bluuebunny/crossref_metadata_2025 huggingface dataset:
How does generative AI promote autonomy and inclusivity in language teaching?
Authors: Szabó Fruzsina , Szoke Joanna
Published: September 2024

In recent years, artificial intelligence (AI) has increasingly made advances across various fields, including ELT. In this article we embrace an egalitarian dialogue framework to explore and understand the role of AI in language education. This format provides a useful backdrop for navigating the dual responses—enthusiasm and scepticism—by which AI’s influence in education has often been characterized. We critically assess both the advantages and limitations of AI in ELT, highlighting and praising how AI-powered tools can assist educators in differentiating instruction, promoting learner autonomy, and creating personalized and inclusive learning environments, thus making education more accessible to students with diverse and individual needs. However, the article also addresses the challenges posed by the digital divide, particularly the inequities in access to (AI) technologies in low-socioeconomic-status regions. We also reflect upon how AI can become an obstacle in developing learner autonomy due to the risks associated with overdependence on such technologies and the lack of critical skills. The article concludes that although AI presents exciting opportunities for advancing and facilitating language learning, its integration must be approached with a rational mindset to ensure that it serves to bridge educational gaps rather than intensify them.
Too rare to dare? Leveraging household surveys to boost research on climate migration
Authors: Carletto Calogero , Letta Marco , Montalbano Pierluigi , Paolantonio Adriana , Zezza Alberto
Published: October 2024

Nationally representative household surveys are a potential data source that could shed light on the climate–migration nexus. However, they are rarely designed specifically to measure or study migration and often lack the necessary features to identify connections with climate change. This paper offers a critical reflection on current challenges faced by multi-topic household surveys in responding to these needs while also highlighting the many opportunities embedded in their use. Using the Living Standards Measurement Study household survey programme of the World Bank as an example, this paper proposes a methodological agenda and practical guidance to address data gaps and advance research on climate migration.
Marker recycling in Lentinula edodes via 5-fluoroorotic acid counter-selection
Authors: Narutaki Takuma , Kamiya Ayane , Tsujimoto Yuma , Naruse Masataka , Nishida Shota , Kawauchi Moriyuki , Honda Yoichi , Kamitsuji Hisatoshi , Sato Toshitsugu , Sumita Takuya , Izumitsu Kosuke , Irie Toshikazu
Published: September 2024

Shiitake (Lentinula edodes) contains various beneficial compounds and possesses several notable properties. However, there are few reports on its molecular breeding due to delay in development of its gene-modifying technology. Therefore, here, strain UV30 (pyrG –) was bred from the UV-irradiated protoplasts of strain M2. Strain UV30 was uracil-auxotrophic, and the phenylalanine residue in the active centre of orotidine-5-phosphate decarboxylase encoded by pyrG in the strain was substituted with a serine residue. Next, a recycling marker consisting of the upstream sequence of ku80, a repeat sequence (a portion of the downstream sequence of ku80), pyrG, and the downstream sequence of ku80 was introduced into the strain UV30. Consequently, the prototrophic strain ckp2-1, in which ku80 was replaced with the recycling marker, was obtained. After cultivation in complete medium, mycelia from the edges of ckp2-1 colonies were inoculated into a complete medium containing 5-Fluoroorotic acid (5-FOA). A 5-FOA-resistant strain KaM2, in which pyrG sequence was spliced from the recycling marker sequence via homologous recombination, was obtained. In this study, we developed the first marker recycling system for multigene targeting in L. edodes. Moreover, the resulting ∆ku80 strain may serve as a non-homologous end-joining deficient strain for further genetic manipulations.
US Diplomatic Visits and Allies’ Military Spending
Authors: Kim James D
Published: October 2024

This article develops and tests two competing arguments regarding how a patron’s diplomatic visits influence the military spending of protégés. One argument posits that a patron’s visits will decrease allies’ defense spending by producing reassurance (reassurance hypothesis). Another perspective contends that such visits will increase allies’ burden sharing by fostering allied partnerships (partnership hypothesis). I test these hypotheses by analyzing US presidential visits to allies and the annual percentage changes in allies’ military spending from 1950 to 2007. I find evidence supporting the reassurance hypothesis, indicating that diplomatic visits by US presidents are associated with lower military expenditures by allies the following year. Furthermore, I find that the negative effect is primarily observed when visits are made in the first 3 years of a presidential term, while visits in the final year of a presidency do not result in significant changes in allied burden sharing. The findings highlight the role of a patron’s travel diplomacy in providing reassurance in military alliances, as well as its unintended consequence for protégés’ foreign policy: reduced alliance contribution.
Mass Mobilization, Elite Competition, and Diversionary Use of Sanctions
Authors: Liou Ryan Yu-Lin
Published: October 2024

How does the domestic environment affect a government's incentives to use coercion against another country? Traditional diversionary literature indicates that governments facing internal pressures will initiate military actions overseas to improve popularity. I argue that struggling governments are more inclined to employ economic sanctions over military force because of lower cost and political risk. I further posit that when governments encounter nonviolent protests and strong competition in the legislature, they have more incentives to initiate sanctions. Foreign sanctions are used to project sanctioning leaders’ competence and increase national cohesion. I test the empirical implication of the argument on a sample of 137 countries from 1975 to 2005. The multinomial logit results show that diversionary use of sanctions is more likely when incumbents face maximalist nonviolent mobilization and higher legislative opposition, but these domestic challenges do not prompt military actions. This study presents a domestic explanation for sanctions initiation; it also casts doubt on the conventional predictions that beleaguered governments will resort to the use of force.
Violet LED light-activated MdHY5 positively regulates phenolic accumulation to inhibit fresh-cut apple fruit browning
Authors: Jin Juntong , Qi Liyong , Shen Shurong , Yang Shuran , Yuan Hui , Wang Aide
Published: September 2024

