bluuebunny/crossref_metadata_2025 huggingface dataset:
Bifurcations and pattern formation in a host–parasitoid model with nonlocal effect
Authors: Xiang Chuang , Huang Jicai , Lu Min , Ruan Shigui , Wang Hao
Published: March 2024

In this paper, we analyse Turing instability and bifurcations in a host–parasitoid model with nonlocal effect. For a ordinary differential equation model, we provide some preliminary analysis on Hopf bifurcation. For a reaction–diffusion model with local intraspecific prey competition, we first explore the Turing instability of spatially homogeneous steady states. Next, we show that the model can undergo Hopf bifurcation and Turing–Hopf bifurcation, and find that a pair of spatially nonhomogeneous periodic solutions is stable for a (8,0)-mode Turing–Hopf bifurcation and unstable for a (3,0)-mode Turing–Hopf bifurcation. For a reaction–diffusion model with nonlocal intraspecific prey competition, we study the existence of the Hopf bifurcation, double-Hopf bifurcation, Turing bifurcation, and Turing–Hopf bifurcation successively, and find that a spatially nonhomogeneous quasi-periodic solution is unstable for a (0,1)-mode double-Hopf bifurcation. Our results indicate that the model exhibits complex pattern formations, including transient states, monostability, bistability, and tristability. Finally, numerical simulations are provided to illustrate complex dynamics and verify our theoretical results.
Computer-aided design tool for typical flexible mechanisms synthesis by means of evolutionary algorithms
Authors: Ben Abdallah Mohamed Amine , Khemili Imed , Aifaoui Nizar , Laribi Med Amine
Published: March 2024

Accurate prediction for mechanisms’ dynamic responses has always been a challenging task for designers. For modeling easiness purposes, mechanisms’ synthesis and optimization have been mostly limited to rigid systems, making consequently the designer unable to vow that the manufactured mechanism satisfies the target responses. To address this limitation, flexible mechanism synthesis is aimed in this work. Two benchmark mechanisms being the core of myriad mechanical devices are of scope, mainly, the flexible slider-crank and the four-bar. In addition to the mechanism dimensions, materials properties have been embedded in the synthesis problem. Two responses are of interest for the slider-crank mechanism, the slider velocity, and the midpoint axial displacement for the flexible connecting rod. Whereas five responses have been compiled for the four-bar mechanism synthesis. A comparative analysis of seven optimization techniques to solve the synthesis problem for both mechanisms has been performed. Subsequently, an executable computer-aided design tool for mechanisms synthesis has been developed under MATLAB®. Numerical outcomes emphasize the limits of a single-response-based synthesis for a flexible mechanism. It has been proven that combining different responses alleviates possible error and fulfill high-accuracy requirement.
The Sultans of Zanzibar and the Abolition of Slavery in East Africa
Authors: Liebst Michelle
Published: March 2024

In 1890, Sultan Ali of Zanzibar declared in writing that “we wish by every means to stop the slave trade.” Statements like these, in addition to the actual passing of anti-slavery legislation, call into question the generally accepted scholarly understanding that the sultans of Zanzibar only agreed to pass and enforce anti-slavery legislation because they were under duress from European, mainly British, powers, who negotiated favorable political and economic benefits in return for (gradual) abolition. A close analysis of the sources tells a more complicated story of both collaboration and conflict between the Zanzibari sultans, their subjects, and the British agents. Moreover, each sultan had distinctive political and religious beliefs, as well as individual personal experiences and outlooks. This paper explores the anti-slavery legislation passed under three sultans of Zanzibar: Barghash bin Said (1870–1888) who prohibited the transport of slaves by sea in 1873, Ali bin Said (1890–1893) who passed the Slave Trade Prohibition Decree of 1890, and Hamoud bin Mohammed (1896–1902) who passed the Abolition Decree of 1897. By analyzing draft treaties and correspondence before and after the passing of legislation, this paper argues that the sultans and their advisors were not devoid of ideological interest in ending slavery; and that British agents and explorers in the region were too hastily hailed as abolitionists.
An Argaric Tomb for a Carpathian ‘Princess’?
Authors: López Padilla Juan A. , Jover Maestre Francisco Javier , Basso Rial Ricardo E. , Pastor Quiles María
Published: March 2024

Around 120 years ago, a burial was discovered in the Argaric settlement of San Antón, 60 km southeast of Alicante (Spain). Although it was similar to many others recorded during more than a century of research, some gold objects found made this burial exceptional in the Iberian Bronze Age funerary record. Based on the most recent archaeological data, this article reviews both the context and the whole set of grave goods. It also explores the intersocial relationships that these gold ornaments suggest, which directly or indirectly seem to point towards both eastern Mediterranean Europe as well as to the Carpathian Basin.
Reducing the carbon footprint of diets across socio-demographic groups in Finland: a mathematical optimisation study
Authors: Irz Xavier , Tapanainen Heli , Saarinen Merja , Salminen Jani , Sares-Jäske Laura , Valsta Liisa M
Published: March 2024

Objectives:

To characterise nutritionally adequate, climate-friendly diets that are culturally acceptable across socio-demographic groups. To identify potential equity issues linked to more climate-friendly and nutritionally adequate dietary changes.

