bluuebunny/crossref_metadata_2025 huggingface dataset:
Insights into the deployment of a social robot-augmented telepresence robot in an elder care clinic – perspectives from patients and therapists: a pilot study
Authors: Sobrepera Michael J. , Nguyen Anh T. , Gavin Emily S. , Johnson Michelle J.
Published: March 2024

As the proportion of the elderly population in the USA expands, so will the demand for rehabilitation and social care, which play an important role in maintaining function and mediating motor and cognitive decline in older adults. The use of social robotics and telemedicine are each potential solutions but each have limitations. To address challenges with classical telemedicine for rehabilitation, we propose to use a social robot-augmented telepresence (SRAT), Flo, which was deployed for long-term use in a community-based rehabilitation facility catering to older adults. Our goals were to explore how clinicians and patients would use and respond to the robot during rehab interactions. In this pilot study, three clinicians were recruited and asked to rate usability after receiving training for operating the robot and two of them conducted multiple rehab interactions with their patients using the robot (eleven patients with cognitive impairment and/or motor impairment and 23 rehab sessions delivered via SRAT in total). We report on the experience of both therapists and patients after the interactions.
From patient-reported outcomes (PROs) to family-reported outcomes (FROs): Acceptability and perceived usefulness of routine screening in cancer care
Authors: Lambert Sylvie , Loban Katya , Gignac Anne-Sophie , Magalhaes Mona , Brahim Lydia Ould , Chehayeb Sarah , Wasserman Sydney
Published: March 2024

Objectives

To explore the acceptability of screening for family-reported outcomes (FROs) among cancer caregivers (unpaid family members or friends who provide support to patients with cancer) and identify from their perspective the key components of a FRO screening program.

Methods

Using a qualitative descriptive design, semi-structured interviews were undertaken with 23 adult caregivers of people with cancer between 2020 and 2021. Interview questions focused on acceptability of FRO screening, types of FROs, timing/frequency of screening, preferred resources following screening, and communication of FROs to patients and clinicians. Participants were recruited in Canada. Interviews were audio-recorded, transcribed verbatim, and analyzed using thematic analysis and constant comparison.

Results

Almost all caregivers welcomed FRO screening in usual care and viewed it as an avenue toward obtaining more resources. Other potential benefits of FRO screening included increased self-reflection and role acknowledgment. Caregivers prioritized screening for emotional symptoms, and most preferred that the results be shared with the patient’s treating team rather than their primary care provider. Caregivers did not want results to be shared with patients, instead favoring learning how best to discuss results with patients. Many spoke of a “one stop shop” containing all relevant information on caring for the patient (first) and for themselves (second). Opinions regarding timing and frequency of FRO screening differed. Periodic administration of FRO measures, with each one not exceeding 20 minutes, was deemed appropriate.

Significance of results

This study extends the concept of patient-reported outcome measures to caregivers, and findings can be used to guide the development of FRO screening programs.
A pilot study to evaluate the feasibility and potential effectiveness of an early palliative care model: “Educate, Nurture, Advise, Before Life Ends for Singapore”
Authors: Yang Grace Meijuan , Koh Dawn , Natesan Neela , Ng Jess , Odom J. Nicholas , Bakitas Marie
Published: March 2024

Objective

The main objective was to pilot the culturally adapted “Educate, Nurture, Advise, Before Life Ends” for Singapore (ENABLE-SG) model to evaluate its feasibility and potential effectiveness.

Methods

A single-arm pilot trial of ENABLE-SG among patients with advanced solid tumors and caregivers of these patients was conducted in the outpatient oncology clinic setting. Enrolled participants participated in individual ENABLE-SG psychoeducational sessions weekly. Patients had 6 sessions on the topics of maintaining positivity, self-care, coping with stress, managing symptoms, exploring what matters most and life review. Caregivers had 4 sessions on the topics of maintaining positivity, self-care, coping with stress and managing symptoms. At baseline, 4, 8, and 12 months after enrolment, patient’s quality of life was measured using the Functional Assessment of Chronic Illness Therapy – Palliative Care, patient’s mood was measured using the Center for Epidemiologic Studies – Depression scale, and caregiver quality of life was measured using the Singapore Caregiver Quality of Life Scale.

Results

We enrolled 43 patients and 15 caregivers over a 10-month period from August 2021 to June 2022. Although there was a low approach-to-participation rate, most of those who enrolled completed all ENABLE-SG sessions – 72% for patients and 94% for caregivers. Caregivers had better quality of life over time, specifically in the subscales of mental well-being and experience-meaning.

