bluuebunny/crossref_metadata_2025 huggingface dataset:
PD_EBM: An Integrated Boosting Approach Based on Selective Features for Unveiling Parkinson's Disease Diagnosis With Global and Local Explanations
Authors: Khanom Fahmida , Uddin Mohammad Shorif , Mostafiz Rafid
Published: January 2025

Early detection and characterization are crucial for treating and managing Parkinson's disease (PD). The increasing prevalence of PD and its significant impact on the motor neurons of the brain impose a substantial burden on the healthcare system. Early‐stage detection is vital for improving patient outcomes and reducing healthcare costs. This study introduces an ensemble boosting machine, termed PD_EBM, for the detection of PD. PD_EBM leverages machine learning (ML) algorithms and a hybrid feature selection approach to enhance diagnostic accuracy. While ML has shown promise in medical applications for PD detection, the interpretability of these models remains a significant challenge. Explainable machine learning (XML) addresses this by providing transparency and clarity in model predictions. Techniques such as Local Interpretable Model‐agnostic Explanations (LIME) and SHapley Additive exPlanations (SHAP) have become popular for interpreting these models. Our experiment used a dataset of 195 clinical records of PD patients from the University of California Irvine (UCI) Machine Learning repository. Comprehensive data preparation included encoding categorical features, imputing missing values, removing outliers, addressing data imbalance, scaling data, selecting relevant features, and so on. We propose a hybrid boosting framework that focuses on the most important features for prediction. Our boosting model employs a Decision Tree (DT) classifier with AdaBoost, followed by a linear discriminant analysis (LDA) optimizer, achieving an impressive accuracy of 99.44%, outperforming other boosting models.
Gully erosion susceptibility mapping in the Loess Plateau and the Northeast China Mollisol region: Optimal resolution and algorithms, influencing factors and spatial distribution
Authors: Yang Annan , Wang Chunmei , Yang Qinke , Pang Guowei , Long Yongqing , Wang Lei , Cruse Richard M.
Published: January 2025

Gully erosion susceptibility (GES) mapping is crucial for controlling gully erosion hazards and has become a significant focus of global research and management efforts. Machine learning models have proven effective in this field. However, in areas with different terrain complexity, the model shows significant variation in optimal resolution and algorithms, factor importance and spatial distribution of the model results, which limits their broader application. This study compares GES mapping in two small watersheds: one located in the complex terrain of the Loess Plateau and the other in the relatively flat terrain of the Northeast China Mollisol region. The model predictive accuracy was evaluated using 30% of the datasets that were excluded from model training. The results revealed that: 1) significant differences in optimal resolution of GES mapping in the two regions, which were 1–2.5 m for the Mollisol region, and 2.5–5 m for the Loess Plateau. The extreme boosting tree (XGBoost) algorithm achieved the best simulation results compared to random forest (RF) and gradient boosting decision tree (GBDT) in both regions. 2) Slope gradient and contributing area influenced gully distribution in both watersheds, with land use being critical in the Loess Plateau and distance from streams more important in the Mollisol region. 3) In the Loess Plateau watershed, 25% of the area was highly susceptible to gully erosion, while only 1% of the Mollisol watershed was highly susceptible. This research compared GES mapping in two watersheds with different terrain complexity, which would be beneficial for better use of machine learning in gully research.
Early Pleistocene initiation of Simav Graben: Implications for widespread extension and landscape change in West Anatolia
Authors: Ocakoğlu Faruk , Tün Muammer , Şahiner Eren
Published: January 2025

The prevailing model of west Anatolian extension posits that the westward extrusion of Anatolia, driven by the Northern and Eastern Anatolian transform faults and slab rollback across the Hellenic Trench, governs ongoing extension from Gökova Graben to the Eskişehir Graben in Western Anatolia. However, data gaps and conflicting datasets constrain our understanding of the most recent phase of extension and the underlying geodynamic processes. To address these uncertainties, we investigated the sediment thickness and chronology of the Simav Graben (NW Anatolia) using microtremor surveys, radiocarbon dating and optically stimulated luminescence (OSL) dating from drill cores. Additionally, we examined the geomorphological characteristics of the graben and identified knickpoints along select rivers. Our findings indicate that the Simav Graben is an early Pleistocene (~1.1 Ma) structure with a maximum sediment thickness of approximately 540 m, accompanied by 900 m of maximum vertical displacement along the main bounding fault. Based on alluvial terraces, we infer an uplift rate of 1.1–1.3 mm/year for the last 85 ka, with an average long‐term uplift rate of 0.8 mm/year over the graben's lifespan. Our morphological analysis reveals a series of knickpoints unrelated to lithology, beginning at 1300 m and descending to 800 m on hillslopes inclined toward the Sea of Marmara. The synchronous initiation of the Southern Splay of the Northern Anatolian Fault in the Marmara region and the Simav Graben suggests a causal relationship. We propose that the formation of the Northern Anatolian Fault in southern Marmara during the early Pleistocene triggered widespread extension in western Anatolia. Consequently, the north‐flowing river networks, except for those associated with the Simav Graben, experienced regional incision.
Impact of pH on the Physicochemical, Structural, and Techno‐Functional Properties of Sesame Protein Isolate
Authors: Ghorbani Azade , Rafe Ali , Hesarinejad Mohammad Ali , Lorenzo Jose M.
Published: January 2025