Design:

An optimisation model minimises distance from observed diets subject to nutritional, greenhouse gas emissions (GHGE) and food-habit constraints. It is calibrated to socio-demographic groups differentiated by sex, education and income levels using dietary intake data. The environmental coefficients are derived from life cycle analysis and an environmentally extended input–output model.

Setting:

Finland.

Participants:

Adult population.

Results:

Across all population groups, we find large synergies between improvements in nutritional adequacy and reductions in GHGE, set at one-third or half of the current level. Those reductions result mainly from the substitution of meat with cereals, potatoes and roots and the intra-category substitution of foods, such as beef with poultry in the meat category. The simulated more climate-friendly diets are thus flexitarian. Moving towards reduced-impact diets would not create major inadequacies related to protein and fatty acid intakes, but Fe could be an issue for pre-menopausal females. The initial socio-economic gradient in the GHGE of diets is small, and the patterns of adjustments to more climate-friendly diets are similar across socio-demographic groups.

Conclusions:

A one-third reduction in GHGE of diets is achievable through moderate behavioural adjustments, but achieving larger reductions may be difficult. The required changes are similar across socio-demographic groups and do not raise equity issues. A population-wide policy to promote behavioural change for diet sustainability would be appropriate.
Adherence to the national guidance on foods and drinks to limit or avoid during pregnancy in England: the PEAR Study
Authors: Beasant Lucy , Ingram Jenny , Emmett Pauline M , Cade Janet E , Taylor Caroline M
Published: March 2024

Objective:

The National Health Service (NHS) England website provides guidance on foods/drinks to avoid or limit during pregnancy because of microbiological, toxicological or teratogenic hazards. The aims were to determine adherence and whether demographic characteristics were associated with adherence.

Design:

Cross-sectional study.

Setting:

Online survey of postpartum women resident in England during pregnancy.

Participants:

Recently, postpartum women resident in England during their pregnancy (n 598; median age 33 (IQR 30–36) years) completed an online questionnaire (April–November 2022). Questions included those on consumption of twenty-one food/drink items that the NHS advises pregnant women to avoid/limit. The study is part of the Pregnancy, the Environment And nutRition (PEAR) Study. Summary statistics were used to determine proportions adhering to the guidance. Adjusted logistic regression was used to model the associations of adherence with demographic characteristics.

Results:

Adherence was generally high (>90 % for eight of ten food/drink items to be avoided). However, among pre-pregnancy consumers, several items were not completely avoided, for example, 81 % (128/158) for game meat/gamebirds, 37 % (176/478) for cured meats and 17 % (81/467) for soft cheeses. Greater educational attainment (e.g. caffeinated soft drinks OR 2·25 (95 % CI 1·28, 3·94)), greater maternal age (e.g. oily fish 1·64 (1·05, 2·56)) and lower parity (e.g. caffeinated coffee 0.28 (0.11, 0.69)) were the most usual characteristics associated with adherence.

Conclusion:

Evidence of concerning levels of non-adherence for some food/drink items suggests a case for more education on some of the guidance, particularly for women with lower educational attainment, greater parity and greater maternal age. Further research on barriers to the implementation of the guidance is needed.
ENERGY BOUNDS FOR MODULAR ROOTS AND THEIR APPLICATIONS
Authors: Kerr Bryce , Shkredov Ilya D. , Shparlinski Igor E. , Zaharescu Alexandru
Published: March 2024

We generalise and improve some recent bounds for additive energies of modular roots. Our arguments use a variety of techniques, including those from additive combinatorics, algebraic number theory and the geometry of numbers. We give applications of these results to new bounds on correlations between Salié sums and to a new equidistribution estimate for the set of modular roots of primes.
Rare inheritance studies on yellow sarson for petalous and apetalous traits
Authors: Bisht Charu , Prasad Birendra , Pant Usha , Verma Sanjay Kumar , Gaur Amit Kumar , Gupta Shubham , Panwar Neha , Joshi Sivendra , Bisht Yashpal Singh , Prashad Himanshu , Deep Harsh
Published: March 2024

This study investigates the inheritance pattern of petalous and apetalous traits in yellow sarson (Brassica rapa var yellow sarson) and its significance for breeding efforts. Utilizing three crucial crosses between petalous (Pant Sweta, Pant Girija, YSH0401) and ‘apetalous’ parents, we observed the absence of apetalous plants in the F1 generation, indicating dominant inheritance of petalous plants. The F2 generation consistently displayed a 3:1 ratio of petalous to apetalous plants, confirming the dominance of the petalous trait. Chi-squared tests on each generation supported this conclusion. Backcrosses with petalous parents yielded no fruit, reinforcing the dominance of the petalous trait. Chi-squared tests on these backcrosses further confirmed the dominance inheritance pattern. Conversely, backcrosses with apetalous parents consistently exhibited a 1:1 ratio, highlighting the recessive nature of the apetalous trait. The study underscores the importance of understanding the inheritance pattern of petalous and apetalous traits in B. rapa var yellow sarson crop, as it has implications for breeding goals. Knowledge on trait inheritance can guide future breeding strategies, facilitating the transfer of the apetalous trait as needed. This study provides valuable insights for genetic investigations and breeding initiatives in B. rapa var yellow sarson.
Strong Lensing by Galaxies: Past Highlights, Current Status, and Future Prospects
Authors: Shajib Anowar J.
Published: March 2024

