bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing a model to predict the early risk of hypertriglyceridemia based on inhibiting lipoprotein lipase (LPL): a translational study
Authors: Hernandez-Baixauli Julia , Chomiciute Gertruda , Alcaide-Hidalgo Juan María , Crescenti Anna , Baselga-Escudero Laura , Palacios-Jordan Hector , Foguet-Romero Elisabet , Pedret Anna , Valls Rosa M. , Solà Rosa , Mulero Miquel , Del Bas Josep M.
Published: December 2023

Hypertriglyceridemia (HTG) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). One of the multiple origins of HTG alteration is impaired lipoprotein lipase (LPL) activity, which is an emerging target for HTG treatment. We hypothesised that early, even mild, alterations in LPL activity might result in an identifiable metabolomic signature. The aim of the present study was to assess whether a metabolic signature of altered LPL activity in a preclinical model can be identified in humans. A preclinical LPL-dependent model of HTG was developed using a single intraperitoneal injection of poloxamer 407 (P407) in male Wistar rats. A rat metabolomics signature was identified, which led to a predictive model developed using machine learning techniques. The predictive model was applied to 140 humans classified according to clinical guidelines as (1) normal, less than 1.7 mmol/L; (2) risk of HTG, above 1.7 mmol/L. Injection of P407 in rats induced HTG by effectively inhibiting plasma LPL activity. Significantly responsive metabolites (i.e. specific triacylglycerols, diacylglycerols, phosphatidylcholines, cholesterol esters and lysophospholipids) were used to generate a predictive model. Healthy human volunteers with the impaired predictive LPL signature had statistically higher levels of TG, TC, LDL and APOB than those without the impaired LPL signature. The application of predictive metabolomic models based on mechanistic preclinical research may be considered as a strategy to stratify subjects with HTG of different origins. This approach may be of interest for precision medicine and nutritional approaches.
Sequential deregulation of histone marks, chromatin accessibility and gene expression in response to PROTAC-induced degradation of ASH2L
Authors: Barsoum Mirna , Sayadi-Boroujeni Roksaneh , Stenzel Alexander T. , Bussmann Philip , Lüscher-Firzlaff Juliane , Lüscher Bernhard
Published: December 2023

The trithorax protein ASH2L is essential for organismal and tissue development. As a subunit of COMPASS/KMT2 complexes, ASH2L is necessary for methylation of histone H3 lysine 4 (H3K4). Mono- and tri-methylation at this site mark active enhancers and promoters, respectively, although the functional relevance of H3K4 methylation is only partially understood. ASH2L has a long half-life, which results in a slow decrease upon knockout. This has made it difficult to define direct consequences. To overcome this limitation, we employed a PROTAC system to rapidly degrade ASH2L and address direct effects. ASH2L loss resulted in inhibition of proliferation of mouse embryo fibroblasts. Shortly after ASH2L degradation H3K4me3 decreased with its half-life varying between promoters. Subsequently, H3K4me1 increased at promoters and decreased at some enhancers. H3K27ac and H3K27me3, histone marks closely linked to H3K4 methylation, were affected with considerable delay. In parallel, chromatin compaction increased at promoters. Of note, nascent gene transcription was not affected early but overall RNA expression was deregulated late after ASH2L loss. Together, these findings suggest that downstream effects are ordered but relatively slow, despite the rapid loss of ASH2L and inactivation of KMT2 complexes. It appears that the systems that control gene transcription are well buffered and strong effects are only beginning to unfold after considerable delay.
Dementia risk analysis using temporal event modeling on a large real-world dataset
Authors: Taylor R. Andrew , Gilson Aidan , Chi Ling , Haimovich Adrian D. , Crawford Anna , Brandt Cynthia , Magidson Phillip , Lai James M. , Levin Scott , Mecca Adam P. , Hwang Ula
Published: December 2023

The objective of the study is to identify healthcare events leading to a diagnosis of dementia from a large real-world dataset. This study uses a data-driven approach to identify temporally ordered pairs and trajectories of healthcare codes in the electronic health record (EHR). This allows for discovery of novel temporal risk factors leading to an outcome of interest that may otherwise be unobvious. We identified several known (Down syndrome RR = 116.1, thiamine deficiency RR = 76.1, and Parkinson's disease RR = 41.1) and unknown (Brief psychotic disorder RR = 68.6, Toxic effect of metals RR = 40.4, and Schizoaffective disorders RR = 40.0) factors for a specific dementia diagnosis. The associations with the greatest risk for any dementia diagnosis were found to be primarily related to mental health (Brief psychotic disorder RR = 266.5, Dissociative and conversion disorders RR = 169.8), or neurologic conditions or procedures (Dystonia RR = 121.9, Lumbar Puncture RR = 119.0). Trajectory and clustering analysis identified factors related to cerebrovascular disorders, as well as diagnoses which increase the risk of toxic imbalances. The results of this study have the ability to provide valuable insights into potential patient progression towards dementia and improve recognition of patients at risk for developing dementia.
Production and purification of 43Sc and 47Sc from enriched [46Ti]TiO2 and [50Ti]TiO2 targets
Authors: Cingoranelli Shelbie J. , Bartels Jennifer L. , Kankanamalage Pavithra H. A. , Loveless C. Shaun , Rotsch David A. , Lapi Suzanne E.
Published: December 2023

