bluuebunny/crossref_metadata_2025 huggingface dataset:
ERISA Principles
Authors: Wiedenbeck Peter J. , Maher Brendan S.
Published: February 2024

ERISA, the detailed and technical amalgam of labor law, trust law, and tax law, directly governs trillions of dollars spent on retirement savings, health care, and other important benefits for more than 100 million Americans. Despite playing this central role in the US economy and social insurance systems, the complexities of ERISA are often understood by only a few specialists. ERISA Principles elucidates employee benefit law from a policy perspective, concisely explaining how common themes apply across a wide range of benefit plans and factual contexts. The book's non-technical language and cross-cutting conceptual organization reveal latent similarities and rationalize differences between the regulatory treatment of apparently disparate programs, including traditional pensions, 401(k), and health care plans. Important legal developments - whether statutory, judicial, or administrative - are framed and analyzed in an accessible, principles-centric manner, explaining how ERISA functions as a coherent whole.
María de Zayas and her Tales of Desire, Death and Disillusion
Authors: Greer Margaret R.
Published: February 2024

A pioneer of early modern feminism, María de Zayas y Sotomayor wrote poetry, drama and prose but is best known for two page-turning collections of short stories: Exemplary Tales of Love (1637) and Tales of Disillusion (1647). This book provides an engaging introduction to Zayas and her work. It begins by relating what we know of her life, placing her in her socio-political and economic context and addressing the issue of women's literacy. Following chapters examine her use of sexual desire, violence and humour in her tales; her narrative structures; and her oral style. The book then turns to identity construction in her tales and in society, analysing questions of gender, class, family and 'race', and to her treatment of religion, magic and the supernatural. The final chapters explore Zayas's status as a proto-feminist; her early modern reception in Spain and elsewhere; and various critical readings of her work.
Mahler's Nietzsche
Authors: Batstone Leah
Published: February 2024

Examines how Nietzschean ideas influenced the composition of Mahler's first four, so-called Wunderhorn, symphonies.
Shakespeare and Machiavelli
Authors: Roe John
Published: February 2024

A detailed comparison of Machiavelli with Shakespeare, grounded in their common use of rhetoric.
Expressive mortality models through Gaussian process kernels
Authors: Risk Jimmy , Ludkovski Mike
Published: February 2024

We develop a flexible Gaussian process (GP) framework for learning the covariance structure of Age- and Year-specific mortality surfaces. Utilizing the additive and multiplicative structure of GP kernels, we design a genetic programming algorithm to search for the most expressive kernel for a given population. Our compositional search builds off the Age–Period–Cohort (APC) paradigm to construct a covariance prior best matching the spatio-temporal dynamics of a mortality dataset. We apply the resulting genetic algorithm (GA) on synthetic case studies to validate the ability of the GA to recover APC structure and on real-life national-level datasets from the Human Mortality Database. Our machine learning-based analysis provides novel insight into the presence/absence of Cohort effects in different populations and into the relative smoothness of mortality surfaces along the Age and Year dimensions. Our modeling work is done with the PyTorch libraries in Python and provides an in-depth investigation of employing GA to aid in compositional kernel search for GP surrogates.
Development of a mentor training curriculum to support LGBTQIA+ health professionals
Authors: Charlton Brittany M. , Potter Jennifer , Keuroghlian Alex S. , Dalrymple John L. , Katz-Wise Sabra L. , Guss Carly E. , Phillips William R. , Jarvie Emeline , Maingi Shail , Streed Carl , Anglemyer Ethan , Hoatson Tabor , Birren Bruce
Published: February 2024

While mentors can learn general strategies for effective mentoring, existing mentorship curricula do not comprehensively address how to support marginalized mentees, including LGBTQIA+ mentees. After identifying best mentoring practices and existing evidence-based curricula, we adapted these to create the Harvard Sexual and Gender Minority Health Mentoring Program. The primary goal was to address the needs of underrepresented health professionals in two overlapping groups: (1) LGBTQIA+ mentees and (2) any mentees focused on LGBTQIA+ health. An inaugural cohort (N = 12) of early-, mid-, and late-career faculty piloted this curriculum in spring 2022 during six 90-minute sessions. We evaluated the program using confidential surveys after each session and at the program’s conclusion as well as with focus groups. Faculty were highly satisfied with the program and reported skill gains and behavioral changes. Our findings suggest this novel curriculum can effectively prepare mentors to support mentees with identities different from their own; the whole curriculum, or parts, could be integrated into other trainings to enhance inclusive mentoring. Our adaptations are also a model for how mentorship curricula can be tailored to a particular focus (i.e., LGBTQIA+ health). Ideally, such mentor trainings can help create more inclusive environments throughout academic medicine.
Who, Why, When, and Where From? The Peopling of the Canary Islands and the Challenges of Archaeometry
Authors: Cuello del Pozo Paloma
Published: February 2024

Archaeologists in the Canary Islands have gathered substantial quantitative data from radiocarbon measurements and aDNA analyses. While undeniably helpful and necessary for apprehending past human activity, their interpretation, based on theories underpinning models developed for island chains, has lagged, leaving a gap in our understanding of processes of occupation and social network systems. The decontextualized nature of the archaeological landscape of the Canaries and a lack of consensus about proper radiocarbon methodologies are some of the factors contributing to heated scholarly debate. Here, for the Canary Islands, the author reviews the current literature on aDNA and discusses settlement theories, the chronological evidence used for occupation models, and how such perspectives align with current thinking on island colonization.
Non-linear relationship between the body roundness index and metabolic syndrome: data from National Health and Nutrition Examination Survey (NHANES) 1999–2018
Authors: Li Zhenhan , Fan Chunhua , Huang Jun , Chen Zhongpei , Yu Xiaoxia , Qian Jun
Published: February 2024