Galaxy-scale strong lensing is a powerful tool in Astrophysics and Cosmology, enabling studies of massive galaxies’ internal structure, their formation and evolution, stellar initial mass function, and cosmological parameters. In this conference proceeding, we highlight key findings from the past decade in astrophysical applications of strong lensing at the galaxy scale. We then briefly summarize the present status of discovery and analyses of new samples from recent or ongoing surveys. Finally, we offer insights into anticipated developments in the upcoming era of big data shaping the future of this field, thanks to the Rubin, Euclid, and Roman observatories.
Fluent Processing Amplifies Affective Judgments
Authors: Zhou Yizhen , Kawabata Hideaki
Published: March 2024

Abstract: The importance of processing fluency in evaluative judgments has been repeatedly demonstrated across many domains such as liking, beauty, and truth. However, a clear picture of the nature of processing fluency has yet to emerge. Fluent processing has been suggested to form evaluative judgments in a hedonic nature, in which existing judgmental tendencies always shift in a positive direction. Alternatively, fluency has been proposed to amplify evaluative judgments bidirectionally. However, uncertainty remains regarding the influence of processing fluency on pre-existing judgmental tendencies. Specifically, the extent to which the effect of stimuli belonging to specific categories varies within an individual remains unclear. This study assessed the influence of fluent processing on two specific categories (cats/spiders) using a visual search task. Fluency was manipulated by the set size of the stimuli and presentation duration. Fluency intensified pre-existing judgmental tendencies in two divergent directions: The initially favored stimuli were liked more, while the initially unfavored ones were liked less when the processing of stimuli was fluent. There was a significant correlation between favored and unfavored stimuli in terms of the magnitude of the effect, and such effect was influenced by visual attention, suggesting that processing fluency goes beyond a hedonic and unidimensional nature.
A Comprehensive Assessment of Submarine Landslides and Mass Wasting Processes Offshore Southern California
Authors: Walton Maureen A. L. , Conrad James E. , Papesh Antoinette G. , Brothers Daniel S. , Kluesner Jared W. , McGann Mary , Dartnell Peter
Published: March 2024

It is critical to characterize submarine landslide hazards near dense coastal populations, especially in areas with active faults, which can trigger slope failure, subsequent tsunamis, and damage seabed infrastructure during earthquake shaking. Offshore southern California, numerous marine geophysical surveys have been conducted over the past decade, and high‐resolution bathymetric and subsurface data now cover about 60 percent of the total region between Point Conception and the United States‐Mexico border from the California coast out to the base of Patton Escarpment ∼200 km offshore. In a comprehensive compilation and interpretive mapping effort, we find evidence of seafloor failure throughout offshore southern California with nearly 1,500 submarine landslide‐related features, including 63 discrete slide deposits with debris and >1,400 slide‐related scarps. In our analysis, we highlight new mapping of submarine landslides in Catalina Basin, the Del Mar slide, the San Gabriel slide complex, and the 232 km2 San Nicolas slide, the largest area of any known submarine landslide mass offshore southern California. Analysis of the spatial distribution of submarine landslide features suggests that most mapped slide features are located relatively near coastal sediment sources, particularly during sea‐level lowstand conditions, which underscores the importance of sediment supply and sediment accumulation on low‐gradient slopes as failure preconditioning processes. Tectonically driven uplift at shelf edges and along basin flanks is another key preconditioning factor, and our results also suggest that earthquakes along active faults trigger mass wasting, especially for repeated, small‐scale failures on tectonically steepened slopes.
Summer Deep Depressions Increase Over the Eastern North Atlantic
Authors: D'Andrea Fabio , Duvel Jean‐Philippe , Rivière Gwendal , Vautard Robert , Cassou Christophe , Cattiaux Julien , Coumou Dim , Faranda Davide , Happé Tamara , Jézéquel Aglaé , Ribes Aurelien , Yiou Pascal
Published: March 2024

Mid‐tropospheric deep depressions in summer over the North Atlantic are shown to have strongly increased in the eastern and strongly decreased in the western North Atlantic region. This evolution is linked to a change in baroclinicity in the west of the North Atlantic ocean and over the North American coast, likely due to the increased surface temperature there. Deep depressions in the Eastern North Atlantic are linked to a temperature pattern typical of extreme heat events in the region. The same analysis is applied to a sample of CMIP6 model outputs, and no such trends are found. This study suggests a link between the observed increase of summer extreme heat events in the region and the increase of the number of Atlantic depressions. The failure of CMIP6 models to reproduce these events can consequently also reside in an incorrect reproduction of this specific feature of midlatitude atmospheric dynamics.
NF-κB in biology and targeted therapy: new insights and translational implications
Authors: Guo Qing , Jin Yizi , Chen Xinyu , Ye Xiaomin , Shen Xin , Lin Mingxi , Zeng Cheng , Zhou Teng , Zhang Jian
Published: March 2024

NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-κB signaling, and summarize the composition, activation, and regulatory mechanism of NF-κB signaling. We investigate the interaction of NF-κB signaling with other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR signaling. The physiological and pathological states of NF-κB signaling, as well as its intricate involvement in inflammation, immune regulation, and tumor microenvironment, are also explicated. Additionally, we illustrate how NF-κB signaling is involved in a variety of human diseases, including cancers, inflammatory and autoimmune diseases, cardiovascular diseases, metabolic diseases, neurological diseases, and COVID-19. Further, we discuss the therapeutic approaches targeting NF-κB signaling, including IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T. Finally, we provide an outlook for research in the field of NF-κB signaling. We hope to present a stereoscopic, comprehensive NF-κB signaling that will inform future research and clinical practice.
New clinical trial design in precision medicine: discovery, development and direction
Authors: Duan Xiao-Peng , Qin Bao-Dong , Jiao Xiao-Dong , Liu Ke , Wang Zhan , Zang Yuan-Sheng
Published: March 2024