The radioscandium isotopes, 43Sc and 47Sc, compose a promising elementally matched theranostic pair that can be used for the development of imaging and therapeutic radiopharmaceuticals with identical structures. This study aimed to investigate the production of high radionuclidic purity 43Sc from enriched [46Ti]TiO2 targets and 47Sc from enriched [50Ti]TiO2 targets and establish a target recycling technique. Enriched [46Ti]TiO2 targets were irradiated with 18 MeV protons, and enriched [50Ti]TiO2 targets were bombarded with 24 MeV protons. 43Sc and 47Sc were purified using ion chromatography attaining recovery yields of 91.7 ± 7.4% and 89.9 ± 3.9%, respectively. The average radionuclidic purity for 43Sc was 98.8 ± 0.3% and for 47Sc 91.5 ± 0.6%, while the average recovery of enriched titanium target material was 96 ± 4.0%. The highest apparent molar activity for [43Sc]Sc-DOTA was 23.2 GBq/µmol and 3.39 GBq/µmol for [47Sc]Sc-DOTA. This work demonstrates the feasibility of using enriched recycled [46Ti]TiO2 and [50Ti]TiO2 targets to produce high purity 43Sc and 47Sc as an elementally matched theranostic isotope pair.
A priori prediction of breast cancer response to neoadjuvant chemotherapy using quantitative ultrasound, texture derivative and molecular subtype
Authors: Sannachi Lakshmanan , Osapoetra Laurentius O. , DiCenzo Daniel , Halstead Schontal , Wright Frances , Look-Hong Nicole , Slodkowska Elzbieta , Gandhi Sonal , Curpen Belinda , Kolios Michael C. , Oelze Michael , Czarnota Gregory J.
Published: December 2023

The purpose of this study was to investigate the performances of the tumor response prediction prior to neoadjuvant chemotherapy based on quantitative ultrasound, tumour core-margin, texture derivative analyses, and molecular parameters in a large cohort of patients (n = 208) with locally advanced and earlier-stage breast cancer and combined them to best determine tumour responses with machine learning approach. Two multi-features response prediction algorithms using a k-nearest neighbour and support vector machine were developed with leave-one-out and hold-out cross-validation methods to evaluate the performance of the response prediction models. In a leave-one-out approach, the quantitative ultrasound-texture analysis based model attained good classification performance with 80% of accuracy and AUC of 0.83. Including molecular subtype in the model improved the performance to 83% of accuracy and 0.87 of AUC. Due to limited number of samples in the training process, a model developed with a hold-out approach exhibited a slightly higher bias error in classification performance. The most relevant features selected in predicting the response groups are core-to-margin, texture-derivative, and molecular subtype. These results imply that that baseline tumour-margin, texture derivative analysis methods combined with molecular subtype can potentially be used for the prediction of ultimate treatment response in patients prior to neoadjuvant chemotherapy.
The use of photosynthetic pigments and SPAD can help in the selection of bean genotypes under fertilization organic and mineral
Authors: Carreño Siqueira José Andres , Marques Douglas José , Silva Maria Clara Gabriel , Silva Cristian Araújo
Published: December 2023

The common bean is cultivated in all regions of the country, representing a product of great economic and social importance. In order to ensure food security in the world, it is necessary to create alternatives to reduce the dependence on fertilizers and seeds, and in this context, organic agriculture is a sustainable alternative to ensure it. Therefore, it becomes necessary to adapt rapid methods to monitor plant nutrition in real-time. The reflectance index determined by SPAD and pigment determination can be a sustainable alternative to identify genotypes in different fertilizations (organic × mineral fertilizer). The research hypothesis is to monitor nutritional management through pigment levels and reflectance index in common bean cultivars and their adaptation into different types of fertilization (organic × mineral fertilizer). Therefore, the objective of the research was to evaluate the common bean genotypes of the type carioca, in different fertilizations (organic × mineral fertilizer), and their effects on photosynthetic pigments, and the relationship between SPAD reflectance index and productivity. The experimental design used was a 2 × 7 factorial in randomized blocks with four replications: The first factor was the fertilization (organic × mineral fertilizer)and the second were the 7 genotypes (UFU-1; UFU-2; UFU-3; UFU-4; UFU-5; UFU-6 UFU-7), with UFU-1 being a hybrid obtained between genotypes UFU-4 and UFU-7; UFU-2 and UFU-3 were commercial genotypes; and UFU-4, UFU-5, UFU-6 and UFU-7 were genotypes from the UFU germplasm bank, located in the city of Monte Carmelo, Brazil. Evaluations were carried out for the agronomic characteristics of the plants, which were: height, number of branches, length and volume of roots, dry matter, leaf area index, number of flowers, number of pods, number of seeds per pod, 100 seed weight, and productivity of the genotypes. The results were compared with chlorophyll content and SPAD reflectance index, and the genotypes showed distinct behavior for each fertilization (organic × mineral fertilizer). The genotypes recommended for the organic fertilizer were UFU-2, UFU-6, and UFU-7, which showed higher productivity. For themineral fertilizer, the best-adapted genotype was UFU-4, with a higher productive yield. In conclusion, we can affirm that the highest chlorophyll and SPAD indices can help select common bean genotypes with higher productivity and adaptation within the organic fertilizer being this the main focus of this research. However, the other variables carried out during this research also demonstrated to have significant effects, so they could be analyzed individually and could offer valuable information in the selection of the best-adapted genotypes.
Examining acute psychopharmacological effects of nicotine vaping versus heated tobacco products in a randomised crossover study of product naïve adult smokers
Authors: Kale Dimitra , Tattan-Birch Harry , Brown Jamie , Cox Sharon , Dawkins Lynne , Goniewicz Maciej L. , Morris Kierra , Shahab Lion
Published: December 2023