Fresh-cut fruit browning severely affects the appearance of fruit. Light treatment can effectively inhibit fresh-cut apple fruit browning, but the regulatory mechanism remains unknown. Here, we discovered that violet LED (Light-Emitting-Diode) light treatment significantly reduced fresh-cut apple fruit browning. Metabolomic analysis revealed that violet LED light treatment enhanced the phenolic accumulation of fresh-cut apple fruit. Transcriptomic analysis showed that the expression of phenolic degradation genes POLYPHENOL OXIDASE (MdPPO) and PEROXIDASE (MdPOD) was reduced, and the expression of phenolic synthesis gene PHENYLALANINE AMMONIA LYASE (MdPAL) was activated by violet LED light treatment. Moreover, two ELONGATED HYPOCOTYL 5 (MdHY5 and MdHYH) transcription factors involved in light signaling were identified. The expression of MdHY5 and MdHYH was activated by violet LED light treatment. Violet LED light treatment no longer inhibited fresh-cut apple fruit browning in MdHY5- or MdHYH- silenced fruit. Further experiments revealed that MdHY5 and MdHYH suppressed MdPPO and MdPOD expression and promoted MdPAL expression by binding to their promoters. In addition, MdHY5 and MdHYH bound to each other’s promoters and enhanced their expression. Overall, our findings revealed that violet LED light-activated MdHY5 and MdHYH formed a positive transcriptional loop to regulate the transcription of MdPPO, MdPOD, and MdPAL, which in turn inhibited the degradation of phenolics and promoted the synthesis of phenolics, thus inhibiting fresh-cut apple fruit browning. These results provide a theoretical basis for improving the appearance and quality of fresh-cut apple fruit.
Targeting NCAPD2 as a Therapeutic Strategy for Crohn’s Disease: Implications for Autophagy and Inflammation
Authors: Ge Hao , Wang Can , Zhao Haoran , Chen Hao , Gong Yuxia , Qiao Lichao , Zhang Yi , Liu Ping , Yang Bolin
Published: September 2024

Background

Our earlier studies identified that non-SMC condensin I complex subunit D2 (NCAPD2) induces inflammation through the IKK/NF-κB pathway in ulcerative colitis. However, its role in the development of Crohn’s disease (CD) and the specific molecular mechanism still need to be further studied.

Methods

NCAPD2 expression in clinical ileal CD mucosa vs normal mucosa was examined, alongside its correlation with CD patients’ clinical characteristics via their medical records. The biological function and molecular mechanism of NCAPD2 in CD were explored using a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced CD mouse model, along with immunofluorescence, western blot, quantitative real-time PCR, immunohistochemistry, hematoxylin and eosin staining, and cell functional analysis.

Results

NCAPD2 was overexpressed in CD tissues and significantly correlated with disease activity in CD patients (P = .016). In a TNBS-induced CD mouse model, NCAPD2 knockdown inhibited the development of TNBS-induced intestinal inflammation in mice. In addition, we found that NCAPD2 inhibited autophagy. Mechanistically, NCAPD2 promoted the phosphorylation of mammalian target of the rapamycin (mTOR) and its direct effector S6K and downregulated the expression of autophagy-related proteins Beclin1, LC3II, and Atg5. In addition, NCAPD2 activates the NF-κB signaling pathway, and the downstream inflammatory factors are continuously released, leading to the persistence of inflammation.

Conclusions

Our results show that NCAPD2 suppresses autophagy and worsens intestinal inflammation by modulating mTOR signaling and impacting the NF-κB pathway, suggesting a critical role in CD progression. Targeting NCAPD2 could be a promising therapeutic approach to stop CD advancement.
Challenges in the Management of Acute Severe Ulcerative Colitis in a Patient With Guillain-Barré Syndrome Associated With Infliximab
Authors: Carvalho Tânia , Pinto Joana , Araújo José , Fernandes Dália , Gonçalves Raquel , Arroja Bruno
Published: September 2024

Lay Summary

Despite being a rare adverse event, Guillain-Barré syndrome should be a differential diagnosis in patients taking tumor necrosis factor alpha (TNF-α) inhibitors who develop neurological events. Ustekinumab seems to be a safe option after TNF-α inhibitors in these patients.
Thermophile-fermented feed modulates the gut microbiota related to lactate metabolism in pigs
Authors: Yoshikawa Shota , Itaya Kaede , Hoshina Ryo , Tashiro Yukihiro , Suda Wataru , Cho Yuichiro , Matsuura Makiko , Shindo Chie , Ito Toshiyuki , Hattori Masahira , Miyamoto Hirokuni , Kodama Hiroaki
Published: September 2024

Aims

Extracts of fermented feed obtained via fermentation of marine animal resources with thermophilic Bacillaceae bacteria increase the fecundity of livestock. The intestinal bacterial profiles in response to long-term administration of this extract to pigs were investigated.