Significance of results

Based on findings from this study, we are planning a randomized waitlist-controlled trial of ENABLE-SG for patients with advanced cancer and their caregivers.
Das Konfidenz- / Signifikanzniveau impliziert ein bestimmtes Kostenverhältnis zwischen Fehler 1. Art und Fehler 2. Art
Authors: Sterner Philipp , Friemelt Benedikt , Goretzko David , Kraus Elisabeth , Bühner Markus , Pargent Florian
Published: March 2024

Zusammenfassung: Die psychologische Einzelfalldiagnostik erfordert oft konkrete Entscheidungen, z. B. ob Personen in einem psychologischen Bereich „unterdurchschnittlich“ sind. Alle deutschen Lehrbücher empfehlen, die Messunsicherheit von psychologischen Tests zu berücksichtigen, z. B. durch kritische Differenzen, Hypothesentests oder Konfidenzintervalle. Diese Empfehlungen ähneln jedoch Heuristiken ohne eine nachvollziehbare Begründung, wie das geeignete Signifikanz- oder Konfidenzniveau zu wählen ist. Die statistische Entscheidungstheorie ist ein mathematisches Framework, um rationale Entscheidungen zu treffen. Obwohl sie bereits früh in der Psychologie behandelt wurde, findet sie heute wenig Beachtung. Aus einer entscheidungstheoretischen Perspektive betrachtet, lassen sich die impliziten Annahmen aktueller Entscheidungsheuristiken aufzeigen. Die Verwendung zweiseitiger Hypothesentests und Konfidenzintervalle mit einem Signifikanzniveau von alpha = 0.05 impliziert beispielsweise, dass Fehler 1. Art 39-mal schwerwiegender eingestuft werden als Fehler 2. Art. In diesem Artikel geben wir eine kurze Einführung in die Entscheidungstheorie und nutzen dieses Framework, um die Auswirkungen auf die derzeitige Praxis zu erörtern. Außerdem stellen wir eine Umfrage unter klinischen Neuropsycholog_innen vor, die für ein Fallbeispiel ihre internen Kostenverhältnisse angaben. Obwohl die Kostenverhältnisse der Praktiker_innen variierten, wählte die Mehrheit weniger extreme Verhältnisse als die üblichen Heuristiken vermuten ließen. Wir argumentieren, dass die Einzelfalldiagnostik von einer expliziten Berücksichtigung entscheidungstheoretischer Implikationen profitieren würde und skizzieren mögliche zukünftige Forschungsrichtungen.
Architecture of Fluvial and Deltaic Deposits Exposed Along the Eastern Edge of the Western Fan of Jezero Crater, Mars
Authors: Mangold N. , Caravaca G. , Gupta S. , Williams R. M. E. , Dromart G. , Gasnault O. , Le Mouélic S. , Paar G. , Bell J. , Beyssac O. , Carlot N. , Cousin A. , Dehouck E. , Horgan B. , Kah L. C. , Lasue J. , Maurice S. , Núñez J. I. , Shuster D. , Stack K. M. , Weiss B. P. , Wiens R. C.
Published: March 2024

Early observations from the Perseverance rover suggested a deltaic origin for the western fan of Jezero crater only from images of the Kodiak butte. Here, we use images from the SuperCam Remote Micro‐Imager and the Mastcam‐Z camera to analyze the western fan front along the rover traverse, and further assess its depositional origin. Outcrops in the middle to lower half of the hillslopes comprise planar and inclined beds of sandstone that are interpreted as foresets of deltaic deposits. Foresets are locally structured in ∼20–25 m thick, ∼80–100 m long, antiformal structures interpreted as deltaic mouth bars. Above these foresets, interbedded sandstones and boulder conglomerates are interpreted as fluvial topset beds. One well‐preserved lens of boulder conglomerate displays rounded clasts within well‐sorted sediment deposited in overall fining upward beds. We interpret these deposits as resulting from lateral accretion within fluvial channels. Estimations of peak discharge rates give a range between ∼100 and ∼500 m3 s−1. By contrast, boulder conglomerates exposed in the uppermost part of hillslopes are poorly sorted and truncate the underlying beds. The presence of these boulder deposits suggests that intense sediment‐laden flood episodes occurred after the deltaic foreset and topset beds were deposited, although the origin, timing, and relationship of these boulder deposits to the ancient lake that once filled Jezero crater remains undetermined. Overall, these observations confirm the deltaic nature of the fan front, and suggest a highly variable fluvial input.
Deep Learning Integrating Scale Conversion and Pedo‐Transfer Function to Avoid Potential Errors in Cross‐Scale Transfer
Authors: Li Peijun , Zha Yuanyuan , Zhang Yonggen , Michael Tso Chak‐Hau , Attinger Sabine , Samaniego Luis , Peng Jian
Published: March 2024