In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to the underestimation of the significant heterogeneity across participants in traditional “one-size-fits-all” trials, patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed including the basket, umbrella, and platform trial designs under the master protocol framework. In recent years, the successive FDA approval of indications based on biomarker-guided master protocol designs has demonstrated that these new clinical trials are ushering in tremendous opportunities. Despite the rapid increase in the number of basket, umbrella, and platform trials, the current clinical and research understanding of these new trial designs, as compared with traditional trial designs, remains limited. The majority of the research focuses on methodologies, and there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs. Therefore, we provide this comprehensive review of the discovery and development of basket, umbrella, and platform trials and their underlying logic from the perspective of precision medicine. Meanwhile, we discuss future directions on the potential development of these new clinical design in view of the “Precision Pro”, “Dynamic Precision”, and “Intelligent Precision”. This review would assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs by expounding the underlying logic, which be essential to accelerate the progression of precision medicine.
Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS homeostasis
Authors: Yan Yuanliang , Zhou Shangjun , Chen Xi , Yi Qiaoli , Feng Songshan , Zhao Zijin , Liu Yuanhong , Liang Qiuju , Xu Zhijie , Li Zhi , Sun Lunquan
Published: March 2024

Temozolomide (TMZ) represents a standard-of-care chemotherapeutic agent in glioblastoma (GBM). However, the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma. Although specific innovative approaches, such as immunotherapy, have shown favorable clinical outcomes, the inherent invasiveness of most gliomas continues to make them challenging to treat. Consequently, there is an urgent need to identify effective therapeutic targets for gliomas to overcome chemoresistance and facilitate drug development. This investigation used mass spectrometry to examine the proteomic profiles of six pairs of GBM patients who underwent standard-of-care treatment and surgery for both primary and recurrent tumors. A total of 648 proteins exhibiting significant differential expression were identified. Gene Set Enrichment Analysis (GSEA) unveiled notable alterations in pathways related to METABOLISM_OF_LIPIDS and BIOLOGICAL_OXIDATIONS between the primary and recurrent groups. Validation through glioma tissue arrays and the Xiangya cohort confirmed substantial upregulation of inositol 1,4,5-triphosphate (IP3) kinase B (ITPKB) in the recurrence group, correlating with poor survival in glioma patients. In TMZ-resistant cells, the depletion of ITPKB led to an increase in reactive oxygen species (ROS) related to NADPH oxidase (NOX) activity and restored cell sensitivity to TMZ. Mechanistically, the decreased phosphorylation of the E3 ligase Trim25 at the S100 position in recurrent GBM samples accounted for the weakened ITPKB ubiquitination. This, in turn, elevated ITPKB stability and impaired ROS production. Furthermore, ITPKB depletion or the ITPKB inhibitor GNF362 effectively overcome TMZ chemoresistance in a glioma xenograft mouse model. These findings reveal a novel mechanism underlying TMZ resistance and propose ITPKB as a promising therapeutic target for TMZ-resistant GBM.
The role of comprehensive rehabilitation in the care of degenerative cervical myelopathy
Authors: Catz Amiram , Watts Yaron , Amir Hagay , Front Lilach , Gelernter Ilana , Michaeli Dianne , Bluvshtein Vadim , Aidinoff Elena
Published: March 2024

Study design

Retrospective cohort study.

Objective

To find out if comprehensive rehabilitation itself can improve daily performance in persons with DCM.

Setting

The spinal department of a rehabilitation hospital.

Methods

Data from 116 DCM inpatients who underwent comprehensive rehabilitation after spinal surgery were retrospectively analyzed. The definitions of the calculated outcome variables made possible analyses that distinguished the effect of rehabilitation from that of spinal surgery. Paired t-tests were used to compare admission with discharge outcomes and functional gains. Spearman’s correlations were used to assess relationships between performance gain during rehabilitation and between time from surgery to rehabilitation.

Results

The Spinal Cord Injury Ability Realization Measurement Index (SCI-ARMI) increased during rehabilitation from 57 (24) to 78 (19) (p < 0.001). The Spinal Cord Independence Measure 3rd version (SCIM III) gain attributed to neurological improvement (dSCIM-IIIn) was 6.3 (9.2), and that attributed to rehabilitation (dSCIM-IIIr) 16 (18.5) (p < 0.001). dSCIM-IIIr showed a rather weak negative correlation with time from spinal surgery to rehabilitation (r = −0.42, p < 0.001).

