bluuebunny/crossref_metadata_2025 huggingface dataset:
L'art de la flûte française
Authors: Sobaskie James William
Published: January 2023

Some albums entail more than meets the ear. In the Age of Ravel and In the Age of Debussy surround representative works of Maurice Ravel (1875–1937) and Claude Debussy (1862–1918) with contextualizing selections from contemporaries. Compellingly rendered by Ransom Wilson and François Dumont, these discs document six decades of innovation. They also illuminate intriguing connections as well as fascinating contrasts among familiar and unfamiliar works. And each celebrates the art of the French flute. But there's more.
Morality and the Glass Ceiling: How Elite Rhetoric Reflects Gendered Strategies and Perspectives
Authors: Brisbane Laura , Hua Whitney , Jamieson Thomas
Published: January 2023

Moral rhetoric presents a strategic dilemma for female politicians, who must navigate stereotypes while appealing to copartisan voters. In this article, we investigate how gender shapes elite moral rhetoric given the influence of partisanship, ideology, gender stereotypes, and moral psychology. Drawing on moral foundations theory, we examine how female and male representatives differ in their emphasis on the five foundations of care, fairness, authority, loyalty, and purity. Using the Moral Foundations Dictionary, we analyze a corpus of 2.23 million tweets by U.S. Congress members between 2013 and 2021. We find that female representatives are more likely to emphasize care and less likely to emphasize authority and loyalty than their male peers. However, when subsetting by party, we find that gender effects are most pronounced among Democrats and largely negligible among Republicans. These findings offer insight into the rhetorical dynamics of political leadership at the intersection of gender and partisan identities.
Detection of Copper by the ChemCam Instrument Along Curiosity's Traverse in Gale Crater, Mars: Elevated Abundances in Glen Torridon
Authors: Goetz Walter , Dehouck Erwin , Gasda Patrick J. , Johnson Jeffrey R. , Meslin Pierre‐Yves , Lanza Nina L. , Wiens Roger C. , Rapin William , Frydenvang Jens , Payré Valerie , Gasnault Olivier
Published: January 2023

Laser‐induced breakdown spectroscopy, as utilized by the ChemCam instrument onboard the Curiosity rover, detected enhanced abundances of the element copper. Since landing in Gale crater (6 August 2012), 10 enhancements in copper abundance were observed during 3007 Martian days (sols) of rover operations and 24 km of driving (as of 20 January 2021). The most prominent ones were found in the Kimberley area on the crater floor (Aeolis Palus) and in Glen Torridon (GT) on the lower flanks of Aeolis Mons (Mt. Sharp). Enhancements in copper record the former existence of modestly acidic and oxidizing fluids, which were more oxidizing in Kimberley than in GT. Of the two main types of bedrock in the lowest part of GT, Mg‐rich “coherent” and K‐rich “rubbly” (named based on their outcrop expression), copper was detected only in coherent, not in rubbly bedrock. The difference between these two types of bedrock may be due to difference in provenance. Alternatively, based on a recently developed lacustrine‐groundwater mixing model, we suggest that rubbly bedrock was altered by modestly acidic, shallow‐subsurface lake water that leached out both copper and manganese, while coherent bedrock was affected by dominantly alkaline fluids which would be consistent with its mineralogical composition (including siderite) as returned by the CheMin instrument onboard the rover. Higher up in GT, ChemCam data indicated significant gradients in the copper concentration in coherent bedrock on a local scale of only a few meters, which suggests a different alteration style and possibly different types of diagenetic fluids.
A 420‐Year Perspective on Winter Lake Erie Levels
Authors: Wiles G. C. , Devereux K. , Gaglioti B. V. , D’Arrigo R. D.
Published: January 2023

Here, we present a 420‐year‐long winter lake level reconstruction for Lake Erie based primarily on temperature‐sensitive tree‐ring chronologies from Alaska, Oregon, and California. This well‐verified model explains more than 51% of the variance in winter lake levels over a 131‐year calibration period (1860–1990) and shows strong decadal fluctuations related to changes in sea surface temperatures in the North Pacific and the North Atlantic, which alternate in terms of their relative influence. Decadal variability is superimposed on a persistent secular lake level rise that began in the mid‐1900s coinciding with a growing influence of the Atlantic sector. In the context of the last 420 years, the instrumental period experienced extreme lake levels, with the lowest over the entire record during the Dustbowl and the highest in 2020. Fluctuations in Lake Erie water levels are primarily determined by climate, and their variability greatly impacts the region's infrastructure and ecosystems.
Air Pollution Unable to Intensify Storms via Warm‐Phase Invigoration
Authors: Romps David M. , Latimer Katie , Zhu Qindan , Jurkat‐Witschas Tina , Mahnke Christoph , Prabhakaran Thara , Weigel Ralf , Wendisch Manfred
Published: January 2023

According to the hypothesis of aerosol invigoration, the higher concentration of aerosols in polluted air intensifies storms. A leading theory for explaining such a relationship is warm‐phase invigoration, in which cloudy updrafts that are more polluted more readily condense water vapor onto liquid drops, thereby releasing latent heat faster, leading to higher buoyancies and higher updraft speeds. For this mechanism to work, water‐vapor supersaturations well in excess of 1% must be typical of relatively unpolluted cloudy updrafts. Here, the supersaturation is calculated from in situ observations of warm‐phase cloudy updrafts over the Amazon. Instead of values well in excess of 1%, the typical values are found to be around 0.2%. These observations imply that cleaner preindustrial air might have generated supersaturations around 1%, but those are still too low for warm‐phase invigoration to have any practically significant impact on cloud buoyancy and updraft speeds.
Interdecadal to Centennial Climate Variability Surrounding the 8.2 ka Event in North China Revealed Through an Annually Resolved Speleothem Record From Beijing
Authors: Duan Pengzhen , Li Hanying , Ma Zhibang , Zhao Jingyao , Dong Xiyu , Sinha Ashish , Hu Peng , Zhang Haiwei , Cai Yanjun , Ning Youfeng , Edwards R. Lawrence , Cheng Hai
Published: January 2023

