bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary evidence for preserved synaptic density in late-life depression
Authors: Vande Casteele Thomas , Laroy Maarten , Van Cauwenberge Margot , Koole Michel , Dupont Patrick , Sunaert Stefan , Van den Stock Jan , Bouckaert Filip , Van Laere Koen , Emsell Louise , Vandenbulcke Mathieu 
Published: March 2024

AbstractLate-life depression has been consistently associated with lower gray matter volume, the origin of which remains largely unexplained. Recent in-vivo PET findings in early-onset depression and Alzheimer’s Disease suggest that synaptic deficits contribute to the pathophysiology of these disorders and may therefore contribute to lower gray matter volume in late-life depression. Here, we investigate synaptic density in vivo for the first time in late-life depression using the synaptic vesicle glycoprotein 2A receptor radioligand 11C-UCB-J. We included 24 currently depressed adults with late-life depression (73.0 ± 6.2 years, 16 female, geriatric depression scale = 19.5 ± 6.8) and 36 age- and gender-matched healthy controls (70.4 ± 6.2 years, 21 female, geriatric depression scale = 2.7 ± 2.9) that underwent simultaneous 11C-UCB-J positron emission tomography (PET) and 3D T1- and T2-FLAIR weighted magnetic resonance (MR) imaging on a 3-tesla PET-MR scanner. We used analyses of variance to test for 11C-UCB-J binding and gray matter volumes differences in regions implicated in depression. The late-life depression group showed a trend in lower gray matter volumes in the hippocampus (p = 0.04), mesial temporal (p = 0.02) and prefrontal cortex (p = 0.02) compared to healthy control group without surviving correction for multiple comparison. However, no group differences in 11C-UCB-J binding were found in these regions nor were any associations between 11C-UCB-J and depressive symptoms. Our data suggests that, in contrast to Alzheimer’s Disease, lower gray matter volume in late-life depression is not associated with synaptic density changes. From a therapeutic standpoint, preserved synaptic density in late-life depression may be an encouraging finding.
Resting-state amygdala subregion and precuneus connectivity provide evidence for a dimensional approach to studying social anxiety disorder
Authors: Mizzi Simone , Pedersen Mangor , Rossell Susan L. , Rendell Peter , Terrett Gill , Heinrichs Markus , Labuschagne Izelle 
Published: March 2024

AbstractSocial anxiety disorder (SAD) is a prevalent and disabling mental health condition, characterized by excessive fear and anxiety in social situations. Resting-state functional magnetic resonance imaging (fMRI) paradigms have been increasingly used to understand the neurobiological underpinnings of SAD in the absence of threat-related stimuli. Previous studies have primarily focused on the role of the amygdala in SAD. However, the amygdala consists of functionally and structurally distinct subregions, and recent studies have highlighted the importance of investigating the role of these subregions independently. Using multiband fMRI, we analyzed resting-state data from 135 participants (42 SAD, 93 healthy controls). By employing voxel-wise permutation testing, we examined group differences of fMRI connectivity and associations between fMRI connectivity and social anxiety symptoms to further investigate the classification of SAD as a categorical or dimensional construct. Seed-to-whole brain functional connectivity analysis using multiple ‘seeds’ including the amygdala and its subregions and the precuneus, revealed no statistically significant group differences. However, social anxiety severity was significantly negatively correlated with functional connectivity of the precuneus - perigenual anterior cingulate cortex and positively correlated with functional connectivity of the amygdala (specifically the superficial subregion) - parietal/cerebellar areas. Our findings demonstrate clear links between symptomatology and brain connectivity in the absence of diagnostic differences, with evidence of amygdala subregion-specific alterations. The observed brain-symptom associations did not include disturbances in the brain’s fear circuitry (i.e., disturbances in connectivity between amygdala - prefrontal regions) likely due to the absence of threat-related stimuli.
Can diode laser 810 nm decrease post endodontic pain in patients with asymptomatic necrotic maxillary incisors? A four-arm randomized controlled trial
Authors: Abbara Mohammad Tamer , Akil Samar , Hamadah Omar , Achour Hassan , Mahayni Ghina , Alsayed Tolibah Yasser 
Published: March 2024

Abstract
Aim
To find the best method for applying the diode laser 810 nm to relieve post-endodontic pain on necrotic maxillary incisors with periapical lesions within a single-visit treatment.

