bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Targeting of P53: A Comparative Analysis of APR-246 and COTI-2 in Human Tumor Primary Culture 3-D Explants
Authors: Nagourney Adam J. , Gipoor Joshua B. , Evans Steven S. , D’Amora Paulo , Duesberg Max S. , Bernard Paula J. , Francisco Federico , Nagourney Robert A.
Published: March 2023

Background: TP53 is the most commonly mutated gene in human cancer with loss of function mutations largely concentrated in “hotspots” affecting DNA binding. APR-246 and COTI-2 are small molecules under investigation in P53 mutated cancers. APR binds to P53 cysteine residues, altering conformation, while COTI-2 showed activity in P53 mutant tumors by a computational platform. We compared APR-246 and COTI-2 activity in human tumor explants from 247 surgical specimens. Methods: Ex vivo analyses of programmed cell death measured drug-induced cell death by delayed-loss-of-membrane integrity and ATP content. The LC50s were compared by Z-Score. Synergy was conducted by the method of Chou and Talalay, and correlations were performed by Pearson moment. Results: APR-246 and COTI-2 activity favored hematologic neoplasms, but solid tumor activity varied by diagnosis. COTI-2 and APR-246 activity did not correlate (R = 0.1028) (NS). COTI-2 activity correlated with nitrogen mustard, cisplatin and gemcitabine, doxorubicin and selumetinib, with a trend for APR-246 with doxorubicin. For ovarian cancer, COTI-2 showed synergy with cisplatin at 25%. Conclusions: COTI-2 and APR-246 activity differ by diagnosis. A lack of correlation supports distinct modes of action. Cisplatin synergy is consistent with P53’s role in DNA damage. Different mechanisms of action may underlie disease specificity and offer better disease targeting.
Homozygous TNNI3 Mutations and Severe Early Onset Dilated Cardiomyopathy: Patient Report and Review of the Literature
Authors: Sorrentino Ugo , Gabbiato Ilaria , Canciani Chiara , Calosci Davide , Rigon Chiara , Zuccarello Daniela , Cassina Matteo
Published: March 2023

The TNNI3 gene encodes for the cardiac isoform of troponin I, a pivotal component of the sarcomeric structure of the myocardium. While heterozygous TNNI3 missense mutations have long been associated with autosomal dominant hypertrophic and restrictive cardiomyopathies, the role of TNNI3 null mutations has been more debated due to the paucity and weak characterization of reported cases and the low penetrance of heterozygous genotypes. In recent years, however, an increasing amount of evidence has validated the hypothesis that biallelic TNNI3 null mutations cause a severe form of neonatal dilated cardiomyopathy. Here, we expand the case series reporting two unrelated patients afflicted with early onset dilated cardiomyopathy, due to homozygosity for the p.Arg98* TNNI3 variant, which had thus far been documented only in heterozygous patients and apparently healthy carriers, and the recurrent p.Arg69Alafs*8 variant, respectively. A review of previously reported biallelic TNNI3 loss-of-function variants and their associated cardiac phenotypes was also performed.
Risk-Reduction, Coping, and Adaptation to Flood Hazards in Manitoba, Canada: Evidence from Communities in the Red River Valley
Authors: Haque C. Emdad , Zaman Jobaed Ragib , Walker David
Published: March 2023

In general, much is known about patterns relating to flood risk reduction, coping, and adaptation in various types of communities; however, knowledge of their drivers—which are critical for building community resilience to natural hazards—is limited. The present study investigates the influencing factors of coping and adaptation measures vis-a-vis flood hazards at the community level and examines their interrelationships. This work employs a “case study” approach and analyzes two towns—St. Adolphe and Ste. Agathe—in the Red River Valley in the province of Manitoba, Canada. Data collection consisted of in-depth interviews with key informants and obtaining oral histories from the locals, along with an examination of secondary official records and documents. The results revealed that the major drivers of local-level coping and adaptation include functioning partnerships among stakeholders, strong institutional structures that facilitate interactive learning, knowledge co-production, resources sharing, communication and information sharing, and infrastructure supports. It was observed that an institutional atmosphere conducive to spontaneous network development yields diverse coping and adaptation strategies. To improve the outcomes of coping and adaptation measures, close collaboration between community-based groups and formal and quasi-formal institutions, and transparency in decision-making processes are vital.
The Impact of Event Scale-Revised: Examining Its Cutoff Scores among Arab Psychiatric Patients and Healthy Adults within the Context of COVID-19 as a Collective Traumatic Event
Authors: Ali Amira Mohammed , Al-Dossary Saeed A. , Almarwani Abdulaziz Mofdy , Atout Maha , Al-Amer Rasmieh , Alkhamees Abdulmajeed A.
Published: March 2023

The Impact of Event Scale-Revised (IES-R) is the most popular measure of post-traumatic stress disorder (PTSD). It has been recently validated in Arabic. This instrumental study aimed to determine optimal cutoff scores of the IES-R and its determined six subscales in Arab samples of psychiatric patients (N = 168, 70.8% females) and healthy adults (N = 992, 62.7% females) from Saudi Arabia during the COVID-19 pandemic as a probable ongoing collective traumatic event. Based on a cutoff score of 14 of the Depression Anxiety Stress Scale 8-items (DASS-8), receiver operator curve (ROC) analysis revealed two optimal points of 39.5 and 30.5 for the IES-R in the samples (area under the curve (AUC) = 0.86 & 0.91, p values = 0.001, 95% CI: 0.80–0.92 & 0.87–0.94, sensitivity = 0.85 & 0.87, specificity = 0.73 & 0.83, Youden index = 0.58 & 0.70, respectively). Different cutoffs were detected for the six subscales of the IES-R, with numbing and avoidance expressing the lowest predictivity for distress. Meanwhile, hyperarousal followed by pandemic-related irritability expressed a stronger predictive capacity for distress than all subscales in both samples. In path analysis, pandemic-related irritability/dysphoric mood evolved as a direct and indirect effect of key PTSD symptoms (intrusion, hyperarousal, and numbing). The irritability dimension of the IES-R directly predicted the traumatic symptoms of sleep disturbance in both samples while sleep disturbance did not predict irritability. The findings suggest the usefulness of the IES-R at a score of 30.5 for detecting adults prone to trauma related distress, with higher scores needed for screening in psychiatric patients. Various PTSD symptoms may induce dysphoric mood, which represents a considerable burden that may induce circadian misalignment and more noxious psychiatric problems/co-morbidities (e.g., sleep disturbance) in both healthy and diseased groups.
Flood Monitoring in the Middle and Lower Basin of the Yangtze River Using Google Earth Engine and Machine Learning Methods
Authors: Wang Jingming , Wang Futao , Wang Shixin , Zhou Yi , Ji Jianwan , Wang Zhenqing , Zhao Qing , Liu Longfei
Published: March 2023