Methods and results

Half of a swine farm was supplied with potable water containing an extract of fermented feed for more than 2 years, whereas the other half was supplied with potable water without the extract. Feces from 6-month-old pigs rearing in these two areas were collected. 16S rRNA gene sequencing and isolation of lactic acid bacteria revealed an increase in the D/L-lactate-producing bacterium, Lactobacillus amylovorus, and a decrease in several members of Clostridiales following administration of fermented feed. A lactate-utilizing bacterium, Megasphaera elsdenii, was more abundant in the feces of pigs in the fermented feed group. All representative isolates of M. elsdenii showed rapid utilization of D-lactate relative to L-lactate, and butyrate and valerate were the main products.

Conclusion

The probiotic effect of fermented feed is associated with the modulation of lactate metabolism in the digestive organs of pigs.
Seasonal host shifts based on midgut residues of Protaetia brevitarsis (Coleoptera: Scarabaeidae)
Authors: Wu Hui , Cui Zhuangzhi , Huang Xiaoqing , Kong Fanfang , Wang Zhongyue , Cui Haizhen , Liu Yongqiang
Published: September 2024

White-spotted flower chafer adult (Protaetia brevitarsis, Coleoptera: Scarabaeidae), a serious omnivorous pest in regions with multiple fruits and crops, was studied to gain a deeper understanding of its damage patterns. DNA molecular tracking technology was used to identify host plant residues in adult P. brevitarsis midgut, and plant species with the most availability were determined during their growing season. Combining the 2019 and 2021 results, it was found that adults in the multi-cropped area fed on 32 plant species from 23 families, with grape (Vitis vinifera, 40%), peach (Prunus perisica, 23%) and mulberry (Morus alba, 14%) making up the majority of their diet. Some adults fed on multiple plant hosts, with four species detected in one adult and two to three species detected in one-third of adults. Adults shifted among host species during the season, moving from mulberry or grape to peach and then back to grape. These results provide a scientific basis for in-depth research to develop green integrated control technologies against P. brevitarsis adults.
Vector resistivity monitoring technology assembled on a TBM
Authors: Gao Zhaofeng , Jiang Zhihai , Li Maofei , Zhu Jiao , Yue Jianhua
Published: September 2024

The traditional geophysical advanced detection methods, which necessitate the placement of transmitting and receiving devices on the tunnel face and the sidewall, encounters significant limitations when confronted with the challenges of water and mud inrush disasters in tunnel boring machine (TBM) tunnels. Given the constraints of efficiency and limited construction space, a vector resistivity monitoring technology is proposed, which involves arranging the current electrodes on the surface and measuring electrodes on TBM. Based on finite element method with unstructured tetrahedral grids, a three-dimensional geophysical model including the tunnel is constructed and forward modelling of low resistivity anomalous bodies with different shapes and positions is carried out. The apparent resistivity in different directions is calculated, and the distance between the anomalous body and TBM is inferred according to the low value anomaly of the vector resistivity curve of both sides. The spatial position of the anomalous body is inferred according to the shape and relative relationship of the vector resistivity curves near the low value anomaly. Finally, the position of the sphere low resistivity anomalous body is predicted through the gated recurrent unit. These results preliminarily verify the feasibility of the vector resistivity monitoring technique assembled on a TBM.
Immunoresponsive gene 1 facilitates TLR4 agonist-induced augmentation of innate antimicrobial immunity
Authors: McBride Margaret A , Caja Katherine R , Patil Tazeen K , Owen Allison M , Luan Liming , Bohannon Julia K , Hernandez Antonio , Stothers Cody L , Trenary Irina A , Rahim Mohsin , Young Jamey D , Calcutt M Wade , Stephens Victoria R , Davis Xenia , Oliver Mary A , Hao Dan , Si Clara , McRae Malik , Nguyen Kenny K , Davis Nicholas S , Wang Jingbin , Patil Naeem K , Sherwood Edward R
Published: October 2024

Treatment with the toll-like receptor 4 agonist monophosphoryl lipid A conditions innate immunocytes to respond robustly to subsequent infection, a phenotype termed innate immune memory. Our published studies show that metabolic reprogramming of macrophages is a prominent feature of the memory phenotype. We undertook studies to define the functional contributions of tricarboxylic acid cycle reprogramming to innate immune memory. We observed that priming of wild-type mice with monophosphoryl lipid A potently facilitated accumulation of the tricarboxylic acid cycle metabolite itaconate at sites of infection and enhanced microbial clearance. Augmentation of itaconate accumulation and microbial clearance was ablated in Irg1-deficient mice. We further observed that monophosphoryl lipid A potently induces expression of Irg1 and accumulation of itaconate in macrophages. Compared to wild-type macrophages, the ability of Irg1-deficient macrophages to kill Pseudomonas aeruginosa was impaired. We further observed that itaconate is directly antimicrobial against P. aeruginosa at pH 5, which is characteristic of the phagolysosome, and is facilitated by reactive oxygen species. Monophosphoryl lipid A–induced augmentation of glycolysis, oxidative phosphorylation, and accumulation of the tricarboxylic acid cycle metabolites succinate and malate was decreased in Irg1 knockout macrophages compared to wild-type controls. RNA sequencing revealed suppressed transcription of genes associated with phagolysosome function and increased expression of genes associated with cytokine production and chemotaxis in Irg1-deficient macrophages. This study identifies a contribution of itaconate to monophosphoryl lipid A–induced augmentation of innate antimicrobial immunity via facilitation of microbial killing as well as impact on metabolic and transcriptional adaptations.
Ad26.COV2.S COVID-19 Vaccine Safety And Immunogenicity in Adolescents 16–17 Years of Age
Authors: Ruiz-Guiñazú Javier , Le Gars Mathieu , Cárdenas Vicky , Vaissière Nathalie , Sadoff Jerald , Truyers Carla , Hendriks Jenny , Scheper Gert , de Groot A Marit , Struyf Frank , Schuitemaker Hanneke , Douoguih Macaya
Published: September 2024