The 8.2 ka event has been extensively studied, whereas its structure is ambiguous in North China. Here we present a high‐resolution (∼1 year) δ18O record from annual laminated speleothem from Beijing to characterize the detailed variability across this event in North China. Our record indicates a dry 8.2 ka event spanning 8.254–8.107 ka BP with a two‐stage structure superimposed by three prominent high δ18O excursions. The identical structure of speleothem δ18O records between North and central China during the event suggests a common forcing/response in East China, whereas the progressively increased offset between their average values may reflect changes in moisture source or rainout effect. A close comparison with the Greenland ice core records suggests a strong linear response of the Asian summer monsoon to the North Atlantic climate changes across the early and middle stages of the event, but a different mechanism in the termination processes.
The Linkage of Serial Cyclone Clustering in Western Europe and Weather Regimes in the North Atlantic‐European Region in Boreal Winter
Authors: Hauser Seraphine , Mueller Sebastian , Chen Xiaoyang , Chen Ting‐Chen , Pinto Joaquim G. , Grams Christian M.
Published: January 2023

Extra‐tropical cyclones are an important source of weather variability in the mid‐latitudes. Multiple occurrences in a short period of time at a particular location are denominated serial cyclone clustering (SCC), and potentially lead to large societal impacts. We investigate the relationship between SCC affecting Western Europe and large‐scale weather regimes (WRs) in the North Atlantic‐European region in boreal winter. We find that SCC in low latitudes (45°N) is predominantly associated with the anticyclonic Greenland Blocking WR. In contrast, SCC in mid and high latitudes (55°N, 65°N) is mostly linked to different cyclonic WRs. Thereby, SCC occurs typically within a well‐established WR that builds up prior to SCC and decays after SCC. Thus, SCC events are closely associated with recurrent, quasi‐stationary and persistent large‐scale flow patterns (WRs). This mutual relationship reveals the potential of WRs in forecasting storm series and associated impacts on sub‐seasonal to seasonal time scales.
Recent Decline of Irrigation‐Induced Cooling Effect Over the North China Plain in Observations and Model Simulations
Authors: Liu Guoshuai , Wang Weiguang , Shao Quanxi
Published: January 2023

Irrigation over the North China Plain (NCP) has been demonstrated to lower temperature by altering the surface energy budget. During past decades, the concurrence of irrigated area variation and reduced irrigation intensity prompted our investigation into whether there has been a temporal change in irrigation cooling effect over the NCP, which is largely unknown. Using historical observations in 1979–2018, we detect a shift in the cooling effect occurring around 1995, when the expansion of irrigated area was going to slow down and water‐conserving irrigation technology was boomingly introduced. After this time, the accelerated process of cooling effect (−0.0045°C year−1) switches to a decelerated one (0.0089°C year−1). Regional climate simulations also show a pronounced slowdown in irrigation‐induced cooling with the rate of 0.0081°C year−1. The irrigation‐induced cooling is expected to be weaker with the persistent reduction in agricultural water use and contribute to a more rapid warming.
Two Types of Martian Magnetotail Current Sheets: MAVEN Observations of Ion Composition
Authors: Li X. Z. , Rong Z. J. , Fraenz M. , Zhang C. , Klinger L. , Shi Z. , Gao J. W. , Dunlop M. W. , Wei Y.
Published: January 2023

Using measurements from the Mars Atmosphere and Volatile EvolutioN mission, we investigate the densities of H+ (), O+ (), and O2+ (), respectively, in the Martian magnetotail current sheet. We find that the current sheet when it is closer to the terminator than 0.75 Mars radii is mostly dominated by heavy ions (()>2 ), regardless of the variation of the upstream solar wind, but that it is sometimes dominated by H+ ( >2()) at downstream distances exceeding 0.75 Mars radii. The occurrence rate of the dominant H+ weakly increases (and that of the heavy ions decreases) with solar wind density and dynamic pressure. Our results suggest that solar wind protons could enter the Martian tail and may become the dominant ion species in the current sheet, particularly when the solar wind density or dynamic pressure is high.
Estimation of Stratospheric Intrusions During Indian Cyclones
Authors: Roy Chaitri , Ravishankara A. R. , Newman Paul A. , David Liji M. , Fadnavis Suvarna , Rathod Sagar D. , Lait Leslie , Krishnan R. , Clark Hannah , Sauvage Bastien
Published: January 2023