Sesame protein isolate (SPI) is a highly nutritious plant protein distinguished by its essential amino acid profile. This study investigates the influence of pH on SPI's physicochemical, structural, and techno‐functional properties, highlighting its potential as a sustainable protein source for various food applications. Our findings revealed that SPI had a protein content of 90.60% and a protein extraction yield of 77.2%. The density is measured at 0.72 g/mL, with a critical compressibility index of 19.22, indicating excellent flowability for weaning foods. Notably, the ζ‐potential shifts from +39 mV at pH 3.0 to 0 at the isoelectric point (pI, 5–5.5) and becomes negative at higher pH levels. We observed a direct correlation between solubility, fluorescence intensity, and functional characteristics of SPI, with peak solubility and functional properties at acidic and alkaline pH levels and lowest values at the pI. Structural analyses confirmed the relationship between electrical charge, hydrophobicity, and functional attributes, with the highest surface hydrophobicity observed at pH 2.0. In conclusion, our findings underscore the critical role of pH in modulating the physicochemical properties of sesame protein isolate, enhancing its applicability in food formulations. SPI demonstrates significant potential as a versatile ingredient in the functional food product development.
Reduced Granitic Rocks and Related Gold Mineralisation: Implications From Chronology, Geochemistry and Sr–Nd–Hf–O Isotopic System of Early Cretaceous Granites From the Wulong Gold Deposit, Liaodong Peninsula, NE China
Authors: Liu Jun , Wang Xiao‐Tong , He Jun‐Cheng , Li Tie‐Gang
Published: January 2025

The Liaodong Peninsula is the northeastern part of the North China Craton and hosts abundant Late Mesozoic granites and associated gold deposits. The Wulong deposit contains 57.5 t Au with an average grade of 7.1 g/t and is the largest gold deposit in the Liaodong Peninsula. The Wulong gold orebodies are hosted in Mesozoic biotite granites and have a close association with synchronous granite porphyry dykes. In this study, we provide a systemic geochemical and chronological study to distinguish fertile granites from barren ones from the Wulong deposit. Our study shows that the Wulong fertile granite porphyry (high Sr/Y) and Sanguliu barren granite (low Sr/Y) have zircon U–Pb ages of 132 ± 1 and 136 ± 0.4 Ma, respectively. The fertile and barren granites share similar REE patterns by characteristic of LREE enrichment and HREE depletion. They are classified as reduced ilmenite‐type granitic rocks. Petrochemistry and Sr–Nd–Hf–O isotopes show that the Wulong fertile and Sanguliu barren granites were derived from intensive crustal reworking in the North China Craton. The Wulong fertile granites were derived from mixing of lithospheric mantle–derived and thickened ancient lower crust–derived magmas. The Sanguliu barren granites were derived from partial melting of the ancient lower crust with normal crustal thickness. Geochemical features of zircon and apatite indicate that the both fertile and barren granites are similar in crystallisation temperature, water content, and oxygen fugacity. Our study suggests that magma source composition is essential to gold metallogeny, and mantle‐derived components are a key indicator to distinguish fertile and barren granitoids. Exploration for gold deposits related to reduced intrusions may be promising within the Liaodong Peninsula.
Iron‐Catalyzed C–H Activation/Aza‐Annulation with 2‐Butyne for Accessing Methylated Aza‐Arenes
Authors: Zhang Yan , Shang Rui , Nakamura Eiichi
Published: January 2025

The incorporation of methyl groups into aza‐arene frameworks not only often improves their biological activity as the “magic methyl” effect, but also notably affects their solid‐state electronic properties by modulating π‐π stackings, which makes them promising candidates for developing organic electronic materials. This study focuses on the iron‐catalyzed C−H annulation of ketones with 2‐butyne via their oxime ethers, offering an efficient pathway to synthesizing methylated π‐extended aza‐arenes. The reactions utilize isobutyl aluminum(III) catecholate as a base and Triphos (bis(2‐diphenylphosphinoethyl)phenylphosphine) as a ligand. Reported C−H activation methods using rhodium catalysis proved less effective with π‐conjugated substrates. Regioselective C−H aza‐annulation with 1‐(trimethylsilyl)propyne following desilylation provides also mono‐methylated azaarenes. The reactions also generate tetra‐methylated aza‐arene products by two‐fold C−H aza‐annulation on chromeno[3,2‐a]xanthene‐13,14‐dione and quinacridone. These methylated aza‐arenes exhibit strong π‐π stacking, a narrow emission band, and tunable photophysical properties, indicating their potential applications as electronic materials.
Association of Cardiovascular Risk Factors With Major and Minor Electrocardiographic Abnormalities: A Report From the Cross‐Sectional Phase of Tehran Cohort Study
Authors: Ahmadi Pooria , Ahmadi‐Renani Sajjad , Pezeshki Parmida Sadat , Nayebirad Sepehr , Jalali Arash , Shafiee Akbar , Ayati Aryan , Afzalian Arian , Alaeddini Farshid , Saadat Soheil , Masoudkabir Farzad , Vasheghani‐Farahani Ali , Sadeghian Saeed , Boroumand Mohamamdali , Karimi Abbasali , Pourbashash Boshra , Hosseini Kaveh , Rosendaal Frits R.
Published: January 2025

Background and Aims

In the current study, we aimed to identify the association between major and minor electrocardiographic abnormalities and cardiovascular risk factors.

Methods

We used the Tehran cohort study baseline data, an ongoing multidisciplinary, longitudinal study designed to identify cardiovascular disease risk factors in the adult population of Tehran. The electrocardiograms (ECGs) of 7630 Iranian adults aged 35 years and above were analyzed. ECG abnormalities were categorized into major or minor groups based on their clinical importance. Results were obtained by multivariable logistic regression and are expressed as odds ratios (ORs).