2.5 × 1010 vp Ad26.COV2.S elicited robust SARS-CoV-2–specific antibody responses in adolescents through 6 months, with acceptable safety and reactogenicity profiles. Compared with adults immunized with 5 × 1010 vp Ad26.COV2.S, adolescents had higher antibody levels, despite being vaccinated with a lower dose.
Whistling in the wind?
Authors: Forbes Kevin F
Published: October 2024

Kevin F. Forbes describes how a misleading statistic is imperilling the transition to renewable energy in Great Britain and Ireland
Presenting data the Significance way - Part 3
Authors: Krause Andreas , Rennie Nicola
Published: October 2024

The latest instalment of our data visualisation guide, created by Andreas Krause and Nicola Rennie for Significance and our sister platform Real World Data Science, offers authors a complete guide to creating the best data visualisation for the needs of both their article and Significance magazine
Five earthenware Mandaic incantation bowls in Ābgīne Museum, Tehrān
Authors: Šafiʿī Ibrāhīm
Published: September 2024

This article presents the editio princeps of the Mandaic texts of five incantation bowls housed in Ābgīne Museum, Tehrān (627–S, 626–S, 110–S, 109–S and 108–S). Presumably dated to the 6th-7th centuries, the texts include protective formulae and name of the clients for whom they were written. The texts of 627–S and 626–S are written in a spiral manner, 110–S and 109–S are written in four segments and 108–S, which includes some of the earliest attested evidence of šapta ḏ-pišra ḏ-ainia, with the text arranged as a spoke, like sunrays.
Real-World Data Versus Probability Surveys for Estimating Health Conditions at the State Level
Authors: Marker David A , Hilton Charity , Zelko Jacob , Duke Jon , Rolka Deborah , Kaufmann Rachel , Boyd Richard
Published: September 2024

Government statistical offices worldwide are under pressure to produce statistics rapidly and for more detailed geographies, to compete with unofficial estimates available from web-based big data sources or from private companies. Commonly suggested sources of improved health information are electronic health records and medical claims data. These data sources are collectively known as real-world data (RWD) because they are generated from routine health care processes, and they are available for millions of patients. It is clear that RWD can provide estimates that are more timely and less expensive to produce—but a key question is whether or not they are very accurate. To test this, we took advantage of a unique health data source that includes a full range of sociodemographic variables and compared estimates using all of those potential weighting variables versus estimates derived when only age and sex are available for weighting (as is common with most RWD sources). We show that not accounting for other variables can produce misleading and quite inaccurate health estimates.
Sexual and reproductive health: level of knowledge and source of information in adolescence
Authors: Zamponi Virginia , Mazzilli Rossella , Nimbi Filippo Maria , Ciocca Giacomo , French Deborah , Limoncin Erika , Lombardo Francesco , Sesti Franz , Todaro Elisabetta , Tenuta Marta , Caserta Donatella , Tubaro Andrea , Gianfrilli Daniele , Faggiano Antongiulio
Published: October 2024

Background

To date, there is a lack of a structured national plan of sexual education in Italy, with large interregional differences and poor uniformity in the promotion and learning of sexual health.

Aim

The aim of this study was to evaluate the level of knowledge on sexuality and reproductive function among adolescents before and after a sexual education program, considering gender differences in the results.

Methods

A longitudinal and interventional study was conducted on high school students. Six sessions for each class were carried out by a multidisciplinary team. Anonymous questionnaires were administered to investigate basic knowledge of human sexuality and reproduction before and after intervention.

Outcomes

Participants were high school students who completed the questionnaires. Outcomes included pre and posttest answers on the knowledge questionnaire in study population.

Results

We obtained data from 842 high school students (mean ± SD age, 16.11 ± 1.74 years). The main informative sources on sexuality were social media in 37.9% of participants; family, school, and scientific material were the main source in 15.1%, 5.2%, and 4.4%, respectively. A total score of 12.6 ± 3.4 (range, 1-20) was obtained on the knowledge questionnaire; specifically, the score was higher in females than males (12.8 ± 3.4 vs 11.9 ± 3.4, P = .0001). In males and females, a statistically significant increase in level of knowledge was found after the multidisciplinary intervention (14.5 ± 3.6, P = .0001).

Clinical Implications

The lack of sexual education programs in schools in Italy compels adolescents to refer to frequently unreliable sources, such as social media and peers, contributing to misinformation and adoption of risky sexual behaviors.

Strengths and Limitations

This study is based on a large sample size and highlights the importance of sexual education programs. The main limitations are a greater representation of the female population and the inclusive nature of the school (ie, an artistic school), attracting students who identify with sexual minorities.