Under the background of intensified human activities and global climate warming, the frequency and intensity of flood disasters have increased, causing many casualties and economic losses every year. Given the difficulty of mountain shadow removal from large-scale watershed flood monitoring based on Sentinel-1 SAR images and the Google Earth Engine (GEE) cloud platform, this paper first adopted the Support Vector Machine (SVM) to extract the water body information during flooding. Then, a function model was proposed based on the mountain shadow samples to remove the mountain shadows from the flood maps. Finally, this paper analyzed the flood disasters in the middle and lower basin of the Yangtze River (MLB) in 2020. The main results showed that: (1) compared with the other two methods, the SVM model had the highest accuracy. The accuracy and kappa coefficients of the trained SVM model in the testing dataset were 97.77% and 0.9521, respectively. (2) The function model proposed based on the samples achieved the best effect compared with other shadow removal methods with a shadow recognition rate of 75.46%, and it alleviated the interference of mountain shadows for flood monitoring in a large basin. (3) The flood inundated area was 8526 km2, among which, cropland was severely affected (6160 km2). This study could provide effective suggestions for relevant stakeholders in policy making.
In Vitro Cell Proliferation and Migration Properties of Oral Mucosal Fibroblasts: A Comparative Study on the Effects of Cord Blood- and Peripheral Blood-Platelet Lysate
Authors: Azmi Arief Faisal , Yahya Mohammad Amirul Asyraff Mohd , Azhar Nur Ain , Ibrahim Norliwati , Ghafar Norzana Abd , Ghani Nur Azurah Abdul , Nizar Muhammad Aiman Mohd , Yunus Siti Salmiah Mohd , Singh Tashveender Kaur Lakhbir , Law Jia-Xian , Ng Sook-Luan
Published: March 2023

Cord blood-platelet lysate (CB-PL), containing growth factors such as a platelet-derived growth factor, has a similar efficacy to peripheral blood-platelet lysate (PB-PL) in initiating cell growth and differentiation, which makes it a unique alternative to be implemented into oral ulceration healing. This research study aimed to compare the effectiveness of CB-PL and PB-PL in promoting oral wound closure in vitro. Alamar blue assay was used to determine the optimal concentration of CB-PL and PB-PL in enhancing the proliferation of human oral mucosal fibroblasts (HOMF). The percentage of wound closure was measured using the wound-healing assay for CB-PL and PB-PL at the optimal concentration of 1.25% and 0.3125%, respectively. The gene expressions of cell phenotypic makers (Col. I, Col. III, elastin and fibronectin) were determined via qRT-PCR. The concentrations of PDGF-BB were quantified using ELISA. We found that CB-PL was as effective as PB-PL in promoting wound-healing and both PL were more effective compared to the control (CTRL) group in accelerating the cell migration in the wound-healing assay. The gene expressions of Col. III and fibronectin were significantly higher in PB-PL compared to CB-PL. The PDGF-BB concentration of PB-PL was the highest and it decreased after the wound closed on day 3. Therefore, we concluded that PL from both sources can be a beneficial treatment for wound-healing, but PB-PL showed the most promising wound-healing properties in this study.
Helicobacter pylori Dormant States Are Affected by Vitamin C
Authors: Di Fermo Paola , Di Lodovico Silvia , Di Campli Emanuela , D’Arcangelo Sara , Diban Firas , D’Ercole Simonetta , Di Giulio Mara , Cellini Luigina
Published: March 2023

Helicobacter pylori colonizes human gastric mucosa, overcoming stressful conditions and entering in a dormant state. This study evaluated: (i) H. pylori’s physiological changes from active to viable-but-non-culturable (VBNC) and persister (AP) states, establishing times/conditions; (ii) the ability of vitamin C to interfere with dormancy generation/resuscitation. A dormant state was induced in clinical MDR H. pylori 10A/13 by: nutrient starvation (for VBNC generation), incubating in an unenriched medium (Brucella broth) or saline solution (SS), and (for AP generation) treatment with 10xMIC amoxicillin (AMX). The samples were monitored after 24, 48, and 72 h, 8–14 days by OD600, CFUs/mL, Live/Dead staining, and an MTT viability test. Afterwards, vitamin C was added to the H. pylori suspension before/after the generation of dormant states, and monitoring took place at 24, 48, and 72 h. The VBNC state was generated after 8 days in SS, and the AP state in AMX for 48 h. Vitamin C reduced its entry into a VBNC state. In AP cells, Vitamin C delayed entry, decreasing viable coccal cells and increasing bacillary/U-shaped bacteria. Vitamin C increased resuscitation (60%) in the VBNC state and reduced the aggregates of the AP state. Vitamin C reduced the incidence of dormant states, promoting the resuscitation rate. Pretreatment with Vitamin C could favor the selection of microbial vegetative forms that are more susceptible to H. pylori therapeutical schemes.
Molecular and Epigenetic Control of Aldosterone Synthase, CYP11B2 and 11-Hydroxylase, CYP11B1
Authors: Takeda Yoshimichi , Demura Masashi , Kometani Mitsuhiro , Karashima Shigehiro , Yoneda Takashi , Takeda Yoshiyu
Published: March 2023

