bluuebunny/crossref_metadata_2025 huggingface dataset:
Association Analysis between Genetic Variants of elovl5a and elovl5b and Poly-Unsaturated Fatty Acids in Common Carp (Cyprinus carpio)
Authors: Zhang Yan , Li Qing-Song , Ye Yu-Qing , Wang Qi , Sun Xiao-Qing , Zhao Ran , Li Jiong-Tang
Published: March 2022

The allo-tetraploid common carp, one widely cultured food fish, is able to produce poly-unsaturated fatty acids (PUFAs). The genetic markers on the PUFA contents for breeding was limited. The polymorphisms in elovl5a and elovl5b, the rate-limiting enzymes in the PUFA biosynthesis, have not been investigated yet. Herein, we identified one coding SNP (cSNP) in elovl5a associated with the content of one PUFA and two cSNPs in elovl5b with the contents of eight PUFAs. The heterozygous genotypes in these three loci were associated with higher contents than the homozygotes. Together with previously identified two associated cSNPs in fads2b, we found the joint effect of these four cSNPs in fads2b and elovl5b on the PUFA contents with the increased explained percentages of PUFA contents. The genotype combinations of more heterozygotes were associated with higher PUFA contents than the other combinations. Using ten genomic selection programs with all cSNPs in fads2b and elovl5b, we obtained the high and positive correlations between the phenotypes and the estimated breeding values of eight PUFAs. These results suggested that elovl5b might be the major gene corresponding to common carp PUFA contents compared with elovl5a. The cSNP combinations in fads2b and elovl5b and the optimal genomic selection program will be used in the future selection breeding to improve the PUFA contents of common carp.
A Comprehensive Survey on the Detection, Classification, and Challenges of Neurological Disorders
Authors: Lima Aklima Akter , Mridha M. Firoz , Das Sujoy Chandra , Kabir Muhammad Mohsin , Islam Md. Rashedul , Watanobe Yutaka
Published: March 2022

Neurological disorders (NDs) are becoming more common, posing a concern to pregnant women, parents, healthy infants, and children. Neurological disorders arise in a wide variety of forms, each with its own set of origins, complications, and results. In recent years, the intricacy of brain functionalities has received a better understanding due to neuroimaging modalities, such as magnetic resonance imaging (MRI), magnetoencephalography (MEG), and positron emission tomography (PET), etc. With high-performance computational tools and various machine learning (ML) and deep learning (DL) methods, these modalities have discovered exciting possibilities for identifying and diagnosing neurological disorders. This study follows a computer-aided diagnosis methodology, leading to an overview of pre-processing and feature extraction techniques. The performance of existing ML and DL approaches for detecting NDs is critically reviewed and compared in this article. A comprehensive portion of this study also shows various modalities and disease-specified datasets that detect and records images, signals, and speeches, etc. Limited related works are also summarized on NDs, as this domain has significantly fewer works focused on disease and detection criteria. Some of the standard evaluation metrics are also presented in this study for better result analysis and comparison. This research has also been outlined in a consistent workflow. At the conclusion, a mandatory discussion section has been included to elaborate on open research challenges and directions for future work in this emerging field.
Effects of Chronic High-Frequency rTMS Protocol on Respiratory Neuroplasticity Following C2 Spinal Cord Hemisection in Rats
Authors: Michel-Flutot Pauline , Jesus Isley , Vanhee Valentin , Bourcier Camille H. , Emam Laila , Ouguerroudj Abderrahim , Lee Kun-Ze , Zholudeva Lyandysha V. , Lane Michael A. , Mansart Arnaud , Bonay Marcel , Vinit Stéphane
Published: March 2022

High spinal cord injuries (SCIs) lead to permanent diaphragmatic paralysis. The search for therapeutics to induce functional motor recovery is essential. One promising noninvasive therapeutic tool that could harness plasticity in a spared descending respiratory circuit is repetitive transcranial magnetic stimulation (rTMS). Here, we tested the effect of chronic high-frequency (10 Hz) rTMS above the cortical areas in C2 hemisected rats when applied for 7 days, 1 month, or 2 months. An increase in intact hemidiaphragm electromyogram (EMG) activity and excitability (diaphragm motor evoked potentials) was observed after 1 month of rTMS application. Interestingly, despite no real functional effects of rTMS treatment on the injured hemidiaphragm activity during eupnea, 2 months of rTMS treatment strengthened the existing crossed phrenic pathways, allowing the injured hemidiaphragm to increase its activity during the respiratory challenge (i.e., asphyxia). This effect could be explained by a strengthening of respiratory descending fibers in the ventrolateral funiculi (an increase in GAP-43 positive fibers), sustained by a reduction in inflammation in the C1–C3 spinal cord (reduction in CD68 and Iba1 labeling), and acceleration of intracellular plasticity processes in phrenic motoneurons after chronic rTMS treatment. These results suggest that chronic high-frequency rTMS can ameliorate respiratory dysfunction and elicit neuronal plasticity with a reduction in deleterious post-traumatic inflammatory processes in the cervical spinal cord post-SCI. Thus, this therapeutic tool could be adopted and/or combined with other therapeutic interventions in order to further enhance beneficial outcomes.
Bio–Cultural Diversities: Why They Matter Now
Authors: Pieroni Andrea
Published: March 2022

