bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alanine and glutathione targeting of dopamine- or ibuprofen-coupled polypeptide nanocarriers increases both crossing and protective effects on a blood–brain barrier model
Authors: Mészáros Mária , Phan Thi Ha My , Vigh Judit P. , Porkoláb Gergő , Kocsis Anna , Szecskó Anikó , Páli Emese K. , Cser Nárcisz M. , Polgár Tamás F. , Kecskeméti Gábor , Walter Fruzsina R. , Schwamborn Jens C. , Janáky Tamás , Jan Jeng-Shiung , Veszelka Szilvia , Deli Mária A. 
Published: February 2025

Abstract

Background
Targeting the blood–brain barrier (BBB) is a key step for effective brain delivery of nanocarriers. We have previously discovered that combinations of BBB nutrient transporter ligands alanine and glutathione (A-GSH), increase the permeability of vesicular and polypeptide nanocarriers containing model cargo across the BBB. Our aim was to investigate dopamine- and ibuprofen-coupled 3-armed poly(l-glutamic acid) nanocarriers targeted by A-GSH for transfer across a novel human co-culture model with induced BBB properties. In addition, the protective effect of ibuprofen containing nanoparticles on cytokine-induced barrier damage was also measured.

Method
Drug-coupled nanocarriers were synthetized and characterized by dynamic light scattering and transmission electron microscopy. Cellular effects, uptake, and permeability of the nanoparticles were investigated on a human stem cell-based co-culture BBB model with improved barrier properties induced by a small molecular cocktail. The model was characterized by immunocytochemistry and permeability for marker molecules. Nanocarrier uptake in human brain endothelial cells and midbrain organoids was quantified by spectrofluorometry and visualized by confocal microscopy. The mechanisms of cellular uptake were explored by addition of free targeting ligands, endocytic and metabolic inhibitors, co-localization of nanocarriers with intracellular organs, and surface charge modification of cells. The protective effect of ibuprofen-coupled nanocarriers was investigated against cytokine-induced barrier damage by impedance and permeability measurements.

Results
Targeted nanoformulations of both drugs showed elevated cellular uptake in a time-dependent, active manner via endocytic mechanisms. Addition of free ligands inhibited the cellular internalization of targeted nanocarriers suggesting the crucial role of ligands in the uptake process. A higher permeability across the BBB model was measured for targeted nanocarriers. After crossing the BBB, targeted dopamine nanocarriers subsequently entered midbrain-like organoids derived from healthy and Parkinson’s disease patient-specific stem cells. The ibuprofen-coupled targeted nanocarriers showed protective effects against cytokine-induced barrier damage.

Conclusion
BBB-targeted polypeptide nanoparticles coupled to therapeutic molecules were effectively taken up by brain organoids or showing a BBB protective effect indicating potential applications in nervous system pathologies.

Graphical Abstract
γ-Secretase modulator resistance of an aggressive Alzheimer-causing presenilin mutant can be overcome in the heterozygous patient state by a set of advanced compounds
Authors: Trambauer Johannes , Sarmiento Rosa Maria Rodriguez , Garringer Holly J. , Salbaum Katja , Pedro Liliana D. , Crusius Dennis , Vidal Ruben , Ghetti Bernardino , Paquet Dominik , Baumann Karlheinz , Lindemann Lothar , Steiner Harald 
Published: February 2025

Abstract

Background
Amyloid-β peptide (Aβ) species of 42 or 43 amino acids in length (Aβ42/43) trigger Alzheimer´s disease (AD) and are produced in abnormal amounts by mutants of the γ-secretase subunit presenilin-1 (PS1), which represent the primary cause of familial AD (FAD). Lowering these peptides by γ-secretase modulators (GSMs) is increasingly considered a safe strategy to treat AD since these compounds do not affect the overall cleavage of γ-secretase substrates. GSMs were shown to modulate not only wild-type (WT) γ-secretase but also FAD mutants, expanding their potential use also to the familial form of the disease. Unlike most other FAD mutants, the very aggressive PS1 L166P mutant is largely resistant to GSMs. However, these data were mostly obtained from overexpression models, which mimic more the less relevant homozygous state rather than the heterozygous patient situation.

