bluuebunny/crossref_metadata_2025 huggingface dataset:
Recovering Classical Indigenous Philosophy
Authors: Wilkinson Eric
Published: February 2024

Indigenous philosophy from the 17th century and earlier is often thought to be irretrievable because of a lack of extant works. There are at least two reasons that this view is mistaken. First, it overlooks the role oral traditions play in preserving the thought of Indigenous peoples. Second, some Indigenous thinkers had their philosophical views recorded by European interlocutors shortly after contact. With these sources, the same techniques used to recover the views of philosophers like Prodicus, whose works are lost, can be applied to Indigenous thinkers. By reconstructing the philosophy of Kondiaronk, I show how this can be done.
Deux enjeux philosophiques entourant la structure des recommandations issues du secteur public
Authors: Daoust Marc-Kevin , Babin Victor
Published: February 2024

L'une des fonctions des institutions publiques des démocraties libérales est de formuler des recommandations à l'attention des décideurs. Or, les institutions publiques savent que leurs recommandations seront souvent ignorées en partie par le décideur. Cette situation de « conformité partielle » aux recommandations soulève plusieurs problèmes de nature philosophique pour les institutions. En nous appuyant sur une analyse de 570 recommandations tirées de 40 documents et rapports du secteur public québécois, nous identifions deux enjeux entourant la structure des recommandations issues du secteur public.
Estimating Stock Market Betas via Machine Learning
Authors: Drobetz Wolfgang , Hollstein Fabian , Otto Tizian , Prokopczuk Marcel
Published: February 2024

Machine learning-based stock market beta estimators outperform established benchmark models both statistically and economically. Analyzing the predictability of time-varying market betas of U.S. stocks, we document that machine learning-based estimators produce the lowest forecast and hedging errors. They also help to create better market-neutral anomaly strategies and minimum variance portfolios. Among the various techniques, random forests perform the best overall. Model complexity is highly time-varying. Historical stock market betas, turnover, and size are the most important predictors. Compared to linear regressions, allowing for nonlinearity and interactions significantly improves predictive performance.
Evaluating clinical decision support software (CDSS): challenges for robust evidence generation
Authors: Laka Mah , Carter Drew , Merlin Tracy
Published: February 2024

Objectives

Computerized clinical decision support software (CDSS) are digital health technologies that have been traditionally categorized as medical devices. However, the evaluation frameworks for traditional medical devices are not well adapted to assess the value and safety of CDSS. In this study, we identified a range of challenges associated with CDSS evaluation as a medical device and investigated whether and how CDSS are evaluated in Australia.

Methods

Using a qualitative approach, we interviewed 11 professionals involved in the implementation and evaluation of digital health technologies at national and regional levels. Data were thematically analyzed using both data-driven (inductive) and theory-based (deductive) approaches.

Results

Our results suggest that current CDSS evaluations have an overly narrow perspective on the risks and benefits of CDSS due to an inability to capture the impact of the technology on the sociotechnical environment. By adopting a static view of the CDSS, these evaluation frameworks are unable to discern how rapidly evolving technologies and a dynamic clinical environment can impact CDSS performance. After software upgrades, CDSS can transition from providing information to specifying diagnoses and treatments. Therefore, it is not clear how CDSS can be monitored continuously when changes in the software can directly affect patient safety.

Conclusion

Our findings emphasize the importance of taking a living health technology assessment approach to the evaluation of digital health technologies that evolve rapidly. There is a role for observational (real-world) evidence to understand the impact of changes to the technology and the sociotechnical environment on CDSS performance.
Administrative Litigation in China: Assessing the Chief Officials’ Appearance System
Authors: Chen Tianhao , Xu Wei , Yu Xiaohong
Published: February 2024

The Chief Officials’ Appearance System (COAS), introduced in 2015, requires government leaders to appear in court and explain their actions. Unlike other post-2014 legal reforms aimed at reducing political influence in administrative litigation, the COAS uniquely actively involves political officials. This approach is based on the belief that increased participation will help officials to gain a better understanding of public concerns and improve administrative litigation quality. However, few studies have examined the system's effectiveness, and existing research relies on anecdotal evidence with limited analysis. To address this gap, we conducted a systematic empirical inquiry using 1,551 administrative litigation cases filed in a Beijing local court and extensive field research in 12 other provinces. Contrary to official expectations, we found the system reproduced the administrative grievances it was tasked with resolving. Moreover, when chief officials appear in court, administrative litigation is characterized by a renewed triad of apathetic state agencies, increasingly agitated plaintiffs and strategically empowered courts.
“But I Have a Pacer…There Is No Point in Engaging in Hypothetical Scenarios”: A Non-Imminently Dying Patient’s Request for Pacemaker Deactivation
Authors: Tracy Bridget A. , Rhodes Rosamond , Goldstein Nathan E.
Published: February 2024

In this case report, we describe a woman with advancing dementia who still retained decisional capacity and was able to clearly articulate her request for deactivation of her implanted cardiac pacemaker—a scenario that would result in her death. In this case, the patient had the autonomy to make her decision, but clinicians at an outside hospital refused to deactivate her pacemaker even though they were in unanimous agreement that the patient had capacity to make this decision, citing personal discomfort and a belief that her decision seemed out of proportion to her suffering. We evaluated her at our hospital, found her to have decision-making capacity, and deactivated her pacer resulting in her death about 9 days later. While some clinicians may be comfortable discussing patient preferences for device deactivation in patients who are imminently dying, we can find no reports in the literature of requests for device deactivation from patients with terminal diagnoses who are not imminently dying.
Using High-Fidelity Virtual Reality for Mass-Casualty Incident Training by First Responders – A Systematic Review of the Literature
Authors: Heldring Sara , Jirwe Maria , Wihlborg Jonas , Berg Lukas , Lindström Veronica
Published: February 2024