The time at which we write these lines is a dramatic time of war [...]
An Alternative Class of Targets for microRNAs Containing CG Dinucleotide
Authors: Dai Wennan , Su Xin , Zhang Bin , Wu Kejing , Zhao Pengshan , Yan Zheng
Published: March 2022

MicroRNAs (miRNAs) are endogenous ~23 nt RNAs which regulate message RNA (mRNA) targets mainly through perfect pairing with their seed region (positions 2–7). Several instances of UTR sequence with an additional nucleotide that might form a bulge within the pairing region, can also be recognized by miRNA as their target (bugle-target). But the prevalence of such imperfect base pairings in human and their roles in the evolution are incompletely understood. We found that human miRNAs with the CG dinucleotides (CG dimer) in their seed region have a significant low mutation rate than their putative binding sites in mRNA targets. Interspecific comparation shows that these miRNAs had very few conservative targets with the perfect seed-pairing, while potentially having a subclass of bulge-targets. Compared with the canonical target (perfect seed-pairing), these bulge-targets had a lower negative correlation with the miRNA expression, and either were down-regulated in the miRNA overexpression experiment or up-regulated in the miRNA knock-down experiment. Our results show that the bulge-targets are widespread in the miRNAs with CG dinucleotide within their seed regions, which could in part explain the rare conserved targets of these miRNAs based on seed rule. Incorporating these bulge-targets, together with conservation information, could more accurately predict the entire targets of these miRNAs.
Is Autophagy Always a Barrier to Cisplatin Therapy?
Authors: Xu Jingwen , Gewirtz David A.
Published: March 2022

Cisplatin has long been a first-line chemotherapeutic agent in the treatment of cancer, largely for solid tumors. During the course of the past two decades, autophagy has been identified in response to cancer treatments and almost uniformly detected in studies involving cisplatin. There has been increasing recognition of autophagy as a critical factor affecting tumor cell death and tumor chemoresistance. In this review and commentary, we introduce four mechanisms of resistance to cisplatin followed by a discussion of the factors that affect the role of autophagy in cisplatin-sensitive and resistant cells and explore the two-sided outcomes that occur when autophagy inhibitors are combined with cisplatin. Our goal is to analyze the potential for the combinatorial use of cisplatin and autophagy inhibitors in the clinic.
Identification of Regions Involved in the Physical Interaction between Melanocortin Receptor Accessory Protein 2 and Prokineticin Receptor 2
Authors: Fullone Maria Rosaria , Maftei Daniela , Vincenzi Martina , Lattanzi Roberta , Miele Rossella
Published: March 2022

Melanocortin Receptor Accessory Protein 2 (MRAP2) modulates the trafficking and signal transduction of several G-protein-coupled receptors (GPCRs) involved in the control of energy homeostasis, such as Prokineticin receptors (PKRs). They bind the endogenous ligand prokineticin 2 (PK2), a novel adipokine that has an anorexic effect and modulates thermoregulation and energy homeostasis. In the present work, we used biochemical techniques to analyze the mechanism of interaction of MRAP2 with PKR2 and we identified the specific amino acid regions involved in the complex formation. Our results indicate that MRAP2 likely binds to the N-terminal region of PKR2, preventing glycosylation and consequently the correct receptor localization. We also identified a C-terminal region of MRAP2 that is critical for the interaction with PKR2. Consequently, we analyzed the role of the prokineticin transduction system in the regulation of MRAP2 expression in tissues involved in the control of food intake: at the central level, in hypothalamic explants, and at the peripheral level, in adipocytes. We demonstrated the modulation of MRAP2 expression by the prokineticin transduction system.
Defining the Protease and Protease Inhibitor (P/PI) Proteomes of Healthy and Diseased Human Skin by Modified Systematic Review
Authors: Stewart-McGuinness Callum , Platt Christopher I. , Ozols Matiss , Goh Brian , Griffiths Tamara W. , Sherratt Michael J.
Published: March 2022

Proteases and protease inhibitors (P/PIs) are involved in many biological processes in human skin, yet often only specific families or related groups of P/PIs are investigated. Proteomics approaches, such as mass spectrometry, can define proteome signatures (including P/PIs) in tissues; however, they struggle to detect low-abundance proteins. To overcome these issues, we aimed to produce a comprehensive proteome of all P/PIs present in normal and diseased human skin, in vivo, by carrying out a modified systematic review using a list of P/PIs from MEROPS and combining this with key search terms in Web of Science. Resulting articles were manually reviewed against inclusion/exclusion criteria and a dataset constructed. This study identified 111 proteases and 77 protease inhibitors in human skin, comprising the serine, metallo-, cysteine and aspartic acid catalytic families of proteases. P/PIs showing no evidence of catalytic activity or protease inhibition, were designated non-peptidase homologs (NPH), and no reported protease inhibitory activity (NRPIA), respectively. MMP9 and TIMP1 were the most frequently published P/PIs and were reported in normal skin and most skin disease groups. Normal skin and diseased skin showed significant overlap with respect to P/PI profile; however, MMP23 was identified in several skin disease groups, but was absent in normal skin. The catalytic profile of P/PIs in wounds, scars and solar elastosis was distinct from normal skin, suggesting that a different group of P/PIs is responsible for disease progression. In conclusion, this study uses a novel approach to provide a comprehensive inventory of P/PIs in normal and diseased human skin reported in our database. The database may be used to determine either which P/PIs are present in specific diseases or which diseases individual P/PIs may influence.
Comparing Ionic Profile of Gingival Crevicular Fluid and Saliva as Distinctive Signature of Severe Periodontitis
Authors: Romano Federica , Iaderosa Giovanni , Corana Matteo , Perotto Stefano , Baima Giacomo , Di Scipio Federica , Abbadessa Giuliana , Mariani Giulia Maria , Aimetti Mario , Berta Giovanni Nicolao
Published: March 2022

