell fate bias during early mouse development. However, how this heterogeneity is established is unknown. Here, we show that Carm1 mRNA is of a variety of specific exon-skipping splicing (ESS) isoforms in mouse two-cell to four-cell embryos that contribute to CARM1 heterogeneity. Disruption of paraspeckles promotes the ESS of Carm1 precursor mRNAs (pre-mRNAs). LincGET, but not Neat1, is required for paraspeckle assembly and inhibits the ESS of Carm1 pre-mRNAs in mouse two-cell to four-cell embryos. We further find that LincGET recruits paraspeckles to the Carm1 gene locus through HNRNPU. Interestingly, PCBP1 binds the Carm1 pre-mRNAs and promotes its ESS in the absence of LincGET. Finally, we find that the ESS seen in mouse two-cell to four-cell embryos decreases CARM1 protein levels and leads to trophectoderm fate bias. Our findings demonstrate that alternative splicing of CARM1 has an important role in first cell fate determination.
Chromosome-level genome assembly of the yellow-cheek carp Elopichthys bambusa
Authors: Li Shunyao , Xiong Xuemei , Qiu Siyu , Shen Zhigang , He Yan , Gao Zexia , Wan Shiming
Published: April 2024

Yellow-cheek carp (Elopichthys bambusa) is a typical large and ferocious carnivorous fish endemic to East Asia, with high growth rate, nutritional value and economic value. In this study, a chromosome-level genome of yellow-cheek carp was generated by combining PacBio reads, Illumina reads and Hi-C data. The genome size is 827.63 Mb with a scaffold N50 size of 33.65 Mb, and 99.51% (823.61 Mb) of the assembled sequences were anchored to 24 pseudo-chromosomes. The genome is predicted to contain 24,153 protein-coding genes, with 95.54% having functional annotations. Repeat elements account for approximately 55.17% of the genomic landscape. The completeness of yellow-cheek carp genome assembly is highlighted by a BUSCO score of 98.4%. This genome will help us understand the genetic diversity of yellow-cheek carp and facilitate its conservation planning.
A new commercial boundary dataset for metropolitan areas in the USA and Canada, built from open data
Authors: Jeong Byeonghwa , Allen Jeff , Chapple Karen
Published: April 2024

The purpose of this study is to define the geographic boundaries of commercial areas by creating a consistent definition, combining various commercial area types, including downtowns, retail centres, financial districts, and other employment subcentres. Our research involved the collection of office, retail and job density data from 69 metropolitan regions across USA and Canada. Using this data, we conducted an unsupervised image segmentation model and clustering methods to identify distinctive commercial geographic boundaries. As a result, we identified 23,751 commercial areas, providing a detailed perspective on the commercial landscape of metropolitan areas in the USA and Canada. In addition, the generated boundaries were successfully validated through comparison with previously established commerce-related boundaries. The output of this study has implications for urban and regional planning and economic development, delivering valuable insights into the overall commercial geography in the region. The commercial boundary and used codes are freely available on the School of Cities Github, and users can reuse, reproduce and modify the boundaries.
Optimization and modelling of magnesium oxide (MgO) photocatalytic degradation of binary dyes using response surface methodology
Authors: Kwang Benno Park Hyeong , Kumar Pushpendra , Kebaili Imen , Boukhris Imed , Hwan Joo Yun , Hyun Sung Tae , Kumar Anuruddh
Published: April 2024

Textile industry dye effluent contains a mixture of different kinds of dyes. Many times, photocatalysis is targeted as a solution for the treatment of dye effluent from the textile industry. Many researches have been published related to the photocatalysis of single textile dyes but in the real-world scenario, effluent is a mixture of dyes. Magnesium oxide (MgO) is used as a photocatalyst to treat a mixture (binary solution) of Methylene blue (MB) and Methylene violet (MV) along with individual MB and MV dyes in this article. MgO shows remarkable photocatalytic activity at about 93 and 88% for MB and MV dye in binary solution within 135 min. Furthermore, to study the influence of process parameters, experiments are designed with the help of the central composite design (CCD), and Response surface methodology (RSM) is used to study the interactions between parameters. For this study, five parameters are selected i.e., Photocatalyst dosage, initial concentration of both dyes, time of exposure to the light source, and pH of the binary solution. The photocatalytic process is also optimized and finally optimization of process parameters is validated with an experiment. The result of the validation experiment is very close to the predicted photocatalytic activity.
Long extrachromosomal circular DNA identification by fusing sequence-derived features of physicochemical properties and nucleotide distribution patterns
Authors: Abbasi Ahtisham Fazeel , Asim Muhammad Nabeel , Ahmed Sheraz , Dengel Andreas
Published: April 2024