Introduction:

First responders’ training and learning regarding how to handle a mass-casualty incident (MCI) is traditionally based on reading and/or training through computer-based scenarios, or sometimes through live simulations with actors. First responders should practice in realistic environments to narrow the theory-practice gap, and the possibility of repeating the training is important for learning. High-fidelity virtual reality (VR) is a promising tool to use for realistic and repeatable simulation training, but it needs to be further evaluated. The aim of this literature review was to provide a comprehensive description of the use of high-fidelity VR for MCI training by first responders.

Methods:

A systematic integrative literature review was used according to Whittemore and Knafl’s descriptions. Databases investigated were PubMed, CINAHL Complete, Academic Search Ultimate, Web of Science, and ERIC to find papers addressing the targeted outcome. The electronic search strategy identified 797 potential studies. Seventeen studies were deemed eligible for final inclusion.

Results:

Training with VR enables repetition in a way not possible with live simulation, and the realism is similar, yet not as stressful. Virtual reality offers a cost-effective and safe learning environment. The usability of VR depends on the level of immersion, the technology being error-free, and the ease of use.

Conclusions:

This integrative review shows that high-fidelity VR training should not rule out live simulation, but rather serve as a complement. First responders became more confident and prepared for real-life MCIs after training with high-fidelity VR, but efforts should be made to solve the technical issues found in this review to further improve the usability.
Psychometric Quality of the German HEXACO-60 Personality	Inventory-Revised
Authors: Wiechers Yannik , Kandler Christian
Published: February 2024

Abstract: Striving for more valid personality judgments is desirable as more sound decisions can be expected with increasing measurement accuracy. In this study, the psychometric qualities of the German HEXACO-60 personality inventory are evaluated. Extending previous studies, we examined the third-person observer-report form in addition to the first-person rating format, which allowed us to examine the psychometric quality beyond self-reports, such as cross-rater agreement, rank-order stability, structural validity, and measurement invariance. Data from 3,046 self-raters (61% female; age range: 14–90) and ratings from 2,199 well-informed acquaintances (partners, friends, or relatives of the self-raters) were analyzed. Satisfying internal consistency, 2-year and 4-year rank-order stabilities, agreement among self- and informant-raters, and consensus among informant-raters were found. Moreover, the six-factor structure was confirmed in structural equation models that incorporated the perspectives of both self-raters and informant-raters. Finally, partial strict measurement invariance was demonstrated across rater perspectives. Previous validation of the German HEXACO-60 self-report form could thus be replicated and expanded by highlighting the psychometric soundness of the third-person observer-report form and the convergent as well as discriminant validity of HEXACO trait measures across rater perspectives. The informant perspective provides valid additional benefits for the assessment of personality traits within the HEXACO framework.
Health Impacts of Future Prescribed Fire Smoke: Considerations From an Exposure Scenario in California
Authors: Rosenberg Andrew , Hoshiko Sumi , Buckman Joseph R. , Yeomans Kirstin R. , Hayashi Thomas , Kramer Samantha J. , Huang ShihMing , French Nancy H. F. , Rappold Ana G.
Published: February 2024

In response to increasing wildfire risks, California plans to expand the use of prescribed fire. We characterized the anticipated change in health impacts from exposure to smoke under a future fire‐management scenario relative to a historical period (2008–2016). Using dispersion models, we estimated daily fine particulate matter (PM2.5) emissions from hypothetical future prescribed fires on 500,000‐acres classified as high priority. To evaluate health impacts, we calculated excess daily cardiorespiratory emergency department visit rates attributed to all‐source PM2.5, distinguishing the portion of the burden attributed to prescribed fire. The total burden was differentiated by fire type and by smoke strata‐specific days to calculate strata‐specific burden rates, which were then applied to estimate the burden in the future scenario. This analysis suggests that the exposure to prescribed fire smoke, measured as the number of persons exposed per year, would be 15 times greater in the future. However, these exposures were associated with lower concentrations compared to the historical period. The increased number of exposure days led to an overall increase in the future health burden. Specifically, the northern, central, and southern regions experienced the largest burden increase. This study introduces an approach that integrates spatiotemporal exposure differences, baseline morbidity, and population size to assess the impacts of prescribed fire under a future scenario. The findings highlight the need to consider both the level and frequency of exposure to guide strategies to safeguard public health as well as aid forest management agencies in making informed decisions to protect communities while mitigating wildfire risks.
Seasonality in Carbon Flux Attenuation Explains Spatial Variability in Transfer Efficiency
Authors: de Melo Viríssimo Francisco , Martin Adrian P. , Henson Stephanie A. , Wilson Jamie D.
Published: February 2024