Obesity is an important characteristic manifestation of metabolic syndrome (MetS), and body roundness index (BRI) is one of the anthropometric indicators associated with obesity. However, studies on the relationship between BRI and MetS risk are limited. We aimed to explore the relationship between baseline BRI and MetS in the USA population. Our study used data from the National Health and Nutrition Examination Survey from 1999 to 2018, ultimately enrolling and analysing 47 303 participants. Data-driven tertiles were used to categorise BRI levels, and multivariate logistic regression models were fitted to investigate the association of BRI with MetS in adults. In addition, receiver operating characteristic curve analysis was used to assess the ability of BRI to predict MetS. The distribution of BRI was different across ethnic groups with a gradual decrease in the proportion of non-Hispanic Whites and other races. In addition, BRI was significantly associated with traditional cardiovascular risk factors. Univariate regression analysis indicated BRI to be a moderate risk factor for MetS, and multivariate logistic regression analysis found that BRI remained an independent risk factor for MetS. After adjusting for confounding variables, a non-linear relationship was found between BRI levels and the prevalence of MetS. More importantly, BRI predicted MetS with the largest AUC among anthropometric measures. In summary, elevated baseline BRI levels are independently associated with the development of MetS, and baseline BRI may assist in identifying patients at risk for MetS, leading to early and optimal treatment to improve their outcomes.
Mutual Funds’ Conditional Performance Free of Data Snooping Bias
Authors: Hsu Po-Hsuan , Kyriakou Ioannis , Ma Tren , Sermpinis Georgios
Published: February 2024

We introduce a test to assess mutual funds’ “conditional” performance that is based on updated information and corrects data snooping bias. Our method, named the functional false discovery rate “plus” (

$ {\mathrm{fFDR}}^{+} $

), incorporates fund characteristics in estimating fund performance free of data snooping bias. Simulations suggest that the

$ {\mathrm{fFDR}}^{+} $

controls well the ratio of false discoveries and gains considerable power over prior methods that do not account for extra information. Portfolios of funds selected by the

$ {\mathrm{fFDR}}^{+} $

outperform other tests not accounting for information updating, highlighting the importance of evaluating mutual funds from a conditional perspective.
Analysis of P-gp genes relative expression associated to ivermectin resistance in Haemonchus contortus larval stages from in vitro cultures (L3 and xL3) and from gerbils (Meriones unguiculatus) (L4) as models of study
Authors: Reyes-Guerrero D.E. , Higuera-Piedrahita R.I. , Maza-Lopez J. , Mendoza-de-Gives P. , Camas-Pereyra R. , López-Arellano M.E.
Published: February 2024

The aim of the study was to compare the relative gene expression of Haemonchus contortus P-glycoprotein genes (Hco-pgp) between fourth (L4), infective (L3), and transitory infective (xL3) larval stages as laboratory models to study ivermectin (IVM) resistance. The H. contortus resistant to IVM (IVMr) and susceptible to IVM (IVMs) strains were used to develop xL3in vitro culture and to infect Meriones unguiculatus (gerbils) to collect L4 stages. Morphometric differences were evaluated from 25 individuals of H. contortus from each strain. Relative gene expression from xL3 and L4 was determined between comparison of IVMr stages and from IVMr vs IVMs stages. Seven Hco-pgp genes (1, 2, 3, 4, 9, 10, and 16) were analysed by RT-qPCR using L3 stage as control group, per strain, and GAPDH and β-tubulin as constitutive genes. Morphological changes were confirmed between xL3 and L4 developing oral shape, oesophagus, and intestinal tube. In addition, the body length and width showed statistical differences (p < 0.05). The Hco-pgp1, 2, 3, and 4 genes (p < 0.05) were upregulated from 7.1- to 463.82-fold changes between IVMr stages, and Hco-pgp9 (13.12-fold) and Hco-pgp10 (13.56-fold) genes showed differences between L4 and xL3, respectively. The comparative study between IVMr vs IVMs strains associated to xL3 and L4 displayed significant upregulation for most of the Hco-pgp genes among 4.89–188.71 fold-change. In conclusion, these results suggest the use of H. contortus xL3 and L4 as suitable laboratory models to study IVMr associated with Hco-pgp genes to contribute to the understanding of anthelmintic resistance.
The influences of temporal-spatial parameters on CPUE of the Atlantic bluefin tuna purse seine fishery in eastern Mediterranean
Authors: Karakulak F. Saadet , Ceyhan Tevfik
Published: February 2024

In this study, we applied generalized additive model to investigate the influence of spatial temporal variables and vessel length on catch per unit-effort (CPUE) of Atlantic bluefin tuna (ABFT) purse seine fishery using catch and effort data from commercial logbooks and field surveys from 1992 to 2006. The vessel lengths of sampled purse seines ranged from 20 to 64 m. The number of ABFT caught within each operation varied between 1 and 2000. A total of 386 CPUE values for ABFT were calculated 0.05 and 60 t ⋅ (haul day)–1 with mean CPUE of 5.51 ± 0.54 t ⋅ (haul day)–1. Although the sea surface temperature had little influence on the CPUE, the effect of time and spatial variables, vessel length and salinity was found as significant. In conclusion, the spatial dynamics of ABFT should be considered if the impact of fisheries on the ecosystem is to be reduced.
Post-growth peacebuilding
Authors: Simangan Dahlia
Published: February 2024