Methods
Mouse embryonic fibroblast and induced pluripotent stem cell-derived neuronal PS1 L166P knock-in (KI) cell models were treated with various GSMs and Aβ responses were assessed by immunoassays and/or gel-based analysis.

Results
We identified GSMs that lower Aβ42 and/or Aβ43 when PS1 L166P is heterozygous, as it is the case in affected patients, and could reduce the amount of pathogenic Aβ species towards WT levels. RO7019009 was the most potent of these compounds, reducing both pathogenic species and concomitantly increasing the short Aβ37 and Aβ38, of which the latter has been associated with delayed AD progression. Another effective compound, the structurally novel indole-type GSM RO5254601 specifically acts on the Aβ42 product line leading to a selective increase of the beneficial Aβ38. Interestingly, we further found that this class of GSMs can bind not only one, but both presenilin fragments suggesting that it targets γ-secretase at an unusual binding site.

Conclusion
Our data show that even highly refractory presenilin FAD mutants are in principle tractable with GSMs extending the possibilities for potential clinical studies in FAD with suitable GSM molecules.
Suitable scale structures for urban multi-functions: an integrative approach grounded in socio-ecological system analysis
Authors: Hong Wuyang , Yang Shuwen , Guo Renzhong , Li Yelin , Jiang Lin , Li Xiaoming 
Published: February 2025

Abstract

Aims
Research on the appropriate scale structure and spatial layout of ecological, urban, and agricultural spaces and the effective and methodical development and protection of urban space can provide a solid foundation for the sustainable development of the complex socio-economic urban environment.

Methods
Based on the perspective of a coupled social-ecological system, this paper constructed an assessment model to determine the ecological protection importance and development suitability of urban space, proposed the ecological-urban-agricultural priority for densely populated urban areas, and established the appropriate functional layout of urban space using a priority matrix-based mapping method.

Results
Through an empirical case study of Shenzhen, this paper determined the optimal scale structure of the types of functional spaces, identified areas of functional conflict, and proposed targeted optimization strategies for functional mismatch areas. The findings show that the appropriate scale ratio of Shenzhen’s urban, ecological, and agricultural functions is 5:4:1, which is consistent with the actual structure ratio of Shenzhen’s land use trends.

Conclusions
The proposed method can predict the appropriate scale structure of urban space development and ecological protection based on the comprehensive multi-perspective consideration of social and economic factors to provide a scientific reference for effective decision-making on urban space optimization and sustainable development.
“We need all hands on deck”: characterizing addiction medicine training in Canada—a mixed methods study of fellowship program directors
Authors: Lu Clara , Chan Kathryn , Martin Leslie , Fairbairn Nadia 
Published: February 2025

Abstract

Background
Addiction Medicine training in Canada has evolved substantially in the last few years with the establishment of accreditation standards and several new fellowship programs. The novelty of these formal training programs, created in response to complex and ever-expanding clinical needs in Addiction Medicine, creates unique educational circumstances that must be understood to support future growth. This study characterizes the current state of these postgraduate training programs in Canada through the perspectives of Program Directors (PDs).

Methods
This study is a mixed methods study of 12 PDs. In Phase 1, participants completed a quantitative survey analyzed through descriptive statistics. In Phase 2, participants underwent a qualitative semi-structured interview that was coded with a thematic analysis approach. Mixing occurred both during the interim analysis between phases and during the interpretation stage.

Results
28 trainees enrolled in a fellowship program in 2021–22 across 10 programs, and 27 trainees enrolled in 2022–23 across 11 programs. In each year, there were significantly fewer available spots than applications (31% and 29%, respectively). PDs identified a funding “bottleneck” as the most difficult and important challenge facing programs, with trainees supported by diverse and unstable funding sources. Qualitative analysis highlighted the need for sustainable funding models, flexibility toward alternative training pathways (shorter durations of training and re-entry from practice), and establishment of a national community of practice to support the co-creation of a robust addictions medical education infrastructure.