Deep convection associated with tropical cyclones leads to stratosphere‐troposphere exchange (STE), which affects the upper‐tropospheric ozone concentrations in the vicinity of the cyclones. This study estimates the ozone enhancements over India due to the North Indian Ocean (NIO) cyclones‐driven STE. Indicators such as stratospheric fraction and potential vorticity calculated using the reanalysis data sets suggest that roughly 70% of the cyclones show anomalously high stratospheric intrusions. Aircraft observations over different locations across India also show elevated ozone concentrations in the mid‐to‐upper troposphere on cyclone days. Further, ozone and stratospheric ozone tracer concentrations from Goddard Earth Observing System‐Chemistry simulations and the Copernicus Atmosphere Monitoring Service reanalysis data sets show up to 40 ppb of excess upper tropospheric ozone over India, of which stratospheric ozone accounts for roughly 60%. Stratospheric intrusion due to the Bay of Bengal and the Arabian Sea cyclones affected the upper tropospheric ozone amounts over North and South India, respectively. The stratospheric ozone was observed to propagate downwards into the troposphere, often reaching ∼600 hPa and, in some cases, even the surface.
Diurnal and Seasonal Variations of Aerosol Optical Depth Observed by MEDA/TIRS at Jezero Crater, Mars
Authors: Smith Michael D. , Martínez Germán M. , Sebastián Eduardo , Lemmon Mark T. , Wolff Michael J. , Apéstigue Victor , Arruego Ignacio , Toledo Daniel , Viúdez‐Moreiras Daniel , Rodriguez‐Manfredi Jose Antonio , Juarez Manuel de la Torre
Published: January 2023

The two upward‐looking Thermal InfraRed Sensor (TIRS) channels from the Mars Environmental Dynamics Analyzer (MEDA) instrument suite on board the Perseverance rover enable the retrieval of total aerosol optical depth (dust plus water ice cloud) above the rover for all observations when TIRS is taken. Because TIRS observes at thermal infrared wavelengths, the retrievals are possible during both the day and night and thus, they provide an excellent way to monitor both the diurnal and seasonal variations of aerosols above Jezero Crater. A retrieval algorithm has been developed for this purpose and here, we describe that algorithm along with our results for the first 400 sols of the Perseverance mission covering nearly the entire aphelion season as well as a regional dust storm and the beginning of the perihelion season. We find systematic diurnal variations in aerosol optical depth that can be associated with dust and water ice clouds as well as a clear change from a cloud‐filled aphelion season to a perihelion season where dust is the dominant aerosol. A comparison of retrieved optical depths between TIRS and the SkyCam camera that is also part of MEDA indicates evidence of possible diurnal variations in cloud height or particle size.
Long‐Term, High‐Resolution Permafrost Monitoring Reveals Coupled Energy Balance and Hydrogeologic Controls on Talik Dynamics Near Umiujaq (Nunavik, Québec, Canada)
Authors: Fortier Philippe , Young Nathan L. , Lemieux Jean‐Michel , Walvoord Michelle A. , Fortier Richard
Published: January 2023

Rising temperatures in the Arctic and subarctic are driving the rapid thaw of permafrost by reducing permafrost cooling, increasing active layer thickness, and promoting talik formation. In this study, the cyrohydrogeology of a permafrost mound located within the discontinuous permafrost zone near Umiujaq (Nunavik, Québec, Canada) is characterized through the analysis of a dataset covering more than two decades of monitoring. This dataset captures a high degree of interannual variability in air temperature and ground thermal conditions, as well as the formation and closure of a supra‐permafrost talik. Data indicate that variable saturation and advective heat transport directly contribute to the expansion and contraction of the talik. Data further indicate the presence of two distinct thermo‐hydrologic settings resulting from differences in surface conditions, as well as subsurface thermal and flow regimes. The first, found at the top of the mound feature, is characterized by very low moisture contents (<0.05 m3/m3), while the second, found at the side of the mound feature, shows higher annual moisture contents that strongly influence the dynamics of heat and groundwater flow. The data were synthesized into a detailed conceptual model of the cyrohydrogeological dynamics that highlights the important role of hydrogeological characterization and long‐term data sets in understanding the effects of groundwater flow on seasonal frost and permafrost dynamics. Specifically, the results presented here show that in the absence of long‐term data sets, longer‐period transient phenomena such as talik opening and closure may be misrepresented as uni‐directional feedback loops, as opposed to highly dynamic temporary phenomena.
Bronchopulmonary dysplasia prediction models: a systematic review and meta-analysis with validation
Authors: Kwok T’ng Chang , Batey Natalie , Luu Ka Ling , Prayle Andrew , Sharkey Don
Published: January 2023

Prediction models could identify infants at the greatest risk of bronchopulmonary dysplasia (BPD) and allow targeted preventative strategies. We performed a systematic review and meta-analysis with external validation of identified models. Studies using predictors available before day 14 of life to predict BPD in very preterm infants were included. Two reviewers assessed 7628 studies for eligibility. Meta-analysis of externally validated models was followed by validation using 62,864 very preterm infants in England and Wales. A total of 64 studies using 53 prediction models were included totalling 274,407 infants (range 32–156,587/study). In all, 35 (55%) studies predated 2010; 39 (61%) were single-centre studies. A total of 97% of studies had a high risk of bias, especially in the analysis domain. Following meta-analysis of 22 BPD and 11 BPD/death composite externally validated models, Laughon’s day one model was the most promising in predicting BPD and death (C-statistic 0.76 (95% CI 0.70–0.81) and good calibration). Six models were externally validated in our cohort with C-statistics between 0.70 and 0.90 but with poor calibration. Few BPD prediction models were developed with contemporary populations, underwent external validation, or had calibration and impact analyses. Contemporary, validated, and dynamic prediction models are needed for targeted preventative strategies.

Impact

This review aims to provide a comprehensive assessment of all BPD prediction models developed to address the uncertainty of which model is sufficiently valid and generalisable for use in clinical practice and research.

Published BPD prediction models are mostly outdated, single centre and lack external validation.