Results

A total of 756 (9.9%) participants had major ECG abnormalities, while minor abnormalities were detected in 2526 (33.1%). Males comprised 45.8% of the total population, and 41.8% of them had minor abnormalities. Individuals with older age, diabetes (OR = 1.35; 95% CI: 1.11–1.64), and hypertension (OR = 2.21; 95% CI: 1.82–2.68) had an increased risk of major ECG abnormalities. In contrast, intermediate (OR = 0.69; 95% CI: 0.57–0.84) and high physical activity levels (OR = 0.66; 95% CI: 0.51–0.86) were associated with a lower prevalence of major abnormalities. Male sex, older age, hypertension, and current smoking were also associated with an increased prevalence of ECG abnormalities combined (major or minor).

Conclusion

Major and minor ECG abnormalities are linked with important cardiovascular risk factors such as diabetes and hypertension. Since these abnormalities have been associated with poor outcomes, screening patients with cardiovascular risk factors with an ECG may distinguish high‐risk individuals who require appropriate care and follow‐up.
Intraocular Pressure Changes After Rhinoplasty: A Before‐and‐After Cross‐Sectional Study
Authors: Tabrizi Ali Goljanian , Ghazizadeh Matin , Zahedi Atiyeh
Published: January 2025

Background and Aims

Rhinoplasty, a prevalent cosmetic surgery, often involves lateral osteotomy, which can lead to ocular complications such as edema and ecchymosis. A potential complication is increased intraocular pressure (IOP) postoperatively. This study aims to investigate the impact of lateral osteotomy during rhinoplasty on IOP in patients.

Methods

This prospective before‐and‐after cross‐sectional study evaluated the effect of lateral osteotomy during rhinoplasty on IOP in 96 patients. Preoperative ophthalmologic examinations included best‐corrected visual acuity, slit lamp biomicroscopy, Goldmann tonometry, and dilated fundoscopy. IOP measurements were taken three times per eye at baseline, during surgery, on the first postoperative day, after nasal pin removal on the seventh postoperative day, and on the thirtieth postoperative day using a Goldmann tonometer. The mean IOP was recorded at each time point.

Results

The study found no significant changes in IOP at 1, 7, or 30 days postsurgery (p = 0.194). Additionally, the type of surgery did not significantly affect ocular internal pressure (p = 0.622).

Conclusion

Rhinoplasty with lateral osteotomy appears to be safe concerning IOP. However, monitoring IOP during rhinoplasty is advisable.
A New Hope for the Patients of Non‐Alcoholic Steatohepatitis: FDA Gives Green Signal for Resmetirom Use
Authors: Hasan Abdul Haseeb , Abid Muhammad Ali , Abid Muhammad Hafi , Suhail Laiba , Nazir Abubakar
Published: January 2025

Background and Aims

Non‐Alcoholic Steatohepatitis (NASH), a severe form of Non‐Alcoholic Fatty Liver Disease (NAFLD), is characterized by inflammation and fibrosis in the liver, often progressing to cirrhosis and hepatocellular carcinoma. Despite its rising prevalence and significant disease burden, effective pharmacological treatments have been limited to lifestyle modifications and surgical interventions. Recently, resmetirom, a thyroid hormone receptor‐β agonist, received FDA approval for treating NASH, offering new hope to patients. This review explores the current understanding of NASH and the role of resmetirom as a breakthrough therapeutic option.

Methods

This study is a comprehensive literature review analyzing peer‐reviewed articles, clinical trial data, and public health reports. No original analyses were conducted, and no statistical software was utilized in this review.

Results

Resmetirom demonstrated efficacy in resolving NASH without fibrosis progression and improving fibrosis scores in patients with biopsy‐confirmed NASH. In a randomized Phase 3 trial, significant histological improvements were observed in 25.9% and 29.9% of patients receiving 80 and 100 mg doses, respectively, compared to 9.7% in the placebo group. Similar trends were noted in fibrosis improvement, with 24.2% and 25.9% of patients showing ≥ 1 stage improvement compared to 14.2% in the placebo group. Adverse effects, including nausea and diarrhea, were reported more frequently in the treatment groups, but the rates of serious adverse events were comparable across groups.

Conclusion

The approval of resmetirom marks a significant advancement in the treatment of NASH, addressing the limitations of lifestyle‐based interventions. As the obesity epidemic drives the increasing prevalence of NASH, resmetirom provides a promising therapeutic option, paving the way for improved patient outcomes and future research.
Enhanced River Connectivity Assessment Across Larger Areas Through Deep Learning With Dam Detection
Authors: Zhang Xiao , Liu Qi , Gui Dongwei , Zhao Jianping , Chen Yu , Liu Yunfei , Martínez‐Valderrama Jaime
Published: January 2025

Monitoring river connectivity across large regions is essential for understanding hydrological processes and environmental management. However, comprehensive assessments of river connectivity are often hindered by inaccurate dam databases, which are biased towards larger dams while overlooking smaller or low‐head dams. To enhance the accuracy of river connectivity assessments, we developed three advanced convolutional neural networks (CNNs; YOLOv5, Advance‐You Only Look Once [YOLO], and Faster R‐CNN) to accurately classify dams and evaluate river connectivity using high‐resolution (1 m) remote sensing imagery. The evaluation results showed that Advance‐YOLO performs best with an average mean average precision (mAP) of 86.6%, while Faster R‐CNN performs mediocrely with an average mAP of 77.9%. Applying the well‐trained model in the Tarim River Basin (China), one of the largest inland river basins around the globe, we found that there are currently 135 dams in total on the Tarim River and its sources. Conversely, the existing public dam database underestimates 85.9% of the dams. Notably, we found a 14.3% decline in river connectivity of the Tarim River over the past decade, and the current dam density of the Tarim River and its four source rivers is 1.12 per 10 000 km2. However, the existing public dam database overestimated river connectivity by 83.9%. The model developed here enhances river connectivity assessment across larger areas over a long period, thereby fostering more advanced research on hydrological processes and effective water resource management.
Toward Automated Scientific Discovery in Hydrology: The Opportunities and Dangers of AI Augmented Research Frameworks
Authors: Eythorsson Darri , Clark Martyn
Published: January 2025

