bluuebunny/crossref_metadata_2025 huggingface dataset:
Selecting Appropriate Model Complexity: An Example of Tracer Inversion for Thermal Prediction in Enhanced Geothermal Systems
Authors: Wu Hui , Jin Zhijun , Jiang Su , Tang Hewei , Morris Joseph P. , Zhang Jinjiang , Zhang Bo
Published: June 2024

A major challenge in the inversion of subsurface parameters is the ill‐posedness issue caused by the inherent subsurface complexities and the generally spatially sparse data. Appropriate simplifications of inversion models are thus necessary to make the inversion process tractable and meanwhile preserve the predictive ability of the inversion results. In this study, we investigate the effect of model complexity on fracture aperture inversion and thermal performance prediction in a field‐scale EGS model. Principal component analysis was used to map the aperture field to a low‐dimensional latent space. The complexity of the inversion model was quantitatively represented by the percentage of total variance in the original aperture fields preserved by the latent space. Tracer, pressure and flow rate data were used to invert for fracture aperture through an ensemble‐based inversion method, and the inferred aperture field was used to predict thermal performance. With an over‐simplified aperture model, ensemble collapse occurred. The inverted aperture models failed to resolve necessary flow and transport features, leading to a biased thermal performance prediction. A complex aperture model involved excessive features and was prone to overinterpreting the inversion data. Both the tracer/pressure/flow rate data reproduction and thermal prediction showed significant uncertainties, making it difficult to properly estimate long‐term thermal performance. Fortunately, our results indicate that there exists an appropriate model complexity which can simultaneously match inversion data and predict thermal performance with an acceptable uncertainty. The quality of the fit of tracer data appears to be a useful indicator of such an appropriate model complexity.
In‐Phase PDO and El Niño Events Enhance the Summer CO2 Emissions in Saline Lakes on the Qinghai‐Tibet Plateau
Authors: Shi Fangzhong , Li Xiaoyan , Zhao Shaojie , Wei Junqi , Zhang Yu , Yang Xiaofan
Published: June 2024

Saline lakes contributions to the carbon cycle is crucial to the Qinghai‐Tibetan Plateau (QTP) carbon budget. Here, based on the 8‐year direct measurement of CO2 flux over the Qinghai Lake (QHL) and 83 collected CO2 flux data estimated by pCO2 sampling from 45 lakes over the QTP, we identified the interannual variations of CO2 flux and its response to the extreme climate events. Results showed: (a) the QHL CO2 absorption weakened in the spring, autumn and winter and turn to CO2 emissions in the summer during 2013–2020; (b) with higher Ts and less precipitation, coupling of positive Pacific Decadal Oscillation (PDO) and El Niño enhanced the summer CO2 emissions; and (c) the PDO and ENSO had obvious superposition effect on the decrease of CO2 absorption in autumn. Our results show the potential mechanism of lake CO2 flux responses to extreme climate and further defines the significance of the QTP carbon budget and cycling.
Emerging probing perspective of two-dimensional materials physics: terahertz emission spectroscopy
Authors: Wu Yifei , Wang Yuqi , Bao Di , Deng Xiaonan , Zhang Simian , Yu-chun Lin , Ke Shengxian , Liu Jianing , Liu Yingjie , Wang Zeli , Ham Pingren , Hanna Andrew , Pan Jiaming , Hu Xinyue , Li Zhengcao , Zhou Ji , Wang Chen
Published: July 2024

Terahertz (THz) emission spectroscopy (TES) has emerged as a highly effective and versatile technique for investigating the photoelectric properties of diverse materials and nonlinear physical processes in the past few decades. Concurrently, research on two-dimensional (2D) materials has experienced substantial growth due to their atomically thin structures, exceptional mechanical and optoelectronic properties, and the potential for applications in flexible electronics, sensing, and nanoelectronics. Specifically, these materials offer advantages such as tunable bandgap, high carrier mobility, wideband optical absorption, and relatively short carrier lifetime. By applying TES to investigate the 2D materials, their interfaces and heterostructures, rich information about the interplay among photons, charges, phonons and spins can be unfolded, which provides fundamental understanding for future applications. Thus it is timely to review the nonlinear processes underlying THz emission in 2D materials including optical rectification, photon-drag, high-order harmonic generation and spin-to-charge conversion, showcasing the rich diversity of the TES employed to unravel the complex nature of these materials. Typical applications based on THz emissions, such as THz lasers, ultrafast imaging and biosensors, are also discussed. Step further, we analyzed the unique advantages of spintronic terahertz emitters and the future technological advancements in the development of new THz generation mechanisms leading to advanced THz sources characterized by wide bandwidth, high power and integration, suitable for industrial and commercial applications. The continuous advancement and integration of TES with the study of 2D materials and heterostructures promise to revolutionize research in different areas, including basic materials physics, novel optoelectronic devices, and chips for post-Moore’s era.
GluK1 kainate receptors are necessary for functional maturation of parvalbumin interneurons regulating amygdala circuit function
Authors: Haikonen Joni , Szrinivasan Rakenduvadhana , Ojanen Simo , Rhee Jun Kyu , Ryazantseva Maria , Sulku Janne , Zumaraite Gabija , Lauri Sari E.
Published: June 2024

