bluuebunny/crossref_metadata_2025 huggingface dataset:
Gender-Specific Fine Motor Skill Learning Is Impaired by Myelin-Targeted Neurofibromatosis Type 1 Gene Mutation
Authors: Hernandez Daniella P. , Cruz Daniela M. , Martinez Celeste S. , Garcia Larisa M. , Figueroa Ashley , Villarreal Marisol , Manoj Liya M. , Lopez Saul , López-Lorenzo Karla D. , López-Juárez Alejandro
Published: January 2024

Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene. The clinical presentation of NF1 includes diverse neurological issues in pediatric and adult patients, ranging from learning disabilities, motor skill issues, and attention deficit disorder, to increased risk of depression and dementia. Preclinical research suggests that abnormal neuronal signaling mediates spatial learning and attention issues in NF1; however, drugs that improve phenotypes in models show inconclusive results in clinical trials, highlighting the need for a better understanding of NF1 pathophysiology and broader therapeutic options. Most NF1 patients show abnormalities in their brain white matter (WM) and myelin, and links with NF1 neuropathophysiology have been suggested; however, no current data can clearly support or refute this idea. We reported that myelin-targeted Nf1 mutation impacts oligodendrocyte signaling, myelin ultrastructure, WM connectivity, and sensory–motor behaviors in mice; however, any impact on learning and memory remains unknown. Here, we adapted a voluntary running test—the complex wheel (CW; a wheel with unevenly spaced rungs)—to delineate fine motor skill learning curves following induction of an Nf1 mutation in pre-existing myelinating cells (pNf1 mice). We found that pNf1 mutant females experience delayed or impaired learning in the CW, while proper learning in pNf1 males is predominantly disrupted; these phenotypes add complexity to the gender-dependent learning differences in the mouse strain used. No broad differences in memory of acquired CW skills were detected in any gender, but gene-dose effects were observed at the studied time points. Finally, nitric oxide signaling regulation differentially impacted learning in wild type (WT)/pNf1, male/female mice. Our results provide evidence for fine motor skill learning issues upon induction of an Nf1 mutation in mature myelinating cells. Together with previous connectivity, cellular, and molecular analyses, these results diversify the potential treatments for neurological issues in NF1.
Exploring the Influence of the Selected Conjugated Fatty Acids Isomers and Cancerous Process on the Fatty Acids Profile of Spleen
Authors: Lepionka Tomasz , Białek Małgorzata , Czauderna Marian , Wojtak Wiktoria , Maculewicz Ewelina , Białek Agnieszka
Published: January 2024

The spleen, traditionally associated with blood filtration and immune surveillance, has recently been recognized for its role in systemic lipid metabolism and potential influence on cancer development and progression. This study investigates effects of dietary supplements, specifically conjugated linolenic acids from pomegranate seed oil and bitter melon extract, on the fatty acid (FA) composition of the spleen in the context of cancerous processes. Advanced methods, including gas chromatography–mass spectrometry and silver ion-impregnated high-performance liquid chromatography, were employed to analyze the spleen’s FA profile. Our research uncovered that dietary supplementation leads to alterations in the spleen’s FA profile, especially under the carcinogenic influence of 7,12-dimethylbenz[a]anthracene. These changes did not align with a simple protective or anti-carcinogenic pattern, as previously suggested in in vitro studies. We observed shifts in conjugated FA isomer concentrations and variations in desaturase activities, suggesting disrupted lipid metabolism in cancerous conditions. The findings underscore the spleen’s vital role in lipid metabolism within the body’s systemic health framework, highlighting the complexity of dietary supplements’ impact on FA profiles in the spleen and their potential implications in cancer progression and treatment. This study adds valuable insight into the complex interplay between diet, disease, and metabolic regulation, particularly in cancerous environments.
Incorporating Novel Technologies in Precision Oncology for Colorectal Cancer: Advancing Personalized Medicine
Authors: Ahluwalia Pankaj , Ballur Kalyani , Leeman Tiffanie , Vashisht Ashutosh , Singh Harmanpreet , Omar Nivin , Mondal Ashis K. , Vaibhav Kumar , Baban Babak , Kolhe Ravindra
Published: January 2024

Colorectal cancer (CRC) is one of the most heterogeneous and deadly diseases, with a global incidence of 1.5 million cases per year. Genomics has revolutionized the clinical management of CRC by enabling comprehensive molecular profiling of cancer. However, a deeper understanding of the molecular factors is needed to identify new prognostic and predictive markers that can assist in designing more effective therapeutic regimens for the improved management of CRC. Recent breakthroughs in single-cell analysis have identified new cell subtypes that play a critical role in tumor progression and could serve as potential therapeutic targets. Spatial analysis of the transcriptome and proteome holds the key to unlocking pathogenic cellular interactions, while liquid biopsy profiling of molecular variables from serum holds great potential for monitoring therapy resistance. Furthermore, gene expression signatures from various pathways have emerged as promising prognostic indicators in colorectal cancer and have the potential to enhance the development of equitable medicine. The advancement of these technologies for identifying new markers, particularly in the domain of predictive and personalized medicine, has the potential to improve the management of patients with CRC. Further investigations utilizing similar methods could uncover molecular subtypes specific to emerging therapies, potentially strengthening the development of personalized medicine for CRC patients.
Hypercalcemic Crisis Due to a Giant Intrathyroidal Parathyroid Adenoma, with Postsurgical Severe Hypocalcemia and Hungry Bone Syndrome: A Case Report
Authors: Papanikos Vasileios , Papadodima Elli , Bantouna Dimitra , Paparodis Rodis D. , Livadas Sarantis , Angelopoulos Nicholaos , Karvounis Evangelos
Published: January 2024