Nicotine vaping products (NVPs) and heated tobacco products (HTPs) are designed to replicate the sensory and behavioural aspects of smoking cigarettes while avoiding combustion. The success of these products as harm reduction tools will partially depend on their ability to satisfy smokers and alleviate nicotine-related withdrawal symptoms. This study aims to compare short-term effects of NVPs (Juul and Aspire PockeX) versus HTPs (IQOS) on smoking-related withdrawal relief, product satisfaction, intention to switch to NVP/HTP, perceptions and attitudes in UK adult cigarette smokers naïve to these products. In a randomized cross-over study, 45 participants visited the lab twice, at each visit trying one of the two products (NVP/HTP) and completing a questionnaire. Responses were normalized on a 0–100% scale and mean differences (MD) between NVP and HTP scores computed, with positive and negative MD values indicating greater endorsement for NVP and HTP, respectively. Cigarette cravings were reduced similarly (~ 20.0%) by both products (MD = 4.5%, 95%Confidence Interval (CI) − 4.8, 13.8). Direct positive effects (MD = − 3.5%, 95%CI − 7.2, 0.2) and adverse side effects (MD = 1.8%, 95%CI − 0.3, 3.8) were comparable after each product use, though marginally favouring HTPs. HTPs were perceived as more satisfying overall (MD = − 13.2%, 95%CI − 20.3 − 6.1) than NVPs but both were perceived as similarly addictive (MD = 3.6%, 95%CI − 4.6, 11.8), relative to cigarettes. Intention to switch to either product was comparable (MD = 4.0%, 95%CI − 5.7, 13.8). Comparison of acute use of NVP versus HTP in a sample of UK smokers naïve to these products suggests that HTPs are perceived as more satisfying than NVPs, though still less satisfying than cigarettes.

Registration: The analysis plan was pre-registered, and it is available athttps://osf.io/6ymdu
Role of the autonomic nervous system in young, middle-aged, and older individuals with essential hypertension and sleep-related changes in neurocardiac regulation
Authors: Yeh Chia-Hsin , Chen Chun-Yu , Kuo Yu-En , Chen Chieh-Wen , Kuo Terry B. J. , Kuo Kuan-Liang , Chen Hong-Ming , Huang Hsin-Yi , Chern Chang-Ming , Yang Cheryl C. H.
Published: December 2023

Essential hypertension involves complex cardiovascular regulation. The autonomic nervous system function fluctuates throughout the sleep–wake cycle and changes with advancing age. However, the precise role of the autonomic nervous system in the development of hypertension during aging remains unclear. In this study, we characterized autonomic function during the sleep–wake cycle in different age groups with essential hypertension. This study included 97 men (53 with and 44 without hypertension) aged 30–79 years. They were stratified by age into young (< 40 years), middle-aged (40–59 years), and older (60–79 years) groups. Polysomnography and blood pressure data were recorded for 2 min before and during an hour-long nap. Autonomic function was assessed by measuring heart rate variability and blood pressure variability. Data were analyzed using t tests, correlation analyses, and two-way analysis of variance. During nonrapid eye movement (nREM), a main effect of age was observed on cardiac parasympathetic measures and baroreflex sensitivity (BRS), with the highest and lowest levels noted in the younger and older groups, respectively. The coefficients of the correlations between these measures and age were lower in patients with hypertension than in normotensive controls. The BRS of young patients with hypertension was similar to that of their middle-aged and older counterparts. However, cardiac sympathetic activity was significantly higher (p = 0.023) and BRS was significantly lower (p = 0.022) in the hypertension group than in the control group. During wakefulness, the results were similar although some of the above findings were absent. Autonomic imbalance, particularly impaired baroreflex, plays a more significant role in younger patients with hypertension. The nREM stage may be suitable for gaining insights into the relevant mechanisms.
Inductive detection of influence operations via graph learning
Authors: Gabriel Nicholas A. , Broniatowski David A. , Johnson Neil F.
Published: December 2023

Influence operations are large-scale efforts to manipulate public opinion. The rapid detection and disruption of these operations is critical for healthy public discourse. Emergent AI technologies may enable novel operations that evade detection and influence public discourse on social media with greater scale, reach, and specificity. New methods of detection with inductive learning capacity will be needed to identify novel operations before they indelibly alter public opinion and events. To this end, we develop an inductive learning framework that: (1) determines content- and graph-based indicators that are not specific to any operation; (2) uses graph learning to encode abstract signatures of coordinated manipulation; and (3) evaluates generalization capacity by training and testing models across operations originating from Russia, China, and Iran. We find that this framework enables strong cross-operation generalization while also revealing salient indicators-illustrating a generic approach which directly complements transductive methodologies, thereby enhancing detection coverage.
Gene expression profiling and protein–protein network analysis revealed prognostic hub biomarkers linking cancer risk in type 2 diabetic patients
Authors: Kasera Harshita , Shekhawat Rajveer Singh , Yadav Pankaj , Singh Priyanka
Published: December 2023

Type 2 diabetes mellitus (T2DM) and cancer are highly prevalent diseases imposing major health burden globally. Several epidemiological studies indicate increased susceptibility to cancer in T2DM patients. However, genetic factors linking T2DM with cancer have been poorly studied. In this study, we followed computational approaches using the raw gene expression data of peripheral blood mononuclear cells of T2DM and cancer patients available in the gene expression omnibus (GEO) database. Our analysis identified shared differentially expressed genes (DEGs) in T2DM and three common cancer types, namely, pancreatic cancer (PC), liver cancer (LC), and breast cancer (BC). The functional and pathway enrichment analysis of identified common DEGs highlighted the involvement of critical biological pathways, including cell cycle events, immune system processes, cell morphogenesis, gene expression, and metabolism. We retrieved the protein–protein interaction network for the top DEGs to deduce molecular-level interactions. The network analysis found 7, 6, and 5 common hub genes in T2DM vs. PC, T2DM vs. LC, and T2DM vs. BC comparisons, respectively. Overall, our analysis identified important genetic markers potentially able to predict the chances of PC, LC, and BC onset in T2DM patients.
Investigation of perfusion impairment in degenerative cervical myelopathy beyond the site of cord compression
Authors: Lebret Anna , Lévy Simon , Pfender Nikolai , Farshad Mazda , Altorfer Franziska C. S. , Callot Virginie , Curt Armin , Freund Patrick , Seif Maryam
Published: December 2023