Although increasing evidence is emerging on the contribution of chemical elements in periodontal health, no studies have concomitantly evaluated the ionic profile in gingival crevicular fluid (GCF) and saliva in relation to the underlying periodontal status. Our hypothesis is that these biofluids have distinctive ionic content. Therefore, the aim of this cross-sectional study was to analyze the elemental composition of GCF and saliva in order to explore which biological matrix and which combination of elements could discriminate between periodontitis and periodontal health. Twelve ions were analyzed in GCF and unstimulated saliva from 54 subjects (18 periodontally healthy, 18 untreated severe periodontitis and 18 treated severe periodontitis) using inductively coupled plasma–mass spectrometry (ICP-MS) and inductively coupled plasma–optical emission spectroscopy (ICP-OES). These analytical techniques were able to determine levels of sodium (Na), potassium (K), calcium (Ca) and magnesium (Mg), while the other elements were below the detection threshold. Na and K ions were detected at elevated concentration in untreated periodontitis compared with treated periodontitis and healthy periodontium. Ca was increased in untreated periodontitis, but the difference was not significant. In saliva, only Na was significantly associated with periodontitis. The combination of Na and K in GCF enabled the correct assignment of a subject to the periodontitis or healthy group. Based on these preliminary results, GCF demonstrated higher clustering potential than saliva.
Definition of Castrate Resistant Prostate Cancer: New Insights
Authors: Morote Juan , Aguilar Adriana , Planas Jacques , Trilla Enrique
Published: March 2022

The term castrate resistant prostate cancer (CRPC) was initially proposed by the Prostate Cancer Working Group 2 in 2008 to define the state of clinical and/or biochemical progression of prostate cancer (PCa) in an environment with very low serum testosterone concentration. Clinical progression is based on the radiological imaging proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) adapted to PCa. Biochemical progression is defined as an over 25% increase in serum prostate-specific antigen within two consecutive measurements separated by at least one week, and an absolute value above 2.0 ng/mL. Finally, the castrate environment is usually defined as a serum testosterone concentration maintained below 50 ng/dL or 1.7 nmol/dL. This definition does not incorporate the new and more accurate imaging modalities to assess clinical progression and the capability of the new biochemical measurements to assess the true castration environment. Ga-68-PSMA-11 PET CT/MRI and whole-body MRI are the new imaging modalities that should replace the classic thoracic CT scan, abdomino-pelvic CT scan, and technetium 99-m bone scintigraphy. In addition, Ga-68-PSMA-11 PET is the current basis for the new therapies targeting metastatic sites. Moreover, the current methods for measuring the very low serum testosterone concentrations in clinical laboratories are the widespread chemiluminescent assays, which are inappropriate, while LC-MSMS is the only method recommended to assess the castrate environment. In addition, recent research shows that serum luteinising hormone concentration associates better than serum testosterone with the castration environment, even when it is measured with LC-MSMS. In summary, the current definition of CRPC seems outdated. An extensive update to diagnose true CRPC is also needed to differentiate CRPC men with M0 (non-metastatic) from those with M1 (metastatic) CRPC. WC: 277.
Proteomic Profiling and T Cell Receptor Usage of Abacavir Susceptible Subjects
Authors: Gall Eline , Stieglitz Florian , Pich Andreas , Behrens Georg Martin Norbert , Kuhn Joachim , Blasczyk Rainer , Haukamp Funmilola Josephine , Bade-Döding Christina
Published: March 2022

Type B adverse drug reactions (ADRs) represent a significant threat as their occurrence arises unpredictable and despite proper application of the drug. The severe immune reaction Abacavir Hypersensitivity Syndrome (AHS) that arises in HIV+ patients treated with the antiretroviral drug Abacavir (ABC) strongly correlates to the presence of the human leukocyte antigen (HLA) genotype HLA-B*57:01 and discriminates HLA-B*57:01+ HIV+ patients from ABC treatment. However, not all HLA-B*57:01+ HIV+ patients are affected by AHS, implying the involvement of further patient-specific factors in the development of AHS. The establishment of a reliable assay to classify HLA-B*57:01 carriers as ABC sensitive or ABC tolerant allowed to investigate the T cell receptor (TCR) Vβ chain repertoire of effector cells and revealed Vβ6 and Vβ24 as potential public TCRs in ABC sensitive HLA-B*57:01 carriers. Furthermore, distinct effects of ABC on the cellular proteome of ABC sensitive and tolerant volunteers were observed and suggest enhanced activation and maturation of dentritic cells (DC) in ABC sensitive volunteers. Analysis of ABC-naïve cellular proteomes identified the T cell immune regulator 1 (TCIRG1) as a potential prognostic biomarker for ABC susceptibility and the involvement of significantly upregulated proteins, particularly in peptide processing, antigen presentation, interferon (IFN), and cytokine regulation.
Elevated Pre-Treatment Serum MMP-7 Levels Are Associated with the Presence of Metastasis and Poor Survival in Upper Tract Urothelial Carcinoma
Authors: Kovács Petra Terézia , Mayer Tamás , Csizmarik Anita , Váradi Melinda , Oláh Csilla , Széles Ádám , Tschirdewahn Stephan , Krafft Ulrich , Hadaschik Boris , Nyirády Péter , Riesz Péter , Szarvas Tibor
Published: March 2022