Background: Parathyroid adenoma is the most common cause of hypercalcemia and rarely leads to a hypercalcemic crisis, which is an unusual endocrine emergency that requires timely surgical excision. Case presentation: A 67-year-old male was admitted to the ER of the Euroclinic Hospital, Athens, Greece, because of elevated calcium levels and a palpable right-sided neck mass, which were accompanied by symptoms of nausea, drowsiness, and weakness for six months that increased prior to our evaluation. A gradual creatinine elevation and decreasing mental state were observed as well. The initial laboratory investigation identified severely elevated serum calcium (3.6 mmol/L) levels consistent with a hypercalcemic crisis (HC) and parathyroid hormone PTH (47.6 pmol/L) due to primary hyperparathyroidism. Neck ultrasonography (USG) identified a large, well-shaped cystic mass in the right thyroid lobe. With a serum calcium concentration of 19.5 mg/dL and a PTH of 225.3 pmol/L, the patient underwent partial parathyroidectomy and total thyroidectomy, which decreased serum calcium and PTH to 2.5 mmol/L and 1.93 pmol/L, respectively. Histology revealed a giant intrathyroidal cystic parathyroid adenoma, which was responsible for the hypercalcemic crisis. Postoperatively, the patient developed severe biochemical and clinical hypocalcemia, with calcium concentrations as low as 1.65 mmol/L, consistent with hungry bone syndrome (HBS), which was treated with high doses of intravenous calcium gluconate and oral alfacalcidol, and a slow recovery of serum calcium. After discharge, parathyroid function recovered, and symptomatology resolved entirely in more than one month. Discussion/conclusions: We present a case involving an exceptionally large intrathyroidal parathyroid adenoma that is characterized by clinical manifestations that mimic malignancy. The identification and treatment of such tumors is challenging and requires careful preoperative evaluation and postoperative care for the risk of hungry bone syndrome.
Cross-Species Transferability of Specific SSR Markers from Carex curvula (Cyperaceae) to Other Carex Species
Authors: Șuteu Dana , Pușcaș Mihai , Băcilă Ioan , Balázs Zoltán Robert , Choler Philippe
Published: January 2024

Microsatellites are codominant markers that, due to their high polymorphism, are a common choice for detecting genetic variability in various organisms, including fungi, plants, and animals. However, the process of developing these markers is both costly and time-consuming. As a result, the cross-species amplification has become a more rapid and more affordable alternative in biological studies. The objective of this study was to assess the applicability of 13 SSR markers, originally designed for Carex curvula, in other 14 species belonging to different sections of the genus. All the markers were successfully transferred with a mean of 90.76%, and 100% transferability was reached in two species (C. baldensis and C. rupestris). The lowest transferability was registered in the G165 marker, which did not produce amplification in six species. Together, the microsatellites amplified a total of 183 alleles, ranging from 10 to 19 alleles per locus, with an average of 14.07. The mean number of different alleles ranged from 0.846 to a maximum of 2.077 per locus. No significant departures from the Hardy–Weinberg equilibrium were detected in polymorphic loci. The transferability of the 13 SSR markers proved highly successful in various Carex species, across different clades and sections of the genus.
How the Post-Data Severity Converts Testing Results into Evidence for or against Pertinent Inferential Claims
Authors: Spanos Aris
Published: January 2024

The paper makes a case that the current discussions on replicability and the abuse of significance testing have overlooked a more general contributor to the untrustworthiness of published empirical evidence, which is the uninformed and recipe-like implementation of statistical modeling and inference. It is argued that this contributes to the untrustworthiness problem in several different ways, including [a] statistical misspecification, [b] unwarranted evidential interpretations of frequentist inference results, and [c] questionable modeling strategies that rely on curve-fitting. What is more, the alternative proposals to replace or modify frequentist testing, including [i] replacing p-values with observed confidence intervals and effects sizes, and [ii] redefining statistical significance, will not address the untrustworthiness of evidence problem since they are equally vulnerable to [a]–[c]. The paper calls for distinguishing between unduly data-dependant ‘statistical results’, such as a point estimate, a p-value, and accept/reject H0, from ‘evidence for or against inferential claims’. The post-data severity (SEV) evaluation of the accept/reject H0 results, converts them into evidence for or against germane inferential claims. These claims can be used to address/elucidate several foundational issues, including (i) statistical vs. substantive significance, (ii) the large n problem, and (iii) the replicability of evidence. Also, the SEV perspective sheds light on the impertinence of the proposed alternatives [i]–[iii], and oppugns [iii] the alleged arbitrariness of framing H0 and H1 which is often exploited to undermine the credibility of frequentist testing.
Automatic Vertebral Rotation Angle Measurement of 3D Vertebrae Based on an Improved Transformer Network
Authors: Huo Xing , Li Hao , Shao Kun
Published: January 2024