This commentary explores the potential of artificial intelligence (AI) to transform hydrological modelling workflows. We introduce a prototype AI‐assisted framework called INDRA (Intelligent Network for Dynamic River Analysis) that leverages a multi‐agent architecture composed of specialised large language models (LLMs) to assist in model conceptualization, configuration, execution, and interpretation. INDRA integrates with CONFLUENCE, a comprehensive modelling framework, to provide context‐aware guidance and automation throughout the modelling process. We discuss the opportunities and dangers of AI‐augmented research frameworks, emphasising the importance of maintaining human oversight while harnessing AI's potential to enhance efficiency, reproducibility, and scientific understanding. We argue that AI‐assisted workflows could democratise advanced hydrological modelling, enabling researchers worldwide to address critical water resources challenges, particularly in understudied regions. While acknowledging potential biases and risks, we advocate for responsible AI integration to catalyse a new paradigm in hydrological science.
Impact of the WHO safe childbirth checklist on birth attendant behavior and maternal‐newborn outcomes: A systematic review and meta‐analysis
Authors: Fernández‐Elorriaga María , Fifield Jocelyn , Semrau Katherine E. A. , Lipsitz Stuart , Tuller Danielle E. , Mita Carol , Cho Chelsea , Scott Heather , Taha Ayda , Dhingra‐Kumar Neelam , Moran Allisyn , Molina Rose L.
Published: January 2025

Background

The intrapartum period is critical for reducing maternal and perinatal morbidity and mortality. The WHO's Safe Childbirth Checklist (SCC) was designed as a reminder of the most critical, evidence‐based practices (EBPs) to improve quality care and reduce preventable complications and deaths.

Objective

To assess the impact of SCC on birth attendant behavior and maternal and newborn health outcomes.

Search Strategy

A systematic review and meta‐analysis was performed searching across five databases from 2009 to 2023.

Selection Criteria

We included randomized controlled trials, quasi‐experimental studies, and pre/post studies.

Data Analysis

A meta‐analysis yielded a pooled estimate of relative risk (RR) for adherence to and effectiveness of the SCC.

Main Results

Of 1070 articles identified, 16 were included. Use of the SCC increased adherence to EBPs by 65% (RR 1.65; 95% confidence interval [CI] 1.34–2.02). The behaviors that improved the most were danger sign counseling (RR 12.37; 95% CI 1.95–78.52; P = 0.008) and pre‐eclampsia management (RR 3.43; 95% CI 1.33–8.88; P = 0.011). There was moderate evidence for stillbirth reduction (RR 0.89; 95% CI 0.80–0.99; P = 0.034).

Conclusion

There is moderate evidence demonstrating the effectiveness of the SCC in reducing stillbirths and improving adherence to EBPs.
Photobiomodulation Combined With Human Umbilical Cord Mesenchymal Stem Cells Modulates the Polarization of Microglia
Authors: Ma Chunyan , Zhu Hongyu , Cai Yuanhao , Li Na , Han Zhibo , Wu Huancheng , Chen Hongli
Published: January 2025

Neuroinflammation plays a key role in the development of neurodegenerative diseases, with microglia regulating this process through pro‐inflammatory M1 and anti‐inflammatory M2 phenotypes. Studies have shown that human umbilical cord mesenchymal stem cells (hUCMSCs) modulate neuroinflammation by secreting anti‐inflammatory cytokines. Photobiomodulation (PBM), a non‐invasive therapy, has demonstrated significant potential in alleviating neuroinflammation. This study examines the combined effects of PBM and hUCMSCs in an in vitro microglial inflammation model and an LPS‐induced mouse model. The results show that PBM‐pretreated hUCMSCs promoted M2 polarization and improved cognitive function in mice by downregulating the Notch signaling pathway, suggesting a promising new approach for treating neurodegenerative diseases.
Biomechanical comparison of all‐inside meniscal suture configurations for posterior root tear: Three conventional stitches versus delta‐grip stitch
Authors: Ishibashi Kyohei , Ishibashi Kyota , Tsushima Takahiro , Sasaki Eiji , Yamauchi Shohei , Kimura Yuka , Ishibashi Yasuyuki
Published: January 2025

Purpose

This study aimed to compare the biomechanical properties of four meniscal suture configurations—two simple sutures (TSS), two cinch sutures, a locking loop stitch (LLS), and a delta‐grip stitch (DGS)—for transtibial pullout repair of medial meniscus posterior root tears (MMPRTs) using porcine menisci.

Methods

Forty porcine menisci were randomly assigned to each suture configuration with all‐inside repair. All specimens were subjected to cyclic loading for 1000 cycles, followed by a load‐to‐failure test. We evaluated displacement after cyclic loading, the ultimate failure load and the mode of failure.

Results

No significant differences in displacement were observed between the configurations (p = 0.709). The DGS exhibited significantly higher ultimate failure loads (281.4 ± 53.5 N) compared to TSS (166.8 ± 84.5 N) and the LLS (119.7 ± 46.7 N) (p = 0.006 and p < 0.001, respectively). Suture breakage was observed in the DGS group, while meniscus cutout was observed in the other suture configuration models.

