bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of COL12A1 rs970547 Polymorphism with Elite Athlete Status
Authors: Ginevičienė Valentina , Urnikytė Alina
Published: October 2022

The role of genetics, as an intrinsic factor, in research of sports performance increases with every passing year. The polymorphism rs970547 of the COL12A1 gene is one of the most promising genetic markers linked to soft-tissue injuries. This study aimed to investigate whether COL12A1 rs970547 genotypes are associated with elite Lithuanian athletes from high-risk various sports, such as running, throwing, jumping, and football. The study involved 293 Lithuanian elite athletes and 287 healthy untrained individuals from the Lithuanian population. The results of this study suggest that the rs970547 T allele and TT genotype were significantly over-represented in the total athlete group compared to controls (p < 0.05). There was a significantly lower C allele frequency in the sprint/power group (16.9%) as well as in footballers (19.4%) compared to controls (33.3%, p < 0.05). Positive selection analysis results showed that the derived allele experiences selection pressure within the general population of Lithuanians. Taken together, the findings of this study suggested that COL12A1 rs970547 (T allele and TT genotype) is associated with elite athlete status, especially with sprint/power athlete and footballer`s performance. However, larger-scale studies within different ethnic backgrounds are still warranted to confirm the findings of our study.
How Risk Factors Affect Head and Neck Squamous Cell Carcinoma (HNSCC) Tumor Immune Microenvironment (TIME): Their Influence on Immune Escape Mechanisms and Immunotherapy Strategy
Authors: Galizia Danilo , Minei Silvia , Maldi Elena , Chilà Giovanna , Polidori Alessio , Merlano Marco Carlo
Published: October 2022

Most head and neck squamous cell carcinomas (HNSCCs) are caused by lifestyle, such as cigarette smoking, or by viruses, such as human papillomavirus (HPV) and Epstein–Barr virus (EBV). HNSCC remains a clinical challenge, notwithstanding the improvements observed in the past years, involving surgery, radiotherapy, and chemotherapy. Recurrent/metastatic (R/M) disease represents an unmet clinical need. Immunotherapy has improved the prognosis of a small proportion of these patients, but most still do not benefit. In the last decade, several preclinical and clinical studies have explored the HNSCC tumor immune microenvironment (TIME), identifying important differences between smoking-associated and virus-associated HNSCCs. This review aims to present how different etiologies affect the HNSCC TIME, affecting immune escape mechanisms and sensitivity to immunotherapy.
Pathophysiological Role of Chymase-Activated Matrix Metalloproteinase-9
Authors: Takai Shinji , Jin Denan
Published: October 2022

Chymase present in mast cells can directly form matrix metalloproteinase (MMP)-9 from proMMP-9. Chymase-activated MMP-9 has been reportedly closely related to the pathogenesis of various diseases, and inflammation-related diseases in particular. Upregulated chymase and MMP-9 have been observed in tissues from patients and animal models of aortic aneurysm, inflammatory gastrointestinal and hepatic diseases, acute pancreatic failure, atopic dermatitis and rheumatoid arthritis. Chymase at these regions is only derived from mast cells, while MMP-9 is derived from macrophages and neutrophils in addition to mast cells. Chymase inhibitors attenuate MMP-9 formation from pro-MMP-9, and ameliorate the development and progression of these disorders, along with reduction in inflammatory cell numbers. MMP-9 activated by chymase might also be involved in angiogenesis in the tumor environment. Development of angiogenesis around several cancers is closely related to the expression of chymase and MMP-9, and postoperative survival curves have revealed that patients with a higher number of chymase positive cells have lower survival rates. In this review, we wanted to clarify the role of chymase-activated MMP-9, which might become an important therapeutic target for various inflammatory disorders.
Natural Compounds Such as Hericium erinaceus and Coriolus versicolor Modulate Neuroinflammation, Oxidative Stress and Lipoxin A4 Expression in Rotenone-Induced Parkinson’s Disease in Mice
Authors: Cordaro Marika , Modafferi Sergio , D’Amico Ramona , Fusco Roberta , Genovese Tiziana , Peritore Alessio Filippo , Gugliandolo Enrico , Crupi Rosalia , Interdonato Livia , Di Paola Davide , Impellizzeri Daniela , Cuzzocrea Salvatore , Calabrese Vittorio , Di Paola Rosanna , Siracusa Rosalba
Published: October 2022