Conclusions

The study showed, for the first time, that comprehensive rehabilitation can achieve considerable functional improvement for persons with DCM of any degree, beyond that of spinal surgery. Combined with previously published evidence, this indicates that comprehensive rehabilitation can be considered for persons with DCM of any functional degree, before surgery.
Pharmacogenetic and clinical risk factors for bevacizumab-related gastrointestinal hemorrhage in prostate cancer patients treated on CALGB 90401 (Alliance)
Authors: Patel Jai N. , Jiang Chen , Owzar Kouros , Hertz Daniel L. , Wang Janey , Mulkey Flora A. , Kelly William K. , Halabi Susan , Furukawa Yoichi , Lassiter Cameron , Dorsey Susan G. , Friedman Paula N. , Small Eric J. , Carducci Michael A. , Kelley Michael J. , Nakamura Yusuke , Kubo Michiaki , Ratain Mark J. , Morris Michael J. , McLeod Howard L.
Published: March 2024

The objective of this study was to discover clinical and pharmacogenetic factors associated with bevacizumab-related gastrointestinal hemorrhage in Cancer and Leukemia Group B (Alliance) 90401. Patients with metastatic castration-resistant prostate cancer received docetaxel and prednisone ± bevacizumab. Patients were genotyped using Illumina HumanHap610-Quad and assessed using cause-specific risk for association between single nucleotide polymorphisms (SNPs) and gastrointestinal hemorrhage. In 1008 patients, grade 2 or higher gastrointestinal hemorrhage occurred in 9.5% and 3.8% of bevacizumab (n = 503) and placebo (n = 505) treated patients, respectively. Bevacizumab (P < 0.001) and age (P = 0.002) were associated with gastrointestinal hemorrhage. In 616 genetically estimated Europeans (n = 314 bevacizumab and n = 302 placebo treated patients), grade 2 or higher gastrointestinal hemorrhage occurred in 9.6% and 2.0% of patients, respectively. One SNP (rs1478947; HR 6.26; 95% CI 3.19–12.28; P = 9.40 × 10−8) surpassed Bonferroni-corrected significance. Grade 2 or higher gastrointestinal hemorrhage rate was 33.3% and 6.2% in bevacizumab-treated patients with the AA/AG and GG genotypes, versus 2.9% and 1.9% in the placebo arm, respectively. Prospective validation of these findings and functional analyses are needed to better understand the genetic contribution to treatment-related gastrointestinal hemorrhage.
Hematopoietic cell transplantation and cellular therapies in Europe 2022. CAR-T activity continues to grow; transplant activity has slowed: a report from the EBMT
Authors: Passweg Jakob R. , Baldomero Helen , Ciceri Fabio , de la Cámara Rafael , Glass Bertram , Greco Raffaella , Hazenberg Mette D. , Kalwak Krzysztof , McLornan Donal P. , Neven Bénédicte , Perić Zinaida , Risitano Antonio M. , Ruggeri Annalisa , Snowden John A. , Sureda Anna
Published: March 2024

In 2022, 46,143 HCT (19,011 (41.2%) allogeneic and 27,132 (58.8%) autologous) in 41,854 patients were reported by 689 European centers. 4329 patients received advanced cellular therapies, 3205 of which were CAR-T. An additional 2854 patients received DLI. Changes compared to the previous year were an increase in CAR-T treatments (+27%) and decrease in allogeneic (−4.0%) and autologous HCT (−1.7%). Main indications for allogeneic HCT were myeloid malignancies (10,433; 58.4%), lymphoid malignancies (4,674; 26.2%) and non-malignant disorders (2572; 14.4%). Main indications for autologous HCT were lymphomas (7897; 32.9%), PCD (13,694; 57.1%) and solid tumors (1593; 6.6%). In allogeneic HCT, use of sibling donors decreased by −7.7%, haploidentical donors by −6.3% and unrelated donors by −0.9%. Overall cord blood HCT decreased by −16.0%. Use of allogeneic, and to a lesser degree autologous HCT, decreased for lymphoid malignancies likely reflecting availability of new treatment modalities, including small molecules, bispecific antibodies, and CAR-T cells. Pediatric HCT activity remains stable (+0.3%) with differences between allogeneic and autologous HCT. Use of CAR-T continues to increase and reached a cumulative total of 9039 patients treated with wide differences across European countries. After many years of continuous growth, increase in application of HCT seems to have slowed down.
Somatic CAG repeat instability in intermediate alleles of the HTT gene and its potential association with a clinical phenotype
Authors: Ruiz de Sabando Ainara , Ciosi Marc , Galbete Arkaitz , Cumming Sarah A. ,   Spanish HD Collaborative Group, Álvarez Victoria , Martinez-Descals Asunción , Mila Montserrat , Trujillo-Tiebas Maria José , López-Sendón Jose Luis , Fenollar-Cortés María , Legarda Inés , Bernal Noguera Sara , Millán Jose M. , Durán-Herrera Camen , Ruiz-Martínez Javier , Ruiz Onandi Rebeca , Monckton Darren G. , Ramos-Arroyo Maria A.
Published: March 2024