Conclusion

The results suggest that the DGS provides superior fixation strength and enhances MMPRT repair outcomes.

Level of Evidence

Level IV.
Uncovering a new family of conserved virulence factors that promote the production of host‐damaging outer membrane vesicles in gram‐negative bacteria
Authors: Goman Audrey , Ize Bérengère , Jeannot Katy , Pin Camille , Payros Delphine , Goursat Cécile , Ravon‐Katossky Léa , Murase Kazunori , Chagneau Camille V. , Revillet Hélène , Taieb Frédéric , Bleves Sophie , David Laure , Meunier Etienne , Branchu Priscilla , Oswald Eric
Published: January 2025

CprA is a short‐chain dehydrogenase/reductase (SDR) that contributes to resistance against colistin and antimicrobial peptides. The cprA gene is conserved across Pseudomonas aeruginosa clades and its expression is directly regulated by the two‐component system PmrAB. We have shown that cprA expression leads to the production of outer membrane vesicles (OMVs) that block autophagic flux and have a greater capacity to activate the non‐canonical inflammasome pathway. In a murine model of sepsis, a P. aeruginosa strain deleted for cprA was less virulent than the wild‐type (WT) strain. These results demonstrate the important role of CprA in the pathogenicity of P. aeruginosa. It is worth noting that CprA is also a functional ortholog of hemolysin F (HlyF), which is encoded by virulence plasmids of Escherichia coli. We have shown that other cryptic SDRs encoded by mammalian and plant pathogens, such as Yersinia pestis and Ralstonia solanacearum are functional orthologs of CprA and HlyF. These SDRs also induce the production of OMVs which block autophagic flux. This study uncovers a new family of virulence determinants in Gram‐negative bacteria, offering potential for innovative therapeutic interventions and deeper insights into bacterial pathogenesis.
A Non‐Centrifugation Method to Concentrate and Purify Extracellular Vesicles Using Superabsorbent Polymer Followed by Size Exclusion Chromatography
Authors: Bergqvist Markus , Lässer Cecilia , Crescitelli Rossella , Park Kyong‐Su , Lötvall Jan
Published: January 2025

Extracellular vesicles (EVs) can be isolated and purified from cell cultures and biofluids using different methodologies. Here, we explored a novel EV isolation approach by combining superabsorbent polymers (SAP) in a dialysis membrane with size exclusion chromatography (SEC) to achieve high concentration and purity of EVs without the use of ultracentrifugation (UC). Suspension HEK293 cells transfected with CD63 coupled with Thermo Luciferase were used to quantify the EV yield and purity. The 500 mL conditioned medium volume was initially reduced by pressure ultrafiltration, followed by UC, SAP or a centrifugal filter unit (CFU). Using either of these methods, the EVs were concentrated to a final volume of approximately 1 mL, with retained functionality. The yield, quantified by luciferase activity, was highest with UC (70%–80%), followed by SAP (60%–70%) and CFU (50%–60%). Further purification of the EVs was performed by iodixanol density cushion (IDC) or SEC (Sepharose CL‐2B or 6B, in either 10 or 20 mL columns). Although the IDC and Sepharose CL‐2B (10 mL) achieved the highest yields, the purity was slightly higher (30%) with IDC. In conclusion, combining SAP concentration with CL‐2B SEC is an alternative and efficient way to isolate EVs without using UC.
Revealing the Complex Interaction of Noncoding RNAs, Sirtuin Family, and Mitochondrial Function
Authors: Yuan Ludong , Yin Leijing , Lin Xiaofang , Li Jing , Liang Pengfei , Jiang Bimei
Published: January 2025

Mitochondria are key organelles that perform and coordinate various metabolic processes in the cell, and their homeostasis is essential for the maintenance of eukaryotic life. To maintain mitochondrial homeostasis and cellular health, close communication between noncoding RNAs (ncRNAs) and proteins is required. For example, there are numerous crosstalk between ncRNAs and the sirtuin (SIRT1–7) family, which is a group of nicotinamide adenine dinucleotides (NAD(+))–dependent Type III deacetylases. NcRNAs are involved in the regulation of gene expression of sirtuin family members, and deacetylation of sirtuin family members can also influence the generation of ncRNAs. This review focuses on the relationship between the two mentioned above and summarizes the impact of their interactions on mitochondrial metabolism, oxidative stress, mitochondrial apoptotic pathways, mitochondrial biogenesis, mitochondrial dynamics, and other mitochondria‐related pathophysiological processes. Finally, the review also describes targeted and appropriate treatment strategies. In conclusion, we provide an overview of the ncRNA‐sirtuins/mitochondria relationship that could provide a reference for related research in the mitochondrial field and help the future development of new biomedical applications in this area.
Spermidine Recovers the Autophagy Defects Underlying the Pathophysiology of Cell Trafficking Disorders
Authors: Díaz‐Osorio Yaiza , Gimeno‐Agud Helena , Mari‐Vico Rosanna , Illescas Sofía , Ramos Jose Miguel , Darling Alejandra , García‐Cazorla Àngels , Oyarzábal Alfonso
Published: January 2025