Background: A growing body of research suggests that oxidative stress and neuroinflammation are early pathogenic features of neurodegenerative disorders. In recent years, the vitagene system has emerged as a potential target, as it has been shown to have a high neuroprotective power. Therefore, the discovery of molecules capable of activating this system may represent a new therapeutic target to limit the deleterious consequences induced by oxidative stress and neuroinflammation, such as neurodegeneration. Lipoxins are derived from arachidonic acid, and their role in the resolution of systemic inflammation is well established; however, they have become increasingly involved in the regulation of neuroinflammatory and neurodegenerative processes. Our study aimed at activating the NF-E2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) redox system and increasing lipoxin A4 for the modulation of antioxidant stress and neuroinflammation through the action of two fungi in a rotenone-induced Parkinson’s model. Methods: During the experiment, mice received Hericium erinaceus, Coriolus versicolor or a combination of the two (200 mg/kg, orally) concomitantly with rotenone (5 mg/kg, orally) for 28 days. Results: The results obtained highlighted the ability of these two fungi and, in particular, their ability through their association to act on neuroinflammation through the nuclear factor-kB pathway and on oxidative stress through the Nrf2 pathway. This prevented dopaminergic neurons from undergoing apoptosis and prevented the alteration of typical Parkinson’s disease (PD) markers and α-synuclein accumulation. The action of Hericium erinaceus and Coriolus versicolor was also able to limit the motor and non-motor alterations characteristic of PD. Conclusions: Since these two mushrooms are subject to fewer regulations than traditional drugs, they could represent a promising nutraceutical choice for preventing PD.
Inhibin Alpha Expression in Human Tumors: A Tissue Microarray Study on 12,212 Tumors
Authors: Weidemann Sören , Noori Nessar Ahmad , Lennartz Maximilian , Reiswich Viktor , Dum David , Menz Anne , Chirico Viktoria , Hube-Magg Claudia , Fraune Christoph , Bawahab Ahmed Abdulwahab , Bernreuther Christian , Simon Ronald , Clauditz Till S. , Sauter Guido , Hinsch Andrea , Kind Simon , Jacobsen Frank , Steurer Stefan , Minner Sarah , Burandt Eike , Marx Andreas H. , Krech Till , Lebok Patrick , Büscheck Franziska , Höflmayer Doris
Published: October 2022

As a result of its expression in corresponding normal cell types, inhibin alpha (INHA) is used as an immunohistochemical marker for adrenocortical neoplasms and testicular or ovarian sex cord stromal tumors. However, other tumors can also express INHA. To comprehensively determine INHA expression in cancer, a tissue microarray containing 15,012 samples from 134 different tumor types and subtypes was analyzed by immunohistochemistry. INHA positivity was found in 72 of 134 tumor categories, including 26 categories with ≥1 strongly positive case. A moderate to strong INHA positivity was found in 100% of 37 granulosa cell tumors of the ovary, 100% of 43 other sex cord stromal tumors of the ovary/testis, 100% of 31 granular cell tumors, 78.5% of 28 adenomas, 44% of 25 carcinomas of the adrenal cortex, and 46.7% of 15 pancreatic acinar cell carcinomas. At least a weak INHA positivity was seen in <33% of cases of 46 additional tumor entities. In summary, these data support the use of INHA antibodies for detecting sex cord stromal tumors, granular cell tumors, and adrenocortical neoplasms. Since INHA can also be found in other tumor entities, INHA immunohistochemistry should only be considered as a part of any panel for the distinction of tumor entities.
The Role of Probiotic Bacillus Spores and Amino Acids with Immunoglobulins on a Rat Enteropathy Model
Authors: Neag Maria-Adriana , Melincovici Carmen-Stanca , Catinean Adrian , Muntean Dana-Maria , Pop Raluca-Maria , Bocsan Ioana-Corina , Mitre Andrei-Otto , Cardos Mihai-Bogdan , Inceu Andreea-Ioana , Buzoianu Anca-Dana
Published: October 2022

Non-steroidal anti-inflammatory drugs (NSAIDs) are some of the most widely used drugs due to their anti-inflammatory, analgesic and antipyretic pharmacological effects. Gastrointestinal side effects are some of the most severe and frequent side effects of NSAIDs. These depend on the balance of the gut microbiome, the abundance of Gram-negative bacteria, and the amount of lipopolysaccharide released. Therefore, restoring or improving gut bacteria balance with probiotic supplements could prove to be an adjuvant therapy against mild NSAID-induced enteropathy. Twenty-five Wistar albino male rats were divided into five groups. The negative control group was administered carboxymethylcellulose and the positive control group diclofenac (DIC), 8 mg/kg for 7 days, which represented the enteropathy model. Treatment groups consisted of a combination of pro-biotic spores (MSB), amino acids and immunoglobulins supplement (MM), which were also administered for 7 days. We analyzed hepatic injury markers (AST, ALT) and creatinine, and inflammatory markers, IL-6, TNF-α, PGE2, iNOS, as well as total antioxidant capacity. The results obtained in the present study suggest that the modulation of the intestinal microbiota by administration of probiotics (Bacillus spores), alone or in combination with immunoglobulins and amino acids, represents an attractive therapy for the prevention of NSAID-induced enteropathy.
Long-Term Excessive Dietary Phosphate Intake Increases Arterial Blood Pressure, Activates the Renin–Angiotensin–Aldosterone System, and Stimulates Sympathetic Tone in Mice
Authors: Latic Nejla , Peitzsch Mirko , Zupcic Ana , Pietzsch Jens , Erben Reinhold G.
Published: October 2022