Conclusions

Adolescents have limited knowledge about sexuality and reproduction, with a notable gender disparity; sexual education programs in schools, providing information from sexuality experts, led to a substantial increase in knowledge and a reduction in the gender gap.
Simulated analogues I: apparent and physical evolution of young binary protostellar systems
Authors: Tuhtan Vito , Al-Belmpeisi Rami , Christensen Mikkel Bregning , Kuruwita Rajika , Haugbølle Troels
Published: September 2024

Protostellar binaries harbour complex environment morphologies. Observations represent a snapshot in time, and projection and optical depth effects impair our ability to interpret them. Careful comparison with high-resolution models that include the larger star-forming region can help isolate the driving physical processes and give context in the time domain to the observations. We carry out four zoom-in simulations with au scale resolution that result in three binaries and a single star. For the first time ever, we follow the detailed evolution of a protobinary in a full molecular cloud context until a circumbinary disc forms. We investigate the gas dynamics around the young stars and extract disc sizes. Using radiative transfer, we obtain the evolutionary tracer Tbol of the binary systems. We find that the centrifugal radius in prestellar cores is a poor estimator of the resulting disc size due to angular momentum transport at all scales. For binaries, the disc sizes are regulated periodically by the binary orbit, having larger radii close to the apastron. The bolometric temperature differs systematically between edge-on and face-on views and shows a high-frequency time dependence correlated with the binary orbit and a low-frequency time dependence with larger episodic accretion events. These oscillations can cause the appearance of the system to change rapidly from class 0 to class I and, for short periods, even bring it to class II. The highly complex structure in early stages, as well as the binary orbit itself, affects the classical interpretation of protostellar classes, and the direct translation to evolutionary stages has to be done with caution and include other evolutionary indicators such as the extent of envelope material.
JWST/NIRISS and HST: Exploring the improved ability to characterize exoplanet atmospheres in the JWST era
Authors: Fisher Chloe , Taylor Jake , Parmentier Vivien , Kitzmann Daniel , Birkby Jayne L , Radica Michael , Barstow Joanna , Yang Jingxuan , Morello Giuseppe
Published: September 2024

The Hubble Space Telescope has been a pioneering instrument for studying the atmospheres of exoplanets, specifically its WFC3 and STIS instruments. With the launch of JWST, we are able to observe larger spectral ranges at higher precision. NIRISS/SOSS covers the range 0.6–2.8 microns, and thus, it can serve as a direct comparison to WFC3 (0.8–1.7 microns). We perform atmospheric retrievals of WFC3 and NIRISS transmission spectra of WASP-39 b in order to compare their constraining power. We find that NIRISS is able to retrieve precise $\mathrm{H_{2}O}$ abundances that do not suffer a degeneracy with the continuum level due to the coverage of multiple spectral features. We also combine these data sets with spectra from STIS and find that challenges associated with fitting the steep optical slope can bias the retrieval results. In an effort to diagnose the differences between the WFC3 and NIRISS retrievals, we perform the analysis again on the NIRISS data cut to the same wavelength range as WFC3. We find that the water abundance is in strong disagreement with both the WFC3 and full NIRISS retrievals, highlighting the importance of wide wavelength coverage. Finally, we carry out mock retrievals on the different instruments, which shows further evidence of the challenges in constraining water abundance from the WFC3 data alone. Our study demonstrates the vast information gain of JWST’s NIRISS instrument over WFC3, highlighting the insights to be obtained from our new era of space-based instruments.
Combining Nanopore direct RNA sequencing with genetics and mass spectrometry for analysis of T-loop base modifications across 42 yeast tRNA isoacceptors
Authors: Shaw Ethan A , Thomas Niki K , Jones Joshua D , Abu-Shumays Robin L , Vaaler Abigail L , Akeson Mark , Koutmou Kristin S , Jain Miten , Garcia David M
Published: September 2024

Transfer RNAs (tRNAs) contain dozens of chemical modifications. These modifications are critical for maintaining tRNA tertiary structure and optimizing protein synthesis. Here we advance the use of Nanopore direct RNA-sequencing (DRS) to investigate the synergy between modifications that are known to stabilize tRNA structure. We sequenced the 42 cytosolic tRNA isoacceptors from wild-type yeast and five tRNA-modifying enzyme knockout mutants. These data permitted comprehensive analysis of three neighboring and conserved modifications in T-loops: 5-methyluridine (m5U54), pseudouridine (Ψ55), and 1-methyladenosine (m1A58). Our results were validated using direct measurements of chemical modifications by mass spectrometry. We observed concerted T-loop modification circuits—the potent influence of Ψ55 for subsequent m1A58 modification on more tRNA isoacceptors than previously observed. Growing cells under nutrient depleted conditions also revealed a novel condition-specific increase in m1A58 modification on some tRNAs. A global and isoacceptor-specific classification strategy was developed to predict the status of T-loop modifications from a user-input tRNA DRS dataset, applicable to other conditions and tRNAs in other organisms. These advancements demonstrate how orthogonal technologies combined with genetics enable precise detection of modification landscapes of individual, full-length tRNAs, at transcriptome-scale.
The Swi5–Sfr1 complex regulates Dmc1- and Rad51-driven DNA strand exchange proceeding through two distinct three-stranded intermediates by different mechanisms
Authors: Ito Kentaro , Maki Takahisa , Kanamaru Shuji , Takahashi Masayuki , Iwasaki Hiroshi
Published: September 2024