Huntington disease (HD) is a neurodegenerative disorder caused by ≥36 CAGs in the HTT gene. Intermediate alleles (IAs) (27–35 CAGs) are not considered HD-causing, but their potential association with neurocognitive symptoms remains controversial. As HTT somatic CAG expansion influences HD onset, we hypothesised that IAs are somatically unstable, and that somatic CAG expansion may drive phenotypic presentation in some IA carriers. We quantified HTT somatic CAG expansions by MiSeq sequencing in the blood DNA of 164 HD subjects and 191 IA (symptomatic and control) carriers, and in the brain DNA of a symptomatic 33 CAG carrier. We also performed genotype-phenotype analysis. The phenotype of symptomatic IA carriers was characterised by motor (85%), cognitive (27%) and/or behavioural (29%) signs, with a late (58.7 ± 18.6 years), but not CAG-dependent, age at onset. IAs displayed somatic expansion that were CAG and age-dependent in blood DNA, with 0.4% and 0.01% of DNA molecules expanding by CAG and year, respectively. Somatic expansions of +1 and +2 CAGs were detected in the brain of the individual with 33 CAGs, with the highest expansion frequency in the putamen (10.3%) and the lowest in the cerebellum (4.8%). Somatic expansion in blood DNA was not different in symptomatic vs. control IA carriers. In conclusion, we show that HTT IAs are somatically unstable, but we found no association with HD-like phenotypes. It is plausible, however, that some IAs, close to the HD pathological threshold and with a predisposing genetic background, could manifest with neurocognitive symptoms.
The inclusion of Amazon mangroves in Brazil’s REDD+ program
Authors: Bernardino Angelo F. , Mazzuco Ana Carolina A. , Costa Rodolfo F. , Souza Fernanda , Owuor Margaret A. , Nobrega Gabriel N. , Sanders Christian J. , Ferreira Tiago O. , Kauffman J. Boone
Published: March 2024

The Legal Amazon of Brazil holds vast mangrove forests, but a lack of awareness of their value has prevented their inclusion into results-based payments established by the United Nations Framework Convention on Climate Change. Based on an inventory from over 190 forest plots in Amazon mangroves, we estimate total ecosystem carbon stocks of 468 ± 67 Megagrams (Mg) ha−1; which are significantly higher than Brazilian upland biomes currently included into national carbon offset financing. Conversion of mangroves results in potential emissions of 1228 Mg CO2e ha−1, which are 3-fold higher than land use emissions from conversion of the Amazon rainforest. Our work provides the foundation for the inclusion of mangroves in Brazil’s intended Nationally Determined Contribution, and here we show that halting mangrove deforestation in the Legal Amazon would generate avoided emissions of 0.9 ± 0.3 Teragrams (Tg) CO2e yr−1; which is equivalent to the annual carbon accumulation in 82,400 ha of secondary forests.
Inactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity in mice
Authors: Soudais Claire , Schaus Romane , Bachelet Camille , Minet Norbert , Mouasni Sara , Garcin Cécile , Souza Caique Lopes , David Pierre , Cousu Clara , Asnagli Hélène , Parker Andrew , Palmquist-Gomes Paul , Sepulveda Fernando E. , Storck Sébastien , Meilhac Sigolène M. , Fischer Alain , Martin Emmanuel , Latour Sylvain
Published: March 2024

De novo synthesis of the pyrimidine, cytidine triphosphate (CTP), is crucial for DNA/RNA metabolism and depends on the CTP synthetases, CTPS1 and −2. Partial CTPS1 deficiency in humans has previously been shown to lead to immunodeficiency, with impaired expansion of T and B cells. Here, we examine the effects of conditional and inducible inactivation of Ctps1 and/or Ctps2 on mouse embryonic development and immunity. We report that deletion of Ctps1, but not Ctps2, is embryonic-lethal. Tissue and cells with high proliferation and renewal rates, such as intestinal epithelium, erythroid and thymic lineages, activated B and T lymphocytes, and memory T cells strongly rely on CTPS1 for their maintenance and growth. However, both CTPS1 and CTPS2 are required for T cell proliferation following TCR stimulation. Deletion of Ctps1 in T cells or treatment with a CTPS1 inhibitor rescued Foxp3-deficient mice from fatal systemic autoimmunity and reduced the severity of experimental autoimmune encephalomyelitis. These findings support that CTPS1 may represent a target for immune suppression.
A humanized mouse model for adeno-associated viral gene therapy
Authors: Barzi Mercedes , Chen Tong , Gonzalez Trevor J. , Pankowicz Francis P. , Oh Seh Hoon , Streff Helen L. , Rosales Alan , Ma Yunhan , Collias Sabrina , Woodfield Sarah E. , Diehl Anna Mae , Vasudevan Sanjeev A. , Galvan Thao N. , Goss John , Gersbach Charles A. , Bissig-Choisat Beatrice , Asokan Aravind , Bissig Karl-Dimiter
Published: March 2024

Clinical translation of AAV-mediated gene therapy requires preclinical development across different experimental models, often confounded by variable transduction efficiency. Here, we describe a human liver chimeric transgene-free Il2rg−/−/Rag2−/−/Fah−/−/Aavr−/− (TIRFA) mouse model overcoming this translational roadblock, by combining liver humanization with AAV receptor (AAVR) ablation, rendering murine cells impermissive to AAV transduction. Using human liver chimeric TIRFA mice, we demonstrate increased transduction of clinically used AAV serotypes in primary human hepatocytes compared to humanized mice with wild-type AAVR. Further, we demonstrate AAV transduction in human teratoma-derived primary cells and liver cancer tissue, displaying the versatility of the humanized TIRFA mouse. From a mechanistic perspective, our results support the notion that AAVR functions as both an entry receptor and an intracellular receptor essential for transduction. The TIRFA mouse should allow prediction of AAV gene transfer efficiency and the study of AAV vector biology in a preclinical human setting.
Prediction of highly stable 2D carbon allotropes based on azulenoid kekulene
Authors: Zhang Zhenzhe , Pham Hanh D. M. , Perepichka Dmytro F. , Khaliullin Rustam Z.
Published: March 2024