Increased dietary phosphate intake has been associated with severity of coronary artery disease, increased carotid intima–media thickness, left ventricular hypertrophy (LVH), and increased cardiovascular mortality and morbidity in individuals with normal renal function as well as in patients suffering from chronic kidney disease. However, the underlying mechanisms are still unclear. To further elucidate the cardiovascular sequelae of long-term elevated phosphate intake, we maintained male C57BL/6 mice on a calcium, phosphate, and lactose-enriched diet (CPD, 2% Ca, 1.25% P, 20% lactose) after weaning them for 14 months and compared them with age-matched male mice fed a normal mouse diet (ND, 1.0% Ca, 0.7% P). Notably, the CPD has a balanced calcium/phosphate ratio, allowing the effects of elevated dietary phosphate intake largely independent of changes in parathyroid hormone (PTH) to be investigated. In agreement with the rationale of this experiment, mice maintained on CPD for 14 months were characterized by unchanged serum PTH but showed elevated concentrations of circulating intact fibroblast growth factor-23 (FGF23) compared with mice on ND. Cardiovascular phenotyping did not provide evidence for LVH, as evidenced by unchanged LV chamber size, normal cardiomyocyte area, lack of fibrosis, and unchanged molecular markers of hypertrophy (Bnp) between the two groups. However, intra-arterial catheterization revealed increases in systolic pressure, mean arterial pressure, and pulse pressure in mice fed the CPD. Interestingly, chronically elevated dietary phosphate intake stimulated the renin–angiotensin–aldosterone system (RAAS) as evidenced by increased urinary aldosterone in animals fed the CPD, relative to the ND controls. Furthermore, the catecholamines epinephrine, norepinephrine, and dopamine as well as the catecholamine metabolites metanephrine. normetanephrine and methoxytyramine as measured by mass spectrometry were elevated in the urine of mice on CPD, relative to mice on the ND. These changes were partially reversed by switching 14-month-old mice on CPD back to ND for 2 weeks. In conclusion, our data suggest that excess dietary phosphate induces a rise in blood pressure independent of secondary hyperparathyroidism, and that this effect may be mediated through activation of the RAAS and stimulation of the sympathetic tone.
Trichosanthes kirilowii Extract Promotes Wound Healing through the Phosphorylation of ERK1/2 in Keratinocytes
Authors: Kim Minho , Kim Jae-Goo , Kim Ki-Young
Published: October 2022

The proliferation of keratinocytes is one of the important steps in the wound-healing process, which is regulated by various signals. Prior studies have shown that Trichosanthes kirilowii extract has the ability to promote angiogenesis. Therefore, in this study, we tested the wound-healing efficacy of Trichosanthes kirilowii extract with respect to promoting keratinocyte proliferation. A total of 100 μg/mL of Trichosanthes kirilowii extract treatment improved 145.38% of keratinocyte proliferation compared with DMSO-treated control in an MTT assay and increased 238.2% of wound closure by re-epithelialization in an in vitro wound-healing assay. Trichosanthes kirilowii extract promoted ERK1/2 phosphorylation in western blot analysis and induced the expression of the c-fos and c-jun (AP-1 transcription factors), cyclins (cell cycle regulator), and growth factors CTGF and VEGF (stimulator of angiogenesis) in qRT-PCR analysis. An in vivo wound-healing assay showed that Trichosanthes kirilowii extract improved wound healing, and the significant difference in wound closure compared with DMSO-treated control was shown on days 6 and 7 with a mouse model. Taken together, we demonstrate that Trichosanthes kirilowii extract promotes the proliferation of keratinocytes by activating ERK1/2 and increasing the mRNA expression of c-fos, c-jun, CTGF, and VEGF. Therefore, we suggest Trichosanthes kirilowii extract as a new component for skin care and as a wound-healing substance.
Progress in the Development of Biosensors Based on Peptide–Copper Coordination Interaction
Authors: Liu Gang , Xia Ning , Tian Linxu , Sun Zhifang , Liu Lin
Published: October 2022

Copper ions, as the active centers of natural enzymes, play an important role in many physiological processes. Copper ion-based catalysts which mimic the activity of enzymes have been widely used in the field of industrial catalysis and sensing devices. As an important class of small biological molecules, peptides have the advantages of easy synthesis, excellent biocompatibility, low toxicity, and good water solubility. The peptide–copper complexes exhibit the characteristics of low molecular weight, high tenability, and unique catalytic and photophysical properties. Biosensors with peptide–copper complexes as the signal probes have promising application prospects in environmental monitoring and biomedical analysis and diagnosis. In this review, we discussed the design and application of fluorescent, colorimetric and electrochemical biosensors based on the peptide–copper coordination interaction.
Cr-MOF-Based Electrochemical Sensor for the Detection of P-Nitrophenol
Authors: Hu Chao , Pan Ping , Huang Haiping , Liu Hongtao
Published: October 2022

Cr-MOF nanoparticles were synthesized by a simple hydrothermal method, and their morphology and structure were characterized by SEM, TEM, and XRD techniques. The Cr-MOF modified glassy carbon electrode (Cr-MOF/GCE) was well constructed and served as an efficient electrochemical sensor for the detection of p-nitrophenol (p-NP). It was found that the Cr-MOF nanoparticles had significant electrocatalytic activity toward the reduction of p-NP. The Cr-MOF-based electrochemical sensor exhibited a low detection limit of 0.7 μM for p-NP in a wide range of 2~500 μM and could maintain excellent detection stability in a series of interfering media. The electrochemical sensor was also practically applied to detect p-NP in a local river and confirmed its validity, showing potential application prospects.
Toward In Vivo MRI of the Tissue Proton Exchange Rate in Humans
Authors: Shaghaghi Mehran , Cai Kejia
Published: October 2022

Quantification of proton exchange rate (kex) is a challenge in MR studies. Current techniques either have low resolutions or are dependent on the estimation of parameters that are not measurable. The Omega plot method, on the other hand, provides a direct way for determining kex independent of the agent concentration. However, it cannot be used for in vivo studies without some modification due to the contributions from the water signal. In vivo tissue proton exchange rate (kex) MRI, based on the direct saturation (DS) removed Omega plot, quantifies the weighted average of kex of the endogenous tissue metabolites. This technique has been successfully employed for imaging the variation in the kex of ex vivo phantoms, as well as in vivo human brains in healthy subjects, and stroke or multiple sclerosis (MS) patients. In this paper, we present a brief review of the methods used for kex imaging with a focus on the development of in vivo kex MRI technique based on the DS-removed Omega plot. We then review the recent clinical studies utilizing this technique for better characterizing brain lesions. We also outline technical challenges for the presented technique and discuss its prospects for detecting tissue microenvironmental changes under oxidative stress.
A Paper-Based Photoelectrochemical Sensing Platform Based on In Situ Grown ZnO/ZnIn2S4 Heterojunctions onto Paper Fibers for Sensitively Detecting AFP
Authors: Huang Jiali , Li Xu , Xiu Mingzhen , Huang Kang , Cui Kang , Zhang Jing , Ge Shenguang , Hao Shiji , Yu Jinghua , Huang Yizhong
Published: October 2022