Economic development is considered one of the pillars of international peacebuilding. The mandates of the United Nations (UN) peacekeeping operations often contain the promotion of economic growth as a prerequisite for post-conflict recovery and sustainable peace. However, the relationship between peace and economic growth needs re-examination in light of urgent calls for global sustainability and climate action. To do this, I first review the claims and critiques that economic growth is a precondition for peace. I then revisit past peacebuilding cases where the promotion of economic growth has either corresponded with or led to environmental degradation and unequal distribution of resources, contributing to new or renewed forms of violence. Finally, I explore the prospects of post-growth peacebuilding based on recent efforts to make UN peacekeeping operations more attuned to environmental considerations and the changing climate. Post-growth peacebuilding is not just about reducing the environmental footprint of peacekeeping; it is, more importantly, about breaking away from the linear and growth-driven path of peace and development towards intergenerational and ecological justice.
At the Limits of Knowledge: the Iron Poetics of Old English Verse in the Nineteenth Century
Authors: Luo Shu-han
Published: February 2024

Scholars in recent decades have critiqued the notion of Old English as a poetry of iron: evoking a hypermasculine, primitive past, the metaphor is emblematic of outdated practices in the field. This article builds upon these critiques, while showing that they oversimplify the metaphor’s function in disciplinary history. Part I traces desires and unknowns in the nineteenth century that made iron embody Saxon poetry’s primitive artlessness. From these struggles, Part II turns to draw forth a counter-narrative, in which Bosworth’s metaphor of the hammering smith served to clarify difficulties of metrical knowledge c.1825. Part III then situates a later extension of iron imagery in the potentialities of late nineteenth-century iron architecture. Examining the challenges that early scholars faced helps us better perceive the literary, linguistic, and political ramifications of their solutions. Spotlighting the metaphor’s changing relationship to beauty versus utility also points forward, as we imagine new metaphors that might once more be productive for conceptualising poetic structure.
Giving fruits and vegetables a tax break: lessons from a Dutch attempt
Authors: Hagenaars Luc L , Fazzino Tera L , Mackenbach Joreintje Dingena
Published: February 2024

Objective:

Food taxation can improve diets by making unhealthy foods more expensive and by making healthy foods cheaper. In the Netherlands, a political window of opportunity arose in December 2021 to reduce the value-added tax (VAT) on fruits and vegetables to zero percent. The policy is now facing institutional friction along several fronts, however, delaying and potentially averting its implementation. We analysed this institutional friction to inform future food tax policies.

Design:

We qualitatively analysed open-access fiscal and health experts’ position papers about benefits and downsides of the zero-rate that were discussed with members of parliament in June 2023.

Setting:

The Netherlands.

Participants:

Not applicable.

Results:

Health and fiscal experts expressed noticeably different viewpoints towards the utility of the zero-rate. One important argument fiscal experts based their negative advice upon pertained to the legal restrictions for distinguishing between healthier and unhealthier forms of fruits and vegetables (i.e. the principle of neutrality). A zero-rate VAT on unhealthier forms of fruits and vegetables, e.g. processed cucumber, mixed with salt and sugar, would be undesirable, but differentiating between raw and processed cucumber would offend the neutrality principle.

Conclusions:

The Dutch attempt to give fruits and vegetables a tax break highlights the need for crystal-clear food classifications when designing food tax policies. Public health nutritionists should combine classifications based on caloric density, palatability, degree of processing and nutrient content to provide a database for evidence-informed tax differentiation according to food item healthfulness.
ON THE ITERATIONS AND THE ARGUMENT DISTRIBUTION OF MEROMORPHIC FUNCTIONS
Authors: DING JIE , ZHENG JIANHUA
Published: February 2024

This paper consists of two parts. The first is to study the existence of a point a at the intersection of the Julia set and the escaping set such that a goes to infinity under iterates along Julia directions or Borel directions. Additionally, we find such points that approximate all Borel directions to escape if the meromorphic functions have positive lower order. We confirm the existence of such slowly escaping points under a weaker growth condition. The second is to study the connection between the Fatou set and argument distribution. In view of the filling disks, we show nonexistence of multiply connected Fatou components if an entire function satisfies a weaker growth condition. We prove that the absence of singular directions implies the nonexistence of large annuli in the Fatou set.
TRILINEAR FOURIER MULTIPLIERS ON HARDY SPACES
Authors: Lee Jin Bong , Park Bae Jun
Published: February 2024

In this paper, we obtain the
$H^{p_1}\times H^{p_2}\times H^{p_3}\to H^p$
boundedness for trilinear Fourier multiplier operators, which is a trilinear analogue of the multiplier theorem of Calderón and Torchinsky [4]. Our result improves the trilinear estimate in [22] by additionally assuming an appropriate vanishing moment condition, which is natural in the boundedness into the Hardy space
$H^p$
for
$0<p\le 1$
.
Rawson Rawson and Early Victorian Poverty Knowledge
Authors: Heaman E. A.
Published: February 2024