Each year, the biological carbon pump (BCP) transports large quantities of carbon from the ocean surface to the interior. The efficiency of this transfer varies geographically, and is a key determinant of the atmosphere‐ocean carbon dioxide balance. Traditionally, the attention has been focused on explaining perceived geographical variations in this transfer efficiency (TE) in an attempt to understand it, an approach that has led to conflicting results. Here we combine observations and modeling to show that the spatial variability in TE can instead be explained by the seasonal variability in carbon flux attenuation. We also show that seasonality can explain the contrast between known global estimates of TE, due to differences in the date and duration of sampling. Our results suggest caution in the mechanistic interpretation of annual‐mean patterns in TE and demonstrates that seasonally and spatially resolved data sets and models might be required to generate accurate evaluations of the BCP.
Duplex Underplating, Sediment Dehydration and Quartz Vein Mineralization in the Deep Tremor Source Region
Authors: Ujiie Kohtaro , Nishiyama Naoki , Yamamoto Hisaki , Yamashita Minoru , Nagaya Takayoshi , Sano Takashi , Kouketsu Yui
Published: February 2024

Deep tectonic tremor downdip of the seismogenic zone in warm subduction zones is thought to occur in the region of high fluid pressures. However, the deformation and fluid processes responsible for tremor are poorly understood. We examined the Tomuru metamorphic rocks on Ishigaki Island, southern Ryukyu Arc, deformed at ∼40 km depth and ∼450°C under epidote‐blueschist metamorphism comparable to the tremor source region in northern Cascadia subduction zone. Here, quartz vein‐rich metapelite and metabasite are repeated many times as a result of duplex underplating. The spatiotemporal relationship between clustered quartz veins and the juxtaposition of metapelite and metabasite suggests that quartz vein formation and duplex underplating are contemporaneous. Viscous shear in metapelite is accommodated by dissolution‐precipitation creep. Metabasite records heterogeneous dehydration, resulting in rheological heterogeneity characterized by greenschist lenses in the foliated blueschist matrix. Viscous shear in the blueschist matrix was mainly accommodated by dissolution‐precipitation creep of glaucophane. Geochemical and strontium‐neodymium isotope analyses indicated that quartz veins were derived from sediment dehydration, whereas dehydration from oceanic crust contributed neither to quartz vein formation nor to fluid overpressures. We suggest that high fluid pressure in the deep tremor source region is primarily controlled by dehydration of subducting sediments, and the clustered quartz veins in underplated rocks correlate with the overpressured tremor source in low shear‐wave velocity zones.
Development of Interpretable Probability Ellipse in Tropical Cyclone Track Forecasts Using Multiple Operational Ensemble Prediction Systems
Authors: Yoo Seungwoo , Ho Chang‐Hoi
Published: February 2024

Most tropical cyclone (TC) forecasting centers have implemented a probabilistic circle to represent track uncertainty at a specified lead time. Recent studies suggest that probability ellipses constructed from ensemble prediction systems can convey the anisotropy of track predictability. In this study, a new probability ellipse model is developed to interpret the extent of forward speed and heading uncertainties in ensemble forecasts by selecting an equal proportion of members in the along‐ and cross‐track directions. This method is validated using the 2019–2021 western North Pacific (WNP) TC track forecasts from the ensemble predictions of the European Centre for Medium‐Range Weather Forecasts, the United States National Centers for Environmental Prediction, and the Korea Meteorological Administration. When the proportion of ensemble members in the ellipse is set to 70%, more than one‐half (50.0%–73.6%) of the forecasts, depending on the lead time, indicate reduced area compared with that of the circle. The mean areas of the probability ellipses are 4.9%, 7.0%, 10.0%, and 11.5% smaller than those of the circle in 48‐, 72‐, 96‐, and 120‐hr forecasts, respectively. The forward speed shows greater uncertainty than the heading, as evidenced by the along‐track radii being larger than the cross‐track counterpart in ∼60% of the samples, regardless of the lead time. In addition, the regional distribution of the along‐track/cross‐track ratio in the probability ellipses can explain the dominant direction of the track error in a particular location. The proposed probability ellipse shows potential for application in operational TC track predictions.
Excess Ground Ice Profiles in Continuous Permafrost Mapped From InSAR Subsidence
Authors: Zwieback S. , Iwahana G. , Sakhalkar S. , Biessel R. , Taylor S. , Meyer F. J.
Published: February 2024