Laughon’s 2011 model is the most promising but more robust models, using contemporary data with external validation are needed to support better treatments.
A phase I trial of LXS196, a protein kinase C (PKC) inhibitor, for metastatic uveal melanoma
Authors: Piperno-Neumann S. , Carlino M. S. , Boni V. , Loirat D. , Speetjens F. M. , Park J. J. , Calvo E. , Carvajal R. D. , Nyakas M. , Gonzalez-Maffe J. , Zhu X. , Shirley M. D. , Ramkumar T. , Fessehatsion A. , Burks H. E. , Yerramilli-Rao P. , Kapiteijn E.
Published: January 2023

Background

Up to 50% of patients with uveal melanoma develop metastases (MUM) with a poor prognosis and median overall survival of approximately 1 year.

Methods

This phase I study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of the oral protein kinase C inhibitor LXS196 in 68 patients with MUM (NCT02601378). Patients received LXS196 doses ranging from 100–1000 mg once daily (QD; n = 38) and 200–400 mg twice daily (BID; n = 30).

Results

First cycle dose-limiting toxicities (DLTs) were observed in 7/38 (18.4%) QD and 2/17 (11.8%) BID patients. Hypotension was the most common DLT, occurring at doses ≥500 mg/day, and manageable with LXS196 interruption and dose reduction. Median duration of exposure to LXS196 was 3.71 months (range: 1.81–15.28) for QD and 4.6 months (range: 0.33–58.32) for BID dosing. Clinical activity was observed in 6/66 (9.1%) evaluable patients achieving response (CR/PR), with a median duration of response of 10.15 months (range: 2.99–41.95); 45/66 had stable disease (SD) per RECIST v1.1. At 300 mg BID, the recommended dose for expansion, 2/18 (11.1%) evaluable patients achieved PR and 12/18 (66.7%) had SD.

Conclusion

These results suggest manageable toxicity and encouraging clinical activity of single-agent LXS196 in patients with MUM.
CSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model
Authors: Johnson Noah R. , Yuan Peng , Castillo Erika , Lopez T. Peter , Yue Weizhou , Bond Annalise , Rivera Brianna M. , Sullivan Miranda C. , Hirouchi Masakazu , Giles Kurt , Aoyagi Atsushi , Condello Carlo
Published: January 2023

Microglia are central to pathogenesis in many neurological conditions. Drugs targeting colony-stimulating factor-1 receptor (CSF1R) to block microglial proliferation in preclinical disease models have shown mixed outcomes, thus the therapeutic potential of this approach remains unclear. Here, we show that CSF1R inhibitors given by multiple dosing paradigms in the Tg2541 tauopathy mouse model cause a sex-independent reduction in pathogenic tau and reversion of non-microglial gene expression patterns toward a normal wild type signature. Despite greater drug exposure in male mice, only female mice have functional rescue and extended survival. A dose-dependent upregulation of immediate early genes and neurotransmitter dysregulation are observed in the brains of male mice only, indicating that excitotoxicity may preclude functional benefits. Drug-resilient microglia in male mice exhibit morphological and gene expression patterns consistent with increased neuroinflammatory signaling, suggesting a mechanistic basis for sex-specific excitotoxicity. Complete microglial ablation is neither required nor desirable for neuroprotection and therapeutics targeting microglia must consider sex-dependent effects.
Thermodynamic architecture and conformational plasticity of GPCRs
Authors: Anantakrishnan Sathvik , Naganathan Athi N.
Published: January 2023

G-protein-coupled receptors (GPCRs) are ubiquitous integral membrane proteins involved in diverse cellular signaling processes. Here, we carry out a large-scale ensemble thermodynamic study of 45 ligand-free GPCRs employing a structure-based statistical mechanical framework. We find that multiple partially structured states co-exist in the GPCR native ensemble, with the TM helices 1, 6 and 7 displaying varied folding status, and shaping the conformational landscape. Strongly coupled residues are anisotropically distributed, accounting for only 13% of the residues, illustrating that a large number of residues are inherently dynamic. Active-state GPCRs are characterized by reduced conformational heterogeneity with altered coupling-patterns distributed throughout the structural scaffold. In silico alanine-scanning mutagenesis reveals that extra- and intra-cellular faces of GPCRs are coupled thermodynamically, highlighting an exquisite structural specialization and the fluid nature of the intramolecular interaction network. The ensemble-based perturbation methodology presented here lays the foundation for understanding allosteric mechanisms and the effects of disease-causing mutations in GCPRs.
Gray matter volume drives the brain age gap in schizophrenia: a SHAP study
Authors: Ballester Pedro L. , Suh Jee Su , Ho Natalie C. W. , Liang Liangbing , Hassel Stefanie , Strother Stephen C. , Arnott Stephen R. , Minuzzi Luciano , Sassi Roberto B. , Lam Raymond W. , Milev Roumen , Müller Daniel J. , Taylor Valerie H. , Kennedy Sidney H. , Reilly James P. , Palaniyappan Lena , Dunlop Katharine , Frey Benicio N.
Published: January 2023