Aldosterone and cortisol serve important roles in the pathogenesis of cardiovascular diseases and metabolic disorders. Epigenetics is a mechanism to control enzyme expression by genes without changing the gene sequence. Steroid hormone synthase gene expression is regulated by transcription factors specific to each gene, and methylation has been reported to be involved in steroid hormone production and disease. Angiotensin II or potassium regulates the aldosterone synthase gene, CYP11B2. The adrenocorticotropic hormone controls the 11b-hydroxylase, CYP11B1. DNA methylation negatively controls the CYP11B2 and CYP11B1 expression and dynamically changes the expression responsive to continuous stimulation of the promoter gene. Hypomethylation status of the CYP11B2 promoter region is seen in aldosterone-producing adenomas. Methylation of recognition sites of transcription factors, including cyclic AMP responsive element binding protein 1 or nerve growth factor-induced clone B, diminish their DNA-binding activity. A methyl-CpG-binding protein 2 cooperates directly with the methylated CpG dinucleotides of CYP11B2. A low-salt diet, treatment with angiotensin II, and potassium increase the CYP11B2 mRNA levels and induce DNA hypomethylation in the adrenal gland. A close association between a low DNA methylation ratio and an increased CYP11B1 expression is seen in Cushing’s adenoma and aldosterone-producing adenoma with autonomous cortisol secretion. Epigenetic control of CYP11B2 or CYP11B1 plays an important role in autonomic aldosterone or cortisol synthesis.
Synergy between Membrane Currents Prevents Severe Bradycardia in Mouse Sinoatrial Node Tissue
Authors: Arbel Ganon Limor , Davoodi Moran , Alexandrovich Alexandra , Yaniv Yael
Published: March 2023

Bradycardia is initiated by the sinoatrial node (SAN), which is regulated by a coupled-clock system. Due to the clock coupling, reduction in the ‘funny’ current (If), which affects SAN automaticity, can be compensated, thus preventing severe bradycardia. We hypothesize that this fail-safe system is an inherent feature of SAN pacemaker cells and is driven by synergy between If and other ion channels. This work aimed to characterize the connection between membrane currents and their underlying mechanisms in SAN cells. SAN tissues were isolated from C57BL mice and Ca2+ signaling was measured in pacemaker cells within them. A computational model of SAN cells was used to understand the interactions between cell components. Beat interval (BI) was prolonged by 54 ± 18% (N = 16) and 30 ± 9% (N = 21) in response to If blockade, by ivabradine, or sodium current (INa) blockade, by tetrodotoxin, respectively. Combined drug application had a synergistic effect, manifested by a BI prolonged by 143 ± 25% (N = 18). A prolongation in the local Ca2+ release period, which reports on the level of crosstalk within the coupled-clock system, was measured and correlated with the prolongation in BI. The computational model predicted that INa increases in response to If blockade and that this connection is mediated by changes in T and L-type Ca2+ channels.
Regulation of Aqueous Humor Secretion by Melatonin in Porcine Ciliary Epithelium
Authors: Li Ka-Lok , Shan Sze-Wan , Lin Fang-Yu , Ling Choi-Ying , Wong Nga-Wai , Li Hoi-Lam , Han Wei , To Chi-Ho , Do Chi-Wai
Published: March 2023

Secretion of melatonin, a natural hormone whose receptors are present in the ciliary epithelium, displays diurnal variation in the aqueous humor (AH), potentially contributing to the regulation of intraocular pressure. This study aimed to determine the effects of melatonin on AH secretion in porcine ciliary epithelium. The addition of 100 µM melatonin to both sides of the epithelium significantly increased the short-circuit current (Isc) by ~40%. Stromal administration alone had no effect on the Isc, but aqueous application triggered a 40% increase in Isc, similar to that of bilateral application without additive effect. Pre-treatment with niflumic acid abolished melatonin-induced Isc stimulation. More importantly, melatonin stimulated the fluid secretion across the intact ciliary epithelium by ~80% and elicited a sustained increase (~50–60%) in gap junctional permeability between pigmented ciliary epithelial (PE) cells and non-pigmented ciliary epithelial (NPE) cells. The expression of MT3 receptor was found to be >10-fold higher than that of MT1 and MT2 in porcine ciliary epithelium. Aqueous pre-treatment with MT1/MT2 antagonist luzindole failed to inhibit the melatonin-induced Isc response, while MT3 antagonist prazosin pre-treatment abolished the Isc stimulation. We conclude that melatonin facilitates Cl− and fluid movement from PE to NPE cells, thereby stimulating AH secretion via NPE-cell MT3 receptors.
Graphene Oxide/RhPTH(1-34)/Polylactide Composite Nanofibrous Scaffold for Bone Tissue Engineering
Authors: Fei Fan , Yao Haiyan , Wang Yujiang , Wei Junchao
Published: March 2023