The measurement of vertebral rotation angles serves as a crucial parameter in spinal assessments, particularly in understanding conditions such as idiopathic scoliosis. Historically, these angles were calculated from 2D CT images. However, such 2D techniques fail to comprehensively capture the intricate three-dimensional deformities inherent in spinal curvatures. To overcome the limitations of manual measurements and 2D imaging, we introduce an entirely automated approach for quantifying vertebral rotation angles using a three-dimensional vertebral model. Our method involves refining a point cloud segmentation network based on a transformer architecture. This enhanced network segments the three-dimensional vertebral point cloud, allowing for accurate measurement of vertebral rotation angles. In contrast to conventional network methodologies, our approach exhibits notable improvements in segmenting vertebral datasets. To validate our approach, we compare our automated measurements with angles derived from prevalent manual labeling techniques. The analysis, conducted through Bland–Altman plots and the corresponding intraclass correlation coefficient results, indicates significant agreement between our automated measurement method and manual measurements. The observed high intraclass correlation coefficients (ranging from 0.980 to 0.993) further underscore the reliability of our automated measurement process. Consequently, our proposed method demonstrates substantial potential for clinical applications, showcasing its capacity to provide accurate and efficient vertebral rotation angle measurements.
Optimizing Customer Retention in the Telecom Industry: A Fuzzy-Based Churn Modeling with Usage Data
Authors: Zdziebko Tomasz , Sulikowski Piotr , Sałabun Wojciech , Przybyła-Kasperek Małgorzata , Bąk Iwona
Published: January 2024

Churn is a serious challenge for the telecommunications industry because of the much higher costs of gaining new customers than maintaining existing ones. Therefore, efforts to increase loyalty and decrease customer churn are the focus of telecom’s retention departments. In order to direct antichurn activities, profitable clients who have the highest probability of churning need to be identified. The data used to identify churners are often inaccurate and vague. In this paper, a fuzzy approach to modeling churn intent based on usage data in mobile telecommunications is presented. It appreciates the uncertainty of the data and provides insights into churn modeling. The goal of the study was to evaluate the applicability of the Mamdani and Sugeno models for building a churn model based on a limited but real-world dataset enriched with feature engineering. The additional goal was to find features most usable for churn modeling. Four metrics—accuracy, recall, precision, and F1-score—were used to estimate the performance of the models. The developed fuzzy rule-based systems show that to generalize possible churn identification factors with fuzzy rules, it is advisable to begin with features such as the change in the total amount of the invoice in the last period before the churning compared to the previous one, the total amount of the invoice in the period preceding the churning, the total amount of subscription in two months before the churning, the time of cooperation with the operator, and the number of calls out of the last quarter before leaving.
Improving MLP-Based Weakly Supervised Crowd-Counting Network via Scale Reasoning and Ranking
Authors: Gao Ming , Deng Mingfang , Zhao Huailin , Chen Yangjian , Chen Yongqi
Published: January 2024

MLP-based weakly supervised crowd counting approaches have made significant advancements over the past few years. However, owing to the limited datasets, the current MLP-based methods do not consider the problem of region-to-region dependency in the image. For this, we propose a weakly supervised method termed SR2. SR2 consists of three parts: scale-reasoning module, scale-ranking module, and regression branch. In particular, the scale-reasoning module extracts and fuses the region-to-region dependency in the image and multiple scale feature, then sends the fused features to the regression branch to obtain estimated counts; the scale-ranking module is used to understand the internal information of the image better and expand the datasets efficiently, which will help to improve the accuracy of the estimated counts in the regression branch. We conducted extensive experiments on four benchmark datasets. The final results showed that our approach has better and higher competing counting performance with respect to other weakly supervised counting networks and with respect to some popular fully supervised counting networks.
Part Defect Detection Method Based on Channel-Aware Aggregation and Re-Parameterization Asymptotic Module
Authors: Bian Enyuan , Yin Mingfeng , Fu Shiyu , Gao Qi , Li Yaozong
Published: January 2024

In industrial production, the quality, reliability, and precision of parts determine the overall quality and performance of various mechanical equipment. However, existing part defect detection methods have shortcomings in terms of feature extraction and fusion, leading to issues of missed detection. To address this challenge, this manuscript proposes a defect detection algorithm for parts (CRD-YOLO) based on the improved YOLOv5. Our first aim is to increase the regional features of small targets and improve detection accuracy. In this manuscript, we design the channel- aware aggregation (CAA) module, utilizing a multi-branch convolutional segmentation structure and incorporating an attention mechanism and ConvNeXt V2 Block as bottleneck layers for feature processing. Secondly, the re-parameterization asymptotic module (RAFPN) is used to replace the original model neck structure in order to improve the interaction between shallow-detail features and deeper semantic features, and to avoid the large semantic gaps between non-neighboring layers. Then, the DO-DConv module is encapsulated within the BN layer and the LeakyReLU activation function to become the DBL module, which further processes the feature output from the backbone network and fuses neck features more comprehensively. Finally, experiments with the self-made dataset show that the model proposed in this paper improves the accuracy of detecting various types of defect. In particular, it increased the accuracy of detecting bearing scuffing defects with significant dimensional variations, with an improvement of 6%, and gear missing teeth defects with large shape differences, with an 8.3% enhancement. Additionally, the mean average precision (mAP) reached 96.7%, an increase of 5.5% and 6.4% compared to YOLOv5s and YOLOv8s, respectively.
State-of-the-Art and Recent Advances in the Abatement of Gaseous Pollutants from Waste-to-Energy
Authors: Schiavon Marco , Ravina Marco , Zanetti Mariachiara , Panepinto Deborah
Published: January 2024