Long extrachromosomal circular DNA (leccDNA) regulates several biological processes such as genomic instability, gene amplification, and oncogenesis. The identification of leccDNA holds significant importance to investigate its potential associations with cancer, autoimmune, cardiovascular, and neurological diseases. In addition, understanding these associations can provide valuable insights about disease mechanisms and potential therapeutic approaches. Conventionally, wet lab-based methods are utilized to identify leccDNA, which are hindered by the need for prior knowledge, and resource-intensive processes, potentially limiting their broader applicability. To empower the process of leccDNA identification across multiple species, the paper in hand presents the very first computational predictor. The proposed iLEC-DNA predictor makes use of SVM classifier along with sequence-derived nucleotide distribution patterns and physicochemical properties-based features. In addition, the study introduces a set of 12 benchmark leccDNA datasets related to three species, namely Homo sapiens (HM), Arabidopsis Thaliana (AT), and Saccharomyces cerevisiae (SC/YS). It performs large-scale experimentation across 12 benchmark datasets under different experimental settings using the proposed predictor, more than 140 baseline predictors, and 858 encoder ensembles. The proposed predictor outperforms baseline predictors and encoder ensembles across diverse leccDNA datasets by producing average performance values of 81.09%, 62.2% and 81.08% in terms of ACC, MCC and AUC-ROC across all the datasets. The source code of the proposed and baseline predictors is available at https://github.com/FAhtisham/Extrachrosmosomal-DNA-Prediction. To facilitate the scientific community, a web application for leccDNA identification is available at https://sds_genetic_analysis.opendfki.de/iLEC_DNA/.
Failure probability analysis of high fill levee considering multiple uncertainties and correlated failure modes
Authors: Sun Ruirui , Reheman Yimingjiang , Wang Xiaoling , Fei Kaixuan , Zhou Jinjun , Jiao Ding
Published: April 2024

Such complex causative factors in current failure probability models are represented by simply random uncertainty and completely independent or correlation of failure modes, which can often limit the model utility. In this study, we developed a methodology to construct failure probability models for high fill levees, incorporating the identification of uncertainties and an analysis of failure modes. Based on quantification of stochastic-grey-fuzzy uncertainties, probability analysis involved with overtopping, instability and seepage failure modes was implemented combined with probability and non-probability methods. Given that the interaction among failure modes typically exhibits nonlinear behavior, rather than linear correlation or complete independence, a simple methodology for the binary Copula function was established and implemented in MATLAB. This methodology was applied to the high fill segments of a long-distance water transfer project characterized by high population density. It shows that the failure probability of a single failure mode is overestimated when uncertainties are not considered, because of the randomness and fuzziness of some parameters and the greyness of information. Meanwhile, it is found that the magnitude of failure probability related to levee breach is overestimated without respect to failure modes correlation, especially when the probabilities of seepage and instability are both significant and closely aligned.
Mobile monitoring system detects the disease activity pattern and shows the association with clinical outcomes in patients with newly diagnosed Crohn’s disease
Authors: Lee Yoo Jin , Kwak Sang Gyu , Kim Eun Soo , Kim Sung Kook , Lee Hyun Seok , Chung Yun Jin , Jang Byung Ik , Kim Kyeong Ok , Kim Jeongseok , Jo Hyeong Ho , Kim Eun Young
Published: April 2024

We aimed to determine whether Crohn’s disease (CD) activity patterns assessed via a web-based symptom diary can help predict clinical outcomes in patients with newly diagnosed CD. Patients diagnosed with CD within the preceding 3 months were prospectively enrolled at four tertiary centers. All patients recorded their symptoms on a website using a smartphone at least once a week. The index outcomes were disease-related admission and surgery during follow-up. The disease activity from enrollment to outcome or last follow-up was reviewed for pattern analysis. Cox regression analysis was used to identify the predictors of disease outcomes. A total of 102 patients were enrolled. During a median follow-up period of 42 months, 25 (24.5%) and 6 (5.9%) patients required admission and surgery, respectively. Poor activity pattern was an independent predictor of disease-related hospitalization (adjusted hazard ratio [aHR], 3.96; 95% confidence interval [CI] 1.5–10.45; p = 0.005). A poor activity pattern (aHR, 19.48; 95% CI 1.86–203.95; p = 0.013) and female sex (aHR, 11.28; 95% CI 1.49–85.01; p = 0.018) were found to be independent predictors of bowel resection. CD disease activity patterns monitored through the mobile monitoring system may help predict clinical outcomes, such as disease-related hospitalization and surgery, in patients with newly diagnosed CD.
Biological toxicity of sulfamethoxazole in aquatic ecosystem on adult zebrafish (Danio rerio)
Authors: Zhou Jie , Yun Xiao , Wang Jiting , Li Qi , Wang Yanli , Zhang Wenjing , Fan Zhicheng
Published: April 2024

This study evaluated the impacts of sulfamethoxazole (SMX) on antioxidant, immune, histopathological dynamic changes, and gut microbiota of zebrafish. SMX was carried out five groups: 0 (C), 3 mg/L (T3), 6 mg/L (T6), 12 mg/L (T12), and 24 mg/L (T24), with 5 replicates per group for an 8-weeks chronic toxicity test. It was found that SMX is considered to have low toxicity to adult zebrafish. SMX with the concentration not higher than 24 mg/L has no obvious inhibitory effect on the growth of fish. Under different concentrations of SMX stress, oxidative damage and immune system disorder were caused to the liver and gill, with the 12 and 24 mg/L concentration being the most significant. At the same time, it also causes varying degrees of pathological changes in both intestinal and liver tissues. As the concentration of SMX increases, the composition and abundance of the gut microbiota in zebrafish significantly decrease.
Tackling new psychoactive substances through metabolomics: UHPLC-HRMS study on natural and synthetic opioids in male and female murine models
Authors: Di Francesco Gaia , Montesano Camilla , Vincenti Flaminia , Bilel Sabrine , Corli Giorgia , Petrella Greta , Cicero Daniel Oscar , Gregori Adolfo , Marti Matteo , Sergi Manuel
Published: April 2024