The aim of this study was to determine tissue-specific blood perfusion impairment of the cervical cord above the compression site in patients with degenerative cervical myelopathy (DCM) using intravoxel incoherent motion (IVIM) imaging. A quantitative MRI protocol, including structural and IVIM imaging, was conducted in healthy controls and patients. In patients, T2-weighted scans were acquired to quantify intramedullary signal changes, the maximal canal compromise, and the maximal cord compression. T2*-weighted MRI and IVIM were applied in all participants in the cervical cord (covering C1–C3 levels) to determine white matter (WM) and grey matter (GM) cross-sectional areas (as a marker of atrophy), and tissue-specific perfusion indices, respectively. IVIM imaging resulted in microvascular volume fraction ($$F$$
F
), blood velocity ($$D^{*}$$

D

∗

), and blood flow ($$F \cdot D^{*}$$

F
·

D

∗

) indices. DCM patients additionally underwent a standard neurological clinical assessment. Regression analysis assessed associations between perfusion parameters, clinical outcome measures, and remote spinal cord atrophy. Twenty-nine DCM patients and 30 healthy controls were enrolled in the study. At the level of stenosis, 11 patients showed focal radiological evidence of cervical myelopathy. Above the stenosis level, cord atrophy was observed in the WM (− 9.3%; p = 0.005) and GM (− 6.3%; p = 0.008) in patients compared to healthy controls. Blood velocity (BV) and blood flow (BF) indices were decreased in the ventral horns of the GM (BV: − 20.1%, p = 0.0009; BF: − 28.2%, p = 0.0008), in the ventral funiculi (BV: − 18.2%, p = 0.01; BF: − 21.5%, p = 0.04) and lateral funiculi (BV: − 8.5%, p = 0.03; BF: − 16.5%, p = 0.03) of the WM, across C1–C3 levels. A decrease in microvascular volume fraction was associated with GM atrophy (R = 0.46, p = 0.02). This study demonstrates tissue-specific cervical perfusion impairment rostral to the compression site in DCM patients. IVIM indices are sensitive to remote perfusion changes in the cervical cord in DCM and may serve as neuroimaging biomarkers of hemodynamic impairment in future studies. The association between perfusion impairment and cervical cord atrophy indicates that changes in hemodynamics caused by compression may contribute to the neurodegenerative processes in DCM.
Construction and validation of a novel lysosomal signature for hepatocellular carcinoma prognosis, diagnosis, and therapeutic decision-making
Authors: Chen Jianlin , Gao Gan , He Yufang , Zhang Yi , Wu Haixia , Dai Peng , Zheng Qingzhu , Huang Hengbin , Weng Jiamiao , Zheng Yue , Huang Yi
Published: December 2023

Lysosomes is a well-recognized oncogenic driver and chemoresistance across variable cancer types, and has been associated with tumor invasiveness, metastasis, and poor prognosis. However, the significance of lysosomes in hepatocellular carcinoma (HCC) is not well understood. Lysosomes-related genes (LRGs) were downloaded from Genome Enrichment Analysis (GSEA) databases. Lysosome-related risk score (LRRS), including eight LRGs, was constructed via expression difference analysis (DEGs), univariate and LASSO-penalized Cox regression algorithm based on the TCGA cohort, while the ICGC cohort was obtained for signature validation. Based on GSE149614 Single-cell RNA sequencing data, model gene expression and liver tumor niche were further analyzed. Moreover, the functional enrichments, tumor microenvironment (TME), and genomic variation landscape between LRRSlow/LRRShigh subgroup were systematically investigated. A total of 15 Lysosomes-related differentially expressed genes (DELRGs) in HCC were detected, and then 10 prognosis DELRGs were screened out. Finally, the 8 optimal DELRGs (CLN3, GBA, CTSA, BSG, APLN, SORT1, ANXA2, and LAPTM4B) were selected to construct the LRRS prognosis signature of HCC. LRRS was considered as an independent prognostic factor and was associated with advanced clinicopathological features. LRRS also proved to be a potential marker for HCC diagnosis, especially for early-stage HCC. Then, a nomogram integrating the LRRS and clinical parameters was set up displaying great prognostic predictive performance. Moreover, patients with high LRRS showed higher tumor stemness, higher heterogeneity, and higher genomic alteration status than those in the low LRRS group and enriched in metabolism-related pathways, suggesting its underlying role in the progression and development of liver cancer. Meanwhile, the LRRS can affect the proportion of immunosuppressive cell infiltration, making it a vital immunosuppressive factor in the tumor microenvironment. Additionally, HCC patients with low LRRS were more sensitive to immunotherapy, while patients in the high LRRS group responded better to chemotherapy. Upon single-cell RNA sequencing, CLN3, GBA, and LAPTM4B were found to be specially expressed in hepatocytes, where they promoted cell progression. Finally, RT-qPCR and external datasets confirmed the mRNA expression levels of model genes. This study provided a direct links between LRRS signature and clinical characteristics, tumor microenvironment, and clinical drug-response, highlighting the critical role of lysosome in the development and treatment resistance of liver cancer, providing valuable insights into the prognosis prediction and treatment response of HCC, thereby providing valuable insights into prognostic prediction, early diagnosis, and therapeutic response of HCC.
Validation of cost-efficient EEG experimental setup for neural tracking in an auditory attention task
Authors: Ha Jiyeon , Baek Seung-Cheol , Lim Yoonseob , Chung Jae Ho
Published: December 2023