Parvalbumin expressing interneurons (PV INs) are key players in the local inhibitory circuits and their developmental maturation coincides with the onset of adult-type network dynamics in the brain. Glutamatergic signaling regulates emergence of the unique PV IN phenotype, yet the receptor mechanisms involved are not fully understood. Here we show that GluK1 subunit containing kainate receptors (KARs) are necessary for development and maintenance of the neurochemical and functional properties of PV INs in the lateral and basal amygdala (BLA). Ablation of GluK1 expression specifically from PV INs resulted in low parvalbumin expression and loss of characteristic high firing rate throughout development. In addition, we observed reduced spontaneous excitatory synaptic activity at adult GluK1 lacking PV INs. Intriguingly, inactivation of GluK1 expression in adult PV INs was sufficient to abolish their high firing rate and to reduce PV expression levels, suggesting a role for GluK1 in dynamic regulation of PV IN maturation state. The PV IN dysfunction in the absence of GluK1 perturbed the balance between evoked excitatory vs. inhibitory synaptic inputs and long-term potentiation (LTP) in LA principal neurons, and resulted in aberrant development of the resting-state functional connectivity between mPFC and BLA. Behaviorally, the absence of GluK1 from PV INs associated with hyperactivity and increased fear of novelty. These results indicate a critical role for GluK1 KARs in regulation of PV IN function across development and suggest GluK1 as a potential therapeutic target for pathologies involving PV IN malfunction.
Progression of brain injuries associated with methotrexate chemotherapy in childhood acute lymphoblastic leukemia
Authors: Bansal Ravi , Bhojwani Deepa , Sun Bernice F. , Sawardekar Siddhant , Wayne Alan S. , Ouassil Hannah , Gupte Chaitanya , Marcelino Courtney , Gonzalez Anaya Maria J. , Luna Natalia , Peterson Bradley S.
Published: July 2024

Background

Brain bases and progression of methotrexate-associated neurotoxicity and cognitive disturbances remain unknown. We tested whether brain abnormalities worsen in proportion to intrathecal methotrexate(IT-MTX) doses.

Methods

In this prospective, longitudinal study, we recruited 19 patients with newly diagnosed acute lymphoblastic leukemia 4-to-20 years of age and 20 matched controls. We collected MRI and neuropsychological assessments at a pre-methotrexate baseline and at week 9, week 22, and year 1 during treatment.

Results

Patients had baseline abnormalities in cortical and subcortical gray matter(GM), white matter(WM) volumes and microstructure, regional cerebral blood flow, and neuronal density. Abnormalities of GM, blood flow, and metabolites worsened in direct proportions to IT-MTX doses. WM abnormalities persisted until week 22 but normalized by year 1. Brain injuries were localized to dorsal and ventral attentional and frontoparietal cognitive networks. Patients had cognitive deficits at baseline that persisted at 1-year follow-up.

Conclusions

Baseline abnormalities are likely a consequence of neuroinflammation and oxidative stress. Baseline abnormalities in WM microstructure and volumes, and blood flow persisted until week 22 but normalized by year 1, likely due to treatment and its effects on reducing inflammation. The cytotoxic effects of IT-MTX, however, likely contributed to continued, progressive cortical thinning and reductions in neuronal density, thereby contributing to enduring cognitive deficits.

Impact

Brain abnormalities at a pre-methotrexate baseline likely are due to acute illness. The cytotoxic effects of intrathecal MTX contribute to progressive cortical thinning, reductions in neuronal density, and enduring cognitive deficits.

Baseline white matter abnormalities may have normalized via methotrexate treatment and decreasing neuroinflammation. Corticosteroid and leucovorin conferred neuroprotective effects.

Our findings suggest that the administration of neuroprotective and anti-inflammatory agents should be considered even earlier than they are currently administered. The neuroprotective effects of leucovorin suggest that strategies may be developed that extend the duration of this intervention or adapt it for use in standard risk patients.
Management of rarely seen internal tunnelling root resorption associated with a maxillary permanent incisor
Authors: Carney Kirsty A. , Colloc Thibault N. E. , Kilgariff Julie K.
Published: June 2024

This case presents clinical techniques and materials that may be applied in the management of internal tunnelling root resorption, a rare condition which has little published literature.

A 25-year-old woman was referred to a specialist centre by her general dental practitioner following an incidental finding of a radiographic radiolucency, suggestive of root resorption associated with tooth 21. A provisional diagnosis of external cervical resorption was made, and following cone beam computed tomography (CBCT), a definitive diagnosis of internal tunnelling root resorption given. Non-surgical endodontic treatment was completed using continuous wave compaction with a calcium-silicate based sealer. No further intervention has been required.

A summary of the histology, aetiology, prevalence, diagnosis, management and prognosis of internal tunnelling root resorption is provided. The benefits of CBCT for diagnosing and managing internal tunnelling resorption defects and using continuous wave compaction with a calcium-silicate based sealer, compared to cold obturation techniques, are discussed.
Synergy of retinoic acid and BH3 mimetics in MYC(N)-driven embryonal nervous system tumours
Authors: Seiboldt Till , Zeiser Constantia , Nguyen Duy , Celikyürekli Simay , Herter Sonja , Najafi Sara , Stroh-Dege Alexandra , Meulenbroeks Chris , Mack Norman , Salem-Altintas Rabia , Westermann Frank , Schlesner Matthias , Milde Till , Kool Marcel , Holland-Letz Tim , Vogler Meike , Peterziel Heike , Witt Olaf , Oehme Ina
Published: June 2024

Background

Certain paediatric nervous system malignancies have dismal prognoses. Retinoic acid (RA) is used in neuroblastoma treatment, and preclinical data indicate potential benefit in selected paediatric brain tumour entities. However, limited single-agent efficacy necessitates combination treatment approaches.