Methods
Eighty patients with a necrotic incisor, diagnosed with asymptomatic apical periodontitis, received standardized cleaning and shaping procedures, then divided randomly with a 1:1:1:1 allocation ratio into four groups: Group 1: control group with no laser application, Group 2: applying the diode laser as an irrigation activation system (IAS), Group 3: applying the diode laser from the buccal and palatal mucosa, Group 4: applying the diode laser as an IAS and from buccal and palatal mucosa. The postoperative pain was assessed using the visual analog scale (VAS) 1, 3, 7, and 14 days after the treatment. The mean values of the VAS score were statistically analyzed used Kruskal–Walis and Mann–Whitney U tests. The level of significance was set at a = 0.05.

Results
During 14 days after treatment, there was a statistically significant difference between mean values of VAS scores in the four groups (P value < 0.05); Group 1 scored the highest score, whereas Group 4 showed the lowest one. Moreover, Group 4 showed favorable outcomes compared with Group 2 and Group 3 during the first three days after treatment.

Conclusion
Diode laser reduced postoperative pain after necrotic teeth with large-sized apical lesion treatment, whereas using diode laser either as an IAS or LLLT reduced the postoperative pain compared with the control group. Moreover, the usage of a diode laser in both previous techniques represents the best protocol for postoperative pain relief during 14 days of treatment.

Clinical relevance
The clinical significance of this study is to investigate the best method to reduce postoperative pain using diode lasers 810 nm; where the results of this study indicated that the more diode laser exposer in LLLT and IAS, the less postoperative pain after endodontic procedures.
Treatment pattern and outcomes of re-induction therapy prior to stem cell transplantation in patients with relapsed/refractory multiple myeloma in Germany
Authors: Sauer Sandra , Engelhardt Monika , Trautmann-Grill Karolin , Kimmich Christoph , Hänel Mathias , Schmidt-Hieber Martin , Salwender Hans , Flossmann Carmen , Heckmann Hiltrud , Ertel Franziska , Friederich Andrea , Patel Sachin , Thun Barbara , Raab Marc S. 
Published: March 2024

AbstractThere are limited data guiding choice of re-induction therapies for patients with relapsed/refractory multiple myeloma (RRMM) prior to stem cell transplantation (SCT). We performed a retrospective medical chart review of 171 patients with RRMM in Germany who received re-induction therapy in second line (78%; n = 134) or third line (22%; n = 37) prior to re-SCT. Index therapy was defined as first completed re-induction therapy for planned myeloablative conditioning and SCT in second/third line within the eligibility period (1/2016–12/2019). Most common pre-index first line and maintenance therapy used were bortezomib-based combinations (91%; n = 155/171) and lenalidomide (55%; n = 29/53), respectively. Median duration of index therapy line was 9 months; carfilzomib-based combinations were the most widely used in second/third line re-induction therapy (49%; n = 83/171), followed by daratumumab-based combinations (21%; n = 36/171). Overall response rates in second/third line were 87% after re-induction and 96% after SCT; median time to next treatment line after start of index therapy was 31 months; median progression-free survival (PFS) was 29 months; and median overall survival after index date was not reached. Based on these data, re-induction therapy with salvage SCT appears to be beneficial in selected patients with RRMM in clinical practice in Germany, translating into deep responses, long PFS and prolonged time to next treatment.
Selective deletion of E3 ubiquitin ligase FBW7 in VE-cadherin-positive cells instigates diffuse large B-cell lymphoma in mice in vivo
Authors: Cai Zhaohua , You Shaojin , Liu Zhixue , Song Ping , Zhao Fujie , An Junqing , Ding Ye , He Ben , Zou Ming-Hui 
Published: March 2024