Neuroimaging-based brain age is a biomarker that is generated by machine learning (ML) predictions. The brain age gap (BAG) is typically defined as the difference between the predicted brain age and chronological age. Studies have consistently reported a positive BAG in individuals with schizophrenia (SCZ). However, there is little understanding of which specific factors drive the ML-based brain age predictions, leading to limited biological interpretations of the BAG. We gathered data from three publicly available databases - COBRE, MCIC, and UCLA - and an additional dataset (TOPSY) of early-stage schizophrenia (82.5% untreated first-episode sample) and calculated brain age with pre-trained gradient-boosted trees. Then, we applied SHapley Additive Explanations (SHAP) to identify which brain features influence brain age predictions. We investigated the interaction between the SHAP score for each feature and group as a function of the BAG. These analyses identified total gray matter volume (group × SHAP interaction term β = 1.71 [0.53; 3.23]; pcorr < 0.03) as the feature that influences the BAG observed in SCZ among the brain features that are most predictive of brain age. Other brain features also presented differences in SHAP values between SCZ and HC, but they were not significantly associated with the BAG. We compared the findings with a non-psychotic depression dataset (CAN-BIND), where the interaction was not significant. This study has important implications for the understanding of brain age prediction models and the BAG in SCZ and, potentially, in other psychiatric disorders.
LAP1 supports nuclear adaptability during constrained melanoma cell migration and invasion
Authors: Jung-Garcia Yaiza , Maiques Oscar , Monger Joanne , Rodriguez-Hernandez Irene , Fanshawe Bruce , Domart Marie-Charlotte , Renshaw Matthew J. , Marti Rosa M. , Matias-Guiu Xavier , Collinson Lucy M. , Sanz-Moreno Victoria , Carlton Jeremy G.
Published: January 2023

Metastasis involves dissemination of cancer cells away from a primary tumour and colonization at distal sites. During this process, the mechanical properties of the nucleus must be tuned since they pose a challenge to the negotiation of physical constraints imposed by the microenvironment and tissue structure. We discovered increased expression of the inner nuclear membrane protein LAP1 in metastatic melanoma cells, at the invasive front of human primary melanoma tumours and in metastases. Human cells express two LAP1 isoforms (LAP1B and LAP1C), which differ in their amino terminus. Here, using in vitro and in vivo models that recapitulate human melanoma progression, we found that expression of the shorter isoform, LAP1C, supports nuclear envelope blebbing, constrained migration and invasion by allowing a weaker coupling between the nuclear envelope and the nuclear lamina. We propose that LAP1 renders the nucleus highly adaptable and contributes to melanoma aggressiveness.
Improved cytosine base editors generated from TadA variants
Authors: Lam Dieter K. , Feliciano Patricia R. , Arif Amena , Bohnuud Tanggis , Fernandez Thomas P. , Gehrke Jason M. , Grayson Phil , Lee Kin D. , Ortega Manuel A. , Sawyer Courtney , Schwaegerle Noah D. , Peraro Leila , Young Lauren , Lee Seung-Joo , Ciaramella Giuseppe , Gaudelli Nicole M.
Published: January 2023

Cytosine base editors (CBEs) enable programmable genomic C·G-to-T·A transition mutations and typically comprise a modified CRISPR–Cas enzyme, a naturally occurring cytidine deaminase, and an inhibitor of uracil repair. Previous studies have shown that CBEs utilizing naturally occurring cytidine deaminases may cause unguided, genome-wide cytosine deamination. While improved CBEs that decrease stochastic genome-wide off-targets have subsequently been reported, these editors can suffer from suboptimal on-target performance. Here, we report the generation and characterization of CBEs that use engineered variants of TadA (CBE-T) that enable high on-target C·G to T·A across a sequence-diverse set of genomic loci, demonstrate robust activity in primary cells and cause no detectable elevation in genome-wide mutation. Additionally, we report cytosine and adenine base editors (CABEs) catalyzing both A-to-I and C-to-U editing (CABE-Ts). Together with ABEs, CBE-Ts and CABE-Ts enable the programmable installation of all transition mutations using laboratory-evolved TadA variants with improved properties relative to previously reported CBEs.
Cell-type-specific prediction of 3D chromatin organization enables high-throughput in silico genetic screening
Authors: Tan Jimin , Shenker-Tauris Nina , Rodriguez-Hernaez Javier , Wang Eric , Sakellaropoulos Theodore , Boccalatte Francesco , Thandapani Palaniraja , Skok Jane , Aifantis Iannis , Fenyö David , Xia Bo , Tsirigos Aristotelis
Published: January 2023

Investigating how chromatin organization determines cell-type-specific gene expression remains challenging. Experimental methods for measuring three-dimensional chromatin organization, such as Hi-C, are costly and have technical limitations, restricting their broad application particularly in high-throughput genetic perturbations. We present C.Origami, a multimodal deep neural network that performs de novo prediction of cell-type-specific chromatin organization using DNA sequence and two cell-type-specific genomic features—CTCF binding and chromatin accessibility. C.Origami enables in silico experiments to examine the impact of genetic changes on chromatin interactions. We further developed an in silico genetic screening approach to assess how individual DNA elements may contribute to chromatin organization and to identify putative cell-type-specific trans-acting regulators that collectively determine chromatin architecture. Applying this approach to leukemia cells and normal T cells, we demonstrate that cell-type-specific in silico genetic screening, enabled by C.Origami, can be used to systematically discover novel chromatin regulation circuits in both normal and disease-related biological systems.
SARS-CoV-2 diagnostic testing rates determine the sensitivity of genomic surveillance programs
Authors: Han Alvin X. , Toporowski Amy , Sacks Jilian A. , Perkins Mark D. , Briand Sylvie , van Kerkhove Maria , Hannay Emma , Carmona Sergio , Rodriguez Bill , Parker Edyth , Nichols Brooke E. , Russell Colin A.
Published: January 2023