Conclusion
For Addiction Medicine training to meet workforce demands, PDs stressed that funding was the challenge of prime importance. Future studies should examine the perspectives of Addiction Medicine fellows, the clinical and research impacts of fellowship graduates, and the cost-effectiveness of fellowship funding models.
Recent updates on cold adaptation in population and laboratory studies, including cross-adaptation with nonthermal factors
Authors: Wakabayashi Hitoshi , Sakaue Hiroyuki , Nishimura Takayuki 
Published: February 2025

Abstract
This review aims to update our understanding of human cold adaptation. First, an overview of the thermoregulatory response to cold is provided, with some recent updates in human brown adipose tissue (BAT). Variation in BAT activity and multiorgan contributions to cold-induced thermogenesis were introduced. We found that individuals with less BAT activity rely more on shivering to compensate for less non-shivering thermogenesis (NST). The mechanisms of cold-induced vasoconstriction are summarized, including the role of arteriovenous anastomoses, adrenergic neural function, and inhibition of the nitric oxide vasodilator pathway. In addition, cold-induced vasodilation (CIVD) during cold immersion of the distal extremities is summarized with some recent updates in physiological mechanism. Furthermore, the cold shock response at the onset of cold immersion is introduced. Next, categorization of cold acclimatization/acclimation into habituation of shivering and metabolic and insulative adaptation are provided, with some recent updates. Especially, the rediscovery of human BAT has clarified metabolic acclimation, where increased NST replace shivering. Then, a greater CIVD response in populations in cold regions has been reported, whereas recent laboratory studies suggest no increase in CIVD after repeated cold exposure. To prevent cold injuries, individuals should not rely on habituation through repeated cold exposure. In addition, habituation to the cold shock response after repeated cold water immersion could help reduce the number of drownings. Furthermore, cross-adaptation between cold and nonthermal factors in the thermoregulatory response is summarized. Recent studies explored the relationship between exercise training and BAT activity, although this remains unresolved, depending on the exercise intensity and environmental conditions. The effects of exercise with cold exposure on the thermoregulatory response to cold are summarized in studies including divers working in cold water. We investigated the effect of exercise training in cold water, which resulted in increased muscle deoxygenation during submaximal exercise and greater anerobic power. Moreover, the effects of a hypoxic environment on cold adaptation are summarized. Elevated basal metabolism and higher distal skin temperature in highlanders could improve their cold tolerance. Finally, factors affecting cold adaptation are discussed. The type of cold adaptation may depend on the specific thermoregulatory responses repeated during the adaptation process.
Deep learning can reduce acquisition time of T2-weighted image in brain imaging
Authors: Abou-ELMagd Eman Hassan El-Saeed , Elmogy Sabry Alameldin , Abdelzaher Dina Gamal 
Published: February 2025

Abstract

Background
We used the deep learning-based reconstruction algorithm to reduce the scan time for brain T2-weighted images (T2WI) with reduction of image noise and preservation of image quality. The current prospective study included 22 cases; they were subjected to brain magnetic resonance. The aim was to investigate how much could deep learning reduce acquisition time of T2WI in brain imaging.

Results
There was a statistically significantly higher air noise (N) in conventional image analysis versus DL image analysis, but no statistically significant difference in image signal (S). Signal-to-noise ratio (SNR) was statistically significantly higher in DL image analysis versus conventional image analysis. This showed that the improvement in SNR was explained by significant decrease in N without significant change in S.

Conclusions
We concluded that deep learning-based reconstruction provides advantages of maintaining optimum image quality, reduction of image noise and obtaining the images in short time while applied during acquisition of brain magnetic resonance imaging (MRI) by T2WI. Yet, the diagnostic value of this technique to be verified, large-scale clinical studies should be conducted on this issue.
Clinical and epidemiological overview of hyperacute ischemic stroke patients treated with intravenous thrombolysis
Authors: Amalia Lisda , Qonitah Putri 
Published: February 2025

Abstract

Background
Hyperacute ischemic stroke is a type of ischemic stroke that occurs rapidly and suddenly due to blockage of blood flow to the brain, with onset within 0–24 h. The recommended treatment for hyperacute ischemic stroke patients is a recombinant tissue plasminogen activator (rtPA) according to the guidelines of the American Heart Association/American Stroke Association (AHA/ASA) and the European Stroke Organization (ESO). In Indonesia, there is still limited adoption of intravenous thrombolysis, and the researchers hope that hospitals in Indonesia will adopt this treatment for managing hyperacute ischemic stroke patients.

Objective
This study aims to describe the clinical characteristics of hyperacute ischemic stroke patients treated with intravenous thrombolysis.