When individuals listen to speech, their neural activity phase-locks to the slow temporal rhythm, which is commonly referred to as “neural tracking”. The neural tracking mechanism allows for the detection of an attended sound source in a multi-talker situation by decoding neural signals obtained by electroencephalography (EEG), known as auditory attention decoding (AAD). Neural tracking with AAD can be utilized as an objective measurement tool for diverse clinical contexts, and it has potential to be applied to neuro-steered hearing devices. To effectively utilize this technology, it is essential to enhance the accessibility of EEG experimental setup and analysis. The aim of the study was to develop a cost-efficient neural tracking system and validate the feasibility of neural tracking measurement by conducting an AAD task using an offline and real-time decoder model outside the soundproof environment. We devised a neural tracking system capable of conducting AAD experiments using an OpenBCI and Arduino board. Nine participants were recruited to assess the performance of the AAD using the developed system, which involved presenting competing speech signals in an experiment setting without soundproofing. As a result, the offline decoder model demonstrated an average performance of 90%, and real-time decoder model exhibited a performance of 78%. The present study demonstrates the feasibility of implementing neural tracking and AAD using cost-effective devices in a practical environment.
Incidence of bacterial and fungal infections in Polish pediatric patients with acute lymphoblastic leukemia during the pandemic
Authors: Zawitkowska Joanna , Drabko Katarzyna , Lejman Monika , Kowalczyk Adrian , Czyżewski Krzysztof , Dziedzic Magdalena , Jaremek Kamila , Zalas-Więcek Patrycja , Szmydki-Baran Anna , Hutnik Łukasz , Czogała Wojciech , Balwierz Walentyna , Żak Iwona , Salamonowicz-Bodzioch Małgorzata , Kazanowska Bernarda , Wróbel Grażyna , Frączkiewicz Jowita , Kałwak Krzysztof , Tomaszewska Renata , Szczepański Tomasz , Zając-Spychała Olga , Wachowiak Jacek , Płonowski Marcin , Krawczuk-Rybak Maryna , Królak Aleksandra , Ociepa Tomasz , Urasiński Tomasz , Pierlejewski Filip , Młynarski Wojciech , Urbańska-Rakus Justyna , Machnik Katarzyna , Pająk Sonia , Badowska Wanda , Brzeski Tomasz , Mycko Katarzyna , Mańko-Glińska Hanna , Urbanek-Dądela Agnieszka , Karolczyk Grażyna , Mizia-Malarz Agnieszka , Stolpa Weronika , Skowron-Kandzia Katarzyna , Musiał Jakub , Chaber Radosław , Irga-Jaworska Ninela , Bień Ewa , Styczyński Jan
Published: December 2023

The most common complications related to the treatment of childhood acute lymphoblastic leukemia (ALL) are infections. The aim of the study was to analyze the incidence and mortality rates among pediatric patients with ALL who were treated in 17 Polish pediatric hematology centers in 2020–2021 during the pandemic. Additionally, we compared these results with those of our previous study, which we conducted in the years 2012–2017. The retrospective analysis included 460 patients aged 1–18 years with newly diagnosed ALL. In our study, 361/460 (78.5%) children were reported to have microbiologically documented bacterial infections during chemotherapy. Ten patients (2.8%) died due to sepsis. Fungal infections were reported in 99 children (21.5%), of whom five (5.1%) died due to the infection. We especially observed an increase in bacterial infections during the pandemic period compared to the previous study. The directions of our actions should be to consider antibiotic prophylaxis, shorten the duration of hospitalization, and educate parents and medical staff about complications (mainly infections) during anticancer therapy. It is necessary to continue clinical studies evaluating infection prophylaxis to improve outcomes in childhood ALL patients.
Diabetic choriocapillaris flow deficits affect the outer retina and are related to hemoglobin A1c and systolic blood pressure levels
Authors: Nagai Norihiro , Mushiga Yasuaki , Ozawa Yoko
Published: December 2023

Patient systemic and ocular data based on optical coherence tomography (OCT) and OCT angiography images were analyzed (n = 45; control and diabetic eyes with or without diabetic retinopathy [DR]; mean age, 49.6 ± 8.1 years). All participants had best-corrected visual acuity < 0.05 in logMAR. The choriocapillaris flow area (CCFA) ratio was lower and the coefficient of variation (CV) of CCFA ratio was higher in diabetic eyes with or without DR than in control eyes. CCFA ratio of DR eyes was lower than that of diabetic eyes without DR. Superficial retinal vessel length density (VLD) was reduced only in DR eyes. CCFA ratio correlated with retinal VLD, photoreceptor outer segment (PROS) length, and retinal pigment epithelium (RPE) volume in the study population; mean PROS decreased in diabetic eyes with or without DR, and RPE volume increased in DR eyes. CCFA ratio < 65.9% and CV of CCFA ratio ≥ 0.140 were more frequently found in diabetic eyes (odds ratio [OR], 13.333; P = 0.001), and related to HbA1c ≥ 7.0% (OR, 4.992; 95% confidence interval [CI] 1.164–21.412; P = 0.030) or systolic blood pressure ≥ 135 mmHg (OR, 5.572; 95% CI 1.156–26.863; P = 0.032). These findings could help understand diabetic pathogenesis in the choriocapillaris and outer retina, and remind clinicians to manage both diabetes and hypertension.
Retina image segmentation using the three-path Unet model
Authors: Liu Ruihua , Pu Wei , Nan Haoyu , Zou Yangyang
Published: December 2023