AbstractDuring the maturation of hematopoietic stem/progenitor cells (HSPCs) to fully differentiated mature B lymphocytes, developing lymphocytes may undergo malignant transformation and produce B-cell lymphomas. Emerging evidence shows that through the endothelial-hematopoietic transition, specialized endothelial cells called the hemogenic endothelium can differentiate into HSPCs. However, the contribution of genetic defects in hemogenic endothelial cells to B-cell lymphomagenesis has not yet been investigated. Here, we report that mice with endothelial cell-specific deletion of Fbw7 spontaneously developed diffuse large B-cell lymphoma (DLBCL) following Bcl6 accumulation. Using lineage tracing, we showed that B-cell lymphomas in Fbw7 knockout mice were hemogenic endothelium-derived. Mechanistically, we found that FBW7 directly interacted with Bcl6 and promoted its proteasomal degradation. FBW7 expression levels are inversely correlated with BCL6 expression. Additionally, pharmacological disruption of Bcl6 abolished Fbw7 deletion-induced B-cell lymphomagenesis. We conclude that selective deletion of E3 ubiquitin ligase FBW7 in VE-cadherin positive endothelial cells instigates diffuse large B-cell lymphoma via upregulation of BCL6 stability. In addition, the mice with endothelial cell-specific deletion of Fbw7 provide a valuable preclinical platform for in vivo development and evaluation of novel therapeutic interventions for the treatment of DLBCL.
STING contributes to lipopolysaccharide-induced tubular cell inflammation and pyroptosis by activating endoplasmic reticulum stress in acute kidney injury
Authors: Cao Yun , Chen Xinghua , Zhu Zijing , Luo Zilv , Hao Yiqun , Yang Xueyan , Feng Jun , Zhang Zongwei , Hu Jijia , Jian Yonghong , Zhu Jiefu , Liang Wei , Chen Zhaowei 
Published: March 2024

AbstractRecently, innate immunity and inflammation were recognized as the key factors for acute kidney injury (AKI) caused by sepsis, which is closely related to high mortality. Stimulator of interferon genes (STING) has emerged as a critical component of innate immune and inflammatory responses. However, the role of STING in the pathogenesis of septic AKI remains unclear. This study demonstrated that the STING was significantly activated in tubular cells induced by lipopolysaccharide (LPS) in vivo and in vitro. Tubule-specific STING knockout attenuated LPS-induced renal dysfunction and pathological changes. Mechanistically, the STING pathway promotes NOD-like receptor protein 3 (NLRP3) activation. STING triggers endoplasmic reticulum (ER) stress to induce mitochondrial reactive oxygen species (mtROS) overproduction, enhancing thioredoxin-interacting protein activation and association with NLRP3. Eventually, the NLRP3 inflammasome leads to tubular cell inflammation and pyroptosis. This study revealed the STING-regulated network and further identified the STING/ER stress/mtROS/NLRP3 inflammasome axis as an emerging pathway contributing to tubular damage in LPS-induced AKI. Hence, targeting STING may be a promising therapeutic strategy for preventing septic AKI.
Purine salvage–associated metabolites as biomarkers for early diagnosis of esophageal squamous cell carcinoma: a diagnostic model–based study
Authors: Sun Yawen , Liu Wenjuan , Su Mu , Zhang Tao , Li Xia , Liu Wenbin , Cai Yuping , Zhao Deli , Yang Ming , Zhu Zhengjiang , Wang Jialin , Yu Jinming 
Published: March 2024

AbstractEsophageal squamous cell carcinoma (ESCC) remains an important health concern in developing countries. Patients with advanced ESCC have a poor prognosis and survival rate, and achieving early diagnosis remains a challenge. Metabolic biomarkers are gradually gaining attention as early diagnostic biomarkers. Hence, this multicenter study comprehensively evaluated metabolism dysregulation in ESCC through an integrated research strategy to identify key metabolite biomarkers of ESCC. First, the metabolic profiles were examined in tissue and serum samples from the discovery cohort (n = 162; ESCC patients, n = 81; healthy volunteers, n = 81), and ESCC tissue-induced metabolite alterations were observed in the serum. Afterward, RNA sequencing of tissue samples (n = 46) was performed, followed by an integrated analysis of metabolomics and transcriptomics. The potential biomarkers for ESCC were further identified by censoring gene-metabolite regulatory networks. The diagnostic value of the identified biomarkers was validated in a validation cohort (n = 220), and the biological function was verified. A total of 457 dysregulated metabolites were identified in the serum, of which 36 were induced by tumor tissues. The integrated analyses revealed significant alterations in the purine salvage pathway, wherein the abundance of hypoxanthine/xanthine exhibited a positive correlation with HPRT1 expression and tumor size. A diagnostic model was developed using two purine salvage–associated metabolites. This model could accurately discriminate patients with ESCC from normal individuals, with an area under the curve (AUC) (95% confidence interval (CI): 0.680–0.843) of 0.765 in the external cohort. Hypoxanthine and HPRT1 exerted a synergistic effect in terms of promoting ESCC progression. These findings are anticipated to provide valuable support in developing novel diagnostic approaches for early ESCC and enhance our comprehension of the metabolic mechanisms underlying this disease.
Advancing rare disease treatment: EMA’s decade-long insights into engineered adoptive cell therapy for rare cancers and orphan designation
Authors: Kalland Maria Elisabeth , Pose-Boirazian Tomas , Palomo Gloria Maria , Naumann-Winter Frauke , Costa Enrico , Matusevicius Darius , Duarte Dinah M. , Malikova Eva , Vitezic Dinko , Larsson Kristina , Magrelli Armando , Stoyanova-Beninska Violeta , Mariz Segundo 
Published: March 2024