Nowadays, developing a cost-effective, easy-to-operate, and efficient signal amplification platform is of important to microfluidic paper-based analytical devices (μPAD) for end-use markets of point-of-care (POC) assay applications. Herein, an ultrasensitive, paper-based photoelectrochemical (PEC) bioassay platform is constructed by in situ grown ZnO/ZnIn2S4 heterojunctions onto paper fibers, which acted as photoactive signal amplification probes for enhancing the sensitivity of antibodies-based diagnostic assays, for the sensitive detection of alpha-fetoprotein (AFP) targets. The crystalline flake-like ZnIn2S4 composited with hexagonal nanorods (NRs) morphology of ZnO is an in situ grown, at the first time, onto cellulose fibers surface supported with Au nanoparticle (Au NP) modification to improve conductivity of the device working zone. The obtained composites on paper fibers are implemented as a flexible paper-based photoelectrode to realize remarkable performance of the fabricated μPAD, resulting from the enhanced PEC activity of heterojunctions with effective electron-hole pair separation for accelerating photoelectric conversion efficiency of the sensing process under light irradiation. Once the target AFP was introduced into the biosensing interface assistant, with a specific recognition interaction of AFP antibody, a drastically photocurrent response was generated, in view of the apparent steric effects. With the concentration increase of AFP targets, more immune conjugates could be confined onto the biosensing interface, eventually leading to the quantitative decrease of photocurrent intensity. Combined with an ingenious origami design and permitting the hydrophobic/hydrophilic conversion procedure in the bioassay process, the ultrasensitive PEC detection of AFP targets was realized. Under the optimized conditions, the level of AFP could be sensitively tracked by the prepared μPAD with a liner range from 0.1 to 100 ng mL−1 and limit of detection of 0.03 ng mL−1. This work provides a great potential application for highly selective and sensitive POC testing of AFP, and finally, developments for clinical disease diagnosis.
Water–Air Interface to Mimic In Vitro Tumoral Cell Migration in Complex Micro-Environments
Authors: Conti Martina , Bolzan Ilaria , Dal Zilio Simone , Parisse Pietro , Andolfi Laura , Lazzarino Marco
Published: October 2022

The long-known role of cell migration in physiological and pathological contexts still requires extensive research to be fully understood, mainly because of the intricate interaction between moving cells and their surroundings. While conventional assays fail to capture this complexity, recently developed 3D platforms better reproduce the cellular micro-environment, although often requiring expensive and time-consuming imaging approaches. To overcome these limitations, we developed a novel approach based on 2D micro-patterned substrates, compatible with conventional microscopy analysis and engineered to create micro-gaps with a length of 150 µm and a lateral size increasing from 2 to 8 µm, where a curved water–air interface is created on which cells can adhere, grow, and migrate. The resulting hydrophilic/hydrophobic interfaces, variable surface curvatures, spatial confinements, and size values mimic the complex micro-environment typical of the extracellular matrix in which aggressive cancer cells proliferate and migrate. The new approach was tested with two breast cancer cell lines with different invasive properties. We observed that invasive cells (MDA-MB-231) can align along the pattern and modify both their morphology and their migration rate according to the size of the water meniscus, while non-invasive cells (MCF-7) are only slightly respondent to the surrounding micro-environment. Moreover, the selected pattern highlighted a significative matrix deposition process connected to cell migration. Although requiring further optimizations, this approach represents a promising tool to investigate cell migration in complex environments.
Emerging Applications of Electrochemical Impedance Spectroscopy in Tear Film Analysis
Authors: Ozdalgic Berin , Gul Munire , Uygun Zihni Onur , Atçeken Nazente , Tasoglu Savas
Published: October 2022

Human tear film, with a flow rate of 1–3 µL/min, is a rich bodily fluid that transmits a variety of metabolites and hormones containing proteins, lipids and electrolytes that provide clues about ocular and systemic diseases. Analysis of disease biomarkers such as proteins, mRNA, enzymes and cytokines in the tear film, collected by noninvasive methods, can provide significant results for sustaining a predictive, preventive and personalized medicine regarding various diseases such as glaucoma, diabetic retinopathy, keratoconus, dry eye, cancer, Alzheimer’s disease, Parkinson’s disease and COVID-19. Electrochemical impedance spectroscopy (EIS) offers a powerful technique for analyzing these biomarkers. EIS detects electrical equivalent circuit parameters related to biorecognition of receptor–analyte interactions on the electrode surface. This method is advantageous as it performs a label-free detection and allows the detection of non-electroactive compounds that cannot be detected by direct electron transfer, such as hormones and some proteins. Here, we review the opportunities regarding the integration of EIS into tear fluid sampling approaches.
An Exosomal miRNA Biomarker for the Detection of Pancreatic Ductal Adenocarcinoma
Authors: Makler Amy , Narayanan Ramaswamy , Asghar Waseem
Published: October 2022