Excess ground ice formation and melt drive surface heave and settlement, and are critical components of the water balance in Arctic soils. Despite the importance of excess ice for the geomorphology, hydrology and biogeochemistry of permafrost landscapes, we lack fine‐scale estimates of excess ice profiles. Here, we introduce a Bayesian inversion method based on remotely sensed subsidence. It retrieves near‐surface excess ice profiles by probing the ice content at increasing depths as the thaw front deepens over summer. Ice profiles estimated from Sentinel‐1 interferometric synthetic aperture radar (InSAR) subsidence observations at 80 m resolution were spatially associated with the surficial geology in two Alaskan regions. In most geological units, the estimated profiles were ice poor in the central and, to a lesser extent, the upper active layer. In a warm summer, units with ice‐rich permafrost had elevated inferred ice contents at the base of the active layer and the (previous years') upper permafrost. The posterior uncertainty and accuracy varied with depth. In simulations, they were best (≲0.1) in the central active layer, deteriorating (≳0.2) toward the surface and permafrost. At two sites in the Brooks Foothills, Alaska, the estimates compared favorably to coring‐derived profiles down to 35 cm, while the increase in excess ice below the long‐term active layer thickness of 40 cm was only reproduced in a warm year. Pan‐Arctic InSAR observations enable novel observational constraints on the susceptibility of permafrost landscapes to terrain instability and on the controls, drivers and consequences of ground ice formation and loss.
White and gray matter alterations in bipolar I and bipolar II disorder subtypes compared with healthy controls – exploring associations with disease course and polygenic risk
Authors: Thiel Katharina , Lemke Hannah , Winter Alexandra , Flinkenflügel Kira , Waltemate Lena , Bonnekoh Linda , Grotegerd Dominik , Dohm Katharina , Hahn Tim , Förster Katharina , Kanske Philipp , Repple Jonathan , Opel Nils , Redlich Ronny , David Friederike , Forstner Andreas J. , Stein Frederike , Brosch Katharina , Thomas-Odenthal Florian , Usemann Paula , Teutenberg Lea , Straube Benjamin , Alexander Nina , Jamalabadi Hamidreza , Jansen Andreas , Witt Stephanie H. , Andlauer Till F. M. , Pfennig Andrea , Bauer Michael , Nenadić Igor , Kircher Tilo , Meinert Susanne , Dannlowski Udo
Published: February 2024

Patients with bipolar disorder (BD) show alterations in both gray matter volume (GMV) and white matter (WM) integrity compared with healthy controls (HC). However, it remains unclear whether the phenotypically distinct BD subtypes (BD-I and BD-II) also exhibit brain structural differences. This study investigated GMV and WM differences between HC, BD-I, and BD-II, along with clinical and genetic associations. N = 73 BD-I, n = 63 BD-II patients and n = 136 matched HC were included. Using voxel-based morphometry and tract-based spatial statistics, main effects of group in GMV and fractional anisotropy (FA) were analyzed. Associations between clinical and genetic features and GMV or FA were calculated using regression models. For FA but not GMV, we found significant differences between groups. BD-I patients showed lower FA compared with BD-II patients (ptfce-FWE = 0.006), primarily in the anterior corpus callosum. Compared with HC, BD-I patients exhibited lower FA in widespread clusters (ptfce-FWE < 0.001), including almost all major projection, association, and commissural fiber tracts. BD-II patients also demonstrated lower FA compared with HC, although less pronounced (ptfce-FWE = 0.049). The results remained unchanged after controlling for clinical and genetic features, for which no independent associations with FA or GMV emerged. Our findings suggest that, at a neurobiological level, BD subtypes may reflect distinct degrees of disease expression, with increasing WM microstructure disruption from BD-II to BD-I. This differential magnitude of microstructural alterations was not clearly linked to clinical and genetic variables. These findings should be considered when discussing the classification of BD subtypes within the spectrum of affective disorders.
Impairments of cerebellar structure and function in a zebrafish KO of neuropsychiatric risk gene znf536
Authors: Kim Tae-Yoon , Roychaudhury Arkaprava , Kim Hyun-Taek , Choi Tae-Ik , Baek Seung Tae , Thyme Summer B. , Kim Cheol-Hee
Published: February 2024

Genetic variants in ZNF536 contribute to the risk for neuropsychiatric disorders such as schizophrenia, autism, and others. The role of this putative transcriptional repressor in brain development and function is, however, largely unknown. We generated znf536 knockout (KO) zebrafish and studied their behavior, brain anatomy, and brain function. Larval KO zebrafish showed a reduced ability to compete for food, resulting in decreased total body length and size. This phenotype can be rescued by segregating the homozygous KO larvae from their wild-type and heterozygous siblings, enabling studies of adult homozygous KO animals. In adult KO zebrafish, we observed significant reductions in anxiety-like behavior and social interaction. These znf536 KO zebrafish have decreased cerebellar volume, corresponding to decreased populations of specific neuronal cells, especially in the valvular cerebelli (Va). Finally, using a Tg[mbp:mgfp] line, we identified a previously undetected myelin structure located bilaterally within the Va, which also displayed a reduction in volume and disorganization in KO zebrafish. These findings indicate an important role for ZNF536 in brain development and implicate the cerebellum in the pathophysiology of neuropsychiatric disorders.
Synergistic induction of tertiary lymphoid structures by chemoimmunotherapy in bladder cancer
Authors: Zhang Lu , Zhang Ruiyun , Jin Di , Zhang Tianxiang , Shahatiaili Akezhouli , Zang Jingyu , Wang Lu , Pu Yuanchun , Zhuang Guanglei , Chen Haige , Fan Jinhai
Published: February 2024

Background

A substantial number of patients with bladder cancer fail to benefit from immune checkpoint inhibitors (ICIs). We aim to investigate whether the addition of other therapeutic modalities into immunotherapy may augment the immune reactivity, thereby improving the overall response rate.

Methods

We conducted a comprehensive assessment of the immunological changes following immunotherapy and chemotherapy, employing both single-cell RNA sequencing and bulk RNA sequencing analyses.

