bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unravelling Plankton Adaptation in Global Oceans through the Analysis of Lipidomes
Authors: Liu Weimin , Holm Henry C. , Lipp Julius S. , Fredricks Helen F. , Van Mooy Benjamin A. S. , Hinrichs Kai-Uwe 
Published: July 2024

AbstractA recent global survey of planktonic lipids showed a fundamental temperature-mediated regulation of lipid unsaturation in the global oceans [Holm H, et al. (2022) Science 376:1487–1491]. We expand the analysis of this dataset, both spatially and methodologically, to examine diverse environmental stressors across the ocean. Utilizing weighted correlation network analysis, we analyzed 3,164 lipid features in the dataset comprising 930 samples of suspended particulate matter, taken across a broad range of oceanographic conditions and water depths up to 600 meters. A total of 16 lipid clusters being co-expressed across diverse environments were identified. This analysis reveals universal relationships between environmental factors and the lipidome of the planktonic community. The largest lipid cluster, comprising 481 lipid features, including glycerolipids with polyunsaturated fatty acids, exhibited a significant enrichment in polar oceans, suggesting the highest lipid diversity in these ocean regions. Remarkably, marine plankton in these regions employ both desaturation and chain shortening for cold acclimation. Additionally, one lipid cluster strongly linked to the plankton residing in the surface of tropical and subtropical oceans was enriched with non-phosphorus lipids. We suggest this adaptive response enables the plankton to cope with phosphorous scarcity and heat stress. Notably, in the subsurface of these regions, a co-expressed cluster of highly unsaturated lipids is consistent with an enhanced production of polyunsaturated fatty acids by phytoplankton, possibly for low light adaptation. This adaptation is important as it may represent a source of essential fatty acids below the warm sea surface where such vital compounds may be diminished in the warmer future.SignificanceMarine plankton is vital for marine ecosystems and climate regulation. We analyzed a large lipidomics dataset of 930 samples collected from global oceans. This allowed us to explore how plankton adapt their lipidomes across different environments. Our findings show distinct lipid clusters correlating with specific environmental conditions, revealing mechanisms like chain shortening to cope with cold stress, enrichment of non-phosphorus lipids in tropical surface waters, and increased polyunsaturated fatty acids in low-light tropical subsurface areas. These adaptations are crucial for understanding how climate change will impact marine ecosystems.
ERβ mediates sex-specific protection in theApp-NL-G-Fmouse model of Alzheimer’s disease
Authors: Demetriou Aphrodite , Lindqvist Birgitta , Ali Heba G. , Shamekh Mohamed M. , Maioli Silvia , Inzunza Jose , Varshney Mukesh , Nilsson Per , Nalvarte Ivan 
Published: July 2024

ABSTRACTMenopausal loss of neuroprotective estrogen is thought to contribute to the sex differences in Alzheimer’s disease (AD). Activation of estrogen receptor beta (ERβ) can be clinically relevant since it avoids the negative systemic effects of ERα activation. However, very few studies have explored ERβ-mediated neuroprotection in AD, and no information on its contribution to the sex differences in AD exists. In the present study we specifically explored the role of ERβ in mediating sex-specific protection against AD pathology in the clinically relevantAppNL-G-Fknock-in mouse model of amyloidosis, and if surgical menopause (ovariectomy) modulates pathology in this model. We treated male and femaleAppNL-G-Fmice with the selective ERβ agonist LY500307 and subset of the females was ovariectomized prior to treatment. Memory performance was assessed and a battery of biochemical assays were used to evaluate amyloid pathology and neuroinflammation. Primary microglial cultures from male and female wild-type and ERβ-knockout mice were used to assess ERβ’s effect on microglial activation and phagocytosis. We find that ERβ activation protects against amyloid pathology and cognitive decline in male and femaleAppNL-G-Fmice. Ovariectomy increased soluble amyloid beta (Aβ) in cortex and insoluble Aβ in hippocampus, but had otherwise limited effects on pathology. We further identify that ERβ does not alter APP processing, but rather exerts its protection through amyloid scavenging that at least in part is mediated via microglia in a sex-specific manner. Combined, we provide new understanding to the sex differences in AD by demonstrating that ERβ protects against AD pathology differently in males and females, warranting reassessment of ERβ in combating AD.
Range geographies, not functional traits, explain convergent range and phenology shifts under climate change
Authors: Sirois-Delisle Catherine , Gordon Susan C.C. , Kerr Jeremy T. 
Published: July 2024