Pancreatic ductal adenocarcinoma (PDAC) remains a difficult tumor to diagnose and treat. To date, PDAC lacks routine screening with no markers available for early detection. Exosomes are 40–150 nm-sized extracellular vesicles that contain DNA, RNA, and proteins. These exosomes are released by all cell types into circulation and thus can be harvested from patient body fluids, thereby facilitating a non-invasive method for PDAC detection. A bioinformatics analysis was conducted utilizing publicly available miRNA pancreatic cancer expression and genome databases. Through this analysis, we identified 18 miRNA with strong potential for PDAC detection. From this analysis, 10 (MIR31, MIR93, MIR133A1, MIR210, MIR330, MIR339, MIR425, MIR429, MIR1208, and MIR3620) were chosen due to high copy number variation as well as their potential to differentiate patients with chronic pancreatitis, neoplasms, and PDAC. These 10 were examined for their mature miRNA expression patterns, giving rise to 18 mature miRs for further analysis. Exosomal RNA from cell culture media was analyzed via RTqPCR and seven mature miRs exhibited statistical significance (miR-31-5p, miR-31-3p, miR-210-3p, miR-339-5p, miR-425-5p, miR-425-3p, and miR-429). These identified biomarkers can potentially be used for early detection of PDAC.
Comparison between Chest-Worn Accelerometer and Gyroscope Performance for Heart Rate and Respiratory Rate Monitoring
Authors: Romano Chiara , Schena Emiliano , Formica Domenico , Massaroni Carlo
Published: October 2022

The demand for wearable devices to simultaneously monitor heart rate (HR) and respiratory rate (RR) values has grown due to the incidence increase in cardiovascular and respiratory diseases. The use of inertial measurement unit (IMU) sensors, embedding both accelerometers and gyroscopes, may ensure a non-intrusive and low-cost monitoring. While both accelerometers and gyroscopes have been assessed independently for both HR and RR monitoring, there lacks a comprehensive comparison between them when used simultaneously. In this study, we used both accelerometers and gyroscopes embedded in a single IMU sensor for the simultaneous monitoring of HR and RR. The following main findings emerged: (i) the accelerometer outperformed the gyroscope in terms of accuracy in both HR and RR estimation; (ii) the window length used to estimate HR and RR values influences the accuracy; and (iii) increasing the length over 25 s does not provide a relevant improvement, but accuracy improves when the subject is seated or lying down, and deteriorates in the standing posture. Our study provides a comprehensive comparison between two promising systems, highlighting their potentiality for real-time cardiorespiratory monitoring. Furthermore, we give new insights into the influence of window length and posture on the systems’ performance, which can be useful to spread this approach in clinical settings.
Sensing Devices for Detecting and Processing Acoustic Signals in Healthcare
Authors: Mallegni Norma , Molinari Giovanna , Ricci Claudio , Lazzeri Andrea , La Rosa Davide , Crivello Antonino , Milazzo Mario
Published: October 2022

Acoustic signals are important markers to monitor physiological and pathological conditions, e.g., heart and respiratory sounds. The employment of traditional devices, such as stethoscopes, has been progressively superseded by new miniaturized devices, usually identified as microelectromechanical systems (MEMS). These tools are able to better detect the vibrational content of acoustic signals in order to provide a more reliable description of their features (e.g., amplitude, frequency bandwidth). Starting from the description of the structure and working principles of MEMS, we provide a review of their emerging applications in the healthcare field, discussing the advantages and limitations of each framework. Finally, we deliver a discussion on the lessons learned from the literature, and the open questions and challenges in the field that the scientific community must address in the near future.
Polymeric Microfluidic Devices Fabricated Using Epoxy Resin for Chemically Demanding and Day-Long Experiments
Authors: Lee Jaeseok , Kim Minseok
Published: October 2022

Polydimethylsiloxane (PDMS) is a widely used material in laboratories for fabricating microfluidic devices with a rapid and reproducible prototypingability, owing to its inherent properties (e.g., flexibility, air permeability, and transparency). However, the PDMS channel is easily deformed under pressures applied to generate flows because of its elasticity, which can affect the robustness of experiments. In addition, air permeability of PDMS causes the pervaporation of water, and its porous structure absorbs oil and even small hydrophobic molecules, rendering it inappropriate for chemically demanding or day-long experiments. In this study, we develop a rapid and reproducible fabrication method for polymer-based rigid microfluidic devices, using epoxy resin that can overcome the limitations of PDMS channels, which are structurally and chemically robust. We first optimize a high-resolution fabrication protocol to achieve convenient and repeatable prototyping of polymeric devices via epoxy casting using PDMS soft molds. In addition, we compare the velocity changes in PDMS microchannels by tracking fluorescent particles in various flows (~133 μL/min) to demonstrate the structural robustness of the polymeric device. Furthermore, by comparing the adsorption of fluorescent hydrophobic chemicals and the pervaporation through channel walls, we demonstrate the excellent chemical resistance of the polymeric device and its suitability for day-long experiments. The rigid polymeric device can facilitate lab-on-chip research and enable various applications, such as high-performance liquid chromatography, anaerobic bacterial culture, and polymerase chain reaction, which require chemically or physically demanding experiments.
Central Feminization of Obese Male Mice Reduces Metabolic Syndrome
Authors: Blackmore Katherine , Young Colin N.
Published: October 2022