Cell trafficking alterations are a growing group of disorders and one of the largest categories of Inherited Metabolic Diseases. They have complex and variable clinical presentation. Regarding neurological manifestations they can present a wide repertoire of symptoms ranging from neurodevelopmental to neurodegnerative disorders. The study of monogenic cell trafficking diseases draws an scenario to understanding this complex group of disorders and to find new therapeutic avenues. Within their pathophysiology, alterations in autophagy outstand as a targetable mechanism of disease, ammended to be modulated through different strategies. In this work we have studied the pathophysiology of two cell trafficking disorders due to mutations in SYNJ1 and NBAS genes. Specifically, we have assesed the autophagic flux in primary fibroblast cultures of the patients and gender/age‐matched controls and whether it could be address with a therapeutic purpose. The results have shaped autophagy as one of the hallmarks of the disease. Moreover, we tested in vitro the effect of spermidine, a natural polyamine that acts as an autopagy inductor. Due to the positive results, its efficacy was evaluated later on the patients as well, in a series of n‐of‐1 clinical trials, achieving improvement in some clinical aspects related to motricity and cognition. Defining autophagy alterations as a common feature in the pathophysiology of cell trafficking disorders is a great step towards their treatment, as it represents a potential actionable target for the personalized treatement of these disorders.
Fractal Performance Under Magnetization Procedures of Fractional Memristive Wilson Neuron Dynamical Model
Authors: Abro Kashif Ali , Mahariq Ibrahim
Published: January 2025

The non‐integer neuron dynamical models are feasible for accurate prediction and perfect estimation of magnetization and de‐magnetization in complicated physiological environments within reliable fractal‐fractional neuronal modeling. The memristive Wilson neuron model is proposed under the comparative performance of two types of fractal‐fractional differentials with two different types of kernels based on two different memories. The non‐classical memristive Wilson neuron model with and without magnetization is simulated for numerical schemes by means of linear multi‐step integration method. The numerical simulations are traced out by discretizing continuum processes of spatial and time domains for the sake of perfect approximations under singular and non‐singular kernel versus local and non‐local kernel. By applying the powerful methodology of fractal‐fractional differential and integral operators on the memristive Wilson neuron model, the antimonotonicity phenomenon and asymmetric coexisting electrical activities have been explored intensively to widen the neuron‐based engineering applications. Remarkably, our results based on magnetization and de‐magnetization procedures of Wilson neuron model have imitated the neuron activities under electrophysiological environment.
Intermittent Fasting Ameliorates β‐Amyloid Deposition and Cognitive Impairment Accompanied by Decreased Lipid Droplet Aggregation Within Microglia in an Alzheimer's Disease Model
Authors: Wu Liangwei , Zhao Yang , Gong Xiaokang , Liang Zheng , Yu Jing , Wang Jiaquan , Zhang Yuheng , Wang Xiaochuan , Shu Xiji , Bao Jian
Published: January 2025

Scope: Alzheimer's disease (AD) is the most prevalent form of dementia, lack of effective therapeutic interventions. In this study, we investigate the impact of intermittent fasting (IF), an alternative strategy of calorie restriction, on cognitive functions and AD‐like pathology in a transgenic mouse model of AD. Methods and results: APP/PS1 mice at 6 months were randomly allocated to two dietary groups: one receiving ad libitum (AL) feeding and the other undergoing IF for 1 month. Y maze, Barnes maze, western blotting, and immunofluorescence were employed. Behavioral assessments revealed that the APP/PS1‐IF group demonstrated notable improvements in cognitive function compared to the AL group. Further analysis showed that microglia in the APP/PS1‐IF mice exhibited enhanced phagocytic activity, characterized by prominent enlargement of soma and reduced complexity of their processes. Importantly, IF significantly decreased the accumulation of lipid droplets (LDs) within microglia. These microglia with less LDs may contribute to enhanced β‐amyloid (Aβ) phagocytosis, thereby ameliorating Aβ deposition in the brains of APP/PS1‐IF mice. Conclusion: Our findings demonstrate that IF ameliorates amyloid deposition and cognitive deficits in the AD model mice, which is associated with the reduction of LDs within microglia, providing support for the use of the dietary intervention against AD pathology.
A Computationally Efficient Technique for Dynamic Sensitivity Filtering in Topology Optimization
Authors: Huang Hongbin , Wang Yiming , Wang Haoyin , Wu Bo , Hu Youmin
Published: January 2025

In this paper, we present a novel approach: a dynamic sensitivity filtering technique designed for density‐based topology optimization. Sensitivity filtering methods have found extensive utility in mitigating numerical instabilities. Nevertheless, conventional sensitivity filtering can introduce numerous gray elements along the topology's boundaries, thereby impeding practical manufacturing within real‐world engineering applications. To address this challenge, we propose a dynamic sensitivity filter that adjusts the sensitivity at each iterative step based on the optimization outcomes of the preceding iteration. Through diverse test examples, our method demonstrates the capacity to effectively solve the numerical instability problem while concurrently achieving a nearly pure black and white design, characterized by significantly reduced computational expense and improved structural stiffness.
Structure Preserving Nodal Continuous Finite Elements via Global Flux Quadrature
Authors: Barsukow Wasilij , Ricchiuto Mario , Torlo Davide
Published: January 2025

Numerical methods for hyperbolic PDEs require stabilization. For linear acoustics, divergence‐free vector fields should remain stationary, but classical Finite Difference methods add incompatible diffusion that dramatically restricts the set of discrete stationary states of the numerical method. Compatible diffusion should vanish on stationary states, e.g., there should be a gradient of the divergence. Some Finite Element methods allow the natural embedding of this grad‐div structure, e.g., the SUPG method or OSS. We prove here that the particular discretization associated with them still fails to be stationarity preserving. We then introduce a new framework on Cartesian grids based on surface (volume in 3D) integrated operators inspired by Global Flux quadrature and related to mimetic approaches. We can construct constraint‐compatible stabilization operators (e.g., of SUPG‐type) and show that the resulting methods are stationarity and vorticity preserving. We show that the Global Flux approach is even super‐convergent on stationary states; we characterize the kernels of the discrete operators and provide projections onto them.
Isocaloric high‐fat diet decreases motivation in the absence of obesity
Authors: Arbuckle Kenny , Sharma Reema , Drake Frannie E. , Usiyevich Abigail , Usman Sarah , Matikainen‐Ankney Bridget A.
Published: January 2025

Objective

Obesogenic diets induce persistent changes in physical activity and motivation. It remains unclear whether these behavioral changes are driven by weight gain or exposure to obesogenic diets themselves. We investigated how exposure to a high‐fat diet (HFD) in the absence of obesity affected physical activity, food motivation, and circadian patterns in mice.