Methods
This descriptive cross-sectional study was conducted at Dr. Hasan Sadikin Hospital in Bandung, which serves as the referral hospital for West Java for stroke cases treated with intravenous thrombolysis. The study employed total sampling from January 2021 to March 2024.

Results
From 23 patients, we found that most hyperacute ischemic stroke patients treated with intravenous thrombolysis were in the late elderly age group, 56–65 years old (43.5%), with onset within ≤ 4.5 h. Of the total sample, 91.3% of patients did not experience complications and approximately 50% of patients have good clinical and functional outcomes (based on NIHSS score).

Conclusion
This demonstrates the effectiveness of intravenous thrombolysis in managing hyperacute ischemic stroke patients. Future research should continue to explore optimal patient selection criteria and refine treatment protocols to further improve outcomes in stroke management.
3D fast forward modeling of DC resistivity data based on multiscale finite element method with oscillatory boundary conditions
Authors: Qi Yanfu , Zhao Yuhui , Cao Huake , Shu Chenchen , Zhou Jianmei 
Published: February 2025

To achieve fast 3D forward modeling of the direct current resistivity method for large complex models, we develop a smooth multiscale finite element algorithm with oscillatory boundary conditions. The oscillatory boundary conditions of the multiscale basis functions are obtained by solving the boundary value problems of 2D partial differential equation on the surface of the multiscale elements, which can accurately describe the conductivity heterogeneity on the boundary of multiscale elements. Then, we construct the multiscale basis functions containing fine conductive structure information by solving the boundary value problems of the local 3D partial differential equation in the multiscale elements. With the help of the oversampling technique, we further reduce the resonance errors and improve the accuracy of the multiscale finite element method. Finally, the original current conduction problem is solved on a large-scale coarse mesh and the computational efficiency is improved. We verify the accuracy of the proposed algorithm by performing 3D multiscale forward modeling on a complex 3D ore-body model and comparing it with the traditional finite element method on fine mesh. On this basis, we further compare the numerical accuracy and calculation efficiency of linear- and oscillatory boundary conditions, and discuss the influence of conductivity contrast on the accuracy of the multiscale finite element method.
NAFLD vs MASLD (metabolic dysfunction associated steatotic liver disease) - why the need for a change of nomenclature?
Authors: Gastaldelli Amalia , Newsome Philip N 
Published: February 2025

Abstract
Several reasons led to the change in the nomenclature from non alcoholic fatty liver disease (NAFLD) to metabolic dysfunction associated steatotic liver disease (MASLD); the most important being limitations due to the reliance on exclusionary confounder terms and the use of potentially stigmatising language (the terms “nonalcoholic” and “fatty”). The new name was decided through a Delphi process and now includes in the name, and definition, the metabolic origin (the presence of at least 1 of 5 cardiometabolic risk factors) without the stigmatising terms. The recognition of a new category termed “metabolic and alcohol related/associated liver disease” (Met-ALD) opens up a new area for exploration although the relative contribution of alcohol and metabolic risk factors requires further evaluation as does the evidencing at a patient rather than population level.
Immune Dysregulation and Endometrial Receptivity Impairment in Women With Repeated Implantation Failure and Dyslipidemia
Authors: Zhang Yuan , Sun Xiaoya , Zhang YuanYuan , Zou Yangyun , Zhang Yue , Wang Jie , Gao Li , Ding Wei , Diao Feiyang , Liu Jiayin , Kwak-Kim Joanne Young Hee , Ma Xiang 
Published: February 2025

Abstract

Context
Dyslipidemia adversely affects reproduction outcomes; however, its relation with repeated implantation failure (RIF) remains unclear.

Objective
This study aims to analyze the impact of dyslipidemia on assisted reproductive technology (ART) outcomes, endometrial transcriptome, and microbiome of RIF women.

Design
A retrospective real-world analysis and prospective study.

Setting
University clinic.

Patients
6499 infertile women, including 5618 non-RIF and 881 RIF.

Interventions
Dyslipidemia.

Main Outcome Measures
Implantation rate (IR), clinical pregnancy rate (CPR), and live birth rate (LBR) were compared in RIF women with or without dyslipidemia. Results of endometrial studies, including RNA sequencing (RNA-seq)-based endometrial receptivity test (ERT), 16S rRNA-based microbiome study, next-generation sequencing (NGS)-based gene comparison, and bulk RNA-seq deconvolution analysis were analyzed.

