bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Progress in Hydrogel-Based Synthetic Cartilage: Focus on Lubrication and Load-Bearing Capacities
Authors: Qiu Fei , Fan Xiaopeng , Chen Wen , Xu Chunming , Li Yumei , Xie Renjian
Published: February 2023

Articular cartilage (AC), which covers the ends of bones in joints, particularly the knee joints, provides a robust interface to maintain frictionless movement during daily life due to its remarkable lubricating and load-bearing capacities. However, osteoarthritis (OA), characterized by the progressive degradation of AC, compromises the properties of AC and thus leads to frayed and rough interfaces between the bones, which subsequently accelerates the progression of OA. Hydrogels, composed of highly hydrated and interconnected polymer chains, are potential candidates for AC replacement due to their physical and chemical properties being similar to those of AC. In this review, we summarize the recent progress of hydrogel-based synthetic cartilage, or cartilage-like hydrogels, with a particular focus on their lubrication and load-bearing properties. The different formulations, current limitations, and challenges of such hydrogels are also discussed. Moreover, we discuss the future directions of hydrogel-based synthetic cartilage to repair and even regenerate the damaged AC.
Homozygous Missense Variant in the Solute Carrier Organic Anion Transporter 2A1 (SLCO2A1) Gene Underlies Isolated Nail Clubbing
Authors: Umair Muhammad , Bilal Muhammad , Shah Khadim , Said Gulab , Ahmad Farooq
Published: February 2023

Background: Inherited isolated nail clubbing is a very rare Mendelian condition in humans, characterized by enlargement of the terminal segments of fingers and toes with thickened nails. Mutations in two genes have been reported to cause isolated nail clubbing in humans, which are the SLCO2A1 gene and the HPGD gene. Objectives: An extended Pakistani family having two affected siblings born of unaffected consanguineous union was included in the study. Predominant isolated congenital nail clubbing (ICNC) without any other systemic abnormalities was observed, which we aimed to characterize at clinico-genetic level. Methods: Whole exome coupled with Sanger sequencing were employed to uncover the sequence variant as a cause of the disease. Furthermore, protein modeling was carried out to reveal the predicted possible effect of the mutation at the protein level. Results: Whole exome sequencing data analysis revealed a novel biallelic sequence variant (c.155T>A; p.Phe52Tyr) in the SLCO2A1 gene. Further, Sanger sequencing analysis validated and confirmed the segregation of the novel variant in the entire family. Subsequently, protein modeling of the wild-type and mutated SLCO2A1 revealed broad-scale change, which might compromise the proteins’ secondary structure and function. Conclusion: The present study adds another mutation to the SLCO2A1-related pathophysiology. The involvement of SLCO2A1 in the pathogenesis of ICNC may open exciting perceptions of this gene in nail development/morphogenesis.
MIR149 rs2292832 and MIR499 rs3746444 Genetic Variants Associated with the Risk of Rheumatoid Arthritis
Authors: Ali Yasir , Chen Yangchao , Islam Zia Ul , Aman Aisha , Almutairi Mashal M. , Alouffi Abdulaziz , Mohammed Aymen , Shah Aftab Ali , Rehman Zia Ur , Hussain Ibrar , Ali Abid , Jalil Fazal
Published: February 2023