Results

The bladder cancer patient treated with ICIs exhibited a higher abundance of B cells and T follicular helper cells compared to the treatment-naïve patient. Analysis of public datasets and the in-house RJBLC-I2N003 cohort revealed the induction of tertiary lymphoid structure (TLS) neogenesis and maturation by immunotherapy. The IMvigor 210 study suggested that TLS could serve as a predictor of immunotherapy response and patient prognosis. In addition, genome-wide transcriptome data unveiled a shift towards the immune-enriched subtype over the desert subtype in patients receiving neoadjuvant chemotherapy. Notably, the proportions of CD20 + B cells, T follicular helper cells, and TLSs were significantly increased. In patients treated with a combination of neoadjuvant chemotherapy and ICIs, TLS positivity and maturity were improved compared to the baseline. Furthermore, neoadjuvant chemoimmunotherapy resulted in a higher rate of pathological complete response compared to monotherapies.

Conclusions

This work pinpointed the individual effect of immunotherapy and chemotherapy in fostering TLS development, and underscored the superior effectiveness of combined modalities in enhancing TLS maturation and response rates.
ACSS2 controls PPARγ activity homeostasis to potentiate adipose-tissue plasticity
Authors: Chen Nuo , Zhao Ming , Wu Nan , Guo Yaxin , Cao Baihui , Zhan Bing , Li Yubin , Zhou Tian , Zhu Faliang , Guo Chun , Shi Yongyu , Wang Qun , Li Yan , Zhang Lining
Published: February 2024

The appropriate transcriptional activity of PPARγ is indispensable for controlling inflammation, tumor and obesity. Therefore, the identification of key switch that couples PPARγ activation with degradation to sustain its activity homeostasis is extremely important. Unexpectedly, we here show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) critically controls PPARγ activity homeostasis via SIRT1 to enhance adipose plasticity via promoting white adipose tissues beiging and brown adipose tissues thermogenesis. Mechanistically, ACSS2 binds directly acetylated PPARγ in the presence of ligand and recruits SIRT1 and PRDM16 to activate UCP1 expression. In turn, SIRT1 triggers ACSS2 translocation from deacetylated PPARγ to P300 and thereafter induces PPARγ polyubiquitination and degradation. Interestingly, D-mannose rapidly activates ACSS2-PPARγ-UCP1 axis to resist high fat diet induced obesity in mice. We thus reveal a novel ACSS2 function in coupling PPARγ activation with degradation via SIRT1 and suggest D-mannose as a novel adipose plasticity regulator via ACSS2 to prevent obesity.
Blockade of C5aR1 resets M1 via gut microbiota-mediated PFKM stabilization in a TLR5-dependent manner
Authors: Zhao Jie , Yao Chen , Qin Yongqin , Zhu Hanyong , Guo Hui , Ji Binbin , Li Xueqin , Sun Na , Li Rongqing , Wu Yuzhang , Zheng Kuiyang , Pan Yuchen , Zhao Tingting , Yang Jing
Published: February 2024

Targeting C5aR1 modulates the function of infiltrated immune cells including tumor-associated macrophages (TAMs). The gut microbiome plays a pivotal role in colorectal cancer (CRC) tumorigenesis and development through TAM education. However, whether and how the gut flora is involved in C5aR1 inhibition-mediated TAMs remains unclear. Therefore, in this study, genetic deletion of C5ar1 or pharmacological inhibition of C5aR1 with anti-C5aR1 Ab or PMX-53 in the presence or absence of deletion Abs were utilized to verify if and how C5aR1 inhibition regulated TAMs polarization via affecting gut microbiota composition. We found that the therapeutic effects of C5aR1 inhibition on CRC benefited from programming of TAMs toward M1 polarization via driving AKT2-mediated 6-phosphofructokinase muscle type (PFKM) stabilization in a TLR5-dependent manner. Of note, in the further study, we found that C5aR1 inhibition elevated the concentration of serum IL-22 and the mRNA levels of its downstream target genes encoded antimicrobial peptides (AMPs), leading to gut microbiota modulation and flagellin releasement, which contributed to M1 polarization. Our data revealed that high levels of C5aR1 in TAMs predicted poor prognosis. In summary, our study suggested that C5aR1 inhibition reduced CRC growth via resetting M1 by AKT2 activation-mediated PFKM stabilization in a TLR5-dependent manner, which relied on IL-22-regulated gut flora.
CUL4B mutations impair human cortical neurogenesis through PP2A-dependent inhibition of AKT and ERK
Authors: Ma Yanyan , Liu Xiaolin , Zhou Min , Sun Wenjie , Jiang Baichun , Liu Qiao , Wang Molin , Zou Yongxin , Liu Qiji , Gong Yaoqin , Sun Gongping
Published: February 2024

Mutation in CUL4B gene is one of the most common causes for X-linked intellectual disability (XLID). CUL4B is the scaffold protein in CUL4B-RING ubiquitin ligase (CRL4B) complex. While the roles of CUL4B in cancer progression and some developmental processes like adipogenesis, osteogenesis, and spermatogenesis have been studied, the mechanisms underlying the neurological disorders in patients with CUL4B mutations are poorly understood. Here, using 2D neuronal culture and cerebral organoids generated from the patient-derived induced pluripotent stem cells and their isogenic controls, we demonstrate that CUL4B is required to prevent premature cell cycle exit and precocious neuronal differentiation of neural progenitor cells. Moreover, loss-of-function mutations of CUL4B lead to increased synapse formation and enhanced neuronal excitability. Mechanistically, CRL4B complex represses transcription of PPP2R2B and PPP2R2C genes, which encode two isoforms of the regulatory subunit of protein phosphatase 2 A (PP2A) complex, through catalyzing monoubiquitination of H2AK119 in their promoter regions. CUL4B mutations result in upregulated PP2A activity, which causes inhibition of AKT and ERK, leading to premature cell cycle exit. Activation of AKT and ERK or inhibition of PP2A activity in CUL4B mutant organoids rescues the neurogenesis defect. Our work unveils an essential role of CUL4B in human cortical development.
The mechanisms, regulations, and functions of histone lysine crotonylation
Authors: Xie Jing-yi , Ju Jie , Zhou Ping , Chen Hao , Wang Shao-cong , Wang Kai , Wang Tao , Chen Xin-zhe , Chen Yan-chun , Wang Kun
Published: February 2024