Metabolic syndrome encompasses a spectrum of conditions that increases the risk for cardiovascular and metabolic diseases. It is widely accepted that the sex hormone estrogen plays a protective metabolic role in premenopausal women, in part through central nervous system (CNS) mechanisms. However, most work to date has focused on the loss of estrogen in females (e.g., menopause). Interestingly, transgender individuals receiving feminizing gender affirming therapy (i.e., estrogen) are relatively protected from metabolic syndrome conditions, pointing to a role for CNS estrogen in the development of metabolic syndrome in men. Here, we show that estrogen signaling in the brain protects males from metabolic syndrome and obesity related complications. First, short-term CNS specific supplementation of low-dose 17-β-estradiol in diet-induced obese male mice resulted in a significant reduction in body weight in parallel with a decrease in food intake without alterations in energy expenditure. In conjunction, central supplementation of estrogen reduced visceral adiposity, including epididymal and abdominal regions, with slighter decreases in subcutaneous inguinal and thermogenic brown adipose tissue. Furthermore, central estrogen administration reduced the liver manifestation of metabolic syndrome including hepatomegaly and hepatic steatosis. Collectively, these findings indicate that a lack of estrogen action in the brain may predispose males to metabolic syndrome pathogenesis.
Special Issue “New Insights into Pathophysiology, Diagnosis and Treatment of Tinnitus”
Authors: Cobo Pedro , Cuesta María
Published: October 2022

We are honoured to have been involved with Brain Sciences in the production of the Special Issue “New Insights into Pathophysiology; Diagnosis and Treatment of Tinnitus” aiming to address recent advances in the field of tinnitus [...]
Experimental Sleep Deprivation Results in Diminished Perceptual Stability Independently of Psychosis Proneness
Authors: Balter Leonie J. T. , Matheson Granville J. , Sundelin Tina , Sterzer Philipp , Petrovic Predrag , Axelsson John
Published: October 2022

Psychotic disorders as well as psychosis proneness in the general population have been associated with perceptual instability, suggesting weakened predictive processing. Sleep disturbances play a prominent role in psychosis and schizophrenia, but it is unclear whether perceptual stability diminishes with sleep deprivation, and whether the effects of sleep deprivation differ as a function of psychosis proneness. In the current study, we aimed to clarify this matter. In this preregistered study, 146 participants successfully completed an intermittent version of the random dot kinematogram (RDK) task and the 21-item Peters Delusion Inventory (PDI-21) to assess perceptual stability and psychosis proneness, respectively. Participants were randomized to sleep either as normal (8 to 9 h in bed) (n = 72; Mage = 24.7, SD = 6.2, 41 women) or to stay awake through the night (n = 74; Mage = 24.8, SD = 5.1, 44 women). Sleep deprivation resulted in diminished perceptual stability, as well as in decreases in perceptual stability over the course of the task. However, we did not observe any association between perceptual stability and PDI-21 scores, nor a tendency for individuals with higher PDI-21 scores to be more vulnerable to sleep-deprivation-induced decreases in perceptual stability. The present study suggests a compromised predictive processing system in the brain after sleep deprivation, but variation in psychosis trait is not related to greater vulnerability to sleep deprivation in our dataset. Further studies in risk groups and patients with psychosis are needed to evaluate whether sleep loss plays a role in the occurrence of objectively measured perceptual-related clinical symptoms.
Blast Exposure Dysregulates Nighttime Melatonin Synthesis and Signaling in the Pineal Gland: A Potential Mechanism of Blast-Induced Sleep Disruptions
Authors: Govindarajulu Manoj , Patel Mital Y. , Wilder Donna M. , Long Joseph B. , Arun Peethambaran
Published: October 2022

Blast-induced traumatic brain injury (bTBI) frequently results in sleep-wake disturbances. However, limited studies have investigated the molecular signaling mechanisms underlying these sleep disturbances, and potentially efficacious therapies are lacking. We investigated the levels of melatonin and genes involved in melatonin synthesis pathway in the pineal glands of Sprague Dawley rats exposed to single and tightly coupled repeated blasts during the night and daytime. Rats were exposed to single and tightly coupled repeated blasts using an advanced blast simulator. The plasma, cerebrospinal fluid (CSF), and pineal gland were collected at 6 h, 24 h, or 1 month postblast at two different time points: one during the day (1000 h) and one at night (2200 h). Differential expressions of genes involved in pineal melatonin synthesis were quantified using quantitative real-time polymerase chain reaction (qRT-PCR). Plasma and CSF melatonin levels were assessed using a commercial melatonin ELISA kit. The plasma and CSF melatonin levels showed statistically significant decreases at 6 h and 24 h in the blast-exposed rats euthanized in the night (in dim light), with no significant alterations noted in rats euthanized in the morning (daylight) at all three-time points. Blast-exposed rats showed statistically significant decreases in Tph1, Aanat, Asmt, and Mtnr1b mRNA levels, along with increased Tph2 mRNA, in the pineal gland samples collected at night at 6 h and 24 h. No significant changes in the mRNA levels of these genes were noted at 1 month. These findings imply that the melatonin circadian rhythm is disrupted following blast exposure, which may be a factor in the sleep disturbances that blast victims frequently experience.
The ALFF Alterations of Spontaneous Pelvic Pain in the Patients of Chronic Prostatitis/Chronic Pelvic Pain Syndrome Evaluated by fMRI
Authors: Ge Shengyang , Hu Qingfeng , Xia Guowei , Tan Yifan , Guo Yijun , Sun Chuanyu
Published: October 2022