This article scrutinizes Rawson W. Rawson over seven years, from 1837 to 1844, during which he served as founding editor of the Journal of the Statistical Society of London and then as civil secretary to successive Canadian governors-general. Rawson studied poverty in London, amplified criticisms of Malthusian Poor Law disciplines in Scotland, and applied that logic to Indigenous poverty on the colonial frontier. The statisticians sought generic definitions of property and agency that sometimes challenged a more binary logic of civilization. But in Canada, Rawson's very critique of dispossession became an instrument of that dispossession.
Benchmarking commercially available soft and rigid passive back exoskeletons for an industrial workplace
Authors: Mohamed Refai Mohamed I. , Moya-Esteban Alejandro , van Zijl Lynn , van der Kooij Herman , Sartori Massimo
Published: February 2024

Low-back pain is a common occupational hazard for industrial workers. Several studies show the advantages of using rigid and soft back-support passive exoskeletons and exosuits (exos) to reduce the low-back loading and risk of injury. However, benefits of using these exos have been shown to be task-specific. Therefore, in this study, we developed a benchmarking approach to assess exos for an industrial workplace at Hankamp Gears B.V. We assessed two rigid (Laevo Flex, Paexo back) and two soft (Auxivo Liftsuit 1.0, and Darwing Hakobelude) exos for tasks resembling the workplace. We measured the assistive moment provided by each exo and their respective influence on muscle activity as well as the user’s perception of comfort and exertion. Ten participants performed four lifting tasks (Static hold, Asymmetric, Squat, and Stoop), while their electromyography and subjective measures were collected. The two rigid exos provided the largest assistance during the Dynamic tasks. Reductions in erector spinae activity were seen to be task-specific, with larger reductions for the two rigid exos. Overall, Laevo Flex offered a good balance between assistive moments, reductions in muscle activity, as well as user comfort and reductions in perceived exertion. Thus, we recommend benchmarking exos for intended use in the industrial workplace. This will hopefully result in a better adoption of the back-support exoskeletons in the workplace and help reduce low-back pain.
GNSS Radio Occultation Data in the AWS Cloud
Authors: Leroy S. S. , McVey A. E. , Leidner S. M. , Zhang H. , Gleisner H.
Published: February 2024

Radio occultation (RO) by the Earth's atmosphere of the transmitted signals of the Global Navigation Satellite Systems' satellites has improved numerical weather prediction, has benefited atmospheric process studies, and benchmarked climate change by its strong traceability to the international definition of the second. Until now, research with RO has been isolated to the few centers that actually process the data and impracticable elsewhere because of limitations on data formats, organization and volume of the data, download bandwidth, and the lack of a database that can be queried before downloading data. We announce the availability of RO data in the Registry of Open Data of Amazon Web Services (AWS). RO data are freely available for download for the user and free to process and store for the manager of the repository. RO data as processed by the COSMIC Program Office at the University Corporation for Atmospheric Research, by the Radio Occultation Meteorology Satellite Application Facility (ROM SAF), by EUMETSAT, and by the NASA Jet Propulsion Laboratory are available beginning with calibrated (excess) phase, extending to bending angle and refractivity and to retrievals of pressure, temperature and water vapor. The same RO repository also contains a metadata database that permits simple querying, filtering, and download of data using a Python application programming interface provided by this same project. Four tutorial demonstrations are provided as jupyter notebooks to provide representative samples of code to perform common research activities with RO data, including database querying and analysis, inter‐center comparison of RO retrieval performance, and atmospheric process studies.
The Need for Multi‐Century Projections of Sea Level Rise
Authors: Palmer Matthew D. , Weeks Jennifer H.
Published: February 2024

The latest assessment report of the Intergovernmental Panel on Climate Change (IPCC) provided scenario‐based local sea level projections to 2150 and characterized the long‐term committed global mean sea level rise on 2,000‐ and 10,000‐year time horizons associated with peak surface warming levels. Turner et al. build on the scientific assessment of the IPCC to provide time‐continuous projections of future sea level rise to 2500. These projections fill an important knowledge gap to help inform coastal decision‐making processes and more fully quantify the benefits of mitigation actions in terms of limiting future sea level rise. However, limited understanding of ice instability processes remains a key scientific challenge and improved observational and modeling capability are critical to reducing uncertainties and monitoring the trajectory of observed change.
A Seismic Tomography, Gravity, and Flexure Study of the Crust and Upper Mantle Structure Across the Hawaiian Ridge: 2. Ka'ena
Authors: Dunn R. A. , Watts A. B. , Xu C. , Shillington D. J.
Published: February 2024

The Hawaiian Ridge, a classic intraplate volcanic chain in the Central Pacific Ocean, has long attracted researchers due to its origin, eruption patterns, and impact on lithospheric deformation. Thought to arise from pressure‐release melting within a mantle plume, its mass‐induced deformation of Earth's surface depends on load distribution and lithospheric properties, including elastic thickness (Te). To investigate these features, a marine geophysical campaign was carried out across the Hawaiian Ridge in 2018. Westward of the island of O'ahu, a seismic tomographic image, validated by gravity data, reveals a large mass of volcanic material emplaced on the oceanic crust, flanked by an apron of volcaniclastic material filling the moat created by plate flexure. The ridge adds ∼7 km of material to pre‐existing ∼6‐km‐thick oceanic crust. A high‐velocity and high‐density core resides within the volcanic edifice, draped by alternating lava flows and mass wasting material. Beneath the edifice, upper mantle velocities are slightly higher than that of the surrounding mantle, and there is no evidence of extensive magmatic underplating of the crust. There is ∼3.5 km of downward deflection of the sediment‐crust and crust‐mantle boundaries due to flexure in response to the volcanic load. At Ka'ena Ridge, the volcanic edifice's height and cross‐sectional area are no more than half as large as those determined at Hawai'i Island. Together, these studies confirm that volcanic loads to the west of Hawai'i are largely compensated by flexure. Comparisons to the Emperor Seamount Chain confirm the Hawaiian Ridge's relatively stronger lithospheric rigidity.
Prediction of the SYM‐H Index Using a Bayesian Deep Learning Method With Uncertainty Quantification
Authors: Abduallah Yasser , Alobaid Khalid A. , Wang Jason T. L. , Wang Haimin , Jordanova Vania K. , Yurchyshyn Vasyl , Cavus Huseyin , Jing Ju
Published: February 2024