Methods

We performed drug sensitivity profiling of 76 clinically relevant drugs in combination with RA in 16 models (including patient-derived tumouroids) of the most common paediatric nervous system tumours. Drug responses were assessed by viability assays, high-content imaging, and apoptosis assays and RA relevant pathways by RNAseq from treated models and patient samples obtained through the precision oncology programme INFORM (n = 2288). Immunoprecipitation detected BCL-2 family interactions, and zebrafish embryo xenografts were used for in vivo efficacy testing.

Results

Group 3 medulloblastoma (MBG3) and neuroblastoma models were highly sensitive to RA treatment. RA induced differentiation and regulated apoptotic genes. RNAseq analysis revealed high expression of BCL2L1 in MBG3 and BCL2 in neuroblastomas. Co-treatments with RA and BCL-2/XL inhibitor navitoclax synergistically decreased viability at clinically achievable concentrations. The combination of RA with navitoclax disrupted the binding of BIM to BCL-XL in MBG3 and to BCL-2 in neuroblastoma, inducing apoptosis in vitro and in vivo.

Conclusions

RA treatment primes MBG3 and NB cells for apoptosis, triggered by navitoclax cotreatment.
A population-based study on trajectories of HER2 status during neoadjuvant chemotherapy for early breast cancer and metastatic progression
Authors: Boman Caroline , Liu Xingrong , Eriksson Bergman Louise , Sun Wenwen , Tranchell Christian , Toli Maria Angeliki , Acs Balazs , Bergh Jonas , Foukakis Theodoros , Matikas Alexios
Published: June 2024

Background

This study aimed to investigate the distribution and changes of HER2 status in untreated tumours, in residual disease and in metastasis, and their long-term prognostic implications.

Methods

This is a population-based cohort study of patients treated with neoadjuvant chemotherapy for breast cancer during 2007–2020 in the Stockholm–Gotland region which comprises 25% of the entire Swedish population. Information was extracted from the National Breast Cancer Registry and electronic patient charts to minimize data missingness and misclassification.

Results

In total, 2494 patients received neoadjuvant chemotherapy, of which 2309 had available pretreatment HER2 status. Discordance rates were 29.9% between primary and residual disease (kappa = 0.534), 31.2% between primary tumour and metastasis (kappa = 0.512) and 33.3% between residual disease to metastasis (kappa = 0.483). Adjusted survival curves differed between primary HER2 0 and HER2-low disease (p < 0.001), with the former exhibiting an early peak in risk for death which eventually declined below the risk of HER2-low. Across all disease settings, increasing the number of biopsies increased the likelihood of detecting HER2-low status.

Conclusion

HER2 status changes during neoadjuvant chemotherapy and metastatic progression, and the long-term behaviours of HER2 0 and HER2-low disease differ, underscoring the need for obtaining tissue biopsies and for extended follow-up in breast cancer studies.
Limiting factors for charge generation in low-offset fullerene-based organic solar cells
Authors: Jungbluth Anna , Cho Eunkyung , Privitera Alberto , Yallum Kaila M. , Kaienburg Pascal , Lauritzen Andreas E. , Derrien Thomas , Kesava Sameer V. , Habib Irfan , Pratik Saied Md , Banerji Natalie , Brédas Jean-Luc , Coropceanu Veaceslav , Riede Moritz
Published: June 2024

Free charge generation after photoexcitation of donor or acceptor molecules in organic solar cells generally proceeds via (1) formation of charge transfer states and (2) their dissociation into charge separated states. Research often either focuses on the first component or the combined effect of both processes. Here, we provide evidence that charge transfer state dissociation rather than formation presents a major bottleneck for free charge generation in fullerene-based blends with low energetic offsets between singlet and charge transfer states. We investigate devices based on dilute donor content blends of (fluorinated) ZnPc:C60 and perform density functional theory calculations, device characterization, transient absorption spectroscopy and time-resolved electron paramagnetic resonance measurements. We draw a comprehensive picture of how energies and transitions between singlet, charge transfer, and charge separated states change upon ZnPc fluorination. We find that a significant reduction in photocurrent can be attributed to increasingly inefficient charge transfer state dissociation. With this, our work highlights potential reasons why low offset fullerene systems do not show the high performance of non-fullerene acceptors.
A unifying model to explain frequent SARS-CoV-2 rebound after nirmatrelvir treatment and limited prophylactic efficacy
Authors: Esmaeili Shadisadat , Owens Katherine , Wagoner Jessica , Polyak Stephen J. , White Judith M. , Schiffer Joshua T.
Published: June 2024