AbstractAdoptive cell therapy (ACT), particularly chimeric antigen receptor (CAR)-T cell therapy, has emerged as a promising approach for targeting and treating rare oncological conditions. The orphan medicinal product designation by the European Union (EU) plays a crucial role in promoting development of medicines for rare conditions according to the EU Orphan Regulation.This regulatory landscape analysis examines the evolution, regulatory challenges, and clinical outcomes of genetically engineered ACT, with a focus on CAR-T cell therapies, based on the European Medicines Agency’s Committee for Orphan Medicinal Products review of applications evaluated for orphan designation and maintenance of the status over a 10-year period. In total, 30 of 36 applications were granted an orphan status, and 14 subsequently applied for maintenance of the status at time of marketing authorisation or extension of indication. Most of the products were autologous cell therapies using a lentiviral vector and were developed for the treatment of rare haematological B-cell malignancies. The findings revealed that 80% (29/36) of the submissions for orphan designation were supported by preliminary clinical data showing a potential efficacy of the candidate products and an added clinical benefit over currently authorised medicines for the proposed orphan condition. Notably, in 89% (32/36) of the cases significant benefit of the new products was accepted based on a clinically relevant advantage over existing therapies. Twelve of fourteen submissions reviewed for maintenance of the status at time of marketing authorisation or extension of indication demonstrated significant benefit of the products over existing satisfactory methods of treatment within the approved therapeutic indications, but one of the applications was withdrawn during the regulatory evaluation.This article summarises the key findings related to the use of engineered ACT, primarily CAR-T cell therapies, in targeting and treating rare cancers in the EU. It emphasises the importance of use of clinical data in supporting medical plausibility and significant benefit at the stage of orphan designation and highlights the high success rate for these products in obtaining initial orphan designations and subsequent maintaining the status at the time of marketing authorisation or extension of indication.
Compact terahertz harmonic generation in the Reststrahlenband using a graphene-embedded metallic split ring resonator array
Authors: Di Gaspare Alessandra , Song Chao , Schiattarella Chiara , Li Lianhe H. , Salih Mohammed , Giles Davies A. , Linfield Edmund H. , Zhang Jincan , Balci Osman , Ferrari Andrea C. , Dhillon Sukhdeep , Vitiello Miriam S. 
Published: March 2024

AbstractHarmonic generation is a result of a strong non-linear interaction between light and matter. It is a key technology for optics, as it allows the conversion of optical signals to higher frequencies. Owing to its intrinsically large and electrically tunable non-linear optical response, graphene has been used for high harmonic generation but, until now, only at frequencies < 2 THz, and with high-power ultrafast table-top lasers or accelerator-based structures. Here, we demonstrate third harmonic generation at 9.63 THz by optically pumping single-layer graphene, coupled to a circular split ring resonator (CSRR) array, with a 3.21 THz frequency quantum cascade laser (QCL). Combined with the high graphene nonlinearity, the mode confinement provided by the optically-pumped CSRR enhances the pump power density as well as that at the third harmonic, permitting harmonic generation. This approach enables potential access to a frequency range (6-12 THz) where compact sources remain difficult to obtain, owing to the Reststrahlenband of typical III-V semiconductors.
Dual receptor-sites reveal the structural basis for hyperactivation of sodium channels by poison-dart toxin batrachotoxin
Authors: Tonggu Lige , Wisedchaisri Goragot , Gamal El-Din Tamer M. , Lenaeus Michael J. , Logan Matthew M. , Toma Tatsuya , Du Bois Justin , Zheng Ning , Catterall William A. 
Published: March 2024