Unsupervised image segmentation is a technique that divides an image into distinct regions or objects without prior labeling. This approach offers flexibility and adaptability to various types of image data. Particularly for large datasets, it eliminates the need for manual labeling, thereby it presents advantages in terms of time and labor costs. However, when applied to retinal image segmentation, challenges arise due to variations in data, presence of noise, and manual threshold adjustments, which can lead to over-segmentation or under-segmentation of small blood vessel boundaries and endpoints. In order to enhance the precision and accuracy of retinal image segmentation, we propose a novel image supervised segmentation network based on three-path Unet model.Firstly, the Haar wavelet transform is employed to extract high-frequency image information, which forms the foundation for the proposed HaarNet, a Unet-inspired architecture. Next, the HaarNet is integrated with the Unet and SegNet frameworks to develop a three-path Unet model, referred to as TP-Unet. Finally, the model is further refined into TP-Unet+AE+DSL by incorporating the advantages of auto-encoding (AE) and deep supervised learning (DSL) techniques, thereby enhancing the overall performance of the system. To evaluate the effectiveness of our proposed model, we conduct experiments using the DRIVE and CHASE public datasets. On the DRIVE dataset, our recommended model achieves a Dice coefficient of 0.8291 and a sensitivity index of 0.8184. These results significantly outperform the Unet model by $$1.34\%$$

1.34
%

and $$2.60\%$$

2.60
%

, respectively. Furthermore, our model demonstrates excellent performance on the CHASE dataset, with a Dice coefficient of 0.8162, a sensitivity of 0.8242, and an accuracy of 0.9664. These metrics surpass the Unet model by $$3.20\%$$

3.20
%

, $$6.66\%$$

6.66
%

, and $$0.42\%$$

0.42
%

, respectively. Our proposed model provides more accurate and reliable results for retinal vessel segmentation, which holds significant potential for assisting doctors in their diagnosis.
Targeted inhibition of the ATR/CHK1 pathway overcomes resistance to olaparib and dysregulates DNA damage response protein expression in BRCA2MUT ovarian cancer cells
Authors: Biegała Łukasz , Gajek Arkadiusz , Szymczak-Pajor Izabela , Marczak Agnieszka , Śliwińska Agnieszka , Rogalska Aneta
Published: December 2023

Olaparib is a PARP inhibitor (PARPi) approved for targeted treatment of ovarian cancer (OC). However, its efficacy is impeded by the inevitable occurrence of resistance. Here, we investigated whether the cytotoxic activity of olaparib could be synergistically enhanced in olaparib-resistant OC cells with BRCA2 reversion mutation by the addition of inhibitors of the ATR/CHK1 pathway. Moreover, we provide insights into alterations in the DNA damage response (DDR) pathway induced by combination treatments. Antitumor activity of olaparib alone or combined with an ATR inhibitor (ATRi, ceralasertib) or CHK1 inhibitor (CHK1i, MK-8776) was evaluated in OC cell lines sensitive (PEO1, PEO4) and resistant (PEO1-OR) to olaparib. Antibody microarrays were used to explore changes in expression of 27 DDR-related proteins. Olaparib in combination with ATR/CHK1 inhibitors synergistically induced a decrease in viability and clonogenic survival and an increase in apoptosis mediated by caspase-3/7 in all OC cells. Combination treatments induced cumulative alterations in expression of DDR-related proteins mediating distinct DNA repair pathways and cell cycle control. In the presence of ATRi and CHK1i, olaparib-induced upregulation of proteins determining cell fate after DNA damage (PARP1, CHK1, c-Abl, Ku70, Ku80, MDM2, and p21) was abrogated in PEO1-OR cells. Overall, the addition of ATRi or CHK1i to olaparib effectively overcomes resistance to PARPi exerting anti-proliferative effect in BRCA2MUT olaparib-resistant OC cells and alters expression of DDR-related proteins. These new molecular insights into cellular response to olaparib combined with ATR/CHK1 inhibitors might help improve targeted therapies for olaparib-resistant OC.
Treatment cessation in HBeAg-negative chronic hepatitis B: clinical response is associated with increase in specific proinflammatory cytokines
Authors: Holmberg Marte , Aass Hans Christian D. , Dalgard Olav , Samuelsen Ellen , Sun Dan , Björkström Niklas K. , Johannessen Asgeir , Reikvam Dag Henrik
Published: December 2023

Patients with HBeAg-negative chronic hepatitis B may experience an immune response after stopping nucleos(t)ide analogue (NA)therapy, which may potentially trigger HBsAg loss or off-therapy sustained viral control. The immunological mechanisms determining clinical response remain poorly understood. To identify inflammatory signatures associated with defined outcomes, we analysed plasma cytokines and chemokines from 57 HBeAg-negative patients enrolled in the Nuc-Stop Study at baseline and 12 weeks after NA cessation. Clinical response at 12 weeks was classified into four groups: immune control, viral relapse, evolving clinical relapse, and resolving clinical relapse. Twelve weeks after treatment cessation 17 patients (30%) experienced immune control, 19 (33%) viral relapse, 6 (11%) evolving clinical relapse, and 15 (26%) resolving clinical relapse. There was a significant increase in interferon-γ-induced protein 10 (IP-10; p = 0.012) and tumor necrosis factor (TNF; p = 0.032) in patients with evolving clinical relapse. Sparse partial least-squares multivariate analyses (sPLS-DA) showed higher first component values for the clinical relapse group compared to the other groups, separation was driven mainly by IP-10, TNF, IL-9, IFN-γ, MIP-1β, and IL-12. Our results demonstrate that evolving clinical relapse after NA cessation is associated with a systemic increase in the proinflammatory cytokines IP-10 and TNF.