AbstractClimate change may introduce conditions beyond species’ tolerances; to survive, species must avoid these extremes. Phenological shifts are one strategy, as species move their activity or life history events in time to avoid extreme conditions. Species may also shift in space, moving their ranges poleward to escape extremes. However, whether species are more likely to exhibit one or both strategies, and whether this can be predicted based on a species’ functional traits, is unknown. Using a powerful macroecological dataset of European and North American odonate observations, we assessed range and phenology shifts between two time periods (1980-2002 and 2008-2018) to measure the strength and direction of the association between responses. Species with the greatest poleward range shifts also showed the largest phenological shifts toward earlier annual activity periods, with half of all species shifting in both space and time. This response was consistent across continents, despite highly divergent land use and biogeographical histories in these regions. Surprisingly, species’ range and phenology shifts were not related to functional traits; rather, southern species shifted their range limits more strongly, while increasing temperature variability hindered range shifts. By reducing risk through phenological shifts, the resulting larger populations may be more likely to disperse and expand species’ ranges. While species shifting in both space and time may be more resilient to extreme conditions, we identified a small number of species (approximately 10%) that failed to shift at all; these species are likely to be particularly vulnerable to climate change, and should be prioritized for conservation intervention.
ASO-enhancement ofTARDBPexitron splicing mitigates TDP-43 proteinopathies
Authors: Yamagishi Takuma , Koide Shingo , Toyama Genri , Washida Aya , Yamada Yumi , Hanyu Ryutaro , Nadbitova Ekaterina , Koike Yuka Mitsuhashi , Konno Takuya , Ishihara Tomohiko , Kato Taisuke , Onodera Osamu , Sugai Akihiro 
Published: July 2024

AbstractAmyotrophic lateral sclerosis and frontotemporal lobar degeneration are fatal neurodegenerative diseases characterized by pathological aggregation and nuclear functional loss of TDP-431,2. Current therapies inadequately address this core pathology3,4, necessitating innovative approaches that target aggregation while preserving TDP-43’s essential functions. Here we demonstrate that enhancing the splicing of theTARDBPexitron—a cryptic intron encoding the aggregation-prone intrinsically disordered region (IDR) of TDP-435,6— effectively mitigates TDP-43 pathology. This exitron splicing event, directly regulated by nuclear TDP-437–9, suppresses the expression of IDR-containing TDP-43 isoforms and generates IDR-spliced-out TDP-43 isoforms7,9,10(which we term “IDRsTDP”). Our findings reveal that IDRsTDP, known to heterodimerize with full-length TDP-4310, inhibits TDP-43 aggregation by suppressing IDR-mediated clustering and enhances TDP-43 clearance via chaperone-mediated autophagy. In disease states, however, impaired nuclear TDP-43 function disrupts exitron splicing, leading to increased levels of IDR-containing TDP-439,11and reduced levels of IDRsTDP, exacerbating aggregation and nuclear dysfunction6,12–17. By identifying HNRNPA1 and HNRNPC as key repressors ofTARDBPexitron splicing, we designed antisense oligonucleotides (ASOs) to block their binding and restore splicing. These ASOs suppressed TDP-43 pathology and neurodegeneration in both neuronal cell models with impaired nuclear transport and a mouse model of proteasome dysfunction-induced TDP-43 proteinopathy. Our strategy, by rescuing the impaired autoregulatory pathway, inhibits the pathological cycle of TDP-43 aggregation and nuclear dysfunction, offering a promising avenue for treating these currently intractable neurodegenerative diseases.
The Physical Basis of Osmosis in a Donnan Ionic System
Authors: Manning Gerald S. 
Published: July 2024

1AbstractThe osmotic flow of water is driven by the repulsive force between semipermeable membrane and impermeable solute that creates a pressure drop at the interface between membrane and aqueous solution. An analysis of the physical principles involved is relatively simple for a neutral solute that is absolutely impermeable. Extension to partially permeable neutral solutes is more complicated but has been accomplished. In this paper the analysis is further extended to include Donnan ionic systems. The electric forces due to the charges on the ions give rise to non-uniform ionic concentrations and trans-membrane electric voltages as well as pressure gradients, and the relationships among all of these Donnan effects have an impact on osmosis. The supplementary effect of an ion pump, acting to prevent the osmotic danger of cell swelling and rupture, is explored.
mRNA stability fine tunes gene expression in the developing cortex to control neurogenesis
Authors: Serdar Lucas D. , Egol Jacob R. , Lackford Brad , Bennett Brian D. , Hu Guang , Silver Debra L. 
Published: July 2024