Polylactide (PLA) is one of the most promising polymers that has been widely used for the repair of damaged tissues due to its biocompatibility and biodegradability. PLA composites with multiple properties, such as mechanical properties and osteogenesis, have been widely investigated. Herein, PLA/graphene oxide (GO)/parathyroid hormone (rhPTH(1-34)) nanofiber membranes were prepared using a solution electrospinning method. The tensile strength of the PLA/GO/rhPTH(1-34) membranes was 2.64 MPa, nearly 110% higher than that of a pure PLA sample (1.26 MPa). The biocompatibility and osteogenic differentiation test demonstrated that the addition of GO did not markedly affect the biocompatibility of PLA, and the alkaline phosphatase activity of PLA/GO/rhPTH(1-34) membranes was about 2.3-times that of PLA. These results imply that the PLA/GO/rhPTH(1-34) composite membrane may be a candidate material for bone tissue engineering.
Characterization of the Involvement of Tumour Necrosis Factor (TNF)-α-Stimulated Gene 6 (TSG-6) in Ischemic Brain Injury Caused by Middle Cerebral Artery Occlusion in Mouse
Authors: Di Santo Chiara , La Russa Daniele , Greco Rosaria , Persico Alessandra , Zanaboni Anna Maria , Bagetta Giacinto , Amantea Diana
Published: March 2023

The identification of novel targets to modulate the immune response triggered by cerebral ischemia is crucial to promote the development of effective stroke therapeutics. Since tumour necrosis factor (TNF)-α-stimulated gene 6 (TSG-6), a hyaluronate (HA)-binding protein, is involved in the regulation of immune and stromal cell functions in acute neurodegeneration, we aimed to characterize its involvement in ischemic stroke. Transient middle cerebral artery occlusion (1 h MCAo, followed by 6 to 48 of reperfusion) in mice resulted in a significant elevation in cerebral TSG-6 protein levels, mainly localized in neurons and myeloid cells of the lesioned hemisphere. These myeloid cells were clearly infiltrating from the blood, strongly suggesting that brain ischemia also affects TSG-6 in the periphery. Accordingly, TSG-6 mRNA expression was elevated in peripheral blood mononuclear cells (PBMCs) from patients 48 h after ischemic stroke onset, and TSG-6 protein expression was higher in the plasma of mice subjected to 1 h MCAo followed by 48 h of reperfusion. Surprisingly, plasma TSG-6 levels were reduced in the acute phase (i.e., within 24 h of reperfusion) when compared to sham-operated mice, supporting the hypothesis of a detrimental role of TSG-6 in the early reperfusion stage. Accordingly, systemic acute administration of recombinant mouse TSG-6 increased brain levels of the M2 marker Ym1, providing a significant reduction in the brain infarct volume and general neurological deficits in mice subjected to transient MCAo. These findings suggest a pivotal role of TSG-6 in ischemic stroke pathobiology and underscore the clinical relevance of further investigating the mechanisms underlying its immunoregulatory role.
Adiponectin Enhances Fatty Acid Signaling in Human Taste Cells by Increasing Surface Expression of CD36
Authors: Lin Fangjun , Liu Yan , Rudeski-Rohr Trina , Dahir Naima , Calder Ashley , Gilbertson Timothy A.
Published: March 2023

Adiponectin, a key metabolic hormone, is secreted into the circulation by fat cells where it enhances insulin sensitivity and stimulates glucose and fatty acid metabolism. Adiponectin receptors are highly expressed in the taste system; however, their effects and mechanisms of action in the modulation of gustatory function remain unclear. We utilized an immortalized human fungiform taste cell line (HuFF) to investigate the effect of AdipoRon, an adiponectin receptor agonist, on fatty acid-induced calcium responses. We showed that the fat taste receptors (CD36 and GPR120) and taste signaling molecules (Gα-gust, PLCβ2, and TRPM5) were expressed in HuFF cells. Calcium imaging studies showed that linoleic acid induced a dose-dependent calcium response in HuFF cells, and it was significantly reduced by the antagonists of CD36, GPR120, PLCβ2, and TRPM5. AdipoRon administration enhanced HuFF cell responses to fatty acids but not to a mixture of sweet, bitter, and umami tastants. This enhancement was inhibited by an irreversible CD36 antagonist and by an AMPK inhibitor but was not affected by a GPR120 antagonist. AdipoRon increased the phosphorylation of AMPK and the translocation of CD36 to the cell surface, which was eliminated by blocking AMPK. These results indicate that AdipoRon acts to increase cell surface CD36 in HuFF cells to selectively enhance their responses to fatty acids. This, in turn, is consistent with the ability of adiponectin receptor activity to alter taste cues associated with dietary fat intake.
Nuclear Epidermal Growth Factor Receptor Overexpression as a Survival Predictor in Oral Squamous Cell Carcinoma
Authors: Tarle Marko , Raguž Marina , Muller Danko , Lukšić Ivica
Published: March 2023

The aim of this study was to determine, by immunohistochemical methods, the expression of nEGFR and markers of cell proliferation (Ki-67), cell cycle (mEGFR, p53, cyclin D1), and tumor stem cells (ABCG2) in 59 pathohistological samples of healthy oral mucosa, 50 oral premalignant changes (leukoplakia and erythroplakia), and 52 oral squamous cell carcinomas (OSCC). An increase in the expression of mEGFR and nEGFR was found with the development of the disease (p < 0.0001). In the group of patients with leukoplakia and erythroplakia, we found a positive correlation between nEGFR and Ki67, p53, cyclin D1, and mEGFR, whereas in the group of patients with OSCC, we found a positive correlation between nEGFR and Ki67, mEGFR (p < 0.05). Tumors without perineural (PNI) invasion had a higher expression of p53 protein than tumors with PNI (p = 0.02). Patients with OSCC and overexpression of nEGFR had shorter overall survival (p = 0.004). The results of this study suggest a potentially important independent role of nEGFR in oral carcinogenesis.
Pharmacological Chaperones and Protein Conformational Diseases: Approaches of Computational Structural Biology
Authors: Grasso Daniela , Galderisi Silvia , Santucci Annalisa , Bernini Andrea
Published: March 2023