Histone lysine crotonylation (Kcr) is a new acylation modification first discovered in 2011, which has important biological significance for gene expression, cell development, and disease treatment. In the past over ten years, numerous signs of progress have been made in the research on the biochemistry of Kcr modification, especially a series of Kcr modification-related “reader”, “eraser”, and “writer” enzyme systems are identified. The physiological function of crotonylation and its correlation with development, heredity, and spermatogenesis have been paid more and more attention. However, the development of disease is usually associated with abnormal Kcr modification. In this review, we summarized the identification of crotonylation modification, Kcr-related enzyme system, biological functions, and diseases caused by abnormal Kcr. This knowledge supplies a theoretical basis for further exploring the function of crotonylation in the future.
Efficacy and safety of using auditory-motor entrainment to improve walking after stroke: a multi-site randomized controlled trial of InTandemTM
Authors: Awad Louis N. , Jayaraman Arun , Nolan Karen J. , Lewek Michael D. , Bonato Paolo , Newman Mark , Putrino David , Raghavan Preeti , Pohlig Ryan T. , Harris Brian A. , Parker Danielle A. , Taylor Sabrina R.
Published: February 2024

Walking slowly after stroke reduces health and quality of life. This multi-site, prospective, interventional, 2-arm randomized controlled trial (NCT04121754) evaluated the safety and efficacy of an autonomous neurorehabilitation system (InTandemTM) designed to use auditory-motor entrainment to improve post-stroke walking. 87 individuals were randomized to 5-week walking interventions with InTandem or Active Control (i.e., walking without InTandem). The primary endpoints were change in walking speed, measured by the 10-meter walk test pre-vs-post each 5-week intervention, and safety, measured as the frequency of adverse events (AEs). Clinical responder rates were also compared. The trial met its primary endpoints. InTandem was associated with a 2x larger increase in speed (Δ: 0.14 ± 0.03 m/s versus Δ: 0.06 ± 0.02 m/s, F(1,49) = 6.58, p = 0.013), 3x more responders (40% versus 13%, χ2(1) ≥ 6.47, p = 0.01), and similar safety (both groups experienced the same number of AEs). The auditory-motor intervention autonomously delivered by InTandem is safe and effective in improving walking in the chronic phase of stroke.
Shear margins in upper half of Northeast Greenland Ice Stream were established two millennia ago
Authors: Jansen Daniela , Franke Steven , Bauer Catherine C. , Binder Tobias , Dahl-Jensen Dorthe , Eichler Jan , Eisen Olaf , Hu Yuanbang , Kerch Johanna , Llorens Maria-Gema , Miller Heinrich , Neckel Niklas , Paden John , de Riese Tamara , Sachau Till , Stoll Nicolas , Weikusat Ilka , Wilhelms Frank , Zhang Yu , Bons Paul D.
Published: February 2024

Only a few localised ice streams drain most of the ice from the Greenland Ice Sheet. Thus, understanding ice stream behaviour and its temporal variability is crucially important to predict future sea-level change. The interior trunk of the 700 km-long North-East Greenland Ice Stream (NEGIS) is remarkable due to the lack of any clear bedrock channel to explain its presence. Here, we present a 3-dimensional analysis of the folding and advection of its stratigraphic horizons, which shows that the localised flow and shear margins in the upper NEGIS were fully developed only ca 2000 years ago. Our results contradict the assumption that the ice stream has been stable throughout the Holocene in its current form and show that upper NEGIS-type development of ice streaming, with distinct shear margins and no bed topography relationship, can be established on time scales of hundreds of years, which is a major challenge for realistic mass-balance and sea-level rise projections.
The genetic basis of autoimmunity seen through the lens of T cell functional traits
Authors: Lagattuta Kaitlyn A. , Park Hannah L. , Rumker Laurie , Ishigaki Kazuyoshi , Nathan Aparna , Raychaudhuri Soumya
Published: February 2024

Autoimmune disease heritability is enriched in T cell-specific regulatory regions of the genome. Modern-day T cell datasets now enable association studies between single nucleotide polymorphisms (SNPs) and a myriad of molecular phenotypes, including chromatin accessibility, gene expression, transcriptional programs, T cell antigen receptor (TCR) amino acid usage, and cell state abundances. Such studies have identified hundreds of quantitative trait loci (QTLs) in T cells that colocalize with genetic risk for autoimmune disease. The key challenge facing immunologists today lies in synthesizing these results toward a unified understanding of the autoimmune T cell: which genes, cell states, and antigens drive tissue destruction?
Protection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R
Authors: Lund Camilla , Ranea-Robles Pablo , Falk Sarah , Rausch Dylan M. , Skovbjerg Grethe , Vibe-Petersen Victoria Kamma , Krauth Nathalie , Skytte Jacob Lercke , Vana Vasiliki , Roostalu Urmas , Pers Tune H. , Lund Jens , Clemmensen Christoffer
Published: February 2024