Methods

C57Bl6/J mice were given ~80% of their daily calories in an HFD, known as isocaloric feeding, along with ad libitum access to laboratory chow. Weekly weights, physical activity levels, circadian patterns, operant behavior, and peripheral blood metabolic markers were measured to determine how an isocaloric HFD affected behavior and physiology. Following this period, the same cohort was exposed to an ad libitum HFD to monitor changes in weight gain and physical activity.

Results

An isocaloric HFD did not significantly increase weight or change physical activity levels. An isocaloric HFD decreased motivation for sucrose pellets but did not alter weight gain with ad libitum HFD exposure.

Conclusions

An isocaloric HFD was associated with decreased motivation for sucrose, as observed in reports of rodent models of obesity. These findings suggest that exposure to an obesogenic diet, even in the absence of significant weight gain, can induce behavioral changes associated with obesity.
Results of the Latin American Pediatric Oncology Group (GALOP‐2011) Trial for Patients With Localized Ewing Sarcoma: A Multicentric Study of Interval‐Compressed Multiagent Chemotherapy
Authors: Gregianin Lauro José , Rose Adriana , Villarroel Milena , Almeida Maria Tereza , Siqueira Laurice , Salgado Carmen , da Costa Gildene Alves , Castillo Luis , Santos Pestilho Julie Francine Cerutti , Brunetto Algemir Lunardi ,   GALOP Latin American Pediatric Oncology Group Ewing Sarcoma Investigators
Published: January 2025

Background

GALOP investigators developed a prospective cooperative protocol for localized Ewing sarcoma (ES) incorporating interval‐compressed chemotherapy (VDC/IE, vincristine, doxorubicin, cyclophosphamide/ifosfamide and etoposide). After completing conventional treatment, patients were randomized to 1 year of metronomic chemotherapy (vinblastine and cyclophosphamide).

Methods

Phase III randomized prospective trial. Induction consisted of six alternating cycles of VDC/IE every 14 days, followed by local control, and eight cycles of consolidation every 21 days. After consolidation, patients were randomized 1:1 to metronomic chemotherapy or stop treatment, balanced by age (>/< 14 years‐old), sex (M/F), site (pelvic/non‐pelvic), and size (>/< 8 cm). The results of randomization will be published elsewhere with longer follow‐up.

Results

Between 2011 and 2019, 315 patients (59.7% male, median age 11.0 years) were recruited across 34 centers in Argentina, Brazil, Chile, and Uruguay. The most frequent localizations were axial (45.1%), extremity (38.1%), and pelvic (16.8%). The median time interval between cycles was 19 and 22 days at induction and consolidation, respectively. There were no unexpected toxicity or toxic deaths related to interval compression. The overall response rate post‐induction was 81.6%. Local treatment with surgery (50.8%), radiotherapy (19.7%), or a combination (26%) was performed in 304 (96.5%) patients. With a median follow‐up of 50 months (range: 1.67–121.7), the 5‐year overall and event‐free survivals were 68.6% (SE: 0.030) and 63.7% (SE: 0.029), respectively.

Conclusion

Implementation of a multi‐institutional protocol with the strategy of interval‐compressed induction for ES in South America was feasible with favorable results. This success is attributed to rigorous protocol adherence, extensive educational efforts, and a strong emphasis on data quality maintenance, demonstrating a reproducible model for countries with similar resource limitations.
The Significant Effects of Threshold Selection for Advancing Nitrogen Use Efficiency in Whole Genome of Bread Wheat
Authors: Sadeqi Mohammad Bahman , Ballvora Agim , Dadshani Said , Siddiqui Md. Nurealam , Kamruzzaman Mohammad , Koua Ahossi Patrice , Léon Jens
Published: January 2025

Currently in wheat breeding, genome wide association studies (GWAS) have successfully revealed the genetic basis of complex traits such as nitrogen use efficiency (NUE) and its biological processes. In the GWAS model, thresholding is common strategy to indicate deviation of expected range of p‐value(s), and it can be used to find the distribution of true positive associations under or over of test statistics. Therefore, the threshold plays a critical role to identify reliable and significant associations in wide genome, while the proportion of false positive results is relatively low. The problem of multiple comparisons arises when a statistical analysis involves multiple simultaneous statistical tests, each of them has the potential to be a discovery. There are several ways to address this problem, including the family‐wise error rate and false discovery rate (FDR), raw and adjusted p‐value(s), consideration of threshold coherence and consonance, and the properties of proportional hypothesis tests in the threshold definition. We encountered some limitations in the definition of FDR threshold, particularly in the upper bounds of linear and nonlinear approaches. We emphasize that empirical null distributions based on permutation test can be useful when the assumption of linear or parametric FDR approaches do not hold. Nevertheless, we believe that it is necessary to utilize modern statistical optimization techniques to evaluate the stability and performance of our results and to select significant FDR threshold. By incorporating the neural network algorithm, it is possible to improve the reliability of FDR threshold and increase the probability of identifying true genetic associations while minimizing the risk of false positives in GWAS results.
LEA_4 motifs function alone and in conjunction with synergistic cosolutes to protect a labile enzyme during desiccation
Authors: Nicholson Vincent , Nguyen Kenny , Gollub Edith , McCoy Mary , Yu Feng , Holehouse Alex S. , Sukenik Shahar , Boothby Thomas C.
Published: January 2025