Results
The prevalence of dyslipidemia in RIF women was significantly higher. In dyslipidemia women, IR, CPR, and LBR were significantly lower, and the prevalence of nonreceptive ERT and the presence of endometrial pathogenic bacteria were higher than those of controls. After the personalized treatment, CPR 73.3% and LBR 60.0% were achieved in dyslipidemia women. NGS revealed that 176 differentially expressed genes in the endometrium of RIF women with dyslipidemia compared to those without, suggesting highly enriched in cholesterol and steroid biosynthesis and monocyte differentiation processes. An increased endometrial CD56dim natural killer cells and macrophage M1/M2 ratio with dysregulated immune factors were found by bulk RNA-seq deconvolution analysis.

Conclusion
RIF women with dyslipidemia have significantly poorer ART outcomes. In women with dyslipidemia, immune homeostasis was breached in the luteal phase endometrium, implicating a possible immune mechanism for dyslipidemia-related implantation failure.
Machine Learning-Based Biomarker Identification for Early Diagnosis of Metabolic Dysfunction-Associated Steatotic Liver Disease
Authors: Boullion Jolie , Husein Amanda , Agrawal Akshat , Xing Diensn , Hossain Md Ismail , Bhuiyan Md Shenuarin , Rom Oren , Conrad Steven A , Vanchiere John A , Orr A Wayne , Kevil Christopher G , Bhuiyan Mohammad Alfrad Nobel 
Published: February 2025

Abstract

Aim
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an umbrella term for simple hepatic steatosis and the more severe metabolic dysfunction-associated steatohepatitis. The current reliance on liver biopsy for diagnosis and a lack of validated biomarkers are major factors contributing to the overall burden of MASLD. This study investigates the association between biomarkers and hepatic steatosis and stiffness measurements, measured by FibroScan®.

Methods
Data from the National Health and Nutritional Examination Survey (2017-2020) was collected for 15,560 patients. Propensity score matching balanced the data with a 1:1 case-to-control for age and sex allowing for preliminary trend assessment. Random Forest machine learning determined variable importance for the incorporation of key biomarkers (age, sex, race, BMI, HbA1C, PFG, insulin, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, ALT, AST, ALP, albumin, GGT, LDH, iron, total bilirubin, total protein, uric acid, BUN, and hs-CRP) into logistic regression models predicting steatosis (MASLD indicated by a controlled attenuation parameter™ score of &gt;238 dB/m) and stiffness (hepatic fibrosis indicated by a median liver stiffness &gt;7 kPa). Sensitivity analysis using XGBoost and Recursive Feature Elimination was performed.

Results
The Random Forest models (the most accurate) predicted MASLD with 79.59% accuracy (p&lt;0.001) and specificity of 84.65% and, hepatic fibrosis with 86.07% accuracy (p&lt;0.001) and sensitivity of 98.01%. Both the steatosis and stiffness models identified statistically significant biomarkers, with age, BMI, and insulin appearing significant to both.

Conclusion
These findings indicate that assessing a variety of biomarkers, across demographic, metabolic, lipid, and standard biochemistry categories, may provide valuable initial insights for diagnosing patients for MASLD and hepatic fibrosis.
Management by Originals: Inventor CEOs and Firms’ Strategic Change
Authors: Kang Yungu , Zhu David 
Published: February 2025

We build upon theories and studies regarding inventors and strategic leadership to explain how inventor CEOs are likely to drive a firm’s strategic change. We explain why inventor CEOs have the unique attributes of divergent thinking and intrinsic motivation and, accordingly, pursue strategies that deviate from the past. We further suggest that the positive relationship between inventor CEO status and strategic change is strengthened by CEO liberalism, CEO career variety, and industry dynamism. Using a comprehensive longitudinal database of S&P 1500 firms, we test our theoretical predictions and find empirical support for most of our hypotheses except for the moderating effect of industry dynamism. In highlighting the prevalence of inventor CEOs and showing how this achievement-based experience of CEOs is related to strategic change, our study identifies an important and novel antecedent of this important strategic outcome. Supplemental Material: The online appendix is available at https://doi.org/10.1287/stsc.2023.0058 .