Despite their key role in integrated waste management, direct (incineration) and indirect (gasification/pyrolysis) waste combustion processes are still opposed by some of the general public due to the past emission levels of air pollutants. In fact, although the release of air pollutants (especially dioxin) to the atmosphere from waste combustion processes has gradually decreased over the years, thanks to the introduction of stricter regulations and more advanced removal technologies, there is still an unsolved problem regarding the public acceptance of waste-to-energy facilities. The aim of this paper is to provide an overview of the state-of-the-art air pollution control (APC) technologies used in waste combustion facilities. Air pollution control technologies are designed to reduce or eliminate the emissions of harmful pollutants into the atmosphere. These technologies are important for safeguarding public health, protecting ecosystems, complying with regulations, and promoting a more sustainable and resilient future for both local and global communities. This paper will highlight the complexity behind emission control and the efforts made by this sector over the years. This paper will also propose suggested configurations based on the interactions/complementarity between different APC technologies and recent findings to improve their performance.
Assessing the Impact of Pomegranate Peel Extract Active Packaging and High Hydrostatic Pressure Processing on Color and Oxidative Stability in Sliced Nitrate/Nitrite-Reduced Iberian Dry-Cured Loins
Authors: Cava Ramón , Ladero Luis , Riaguas Enrique , Vidal-Aragón M. Carmen
Published: January 2024

Our study aimed to assess the impact of active packaging with pomegranate peel extract (0.06 mg gallic acid eq./cm2) and/or high-pressure treatment (600 MPa, 7 min) on the instrumental color, lipid, and protein oxidation of Iberian dry loins formulated with reduced nitrate/nitrite levels (0, 37.5, and 150 mg/kg) during 100-day refrigerated storage (4 °C). CIE L*a*b* coordinates were measured, and malondialdehyde, carbonyls, and free thiol contents served as markers for lipid and protein oxidation. Active packaging lowered CIE L* (35.4 vs. 34.1) and a* (15.5 vs. 14.5) and increased yellowness (15.6 vs. 16.3) and hue (45.2 vs. 48.4), while pressurization increased CIE L* (33.1 vs. 36.3) and diminished a* values (16.1 vs. 13.9). Ongoing nitrate/nitrite amounts significantly influenced lipid peroxidation, protein carbonyl formation, and free thiol loss. Active packaging and high-pressure processing had varying effects on carbonyl and thiol contents. Neither pressurization nor active packaging impacted malondialdehyde formation. Pressurization enhanced the formation of 4-HNE (503 vs. 697 pg/g). Protein oxidation proved more sensitive to changes, with active packaging offering protection against protein carbonylation (15.4 vs. 14.7 nmol carbonyls/mg protein), while pressurization induced thiol loss (34.3 vs. 28.0 nmol Cys eq./mg protein). This comprehensive understanding provides essential insights for the meat industry, emphasizing the necessity for customized processing conditions to enhance color stability, lipid preservation, and protein integrity in dry-cured loin slices.
Contamination Status and Acute Dietary Exposure Assessment of Paralytic Shellfish Toxins in Shellfish in the Dalian Area of the Yellow-Bohai Sea, China
Authors: Cao Pei , Zhang Lei , Huang Yaling , Li Shuwen , Wang Xiaodan , Pan Feng , Yu Xiaojin , Sun Jinfang , Liang Jiang , Zhou Pingping , Xu Xiaomin
Published: January 2024

The Yellow-Bohai Sea is an important semi-enclosed continental shelf marginal seas with an intensive aquaculture industry in China. The current study analyzed the contamination status and the time variations of paralytic shellfish toxins (PSTs) in shellfish between 2019 and 2020 from the Yellow-Bohai Sea in the Dalian area and estimated the acute health risks to consumers in China. A total of 199 shellfish samples (including 34 Pacific oysters, 25 Mediterranean blue mussels, 34 Manila clams, 36 bay scallops, 34 veined rapa whelks and 36 bloody clams) were analyzed from four representative aquaculture zones around the Yellow-Bohai Sea in Dalian. Among the samples, scallops and blood clams were the shellfish species with the highest detection rate of PSTs (94.4%), and the highest level of PSTs was detected in scallops with 3953.5 μg STX.2HCl eq./kg (μg STX.2HCL equivalents per kg shellfish tissue), followed by blood clams with 993.4 μg STX.2HCl eq./kg. The contents of PSTs in shellfish showed a time variation trend, and autumn was the season of concern for PST contamination in Dalian. For general Chinese consumers, the probability of acute health risks to shellfish consumers from dietary exposure to PSTs was around 13%. For typical consumers in coastal areas of China, especially those with higher shellfish intake, there was an acute health risk associated with exposure to PSTs through shellfish consumption during the occurrence of harmful algal blooms. It is suggested that the government continue to strengthen the monitoring of the source of PSTs and the monitoring of harmful algal blooms and give reasonable advice on shellfish consumption for consumers in coastal areas, such as not eating scallop viscera.
Rapid and Simultaneous Authentication of Six Laver Species Using Capillary Electrophoresis-Based Multiplex PCR
Authors: Yang Seung-Min , Kim Jun-Su , Kim Eiseul , Kim Hae-Yeong
Published: January 2024