Introduction: MicroRNAs (miRNAs) are small non-coding RNAs that play a key role in post-transcriptional modulation of individual genes’ expression. Several miRNA variants from different populations are known to be associated with an increased risk of rheumatoid arthritis (RA). Aim: This study was undertaken with the aim to investigate the association of single nucleotide variants; namely, rs2292832, rs3746444, rs11614913, rs1044165, and rs767649 of MIR149, MIR499, MIR196, MIR223, and MIR155, respectively, with RA in the Pakistani population. Methods: A case-control study was performed by recruiting and genotyping a total of 600 individuals (300 cases and 300 controls) for these five variants using a TaqMan single-nucleotide polymorphism (SNP) genotyping assay. The resultant genotypic data was statistically analyzed through a chi-squared test for its association with RA under different inheritance models. Results: We found a significant association of rs2292832 with RA at genotypic (co-dominant (p < 0.0001), dominant (CC vs. TT + CT: OR 2.063 (1.437–2.962); p = 0.0001), recessive (TT vs. CT + CC: OR 0.376 (0.259–0.548); p < 0.0001)), and allelic (allele C) levels ((OR 0.506 (0.402–0637); p < 0.0001)). Similarly, the rs3746444 showed a significant association with RA under co-dominant (p = 0.0001), dominant (GG vs. AA + AG: OR 5.246 (3.414–8.061); p < 0.0001), recessive (AA vs. GG + AG: OR 0.653 (0.466–0.916); p = 0.014), and additive models (G vs. A; OR 0.779 (0.620–0.978); p = 0.03). However, we did not observe any significant association of rs11614913, rs1044165, or rs767649 with RA in our subjects. Conclusion: To our knowledge, this was the first study that investigated and found an association between functional polymorphisms in miRNAs and RA in the Pakistani population.
Spotlight on hTERT Complex Regulation in Cutaneous T-Cell Lymphomas
Authors: Ropio Joana , Prochazkova-Carlotti Martina , Batista Rui , Pestana Ana , Chebly Alain , Ferrer Jacky , Idrissi Yamina , Cappellen David , Durães Cecília , Boaventura Paula , Vinagre João , Azzi-Martin Lamia , Poglio Sandrine , Cabeçadas José , Campos Manuel António , Beylot-Barry Marie , Sobrinho-Simões Manuel , Merlio Jean-Philippe , Soares Paula , Chevret Edith
Published: February 2023

As a major cancer hallmark, there is a sustained interest in understanding the telomerase contribution to carcinogenesis in order to therapeutically target this enzyme. This is particularly relevant in primary cutaneous T-cell lymphomas (CTCL), a malignancy showing telomerase dysregulation with few investigative data available. In CTCL, we examined the mechanisms involved in telomerase transcriptional activation and activity regulation. We analyzed 94 CTCL patients from a Franco-Portuguese cohort, as well as 8 cell lines, in comparison to 101 healthy controls. Our results showed that not only polymorphisms (SNPs) located at the promoter of human telomerase reverse transcriptase (hTERT) gene (rs2735940 and rs2853672) but also an SNP located within the coding region (rs2853676) could influence CTCL occurrence. Furthermore, our results sustained that the post-transcriptional regulation of hTERT contributes to CTCL lymphomagenesis. Indeed, CTCL cells present a different pattern of hTERT spliced transcripts distribution from the controls, mostly marked by an increase in the hTERT β+ variants proportion. This increase seems to be associated with CTCL development and progression. Through hTERT splicing transcriptome modulation with shRNAs, we observed that the decrease in the α-β+ transcript induced a decrease in the cell proliferation and tumorigenic capacities of T-MF cells in vitro. Taken together, our data highlight the major role of post-transcriptional mechanisms regulating telomerase non canonical functions in CTCL and suggest a new potential role for the α-β+ hTERT transcript variant.
Editorial of Special Issue “Soil–Structure Interaction”
Authors: Ong Dominic E. L. , Cheng Wen-Chieh , Zhou Hannah
Published: February 2023

In today’s world, construction projects tend to be more complex due to one or a combination of the following reasons: climate change impacting design requirements; enhanced material properties; the scarcity of greenfield sites in highly built-up cities, leading to challenging underground construction; easily accessible scientific knowledge; the prowess of computational speed; the advent of new technologies driving innovation; and stringent health and safety requirements to safeguard the public [...]
Knowledge and Attitude toward E-Cigarettes among First Year University Students in Riyadh, Saudi Arabia
Authors: Alduraywish Shatha A. , Aldakheel Fahad M. , Alsuhaibani Omar S. , Jabaan Anas D. Bin , Alballa Rasheed S. , Alrashed Ahmad W. , Alhassan Mohammed K. , Aldwaighri Mohammed K.
Published: February 2023