Overfeeding triggers homeostatic compensatory mechanisms that counteract weight gain. Here, we show that both lean and diet-induced obese (DIO) male mice exhibit a potent and prolonged inhibition of voluntary food intake following overfeeding-induced weight gain. We reveal that FGF21 is dispensable for this defense against weight gain. Targeted proteomics unveiled novel circulating factors linked to overfeeding, including the protease  legumain (LGMN). Administration of recombinant LGMN lowers body weight and food intake in DIO mice. The protection against weight gain is also associated with reduced vascularization in the hypothalamus and sustained reductions in the expression of the orexigenic neuropeptide genes, Npy and Agrp, suggesting a role for hypothalamic signaling in this homeostatic recovery from overfeeding. Overfeeding of melanocortin 4 receptor (MC4R) KO mice shows that these mice can suppress voluntary food intake and counteract the enforced weight gain, although their rate of weight recovery is impaired. Collectively, these findings demonstrate that the defense against overfeeding-induced weight gain remains intact in obesity and involves mechanisms independent of both FGF21 and MC4R.
Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor
Authors: Sake Svenja M. , Zhang Xiaoyu , Rajak Manoj Kumar , Urbanek-Quaing Melanie , Carpentier Arnaud , Gunesch Antonia P. , Grethe Christina , Matthaei Alina , Rückert Jessica , Galloux Marie , Larcher Thibaut , Le Goffic Ronan , Hontonnou Fortune , Chatterjee Arnab K. , Johnson Kristen , Morwood Kaycie , Rox Katharina , Elgaher Walid A. M. , Huang Jiabin , Wetzke Martin , Hansen Gesine , Fischer Nicole , Eléouët Jean-Francois , Rameix-Welti Marie-Anne , Hirsch Anna K. H. , Herold Elisabeth , Empting Martin , Lauber Chris , Schulz Thomas F. , Krey Thomas , Haid Sibylle , Pietschmann Thomas
Published: February 2024

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC50: 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor.
Experimental warming accelerates positive soil priming in a temperate grassland ecosystem
Authors: Tao Xuanyu , Yang Zhifeng , Feng Jiajie , Jian Siyang , Yang Yunfeng , Bates Colin T. , Wang Gangsheng , Guo Xue , Ning Daliang , Kempher Megan L. , Liu Xiao Jun A. , Ouyang Yang , Han Shun , Wu Linwei , Zeng Yufei , Kuang Jialiang , Zhang Ya , Zhou Xishu , Shi Zheng , Qin Wei , Wang Jianjun , Firestone Mary K. , Tiedje James M. , Zhou Jizhong
Published: February 2024

Unravelling biosphere feedback mechanisms is crucial for predicting the impacts of global warming. Soil priming, an effect of fresh plant-derived carbon (C) on native soil organic carbon (SOC) decomposition, is a key feedback mechanism that could release large amounts of soil C into the atmosphere. However, the impacts of climate warming on soil priming remain elusive. Here, we show that experimental warming accelerates soil priming by 12.7% in a temperate grassland. Warming alters bacterial communities, with 38% of unique active phylotypes detected under warming. The functional genes essential for soil C decomposition are also stimulated, which could be linked to priming effects. We incorporate lab-derived information into an ecosystem model showing that model parameter uncertainty can be reduced by 32–37%. Model simulations from 2010 to 2016 indicate an increase in soil C decomposition under warming, with a 9.1% rise in priming-induced CO2 emissions. If our findings can be generalized to other ecosystems over an extended period of time, soil priming could play an important role in terrestrial C cycle feedbacks and climate change.
The scientific journey of a novel adjuvant (AS37) from bench to bedside
Authors: D’Oro Ugo , O’Hagan Derek T.
Published: February 2024

A decade ago, we described a new approach to discover next generation adjuvants, identifying small-molecule immune potentiators (SMIPs) as Toll-like receptor (TLR)7 agonists. We also optimally formulated these drugs through adsorption to aluminum salts (alum), allowing them to be evaluated with a range of established and early-stage vaccines. Early proof-of-concept studies showed that a TLR7 agonist (TLR7a)-based SMIP, when adsorbed to alum, could perform as an effective adjuvant for a variety of different antigens, in both small and large animals. Studies in rodents demonstrated that the adjuvant enhanced immunogenicity of a recombinant protein-based vaccine against Staphylococcus aureus, and also showed potential to improve existing vaccines against pertussis or meningococcal infection. Extensive evaluations showed that the adjuvant was effective in non-human primates (NHPs), exploiting a mechanism of action that was consistent across the different animal models. The adjuvant formulation (named AS37) has now been advanced into clinical evaluation. A systems biology-based evaluation of the phase I clinical data with a meningococcal C conjugate vaccine showed that the AS37-adjuvanted formulation had an acceptable safety profile, was potent, and activated the expected immune pathways in humans, which was consistent with observations from the NHP studies. In the intervening decade, several alternative TLR7 agonists have also emerged and advanced into clinical development, such as the alum adsorbed TLR7/8 SMIP present in a widely distributed COVID-19 vaccine. This review summarizes the research and early development of the new adjuvant AS37, with an emphasis on the steps taken to allow its progression into clinical evaluations.
ezBIDS: Guided standardization of neuroimaging data interoperable with major data archives and platforms
Authors: Levitas Daniel , Hayashi Soichi , Vinci-Booher Sophia , Heinsfeld Anibal , Bhatia Dheeraj , Lee Nicholas , Galassi Anthony , Niso Guiomar , Pestilli Franco
Published: February 2024