Lavers are typically consumed in dried or seasoned forms. However, commercially processed lavers can lead to seafood fraud because it is impossible to authenticate the original species based on morphological characteristics alone. In this study, we developed a capillary electrophoresis-based multiplex polymerase chain reaction (PCR) to authenticate six different laver species. The species-specific primer sets to target the chloroplast rbcL or rbcS genes were newly designed. We successfully established both singleplex and multiplex conditions, which resulted in specific amplicons for each species (N. dentata, 274 bp; N. yezoensis, 211 bp; N. seriata, 195 bp; N. tenera, 169 bp; N. haitanensis, 127 bp; P. suborbiculata, 117 bp). Moreover, the assays were sensitive enough to detect DNA ranging from 10 to 0.1 pg of DNA. The optimized capillary electrophoresis-based multiplex PCR was successfully applied to 40 commercial laver products. In addition to detecting the laver species as stated on the commercial label, the assay discovered cases where less expensive species were mixed in. With its advantageous properties, such as short amplicon size, high specificity, and superior sensitivity, this assay could be used for the authentication of the six laver species.
Outcomes and Predictors of 30-Day Readmission in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization between 2016 and 2018
Authors: Fatima Ifrah , Ahmed Mohamed , Mohamed Wael T. , Jahagirdar Vinay , Kennedy Kevin F. , Likhitsup Alisa
Published: January 2024

Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. The 5-year survival rate for liver cancer in the US has improved from 3% four decades ago to 20% now. Transarterial chemoembolization (TACE) is the treatment of choice for stage B/intermediate-stage HCC. Complications of TACE include hepatic encephalopathy, liver failure, post-embolization syndrome, duodenal ulcers, liver abscesses, acute cholecystitis, and injury to the biliary tract. This study evaluates the 30-day readmission rate and predictors of readmission among patients with HCC undergoing TACE. Methods: The 2016–2018 Healthcare Cost and Utilization Project (HCUP) database, which includes the National Readmission Database (NRD), was used. All adult patients with HCC who underwent TACE were identified using the International Classification of Diseases (ICD-10). The rate of 30-day readmissions after TACE and the associated diagnoses were identified. Logistic regression was used to obtain adjusted odds ratios for variables associated with 30-day readmission. Results: A total of 566 patients underwent TACE between 2016–2018. Sixty-five patients were excluded due to death and unavailability of 30-day readmission data. The procedure was performed in large (80.4%), metro-teaching hospitals (94.5%). Mean patient age was 65.1 ± 9.9 years, and 74% of patients were male. Among the 501 patients, 81 (16.2%) were readmitted within 30 days. The mean age for readmitted patients was 63.2 ± 11.0 and 69.1% were male. The mean length of stay at readmission was 5.5 ± 7.3 days. A total of 7.4% of patients had neurological disorders, 17.3% had weight loss, 30.9% had fluid and electrolyte imbalance, and 21.0% had hepatic encephalopathy. The most common primary diagnoses at 30-day readmission were liver cell carcinoma, sepsis, and liver failure. Univariate analysis for variables associated with 30-day readmission included hepatic encephalopathy (OR 3.45; 95% CI 1.8–6.62; p = 0.0002), underlying neurological disorders (OR 3.28; 95% CI 1.16–9.3; p = 0.03), weight loss (OR 2.82; 95% CI 1.42–5.61; p = 0.003), and Medicaid status (OR 1.74; 95% CI 1.05–2.88; p = 0.03). Multivariable analysis showed hepatic encephalopathy (OR 2.91; 95% CI 1.4, 6.04; p = 0.04) and weight loss (OR 2.37; 95% CI 1.13–4.96; p = 0.02) were associated with hospital readmission. Conclusions: Weight loss and hepatic encephalopathy were predictors for 30-day readmission after a TACE procedure for HCC.
Conservative Management of Acute Sports-Related Concussions: A Narrative Review
Authors: Kureshi Sohaib , Mendizabal Maria , Francis John , Djalilian Hamid R.
Published: January 2024

This review explores the application of the conservative management model for pain to sports-related concussions (SRCs), framing concussions as a distinct form of pain syndrome with a pathophysiological foundation in central sensitization. Drawing parallels with proven pain management models, we underscore the significance of a proactive approach to concussion management. Recognizing concussions as a pain syndrome allows for the tailoring of interventions in alignment with conservative principles. This review first covers the epidemiology and controversies surrounding prolonged concussion recovery and persistent post-concussion symptoms (PPCS). Next, the pathophysiology of concussions is presented within the central sensitization framework, emphasizing the need for early intervention to mitigate the neuroplastic changes that lead to heightened pain sensitivity. Five components of the central sensitization process specific to concussion injuries are highlighted as targets for conservative interventions in the acute period: peripheral sensitization, cerebral metabolic dysfunction, neuroinflammation, glymphatic system dysfunction, and pain catastrophizing. These proactive interventions are emphasized as pivotal in accelerating concussion recovery and reducing the risk of prolonged symptoms and PPCS, in line with the philosophy of conservative management.
Activated Inositol Phosphate, Substrate for Synthesis of Prostaglandylinositol Cyclic Phosphate (Cyclic PIP)—The Key for the Effectiveness of Inositol-Feeding
Authors: Gypakis Antonios , Adelt Stephan , Lemoine Horst , Vogel Günter , Wasner Heinrich
Published: January 2024