Organisms from all kingdoms of life depend on Late Embryogenesis Abundant (LEA) proteins to survive desiccation. LEA proteins are divided into broad families distinguished by the presence of family‐specific motif sequences. The LEA_4 family, characterized by 11‐residue motifs, plays a crucial role in the desiccation tolerance of numerous species. However, the role of these motifs in the function of LEA_4 proteins is unclear, with some studies finding that they recapitulate the function of full‐length LEA_4 proteins in vivo, and other studies finding the opposite result. In this study, we characterize the ability of LEA_4 motifs to protect a desiccation‐sensitive enzyme, citrate synthase (CS), from loss of function during desiccation. We show here that LEA_4 motifs not only prevent the loss of function of CS during desiccation but also that they can do so more robustly via synergistically interactions with cosolutes. Our analysis further suggests that cosolutes induce synergy with LEA_4 motifs in a manner that correlates with transfer free energy. This research advances our understanding of LEA_4 proteins by demonstrating that during desiccation their motifs can protect specific clients to varying degrees and that their protective capacity is modulated by their chemical environment. Our findings extend beyond the realm of desiccation tolerance, offering insights into the interplay between IDPs and cosolutes. By investigating the function of LEA_4 motifs, we highlight broader strategies for understanding protein stability and function.
Human recombinant tyrosinase destabilization caused by the double mutation R217Q/R402Q
Authors: Toay Sarah , Sheri Narin , MacDonald Ian , Sergeev Yuri V.
Published: January 2025

Oculocutaneous albinism is an autosomal recessive inherited disorder associated with mutations in the TYR gene. A single missense change in the tyrosinase (Tyr) could result in partial or complete loss of catalytic activity. The effect of two genetic mutations in the same Tyr as the molecule is less studied. Here, we study single mutation variants, R217Q, R402Q, and a double mutant variant, R217Q/R402Q, to establish a link between alterations at the level of the atomic model of the protein and the disease phenotype. Human recombinant intra‐melanosomal Tyr domains of Tyr and three mutant variants were expressed in T. ni. Larvae were purified using the combination of IMAC and SEC, and diphenolase activities were measured. The Tyr homology model was equilibrated using 100 ns molecular dynamics and analyzed using computational methods. The purified R217Q and R217Q/R402Q variants show decreased catalytic activities compared to those of the Tyr and R402Q variants. The R217Q/R402Q variant has the lowest protein activity and is significantly reduced.
AFFIPred: AlphaFold2 structure‐based Functional Impact Prediction of missense variations
Authors: Pir Mustafa S , Timucin Emel
Published: January 2025

Protein structure holds immense potential for pathogenicity prediction, albeit structure‐based predictors are limited compared to the sequence‐based counterparts due to the “structure knowledge gap” between large number of available protein sequences and relatively limited number of structures. Leveraging the highly accurate protein structures predicted by AlphaFold2 (AF2), we introduce AFFIPred, an ensemble machine learning classifier that combines sequence and AF2‐based structural characteristics to predict missense variant pathogenicity. Based on the assessments on unseen datasets, AFFIPred reached a comparable level of performance with the state‐of‐the‐art predictors such as AlphaMissense. We also showed that the recruitment of AF2 structures that are full‐length and represent the unbound states ensures more precise SASA calculations compared to the recruitment of experimental structures. In line with the completeness of the AF2 structures, their use provide a more comprehensive view of the structural characteristics of the missense variation datasets by capturing all variants. AFFIPred maintains high‐level accuracy without the limitations of PDB‐based classifiers. AFFIPred has predicted over 210 million variations of the human proteome, which are accessible at https://affipred.timucinlab.com/.
AggNet: Advancing protein aggregation analysis through deep learning and protein language model
Authors: He Wenjia , Xu Xiaopeng , Li Haoyang , Zhou Juexiao , Gao Xin
Published: January 2025

Protein aggregation is critical to various biological and pathological processes. Besides, it is also an important property in biotherapeutic development. However, experimental methods to profile protein aggregation are costly and labor‐intensive, driving the need for more efficient computational alternatives. In this study, we introduce “AggNet,” a novel deep learning framework based on the protein language model ESM2 and AlphaFold2, which utilizes physicochemical, evolutionary, and structural information to discriminate amyloid and non‐amyloid peptides and identify aggregation‐prone regions (APRs) in diverse proteins. Benchmark comparisons show that AggNet outperforms existing methods and achieves state‐of‐the‐art performance on protein aggregation prediction. Also, the predictive ability of AggNet is stable across proteins with different secondary structures. Feature analysis and visualizations prove that the model effectively captures peptides' physicochemical properties effectively, thereby offering enhanced interpretability. Further validation through a case study on MEDI1912 confirms AggNet's practical utility in analyzing protein aggregation and guiding mutation for aggregation mitigation. This study enhances computational tools for predicting protein aggregation and highlights the potential of AggNet in protein engineering. Finally, to improve the accessibility of AggNet, the source code can be accessed at: https://github.com/Hill-Wenka/AggNet.