Background: Electronic cigarettes are immensely popular among youths across the globe. However, knowledge, attitudes, and perceptions regarding their use vary by country. The present study investigated the knowledge and attitudes toward e-cigarette use among first-year university students in Saudi Arabia. Methods: A cross-sectional design was adopted, and an online, self-administered questionnaire assessing the knowledge of and attitudes toward e-cigarette use was utilized to conduct this study. The study population included students from all streams enrolled in their first year of university. Descriptive statistics were used to report percentages and frequencies, while advanced statistics, such as multiple logistic regression analyses, were used to determine associations. Results: The lifetime and current prevalence of e-cigarette use was 27.4% and 13.5%, respectively, among first-year university students. The mean age of smoking initiation was 16.4 ± 1.2 years. Of e-cigarette users, 31.3% smoked every day and 86.7% used flavored e-cigarettes. Knowledge of the harmful effects of e-cigarettes was high (addiction, 61.2%; asthma, 61%; nicotine content, 75.2%). However, when comparing e-cigarettes to regular cigarettes, only 22.5% and 48.4% of the students reported that they carry the same risk and contain the same chemicals as regular cigarettes do. There was a lack of knowledge (17.1%) regarding government regulations related to e-cigarettes. An attitude of support was observed regarding banning e-cigarettes (2.6 ± 1.5 on a scale of 0 to 4), while at the same time, some associated e-cigarette use with helping to reduce tobacco dependency (2.1 ± 1.2). Marketing adverts were agreed upon to positively influence youth (1.9 ± 1.4). However, the participants’ perceptions relating e-cigarette use to style were not well articulated. Significant gender differences were found: most of the women who participated in the study had better knowledge of e-cigarettes (p < 0.001). Being male, having higher income status (OR = 1.67; p = 0.013), being a current smoker (OR = 11.6; p < 0.001), and having intention for future use (OR = 3.45; p < 0.001) were strong predictors of e-cigarette use. Conclusions: These findings suggested the increasing popularity of e-cigarette use among male first-year university students. More educational campaigns and stricter regulations are needed to curb this trend.
A Low-Cost System Using a Big-Data Deep-Learning Framework for Assessing Physical Telerehabilitation: A Proof-of-Concept
Authors: Ramírez-Sanz José , Garrido-Labrador José , Olivares-Gil Alicia , García-Bustillo Álvaro , Arnaiz-González Álvar , Díez-Pastor José-Francisco , Jahouh Maha , González-Santos Josefa , González-Bernal Jerónimo , Allende-Río Marta , Valiñas-Sieiro Florita , Trejo-Gabriel-Galan Jose , Cubo Esther
Published: February 2023

The consolidation of telerehabilitation for the treatment of many diseases over the last decades is a consequence of its cost-effective results and its ability to offer access to rehabilitation in remote areas. Telerehabilitation operates over a distance, so vulnerable patients are never exposed to unnecessary risks. Despite its low cost, the need for a professional to assess therapeutic exercises and proper corporal movements online should also be mentioned. The focus of this paper is on a telerehabilitation system for patients suffering from Parkinson’s disease in remote villages and other less accessible locations. A full-stack is presented using big data frameworks that facilitate communication between the patient and the occupational therapist, the recording of each session, and real-time skeleton identification using artificial intelligence techniques. Big data technologies are used to process the numerous videos that are generated during the course of treating simultaneous patients. Moreover, the skeleton of each patient can be estimated using deep neural networks for automated evaluation of corporal exercises, which is of immense help to the therapists in charge of the treatment programs.
Evaluation of Health Care Professionals’ Knowledge, Attitudes, and Practice to Prevent the Pandemic Spread of COVID-19: A Questionnaire-Based Cross-Sectional Study from Abha, Saudi Arabia
Authors: Khobrani Moteb , Vasudevan Rajalakshimi , Kandasamy Geetha , Gramish Jawaher A. , Prabahar Kousalya , Paulsamy Premalatha
Published: February 2023