Upper tract urothelial carcinoma (UTUC) is a rare cancer with a barely predictable clinical behaviour. Serum MMP-7 is a validated prognostic marker in urothelial bladder cancer, a tumour entity with large clinical, histological, and molecular similarity to UTUC. The serum MMP-7 levels have not yet been investigated in UTUC. In the present study, we determined MMP-7 concentrations in an overall number of 103 serum samples from 57 UTUC patients who underwent surgical or systemic (platinum or immune checkpoint inhibitor) therapy by using the ELISA method. In addition to pre-treatment samples, the serum samples collected at predefined time points after or during therapy were also investigated. Serum MMP-7 concentrations were correlated with clinicopathological and follow-up data. Our results revealed significantly, two-fold elevated pre-treatment serum MMP-7 levels in metastatic cases of UTUC in both the radical surgery- and the chemotherapy-treated cohorts (p = 0.045 and p = 0.040, respectively). In addition, high serum MMP-7 levels significantly decreased after radical surgery, and high pre-treatment MMP-7 concentrations were associated with shorter survival both in the surgery- and chemotherapy-treated cohorts (p = 0.029 and p = 0.001, respectively). Our results revealed pre-treatment serum MMP-7 as a prognostic marker for UTUC, which may help to improve preoperative risk-stratification and thereby improve therapeutic decision-making.
The Importance of Lipid Conjugation on Anti-Fusion Peptides against Nipah Virus
Authors: Marques Marta C. , Lousa Diana , Silva Patrícia M. , Faustino André F. , Soares Cláudio M. , Santos Nuno C.
Published: March 2022

Nipah virus (NiV) is a recently emerging zoonotic virus that belongs to the Paramyxoviridae family and the Henipavirus genus. It causes a range of conditions, from asymptomatic infection to acute respiratory illness and fatal encephalitis. The high mortality rate of 40 to 90% ranks these viruses among the deadliest viruses known to infect humans. Currently, there is no antiviral drug available for Nipah virus disease and treatment is only supportive. Thus, there is an urgent demand for efficient antiviral therapies. NiV F protein, which catalyzes fusion between the viral and host membranes, is a potential target for antiviral drugs, as it is a key protein in the initial stages of infection. Fusion inhibitor peptides derived from the HRC-domain of the F protein are known to bind to their complementary domain in the protein’s transient intermediate state, preventing the formation of a six-helix bundle (6HB) thought to be responsible for driving the fusion of the viral and cell membranes. Here, we evaluated the biophysical and structural properties of four different C-terminal lipid-tagged peptides. Different compositions of the lipid tags were tested to search for properties that might promote efficacy and broad-spectrum activity. Fluorescence spectroscopy was used to study the interaction of the peptides with biomembrane model systems and human blood cells. In order to understand the structural properties of the peptides, circular dichroism measurements and molecular dynamics simulations were performed. Our results indicate a peptide preference for cholesterol-enriched membranes and a lipid conjugation-driven stabilization of the peptide α-helical secondary structure. This work may contribute for the development of highly effective viral fusion against NiV inhibitors.
Klotho an Autophagy Stimulator as a Potential Therapeutic Target for Alzheimer’s Disease: A Review
Authors: Fung Tsz , Iyaswamy Ashok , Sreenivasmurthy Sravan , Krishnamoorthi Senthilkumar , Guan Xin-Jie , Zhu Zhou , Su Cheng-Fu , Liu Jia , Kan Yuxuan , Zhang Yuan , Wong Hoi , Li Min
Published: March 2022

Alzheimer’s disease (AD) is an age-associated neurodegenerative disease; it is the most common cause of senile dementia. Klotho, a single-pass transmembrane protein primarily generated in the brain and kidney, is active in a variety of metabolic pathways involved in controlling neurodegeneration and ageing. Recently, many studies have found that the upregulation of Klotho can improve pathological cognitive deficits in an AD mice model and have demonstrated that Klotho plays a role in the induction of autophagy, a major contributing factor for AD. Despite the close association between Klotho and neurodegenerative diseases, such as AD, the underlying mechanism by which Klotho contributes to AD remains poorly understood. In this paper, we will introduce the expression, location and structure of Klotho and its biological functions. Specifically, this review is devoted to the correlation of Klotho protein and the AD phenotype, such as the effect of Klotho in upregulating the amyloid-beta clearance and in inducing autophagy for the clearance of toxic proteins, by regulating the autophagy lysosomal pathway (ALP). In summary, the results of multiple studies point out that targeting Klotho would be a potential therapeutic strategy in AD treatment.
Biofunctionalization of Xenogeneic Collagen Membranes with Autologous Platelet Concentrate—Influence on Rehydration Protocol and Angiogenesis
Authors: Blatt Sebastian , Schröger Saskia-Vanessa , Pabst Andreas , Kämmerer Peer W. , Sagheb Keyvan , Al-Nawas Bilal
Published: March 2022