Whenever a protein fails to fold into its native structure, a profound detrimental effect is likely to occur, and a disease is often developed. Protein conformational disorders arise when proteins adopt abnormal conformations due to a pathological gene variant that turns into gain/loss of function or improper localization/degradation. Pharmacological chaperones are small molecules restoring the correct folding of a protein suitable for treating conformational diseases. Small molecules like these bind poorly folded proteins similarly to physiological chaperones, bridging non-covalent interactions (hydrogen bonds, electrostatic interactions, and van der Waals contacts) loosened or lost due to mutations. Pharmacological chaperone development involves, among other things, structural biology investigation of the target protein and its misfolding and refolding. Such research can take advantage of computational methods at many stages. Here, we present an up-to-date review of the computational structural biology tools and approaches regarding protein stability evaluation, binding pocket discovery and druggability, drug repurposing, and virtual ligand screening. The tools are presented as organized in an ideal workflow oriented at pharmacological chaperones’ rational design, also with the treatment of rare diseases in mind.
Could Toll-like Receptor 2 Serve as Biomarker to Detect Advanced Gastric Cancer?
Authors: Majewski Marek , Torres Kamil , Mertowska Paulina , Mertowski Sebastian , Korona-Głowniak Izabela , Korulczyk Jan , Zgodziński Witold , Grywalska Ewelina
Published: March 2023

Gastric cancer is one of the five most common types of cancer worldwide. Due to the heterogeneous course and the involvement of many risk factors, its treatment and diagnosis is an important challenge for modern medicine. Recent studies have emphasized the i role of Toll-like receptors (TLRs) expressed on selected cells of the immune system in the pathogenesis of gastric cancer. The aim of this study was to determine the prevalence of TLR2 on T lymphocytes, B lymphocytes, monocytes, and dendritic cells in patients diagnosed with gastric cancer, with particular emphasis on the stage of the disease. Based on the obtained results, we have shown that patients with gastric cancer are characterized by a higher percentage of all tested populations of peripheral blood immune cells expressing TLR2 in relation to patients from the control group. Moreover, a detailed analysis of the collected results showed a significant link between TLR2 and the stage of the disease.
In Silico Exploration of Metabolically Active Peptides as Potential Therapeutic Agents against Amyotrophic Lateral Sclerosis
Authors: Fatoki Toluwase Hezekiah , Chukwuejim Stanley , Udenigwe Chibuike C. , Aluko Rotimi E.
Published: March 2023

Amyotrophic lateral sclerosis (ALS) is regarded as a fatal neurodegenerative disease that is featured by progressive damage of the upper and lower motor neurons. To date, over 45 genes have been found to be connected with ALS pathology. The aim of this work was to computationally identify unique sets of protein hydrolysate peptides that could serve as therapeutic agents against ALS. Computational methods which include target prediction, protein-protein interaction, and peptide-protein molecular docking were used. The results showed that the network of critical ALS-associated genes consists of ATG16L2, SCFD1, VAC15, VEGFA, KEAP1, KIF5A, FIG4, TUBA4A, SIGMAR1, SETX, ANXA11, HNRNPL, NEK1, C9orf72, VCP, RPSA, ATP5B, and SOD1 together with predicted kinases such as AKT1, CDK4, DNAPK, MAPK14, and ERK2 in addition to transcription factors such as MYC, RELA, ZMIZ1, EGR1, TRIM28, and FOXA2. The identified molecular targets of the peptides that support multi-metabolic components in ALS pathogenesis include cyclooxygenase-2, angiotensin I-converting enzyme, dipeptidyl peptidase IV, X-linked inhibitor of apoptosis protein 3, and endothelin receptor ET-A. Overall, the results showed that AGL, APL, AVK, IIW, PVI, and VAY peptides are promising candidates for further study. Future work would be needed to validate the therapeutic properties of these hydrolysate peptides by in vitro and in vivo approaches.
Evaluation of Fruquintinib in the Continuum of Care of Patients with Colorectal Cancer
Authors: Lavacchi Daniele , Roviello Giandomenico , Guidolin Alessia , Romano Silvia , Venturini Jacopo , Caliman Enrico , Vannini Agnese , Giommoni Elisa , Pellegrini Elisa , Brugia Marco , Pillozzi Serena , Antonuzzo Lorenzo
Published: March 2023

The management of patients with metastatic colorectal cancer (mCRC) has the continuum of care as the treatment paradigm. To date, trifluridine/tipiracil, a biochemically modulated fluoropyrimidine, and regorafenib, a multi-kinase inhibitor, remain the main options for the majority of patients who progressed to standard doublet- or triplet-based chemotherapies, although a tailored approach could be indicated in certain circumstances. Being highly selective for vascular endothelial growth factor receptor (VEGFR)-1, -2 and -3, fruquintinib demonstrated a strong anti-tumor activity in preclinical models and received approval from China’s National Medical Products Administration (NMPA) in 2018 for the treatment of patients with chemo-refractory mCRC. The approval was based on the results of the phase III FRESCO trial. Then, in order to overcome geographic differences in clinical practice, the FRESCO-2 trial was conducted in the US, Europe, Japan, and Australia. In a heavily pretreated patient population, the study met its primary endpoint, demonstrating an advantage of fruquintinib over a placebo in overall survival (OS). Here, we review the clinical development of fruquintinib and its perspectives in gastrointestinal cancers. Then, we discuss the introduction of fruquintinib in the continuum of care of CRC paying special attention to unmet needs, including the identification of cross-resistant and potentially susceptible populations, evaluation of radiological response, and identification of novel biomarkers of clinical benefit.
Glucans, Paramylon and Other Algae Bioactive Molecules
Authors: Barsanti Laura , Gualtieri Paolo
Published: March 2023