Despite enormous interest in two-dimensional (2D) carbon allotropes, discovering stable 2D carbon structures with practically useful electronic properties presents a significant challenge. Computational modeling in this work shows that fusing azulene-derived macrocycles – azulenoid kekulenes (AK) – into graphene leads to the most stable 2D carbon allotropes reported to date, excluding graphene. Density functional theory predicts that placing the AK units in appropriate relative positions in the graphene lattice opens the 0.54 eV electronic bandgap and leads to the appearance of the remarkable 0.80 eV secondary gap between conduction bands – a feature that is rare in 2D carbon allotropes but is known to enhance light absorption and emission in 3D semiconductors. Among porous AK structures, one material stands out as a stable narrow-multigap (0.36 and 0.56 eV) semiconductor with light charge carriers (me = 0.17 m0,  mh = 0.19 m0), whereas its boron nitride analog is a wide-multigap (1.51 and 0.82 eV) semiconductor with light carriers (me = 0.39 m0,  mh = 0.32 m0). The multigap engineering strategy proposed here can be applied to other carbon nanostructures creating novel 2D materials for electronic and optoelectronic applications.
PsAF5 functions as an essential adapter for PsPHB2-mediated mitophagy under ROS stress in Phytophthora sojae
Authors: Li Wenhao , Zhu Hongwei , Chen Jinzhu , Ru Binglu , Peng Qin , Miao Jianqiang , Liu Xili
Published: March 2024

Host-derived reactive oxygen species (ROS) are an important defense means to protect against pathogens. Although mitochondria are the main intracellular targets of ROS, how pathogens regulate mitochondrial physiology in response to oxidative stress remains elusive. Prohibitin 2 (PHB2) is an inner mitochondrial membrane (IMM) protein, recognized as a mitophagy receptor in animals and fungi. Here, we find that an ANK and FYVE domain-containing protein PsAF5, is an adapter of PsPHB2, interacting with PsATG8 under ROS stress. Unlike animal PHB2 that can recruit ATG8 directly to mitochondria, PsPHB2 inPhytophthora sojaecannot recruit PsATG8 to stressed mitochondria without PsAF5.PsAF5deletion impairs mitophagy under ROS stress and increases the pathogen’s sensitivity to H2O2, resulting in the attenuation ofP. sojaevirulence. This discovery of a PsPHB2-PsATG8 adapter (PsAF5) in plant-pathogenic oomycetes reveals that mitophagy induction by IMM proteins is conserved in eukaryotes, but with differences in the details of ATG8 recruitment.
A coarse-grained bacterial cell model for resource-aware analysis and design of synthetic gene circuits
Authors: Sechkar Kirill , Steel Harrison , Perrino Giansimone , Stan Guy-Bart
Published: March 2024

Within a cell, synthetic and native genes compete for expression machinery, influencing cellular process dynamics through resource couplings. Models that simplify competitive resource binding kinetics can guide the design of strategies for countering these couplings. However, in bacteria resource availability and cell growth rate are interlinked, which complicates resource-aware biocircuit design. Capturing this interdependence requires coarse-grained bacterial cell models that balance accurate representation of metabolic regulation against simplicity and interpretability. We propose a coarse-grained E. coli cell model that combines the ease of simplified resource coupling analysis with appreciation of bacterial growth regulation mechanisms and the processes relevant for biocircuit design. Reliably capturing known growth phenomena, it provides a unifying explanation to disparate empirical relations between growth and synthetic gene expression. Considering a biomolecular controller that makes cell-wide ribosome availability robust to perturbations, we showcase our model’s usefulness in numerically prototyping biocircuits and deriving analytical relations for design guidance.
The search for CDK4/6 inhibitor biomarkers has been hampered by inappropriate proliferation assays
Authors: Foy Reece , Lew Kah Xin , Saurin Adrian T.
Published: March 2024

CDK4/6 inhibitors are effective at treating advanced HR+ /HER2- breast cancer, however biomarkers that can predict response are urgently needed. We demonstrate here that previous large-scale screens designed to identify which tumour types or genotypes are most sensitive to CDK4/6 inhibitors have misrepresented the responsive cell lines because of a reliance on metabolic proliferation assays. CDK4/6-inhibited cells arrest in G1 but continue to grow in size, thereby producing more mitochondria. We show that this growth obscures the arrest using ATP-based proliferation assays but not if DNA-based assays are used instead. Furthermore, lymphoma lines, previously identified as the most sensitive, simply appear to respond the best using ATP-based assays because they fail to overgrow during the G1 arrest. Similarly, the CDK4/6 inhibitor abemaciclib appears to inhibit proliferation better than palbociclib because it also restricts cellular overgrowth through off-target effects. DepMap analysis of screening data using reliable assay types, demonstrates that palbociclib-sensitive cell types are also sensitive to Cyclin D1, CDK4 and CDK6 knockout/knockdown, whereas the palbociclib-resistant lines are sensitive to Cyclin E1, CDK2 and SKP2 knockout/knockdown. Potential biomarkers of palbociclib-sensitive cells are increased expression of CCND1 and RB1, and reduced expression of CCNE1 and CDKN2A. Probing DepMap with similar data from metabolic assays fails to reveal these associations. Together, this demonstrates why CDK4/6 inhibitors, and any other anti-cancer drugs that arrest the cell cycle but permit continued cell growth, must now be re-screened against a wide-range of cell types using an appropriate proliferation assay. This would help to better inform clinical trials and to identify much needed biomarkers of response.
Acute and short-term fluctuations in gravity are associated with changes in circulatory plasma protein levels
Authors: Lang Alexander , Binneboessel Stephan , Nienhaus Fabian , Bruno Raphael Romano , Wolff Georg , Piayda Kerstin , Pfeiler Susanne , Ezzahoini Hakima , Oehler Daniel , Kelm Malte , Winkels Holger , Gerdes Norbert , Jung Christian
Published: March 2024