We propose a novel deep learning framework, named SYMHnet, which employs a graph neural network and a bidirectional long short‐term memory network to cooperatively learn patterns from solar wind and interplanetary magnetic field parameters for short‐term forecasts of the SYM‐H index based on 1‐ and 5‐min resolution data. SYMHnet takes, as input, the time series of the parameters' values provided by NASA's Space Science Data Coordinated Archive and predicts, as output, the SYM‐H index value at time point t + w hours for a given time point t where w is 1 or 2. By incorporating Bayesian inference into the learning framework, SYMHnet can quantify both aleatoric (data) uncertainty and epistemic (model) uncertainty when predicting future SYM‐H indices. Experimental results show that SYMHnet works well at quiet time and storm time, for both 1‐ and 5‐min resolution data. The results also show that SYMHnet generally performs better than related machine learning methods. For example, SYMHnet achieves a forecast skill score (FSS) of 0.343 compared to the FSS of 0.074 of a recent gradient boosting machine (GBM) method when predicting SYM‐H indices (1 hr in advance) in a large storm (SYM‐H = −393 nT) using 5‐min resolution data. When predicting the SYM‐H indices (2 hr in advance) in the large storm, SYMHnet achieves an FSS of 0.553 compared to the FSS of 0.087 of the GBM method. In addition, SYMHnet can provide results for both data and model uncertainty quantification, whereas the related methods cannot.
Familial confounding of internalising symptoms and obesity in adolescents and young adults; a co-twin analysis
Authors: Campbell Alexander Charles , Calais-Ferreira Lucas , Hahn Elisabeth , Spinath Frank M. , Hopper John L. , Young Jesse T.
Published: February 2024

Background

Obesity and internalising disorders, including depression and anxiety, often co-occur. There is evidence that familial confounding contributes to the co-occurrence of internalising disorders and obesity in adults. However, its impact on this association among young people is unclear. Our study investigated the extent to which familial factors confound the association between internalising disorders and obesity in adolescents and young adults.

Subjects/methods

We used a matched co-twin design to investigate the impact of confounding by familial factors on associations between internalising symptoms and obesity in a sample of 4018 twins aged 16 to 27 years.

Results

High levels of internalising symptoms compared to low levels increased the odds of obesity for the whole cohort (adjusted odds ratio [AOR] = 3.1, 95% confidence interval [CI]: 1.5, 6.8), and in females (AOR = 4.1, 95% CI 1.5, 11.1), but not in males (AOR = 2.8 95% CI 0.8, 10.0). We found evidence that internalising symptoms were associated with an increased between-pair odds of obesity (AOR 6.2, 95% CI 1.7, 22.8), using the paired analysis but not using a within-pair association, which controls for familial confounding. Sex-stratified analyses indicated high internalising symptoms were associated with increased between-pair odds of obesity for females (AOR 12.9, 95% CI 2.2, 76.8), but this attenuated to the null using within-pair analysis. We found no evidence of between or within-pair associations for males and weak evidence that sex modified the association between internalising symptoms and obesity (likelihood ratio test p = 0.051).

Conclusions

Some familial factors shared by twins confound the association between internalising symptoms and obesity in adolescent and young adult females. Internalising symptoms and obesity were not associated for adolescent and young adult males. Therefore, prevention and treatment efforts should especially address familial shared determinants of obesity, particularly targeted at female adolescents and young adults with internalising symptoms and those with a family history of these disorders.
Enhanced Risk Stratification for Children and Young Adults with B-Cell Acute Lymphoblastic Leukemia: A Children’s Oncology Group Report
Authors: DelRocco N. J. , Loh M. L. , Borowitz M. J. , Gupta S. , Rabin K. R. , Zweidler-McKay P. , Maloney K. W. , Mattano L. A. , Larsen E. , Angiolillo A. , Schore R. J. , Burke M. J. , Salzer W. L. , Wood B. L. , Carroll A. J. , Heerema N. A. , Reshmi S. C. , Gastier-Foster J. M. , Harvey R. , Chen I. M. , Roberts K. G. , Mullighan C. G. , Willman C. , Winick N. , Carroll W. L. , Rau R. E. , Teachey D. T. , Hunger S. P. , Raetz E. A. , Devidas M. , Kairalla J. A.
Published: February 2024