Background: The aim of this study was to analyze possible interactions of different xenogeneic collagen membranes (CM) and platelet-rich fibrin (PRF). PH values were evaluated in the CM rehydration process with PRF, and their influence on angiogenesis was analyzed in vivo. Materials and Methods: Porcine (Bio-Gide®, Geistlich)- and bovine-derived collagen membranes (Symbios®, Dentsply Sirona) were biofunctionalized with PRF by plotting process. PRF in comparison to blood, saline and a puffer pH7 solution was analysed for pH-value changes in CM rehydration process in vitro. The yolk sac membrane (YSM) model was used to investigate pro-angiogenic effects of the combination of PRF and the respective CM in comparison to native pendant by vessel in-growth and branching points after 24, 48 and 72 h evaluated light-microscopically and by immunohistochemical staining (CD105, αSMA) in vivo. Results: Significantly higher pH values were found at all points in time in PRF alone and its combined variants with Bio-Gide® and Symbios® compared with pure native saline solution and pH 7 solution, as well as saline with Symbios® and Bio-Gide® (each p < 0.01). In the YSM, vessel number and branching points showed no significant differences at 24 and 48 h between all groups (each p > 0.05). For PRF alone, a significantly increased vessel number and branching points between 24 and 48 h (each p < 0.05) and between 24 and 72 h (each p < 0.05) was shown. After 72 h, CM in combination with PRF induced a statistically significant addition to vessels and branching points in comparison with native YSM (p < 0.01) but not vs. its native pendants (p > 0.05). Summary: PRF represents a promising alternative for CM rehydration to enhance CM vascularization.
ER-phagy in the Occurrence and Development of Cancer
Authors: Zhou Huimin , Wang Kexin , Wang Mengyan , Zhao Wenxia , Zhang Conghui , Cai Meilian , Qiu Yuhan , Zhang Tianshu , Shao Rongguang , Zhao Wuli
Published: March 2022

As an organelle, the endoplasmic reticulum (ER) is closely related to protein synthesis and modification. When physiological or pathological stimuli induce disorders of ER function, misfolded proteins trigger ER-phagy, which is beneficial for restoring cell homeostasis or promoting cell apoptosis. As a double-edged sword, ER-phagy actively participates in various stages of development and progression in tumor cells, regulating tumorigenesis and maintaining tumor cell homeostasis. Through the unfolded protein response (UPR), the B cell lymphoma 2 (BCL-2) protein family, the Caspase signaling pathway, and others, ER-phagy plays an initiating role in tumor occurrence, migration, stemness, and proliferation. At the same time, many vital proteins strongly associated with ER-phagy, such as family with sequence similarity 134 member B (FAM134B), translocation protein SEC62 (SEC62), and C/EBP-homologous protein (CHOP), can produce a marked effect in many complex environments, which ultimately lead to entirely different tumor fates. Our article comprehensively focused on introducing the relationship and interaction between ER-phagy and cancers, as well as their molecular mechanism and regulatory pathways. Via these analyses, we tried to clarify the possibility of ER-phagy as a potential target for cancer therapy and provide ideas for further research.
Natural Compounds Targeting Cancer-Associated Fibroblasts against Digestive System Tumor Progression: Therapeutic Insights
Authors: Chiu Kuan-Jung , Chiou Hsin-Ying Clair , Huang Chi-Han , Lu Pin-Chun , Kuo Hui-Ru , Wang Jiunn-Wei , Lin Ming-Hong
Published: March 2022

Cancer-associated fibroblasts (CAFs) are critical for cancer occurrence and progression in the tumor microenvironment (TME), due to their versatile roles in extracellular matrix remodeling, tumor–stroma crosstalk, immunomodulation, and angiogenesis. CAFs are the most abundant stromal component in the TME and undergo epigenetic modification and abnormal signaling cascade activation, such as transforming growth factor-β (TGF-β) and Wnt pathways that maintain the distinct phenotype of CAFs, which differs from normal fibroblasts. CAFs have been considered therapeutic targets due to their putative oncogenic functions. Current digestive system cancer treatment strategies often result in lower survival outcomes and fail to prevent cancer progression; therefore, comprehensive characterization of the tumor-promoting and -restraining CAF activities might facilitate the design of new therapeutic approaches. In this review, we summarize the enormous literature on natural compounds that mediate the crosstalk of CAFs with digestive system cancer cells, discuss how the biology and the multifaceted functions of CAFs contribute to cancer progression, and finally, pave the way for CAF-related antitumor therapies.
Involvement of Il-33 in the Pathogenesis and Prognosis of Major Respiratory Viral Infections: Future Perspectives for Personalized Therapy
Authors: Murdaca Giuseppe , Paladin Francesca , Tonacci Alessandro , Borro Matteo , Greco Monica , Gerosa Alessandra , Isola Stefania , Allegra Alessandro , Gangemi Sebastiano
Published: March 2022

Interleukin (IL)-33 is a key cytokine involved in type-2 immunity and allergic airway disease. At the level of lung epithelial cells, where it is clearly expressed, IL-33 plays an important role in both innate and adaptive immune responses in mucosal organs. It has been widely demonstrated that in the course of respiratory virus infections, the release of IL-33 increases, with consequent pro-inflammatory effects and consequent exacerbation of the clinical symptoms of chronic respiratory diseases. In our work, we analyzed the pathogenetic and prognostic involvement of IL-33 during the main respiratory viral infections, with particular interest in the recent SARS-CoV-2virus pandemic and the aim of determining a possible connection point on which to act with a targeted therapy that is able to improve the clinical outcome of patients.
Activation of Voltage-Gated Na+ Current by GV-58, a Known Activator of CaV Channels
Authors: Cho Hsin-Yen , Chen Pei-Chun , Chuang Tzu-Hsien , Yu Meng-Cheng , Wu Sheng-Nan
Published: March 2022