Algae (macro- and micro-algae) can be defined as light-driven cell factories that synthesize bioactive compounds consisting of primary metabolites (i [...]
RVG Peptide-Functionalized Favipiravir Nanoparticle Delivery System Facilitates Antiviral Therapy of Neurotropic Virus Infection in a Mouse Model
Authors: Ren Meishen , Zhou You , Tu Teng , Jiang Dike , Pang Maonan , Li Yanwei , Luo Yan , Yao Xueping , Yang Zexiao , Wang Yin
Published: March 2023

Neurotropic viruses severely damage the central nervous system (CNS) and human health. Common neurotropic viruses include rabies virus (RABV), Zika virus, and poliovirus. When treating neurotropic virus infection, obstruction of the blood–brain barrier (BBB) reduces the efficiency of drug delivery to the CNS. An efficient intracerebral delivery system can significantly increase intracerebral delivery efficiency and facilitate antiviral therapy. In this study, a rabies virus glycopeptide (RVG) functionalized mesoporous silica nanoparticle (MSN) packaging favipiravir (T-705) was developed to generate T-705@MSN-RVG. It was further evaluated for drug delivery and antiviral treatment in a VSV-infected mouse model. The RVG, a polypeptide consisting of 29 amino acids, was conjugated on the nanoparticle to enhance CNS delivery. The T-705@MSN-RVG caused a significant decrease in virus titers and virus proliferation without inducing substantial cell damage in vitro. By releasing T-705, the nanoparticle promoted viral inhibition in the brain during infection. At 21 days post-infection (dpi), a significantly enhanced survival ratio (77%) was observed in the group inoculated with nanoparticle compared with the non-treated group (23%). The viral RNA levels were also decreased in the therapy group at 4 and 6 dpi compared with that of the control group. The T-705@MSN-RVG could be considered a promising system for CNS delivery for treating neurotropic virus infection.
ARID1A, NOTCH and WNT Signature in Gynaecological Tumours
Authors: Vaicekauskaitė Ieva , Dabkevičienė Daiva , Šimienė Julija , Žilovič Diana , Čiurlienė Rūta , Jarmalaitė Sonata , Sabaliauskaitė Rasa
Published: March 2023

Ovarian cancer (OC) is among the deadliest gynaecologic malignancies in the world. The majority of OC patients are diagnosed at an advanced stage, with high-grade serous OC (HGSOC). The lack of specific symptoms and suitable screening strategies lead to short progression-free survival times in HGSOC patients. The chromatin-remodelling, WNT and NOTCH pathways are some of the most dysregulated in OC; thus their gene mutations and expression profile could serve as diagnostic or prognostic OC biomarkers. Our pilot study investigated mRNA expression of the SWI/SNF chromatin-remodelling complex gene ARID1A, NOTCH receptors, WNT pathway genes CTNNB1 and FBXW7 mRNA expression in two OC cell cultures as well as 51 gynaecologic tumour tissues. A four-gene panel consisting of ARID1A, CTNNB1, FBXW7 and PPP2R1A was used to investigate mutations in gynaecologic tumour tissue. All seven analysed genes were found to be significantly downregulated in OC when compared with non-malignant gynaecologic tumour tissues. NOTCH3 was also downregulated in SKOV3 cells when compared to A2780. Fifteen mutations were found in 25.5% (13/51) of the tissue samples. ARID1A predicted mutations were the most prevalent with alterations detected in 19% (6/32) HGSOC and 67% (6/9) of other OC cases. Thus, ARID1A and NOTCH/WNT-pathway-related changes could be useful diagnostic biomarkers in OC.
Prediction and Verification of Curcumin as a Potential Drug for Inhibition of PDCoV Replication in LLC-PK1 Cells
Authors: Wang Xuefei , Wang Xue , Zhang Jialu , Shan Qiang , Zhu Yaohong , Xu Chuang , Wang Jiufeng
Published: March 2023

Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus (CoV) that causes lethal watery diarrhea in neonatal pigs and poses economic and public health burdens. Currently, there are no effective antiviral agents against PDCoV. Curcumin is the active ingredient extracted from the rhizome of turmeric, which has a potential pharmacological value because it exhibits antiviral properties against several viruses. Here, we described the antiviral effect of curcumin against PDCoV. At first, the potential relationships between the active ingredients and the diarrhea-related targets were predicted through a network pharmacology analysis. Twenty-three nodes and 38 edges were obtained using a PPI analysis of eight compound-targets. The action target genes were closely related to the inflammatory and immune related signaling pathways, such as the TNF signaling pathway, Jak-STAT signaling pathway, and so on. Moreover, IL-6, NR3C2, BCHE and PTGS2 were identified as the most likely targets of curcumin by binding energy and 3D protein-ligand complex analysis. Furthermore, curcumin inhibited PDCoV replication in LLC-PK1 cells at the time of infection in a dose-dependent way. In poly (I:C) pretreated LLC-PK1 cells, PDCoV reduced IFN-β production via the RIG-I pathway to evade the host’s antiviral innate immune response. Meanwhile, curcumin inhibited PDCoV-induced IFN-β secretion by inhibiting the RIG-I pathway and reduced inflammation by inhibiting IRF3 or NF-κB protein expression. Our study provides a potential strategy for the use of curcumin in preventing diarrhea caused by PDCoV in piglets.
Transcriptomic Modulation Reveals the Specific Cellular Response in Chinese Sea Bass (Lateolabrax maculatus) Gills under Salinity Change and Alkalinity Stress
Authors: Zhu Qing , Li Moli , Lu Wei , Wang Yapeng , Li Xujian , Cheng Jie
Published: March 2023