Novel psychoactive substances (NPS) represent a broad class of drugs new to the illicit market that often allow passing drug-screening tests. They are characterized by a variety of structures, rapid transience on the drug scene and mostly unknown metabolic profiles, thus creating an ever-changing scenario with evolving analytical targets. The present study aims at developing an indirect screening strategy for NPS monitoring, and specifically for new synthetic opioids (NSOs), based on assessing changes in endogenous urinary metabolite levels as a consequence of the systemic response following their intake. The experimental design involved in-vivo mice models: 16 animals of both sex received a single administration of morphine or fentanyl. Urine was collected before and after administration at different time points; the samples were then analysed with an untargeted metabolomics LC-HRMS workflow. According to our results, the intake of opioids resulted in an elevated energy demand, that was more pronounced on male animals, as evidenced by the increase in medium and long chain acylcarnitines levels. It was also shown that opioid administration disrupted the pathways related to catecholamines biosynthesis. The observed alterations were common to both morphine and fentanyl: this evidence indicate that they are not related to the chemical structure of the drug, but rather on the drug class. The proposed strategy may reinforce existing NPS screening approaches, by identifying indirect markers of drug assumption.
Vertical differences in carbon metabolic diversity and dominant flora of soil bacterial communities in farmlands
Authors: Zheng Bufan , Xiao Zhipeng , Liu Jiaqi , Zhu Yi , Shuai Kaifeng , Chen Xiaye , Liu Yongjun , Hu Ruiwen , Peng Guangjue , Li Junlin , Hu Yichao , Su Zan , Fang Ming , Li Juan
Published: April 2024

The carbon cycle in soil is significantly influenced by soil microbes. To investigate the vertical distribution of the dominant groups in agricultural soil and the carbon metabolic diversity of soil bacteria, 45 soil samples from the 0 ~ 50 cm soil layer in Hunan tobacco–rice multiple cropping farmland were collected in November 2017, and the carbon diversity of the soil bacterial community, bacterial community composition and soil physical and chemical properties were determined. The results showed that the carbon metabolic capabilities and functional diversity of the soil bacterial community decreased with depth. The three most widely used carbon sources for soil bacteria were carbohydrates, amino acids, and polymers. The dominant bacterial groups in surface soil (such as Chloroflexi, Acidobacteriota, and Bacteroidota) were significantly positively correlated with the carbon metabolism intensity. The alkali-hydrolysable nitrogen content, soil bulk density and carbon–nitrogen ratio were the key soil factors driving the differences in carbon metabolism of the soil bacterial communities in the different soil layers.
Identifying transcriptomic profiles of iron–quercetin complex treated peripheral blood mononuclear cells from healthy volunteers and diabetic patients
Authors: Innuan Phattarawadee , Sirikul Chonticha , Anukul Nampeung , Rolin Gwenaël , Dechsupa Nathupakorn , Kantapan Jiraporn
Published: April 2024

Peripheral blood is an alternative source of stem/progenitor cells for regenerative medicine owing to its ease of retrieval and blood bank storage. Previous in vitro studies indicated that the conditioned medium derived from peripheral blood mononuclear cells (PBMCs) treated with the iron–quercetin complex (IronQ) contains potent angiogenesis and wound-healing properties. This study aims to unveil the intricate regulatory mechanisms governing the effects of IronQ on the transcriptome profiles of human PBMCs from healthy volunteers and those with diabetes mellitus (DM) using RNA sequencing analysis. Our findings revealed 3741 and 2204 differentially expressed genes (DEGs) when treating healthy and DM PBMCs with IronQ, respectively. Functional enrichment analyses underscored the biological processes shared by the DEGs in both conditions, including inflammatory responses, cell migration, cellular stress responses, and angiogenesis. A comprehensive exploration of these molecular alterations exposed a network of 20 hub genes essential in response to stimuli, cell migration, immune processes, and the mitogen-activated protein kinase (MAPK) pathway. The activation of these pathways enabled PBMCs to potentiate angiogenesis and tissue repair. Corroborating this, quantitative real-time polymerase chain reaction (qRT-PCR) and cell phenotyping confirmed the upregulation of candidate genes associated with anti-inflammatory, pro-angiogenesis, and tissue repair processes in IronQ-treated PBMCs. In summary, combining IronQ and PBMCs brings about substantial shifts in gene expression profiles and activates pathways that are crucial for tissue repair and immune response, which is promising for the enhancement of the therapeutic potential of PBMCs, especially in diabetic wound healing.