Clinical trial registration: ClinicalTrials.gov, Identifier: NCT03681132.
Modulation of memory reconsolidation by adjacent novel tasks: timing defines the nature of change
Authors: Schroeder Matías Nicolás , Fullio Camila L. , Ballarini Fabricio , Moncada Diego
Published: December 2023

Reconsolidation turns memories into a responsive state that allows their modulation until they stabilize again. This phenomenon attracted remarkable attention due to its potential impact on therapeutics and education. Recent evidence revealed that different memories undergo reconsolidation via a behavioral tagging process. Thus, their re-stabilization involves setting “reconsolidation-tags” and synthesizing plasticity-related proteins for their capture at the tagged sites. Here, we studied the possibility of affecting these fundamental mechanisms to modulate reconsolidation. Our findings, in laboratory rats, indicate that exploring a novel environment 60 min before or after memory reactivation improves spatial object recognition memory by promoting protein synthesis. Conversely, experiencing novelty immediately after reactivation impairs the reconsolidation by affecting the tags. Similar effects, but with a different optimal time window for improvement, occur in inhibitory avoidance memory. These results highlight the possibility of modulating existing memories using non-invasive interventions that selectively affect the fundamental mechanisms of behavioral tagging during their reconsolidation.
International bureaucrats’ attitudes toward global climate adaptation
Authors: Dellmuth Lisa
Published: December 2023

The 2015 Paris Agreement has fueled debates about how the international bureaucrats driving international organizations’ engagement with climate adaptation ought to address adaptation challenges. While previous research has predominantly focused on the structural constraints in adaptation governance, this paper develops a distinct argument about the cognitive frames through which international bureaucrats view climate risks. The evidence comes from a survey among bureaucrats in three organizations that have engaged with adaptation to different extents: United Nations Environment, the United Nations High Commissioner for Refugees, and the World Health Organization. The results suggest that the majority of the surveyed bureaucrats view climate risks as a multidimensional problem. The evidence indicates that bureaucrats are more likely to view climate risks through multiple than through single issue frames, the more certain they perceive the knowledge about climate impacts in their issue area to be. By way of conclusion, the paper sketches broader implications for adaptation and international bureaucracy research.
The politics of climate risk assessment
Authors: Hedlund Johanna
Published: December 2023

Almost 25 years ago, sociologist Anthony Giddens wrote that ‘risk and responsibility are in fact closely linked’1. Extending this to climate risk, this perspective paper argues that climate risk assessment is not just a scientific endeavour but also deeply political. As climate risks become more complex and demand more science- and policy-driven integration across sectors and regions, assessments may involve significant political constraints that impede effective and just climate adaptation. Using a framework of integration challenges, this paper uncovers political constraints that may arise in developing integrated climate risk assessment. It argues that the framing and structuring of climate risk assessment may yield political constraints such as biases towards certain groups, sectoral incoherence, decisions not aiding the most exposed, distributional conflicts, and ambiguous responsibility in managing complex climate risks. Left unaddressed, such political constraints may hamper climate adaptation rather than enable progress.
The olfactory receptor Olfr78 promotes differentiation of enterochromaffin cells in the mouse colon
Authors: Dinsart Gilles , Leprovots Morgane , Lefort Anne , Libert Frédérick , Quesnel Yannick , Veithen Alex , Vassart Gilbert , Huysseune Sandra , Parmentier Marc , Garcia Marie-Isabelle
Published: December 2023

The gastrointestinal epithelium constitutes a chemosensory system for microbiota-derived metabolites such as short-chain fatty acids (SCFA). Here, we investigate the spatial distribution of Olfr78, one of the SCFA receptors, in the mouse intestine and study the transcriptome of colon enteroendocrine cells expressing Olfr78. The receptor is predominantly detected in the enterochromaffin and L subtypes in the proximal and distal colon, respectively. Using the Olfr78-GFP and VilCre/Olfr78flox transgenic mouse lines, we show that loss of epithelial Olfr78 results in impaired enterochromaffin cell differentiation, blocking cells in an undefined secretory lineage state. This is accompanied by a reduced defense response to bacteria in colon crypts and slight dysbiosis. Using organoid cultures, we further show that maintenance of enterochromaffin cells involves activation of the Olfr78 receptor via the SCFA ligand acetate. Taken together, our work provides evidence that Olfr78 contributes to colon homeostasis by promoting enterochromaffin cell differentiation.
Multiomics analysis identifies novel facilitators of human dopaminergic neuron differentiation
Authors: Gomez Ramos Borja , Ohnmacht Jochen , de Lange Nikola , Valceschini Elena , Ginolhac Aurélien , Catillon Marie , Ferrante Daniele , Rakovic Aleksandar , Halder Rashi , Massart François , Arena Giuseppe , Antony Paul , Bolognin Silvia , Klein Christine , Krause Roland , Schulz Marcel H , Sauter Thomas , Krüger Rejko , Sinkkonen Lasse
Published: December 2023

Midbrain dopaminergic neurons (mDANs) control voluntary movement, cognition, and reward behavior under physiological conditions and are implicated in human diseases such as Parkinson’s disease (PD). Many transcription factors (TFs) controlling human mDAN differentiation during development have been described, but much of the regulatory landscape remains undefined. Using a tyrosine hydroxylase (TH) human iPSC reporter line, we here generate time series transcriptomic and epigenomic profiles of purified mDANs during differentiation. Integrative analysis predicts novel regulators of mDAN differentiation and super-enhancers are used to identify key TFs. We find LBX1, NHLH1 and NR2F1/2 to promote mDAN differentiation and show that overexpression of either LBX1 or NHLH1 can also improve mDAN specification. A more detailed investigation of TF targets reveals that NHLH1 promotes the induction of neuronal miR-124, LBX1 regulates cholesterol biosynthesis, and NR2F1/2 controls neuronal activity.
Highly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis
Authors: Kim Yoon Tae , Huh Jin Won , Choi Yun Hui , Yoon Hee Kyeong , Nguyen Tram TT , Chun Eunho , Jeong Geunyeol , Park Sunyoung , Ahn Sungwoo , Lee Won-Kyu , Noh Young-Woock , Lee Kyoung Sun , Ahn Hee-Sung , Lee Cheolju , Lee Sang Min , Kim Kyung Su , Suh Gil Joon , Jeon Kyeongman , Kim Sunghoon , Jin Mirim
Published: December 2023