The first step in SARS-CoV-2 genomic surveillance is testing to identify people who are infected. However, global testing rates are falling as we emerge from the acute health emergency and remain low in many low- and middle-income countries (mean = 27 tests per 100,000 people per day). We simulated COVID-19 epidemics in a prototypical low- and middle-income country to investigate how testing rates, sampling strategies and sequencing proportions jointly impact surveillance outcomes, and showed that low testing rates and spatiotemporal biases delay time to detection of new variants by weeks to months and can lead to unreliable estimates of variant prevalence, even when the proportion of samples sequenced is increased. Accordingly, investments in wider access to diagnostics to support testing rates of approximately 100 tests per 100,000 people per day could enable more timely detection of new variants and reliable estimates of variant prevalence. The performance of global SARS-CoV-2 genomic surveillance programs is fundamentally limited by access to diagnostic testing.
Apolipoprotein C3 facilitates internalization of cationic lipid nanoparticles into bone marrow-derived mouse mast cells
Authors: Alam Syed Benazir , Wang Feng , Qian Hui , Kulka Marianna
Published: January 2023

Mast cells (MCs), are hematopoetically-derived secretory immune cells that release preformed as well as de novo synthesized inflammatory mediators in response to activation by several stimuli. Based on their role in inflammatory responses, particularly in the lung and skin, MCs provide an effective target for anti-inflammatory therapeutic strategies. Drug-delivery of lipophilic payloads to MCs can be challenging due to their functionally distinct intracellular structures. In the present study, pH-sensitive cationic lipid-based nanoparticles (LNPs) composed of DODMA, DODAP or DOTAP lipids that encapsulated a GFP or eGFP plasmid were constructed using non-turbulent microfluidic mixing. This approach achieved up to 75–92% encapsulation efficiency. Dynamic light scattering revealed a uniformly sized and homogeneous dispersion of LNPs. To promote cellular internalization, LNPs were complexed with apolipoproteins, amphipathic proteins capable of binding lipids and facilitating their transport into cells. Cryo-TEM analysis showed that LNP structure was differentially modified when associated with different types of apolipoproteins. LNP preparations made up of DODMA or DODMA, DODAP and DOTAP lipids were coated with seven apolipoproteins (Apo A1, B, C3, D, E2, E4 and H). Differentiated bone-marrow derived mouse mast cells (BMMCs) were exposed to apolipoprotein-LNP and internalization was measured using flow cytometry. Out of all the apolipoproteins tested, ApoC3 most efficiently facilitated cellular internalization of the LNP into BMMCs as determined by GFP fluorescence using flow cytometry. These effects were confirmed in a less differentiated but also interleukin-3-dependent model of mouse mast cells, MC/9. ApoC3-LNP enhanced internalization by BMMC in a concentration-dependent manner and this was significantly increased when BMMC were pre-treated with inhibitors of actin polymerization, suggesting a dependence on intracellular shuttling. Activation of peroxisome proliferator-activated receptor gamma (PPARγ) decreased ApoC3-LNP internalization and reduced the expression of apolipoprotein E receptor 2 (ApoER2), suggesting that ApoC3-LNP binding to ApoER2 may be responsible for its enhanced internalization. Furthermore, ApoC3 fails to facilitate internalization of LNPs in Lrp8−/− KO BMMC that do not express ApoER2 on their cell surface. Altogether, our studies reveal an important role of ApoC3 in facilitating internalization of cationic LNPs into MCs.
Prion protein amino acid sequence influences formation of authentic synthetic PrPSc
Authors: Block Alyssa J. , York Taylor C. , Benedict Romilly , Ma Jiyan , Bartz Jason C.
Published: January 2023

Synthetic prions, generated de novo from minimal, non-infectious components, cause bona fide prion disease in animals. Transmission of synthetic prions to hosts expressing syngeneic PrPC results in extended, variable incubation periods and incomplete attack rates. In contrast, murine synthetic prions (MSP) generated via PMCA with minimal cofactors readily infected mice and hamsters and rapidly adapted to both species. To investigate if hamster synthetic prions (HSP) generated under the same conditions as the MSP are also highly infectious, we inoculated hamsters with HSP generated with either hamster wild type or mutant (ΔG54, ΔG54/M139I, M139I/I205M) recombinant PrP. None of the inoculated hamsters developed clinical signs of prion disease, however, brain homogenate from HSPWT- and HSPΔG54-infected hamsters contained PrPSc, indicating subclinical infection. Serial passage in hamsters resulted in clinical disease at second passage accompanied by changes in incubation period and PrPSc conformational stability between second and third passage. These data suggest the HSP, in contrast to the MSP, are not comprised of PrPSc, and instead generate authentic PrPSc via deformed templating. Differences in infectivity between the MSP and HSP suggest that, under similar generation conditions, the amino acid sequence of PrP influences generation of authentic PrPSc.
Rapid prediction of secondary neurologic decline after traumatic brain injury: a data analytic approach
Authors: Podell Jamie , Yang Shiming , Miller Serenity , Felix Ryan , Tripathi Hemantkumar , Parikh Gunjan , Miller Catriona , Chen Hegang , Kuo Yi-Mei , Lin Chien Yu , Hu Peter , Badjatia Neeraj
Published: January 2023

Secondary neurologic decline (ND) after traumatic brain injury (TBI) is independently associated with outcome, but robust predictors of ND are lacking. In this retrospective analysis of consecutive isolated TBI admissions to the R. Adams Cowley Shock Trauma Center between November 2015 and June 2018, we aimed to develop a triage decision support tool to quantify risk for early ND. Three machine learning models based on clinical, physiologic, or combined characteristics from the first hour of hospital resuscitation were created. Among 905 TBI cases, 165 (18%) experienced one or more ND events (130 clinical, 51 neurosurgical, and 54 radiographic) within 48 h of presentation. In the prediction of ND, the clinical plus physiologic data model performed similarly to the physiologic only model, with concordance indices of 0.85 (0.824–0.877) and 0.84 (0.812–0.868), respectively. Both outperformed the clinical only model, which had a concordance index of 0.72 (0.688–0.759). This preliminary work suggests that a data-driven approach utilizing physiologic and basic clinical data from the first hour of resuscitation after TBI has the potential to serve as a decision support tool for clinicians seeking to identify patients at high or low risk for ND.
3D printing of hollow geometries using blocking liquid substitution stereolithography
Authors: Bhanvadia Aftab A. , Farley Richard T. , Noh Youngwook , Nishida Toshikazu
Published: January 2023