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a challenging entity with complicated symptoms for treatment in the male crowd. Accumulating evidence revealed the dysfunction in the central system should be a critical factor for the pathogenesis and development in the CP/CPPS. Therefore, we recruited 20 patients of CP/CPPS and 20 healthy male volunteers, aged 20 to 50 years. Through resting-state functional magnetic resonance imaging (fMRI), we analyzed the mean amplitude of low-frequency fluctuations (mALFF) and the mean fractional amplitude of low-frequency fluctuations (mfALFF) to reflect the spontaneous abnormal activated regions in the brains of CP/CPPS patients. Compared to the healthy controls, the group with CP/CPPS had significantly increased mALFF values in the thalamus and augmented fALFF values in the inferior parietal lobule and cingulate gyrus. Significant positive correlations were observed in the extracted mALFF values in the midbrain periaqueductal gray matter (PAG) and the pain intensity (r = 0.2712, p = 0.0019), mALFF values in the thalamus and the scores of Hospital Anxiety and Depression Scale (HADS) anxiety subscale (r = 0.08477, p = 0.0461), and mfALFF values in the superior frontal gyrus (SFG) and the scores of the HADS anxiety subscale (r = 0.07102, p = 0.0282). Therefore, we delineated the clinical alterations in patients of CP/CPPS that might be attributed to the functional abnormality of the thalamus, inferior parietal lobule, and cingulate gyrus. Among these regions, the PAG, thalamus, and SFG may further play an important role in the pathogenesis, with their regulating effect on pain or emotion.
Esports and Visual Attention: Evaluating In-Game Advertising through Eye-Tracking during the Game Viewing Experience
Authors: Mancini Marco , Cherubino Patrizia , Cartocci Giulia , Martinez Ana , Di Flumeri Gianluca , Petruzzellis Luca , Cimini Michele , Aricò Pietro , Trettel Arianna , Babiloni Fabio
Published: October 2022

In recent years, technological advances and the introduction of social streaming platforms (e.g., Twitch) have contributed to an increase in the popularity of esports, a highly profitable industry with millions of active users. In this context, there is little evidence, if any, on how users perceive in-game advertising (IGA) and other key elements of the game viewing experience (e.g., facecam and chat) in terms of visual attention. The present eye-tracking study aimed at investigating those aspects, and introducing an eye-tracking research protocol specifically designed to accurately measure the visual attention associated with key elements of the game viewing experience. Results showed that (1) the ads available in the game view (IGAs) are capable altogether to attract 3.49% of the users’ visual attention; (2) the chat section draws 10.68% of the users’ visual attention and more than the streamer’s face, known as a powerful attentional driver; (3) the animated ad format elicits higher visual attention (1.46%) than the static format (1.12%); and (4) in some circumstances, the visual attention elicited by the ads is higher in the “Goal” scenes (0.69%) in comparison to “No-Goal” scenes (0.51%). Relevant managerial implications and future directions for the esports industry are reported and discussed.
Activating Interneurons in Local Inhibitory Circuits by High-Frequency Stimulations at the Efferent Fibers of Pyramidal Neurons in Rat Hippocampal CA1 Region
Authors: Ye Xiangyu , Feng Zhouyan , Wang Zhaoxiang , Zheng Lvpiao , Yuan Yue , Hu Yifan , Xu Yipeng
Published: October 2022

Stimulation-induced inhibition is one of the important effects of high-frequency stimulation (HFS) utilized by the therapy of deep brain stimulation (DBS) to treat certain neurological diseases such as epilepsy. In order to explore the stimulation sites to induce inhibition, this study investigated the activation effect of HFS of efferent fibers on the local inhibitory interneurons (IN). Antidromic HFS (A-HFS) of 100 Hz pulses was applied for 2 min at the efferent fibers—the alveus (i.e., the axons of pyramidal neurons) in the hippocampal CA1 region of anesthetized rats. Single unit spikes of INs in local feedback inhibitory circuits, as well as antidromically-evoked population spikes (APS) of pyramidal neurons, were recorded simultaneously in the CA1 region upstream of the stimulation site. Results showed that during the late 60 s of A-HFS, with a substantial suppression in APS amplitudes, the mean firing rate of INs was still significantly greater than the baseline level even when the A-HFS was applied with a weak pulse intensity of 0.08 ± 0.05 mA (9 rats). With a strong pulse intensity of 0.33 ± 0.08 mA (10 rats), the mean firing rate of INs was able to keep at a high level till the end of A-HFS. In addition, the mean latency of IN firing was significantly prolonged during the sustained A-HFS, indicating that alterations had been generated in the pathway to activate INs by the stimulations at efferent fibers. The results suggested that HFS at efferent fibers with various stimulation intensities can modulate the firing of local inhibitory neurons. The finding provides new clues for selecting stimulation sites to enhance inhibition in neural circuits by DBS.
Declarative Memory Impairment and Emotional Bias in Recurrent Depression with a Seasonal Pattern: The Interplay between Emotion and Cognition in Seasonal Affective Disorder
Authors: Iorio Carla , Pacitti Francesca , Rossi Alessandro , Iorio Paola , Pompili Assunta
Published: October 2022