Background: Pharmacists and other healthcare professionals (HCPs) are at risk of transmitting the lethal COVID-19 virus globally and increasing its prevalence. Aim: The aim of this study was to assess knowledge, attitudes, and practices (KAP) about coronavirus disease 2019 (COVID-19) among HCPs in the Asir region for the first time. Methodology: A cross-sectional analysis with 491 healthcare professionals was tested using a pre-tested questionnaire in a tertiary care facility. The association between research variables and questions was determined using Chi-square tests and Kruskal–Wallis tests. Results: Pharmacists and other HCPs exhibited good knowledge, a positive attitude, and a negative practice pattern regarding COVID-19. There was a strong association between knowledge and attitude (correlation coefficient: 0.17; p < 0.001). However, healthcare practitioners had a suboptimal practice score of 2.09 ± 0.62 regarding COVID-19. Conclusion: This study discovered that despite relatively insufficient practices for adherence to recommended techniques regarding COVID-19 prevention during the outbreak, pharmacists and other healthcare professionals have a high level of awareness and a positive attitude towards COVID-19 as a medical condition. There is a need for more involved HCPs, improved COVID-19 management training, and approaches to make healthcare providers feel less anxious.
Contrast-Enhanced Spectral Mammography in the Evaluation of Breast Microcalcifications: Controversies and Diagnostic Management
Authors: Nicosia Luca , Bozzini Anna Carla , Signorelli Giulia , Palma Simone , Pesapane Filippo , Frassoni Samuele , Bagnardi Vincenzo , Pizzamiglio Maria , Farina Mariagiorgia , Trentin Chiara , Penco Silvia , Meneghetti Lorenza , Sangalli Claudia , Cassano Enrico
Published: February 2023

The aim of this study was to evaluate the diagnostic performance of contrast-enhanced spectral mammography (CESM) in predicting breast lesion malignancy due to microcalcifications compared to lesions that present with other radiological findings. Three hundred and twenty-one patients with 377 breast lesions that underwent CESM and histological assessment were included. All the lesions were scored using a 4-point qualitative scale according to the degree of contrast enhancement at the CESM examination. The histological results were considered the gold standard. In the first analysis, enhancement degree scores of 2 and 3 were considered predictive of malignity. The sensitivity (SE) and positive predictive value (PPV) were significative lower for patients with lesions with microcalcifications without other radiological findings (SE = 53.3% vs. 82.2%, p-value < 0.001 and PPV = 84.2% vs. 95.2%, p-value = 0.049, respectively). On the contrary, the specificity (SP) and negative predictive value (NPV) were significative higher among lesions with microcalcifications without other radiological findings (SP = 95.8% vs. 84.2%, p-value = 0.026 and NPV = 82.9% vs. 55.2%, p-value < 0.001, respectively). In a second analysis, degree scores of 1, 2, and 3 were considered predictive of malignity. The SE (80.0% vs. 96.8%, p-value < 0.001) and PPV (70.6% vs. 88.3%, p-value: 0.005) were significantly lower among lesions with microcalcifications without other radiological findings, while the SP (85.9% vs. 50.9%, p-value < 0.001) was higher. The enhancement of microcalcifications has low sensitivity in predicting malignancy. However, in certain controversial cases, the absence of CESM enhancement due to its high negative predictive value can help to reduce the number of biopsies for benign lesions
Rapid Start-Up Characteristics of Anammox under Different Inoculation Conditions
Authors: Tan Qiong , Xia Suhui , Xu Wenlai , Jian Yue
Published: February 2023