Micrometer scale arbitrary hollow geometries within a solid are needed for a variety of applications including microfluidics, thermal management and metamaterials. A major challenge to 3D printing hollow geometries using stereolithography is the ability to retain empty spaces in between the solidified regions. In order to prevent unwanted polymerization of the trapped resin in the hollow spaces—known as print-through—significant constraints are generally imposed on the primary process parameters such as resin formulation, exposure conditions and layer thickness. Here, we report on a stereolithography process which substitutes the trapped resin with a UV blocking liquid to mitigate print-through. We investigate the mechanism of the developed process and determine guidelines for the formulation of the blocking liquid. The reported method decouples the relationship between the primary process parameters and their effect on print-through. Without having to optimize the primary process parameters to reduce print-through, hollow heights that exceed the limits of conventional stereolithography can be realized. We demonstrate fabrication of a variety of complex hollow geometries with cross-sectional features ranging from tens of micrometer to hundreds of micrometers in size. With the framework presented, this method may be employed for 3D printing functional hollow geometries for a variety of applications, and with improved freedom over the printing process (e.g. material choices, speed and resulting properties of the printed parts).
Exploration of body weight in 115 000 young adult dogs of 72 breeds
Authors: Andersson L. , Emanuelson U. , Ringmark S. , Bjørnvad C. R. , Hedhammar Å. , Höglund K.
Published: January 2023

High body weight (BW), due to large size or excess body fat, has been associated with developmental and metabolic alterations, and degenerative diseases in dogs. Study objectives were to determine mean BW in young adult dogs of different breeds, including changes over a 10-year period. Body weight data from the official Swedish hip dysplasia screening program were used, including data from dogs screened at 1–2.5 years of age, in breeds with ≥ 15 individual observations/year during 2007–2016. Mean BW per breed and sex was established from 114 568 dogs representing 72 breeds. Estimates of breed BW showed significant change in 33 (45%) breeds over the 10-year period. Body weight increased in five breeds (2–14% change) and decreased in 26 breeds (1–8% change). In two breeds, BW increased in male and decreased in female dogs. This observational study provides extensive breed BW data on young adult dogs. The change in breed BW, noted in almost half of the breeds, could be due to changes either in size or in body fat mass. In certain breeds, the change in BW over time might have an impact on overall health. Studies with simultaneous evaluation of BW and body condition over time are warranted.
Micro-CT results exhibit ovules enclosed in the ovaries of Nanjinganthus
Authors: Fu Qiang , Hou Yemao , Yin Pengfei , Diez José Bienvenido , Pole Mike , García-Ávila Manuel , Wang Xin
Published: January 2023

The Early Jurassic angiosperm Nanjinganthus has triggered a heated debate among botanists, partially due to the fact that the enclosed ovules were visible to naked eyes only when the ovary is broken but not visible when the closed ovary is intact. Although traditional technologies cannot confirm the existence of ovules in a closed ovary, newly available Micro-CT can non-destructively reveal internal features of fossil plants. Here, we performed Micro-CT observations on three dimensionally preserved coalified compressions of Nanjinganthus. Our outcomes corroborate the conclusion given by Fu et al., namely, that Nanjinganthus is an Early Jurassic angiosperm.
Alleviation of soil acidification and modification of soil bacterial community by biochar derived from water hyacinth Eichhornia crassipes
Authors: Jutakanoke Rumpa , Intaravicha Nuttakorn , Charoensuksai Purin , Mhuantong Wuttichai , Boonnorat Jarungwit , Sichaem Jirapast , Phongsopitanun Wongsakorn , Chakritbudsabong Warunya , Rungarunlert Sasitorn
Published: January 2023

The highly acid sulfate Rangsit soil series of Rangsit, Pathum-Thani district, Thailand poses a major problem for agriculture in the area. Water hyacinth is a naturally occurring weed that can grow aggressively, causing eutrophication and leading to many severe environmental impacts. Here, through the pyrolysis process, we convert water hyacinth to biochar and use it for acid soil amendment. We found the ratio between biochar, soil, and sand suitable for the cultivation of water convolvulus to be 50 g of biochar, 400 g of soil, and 100 g of sand (1:8:2). This soil mixture improved the pH of the soil from 4.73 to 7.57. The plant height of the water convolvulus grown in the soil mixture was the greatest at 20.45 cm and the plant weight with and without roots was greatest at 2.23 g and 2.52 g, respectively. Moreover, we demonstrated the dominance and high abundance of Bacillus among the community in soil with biochar amendment. Here we provide the first assessment of the appropriate amount of water hyacinth-derived biochar for mitigation of soil acidity and promotion of optimal water convolvulus growth. Moreover, biochar can optimally modify soil bacterial communities that benefit plant development.
The association between dietary patterns derived by three statistical methods and type 2 diabetes risk: YaHS-TAMYZ and Shahedieh cohort studies
Authors: Beigrezaei Sara , Jambarsang Sara , Khayyatzadeh Sayyed Saeid , Mirzaei Masoud , Mehrparvar Amir Houshang , Salehi-Abargouei Amin
Published: January 2023