Despite intensive clinical and scientific efforts, the mortality rate of sepsis remains high due to the lack of precise biomarkers for patient stratification and therapeutic guidance. Secreted human tryptophanyl-tRNA synthetase 1 (WARS1), an endogenous ligand for Toll-like receptor (TLR) 2 and TLR4 against infection, activates the genes that signify the hyperinflammatory sepsis phenotype. High plasma WARS1 levels stratified the early death of critically ill patients with sepsis, along with elevated levels of cytokines, chemokines, and lactate, as well as increased numbers of absolute neutrophils and monocytes, and higher Sequential Organ Failure Assessment (SOFA) scores. These symptoms were recapitulated in severely ill septic mice with hypercytokinemia. Further, injection of WARS1 into mildly septic mice worsened morbidity and mortality. We created an anti-human WARS1-neutralizing antibody that suppresses proinflammatory cytokine expression in marmosets with endotoxemia. Administration of this antibody into severe septic mice attenuated cytokine storm, organ failure, and early mortality. With antibiotics, the antibody almost completely prevented fatalities. These data imply that blood-circulating WARS1-guided anti-WARS1 therapy may provide a novel theranostic strategy for life-threatening systemic hyperinflammatory sepsis.
Selective purification and rapid quantitative detection of spores using a “stepped” magnetic flow device
Authors: Li Mengya , Liu Shijie , Guo Shiliang , Liang Dong , Li Miaoyun , Zhu Yaodi , Zhao Lijun , Lee Jong-Hoon , Zhao Gaiming , Ma Yangyang , Liu Yanxia
Published: December 2023

A novel method based on Van-Fe3O4 to selectively capture vegetative cells is used to obtain high-purity spores, and the “stepped” magnetic flow device increases the contact area and its external magnetic field to remove vegetative cells.
GSH/pH dual responsive chitosan nanoparticles for reprogramming M2 macrophages and overcoming cancer chemoresistance
Authors: Zhao Xinzhi , Zheng Chunxiong , Wang Ying , Hao Jialei , Liu Yang
Published: December 2023

A chitosan-based nanoplatform that responds to both GSH and pH levels was developed, which helped to overcome MDR through the integration of chemotherapy and macrophage polarization.
Sialic acids in infection and their potential use in detection and protection against pathogens
Authors: Dedola Simone , Ahmadipour Sanaz , de Andrade Peterson , Baker Alexander N. , Boshra Andrew N. , Chessa Simona , Gibson Matthew I. , Hernando Pedro J. , Ivanova Irina M. , Lloyd Jessica E. , Marín María J. , Munro-Clark Alexandra J. , Pergolizzi Giulia , Richards Sarah-Jane , Ttofi Iakovia , Wagstaff Ben A. , Field Robert A.
Published: December 2023

An overview of sialic acid involvement in infection and exploitation in diagnostics and therapeutics.
Lifetimes and decay mechanisms of isotopically substituted ozone above the dissociation threshold: matching quantum and classical dynamics
Authors: Kokoouline Viatcheslav , Alijah Alexander , Tyuterev Vladimir
Published: December 2023

Energies, wavefunctions and lifetimes of vibrational resonances were computed for 18O-enriched isotopologue 50O3 = {16O16O18O and 16O18O16O} of the ozone molecule using hyperspherical coordinates and the method employing complex absorbing potential.
The single metal atom (Ni, Pd, Pt) anchored on defective hexagonal boron nitride for oxidative desulfurization
Authors: Lv Naixia , Ran Hongshun , Zhang Jinrui , Yin Jie , Zhang Yuan , Li Hongping , Zhu Linhua
Published: December 2023

DFT calculations reveal that single atoms of Ni and Pt anchored on the N and B vacancies of h-BN show excellent activity for O2 activation, aiding the subsequent oxidation of DBT into DBTOO.
Tracking carbon dioxide adsorbate intramolecular dynamics in pure silica zeolite Silicalite-1 by in situ Raman scattering
Authors: Tzankov Dimitar V. , Georgiev Peter A.
Published: December 2023

Dense carbon dioxide phases, confined in the micropores of a pure siliceous zeolite Silicalite-1, are identified and characterised with the use of in situ Raman scattering, by monitoring the dynamics of the corresponding Fermi resonance.
Encapsulation of Co nanoparticles with single-atomic Co sites into nitrogen-doped carbon for electrosynthesis of hydrogen peroxide
Authors: Li Kun , Sun Yanyan , Zhao Ziwei , Zhu Ting
Published: December 2023

The coexistence of Co nanoparticles and single-atomic Co sites in nitrogen-doped carbon in the CoNC-900 catalyst endowed a high H2O2 selectivity of 73.3% with a high faradaic efficiency of 87%.
Numerical one-dimensional investigations on a multi-cylinder spark ignition engine using hydrogen/ethanol, hydrogen/methanol and gasoline in dual fuel mode
Authors: Qadiri Ufaith
Published: December 2023

This study enhances the application of alternative fuels—specifically hydrogen, methanol, and ethanol—in a multi-cylinder gasoline engine.
Concluding remarks: a summary of the Faraday Discussion on rechargeable non-aqueous metal–oxygen batteries
Authors: Hardwick Laurence J.
Published: December 2023

The Faraday Discussion on rechargeable non-aqueous metal–oxygen batteries is summarised.