Salinity and alkalinity are among the important factors affecting the distribution, survival, growth and physiology of aquatic animals. Chinese sea bass (Lateolabrax maculatus) is an important aquaculture fish species in China that can widely adapt to diverse salinities from freshwater (FW) to seawater (SW) but moderately adapt to highly alkaline water (AW). In this study, juvenile L. maculatus were exposed to salinity change (SW to FW) and alkalinity stress (FW to AW). Coordinated transcriptomic responses in L. maculatus gills were investigated and based on the weighted gene co-expression network analysis (WGCNA), 8 and 11 stress-responsive modules (SRMs) were identified for salinity change and alkalinity stress, respectively, which revealed a cascade of cellular responses to oxidative and osmotic stress in L. maculatus gills. Specifically, four upregulated SRMs were enriched with induced differentially expressed genes (DEGs) for alkalinity stress, mainly corresponding to the functions of “extracellular matrix” and “anatomical structure”, indicating a strong cellular response to alkaline water. Both “antioxidative activity” and “immune response” functions were enriched in the downregulated alkaline SRMs, which comprised inhibited alkaline specific DEGs, revealing the severely disrupted immune and antioxidative functions under alkalinity stress. These alkaline-specific responses were not revealed in the salinity change groups with only moderately inhibited osmoregulation and induced antioxidative response in L. maculatus gills. Therefore, the results revealed the diverse and correlated regulation of the cellular process and stress response in saline-alkaline water, which may have arisen through the functional divergence and adaptive recruitment of the co-expression genes and will provide vital insights for the development of L. maculatus cultivation in alkaline water.
LINC01393, a Novel Long Non-Coding RNA, Promotes the Cell Proliferation, Migration and Invasion through MiR-128-3p/NUSAP1 Axis in Glioblastoma
Authors: Li Deheng , Hu Junda , Li Sen , Zhou Changshuai , Feng Mingtao , Li Liangdong , Gao Yang , Chen Xin , Wu Xiaojun , Cao Yiqun , Hao Bin , Chen Lei
Published: March 2023

Nucleolar and spindle-associated protein 1 (NUSAP1) is a potential molecular marker and intervention target for glioblastoma (GBM). In this study, we aim to investigate upstream regulatory lncRNAs and miRNAs of NUSAP1 through both experimental and bioinformatic methods. We screened upstream lncRNAs and miRNAs of NUSAP1 through multiple databases based on ceRNA theory. Then, in vitro and in vivo experiments were performed to elucidate the relevant biological significance and regulatory mechanism among them. Finally, the potential downstream mechanism was discussed. LINC01393 and miR-128-3p were screened as upstream regulatory molecules of NUSAP1 by TCGA and ENCORI databases. The negative correlations among them were confirmed in clinical specimens. Biochemical studies revealed that overexpression or knockdown of LINC01393 respectively enhanced or inhibited malignant phenotype of GBM cells. MiR-128-3p inhibitor reversed LINC01393 knockdown-mediated impacts on GBM cells. Then, dual-luciferase reporter assay and RNA immunoprecipitation assay were conducted to validate LINC01393/miR-128-3p/NUSAP1 interactions. In vivo, LINC01393-knockdown decreased tumor growth and improved mice survival, while restoration of NUSAP1 partially reversed these effects. Additionally, enrichment analysis and western blot revealed that the roles of LINC01393 and NUSAP1 in GBM progression were associated with NF-κB activation. Our findings showed that LINC01393 sponged miR-128-3p to upregulate NUSAP1, thereby promoting GBM development and progression via activating NF-κB pathway. This work deepens understanding of GBM mechanisms and provides potential novel therapeutic targets for GBM.
Efficient Dynamic Reconfigurable CNN Accelerator for Edge Intelligence Computing on FPGA
Authors: Shi Kaisheng , Wang Mingwei , Tan Xin , Li Qianghua , Lei Tao
Published: March 2023

This paper proposes an efficient dynamic reconfigurable CNN accelerator (EDRCA) for FPGAs to tackle the issues of limited hardware resources and low energy efficiency in the deployment of convolutional neural networks on embedded edge computing devices. First, a configuration layer sequence optimization method is proposed to minimize the configuration time overhead and improve performance. Second, accelerator templates for dynamic regions are designed to create a unified high-speed interface and enhance operational performance. The dynamic reconfigurable technology is applied on the Xilinx KV260 FPGA platform to design the EDRCA accelerator, resolving the hardware resource constraints in traditional accelerator design. The YOLOV2-TINY object detection network is used to test the EDRCA accelerator on the Xilinx KV260 platform using floating point data. Results at 250 MHz show a computing performance of 75.1929 GOPS, peak power consumption of 5.25 W, and power efficiency of 13.6219 GOPS/W, indicating the potential of the EDRCA accelerator for edge intelligence computing.
Learned Text Representation for Amharic Information Retrieval and Natural Language Processing
Authors: Yeshambel Tilahun , Mothe Josiane , Assabie Yaregal
Published: March 2023

Over the past few years, word embeddings and bidirectional encoder representations from transformers (BERT) models have brought better solutions to learning text representations for natural language processing (NLP) and other tasks. Many NLP applications rely on pre-trained text representations, leading to the development of a number of neural network language models for various languages. However, this is not the case for Amharic, which is known to be a morphologically complex and under-resourced language. Usable pre-trained models for automatic Amharic text processing are not available. This paper presents an investigation on the essence of learned text representation for information retrieval and NLP tasks using word embeddings and BERT language models. We explored the most commonly used methods for word embeddings, including word2vec, GloVe, and fastText, as well as the BERT model. We investigated the performance of query expansion using word embeddings. We also analyzed the use of a pre-trained Amharic BERT model for masked language modeling, next sentence prediction, and text classification tasks. Amharic ad hoc information retrieval test collections that contain word-based, stem-based, and root-based text representations were used for evaluation. We conducted a detailed empirical analysis on the usability of word embeddings and BERT models on word-based, stem-based, and root-based corpora. Experimental results show that word-based query expansion and language modeling perform better than stem-based and root-based text representations, and fastText outperforms other word embeddings on word-based corpus.
Effects of Managed and Unmanaged Floral Margins on Pollination Services and Production in Melon Crops
Authors: Pérez-Marcos María , Ortiz-Sánchez Francisco Javier , López-Gallego Elena , Ibáñez Helena , Carrasco Aline , Sanchez Juan Antonio
Published: March 2023