GV-58 ((2R)-2-[(6-{[(5-methylthiophen-2-yl)methyl]amino}-9-propyl-9H-purin-2-yl)amino]butan-1-ol) is recognized to be an activator of N- and P/Q-type Ca2+ currents. However, its modulatory actions on other types of ionic currents in electrically excitable cells remain largely unanswered. This study was undertaken to explore the possible modifications caused by GV-58 in ionic currents (e.g., voltage-gated Na+ current [INa], A-type K+ current [IK(A)], and erg-mediated K+ current [IK(erg)]) identified from pituitary GH3 lactotrophs. GH3 cell exposure to GV-58 enhanced the transient and late components of INa with varying potencies; consequently, the EC50 values of GV-58 required for its differential increase in peak and late INa in GH3 cells were estimated to be 8.9 and 2.6 μM, respectively. The INa in response to brief depolarizing pulse was respectively stimulated or suppressed by GV-58 or tetrodotoxin, but it failed to be altered by ω-conotoxin MVIID. Cell exposure to this compound increased the recovery of INa inactivation evoked by two-pulse protocol based on a geometrics progression; however, in its presence, there was a slowing in the inactivation rate of current decay evoked by a train of depolarizing pulses. The existence of GV-58 also resulted in an increase in the amplitude of ramp-induced resurgent and window INa. The presence of this compound inhibited IK(A) magnitude, accompanied by a shortening in inactivation time course of the current; however, it mildly decreased IK(erg). Under current-clamp conditions, GV-58 increased the frequency of spontaneous action potentials in GH3 cells. Moreover, in NSC-34 motor neuron-like cells, the presence of GV-58 not only raised INa amplitude but also reduced current inactivation. Taken together, the overall work provides a noticeable yet unidentified finding which implies that, in addition to its agonistic effect on Ca2+ currents, GV-58 may concertedly modify the amplitude and gating kinetics of INa in electrically excitable cells, hence modifiying functional activities in these cells.
Circular RNAs as Potential Biomarkers in Breast Cancer
Authors: De Palma Fatima Domenica Elisa , Salvatore Francesco , Pol Jonathan G. , Kroemer Guido , Maiuri Maria Chiara
Published: March 2022

Due to the high heterogeneity and initially asymptomatic nature of breast cancer (BC), the management of this disease depends on imaging together with immunohistochemical and molecular evaluations. These tests allow early detection of BC and patient stratification as they guide clinicians in prognostication and treatment decision-making. Circular RNAs (circRNAs) represent a class of newly identified long non-coding RNAs. These molecules have been described as key regulators of breast carcinogenesis and progression. Moreover, circRNAs play a role in drug resistance and are associated with clinicopathological features in BC. Accumulating evidence reveals a clinical interest in deregulated circRNAs as diagnostic, prognostic and predictive biomarkers. Furthermore, due to their covalently closed structure, circRNAs are highly stable and easily detectable in body fluids, making them ideal candidates for use as non-invasive biomarkers. Herein, we provide an overview of the biogenesis and pleiotropic functions of circRNAs, and report on their clinical relevance in BC.
Application of a Novel Biosensor for Salivary Conductivity in Detecting Chronic Kidney Disease
Authors: Lin Chen-Wei , Tsai Yuan-Hsiung , Lu Yen-Pei , Yang Jen-Tsung , Chen Mei-Yen , Huang Tung-Jung , Weng Rui-Cian , Tung Chun-Wu
Published: March 2022

The prevalence of chronic kidney disease (CKD) is increasing, and it brings an enormous healthcare burden. The traditional measurement of kidney function needs invasive blood tests, which hinders the early detection and causes low awareness of CKD. We recently designed a device with miniaturized coplanar biosensing probes for measuring salivary conductivity at an extremely low volume (50 μL). Our preliminary data discovered that the salivary conductivity was significantly higher in the CKD patients. This cross-sectional study aims to validate the relationship between salivary conductivity and kidney function, represented by the estimated glomerular filtration rate (eGFR). We enrolled 214 adult participants with a mean age of 63.96 ± 13.53 years, of whom 33.2% were male. The prevalence rate of CKD, defined as eGFR < 60 mL/min/1.73 m2, is 11.2% in our study. By multivariate linear regression analyses, we found that salivary conductivity was positively related to age and fasting glucose but negatively associated with eGFR. We further divided subjects into low, medium, and high groups according to the tertials of salivary conductivity levels. There was a significant trend for an increment of CKD patients from low to high salivary conductivity groups (4.2% vs. 12.5% vs. 16.9%, p for trend: 0.016). The receiver operating characteristic (ROC) curves disclosed an excellent performance by using salivary conductivity combined with age, gender, and body weight to diagnose CKD (AUC equal to 0.8). The adjusted odds ratio of CKD is 2.66 (95% CI, 1.10–6.46) in subjects with high salivary conductivity levels. Overall, salivary conductivity can serve as a good surrogate marker of kidney function; this real-time, non-invasive, and easy-to-use portable biosensing device may be a reliable tool for screening CKD.
Microfluidics-Based Biosensing Platforms: Emerging Frontiers in Point-of-Care Testing SARS-CoV-2 and Seroprevalence
Authors: Flores-Contreras Elda A. , González-González Reyna Berenice , Rodríguez-Sánchez Iram P. , Yee-de León Juan F. , Iqbal Hafiz M. N. , González-González Everardo
Published: March 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the ongoing COVID-19 (coronavirus disease-2019) outbreak and has unprecedentedly impacted the public health and economic sector. The pandemic has forced researchers to focus on the accurate and early detection of SARS-CoV-2, developing novel diagnostic tests. Among these, microfluidic-based tests stand out for their multiple benefits, such as their portability, low cost, and minimal reagents used. This review discusses the different microfluidic platforms applied in detecting SARS-CoV-2 and seroprevalence, classified into three sections according to the molecules to be detected, i.e., (1) nucleic acid, (2) antigens, and (3) anti-SARS-CoV-2 antibodies. Moreover, commercially available alternatives based on microfluidic platforms are described. Timely and accurate results allow healthcare professionals to perform efficient treatments and make appropriate decisions for infection control; therefore, novel developments that integrate microfluidic technology may provide solutions in the form of massive diagnostics to control the spread of infectious diseases.
Microfluidic-Assisted Fabrication of Dual-Coated pH-Sensitive Mesoporous Silica Nanoparticles for Protein Delivery
Authors: Küçüktürkmen Berrin , Inam Wali , Howaili Fadak , Gouda Mariam , Prabhakar Neeraj , Zhang Hongbo , Rosenholm Jessica M.
Published: March 2022