Data standardization promotes a common framework through which researchers can utilize others’ data and is one of the leading methods neuroimaging researchers use to share and replicate findings. As of today, standardizing datasets requires technical expertise such as coding and knowledge of file formats. We present ezBIDS, a tool for converting neuroimaging data and associated metadata to the Brain Imaging Data Structure (BIDS) standard. ezBIDS contains four major features: (1) No installation or programming requirements. (2) Handling of both imaging and task events data and metadata. (3) Semi-automated inference and guidance for adherence to BIDS. (4) Multiple data management options: download BIDS data to local system, or transfer to OpenNeuro.org or to brainlife.io. In sum, ezBIDS requires neither coding proficiency nor knowledge of BIDS, and is the first BIDS tool to offer guided standardization, support for task events conversion, and interoperability with OpenNeuro.org and brainlife.io.
Tone in politics is not systematically related to macro trends, ideology, or experience
Authors: Pipal Christian , Bakker Bert N. , Schumacher Gijs , van der Velden Mariken A. C. G.
Published: February 2024

What explains the variation in tone in politics? Different literatures argue that changes in the tone of politicians reflect changes in the economy, general language, well-being, or ideology. So far, these claims have been empirically tested only in isolation, in single country studies, or with a small subset of indicators. We offer an overarching view by modelling the use of tone in European national parliaments in 7 countries across 30 years. Using a semi-supervised sentiment-topic model to measure polarity and arousal in legislative debates, we show in a preregistered multiverse analysis that the tone in legislative debates is not systematically related to previously claimed factors. We also replicate the absence of such systematic relationships using national leader speeches and parties’ election manifestos. There is also no universal trend towards more negativity or emotionality in political language. Overall, our results highlight the importance of multi-lingual and cross-country multiverse analyses for generalizing findings on emotions in politics.
Cortical folding correlates to aging and Alzheimer’s Disease’s cognitive and CSF biomarkers
Authors: de Moraes Fernanda Hansen P. , Sudo Felipe , Carneiro Monteiro Marina , de Melo Bruno R. P. , Mattos Paulo , Mota Bruno , Tovar-Moll Fernanda
Published: February 2024

This manuscript presents the quantification and correlation of three aspects of Alzheimer’s Disease evolution, including structural, biochemical, and cognitive assessments. We aimed to test a novel structural biomarker for neurodegeneration based on a cortical folding model for mammals. Our central hypothesis is that the cortical folding variable, representative of axonal tension in white matter, is an optimal discriminator of pathological aging and correlates with altered loadings in Cerebrospinal Fluid samples and a decline in cognition and memory. We extracted morphological features from T1w 3T MRI acquisitions using FreeSurfer from 77 Healthy Controls (age = 66 ± 8.4, 69% females), 31 Mild Cognitive Impairment (age = 72 ± 4.8, 61% females), and 13 Alzheimer’s Disease patients (age = 77 ± 6.1, 62% females) of recruited volunteers in Brazil to test its discriminative power using optimal cut-point analysis. Cortical folding distinguishes the groups with reasonable accuracy (Healthy Control-Alzheimer’s Disease, accuracy = 0.82; Healthy Control-Mild Cognitive Impairment, accuracy = 0.56). Moreover, Cerebrospinal Fluid biomarkers (total Tau, A$$\beta $$
β
1-40, A$$\beta $$
β
1-42, and Lipoxin) and cognitive scores (Cognitive Index, Rey’s Auditory Verbal Learning Test, Trail Making Test, Digit Span Backward) were correlated with the global neurodegeneration in MRI aiming to describe health, disease, and the transition between the two states using morphology.
Improved prediction of clinical pregnancy using artificial intelligence with enhanced inner cell mass and trophectoderm images
Authors: Kim Hyung Min , Ko Taehoon , Kang Hyoeun , Choi Sungwook , Park Jong Hyuk , Chung Mi Kyung , Kim Miran , Kim Na Young , Lee Hye Jun
Published: February 2024

This study aimed to assess the performance of an artificial intelligence (AI) model for predicting clinical pregnancy using enhanced inner cell mass (ICM) and trophectoderm (TE) images. In this retrospective study, we included static images of 2555 day-5-blastocysts from seven in vitro fertilization centers in South Korea. The main outcome of the study was the predictive capability of the model to detect clinical pregnancies (gestational sac). Compared with the original embryo images, the use of enhanced ICM and TE images improved the average area under the receiver operating characteristic curve for the AI model from 0.716 to 0.741. Additionally, a gradient-weighted class activation mapping analysis demonstrated that the enhanced image-trained AI model was able to extract features from crucial areas of the embryo in 99% (506/512) of the cases. Particularly, it could extract the ICM and TE. In contrast, the AI model trained on the original images focused on the main areas in only 86% (438/512) of the cases. Our results highlight the potential efficacy of using ICM- and TE-enhanced embryo images when training AI models to predict clinical pregnancy.