The long multiplication time and extremely demanding enrichment environment requirements of Anammox bacteria (AAOB) have led to difficult reactor start-ups and hindered its practical dissemination. Few feasibility studies have been reported on the recovery of AAOB activity initiation after inlet substrate disconnection caused by an unfavorable condition, and few factors, such as indicators of the recovery process, have been explored. Therefore, in this experiment, two modified expanded granular sludge bed reactors (EGSB) were inoculated with 1.5 L anaerobic granular sludge (AGS) + 1 L Anammox sludge (AMS) (R1) and 2.5 L anaerobic granular sludge (AGS) (R2), respectively. After a long-term (140 days) starvation shock at a high temperature (38 °C), the bacteria population activity recovery experiments were conducted. After 160 days, both reactors were successfully started up, and the total nitrogen removal rates exceeded 87%. Due to the experimental period, the total nitrogen removal rate of R2 was slightly higher than that of R1 in the final stage. However, it is undeniable that R2 had a relatively long activity delay during startup, while R1 had no significant activity delay during startup. The sludge obtained from R1 had a higher specific anammox activity (SAA). Analysis of the extracellular polymer substances (EPS) results showed that the extracellular polymer content in R1 was higher than that in R2 throughout the recovery process, indicating that R1 had higher sludge stability and denitrification performance. Scanning electron microscopy (SEM) analysis showed that more extracellular filamentous bacteria could be seen in the R1 reactor with better morphology of Anammox bacteria. In contrast, the R2 reactor had fewer extracellular hyphae and micropores as a percentage and higher filamentous bacteria content. The results of microbial 16SrDNA analysis showed that R1 used AAOB as inoculum to initiate Anammox, and the reactor was enriched with Anammox bacteria earlier and in much greater abundance than R2. The experimental results indicated that inoculating mixed anaerobic granular sludge and Anammox sludge to initiate an anammox reactor was more effective.
The Impact of Exercise on Immunity, Metabolism, and Atherosclerosis
Authors: Meyer-Lindemann Ulrike , Moggio Aldo , Dutsch Alexander , Kessler Thorsten , Sager Hendrik B.
Published: February 2023

Physical exercise represents an effective preventive and therapeutic strategy beneficially modifying the course of multiple diseases. The protective mechanisms of exercise are manifold; primarily, they are elicited by alterations in metabolic and inflammatory pathways. Exercise intensity and duration strongly influence the provoked response. This narrative review aims to provide comprehensive up-to-date insights into the beneficial effects of physical exercise by illustrating the impact of moderate and vigorous exercise on innate and adaptive immunity. Specifically, we describe qualitative and quantitative changes in different leukocyte subsets while distinguishing between acute and chronic exercise effects. Further, we elaborate on how exercise modifies the progression of atherosclerosis, the leading cause of death worldwide, representing a prime example of a disease triggered by metabolic and inflammatory pathways. Here, we describe how exercise counteracts causal contributors and thereby improves outcomes. In addition, we identify gaps that still need to be addressed in the future.
Antioxidant, Tyrosinase, α-Glucosidase, and Elastase Enzyme Inhibition Activities of Optimized Unripe Ajwa Date Pulp (Phoenix dactylifera) Extracts by Response Surface Methodology
Authors: Alshammari Fanar , Alam Md Badrul , Song Bo-Rim , Lee Sang-Han
Published: February 2023