In a pivotal trial (EPIC-HR), a 5-day course of oral ritonavir-boosted nirmatrelvir, given early during symptomatic SARS-CoV-2 infection (within three days of symptoms onset), decreased hospitalization and death by 89.1% and nasal viral load by 0.87 log relative to placebo in high-risk individuals. Yet, nirmatrelvir/ritonavir failed as post-exposure prophylaxis in a trial, and frequent viral rebound has been observed in subsequent cohorts. We develop a mathematical model capturing viral-immune dynamics and nirmatrelvir pharmacokinetics that recapitulates viral loads from this and another clinical trial (PLATCOV). Our results suggest that nirmatrelvir’s in vivo potency is significantly lower than in vitro assays predict. According to our model, a maximally potent agent would reduce the viral load by approximately 3.5 logs relative to placebo at 5 days. The model identifies that earlier initiation and shorter treatment duration are key predictors of post-treatment rebound. Extension of treatment to 10 days for Omicron variant infection in vaccinated individuals, rather than increasing dose or dosing frequency, is predicted to lower the incidence of viral rebound significantly.
Temperature-dependent jumonji demethylase modulates flowering time by targeting H3K36me2/3 in Brassica rapa
Authors: Xin Xiaoyun , Li Peirong , Zhao Xiuyun , Yu Yangjun , Wang Weihong , Jin Guihua , Wang Jiao , Sun Liling , Zhang Deshuang , Zhang Fenglan , Yu Shuancang , Su Tongbing
Published: June 2024

Global warming has a severe impact on the flowering time and yield of crops. Histone modifications have been well-documented for their roles in enabling plant plasticity in ambient temperature. However, the factor modulating histone modifications and their involvement in habitat adaptation have remained elusive. In this study, through genome-wide pattern analysis and quantitative-trait-locus (QTL) mapping, we reveal that BrJMJ18 is a candidate gene for a QTL regulating thermotolerance in thermotolerant B. rapa subsp. chinensis var. parachinensis (or Caixin, abbreviated to Par). BrJMJ18 encodes an H3K36me2/3 Jumonji demethylase that remodels H3K36 methylation across the genome. We demonstrate that the BrJMJ18 allele from Par (BrJMJ18Par) influences flowering time and plant growth in a temperature-dependent manner via characterizing overexpression and CRISPR/Cas9 mutant plants. We further show that overexpression of BrJMJ18Par can modulate the expression of BrFLC3, one of the five BrFLC orthologs. Furthermore, ChIP-seq and transcriptome data reveal that BrJMJ18Par can regulate chlorophyll biosynthesis under high temperatures. We also demonstrate that three amino acid mutations may account for function differences in BrJMJ18 between subspecies. Based on these findings, we propose a working model in which an H3K36me2/3 demethylase, while not affecting agronomic traits under normal conditions, can enhance resilience under heat stress in Brassica rapa.
Real-time observation of a metal complex-driven reaction intermediate using a porous protein crystal and serial femtosecond crystallography
Authors: Maity Basudev , Shoji Mitsuo , Luo Fangjia , Nakane Takanori , Abe Satoshi , Owada Shigeki , Kang Jungmin , Tono Kensuke , Tanaka Rie , Pham Thuc Toan , Kojima Mariko , Hishikawa Yuki , Tanaka Junko , Tian Jiaxin , Nagama Misaki , Suzuki Taiga , Noya Hiroki , Nakasuji Yuto , Asanuma Asuka , Yao Xinchen , Iwata So , Shigeta Yasuteru , Nango Eriko , Ueno Takafumi
Published: July 2024

Determining short-lived intermediate structures in chemical reactions is challenging. Although ultrafast spectroscopic methods can detect the formation of transient intermediates, real-space structures cannot be determined directly from such studies. Time-resolved serial femtosecond crystallography (TR-SFX) has recently proven to be a powerful method for capturing molecular changes in proteins on femtosecond timescales. However, the methodology has been mostly applied to natural proteins/enzymes and limited to reactions promoted by synthetic molecules due to structure determination challenges. This work demonstrates the applicability of TR-SFX for investigations of chemical reaction mechanisms of synthetic metal complexes. We fix a light-induced CO-releasing Mn(CO)3 reaction center in porous hen egg white lysozyme (HEWL) microcrystals. By controlling light exposure and time, we capture the real-time formation of Mn-carbonyl intermediates during the CO release reaction. The asymmetric protein environment is found to influence the order of CO release. The experimentally-observed reaction path agrees with quantum mechanical calculations. Therefore, our demonstration offers a new approach to visualize atomic-level reactions of small molecules using TR-SFX with real-space structure determination. This advance holds the potential to facilitate design of artificial metalloenzymes with precise mechanisms, empowering design, control and development of innovative reactions.
Taking another look at intelligence and personality using an eye-tracking approach
Authors: Bardach Lisa , Schumacher Aki , Trautwein Ulrich , Kasneci Enkelejda , Tibus Maike , Wortha Franz , Gerjets Peter , Appel Tobias
Published: July 2024

Intelligence and personality are both key drivers of learning. This study extends prior research on intelligence and personality by adopting a behavioral-process-related eye-tracking approach. We tested 182 adults on fluid intelligence and the Big Five personality traits. Eye-tracking information (gaze patterns) was recorded while participants completed the intelligence test. Machine learning models showed that personality explained 3.18% of the variance in intelligence test scores, with Openness and, surprisingly, Agreeableness most meaningfully contributing to the prediction. Facet-level measures of personality explained a larger amount of variance (7.67%) in intelligence test scores than the trait-level measures, with the largest coefficients obtained for Ideas and Values (Openness) and Compliance and Trust (Agreeableness). Gaze patterns explained a substantial amount of variance in intelligence test performance (35.91%). Gaze patterns were unrelated to the Big Five personality traits, but some of the facets (especially Self-Consciousness from Neuroticism and Assertiveness from Extraversion) were related to gaze. Gaze patterns reflected the test-solving strategies described in the literature (constructive matching, response elimination) to some extent. A combined feature vector consisting of gaze-based predictions and personality traits explained 37.50% of the variance in intelligence test performance, with significant unique contributions from both personality and gaze patterns. A model that included personality facets and gaze explained 38.02% of the variance in intelligence test performance. Although behavioral data thus clearly outperformed “traditional” psychological measures (Big Five personality) in predicting intelligence test performance, our results also underscore the independent contributions of personality and gaze patterns in predicting intelligence test performance.
Revisiting the evolution of bow-tie architecture in signaling networks
Authors: Itoh Thoma , Kondo Yohei , Aoki Kazuhiro , Saito Nen
Published: July 2024