Current strategies to treat pediatric acute lymphoblastic leukemia rely on risk stratification algorithms using categorical data. We investigated whether using continuous variables assigned different weights would improve risk stratification. We developed and validated a multivariable Cox model for relapse-free survival (RFS) using information from 21199 patients. We constructed risk groups by identifying cutoffs of the COG Prognostic Index (PICOG) that maximized discrimination of the predictive model. Patients with higher PICOG have higher predicted relapse risk. The PICOG reliably discriminates patients with low vs. high relapse risk. For those with moderate relapse risk using current COG risk classification, the PICOG identifies subgroups with varying 5-year RFS. Among current COG standard-risk average patients, PICOG identifies low and intermediate risk groups with 96% and 90% RFS, respectively. Similarly, amongst current COG high-risk patients, PICOG identifies four groups ranging from 96% to 66% RFS, providing additional discrimination for future treatment stratification. When coupled with traditional algorithms, the novel PICOG can more accurately risk stratify patients, identifying groups with better outcomes who may benefit from less intensive therapy, and those who have high relapse risk needing innovative approaches for cure.
Tau depletion in human neurons mitigates Aβ-driven toxicity
Authors: Ng Bryan , Vowles Jane , Bertherat Féodora , Abey Ajantha , Kilfeather Peter , Beccano-Kelly Dayne , Stefana M. Irina , O’Brien Darragh P. , Bengoa-Vergniory Nora , Carling Phillippa J. , Todd John A. , Caffrey Tara M. , Connor-Robson Natalie , Cowley Sally A. , Wade-Martins Richard
Published: February 2024

Alzheimer’s disease (AD) is an age-related neurodegenerative condition and the most common type of dementia, characterised by pathological accumulation of extracellular plaques and intracellular neurofibrillary tangles that mainly consist of amyloid-β (Aβ) and hyperphosphorylated tau aggregates, respectively. Previous studies in mouse models with a targeted knock-out of the microtubule-associated protein tau (Mapt) gene demonstrated that Aβ-driven toxicity is tau-dependent. However, human cellular models with chronic tau lowering remain unexplored. In this study, we generated stable tau-depleted human induced pluripotent stem cell (iPSC) isogenic panels from two healthy individuals using CRISPR-Cas9 technology. We then differentiated these iPSCs into cortical neurons in vitro in co-culture with primary rat cortical astrocytes before conducting electrophysiological and imaging experiments for a wide range of disease-relevant phenotypes. Both AD brain derived and recombinant Aβ were used in this study to elicit toxic responses from the iPSC-derived cortical neurons. We showed that tau depletion in human iPSC-derived cortical neurons caused considerable reductions in neuronal activity without affecting synaptic density. We also observed neurite outgrowth impairments in two of the tau-depleted lines used. Finally, tau depletion protected neurons from adverse effects by mitigating the impact of exogenous Aβ-induced hyperactivity, deficits in retrograde axonal transport of mitochondria, and neurodegeneration. Our study established stable human iPSC isogenic panels with chronic tau depletion from two healthy individuals. Cortical neurons derived from these iPSC lines showed that tau is essential in Aβ-driven hyperactivity, axonal transport deficits, and neurodegeneration, consistent with studies conducted in Mapt−/− mouse models. These findings highlight the protective effects of chronic tau lowering strategies in AD pathogenesis and reinforce the potential in clinical settings. The tau-depleted human iPSC models can now be applied at scale to investigate the involvement of tau in disease-relevant pathways and cell types.
Social activity mediates locus coeruleus tangle-related cognition in older adults
Authors: Zide Benjamin S. , Donovan Nancy J. , Lee Soyoung , Nag Sukriti , Bennett David A. , Jacobs Heidi I. L.
Published: February 2024

The locus coeruleus-noradrenaline system regulates brain-wide neural activity involved in cognition and behavior. Integrity of this subcortical neuromodulatory system is proposed to be a substrate of cognitive reserve that may be strengthened by lifetime cognitive and social activity. Conversely, accumulation of tau tangles in the brainstem locus coeruleus nuclei is recently studied as a very early marker of Alzheimer’s disease (AD) pathogenesis and cognitive vulnerability, even among older adults without cognitive impairment or significant cerebral AD pathologies. This clinical-pathologic study examined whether locus coeruleus tangle density was cross-sectionally associated with lower antemortem cognitive performance and social activity among 142 cognitively unimpaired and impaired older adults and whether social activity, a putative reserve factor, mediated the association of tangle density and cognition. We found that greater locus coeruleus tangle density was associated with lower social activity for the whole sample and in the cognitively unimpaired group alone and these associations were independent of age, sex, education, depressive symptoms, and burden of cerebral amyloid and tau. The association of locus coeruleus tangle density with lower cognitive performance was partially mediated by level of social activity. These findings implicate the locus coeruleus-noradrenaline system in late-life social function and support that locus coeruleus tangle pathology is associated with lower levels of social activity, independent of cerebral AD pathologies, and specifically among older adults who are cognitively unimpaired. Early brainstem pathology may impact social function, and level of social function, in turn, influences cognition, prior to canonical stages of AD.
RNA-sequencing predicts a role of androgen receptor and aldehyde dehydrogenase 1A1 in osteosarcoma lung metastases
Authors: Heim Tanya E. , Hankins Margaret L. , Belayneh Rebekah , Douglas Nerone , Dinh Vu , Kovvur Murali , Boone David N. , Ukani Vrutika , Bhogal Sumail , Patel Vaidehi , Moniz Taylor M. A. , Bailey Kelly M. , John Ivy , Schoedel Karen , Weiss Kurt R. , Watters Rebecca J.
Published: February 2024