AbstractThe poison dart toxin batrachotoxin is exceptional for its high potency and toxicity, and for its multifaceted modification of the function of voltage-gated sodium channels. By using cryogenic electron microscopy, we identify two homologous, but nonidentical receptor sites that simultaneously bind two molecules of toxin, one at the interface between Domains I and IV, and the other at the interface between Domains III and IV of the cardiac sodium channel. Together, these two bound toxin molecules stabilize α/π helical conformation in the S6 segments that gate the pore, and one of the bound BTX-B molecules interacts with the crucial Lys1421 residue that is essential for sodium conductance and selectivity via an apparent water-bridged hydrogen bond. Overall, our structure provides insight into batrachotoxin’s potency, efficacy, and multifaceted functional effects on voltage-gated sodium channels via a dual receptor site mechanism.
Repurposing CRISPR-Cas13 systems for robust mRNA trans-splicing
Authors: Fiflis David N. , Rey Nicolas A. , Venugopal-Lavanya Harshitha , Sewell Beatrice , Mitchell-Dick Aaron , Clements Katie N. , Milo Sydney , Benkert Abigail R. , Rosales Alan , Fergione Sophia , Asokan Aravind 
Published: March 2024

AbstractType VI CRISPR enzymes have been developed as programmable RNA-guided Cas proteins for eukaryotic RNA editing. Notably, Cas13 has been utilized for site-targeted single base edits, demethylation, RNA cleavage or knockdown and alternative splicing. However, the ability to edit large stretches of mRNA transcripts remains a significant challenge. Here, we demonstrate that CRISPR-Cas13 systems can be repurposed to assist trans-splicing of exogenous RNA fragments into an endogenous pre-mRNA transcript, a method termed CRISPR Assisted mRNA Fragment Trans-splicing (CRAFT). Using split reporter-based assays, we evaluate orthogonal Cas13 systems, optimize guide RNA length and screen for optimal trans-splicing site(s) across a range of intronic targets. We achieve markedly improved editing of large 5’ and 3’ segments in different endogenous mRNAs across various mammalian cell types compared to other spliceosome-mediated trans-splicing methods. CRAFT can serve as a versatile platform for attachment of protein tags, studying the impact of multiple mutations/single nucleotide polymorphisms, modification of untranslated regions (UTRs) or replacing large segments of mRNA transcripts.
High figure-of-merit for ZnO nanostructures by interfacing lowly-oxidized graphene quantum dots
Authors: Choi Myungwoo , An Juyoung , Lee Hyejeong , Jang Hanhwi , Park Ji Hong , Cho Donghwi , Song Jae Yong , Kim Seung Min , Oh Min-Wook , Shin Hosun , Jeon Seokwoo 
Published: March 2024

AbstractThermoelectric technology has potential for converting waste heat into electricity. Although traditional thermoelectric materials exhibit extremely high thermoelectric performances, their scarcity and toxicity limit their applications. Zinc oxide (ZnO) emerges as a promising alternative owing to its high thermal stability and relatively high Seebeck coefficient, while also being earth-abundant and nontoxic. However, its high thermal conductivity (>40 W m−1K−1) remains a challenge. In this study, we use a multi-step strategy to achieve a significantly high dimensionless figure-of-merit (zT) value of approximately 0.486 at 580 K (estimated value) by interfacing graphene quantum dots with 3D nanostructured ZnO. Here, we show the fabrication of graphene quantum dots interfaced 3D ZnO, yielding the highest zT value ever reported for ZnO counterparts; specifically, our experimental results indicate that the fabricated 3D GQD@ZnO exhibited a significantly low thermal conductivity of 0.785 W m−1K−1 (estimated value) and a remarkably high Seebeck coefficient of $$-$$
−
556 μV K−1 at 580 K.
Bidirectional generation of structure and properties through a single molecular foundation model
Authors: Chang Jinho , Ye Jong Chul 
Published: March 2024

AbstractRecent successes of foundation models in artificial intelligence have prompted the emergence of large-scale chemical pre-trained models. Despite the growing interest in large molecular pre-trained models that provide informative representations for downstream tasks, attempts for multimodal pre-training approaches on the molecule domain were limited. To address this, here we present a multimodal molecular pre-trained model that incorporates the modalities of structure and biochemical properties, drawing inspiration from recent advances in multimodal learning techniques. Our proposed model pipeline of data handling and training objectives aligns the structure/property features in a common embedding space, which enables the model to regard bidirectional information between the molecules’ structure and properties. These contributions emerge synergistic knowledge, allowing us to tackle both multimodal and unimodal downstream tasks through a single model. Through extensive experiments, we demonstrate that our model has the capabilities to solve various meaningful chemical challenges, including conditional molecule generation, property prediction, molecule classification, and reaction prediction.