Bow-tie architecture is a layered network structure that has a narrow middle layer with multiple inputs and outputs. Such structures are widely seen in the molecular networks in cells, suggesting that a universal evolutionary mechanism underlies the emergence of bow-tie architecture. The previous theoretical studies have implemented evolutionary simulations of the feedforward network to satisfy a given input-output goal and proposed that the bow-tie architecture emerges when the ideal input-output relation is given as a rank-deficient matrix with mutations in network link intensities in a multiplicative manner. Here, we report that the bow-tie network inevitably appears when the link intensities representing molecular interactions are small at the initial condition of the evolutionary simulation, regardless of the rank of the goal matrix. Our dynamical system analysis clarifies the mechanisms underlying the emergence of the bow-tie structure. Further, we demonstrate that the increase in the input-output matrix reduces the width of the middle layer, resulting in the emergence of bow-tie architecture, even when evolution starts from large link intensities. Our data suggest that bow-tie architecture emerges as a side effect of evolution rather than as a result of evolutionary adaptation.
An estimate of the impact rate on Mars from statistics of very-high-frequency marsquakes
Authors: Zenhäusern Géraldine , Wójcicka Natalia , Stähler Simon C. , Collins Gareth S. , Daubar Ingrid J. , Knapmeyer Martin , Ceylan Savas , Clinton John F. , Giardini Domenico
Published: June 2024

The number density of impact craters on a planetary surface is used to determine its age, which requires a model for the production rate of craters of different sizes. On Mars, however, estimates of the production rate of small craters (<60 m) from orbital imagery and from extrapolation of lunar impact data do not match. Here we provide a new independent estimate of the impact rate by analysing the seismic events recorded by the seismometer onboard NASA’s InSight lander. Some previously confirmed seismically detected impacts are part of a larger class of marsquakes (very high frequency, VF). Although a non-impact origin cannot be definitively excluded for each VF event, we show that the VF class as a whole is plausibly caused by meteorite impacts. We use an empirical scaling relationship to convert between seismic moment and crater diameter. Applying area and time corrections to derive a global impact rate, we find that 280–360 craters >8 m diameter are formed globally per year, consistent with previously published chronology model rates and above the rates derived from freshly imaged craters. Our work shows that seismology is an effective tool for determining meteoroid impact rates and complements other methods such as orbital imaging.
Cabozantinib and nivolumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial
Authors: Ebrahimi Hedyeh , Dizman Nazli , Meza Luis , Malhotra Jasnoor , Li Xiaochen , Dorff Tanya , Frankel Paul , Llamas-Quitiquit Marian , Hsu Joann , Zengin Zeynep B. , Alcantara Marice , Castro Daniela , Mercier Benjamin , Chawla Neal , Chehrazi-Raffle Alex , Barragan-Carrillo Regina , Jaime-Casas Salvador , Govindarajan Ameish , Gillece John , Trent Jeffrey , Lee Peter P. , Parks Thomas P. , Takahashi Motomichi , Hayashi Atsushi , Kortylewski Marcin , Caporaso J. Gregory , Lee Keehoon , Tripathi Abhishek , Pal Sumanta K.
Published: June 2024

Supplementation with CBM588, a bifidogenic live bacterial product, has been associated with improved clinical outcomes in persons with metastatic renal cell carcinoma (mRCC) receiving nivolumab and ipilimumab. However, its effect on those receiving tyrosine kinase inhibitor-based combinations is unknown. In this open-label, randomized, investigator-initiated, phase 1 study, 30 participants with locally advanced or mRCC with histological confirmation of clear cell, papillary or sarcomatoid component were randomized in a 2:1 fashion to receive cabozantinib (an inhibitor of vascular endothelial growth factor receptor, MET and AXL) and nivolumab (anti-programmed cell death protein 1) with or without CBM588 as first-line treatment. Metagenomic sequencing was performed on stool samples to characterize their gut microbiome at baseline and 13 weeks into treatment. The primary endpoint was a change in the relative abundance of Bifidobacterium spp.; secondary endpoints included objective response rate (ORR), progression-free survival (PFS) and toxicity profile. The primary endpoint of the study was not met and the addition of CBM588 to cabozantinib and nivolumab did not result in a difference in the relative abundance of Bifidobacterium spp. or alpha diversity (as measured by the Shannon index). However, ORR was significantly higher in participants treated with CBM588 compared to those in the control arm (14 of 19, 74% versus 2 of 10, 20%; P = 0.01). PFS at 6 months was 84% (16 of 19) and 60% (6 of 10) in the experimental and control arms, respectively. No significant difference in toxicity profile was seen between the study arms. Our results provide a preliminary signal of improved clinical activity with CBM588 in treatment-naive participants with mRCC receiving cabozantinib and nivolumab. Further investigation is needed to confirm these findings and better characterize the underlying mechanism driving this effect.