The natural cyclic AMP antagonist, prostaglandylinositol cyclic phosphate (cyclic PIP), is biosynthesized from prostaglandin E (PGE) and activated inositol phosphate (n-Ins-P), which is synthesized by a particulate rat-liver-enzyme from GTP and a precursor named inositol phosphate (pr-Ins-P), whose 5-ring phosphodiester structure is essential for n-Ins-P synthesis. Aortic myocytes, preincubated with [3H] myo-inositol, synthesize after angiotensin II stimulation (30 s) [3H] pr-Ins-P (65% yield), which is converted to [3H] n-Ins-P and [3H] cyclic PIP. Acid-treated (1 min) [3H] pr-Ins-P co-elutes with inositol (1,4)-bisphosphate in high performance ion chromatography, indicating that pr-Ins-P is inositol (1:2-cyclic,4)-bisphosphate. Incubation of [3H]-GTP with unlabeled pr-Ins-P gave [3H]-guanosine-labeled n-Ins-P. Cyclic PIP synthase binds the inositol (1:2-cyclic)-phosphate part of n-Ins-P to PGE and releases the [3H]-labeled guanosine as [3H]-GDP. Thus, n-Ins-P is most likely guanosine diphospho-4-inositol (1:2-cyclic)-phosphate. Inositol feeding helps patients with metabolic conditions related to insulin resistance, but explanations for this finding are missing. Cyclic PIP appears to be the key for explaining the curative effect of inositol supplementation: (1) inositol is a molecular constituent of cyclic PIP; (2) cyclic PIP triggers many of insulin’s actions intracellularly; and (3) the synthesis of cyclic PIP is decreased in diabetes as shown in rodents.
Nonspecific Inhibition of IL6 Family Cytokine Signalling by Soluble gp130
Authors: Widjaja Anissa A. , Cook Stuart A.
Published: January 2024

IL6 is a proinflammatory cytokine that binds to membrane-bound IL6 receptor (IL6R) or soluble IL6R to signal via gp130 in cis or trans, respectively. We tested the hypothesis that sgp130Fc, which is believed to be a selective IL6 trans-signalling inhibitor, is in fact a non-specific inhibitor of gp130 signalling. In human cancer and primary cells, sgp130Fc inhibited IL6, IL11, OSM and CT1 cis-signalling. The IC50 values of sgp130Fc for IL6 and OSM cis-signalling were markedly (20- to 200-fold) lower than the concentrations of sgp130Fc used in mouse studies and clinical trials. sgp130 inhibited IL6 and OSM signalling in the presence of an ADAM10/17 inhibitor and the absence of soluble IL6R or OSMR, with effects that were indistinguishable from those of a gp130 neutralising antibody. These data show that sgp130Fc does not exclusively block IL6 trans-signalling and reveal instead that broad inhibition of gp130 signalling likely underlies its therapeutic effects. This proposes global or modular inhibition of gp130 as a therapeutic approach for treating human disease.
Transcriptomic and Proteomic Analyses Unveil the Role of Nitrogen Metabolism in the Formation of Chinese Cabbage Petiole Spot
Authors: Mei Ying , Lei Juanli , Liu Wenqi , Yue Zhichen , Hu Qizan , Tao Peng , Li Biyuan , Zhao Yanting
Published: January 2024

Chinese cabbage is the most widely consumed vegetable crop due to its high nutritional value and rock-bottom price. Notably, the presence of the physiological disease petiole spot significantly impacts the appearance quality and marketability of Chinese cabbage. It is well known that excessive nitrogen fertilizer is a crucial factor in the occurrence of petiole spots; however, the mechanism by which excessive nitrogen triggers the formation of petiole spots is not yet clear. In this study, we found that petiole spots initially gather in the intercellular or extracellular regions, then gradually extend into intracellular regions, and finally affect adjacent cells, accompanied by cell death. Transcriptomic and proteomic as well as physiology analyses revealed that the genes/proteins involved in nitrogen metabolism exhibited different expression patterns in resistant and susceptible Chinese cabbage lines. The resistant Chinese cabbage line has high assimilation ability of NH4+, whereas the susceptible one accumulates excessive NH4+, thus inducing a burst of reactive oxygen species (ROS). These results introduce a novel perspective to the investigation of petiole spot induced by the nitrogen metabolism pathway, offering a theoretical foundation for the development of resistant strains in the control of petiole spot.
Inflammatory Biomarkers and Gait Impairment in Older Adults: A Systematic Review
Authors: Brognara Lorenzo , Luna Oscar Caballero , Traina Francesco , Cauli Omar
Published: January 2024