AbstractRNA expression levels are controlled by the complementary processes of synthesis and degradation. Although mis-regulation of RNA turnover is linked to neurodevelopmental disorders, how it contributes to cortical development is largely unknown. Here, we profile the RNA stability landscape of the cortex across development and demonstrate that control of stability by the CCR4-NOT complex is essential for corticogenesisin vivo. First, we use SLAM-seq to measure RNA half-lives transcriptome-wide across multiple stages of cortical development. We characterizecis-acting features associated with RNA stability and find that RNAs that are upregulated across development tend to be more stable, while downregulated RNAs are less stable. To probe how disruption of RNA turnover impacts cortical development, we assess developmental requirements of CNOT3, a core component of the CCR4-NOT deadenylase complex. Mutations inCNOT3are associated with human neurodevelopmental disorders, however its role in cortical development is unknown. Conditional knockout ofCnot3in neural progenitors and their progeny in the developing mouse cortex leads to severe microcephaly due to reduced neuron production and p53-dependent apoptosis. Collectively, our findings demonstrate that fine-tuned control of RNA turnover is crucial for brain development.
An arylsulphonamide that targets cell wall biosynthesis inMycobacterium tuberculosis
Authors: Allen Renee , Ames Lauren , Baldin Vanessa Pietrowski , Butts Arielle , Henry Kenneth J. , Quach Diana , Sugie Joseph , Pogliano Joe , Parish Tanya 
Published: July 2024

AbstractWe investigated the mechanism of action of an arylsulphonamide with whole cell activity againstMycobacterium tuberculosis. We newly synthesized the molecule and confirmed it had activity against both extracellular and intracellular bacilli. The molecule had some activity against HepG2 cells but maintained some selectivity. Bacterial cytological profiling suggested that mechanism of action was via disruption of cell wall synthesis, with similarities to an inhibitor of the mycolic acid exporter MmpL3. The compound induced expression from the IniB promoter and caused a boost in ATP production but did not induce reactive oxygen species. A mutation in MmpL3 (S591I) led to low-level resistance. Taken together these data confirm the molecule targets cell wall biosynthesis with MmpL3 as the most probable target.
Synapse protein signatures in cerebrospinal fluid and plasma predict cognitive maintenance versus decline in Alzheimer’s disease
Authors: Oh Hamilton Se-Hwee , Urey Deniz Yagmur , Karlsson Linda , Zhu Zeyu , Shen Yuanyuan , Farinas Amelia , Timsina Jigyasha , Guldner Ian H. , Morshed Nader , Yang Chengran , Western Daniel , Ali Muhammad , Le Guen Yann , Trelle Alexandra , Herukka Sanna-Kaisa , Rauamaa Tuomas , Hiltunen Mikko , Lipponen Anssi , Luikku Antti J. , Poston Kathleen L. , Mormino Elizabeth , Wagner Anthony D. , Wilson Edward N. , Channappa Divya , Leinonen Ville , Stevens Beth , Ehrenberg Alexander J. , Zetterberg Henrik , Bennett David A. , Franzmeier Nico , Hansson Oskar , Cruchaga Carlos , Wyss-Coray Tony 
Published: July 2024