ClinicalTrials.gov identifier: NCT05122546
A dataset of riverine nitrogen yield across watersheds in the Conterminous United States
Authors: Wang Yiming , Zhang Xuesong , Zhao Kaiguang
Published: July 2024

Riverine nitrogen is a pivotal determinant influencing water quality in inland and coastal waters. Despite the recognized utility, no spatially-explicit data on riverine nitrogen yield is available for large parts of the world, thus hindering our ability to identify the contributors to riverine nitrogen and understand aquatic nitrogen cycling. To fill the data gap for the United States, here we (1) compiled 294,996 total nitrogen (TN), 225,827 nitrate (NO3−), 204,015 ammonium (NH4+), and 158,837 total organic nitrogen (TON) concentrations, with concurrent streamflow data, across the Conterminous United States (CONUS), (2) estimated riverine nitrogen loads for over 1,800 hydrological stations, (3) derived the spatial distribution of annual riverine nitrogen yield by leveraging river and catchment connectivity information contained in the National Hydrography Dataset plus (NHDPlus), and (4) characterized nonpoint-source TN loads by excluding point-source loads. This new spatial dataset quantifies spatial sources of nitrogen yield from point and non-point sources (e.g., up to 36% from point sources across the U.S.) and serves as ground-truthing to validate water quality models.
Study on compaction characteristics and mechanical model of dry crushing filling material under lateral confinement condition
Authors: Xu Youlin , Wu Shaokang , Chen Zhisong , Wu Xukun , Zhang Jitao , Xiao Bing
Published: June 2024

The compaction characteristics and bearing capacity of dry filling materials in goaf have a significant influence on stope control and surface stability. Through acoustic emission monitoring and mechanical model analysis, a series of confined compression tests were conducted on crushed waste with varying particle sizes and Talbot coefficients. The deformation, fragmentation, and acoustic emission characteristics under corresponding working conditions were determined. The results indicate that the stress–strain curves of crushed stone with different particle sizes and Talbot coefficients exhibit similar nonlinear behavior during confined compression. However, the strain response varies with changing stress levels. By analyzing the slope change rate of the stress–strain curve, the lateral uniaxial compression process of waste rock can be divided into three deformation stages: rapid compression, stable crushing, and slow compaction. The compressive deformation characteristics of gravel differ based on particle size and Talbot coefficient. Specimens with a higher Talbot coefficient demonstrate stronger compressive resistance and weaker deformation resistance during initial compaction loading. Notably, the internal pressure structure strength is influenced by factors such as maximum particle size D, grading coefficient n, and particle size distribution continuity, rather than solely by the proportion of large particles. The evolution of acoustic emission signals and energy-time curve during waste rock confined axial compression synchronizes with the compaction process. Overall, compaction plays a critical role in maintaining the stability of goaf in dry crushed waste filling.
Pollen foraging preferences in honey bees and the nutrient profiles of the pollen
Authors: Yokota Seiji C. , Broeckling Corey , H.S. Arathi
Published: July 2024

Honey bees are important insect pollinators that provide critical pollination services to fruit and nut crops in the US. They face challenges likely due to pressures associated with agricultural intensification related habitat loss. To better understand this, pollen preferences of foraging bees and the nutritional profile of pollen brought into hives by foraging bees in crop fields and nut orchards can provide valuable information. We trained bees to forage on bee-collected pollen from hives placed for pollination services in almond orchards, sunflower fields, or mixed species from inter-row plantings. Using bees trained to a certain kind of hive pollen, we applied a binary scoring system, to test preferences of these preconditioned foragers. We also performed metabolomic analyses of the hive pollen used for training and testing to elucidate their nutritional content. Irrespective of preconditioning, bees collected all the available choice pollen types, predominantly choosing hive-collected mixed species pollen (MSP), followed by almond orchard pollen. The hive-collected MSP was chemically diverse, richest in cholesterol, vitamins, and phytochemicals quercetin, kaempferol, coumarin, and quinine, but was not consistently high for essential amino acids and polyunsaturated fatty acids. Although diversity in chemical profiles may not directly relate to plant species diversity, our results suggest that foragers collect a variety of pollen types when available reiterating the importance of diverse floral resources.
Self-assembled monolayers of reduced graphene oxide for robust 3D-printed supercapacitors
Authors: Scarpa Davide , Iuliano Mariagrazia , Cirillo Claudia , Iovane Pierpaolo , Borriello Carmela , Portofino Sabrina , Ponticorvo Eleonora , Galvagno Sergio , Sarno Maria
Published: July 2024

Herein, additive manufacturing, which is extremely promising in different sectors, has been adopted in the electrical energy storage field to fabricate efficient materials for supercapacitor applications. In particular, Al2O3-, steel-, and Cu-based microparticles have been used for the realization of 3D self-assembling materials covered with reduced graphene oxide to be processed through additive manufacturing. Functionalization of the particles with amino groups and a subsequent "self-assembly" step with graphene oxide, which was contextually partially reduced to rGO, was carried out. To further improve the electrical conductivity and AM processability, the composites were coated with a polyaniline-dodecylbenzene sulfonic acid complex and further blended with PLA. Afterward, they were extruded in the form of filaments, printed through the fused deposition modeling technique, and assembled into symmetrical solid-state devices. Electrochemical tests showed a maximum mass capacitance of 163 F/g, a maximum energy density of 15 Wh/Kg at 10 A/g, as well as good durability (85% capacitance retention within 5000 cycles) proving the effectiveness of the preparation and the efficiency of the as-manufactured composites.
Exposure to Gulf war illness-related chemicals exacerbates alcohol-induced liver damage in rodents
Authors: Petrescu Anca D. , Venter Juliet , Danilenko Daria D. , Medina Daniela , Grant Stephanie , An Su Yeon , Williams Elaina , Mireles Patrick , Rhodes Kathryn , Tjahja Matthew , DeMorrow Sharon
Published: July 2024