Peripheral inflammation and gait speed alterations are common in several neurological disorders and in the aging process, but the association between the two is not well established. The aim of this systematic literary review is to determine whether proinflammatory markers are a positive predictor for gait impairments and their complications, such as falls in older adults, and may represent a risk factor for slow gait speed and its complications. The systematic review was performed in line with the Preferred Report Items for Systematic Review and Meta-Analyses (PRISMA). A protocol for literature searches was structured a priori and designed according to the International Perspective Register of Systemic Review (PROSPERO: CRD42023451108). Peer-reviewed original articles were identified by searching seven electronic databases: Excerpta Medica Database (EMBASE), SciVerse (ScienceDirect), Scopus, PubMed, Medline, Web of Science, and the Cochrane Library. The search strategy was formulated based on a combination of controlled descriptors and/or keywords related to the topic and a manual search was conducted of the reference lists from the initially selected studies to identify other eligible studies. The studies were thoroughly screened using the following inclusion criteria: older adults, spatiotemporal gait characteristics, and proinflammatory markers. A meta-analysis was not performed due to the heterogeneity of the studies, and the results were narratively synthesized. Due to the clinical and methodological heterogeneity, the studies were combined in a narrative synthesis, grouped by the type of biomarkers evaluated. A standardized data extraction form was used to collect the following methodological outcome variables from each of the included studies: author, year, population, age, sample size, spatiotemporal gait parameters such as gait velocity, and proinflammatory markers such as TNF-α, high sensitivity C-reactive (CRP) proteins, and IL-6. We included 21 out of 51 studies in our review, which examined the association between inflammatory biomarkers and gait impairment. This review highlights the role of TNF-α, CRP, and IL-6 in gait impairment. Biomarkers play an important role in the decision-making process, and IL-6 can be an effective biomarker in establishing the diagnosis of slow gait speed. Further longitudinal research is needed to establish the use of molecular biomarkers in monitoring gait impairment.
Response to Fingolimod in Multiple Sclerosis Patients Is Associated with a Differential Transcriptomic Regulation
Authors: Sánchez-Sanz Alicia , Muñoz-Viana Rafael , Sabín-Muñoz Julia , Moreno-Torres Irene , Brea-Álvarez Beatriz , Rodríguez-De la Fuente Ofir , García-Merino Antonio , Sánchez-López Antonio J.
Published: January 2024

Fingolimod is an immunomodulatory sphingosine-1-phosphate (S1P) analogue approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). The identification of biomarkers of clinical responses to fingolimod is a major necessity in MS to identify optimal responders and avoid the risk of disease progression in non-responders. With this aim, we used RNA sequencing to study the transcriptomic changes induced by fingolimod in peripheral blood mononuclear cells of MS-treated patients and their association with clinical response. Samples were obtained from 10 RRMS patients (five responders and five non-responders) at baseline and at 12 months of fingolimod therapy. Fingolimod exerted a vast impact at the transcriptional level, identifying 7155 differentially expressed genes (DEGs) compared to baseline that affected the regulation of numerous signaling pathways. These DEGs were predominantly immune related, including genes associated with S1P metabolism, cytokines, lymphocyte trafficking, master transcription factors of lymphocyte functions and the NF-kB pathway. Responder and non-responder patients exhibited a differential transcriptomic regulation during treatment, with responders presenting a higher number of DEGs (6405) compared to non-responders (2653). The S1P, NF-kB and TCR signaling pathways were differentially modulated in responder and non-responder patients. These transcriptomic differences offer the potential of being exploited as biomarkers of a clinical response to fingolimod.
Leucine Zipper Downregulated in Cancer-1 Interacts with Clathrin Adaptors to Control Epidermal Growth Factor Receptor (EGFR) Internalization and Gefitinib Response in EGFR-Mutated Non-Small Cell Lung Cancer
Authors: Huang Hsien-Neng , Hung Pin-Feng , Chen Yai-Ping , Lee Chia-Huei
Published: January 2024

The epidermal growth factor receptor (EGFR) is a common driver of non-small cell lung cancer (NSCLC). Clathrin-mediated internalization (CMI) sustains EGFR signaling. AXL is associated with resistance to EGFR-tyrosine kinase inhibitors (TKIs) in EGFR-mutated (EGFRM) NSCLC. We investigated the effects of Leucine zipper downregulated in cancer-1 (LDOC1) on EGFR CMI and NSCLC treatment. Coimmunoprecipitation, double immunofluorescence staining, confocal microscopy analysis, cell surface labelling assays, and immunohistochemistry studies were conducted. We revealed that LDOC1 interacts with clathrin adaptors through binding motifs. LDOC1 depletion promotes internalization and plasma membrane recycling of EGFR in EGFRM NSCLC PC9 and HCC827 cells. Membranous and cytoplasmic EGFR decreased and increased, respectively, in LDOC1 (−) NSCLC tumors. LDOC1 depletion enhanced and sustained activation of EGFR, AXL, and HER2 and enhanced activation of HER3 in PC9 and HCC827 cells. Sensitivity to first-generation EGFR-TKIs (gefitinib and erlotinib) was significantly reduced in LDOC1-depleted PC9 and HCC827 cells. Moreover, LDOC1 downregulation was significantly associated (p < 0.001) with poor overall survival in patients with EGFRM NSCLC receiving gefitinib (n = 100). In conclusion, LDOC1 may regulate the efficacy of first-generation EGFR-TKIs by participating in the CMI of EGFR. Accordingly, LDOC1 may function as a prognostic biomarker for EGFRM NSCLC.
Characterizing the D-Amino Acid Position in Peptide Epimers by Using Higher-Energy Collisional Dissociation Tandem Mass Spectrometry: A Case Study of Liraglutide
Authors: Chen Yuan-Chih , Wu Hsin-Yi , Lin Lung-Cheng , Chang Chih-Wei , Liao Pao-Chi
Published: January 2024