ABSTRACTRates of cognitive decline in Alzheimer’s disease (AD) are extremely heterogeneous, with ages of symptom onset ranging from age 40-100 years and conversion from mild cognitive impairment to AD dementia taking 2-20 years. Development of biomarkers for amyloid-beta (Aβ) and tau protein aggregates, the hallmark pathologies of AD, have improved patient monitoring/stratification and drug development, but they still only explain 20-40% of the variance in cognitive impairment (CI) in AD. To discover additional molecular drivers and biomarkers of AD dementia, we perform cerebrospinal fluid (CSF) proteomics on 3,416 individuals from six deeply phenotyped prospective AD case-control cohorts. We identify synapse proteins as the strongest correlates of CI, independent of Aβ and tau. Using machine learning we derive the CSF YWHAG:NPTX2 synapse protein ratio, a robust correlate of CI, which explains 27% of the variance in CI beyond CSF PTau181:Aβ42, 10% beyond tau PET, and 50% beyond CSF NfL in Aβ positive individuals. We find YWHAG:NPTX2 also increases with normal aging as early as age 20 and increases at a faster rate inAPOE4carriers and autosomal dominant-AD mutation carriers. Most notably, YWHAG:NPTX2+ individuals (top 25thpercentile) are 15-times (HR=15.4 [10.6-22.2]) more likely to experience cognitive decline over 15 years compared to YWHAG:NPTX2– individuals (bottom 25thpercentile), and this rises to 19-times (HR=18.9 [10.83-32.9]) with additional stratification by Aβ and phosphorylated tau status. Lastly, we perform plasma proteomics on 4,245 individuals to develop a plasma-based signature of CI which partly recapitulates CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 and the corresponding plasma signature as robust prognostic biomarkers for AD onset and progression beyond gold-standard biomarkers of Aβ, tau, and neurodegeneration and implicate synapse dysfunction as a core driver of AD dementia.
Rapid review of Allied Health Professionals working in neonatal services
Authors: Bromham Nathan , Batten Leona , Jarrom David , Gillen Elizabeth , Hounsome Juliet , Davies Jacob , Tudor Edwards Rhiannon , Manton Margaret , Cooper Alison , Edwards Adrian , Lewis Ruth 
Published: July 2024

AbstractBackgroundThis review aimed to quantify the impact of allied health professionals (AHPs) embedded in neonatal services on outcomes by asking the following review questions:Q1. What is the effectiveness of neonatal services with embedded allied health professionals compared to neonatal services without embedded allied health professionals?Q2. What is the effectiveness of early interventions provided by allied health professionals in neonatal units?Research Implications and Evidence GapsThere was very little directly relevant evidence on AHPs embedded in neonatal services. Most of the evidence related to multidisciplinary team working or early interventions provided by AHPs. Few early intervention trials were from the UK, leading to uncertainty about the availability and applicability of interventions in the UK setting. Further UK-based research is needed to better understand the best way to integrate allied health professionals in neonatal services.Economic considerationsThere is no published evidence on the cost of AHPs working within neonatal units. There is marked variability in the reporting of cost estimates for neonatal care units in the UK, making the evaluation of cost implications of adopting AHP recommendations difficult. Subsequent economic evaluations could explore the Budget Impact to the NHS of increasing AHP presence in neonatal units to align with recommendations from AHP professional bodies and Royal Colleges.Funding statementHealth Technology Wales were funded for this work by the Health and Care Research Wales Evidence Centre, itself funded by Health and Care Research Wales on behalf of Welsh Government.
HIBRID: Histology and ct-DNA based Risk-stratification with Deep Learning
Authors: Loeffler Chiara M.L. , Bando Hideaki , Sainath Srividhya , Muti Hannah Sophie , Jiang Xiaofeng , van Treeck Marko , Reitsam Nic Gabriel , Carrero Zunamys I. , Nishikawa Tomomi , Misumi Toshihiro , Mishima Saori , Kotani Daisuke , Taniguchi Hiroya , Takemasa Ichiro , Kato Takeshi , Oki Eiji , Yuan Tanwei , Wankhede Durgesh , Foersch Sebastian , Brenner Hermann , Hoffmeister Michael , Nakamura Yoshiaki , Yoshino Takayuki , Kather Jakob Nikolas 
Published: July 2024