Pedo‐transfer functions (PTFs) relate soil/landscape static properties to a wide range of model inputs (e.g., soil hydraulic parameters) that are essential to soil hydrological modeling. Combining PTFs and hydrological models is a powerful strategy allowing the use of soil/landscape static properties for the generalization of large‐scale modeling. However, since the spatial scales of soil hydraulic parameters required for model inputs and soil/landscape static properties are often not identical, cross‐scale transfer is required, which can be a significant source of errors. Here, we investigate uncertainties in cross‐scale transfer and develop an approach that avoids them. The proposed method uses the convolutional neural network (CNN) as a cross‐scale transfer approach to directly map soil/landscape static properties to soil hydraulic parameters across different spatial scales. The proposed CNN approach is applied under two different estimation strategies to invert the hydraulic parameters of a soil‐water balance model and subsequently the quality of the parameters is assessed. Both synthetical and real‐world results around the conterminous United States indicate that in general the employed end‐to‐end strategy is superior to the two‐step strategy. The CNN‐based integrated model successfully reduces potential errors in cross‐scale transfer and can be applied to other areas lacking information on hydraulic parameters or observations. The proposed method can be extended to improve parameter estimation in earth system models and enhance our understanding of key hydrological processes.
Spatiotemporal Data Augmentation of MODIS‐Landsat Water Bodies Using Adversarial Networks
Authors: Filali Boubrahimi Soukaina , Neema Ashit , Nassar Ayman , Hosseinzadeh Pouya , Hamdi Shah Muhammad
Published: March 2024

With increasing demands for precise water resource management, there is a growing need for advanced techniques in mapping water bodies. The currently deployed satellites provide complementary data that are either of high spatial or high temporal resolutions. As a result, there is a clear trade‐off between space and time when considering a single data source. For the efficient monitoring of multiple environmental resources, various Earth science applications need data at high spatial and temporal resolutions. To address this need, many data fusion methods have been described in the literature, that rely on combining data snapshots from multiple sources. Traditional methods face limitations due to sensitivity to atmospheric disturbances and other environmental factors, resulting in noise, outliers, and missing data. This paper introduces Hydrological Generative Adversarial Network (Hydro‐GAN), a novel machine learning‐based method that utilizes modified GANs to enhance boundary accuracy when mapping low‐resolution MODIS data to high‐resolution Landsat‐8 images. We propose a new non‐saturating loss function for the Hydro‐GAN generator, which maximizes the log of discriminator probabilities to promote stable updates and aid convergence. By focusing on reducing squared differences between real and synthetic images, our approach enhances training stability and overall performance. We specifically focus on mapping water bodies using MODIS and Landsat‐8 imagery due to their relevance in water resource management tasks. Our experimental results demonstrate the effectiveness of Hydro‐GAN in generating high‐resolution water body maps, outperforming traditional methods in terms of boundary accuracy and overall quality.
A von-Neumann-like photonic processor and its application in studying quantum signature of chaos
Authors: Yu Shang , Liu Wei , Tao Si-Jing , Li Zhi-Peng , Wang Yi-Tao , Zhong Zhi-Peng , Patel Raj B. , Meng Yu , Yang Yuan-Ze , Wang Zhao-An , Guo Nai-Jie , Zeng Xiao-Dong , Chen Zhe , Xu Liang , Zhang Ning , Liu Xiao , Yang Mu , Zhang Wen-Hao , Zhou Zong-Quan , Xu Jin-Shi , Tang Jian-Shun , Han Yong-Jian , Li Chuan-Feng , Guo Guang-Can
Published: March 2024

Photonic quantum computation plays an important role and offers unique advantages. Two decades after the milestone work of Knill-Laflamme-Milburn, various architectures of photonic processors have been proposed, and quantum advantage over classical computers has also been demonstrated. It is now the opportune time to apply this technology to real-world applications. However, at current technology level, this aim is restricted by either programmability in bulk optics or loss in integrated optics for the existing architectures of processors, for which the resource cost is also a problem. Here we present a von-Neumann-like architecture based on temporal-mode encoding and looped structure on table, which is capable of multimode-universal programmability, resource-efficiency, phase-stability and software-scalability. In order to illustrate these merits, we execute two different programs with varying resource requirements on the same processor, to investigate quantum signature of chaos from two aspects: the signature behaviors exhibited in phase space (13 modes), and the Fermi golden rule which has not been experimentally studied in quantitative way before (26 modes). The maximal program contains an optical interferometer network with 1694 freely-adjustable phases. Considering current state-of-the-art, our architecture stands as the most promising candidate for real-world applications.
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