In eukaryotes, Dmc1 and Rad51 are key proteins of homologous recombination. The Swi5–Sfr1 complex in fission yeast, a conserved auxiliary factor, stimulates DNA strand exchange driven by both Dmc1 and Rad51. Interestingly, biochemical analysis suggested that Swi5–Sfr1 regulates strand exchange activities of these recombinases differently, but the mechanisms were unclear. We previously developed a real-time system to analyze Rad51-driven DNA strand exchange and identified two topologically distinct three-stranded intermediates (complex 1 (C1) and complex 2 (C2)). Swi5–Sfr1 facilitates the C1–C2 transition and releases single-stranded DNA (ssDNA) from C2, acting as a strand exchange activator. In this study, we investigated fission yeast Dmc1-driven DNA strand exchange and the role of Swi5–Sfr1 in Dmc1 activity in real-time. Kinetic analysis revealed a three-step model for the Dmc1-driven reaction, similar to that of Rad51. Although Swi5–Sfr1 stimulated the Dmc1-driven reaction, it had a weaker impact than Rad51. Furthermore, Swi5–Sfr1 enhanced the association of Dmc1 with ssDNA by promoting filament nucleus formation, acting as a mediator, unlike its role with Rad51. This stimulation mechanism also differs from that of Ca2+ or ATP analog, AMP–PNP. Our findings suggest that Swi5–Sfr1 stimulates strand exchange activities of Dmc1 and Rad51 via different reaction steps.
Intravenous methylprednisolone for nephrotic syndrome with minimal change lesions in adults: a randomized controlled trial
Authors: Chen Jinxia , Li Ruting , Guo Hua , Zhu Tianyu , Xu Yongzhi , Yao Cuiwei , Liu Huafeng
Published: September 2024

Background

Patients with minimal change nephrotic syndrome (MCNS) usually experience severe oedema, which can affect the absorption of oral corticosteroid during the first 2 weeks. We conducted a randomized controlled trial (RCT) to compare the efficacy of intravenous (IV) isovalent methylprednisolone induction followed by oral prednisone therapy with conventional oral prednisone therapy in highly oedematous MCNS patients, aiming to provide a better therapy for MCNS patients.

Methods

A single-centre, open-label, parallel-arm RCT was performed in the Nephrology Department of the Affiliated Hospital of Guangdong Medical University. Patients who met the inclusion criteria were enrolled in our study from May 2015 to October 2020 and were randomized to receive conventional oral steroid or 2 weeks of IV methylprednisolone followed by oral prednisone.

Results

A total of 117 patients were enrolled and randomly assigned to either the sequential group (n = 57) or the oral group (n = 60). The total remission rate in the sequential group was higher than in the oral group after treatment for 2 weeks and 4 weeks (P = .032, P = .027). The complete remission (CR) rate was higher in the sequential group than in the oral group (63.3% versus 41.5%; P = .031) after treatment for 2 weeks. The time to achieve CR was shorter in the sequential group than in the oral group, with a statistically significant difference {14.0 days [95% confidence interval (CI) 13.5–14.5] versus 16.0 days [95% CI 12.7–19.3], P = .024}. There were no significant differences in relapse rate (24.5% versus 28.3%; P = .823) and time to relapse (155 ± 103 days versus 150.7 ± 103.7 days; P = .916) between two groups.

Conclusion

This study suggested that highly oedematous MCNS patients who received IV isovalent methylprednisolone induction therapy followed by oral prednisone achieved earlier remission than the conventional oral prednisone regimen without differences in relapse rates or adverse effects. Short-term IV methylprednisolone followed by oral prednisone may be a better choice for MCNS patients with severe oedema.
Targeted radionuclide therapy for patients with central nervous system metastasis: Overlooked potential?
Authors: Le Rhun Emilie , Albert Nathalie L , Hüllner Martin , Franceschi Enrico , Galldiks Norbert , Karschnia Philipp , Minniti Giuseppe , Weiss Tobias , Preusser Matthias , Ellingson Benjamin M , Weller Michael
Published: October 2024

Targeted radionuclide therapy is an emerging therapeutic concept for metastatic cancer that can be considered if a tumor can be delineated by nuclear medicine imaging and also targeted based on the expression of a particular target (thera-nostics). This mode of treatment can also compete with or supplement conventional radiotherapy, for example, if MRI does not fully capture the extent of the disease, including microscopic metastases. Targeted radionuclide therapy for patients with thyroid cancer, with certain somatostatin receptor 2-expressing tumors and with prostate-specific membrane antigen-expressing prostate cancer is approved, and numerous approaches of targeted radionuclide therapy for patients with metastatic cancer are in development (eg, using fibroblast activation protein as a target). Although brain metastases are rare in cancers with approved targeted radionuclide therapies, there is no a priori reason to assume that such treatments would not be effective against brain metastases if the targets are expressed and not shielded by the blood-brain barrier. Here, we discuss the current state of the art and opportunities of targeted radionuclide therapies for patients with brain and leptomeningeal metastases.
Current views on mechanisms of the FLASH effect in cancer radiotherapy
Authors: Ma Yuqi , Zhang Wenkang , Zhao Ziming , Lv Jianfeng , Chen Junyi , Yan Xueqin , Lin XiaoJi , Zhang Junlong , Wang Bingwu , Gao Song , Xiao Jie , Yang Gen
Published: October 2024