Microfluidics has become a popular method for constructing nanosystems in recent years, but it can also be used to coat other materials with polymeric layers. The polymeric coating may serve as a diffusion barrier against hydrophilic compounds, a responsive layer for controlled release, or a functional layer introduced to a nanocomposite for achieving the desired surface chemistry. In this study, mesoporous silica nanoparticles (MSNs) with enlarged pores were synthesized to achieve high protein loading combined with high protein retention within the MSN system with the aid of a microfluidic coating. Thus, MSNs were first coated with a cationic polyelectrolyte, poly (diallyldimethylammonium chloride) (PDDMA), and to potentially further control the protein release, a second coating of a pH-sensitive polymer (spermine-modified acetylated dextran, SpAcDEX) was deposited by a designed microfluidic device. The protective PDDMA layer was first formed under aqueous conditions, whereby the bioactivity of the protein could be maintained. The second coating polymer, SpAcDEX, was preferred to provide pH-sensitive protein release in the intracellular environment. The optimized formulation was effectively taken up by the cells along with the loaded protein cargo. This proof-of-concept study thus demonstrated that the use of microfluidic technologies for the design of protein delivery systems has great potential in terms of creating multicomponent systems and preserving protein stability.
High-Sensitive Detection and Quantitative Analysis of Thyroid-Stimulating Hormone Using Gold-Nanoshell-Based Lateral Flow Immunoassay Device
Authors: Bikkarolla Santosh Kumar , McNamee Sara E. , Vance Paul , McLaughlin James
Published: March 2022

Au nanoparticles (AuNPs) have been used as signal reporters in colorimetric lateral flow immunoassays (LFAs) for decades. However, it remains a major challenge to significantly improve the detection sensitivity of traditional LFAs due to the low brightness of AuNPs. As an alternative approach, we overcome this problem by utilizing 150 nm gold nanoshells (AuNSs) that were engineered by coating low-density silica nanoparticles with a thin layer of gold. AuNSs are dark green, have 14 times larger surface area, and are approximately 35 times brighter compared to AuNPs. In this study, we used detection of thyroid-stimulating hormone (TSH) in a proof-of-concept assay. The limit of detection (LOD) with AuNS-based LFA was 0.16 µIU/mL, which is 26 times more sensitive than the conventional colorimetric LFA that utilizes AuNP as a label. The dynamic range of the calibration curve was 0.16–9.5 µIU/mL, making it possible to diagnose both hyperthyroidism (<0.5 µIU/mL) and hypothyroidism (>5 µIU/mL) using AuNS-based LFA. Thus, the developed device has a strong potential for early screening and diagnosis of diseases related to the thyroid hormone.
High Performance Integration Pipeline for Viral and Epitope Sequences
Authors: Alfonsi Tommaso , Pinoli Pietro , Canakoglu Arif
Published: March 2022

With the spread of COVID-19, sequencing laboratories started to share hundreds of sequences daily. However, the lack of a commonly agreed standard across deposition databases hindered the exploration and study of all the viral sequences collected worldwide in a practical and homogeneous way. During the first months of the pandemic, we developed an automatic procedure to collect, transform, and integrate viral sequences of SARS-CoV-2, MERS, SARS-CoV, Ebola, and Dengue from four major database institutions (NCBI, COG-UK, GISAID, and NMDC). This data pipeline allowed the creation of the data exploration interfaces VirusViz and EpiSurf, as well as ViruSurf, one of the largest databases of integrated viral sequences. Almost two years after the first release of the repository, the original pipeline underwent a thorough refinement process and became more efficient, scalable, and general (currently, it also includes epitopes from the IEDB). Thanks to these improvements, we constantly update and expand our integrated repository, encompassing about 9.1 million SARS-CoV-2 sequences at present (March 2022). This pipeline made it possible to design and develop fundamental resources for any researcher interested in understanding the biological mechanisms behind the viral infection. In addition, it plays a crucial role in many analytic and visualization tools, such as ViruSurf, EpiSurf, VirusViz, and VirusLab.
In Vivo Basilar Membrane Time Delays in Humans
Authors: Polak Marek , Lorens Artur , Walkowiak Adam , Furmanek Mariusz , Skarzynski Piotr Henryk , Skarzynski Henryk
Published: March 2022