One-third of pediatric patients with osteosarcoma (OS) develop lung metastases (LM), which is the primary predictor of mortality. While current treatments of patients with localized bone disease have been successful in producing 5-year survival rates of 65–70%, patients with LM experience poor survival rates of only 19–30%. Unacceptably, this situation that has remained unchanged for 30 years. Thus, there is an urgent need to elucidate the mechanisms of metastatic spread in OS and to identify targetable molecular pathways that enable more effective treatments for patients with LM. We aimed to identify OS-specific gene alterations using RNA-sequencing of extremity and LM human tissues. Samples of extremity and LM tumors, including 4 matched sets, were obtained from patients with OS. Our data demonstrate aberrant regulation of the androgen receptor (AR) pathway in LM and predicts aldehyde dehydrogenase 1A1 (ALDH1A1) as a downstream target. Identification of AR pathway upregulation in human LM tissue samples may provide a target for novel therapeutics for patients with LM resistant to conventional chemotherapy.
Loss of macrophage TSC1 exacerbates sterile inflammatory liver injury through inhibiting the AKT/MST1/NRF2 signaling pathway
Authors: Ni Ming , Qiu Jiannan , liu Guoqing , Sun Xiaohu , Zhu Wenjie , Wu Peng , Chen Zheng , Qiu Jiajing , Wu Ziming , Zhang Yang , Zhang Feng , Li Changyong , Gao Yuan , Zhou Jun , Zhu Qiang
Published: February 2024

Tuberous sclerosis complex 1 (TSC1) plays important roles in regulating innate immunity. However, the precise role of TSC1 in macrophages in the regulation of oxidative stress response and hepatic inflammation in liver ischemia/reperfusion injury (I/R) remains unknown. In a mouse model of liver I/R injury, deletion of myeloid-specific TSC1 inhibited AKT and MST1 phosphorylation, and decreased NRF2 accumulation, whereas activated TLR4/NF-κB pathway, leading to increased hepatic inflammation. Adoptive transfer of AKT- or MST1-overexpressing macrophages, or Keap1 disruption in myeloid-specific TSC1-knockout mice promoted NRF2 activation but reduced TLR4 activity and mitigated I/R-induced liver inflammation. Mechanistically, TSC1 in macrophages promoted AKT and MST1 phosphorylation, and protected NRF2 from Keap1-mediated ubiquitination. Furthermore, overexpression AKT or MST1 in TSC1-knockout macrophages upregulated NRF2 expression, downregulated TLR4/NF-κB, resulting in reduced inflammatory factors, ROS and inflammatory cytokine-mediated hepatocyte apoptosis. Strikingly, TSC1 induction in NRF2-deficient macrophages failed to reverse the TLR4/NF-κB activity and production of pro-inflammatory factors. Conclusions: Macrophage TSC1 promoted the activation of the AKT/MST1 signaling pathway, increased NRF2 levels via reducing Keap1-mediated ubiquitination, and modulated oxidative stress-driven inflammatory responses in liver I/R injury. Our findings underscore the critical role of macrophage TSC1 as a novel regulator of innate immunity and imply the therapeutic potential for the treatment of sterile liver inflammation in transplant recipients.
CD24 induced cellular quiescence-like state and chemoresistance in ovarian cancer cells via miR-130a/301a-dependent CDK19 downregulation
Authors: Jang Yeonsue , Kang Suki , Han Hyun Ho , Kim Baek Gil , Cho Nam Hoon
Published: February 2024

Cancer stem-like cell (CSC) is thought to be responsible for ovarian cancer recurrence. CD24 serves as a CSC marker for ovarian cancer and regulates the expression of miRNAs, which are regulators of CSC phenotypes. Therefore, CD24-regulated miRNAs may play roles in manifesting the CSC phenotypes in ovarian cancer cells. Our miRNA transcriptome analysis showed that 94 miRNAs were up or down-regulated in a CD24-high clone from an ovarian cancer patient compared to a CD24-low one. The CD24-dependent expression trend of the top 7 upregulated miRNAs (miR-199a-3p, 34c, 199a-5p, 130a, 301a, 214, 34b*) was confirmed in other 8 clones (4 clones for each group). CD24 overexpression upregulated the expression of miR-199a-3p, 34c, 199a-5p, 130a, 301a, 214, and 34b* in TOV112D (CD24-low) cells compared to the control, while CD24 knockdown downregulated the expression of miR-199a-3p, 199a-5p, 130a, 301a, and 34b* in OV90 (CD24-high) cells. miR-130a and 301a targeted CDK19, which induced a cellular quiescence-like state (increased G0/G1 phase cell population, decreased cell proliferation, decreased colony formation, and decreased RNA synthesis) and resistance to platinum-based chemotherapeutic agents. CD24 regulated the expression of miR-130a and 301a via STAT4 and YY1 phosphorylation mediated by Src and FAK. miR-130a and 301a were positively correlated in expression with CD24 in ovarian cancer patient tissues and negatively correlated with CDK19. Our results showed that CD24 expression may induce a cellular quiescence-like state and resistance to platinum-based chemotherapeutic agents in ovarian cancer via miR-130a and 301a upregulation. CD24-miR-130a/301a-CDK19 signaling axis could be a prognostic marker for or a potential therapeutic target against ovarian cancer recurrence.
Melt adsorption of poly(tert-butyl methacrylate) and poly(ethyl methacrylate) on silica studied with chip nanocalorimetry
Authors: Ishihara Minato , Watanabe Tomoya , Hirata Toyoaki , Sasaki Takashi
Published: February 2024