Gulf War Illness (GWI) describes a series of symptoms suffered by veterans of the Gulf war, consisting of cognitive, neurological and gastrointestinal dysfunctions. Two chemicals associated with GWI are the insecticide permethrin (PER) and the nerve gas prophylactic pyridostigmine-bromide (PB). In this study we assessed the effects of PER and PB exposure on the pathology and subsequent alcohol (EtOH)-induced liver injury, and the influence of a macrophage depletor, PLX3397, on EtOH-induced liver damage in PER/PB-treated mice. Male C57BL/6 mice were injected daily with vehicle or PER/PB for 10 days, followed by 4 months recovery, then treatment with PLX3397 and a chronic-plus-single-binge EtOH challenge for 10 days. PER/PB exposure resulted in the protracted increase in liver transaminases in the serum and induced chronic low-level microvesicular steatosis and inflammation in GWI vs Naïve mice up to 4 months after cessation of exposure. Furthermore, prior exposure to PER/PB also resulted in exacerbated response to EtOH-induced liver injury, with enhanced steatosis, ductular reaction and fibrosis. The enhanced EtOH-induced liver damage in GWI-mice was attenuated by strategies designed to deplete macrophages in the liver. Taken together, these data suggest that exposure to GWI-related chemicals may alter the liver’s response to subsequent ethanol exposure.
Mass spectrometry-based metabolomics study of nicotine exposure in THP-1 monocytes
Authors: Uhlig Silvio , Olderbø Bergitte Pearl , Samuelsen Jan Tore , Uvsløkk Solveig , Ivanova Lada , Vanderstraeten Camille , Grutle Lene Aiko , Rangel-Huerta Oscar Daniel
Published: June 2024

The tobacco alkaloid nicotine is known for its activation of neuronal nicotinic acetylcholine receptors. Nicotine is consumed in different ways such as through conventional smoking, e-cigarettes, snuff or nicotine pouches. The use of snuff has been associated with several adverse health effects, such as inflammatory reactions of the oral mucosa and oral cavity cancer. We performed a metabolomic analysis of nicotine-exposed THP-1 human monocytes. Cells were exposed to 5 mM of the alkaloid for up to 4 h, and cell extracts and medium subjected to untargeted liquid chromatography high-resolution mass spectrometry. Raw data processing revealed 17 nicotine biotransformation products. Among these, cotinine and nornicotine were identified as the two major cellular biotransformation products. The application of multi- and univariate statistical analyses resulted in the annotation, up to a certain level of identification, of 12 compounds in the cell extracts and 13 compounds in the medium that were altered by nicotine exposure. Of these, four were verified as methylthioadenosine, cytosine, uric acid, and l-glutamate. Methylthioadenosine levels were affected in both cells and the medium, while cytosine, uric acid, and l-glutamate levels were affected in the medium only. The effects of smoking on the pathways involving these metabolites have been previously demonstrated in humans. Most of the other discriminating compounds, which were merely tentatively or not fully identified, were amino acids or amino acid derivatives. In conclusion, our preliminary data suggest that some of the potentially adverse effects related to smoking may also be expected when nicotine is consumed via snuff or nicotine pouches.
Atmospheric pressure microwave (915 MHz) plasma for hydrogen production from steam reforming of ethanol
Authors: Miotk Robert , Hrycak Bartosz , Czylkowski Dariusz , Jasiński Mariusz , Dors Mirosław , Mizeraczyk Jerzy
Published: June 2024

This work presents experimental results on the energy efficiency in hydrogen production using atmospheric microwave plasma (915 MHz) through steam reforming of ethanol. Ethanol was chosen as a liquid hydrogen carrier due to its high hydrogen atom content, low cost, and wide availability. The experimental work began with the maximization of an energy efficiency of the used microwave plasma source. The process of maximization involved determining a position of a movable plunger that ensures the most efficient transfer of microwave energy from a microwave source to the generated plasma in the microwave plasma source. The aim of the investigations was to test the following working conditions of the microwave plasma source: absorbed microwave power PA by the generated plasma (up to 5.4 kW), the carrier gas volumetric flow rate (up to 3900 Nl/h), and the amount of the introduced ethanol vapours on the efficiency of hydrogen production (up to 2.4 kg/h). In the range of tested working conditions, the highest energy yield for hydrogen production achieved a rate of 26.9 g(H2)/kWh, while the highest hydrogen production was 99.3 g(H2)/h.
Do engagement and behavioural mechanisms underpin the effectiveness of the Drink Less app?
Authors: Garnett Claire , Dinu Larisa-Maria , Oldham Melissa , Perski Olga , Loebenberg Gemma , Beard Emma , Angus Colin , Burton Robyn , Field Matt , Greaves Felix , Hickman Matthew , Kaner Eileen , Michie Susan , Munafò Marcus , Pizzo Elena , Brown Jamie
Published: July 2024