Late-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

Social 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

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

There 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

During 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

Recently, 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

Esophageal 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

Adoptive 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

Harmonic 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

The 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

Type 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

Thermoelectric 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

Recent 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.
Direct observation of tunable thermal conductance at solid/porous crystalline solid interfaces induced by water adsorbates
Authors: Wang Guang , Fan Hongzhao , Li Jiawang , Li Zhigang , Zhou Yanguang
Published: March 2024

Improving interfacial thermal transport is crucial for heat dissipation in devices with interfaces, such as electronics, buildings, and solar panels. Here, we design a strategy by utilizing the water adsorption-desorption process in porous metal-organic frameworks (MOFs) to tune the interfacial heat transfer, which could benefit their potential in cooling or heat dissipation applications. We observe a changeable thermal conductance across the solid/porous MOF interfaces owing to the dense water channel formed by the adsorbed water molecules in MOFs. Our experimental and/or modeling results show that the interfacial thermal conductance of Au/Cu3(BTC)2, Au/Zr6O4(OH)4(BDC)6 and Au/MOF-505 heterointerfaces is increased up to 7.1, 1.7 and 3.1 folds by this strategy, respectively, where Cu3(BTC)2 is referred to as HKUST-1 and Zr6O4(OH)4(BDC)6 is referred to as UiO-66. Our molecular dynamics simulations further show that the surface tension of Au layer will cause the adsorbed water molecules in MOFs to gather at the interfacial region. The dense water channel formed at the interfacial region can activate the high-frequency lattice vibrations and act as an additional thermal pathway, and then enhance heat transfer across the interfaces significantly. Our findings revealed the underlying mechanisms for tailoring thermal transport at the solid/porous MOF heterointerfaces by water adsorbates, which could motivate and benefit the new cooling system design based on MOFs.
Valence-isomer selective cycloaddition reaction of cycloheptatrienes-norcaradienes
Authors: Harada Shingo , Takenaka Hiroki , Ito Tsubasa , Kanda Haruki , Nemoto Tetsuhiro
Published: March 2024

The rapid and precise creation of complex molecules while controlling multiple selectivities is the principal objective in synthetic chemistry. Combining data science and organic synthesis to achieve this goal is an emerging trend, but few examples of successful reaction designs are reported. We develop an artificial neural network regression model using bond orbital data to predict chemical reactivities. Actual experimental verification confirms cycloheptatriene-selective [6 + 2]-cycloaddition utilizing nitroso compounds and norcaradiene-selective [4 + 2]-cycloaddition reactions employing benzynes. Additionally, a one-pot asymmetric synthesis is achieved by telescoping the enantioselective dearomatization of non-activated benzenes and cycloadditions. Computational studies provide a rational explanation for the seemingly anomalous occurrence of thermally prohibited suprafacial [6 + 2]-cycloaddition without photoirradiation.
Pressure-tuned quantum criticality in the large-D antiferromagnet DTN
Authors: Povarov Kirill Yu. , Graf David E. , Hauspurg Andreas , Zherlitsyn Sergei , Wosnitza Joachim , Sakurai Takahiro , Ohta Hitoshi , Kimura Shojiro , Nojiri Hiroyuki , Garlea V. Ovidiu , Zheludev Andrey , Paduan-Filho Armando , Nicklas Michael , Zvyagin Sergei A.
Published: March 2024

Strongly correlated spin systems can be driven to quantum critical points via various routes. In particular, gapped quantum antiferromagnets can undergo phase transitions into a magnetically ordered state with applied pressure or magnetic field, acting as tuning parameters. These transitions are characterized by z = 1 or z = 2 dynamical critical exponents, determined by the linear and quadratic low-energy dispersion of spin excitations, respectively. Employing high-frequency susceptibility and ultrasound techniques, we demonstrate that the tetragonal easy-plane quantum antiferromagnet NiCl2 ⋅ 4SC(NH2)2 (aka DTN) undergoes a spin-gap closure transition at about 4.2 kbar, resulting in a pressure-induced magnetic ordering. The studies are complemented by high-pressure-electron spin-resonance measurements confirming the proposed scenario. Powder neutron diffraction measurements revealed that no lattice distortion occurs at this pressure and the high spin symmetry is preserved, establishing DTN as a perfect platform to investigate z = 1 quantum critical phenomena. The experimental observations are supported by DMRG calculations, allowing us to quantitatively describe the pressure-driven evolution of critical fields and spin-Hamiltonian parameters in DTN.
Thermophoretic glycan profiling of extracellular vesicles for triple-negative breast cancer management
Authors: Li Yike , Zhang Shaohua , Liu Chao , Deng Jinqi , Tian Fei , Feng Qiang , Qin Lili , Bai Lixiao , Fu Ting , Zhang Liqin , Wang Yuguang , Sun Jiashu
Published: March 2024