To date, objective measurements and psychophysical experiments have been used to measure frequency dependent basilar membrane (BM) delays in humans; however, in vivo measurements have not been made. This study aimed to measure BM delays by performing intracochlear electrocochleography in cochlear implant recipients. Sixteen subjects with various degrees of hearing abilities were selected. Postoperative Computer Tomography was performed to determine electrode locations. Electrical potentials in response to acoustic tone pips at 0.25, 0.5, 1, 2, and 4 kHz and clicks were recorded with electrodes at the frequency specific region. The electrode array was inserted up to the characteristic cochlear frequency region of 250 Hz for 6 subjects. Furthermore, the array was inserted in the region of 500 Hz for 15 subjects, and 1, 2, and 4 kHz were reached in all subjects. Intracochlear electrocochleography for each frequency-specific tone pip and clicks showed detectable responses in all subjects. The latencies differed among the cochlear location and the cochlear microphonic (CM) onset latency increased with decreasing frequency and were consistent with click derived band technique. Accordingly, BM delays in humans could be derived. The BM delays increased systematically along the cochlea from basal to apical end and were in accordance with Ruggero and Temchin, 2007.
Brain Connectivity and Graph Theory Analysis in Alzheimer’s and Parkinson’s Disease: The Contribution of Electrophysiological Techniques
Authors: Miraglia Francesca , Vecchio Fabrizio , Pappalettera Chiara , Nucci Lorenzo , Cotelli Maria , Judica Elda , Ferreri Florinda , Rossini Paolo Maria
Published: March 2022

In recent years, applications of the network science to electrophysiological data have increased as electrophysiological techniques are not only relatively low cost, largely available on the territory and non-invasive, but also potential tools for large population screening. One of the emergent methods for the study of functional connectivity in electrophysiological recordings is graph theory: it allows to describe the brain through a mathematic model, the graph, and provides a simple representation of a complex system. As Alzheimer’s and Parkinson’s disease are associated with synaptic disruptions and changes in the strength of functional connectivity, they can be well described by functional connectivity analysis computed via graph theory. The aim of the present review is to provide an overview of the most recent applications of the graph theory to electrophysiological data in the two by far most frequent neurodegenerative disorders, Alzheimer’s and Parkinson’s diseases.
The Influence of the Ventricular-Lumbar Gradient on Cerebrospinal Fluid Analysis in Serial Samples
Authors: Konen Franz , Lange Peter , Wurster Ulrich , Jendretzky Konstantin , Gingele Stefan , Möhn Nora , Sühs Kurt-Wolfram , Stangel Martin , Skripuletz Thomas , Schwenkenbecher Philipp
Published: March 2022

Background: Cerebrospinal fluid (CSF) samples from patients with non-inflammatory neurological diseases are used for control groups in biomarker studies. Since large amounts of CSF are withdrawn, patients with idiopathic intracranial hypertension (IIH) or normal pressure hydrocephalus (NPH) are especially suitable. The serially taken CSF portions are usually collected in different tubes. We aimed to investigate whether the later random choice of one of these tubes for CSF investigations might harbor the risk of different CSF protein findings due to the so-called ventriculo-lumbar CSF gradient. Methods: Patients with IIH (9) and NPH (7) were included. CSF was serially taken and collected in six tubes of 5 mL each. Concentrations and CSF-serum quotients of immunoglobulins, albumin and the virus-specific antibody index (AI) were determined in the first, fourth and sixth CSF fraction. Results: CSF immunoglobulin and albumin concentrations and CSF-serum protein quotients were significantly lower in the fourth and sixth CSF fraction compared with the first CSF fraction. Virus-specific AI did not significantly differ in the different CSF fractions. Conclusions: CSF protein analytics should be performed in the first CSF fraction in order to avoid different measurement results and achieve comparability within a control group and between different control and patient groups.
Should Burnout Be Conceptualized as a Mental Disorder?
Authors: Nadon Lindsey , De Beer Leon T. , Morin Alexandre J. S.
Published: March 2022

Burnout is generally acknowledged by researchers, clinicians, and the public as a pervasive occupational difficulty. Despite this widespread recognition, longstanding debates remain within the scientific community regarding its definition and the appropriateness of classifying burnout as its own pathological entity. The current review seeks to address whether burnout should (or could) be characterized as a distinctive mental disorder to shed light on this debate. After briefly reviewing the history, theoretical underpinnings, and measurement of burnout, we more systematically consider the current evidence for and against its classification as a mental disorder within existing diagnostic systems. Stemming from a lack of conceptual clarity, the current state of burnout research remains, unfortunately, largely circular and riddled with measurement issues. As a result, information regarding the unique biopsychosocial etiology, diagnostic features, differential diagnostic criteria, and prevalence rates of burnout are still lacking. Therefore, we conclude that it would be inappropriate, if not premature, to introduce burnout as a distinct mental disorder within any existing diagnostic classification system. We argue, however, that it would be equally premature to discard burnout as a psychologically relevant phenomenon and that current evidence does support its relevance as an important occupational syndrome. We finally offer several avenues for future research, calling for cross-national collaboration to clarify conceptual and measurement issues while avoiding the reification of outdated definitions. In doing so, we hope that it one day becomes possible to more systematically re-assess the relevance of burnout as a distinctive diagnostic category.