This is a process evaluation of a large UK-based randomised controlled trial (RCT) (n = 5602) evaluating the effectiveness of recommending an alcohol reduction app, Drink Less, compared with usual digital care in reducing alcohol consumption in increasing and higher risk drinkers. The aim was to understand whether participants’ engagement (‘self-reported adherence’) and behavioural characteristics were mechanisms of action underpinning the effectiveness of Drink Less. Self-reported adherence with both digital tools was over 70% (Drink Less: 78.0%, 95% CI = 77.6–78.4; usual digital care: 71.5%, 95% CI = 71.0–71.9). Self-reported adherence to the intervention (average causal mediation effect [ACME] = −0.250, 95% CI = −0.42, −0.11) and self-monitoring behaviour (ACME = −0.235, 95% CI = −0.44, −0.03) both partially mediated the effect of the intervention (versus comparator) on alcohol reduction. Following the recommendation (self-reported adherence) and the tracking (self-monitoring behaviour) feature of the Drink Less app appear to be important mechanisms of action for alcohol reduction among increasing and higher risk drinkers.
Recommendations to advance digital health equity: a systematic review of qualitative studies
Authors: Wilson Sarah , Tolley Clare , Mc Ardle Ríona , Lawson Lauren , Beswick Emily , Hassan Nehal , Slight Robert , Slight Sarah
Published: July 2024

The World Health Organisation advocates Digital Health Technologies (DHTs) for advancing population health, yet concerns about inequitable outcomes persist. Differences in access and use of DHTs across different demographic groups can contribute to inequities. Academics and policy makers have acknowledged this issue and called for inclusive digital health strategies. This systematic review synthesizes literature on these strategies and assesses facilitators and barriers to their implementation. We searched four large databases for qualitative studies using terms relevant to digital technology, health inequities, and socio-demographic factors associated with digital exclusion summarised by the CLEARS framework (Culture, Limiting conditions, Education, Age, Residence, Socioeconomic status). Following the PRISMA guidelines, 10,401 articles were screened independently by two reviewers, with ten articles meeting our inclusion criteria. Strategies were grouped into either outreach programmes or co-design approaches. Narrative synthesis of these strategies highlighted three key themes: firstly, using user-friendly designs, which included software and website interfaces that were easy to navigate and compatible with existing devices, culturally appropriate content, and engaging features. Secondly, providing supportive infrastructure to users, which included devices, free connectivity, and non-digital options to help access healthcare. Thirdly, providing educational support from family, friends, or professionals to help individuals develop their digital literacy skills to support the use of DHTs. Recommendations for advancing digital health equity include adopting a collaborative working approach to meet users’ needs, and using effective advertising to raise awareness of the available support. Further research is needed to assess the feasibility and impact of these recommendations in practice.
A single-cell sequence analysis of mouse subcutaneous white adipose tissue reveals dynamic changes during weaning
Authors: Qian Shuwen , Zhang Chenyang , Tang Yan , Dai Mengyuan , He Zhihui , Ma Hong , Wang Linyuan , Yang Qiqi , Liu Yang , Xu Wei , Zhang Zhao , Tang Qi-qun
Published: July 2024

Adipose tissue development begins in the fetal period, and continues to expand after birth. Dysregulation of adipose tissue during weaning may predispose individuals to lifelong metabolic disorders. However, the developmental remodeling of adipose tissue during weaning remains largely unexplored. Here we comprehensively compare the changes in mouse subcutaneous white adipose tissue from 7 days after birth to 7 days after weaning using single-cell RNA sequencing along with other molecular and histologic assays. We characterize the developmental trajectory of preadipocytes and indicate the commitment of preadipocytes with beige potential during weaning. Meanwhile, we find immune cells unique to weaning period, whose expression of extracellular matrix proteins implies potential regulation on preadipocyte. Finally, the strongest cell-cell interaction during weaning determined by the TGFβ ligand-receptor pairs is between preadipocytes and endotheliocytes. Our results provide a detailed and unbiased cellular landscape and offer insights into the potential regulation of adipose tissue remodeling during weaning.
Molecular organization of fibroin heavy chain and mechanism of fibre formation in Bombyx mori
Authors: Moreno-Tortolero Rafael O. , Luo Yijie , Parmeggiani Fabio , Skaer Nick , Walker Robert , Serpell Louise C. , Holland Chris , Davis Sean A.
Published: July 2024

Fibroins’ transition from liquid to solid is fundamental to spinning and underpins the impressive native properties of silk. Herein, we establish a fibroin heavy chain fold for the Silk-I polymorph, which could be relevant for other similar proteins, and explains mechanistically the liquid-to-solid transition of this silk, driven by pH reduction and flow stress. Combining spectroscopy and modelling we propose that the liquid Silk-I fibroin heavy chain (FibH) from the silkworm, Bombyx mori, adopts a newly reported β-solenoid structure. Similarly, using rheology we propose that FibH N-terminal domain (NTD) templates reversible higher-order oligomerization driven by pH reduction. Our integrated approach bridges the gap in understanding FibH structure and provides insight into the spatial and temporal hierarchical self-assembly across length scales. Our findings elucidate the complex rheological behaviour of Silk-I, solutions and gels, and the observed liquid crystalline textures within the silk gland. We also find that the NTD undergoes hydrolysis during standard regeneration, explaining key differences between native and regenerated silk feedstocks. In general, in this study we emphasize the unique characteristics of native and native-like silks, offering a fresh perspective on our fundamental understanding of silk-fibre production and applications.