FLASH radiotherapy (FLASH-RT) is a new modality of radiotherapy that delivers doses with ultra-high dose rates. The FLASH effect was defined as the ability of FLASH-RT to suppress tumor growth while sparing normal tissues. Although the FLASH effect has been proven to be valid in various models by different modalities of irradiation and clinical trials of FLASH-RT have achieved promising initial success, the exact underlying mechanism is still unclear. This article summarizes mainstream hypotheses of the FLASH effect at physicochemical and biological levels, including oxygen depletion and free radical reactions, nuclear and mitochondria damage, as well as immune response. These hypotheses contribute reasonable explanations to the FLASH effect and are interconnected according to the chronological order of the organism's response to ionizing radiation. By collating the existing consensus, evidence and hypotheses, this article provides a comprehensive overview of potential mechanisms of the FLASH effect and practical guidance for future investigation in the field of FLASH-RT.
Ivermectin-Based Mass Drug Administration for Scabies in Northern India: A Single-Arm Community Intervention Trial
Authors: Engelman Daniel , Singh Rajesh , Woodall Hannah J , O’Brien Howard , Singh Raj Kumari , Zhu Xilin , Grobler Anneke C , Thomas Molly , Steer Andrew C , Grills Nathan
Published: October 2024

Background

Scabies and impetigo cause direct health effects and contribute to severe infectious and immune-mediated complications. Ivermectin-based mass drug administration can reduce scabies and impetigo prevalence in island settings with high prevalence, but the effectiveness in moderate-prevalence settings is not known.

Methods

We conducted a single-arm, before–after community intervention trial. Mass drug administration was offered to the entire population of 4 villages in Uttarakhand, India. The treatment consisted of 2 doses, given 7 days apart, of oral ivermectin (∼200 μg/kg), or topical 5% permethrin if ivermectin was contraindicated. The primary outcome was the prevalence of scabies at 12 months compared with baseline, as diagnosed using clinical assessment and the 2020 International Alliance for the Control of Scabies criteria. Secondary outcomes included the prevalence of impetigo at each time point. The trial was registered with the Australian and New Zealand Trials Registry (ACTRN12619001712190).

Results

In January 2020, 1211 participants were enrolled (100% of the estimated village population). Treatment coverage was high—1204 (99.4%) and 1177 (97.2%) received 1 and 2 doses, respectively. Scabies was diagnosed in 91 participants (7.5%) and impetigo in 15 (1.2%). In February 2021, 1190 (98.3% of baseline) participants re-enrolled, and of these 11 had scabies (0.9%; relative risk reduction, 87.7%; 95% CI, 77.1%–93.4%) and 5 had impetigo (0.4%; relative risk reduction, 66.1%; 95% CI, 7.0%–87.6%).

Conclusions

A single round of ivermectin-based mass drug administration substantially reduced the prevalence of scabies and impetigo in this setting with moderate scabies prevalence in northern India.
Meta-analysis of platinum chemotherapy combinations with immunotherapy in metastatic urothelial carcinoma
Authors: Bolek Hatice , Yazgan Satı Coskun , Yekedüz Emre , Ürün Yüksel
Published: September 2024

The therapeutic landscape for metastatic urothelial carcinoma (mUC) has evolved significantly due to the development of innovative combination treatments, including enfortumab vedotin-pembrolizumab (EVP). Despite these advancements, the limited availability of EVP means that platinum-based chemotherapy regimens continue to serve as the primary treatment modality for many patients with mUC. We evaluated the effect of the type of platinum chemotherapy used in combination with immunotherapy (IO) on treatment outcomes in mUC. The meta-analysis showed that cisplatin-gemcitabine plus IO combination and carboplatin-gemcitabine plus IO combination improve progression-free survival compared to platinum-gemcitabine therapy (hazard ratio [HR] = 0.71, 95% CI: 0.62-0.82; P < .0001 and HR = 0.85, 95% CI: 0.73-0.98; P < .03, respectively). However, only the cisplatin-gemcitabine plus IO combination showed overall survival (OS) benefit (HR = 0.80, 95% CI: 0.69-0.93; P < .003). In comparison to the platinum-gemcitabine combination, neither the cisplatin-gemcitabine plus IO nor the carboplatin-gemcitabine plus IO combinations demonstrated an objective response rate (ORR) benefit. In summary, combining cisplatin-gemcitabine with immunotherapy offers significant overall survival benefits in mUC. The exact mechanisms—whether cisplatin’s immunomodulatory effects or patient demographic differences—are yet to be determined, necessitating further research to understand these outcomes better.
Direct and Indirect Effects of Subsidized Dual Apprenticeships
Authors: Crépon Bruno , Premand Patrick
Published: September 2024

Public interventions in the apprenticeship market often aim to increase demand or returns. We set up a double-sided experiment with youth and firms to analyse a subsidized dual apprenticeship program. This intervention seeks to relax financial constraints for youth by offering a wage subsidy and to make apprenticeship more attractive by providing vocational training in technical skills that complements on-the-job training. We document a large increase in youth participation in apprenticeship, yet the inflow of apprentices induces little crowding out of traditional apprentices in firms. The intervention leads to an increase in youth demand for apprenticeship, enabling firms to fill open apprenticeship positions. The subsidy compensates apprentices for low wages but does not alleviate financial constraints. Consistent with the dual training component contributing to an increase in youth demand for apprenticeship, youth perform more complex tasks and have higher earnings 4 years after the start of the experiment.
Hybrid high and low molecular weight chains of hyaluronan for clitoral injection is an effective modality treatment for increasing female sexual satisfaction: an interventional, randomized-controlled parallel study
Authors: Atef Lina Mohammed , Mohammed Ghada Farouk , Al-Dhubaibi Mohammed Saleh , Soliman Mahmoud , Bahaj Saleh Salem , Saleh Yasser S N
Published: October 2024

Introduction

Hormonal, behavioral, psychological, surgical, and pharmacopsychological treatment approaches contribute to female sexual dysfunction (FSD).