Triple-negative breast cancer (TNBC) is a highly metastatic and heterogeneous type of breast cancer with poor outcomes. Precise, non-invasive methods for diagnosis, monitoring and prognosis of TNBC are particularly challenging due to a paucity of TNBC biomarkers. Glycans on extracellular vesicles (EVs) hold the promise as valuable biomarkers, but conventional methods for glycan analysis are not feasible in clinical practice. Here, we report that a lectin-based thermophoretic assay (EVLET) streamlines vibrating membrane filtration (VMF) and thermophoretic amplification, allowing for rapid, sensitive, selective and cost-effective EV glycan profiling in TNBC plasma. A pilot cohort study shows that the EV glycan signature reaches 91% accuracy for TNBC detection and 96% accuracy for longitudinal monitoring of TNBC therapeutic response. Moreover, we demonstrate the potential of EV glycan signature for predicting TNBC progression. Our EVLET system lays the foundation for non-invasive cancer management by EV glycans.
Intragrain impurity annihilation for highly efficient and stable perovskite solar cells
Authors: Cai Songhua , Li Zhipeng , Zhang Yalan , Liu Tanghao , Wang Peng , Ju Ming-Gang , Pang Shuping , Lau Shu Ping , Zeng Xiao Cheng , Zhou Yuanyuan
Published: March 2024

Intragrain impurities can impart detrimental effects on the efficiency and stability of perovskite solar cells, but they are indiscernible to conventional characterizations and thus remain unexplored. Using in situ scanning transmission electron microscopy, we reveal that intragrain impurity nano-clusters inherited from either the solution synthesis or post-synthesis storage can revert to perovskites upon irradiation stimuli, leading to the counterintuitive amendment of crystalline grains. In conjunction with computational modelling, we atomically resolve crystallographic transformation modes for the annihilation of intragrain impurity nano-clusters and probe their impacts on optoelectronic properties. Such critical fundamental findings are translated for the device advancement. Adopting a scanning laser stimulus proven to heal intragrain impurity nano-clusters, we simultaneously boost the efficiency and stability of formamidinium-cesium perovskite solar cells, by virtual of improved optoelectronic properties and relaxed intra-crystal strain, respectively. This device engineering, inspired and guided by atomic-scale in situ microscopic imaging, presents a new prototype for solar cell advancement.
A blood-based biomarker workflow for optimal tau-PET referral in memory clinic settings
Authors: Brum Wagner S. , Cullen Nicholas C. , Therriault Joseph , Janelidze Shorena , Rahmouni Nesrine , Stevenson Jenna , Servaes Stijn , Benedet Andrea L. , Zimmer Eduardo R. , Stomrud Erik , Palmqvist Sebastian , Zetterberg Henrik , Frisoni Giovanni B. , Ashton Nicholas J. , Blennow Kaj , Mattsson-Carlgren Niklas , Rosa-Neto Pedro , Hansson Oskar
Published: March 2024

Blood-based biomarkers for screening may guide tau positrion emissition tomography (PET) scan referrals to optimize prognostic evaluation in Alzheimer’s disease. Plasma Aβ42/Aβ40, pTau181, pTau217, pTau231, NfL, and GFAP were measured along with tau-PET in memory clinic patients with subjective cognitive decline, mild cognitive impairment or dementia, in the Swedish BioFINDER-2 study (n = 548) and in the TRIAD study (n = 179). For each plasma biomarker, cutoffs were determined for 90%, 95%, or 97.5% sensitivity to detect tau-PET-positivity. We calculated the percentage of patients below the cutoffs (who would not undergo tau-PET; “saved scans”) and the tau-PET-positivity rate among participants above the cutoffs (who would undergo tau-PET; “positive predictive value”). Generally, plasma pTau217 performed best. At the 95% sensitivity cutoff in both cohorts, pTau217 resulted in avoiding nearly half tau-PET scans, with a tau-PET-positivity rate among those who would be referred for a scan around 70%. And although tau-PET was strongly associated with subsequent cognitive decline, in BioFINDER-2 it predicted cognitive decline only among individuals above the referral cutoff on plasma pTau217, supporting that this workflow could reduce prognostically uninformative tau-PET scans. In conclusion, plasma pTau217 may guide selection of patients for tau-PET, when accurate prognostic information is of clinical value.