AbstractBackgroundAlthough surgical resection is the standard therapy for stage II/III colorectal cancer (CRC), recurrence rates exceed 30%. Circulating tumor DNA (ctDNA) emerged as a promising recurrence predictor, detecting molecular residual disease (MRD). However, spatial information about the tumor and its microenvironment is not directly measured by ctDNA. Deep Learning (DL) can predict prognosis directly from routine histopathology slides.MethodsWe developed a DL pipeline utilizing vision transformers to predict disease-free survival (DFS) based on histological hematoxylin & eosin (H&E) stained whole slide images (WSIs) from patients with resectable stage II-IV CRC. This model was trained on the DACHS cohort (n=1766) and independently validated on the GALAXY cohort (n=1555). Patients were categorized into high- or low-risk groups based on the DL-prediction scores. In the GALAXY cohort, the DL-scores were combined with the four-weeks post-surgery MRD status measured by ctDNA for prognostic stratification.ResultsIn GALAXY, the DL-model categorized 307 patients as DL high-risk and 1248 patients as DL low-risk (p<0.001; HR 2.60, CI 95% 2.11-3.21). Combining the DL scores with the MRD status significantly stratified both the MRD-positive group into DL high-risk (n=81) and DL low-risk (n=160) (HR 1.58 (CI 95% 1.17-2.11; p=0.002) and the MRD-negative group into DL high-risk (n=226) and DL low-risk (n=1088) (HR 2.37 CI 95% 1.73-3.23; p<0.001). Moreover, MRD-negative patients had significantly longer DFS when predicted as DL high-risk and treated with ACT (HR 0.48, CI 95% 0.27-0.86; p= 0.01), compared to the MRD-negative patients predicted as DL low-risk (HR=1.14, CI 95% 0.8-1.63; p=0.48).ConclusionDL-based spatial assessment of tumor histopathology slides significantly improves the risk stratification provided by MRD alone. Combining histologic information with ctDNA yields the most powerful predictor for disease recurrence to date, with the potential to improve follow-up, withhold adjuvant chemotherapy in low-risk patients and escalate adjuvant chemotherapy in high-risk patients.Highlights-This study combines MRD status measured by ctDNA with a DL-based risk assessment trained on histological image data to enhance recurrence prediction.-DL-based spatial assessment of tumor histopathology slides significantly improves the risk stratification provided by MRD alone.-MRD-negative patients with high DL-based risk had a significantly longer DFS if treated with ACT, compared to MRD-negative and DL low risk patients-The DL model is fully open-source and publicly available.
Sputum Proteomics reveals unique signatures linked to key outcomes in cystic fibrosis trials
Authors: Pottenger Sian , Nazareth Dilip , Wat Dennis , Bellina Bruno , Langini Maike , Walshaw Martin , Neill Daniel R. , Schwarz Carsten , Frost Freddy , Fothergill Joanne L. 
Published: July 2024

AbstractRationaleLung function (FEV1) and quality of life (QoL) are key outcomes in most interventional clinical trials conducted in people living with cystic fibrosis. However, no robust pre-clinical surrogates for FEV1 and QoL exist. The precise physiological mechanisms leading to treatment-related improvements in these outcomes are incompletely understood. In this post-hoc analysis we explored the relationship between changes in the sputum proteome and these outcomes with the aim of identifying translational biomarkers.MethodsPaired sputum samples collected during the AZTEC-CF study (NCT02894684) pre and post 14 days of antibiotic treatment for an acute pulmonary exacerbation were included. Samples were analysed usingin vitroMesoscale Discovery (MSD) assays and by nano LC-MS/MS. Peptide identification and quantification was performed and the log-fold change for individual proteins and relationships between protein change and changes in FEV1 and QoL were evaluated.ResultsDistinct patterns were found between proteins that correlated with FEV1 and those that correlated with QoL improvements. FEV1 improvement was characterised by increases in bacterially-derived proteins accompanied by decreases in proteins relating to neutrophil degranulation. Conversely, changes in QoL were associated with increases in antiprotease and antioxidant proteins. MSD analysis revealed changes in some neutrophil-associated markers significantly correlated with FEV1 improvements, but no markers significantly correlated with QoL improvements.ConclusionsThese results suggest changes in two key CF clinical trial outcomes (FEV1 and QoL) may be underpinned by different physiological mechanisms. Understanding these divergent mechanisms is vital to fortify optimal clinical trial design in CF and panels of biomarkers may be needed to improve translational confidence.
Possible Wigner states in
CrI3
heterostructures with graphene: A tight-binding model perspective
Authors: Rozhansky Igor , Fal'ko Vladimir 
Published: July 2024

In this study, we present an effective tight-binding model for an accurate description of the lowest energy quadruplet of a conduction band in a ferromagnetic CrX3 monolayer, tuned to the complementary density functional theory simulations. This model, based on a minimum number of chromium orbitals, captures a distinctively flat dispersion in those bands but requires taking into account hoppings beyond nearest neighbors, revealing ligand-mediated electron pathways connecting remote chromium sites. Doping of states in the lowest conduction band of CrX3 requires charge transfer, which, according to recent studies [Tenasini , ; Tseng , ; Cardoso , , can occur in graphene(G)/CrX3 heterostructures. Here, we use the detailed description of the lowest conduction band in CrI3 to show that G/CrI3/G and G/CrI3 are type-II heterostructures where light holes in graphene would coexist with heavy electrons in the magnetic layer, where the latter can be characterized by Wigner-Seitz radius rs∼25−35 (as estimated for hBN-encapsulated structures).

Published by the American Physical Society
2024