Melon is among the most consumed fruits in the world, being a crop that depends almost entirely on insects for its reproduction, which is why it is especially sensitive to declining pollination services. Restoration and maintenance of hedgerows and agricultural borders around crops are generally carried out by sowing flowering herbaceous plants or establishing shrubby species; however, a cost-effective and lower-maintenance alternative for farmers could be as simple as allowing vegetation to regenerate naturally without any management actions. This work aimed to test the effects of three different types of margins (managed herbaceous, managed shrubby, and unmanaged herbaceous) on the overall abundance and richness of wild pollinators in melon crops. The work was performed in three localities in southern Spain over two years. Pollinators were monitored visually using 1 × 1 m sampling squares and pan traps within melon fields. Moreover, crop yield was estimated by measuring fruit weight and the number of seeds. In general, higher abundances of pollinators were observed in melon fields during the second year. In addition, the abundances of Syrphidae, Andrenidae, Apidae (excl. Apis mellifera), and pollinators other than bees, belonging to the orders Diptera, Coleoptera, Hymenoptera, and Lepidoptera, showed higher values in melon fields with shrubby margins than in fields with herbaceous margins (managed or unmanaged). However, no effect of floral margins on the yield of melon crops was found.
Elevated Bile Acid Is Associated with Worsened Impaired Glucose Homeostasis in Pancreatic Ductal Adenocarcinoma Patients with Extrahepatic Cholestasis through Increased Hepatic Insulin Clearance
Authors: Yang Jie , Tan Chunlu , Zheng Zhenjiang , Wang Xing , Liu Xubao , Chen Yonghua
Published: March 2023

Background: Patients after pancreaticoduodenectomy (PD) showed improved glucose tolerance. Evidence for the effect of extrahepatic cholestasis on impaired glucose homeostasis secondary to ductal adenocarcinoma of the pancreatic head is limited. Methods: In this prospective cross-sectional study, 50 patients with ductal adenocarcinoma of the pancreatic head were included to assess the effect of extrahepatic cholestasis on glucose tolerance status based on the oral glucose tolerance test (OGTT) before pancreatic surgery. Results: Patients with extrahepatic cholestasis more frequently suffered from worsened impaired glucose homeostasis (prediabetes and new-onset diabetes, 95.2% vs. 58.6%, p = 0.004). Elevated bile acid level was recognized as an independent risk factor for impaired glucose homeostasis (p = 0.024, OR = 6.85). Hepatic insulin clearance (HIC) was significantly higher in patients with elevated bile acid levels (p = 0.001). A strong positive correlation was found between bile acid levels and HIC (r = 0.45, p = 0.001). Conclusions: This study suggested a connection between elevated bile acid levels and worsened impaired glucose homeostasis through increased insulin clearance function in ductal adenocarcinoma of pancreatic head patients.
Cardiomyopathy: A New Perspective from Diagnostic Strategy
Authors: Hirono Keiichi
Published: March 2023

Cardiomyopathy entails a broad group of diseases, acquired or genetic, which result in a similar phenotype [...]
Small Renal Masses: The Evolving Histologic, Imaging, and Genomic Landscapes
Authors: Chavarriaga Julian , Al-Rumayyan Majed , Kumar Ravi , Bernardino Rui , Sayyid Rashid
Published: March 2023

According to the American Cancer Society, it is currently estimated that approximately 81,800 new cases of kidney cancer will be diagnosed in the United States in 2023 [...]
Male Infertility: A Review of Key Papers Appearing in the Reproductive Medicine and Andrology Section of the Journal of Clinical Medicine
Authors: Caroppo Ettore , Colpi Giovanni M.
Published: March 2023

Male infertility accounts for 30% of infertility cases and its prevalence in the general population approximately ranges between 9 and 15%, according to the available surveys [...]
Impact of Lumbar Surgery on Pharmacological Treatment for Patients with Lumbar Spinal Canal Stenosis: A Single-Center Retrospective Study
Authors: Imai Takaya , Nagai Sota , Michikawa Takehiro , Inagaki Risa , Kawabata Soya , Ito Kaori , Hachiya Kurenai , Takeda Hiroki , Ikeda Daiki , Yamada Shigeki , Fujita Nobuyuki , Kaneko Shinjiro
Published: March 2023

Treatment for lumbar spinal canal stenosis (LSCS) is mainly classified into conservative and surgical therapies. Among conservative therapies, pharmacological treatment is commonly prescribed for LSCS. Meanwhile, surgical treatment is the last option for LSCS. This study aimed to examine the impact of lumbar surgery on pharmacological treatment for patients with LSCS. Consecutive patients aged ≥ 40 years who underwent lumbar surgery for LSCS were identified. A total of 142 patients were retrospectively reviewed for preoperative and 6-month and 1-year postoperative LSCS medications. The results showed that the number of LSCS medications significantly decreased after lumbar surgery. The proportion of the patients taking non-steroidal anti-inflammatory drugs, pregabalin/mirogabalin, opioids, prostaglandin E1 analogs, and neurotropin was significantly decreased after lumbar surgery, but that of the patients taking mecobalamin, acetaminophen, and serotonin-noradrenalin reuptake inhibitors was not significantly changed. Additionally, around 15% of the participants showed an increase in LSCS medications even after lumbar surgery. Multivariable analysis revealed that individuals without improvements in walking ability (RR: 2.7, 95% CI: 1.3–5.9) or social life (RR: 2.3, 95% CI: 1.1–5.0) had a greater risk of a postoperative increase in LSCS medications. The study results may provide physicians with beneficial information on treatment for LSCS.