Irreversible adsorption of polymer chains from a melt on a substrate surface can be strongly affected by interfacial interactions. In this study, we examined the adsorption of two polymers, poly(tert-butyl methacrylate) (PtBMA) and poly(ethyl methacrylate) (PEMA), on a silica surface at temperatures above their glass transition temperatures. The degree of adsorption γ(t) over time was evaluated with variations of storage heat capacity determined with alternating current chip nanocalorimetry (in-situ measurement of a buried interface). γ(t) revealed two-step profiles for both polymers. At the second stage of adsorption (regime II), the slope of a plot of γ(t) vs. log t increased as adsorption proceeded; this trend has not been reported for other polymers and may be characteristic of the present polymers. The trend observed in regime II suggested that the unadsorbed free chains near the interface became less mobile and were incorporated into the adsorbed layer via interactions with the tails of the chains directly attached to the substrate surface. The increasing slope in regime II was more prominent for PtBMA than for PEMA. In addition, a difference was observed for PtBMA and PEMA in the atomic force microscopy images of the exposed adsorption layer surfaces.
Identification of people with Lynch syndrome from those presenting with colorectal cancer in England: baseline analysis of the diagnostic pathway
Authors: McRonald Fiona E. , Pethick Joanna , Santaniello Francesco , Shand Brian , Tyson Adele , Tulloch Oliver , Goel Shilpi , Lüchtenborg Margreet , Borthwick Gillian M. , Turnbull Clare , Shaw Adam C. , Monahan Kevin J. , Frayling Ian M. , Hardy Steven , Burn John
Published: February 2024

It is believed that >95% of people with Lynch syndrome (LS) remain undiagnosed. Within the National Health Service (NHS) in England, formal guidelines issued in 2017 state that all colorectal cancers (CRC) should be tested for DNA Mismatch Repair deficiency (dMMR). We used a comprehensive population-level national dataset to analyse implementation of the agreed diagnostic pathway at a baseline point 2 years post-publication of official guidelines. Using real-world data collected and curated by the National Cancer Registration and Analysis Service (NCRAS), we retrospectively followed up all people diagnosed with CRC in England in 2019. Nationwide laboratory diagnostic data incorporated somatic (tumour) testing for dMMR (via immunohistochemistry or microsatellite instability), somatic testing for MLH1 promoter methylation and BRAF status, and constitutional (germline) testing of MMR genes. Only 44% of CRCs were screened for dMMR; these figures varied over four-fold with respect to geography. Of those CRCs identified as dMMR, only 51% underwent subsequent diagnostic testing. Overall, only 1.3% of patients with colorectal cancer had a germline MMR genetic test performed; up to 37% of these tests occurred outside of NICE guidelines. The low rates of molecular diagnostic testing in CRC support the premise that Lynch syndrome is underdiagnosed, with significant attrition at all stages of the testing pathway. Applying our methodology to subsequent years’ data will allow ongoing monitoring and analysis of the impact of recent investment. If the diagnostic guidelines were fully implemented, we estimate that up to 700 additional people with LS could be identified each year.
Diversity and evolution of the vertebrate chemoreceptor gene repertoire
Authors: Policarpo Maxime , Baldwin Maude W. , Casane Didier , Salzburger Walter
Published: February 2024

Chemoreception – the ability to smell and taste – is an essential sensory modality of most animals. The number and type of chemical stimuli that animals can perceive depends primarily on the diversity of chemoreceptors they possess and express. In vertebrates, six families of G protein-coupled receptors form the core of their chemosensory system, the olfactory/pheromone receptor gene families OR, TAAR, V1R and V2R, and the taste receptors T1R and T2R. Here, we study the vertebrate chemoreceptor gene repertoire and its evolutionary history. Through the examination of 1,527 vertebrate genomes, we uncover substantial differences in the number and composition of chemoreceptors across vertebrates. We show that the chemoreceptor gene families are co-evolving, highly dynamic, and characterized by lineage-specific expansions (for example, OR in tetrapods; TAAR, T1R in teleosts; V1R in mammals; V2R, T2R in amphibians) and losses. Overall, amphibians, followed by mammals, are the vertebrate clades with the largest chemoreceptor repertoires. While marine tetrapods feature a convergent reduction of chemoreceptor numbers, the number of OR genes correlates with habitat in mammals and birds and with migratory behavior in birds, and the taste receptor repertoire correlates with diet in mammals and with aquatic environment in fish.
Structured information extraction from scientific text with large language models
Authors: Dagdelen John , Dunn Alexander , Lee Sanghoon , Walker Nicholas , Rosen Andrew S. , Ceder Gerbrand , Persson Kristin A. , Jain Anubhav
Published: February 2024

Extracting structured knowledge from scientific text remains a challenging task for machine learning models. Here, we present a simple approach to joint named entity recognition and relation extraction and demonstrate how pretrained large language models (GPT-3, Llama-2) can be fine-tuned to extract useful records of complex scientific knowledge. We test three representative tasks in materials chemistry: linking dopants and host materials, cataloging metal-organic frameworks, and general composition/phase/morphology/application information extraction. Records are extracted from single sentences or entire paragraphs, and the output can be returned as simple English sentences or a more structured format such as a list of JSON objects. This approach represents a simple, accessible, and highly flexible route to obtaining large databases of structured specialized scientific knowledge extracted from research papers.