bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractParvalbumin 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

Abstract

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

AbstractThis 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

Abstract
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

Abstract
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

AbstractFree 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

AbstractIn 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

AbstractGlobal 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

AbstractDetermining 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

AbstractIntelligence 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

AbstractBow-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

AbstractThe 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.