Seasonal Affective Disorder (SAD) is a subtype of Major Depressive Disorder (MDD) with a seasonal pattern. Although it is a pathological condition limited to specific seasons of the year, during the symptomatic period, patients may experience a significant impairment of well-being and daily quality of life as a result of the depressed mood, associated with other symptoms defined as atypical of MDD. While extensive evidence of memory deficits has been found in MDD, explicit memory impairments in SAD are insufficiently studied. This study aims to investigate the cognitive processing of emotional stimuli in women with SAD, in particular the interplay between emotions and declarative memory. One hundred and twenty young women, screened from an initial number of 1125 university students, were divided into two groups, an experimental one that included 60 medically untreated women affected by “winter type SAD” and a control group of 60 non-SAD women. Different subjects were randomly submitted to two types of audio–visual stories, neutral or arousal, and then their memory performances were analyzed by means of a free-recall test and a recognition memory test. In both the free-recall test (p < 0.008) and in the recognition memory test (p < 0.002), the SAD group showed impaired memory performances. Taken together, our novel key findings suggest that SAD is characterized by impairment in declarative memory and attentional bias for emotional negative stimuli.
Glioblastoma Multiforme Tumors in Women Have a Lower Expression of Fatty Acid Elongases ELOVL2, ELOVL5, ELOVL6, and ELOVL7 than in Men
Authors: Korbecki Jan , Simińska Donata , Jeżewski Dariusz , Kojder Klaudyna , Tomasiak Patrycja , Tarnowski Maciej , Chlubek Dariusz , Baranowska-Bosiacka Irena
Published: October 2022

One line of research on the possible ways of inhibiting the growth of glioblastoma multiforme (GBM), a brain tumor with a very poor prognosis, is the analysis of its metabolism, such as fatty acid synthesis by desaturases and elongases. This study examines the expression of elongases ELOVL1, ELOVL2, ELOVL3, ELOVL4, ELOVL5, ELOVL6, and ELOVL7 in GBM tumor samples from 28 patients (16 men and 12 women), using a quantitative real-time polymerase chain reaction (qRT-PCR). To demonstrate the influence of the tumor microenvironment on the tested elongases, U-87 MG cells were cultured in nutrient-deficient conditions and with cobalt chloride (CoCl2) as a hypoxia-mimetic agent. The results showed that the expression of ELOVL1 and ELOVL7 in the GBM tumor was lower than in the peritumoral area. The expression of six of the seven studied elongases differed between the sexes. Hypoxia increased the expression of ELOVL5 and ELOVL6 and decreased the expression of ELOVL1, ELOVL3, ELOVL4, and ELOVL7 in U-87 MG cells. These results indicate that the synthesis of fatty acids, especially polyunsaturated fatty acids (PUFA), in GBM tumors may be higher in men than in women. In contrast, the synthesis of saturated fatty acids (SFA) may be higher in women than in men.
Update on Non-Pharmacological Interventions for Treatment of Post-Traumatic Headache
Authors: Lee Matthew J. , Zhou Yi , Greenwald Brian D.
Published: October 2022

Post-traumatic headache (PTH) is the most common sequelae of traumatic brain injury (TBI). Its phenotypic variability, absence of formal evidence-based guidelines for treatment and underdiagnosis have made its management a challenge for clinicians. As a result, treatment of PTH has been mostly empiric. Although analgesics are the most popular drug of choice for PTH, they can present with several adverse effects and fail to address other psychosocial comorbidities associated with TBI. Non-pharmacological interventions thereby offer an intriguing alternative that can provide patients with PTH sustainable and effective care. This review article aims to: (1) provide an update on and describe different non-pharmacological interventions present in the recent literature; (2) provide clinical guidance to providers struggling with the management of patients with PTH; (3) emphasize the need for more high-quality trials examining the effectiveness of non-pharmacological treatments in patients with PTH. This review discusses 21 unique non-pharmacological treatments used for the management of PTH. Current knowledge of non-pharmacological interventions for the treatment of PTH is based on smaller scale studies, highlighting the need for larger randomized controlled trials to help establish formal evidence-based guidelines.
The Effect of Coil Orientation on the Stimulation of the Pre–Supplementary Motor Area: A Combined TMS and EEG Study
Authors: Casula Elias P. , Leodori Giorgio , Ibáñez Jaime , Benussi Alberto , Rawji Vishal , Tremblay Sara , Latorre Anna , Rothwell John C. , Rocchi Lorenzo
Published: October 2022

Studies using transcranial magnetic stimulation (TMS) have demonstrated the importance of direction and intensity of the applied current when the primary motor cortex (M1) is targeted. By varying these, it is possible to stimulate different subsets of neural elements, as demonstrated by modulation of motor evoked potentials (MEPs) and motor behaviour. The latter involves premotor areas as well, and among them, the presupplementary motor area (pre–SMA) has recently received significant attention in the study of motor inhibition. It is possible that, similar to M1, different neuronal populations can be activated by varying the direction and intensity of TMS; however, the absence of a direct electrophysiological outcome has limited this investigation. The problem can be solved by quantifying direct cortical responses by means of combined TMS and electroencephalography (TMS–EEG). We investigated the effect of variable coil orientations (0°, 90°, 180° and 270°) and stimulation intensities (100%, 120% and 140% of resting motor threshold) on local mean field potential (LMFP), transcranial evoked potential (TEP) peaks and TMS–related spectral perturbation (TRSP) from pre–SMA stimulation. As a result, early and late LMFP and peaks were larger, with the coil handle pointing posteriorly (0°) and laterally (90°). This was true also for TRSP in the β–γ range, but, surprisingly, θ–α TRSP was larger with the coil pointing at 180°. A 90° orientation activated the right M1, as shown by MEPs elicitation, thus limiting the spatial specificity of the stimulation. These results suggest that coil orientation and stimulation intensity are critical when stimulating the pre–SMA.