Gravitational changes between micro- and hypergravity cause several adaptations and alterations in the human body. Besides muscular atrophy and immune system impairment, effects on the circulatory system have been described, which can be associated with a wide range of blood biomarker changes. This study examined nine individuals (seven males, two females) during a parabolic flight campaign (PFC). Thirty-one parabolas were performed in one flight day, resulting in ~22 s of microgravity during each parabola. Each participant was subjected to a single flight day with a total of 31 parabolas, totaling 11 min of microgravity during one parabolic flight. Before and after (1 hour (h) and 24 h), the flights blood was sampled to examine potential gravity-induced changes of circulating plasma proteins. Proximity Extension Assay (PEA) offers a proteomic solution, enabling the simultaneous analysis of a wide variety of plasma proteins. From 2925 unique proteins analyzed, 251 (8.58%) proteins demonstrated a differential regulation between baseline, 1 h and 24 h post flight. Pathway analysis indicated that parabolic flights led to altered levels of proteins associated with vesicle organization and apoptosis up to 24 h post microgravity exposure. Varying gravity conditions are associated with poorly understood physiological changes, including stress responses and fluid shifts. We provide a publicly available library of gravity-modulated circulating protein levels illustrating numerous changes in cellular pathways relevant for inter-organ function and communication.
A register and questionnaire study of long-term general health symptoms following SARS-CoV-2 vaccination in Denmark
Authors: O’Regan Elisabeth , Svalgaard Ingrid Bech , Sørensen Anna Irene Vedel , Spiliopoulos Lampros , Bager Peter , Nielsen Nete Munk , Hansen Jørgen Vinsløv , Koch Anders , Meder Inger Kristine , Videbech Poul , Ethelberg Steen , Hviid Anders
Published: March 2024

Many individuals who refuse COVID-19 vaccination have concerns about long-term side effects. Here, we report findings on self-reported symptoms from a Danish survey- and register study. The study included 34,868 vaccinated primary course recipients, 95.8% of whom received mRNA vaccines, and 1,568 unvaccinated individuals. Participants had no known history of SARS-CoV-2 infection. Using g-computation on logistic regression, risk differences (RDs) for symptoms between vaccinated and unvaccinated persons were estimated with adjustments for possible confounders. Within six weeks after vaccination, higher risks were observed for physical exhaustion (RD 4.9%, 95% CI 1.1% to 8.4%), fever or chills (RD 4.4%, 95% CI 2.1% to 6.7%), and muscle/joint pain (RD 7.0%, 95% CI 3.1% to 10.7%), compared to unvaccinated individuals. Beyond twenty-six weeks, risks were higher among the vaccinated for sleeping problems (RD 3.0, 95% 0.2 to 5.8), fever or chills (RD 2.0, 95% CI 0.4 to 3.6), reduced/altered taste (RD 1.2, 95% CI 0.2 to 2.3) and shortness of breath (RD 2.6, 95% CI 0.9 to 4.0). However, when examining pre-omicron responses only, the difference for reduced/altered taste was significant. As expected, the risk of experiencing physical exhaustion, fever or chills, and muscle/joint pain was higher among persons who responded within six weeks of completing the primary course. No significant differences were observed for the 7-25-week period after vaccination. Associations for the period beyond 26 weeks must be interpreted with caution and in the context of undetected SARS-CoV-2 infection, wide confidence intervals, and multiple testing. Overall, we observe no concerning signs of long-term self-reported physical, cognitive, or fatigue symptoms after vaccination.
Phage proteins target and co-opt host ribosomes immediately upon infection
Authors: Gerovac Milan , Chihara Kotaro , Wicke Laura , Böttcher Bettina , Lavigne Rob , Vogel Jörg
Published: March 2024

Bacteriophages must seize control of the host gene expression machinery to replicate. To bypass bacterial anti-phage defence systems, this host takeover occurs immediately upon infection. A general understanding of phage mechanisms for immediate targeting of host transcription and translation processes is lacking. Here we introduce an integrative high-throughput approach to uncover phage-encoded proteins that target the gene expression machinery of Pseudomonas aeruginosa immediately upon infection with the jumbo phage ΦKZ. By integrating biochemical, genetic and structural analyses, we identify an abundant and conserved phage factor ΦKZ014 that targets the large ribosomal subunit by binding the 5S ribosomal RNA, and rapidly promotes replication in several clinical isolates. ΦKZ014 is among the earliest ΦKZ proteins expressed after infection and remains bound to ribosomes during the entire translation cycle. Our study provides a strategy to decipher molecular components of phage-mediated host takeover and argues that phage genomes represent an untapped discovery space for proteins that modulate the host gene expression machinery.