D-amino acid-containing peptides (DAACPs) occur in biological and artificial environments. Since the importance of DAACPs has been recognized, various mass spectrometry-based analytical approaches have been developed. However, the capability of higher-energy collisional dissociation (HCD) fragmentation to characterize DAACP sites has not been evaluated. In this study, we compared the normalized spectra intensity under different conditions of HCD and used liraglutide along with its DAACPs as examples. Our results indicated that the difference in the intensity of y ions between DAACPs and all-L liraglutide could not only distinguish them but also localize the sites of D-amino acids in the DAACPs. Our data demonstrate the potential of using HCD for the site characterization of DAACPs, which may have great impact in biological studies and peptide drug development.
γδ T Cells: A Game Changer in the Future of Hepatocellular Carcinoma Immunotherapy
Authors: Papadakos Stavros P. , Arvanitakis Konstantinos , Stergiou Ioanna E. , Koutsompina Maria-Loukia , Germanidis Georgios , Theocharis Stamatios
Published: January 2024

Hepatocellular carcinoma (HCC) remains a global health challenge with limited treatment options and a poor prognosis for advanced-stage patients. Recent advancements in cancer immunotherapy have generated significant interest in exploring novel approaches to combat HCC. One such approach involves the unique and versatile subset of T cells known as γδ T cells. γδ T cells represent a distinct subset of T lymphocytes that differ from conventional αβ T cells in terms of antigen recognition and effector functions. They play a crucial role in immunosurveillance against various malignancies, including HCC. Recent studies have demonstrated that γδ T cells can directly recognize and target HCC cells, making them an attractive candidate for immunotherapy. In this article, we aimed to explore the role exerted by γδ T cells in the context of HCC. We investigate strategies designed to maximize the therapeutic effectiveness of these cells and examine the challenges and opportunities inherent in applying these research findings to clinical practice. The potential to bring about a revolutionary shift in HCC immunotherapy by capitalizing on the unique attributes of γδ T cells offers considerable promise for enhancing patient outcomes, warranting further investigation.
Characterization of the Increase in Narcolepsy following the 2009 H1N1 Pandemic in Sweden
Authors: Gauffin Helena , Boström Inger , Berntsson Shala Ghaderi , Kristoffersson Anna , Fredrikson Mats , Landtblom Anne-Marie
Published: January 2024

(1) Background: In the context of the H1N1 pandemic and the Pandemrix vaccination campaign, an increased number of narcolepsy cases were noted in several countries. In Sweden, this phenomenon was attributed to the effect of the Pandemrix vaccination in the first place. Studies from China indicated that narcolepsy could occur as a consequence of the H1N1 infection itself. We performed an analysis of the increase, with a specific interest in age and sex distribution. We also aimed to validate the origin of the excess cases, post hoc. (2) Methods: Data for narcolepsy patients (ICD code G 47.4, both type 1 and type 2) distributed by sex and age at 5-year intervals, annually between 2005 and 2017, were retrieved from the National Patient Register. Information on the total population was collected from the Swedish Population Register. (3) Results: The number of narcolepsy cases increased markedly from 2009 to 2014 compared to the period before 2009. A particular increase in 2011 among children and teenagers was observed. The sex ratio did not change significantly during the study period. (4) Conclusions: Our results support an association between the increased prevalence of narcolepsy cases and Pandemrix vaccination, but the effect of the virus itself cannot be ruled out as a contributing factor.
Evaluating Computer Vision, Large Language, and Genome-Wide Association Models in a Limited Sized Patient Cohort for Pre-Operative Risk Stratification in Adult Spinal Deformity Surgery
Authors: Schonfeld Ethan , Pant Aaradhya , Shah Aaryan , Sadeghzadeh Sina , Pangal Dhiraj , Rodrigues Adrian , Yoo Kelly , Marianayagam Neelan , Haider Ghani , Veeravagu Anand
Published: January 2024

Background: Adult spinal deformities (ASD) are varied spinal abnormalities, often necessitating surgical intervention when associated with pain, worsening deformity, or worsening function. Predicting post-operative complications and revision surgery is critical for surgical planning and patient counseling. Due to the relatively small number of cases of ASD surgery, machine learning applications have been limited to traditional models (e.g., logistic regression or standard neural networks) and coarse clinical variables. We present the novel application of advanced models (CNN, LLM, GWAS) using complex data types (radiographs, clinical notes, genomics) for ASD outcome prediction. Methods: We developed a CNN trained on 209 ASD patients (1549 radiographs) from the Stanford Research Repository, a CNN pre-trained on VinDr-SpineXR (10,468 spine radiographs), and an LLM using free-text clinical notes from the same 209 patients, trained via Gatortron. Additionally, we conducted a GWAS using the UK Biobank, contrasting 540 surgical ASD patients with 7355 non-surgical ASD patients. Results: The LLM notably outperformed the CNN in predicting pulmonary complications (F1: 0.545 vs. 0.2881), neurological complications (F1: 0.250 vs. 0.224), and sepsis (F1: 0.382 vs. 0.132). The pre-trained CNN showed improved sepsis prediction (AUC: 0.638 vs. 0.534) but reduced performance for neurological complication prediction (AUC: 0.545 vs. 0.619). The LLM demonstrated high specificity (0.946) and positive predictive value (0.467) for neurological complications. The GWAS identified 21 significant (p < 10−5) SNPs associated with ASD surgery risk (OR: mean: 3.17, SD: 1.92, median: 2.78), with the highest odds ratio (8.06) for the LDB2 gene, which is implicated in ectoderm differentiation. Conclusions: This study exemplifies the innovative application of cutting-edge models to forecast outcomes in ASD, underscoring the utility of complex data in outcome prediction for neurosurgical conditions. It demonstrates the promise of genetic models when identifying surgical risks and supports the integration of complex machine learning tools for informed surgical decision-making in ASD.