Findings were inconsistent regarding the superiority of using recently introduced hybrid methods to derive DPs compared to widely used statistical methods like principal component analysis (PCA) in assessing dietary patterns and their association with type 2 diabetes mellitus (T2DM). We aimed to investigate the association between DPs extracted using principal component analysis (PCA), partial least-squares (PLS), and reduced-rank regressions (RRR) in identifying DPs associated with T2DM risk. The study was conducted in the context of two cohort studies accomplished in central Iran. Dietary intake data were collected by food frequency questionnaires (FFQs). DPs were derived by using PCA, PLS, and RRR methods considering. The association between DPs with the risk of T2DM was assessed using log-binomial logistic regression test. A total of 8667 participants aged 20–70 years were included in this study. In the multivariate-adjusted models, RRR-DP3 characterized by high intake of fruits, tomatoes, vegetable oils, and refined grains and low intake of processed meats, organ meats, margarine, and hydrogenated fats was significantly associated with a reduced T2DM risk (Q5 vs Q1: RR 0.540, 95% CI 0.33–0.87, P-trend = 0.020). No significant highest-lowest or trend association was observed between DPs derived using PCA or PLS and T2DM. The findings indicate that RRR method was more promising in identifying DPs that are related to T2DM risk compared to PCA and PLS methods.
The enhanced dewaterability of sludge by a starch-based flocculant combined with attapulgite
Authors: Shen Shaohang , Wei Hua , Pan Yu , Hu Pan , Yang Hu
Published: January 2023

Coagulation/flocculation is one of the most widely used and cost-effective pretreatment methods for improving the dewaterability of sludge. In this study, a cationic modified starch-based flocculant (St-CTA) in conjunction with a popular clay, attapulgite (ATP), was used for the conditioning of waste-activated sludge. The dewatering properties, including the filter cake moisture content, filtration specific resistance, capillary suction time, filtration rate and compressibility coefficient, were measured and compared by varying the doses of St-CTA and ATP. By combination of the apparent dewatering performance and the changes in the contents and distributions of the extracellular polymeric substance (EPS) fractions and components, sludge flocs, and microstructures of sludge cakes, the dewatering mechanisms were discussed in detail. St-CTA in conjunction with ATP can exhibit an enhanced dewaterability of sludge and the water content in final sludge cake can be stably reduced below 80% owing to the synergistic effects of St-CTA and ATP. In addition to the efficient charge neutralization of St-CTA, ATP not only acts as a skeleton builder in the sludge dewatering process which makes the sludge flocs more compact and improves the filterability and permeability, but also tightly interacts with the proteins in EPS of the sludge which reduces the protein content and further enhances the dewatering effect. This study provides an economical, green, and effective way to further improve the dewaterability of sludge.
Choroidal thickness as a possible predictor of non-response to intravitreal bevacizumab for macular edema after retinal vein occlusion
Authors: Aljundi Wissam , Gradinger Florian , Langenbucher Achim , Sideroudi Haris , Seitz Berthold , Abdin Alaa Din
Published: January 2023

To evaluate outcomes of intravitreal bevacizumab (IVB) treating macular edema (ME) after retinal vein occlusion (RVO) following pro re nata (PRN) regimen and investigate potential predictors of non-response. Retrospective analysis of 126 treatment-naive eyes with ME after RVO. Eyes were treated initially with IVB of 1.25 mg/ml. Therapy was switched in case of non-response. Outcome measures included best-corrected visual acuity (BCVA) and central macular thickness (CMT), which were recorded over 4 years of treatment. BCVA improved significantly during first 2 years. CMT decreased significantly during the 4-year follow-up period. Switching was required in 42 eyes (33%). 34 eyes (26.9%) were switched to steroids, while 8 eyes (6.3%) were switched to other anti-VEGF due to diagnosed glaucoma. Switching occurred after 12.4 ± 8.3 months and an average of 8 ± 4.1 IVBs. Compared with the treatment-responsive group, the treatment-unresponsive group had significantly worse BCVA, higher CMT and subfoveal choroidal thickness (SFCT) at baseline. Treatment IVB following PRN regimen showed significant functional and anatomic improvement in patients with ME after RVO. Switching was required in more than one third of eyes. Higher baseline SFCT could be considered as predictor for non-response to such therapy and thus an indicator of early switching.
Polymerization boosting cascade energy transfer based on opened glucopyranosyl β-cyclodextrin
Authors: Yu Jie , Wang Hui , Dai Xian-Yin , Niu Jie , Liu Yu
Published: January 2023

Opened β-cyclodextrin was cross-linked with chitosan to form luminescent hydrogel, which not only benefits the clustering-triggered emission of the polymer, but also could co-assemble with acceptors achieving efficient cascade energy transfer.
Flanking-donor-controlled diversity in mechanical-force-induced reversible fluorochromism and enhanced emission for carboxylic acid and ester linked solid-state emitters
Authors: Chakraborty Madhuparna , Chakravarty Manab
Published: January 2023

Flanking donor-controlled diverse mechano-induced emission switching (MFC) and enhanced emission (MIEE).
A BC2N/blue phosphorene heterostructure as an anode material for high-performance sodium-ion batteries: first principles insights
Authors: Mansouri Zouhir , Al-Shami Ahmed , Sibari Anass , Lahbabi Salma , El Kenz Abdallah , Benyoussef Abdelilah , El Fatimy Abdelouahed , Mounkachi Omar
Published: January 2023

The electronic and electrochemical investigations of a Na-adsorbed BC2N/Blue phosphorene van der Waals heterostructure show that it may operate as a promising anode material for sodium-ion batteries.