Aim: The study is conducted to assess the effectiveness of hyaluronan high and low molecular weight hybrid cooperative complexes (hybrid H-HA/L-HA) in treating females with SD and to compare the female sexual function index (FSFI), dermatological life quality index (DLQI), and female genital self-image scale (FGSIS) before and after therapy.

Methods

We divided the 60 female participants into two groups. Hybrid H-HA/L-HA was administered to form pili of 0.25 cc around the clitoris in the direction of clock positions of 12, 3, 6, and 9. In Skene’s gland; 0.25 cc for each and 0.5 cc into the corpus/body of the clitoris. Two treatments were held 30 days apart.

The same procedure was repeated on the control group, but with saline as a placebo.

Outcomes

Women completed self-report questionnaires assessing sexual functioning using the FSFI, DLQI, and FGSIS before and after therapy.

Result

There was a significant (P = 634.152; P < .05) increase in the study group’s weekly sexual interactions compared with the controls. The study group showed statistically significant amelioration in desire, arousal, lubrication, orgasm, satisfaction domains, overall score, and a decrease in pain following the first and second injection sessions (P = .014, .031, .003, .001, .011, .004, and .011, respectively). A comparison of the results between the two groups revealed significant improvement were found (P = .025).

There were significant improvements in the domains of the FGSIS compared with the controls (P = .026). The study group showed a substantial improvement in satisfaction with the way their genital area looked, comfort level when allowing a sexual partner to view their genital area, belief that their genitals smell perfectly fine without being self-conscious about them, and overall score (P = .022, .031, .003, .001, and .004, respectively) (P < .05).

The hybrid H-HA/L-HA sessions resulted in significantly greater positive perceptions and feelings, leisure activities, interpersonal interactions, and general assessments (P = .021, .021, and .020, respectively) (P < .05).

Clinical Implications

Female individuals with SD experience sexual improvements after hybrid H-HA/L-HA injection.

Strengths and Limitations

This is the first study focusing on female individuals with SD. We recommend conducting the study on a larger population and including their partners.

Conclusion

Hybrid H-HA/L-HA injection for rejuvenating the clitoral injection appears to be a reliable and safe method for enhancing female genital self-image, sexuality, and quality of life.
Jawbone periosteum‐derived cells with high osteogenic potential controlled by R‐spondin 3
Authors: Zhang Shu , Zhu Jingxian , Jin Siyu , Sun Wei , Ji Wei , Chen Zhi
Published: September 2024

The jawbone periosteum, the easily accessible tissue responding to bone repair, has been overlooked in the recent development of cell therapy for jawbone defect reconstruction. Therefore, this study aimed to elucidate the in vitro and in vivo biological characteristics of jawbone periosteum‐derived cells (jb‐PDCs). For this purpose, we harvested the jb‐PDCs from 8‐week‐old C57BL/6 mice. The in vitro cultured jb‐PDCs (passages 1 and 3) contained skeletal stem/progenitor cells and exhibited clonogenicity and tri‐lineage differentiation capacity. When implanted in vivo, the jb‐PDCs (passage 3) showed evident ectopic bone formation after 4‐week subcutaneous implantation, and active contribution to repair the critical‐size jawbone defects in mice. Molecular profiling suggested that R‐spondin 3 was strongly associated with the superior in vitro and in vivo osteogenic potentials of jb‐PDCs. Overall, our study highlights the significance of comprehending the biological characteristics of the jawbone periosteum, which could pave the way for innovative cell‐based therapies for the reconstruction of jawbone defects.
Understanding the relationship between inflammation, apoptosis, and diabetes osteoporosis: A bioinformatics approach and experimental verification
Authors: Li Jun Quan , Li Bo , Fei Zhang Qing , Lei Shan Shan
Published: September 2024

Diabetes osteoporosis (DOP) is a chronic metabolic bone disease. This study aimed to identify potential biomarkers of DOP and explore their underlying mechanisms through bioinformatics methods and experimental verification. Bioinformatics methods were used to identify differentially expressed genes (DEGs) for DOP based on GEO data and the GeneCards database. GO and KEGG enrichment analyses were used to search the key pathways. The STRING website was used to construct a protein–protein interaction (PPI) network and identify key genes. Then, 50 mg/mL glucose was used to interveneosteoblasts (OBs).CCK‐8 and Alizarin Red staining were used to investigate the proliferation and differentiation changes in OBs. Flowcytometry was used to investigate apoptosis. The membrane protein chip, WB, and RT‐PCR were used to verify the expression of key targets or pathways about DOP. Forty‐two common genes were screened between DOP‐related targets and DEGs. GO and KEGG enrichment analysis showed that DOP was mainly associated with cytokine‐cytokine receptor interactions, and apoptosis. PPI network analysis showed that TNF, IL1A, IL6, IL1B, IL2RA, Fas ligand (FASLG), and Fas cell surface death receptor (FAS) were key up‐regulated genes in the occurrence of DOP. The experiment results show that 50 mg/mL glucose significantly inhibited OBs proliferation but presented an increase in apoptosis. Membrane protein chip, WB, and RT‐PCR‐verified a significantly active in the expression of TNF/FASLG/FAS pathway. High glucose activated the TNF‐α/FAS/FASLG pathway and induced the inflammatory microenvironment and apoptosis, then impaired osteogenic differentiation of OBs. These may be an important mechanism for the occurrence and development of DOP.