The Ajwa date (Phoenix dactylifera L., Arecaceae family) is a popular edible fruit consumed all over the world. The profiling of the polyphenolic compounds of optimized unripe Ajwa date pulp (URADP) extracts is scarce. The aim of this study was to extract polyphenols from URADP as effectively as possible by using response surface methodology (RSM). A central composite design (CCD) was used to optimize the extraction conditions with respect to ethanol concentration, extraction time, and temperature and to achieve the maximum amount of polyphenolic compounds. High-resolution mass spectrometry was used to identify the URADP’s polyphenolic compounds. The DPPH-, ABTS-radical scavenging, α-glucosidase, elastase and tyrosinase enzyme inhibition of optimized extracts of URADP was also evaluated. According to RSM, the highest amounts of TPC (24.25 ± 1.02 mgGAE/g) and TFC (23.98 ± 0.65 mgCAE/g) were obtained at 52% ethanol, 81 min time, and 63 °C. Seventy (70) secondary metabolites, including phenolic, flavonoids, fatty acids, and sugar, were discovered using high-resolution mass spectrometry. In addition, twelve (12) new phytoconstituents were identified for the first time in this plant. Optimized URADP extract showed inhibition of DPPH-radical (IC50 = 87.56 mg/mL), ABTS-radical (IC50 = 172.36 mg/mL), α-glucosidase (IC50 = 221.59 mg/mL), elastase (IC50 = 372.25 mg/mL) and tyrosinase (IC50 = 59.53 mg/mL) enzymes. The results revealed a significant amount of phytoconstituents, making it an excellent contender for the pharmaceutical and food industries.
Enhanced UV-B Radiation Induced the Proanthocyanidins Accumulation in Red Rice Grain of Traditional Rice Cultivars and Increased Antioxidant Capacity in Aging Mice
Authors: Li Xiang , Sheng Jianjun , Li Zuran , He Yongmei , Zu Yanqun , Li Yuan
Published: February 2023

Proanthocyanidins are major UV-absorbing compounds. To clarify the effect of enhanced UV-B radiation on the proanthocyanidin synthesis and antioxidant capacity of traditional rice varieties in Yuanyang terraced fields, we studied the effects of enhanced UV-B radiation (0, 2.5, 5.0, 7.5 kJ·m−2·d−1) on the rice grain morphology, proanthocyanidins content, and synthesis. The effects of UV-B radiation on the antioxidant capacity of rice were evaluated by feeding aging model mice. The results showed that UV-B radiation significantly affected the grain morphology of red rice and increased the compactness of starch grains in the starch storage cells of central endosperm. The content of proanthocyanidin B2 and C1 in the grains was significantly increased by 2.5 and 5.0 kJ·m−2·d−1 UV-B radiation. The activity of leucoanthocyanidin reductase was higher in rice treated by 5.0 kJ·m−2·d−1 than other treatments. The number of neurons in the hippocampus CA1 of mice brain fed red rice increased. After 5.0 kJ·m−2·d−1 treatment, red rice has the best antioxidant effect on aging model mice. UV-B radiation induces the synthesis of rice proanthocyanidins B2 and C1, and the antioxidant capacity of rice is related to the content of proanthocyanidins.
Galangin Rescues Alzheimer’s Amyloid-β Induced Mitophagy and Brain Organoid Growth Impairment
Authors: Zhang Ru , Lu Juan , Pei Gang , Huang Shichao
Published: February 2023

Dysfunctional mitochondria and mitophagy are hallmarks of Alzheimer’s disease (AD). It is widely accepted that restoration of mitophagy helps to maintain cellular homeostasis and ameliorates the pathogenesis of AD. It is imperative to create appropriate preclinical models to study the role of mitophagy in AD and to assess potential mitophagy-targeting therapies. Here, by using a novel 3D human brain organoid culturing system, we found that amyloid-β (Aβ1-42,10 μM) decreased the growth level of organoids, indicating that the neurogenesis of organoids may be impaired. Moreover, Aβ treatment inhibited neural progenitor cell (NPC) growth and induced mitochondrial dysfunction. Further analysis revealed that mitophagy levels were reduced in the brain organoids and NPCs. Notably, galangin (10 μM) treatment restored mitophagy and organoid growth, which was inhibited by Aβ. The effect of galangin was blocked by the mitophagy inhibitor, suggesting that galangin possibly acted as a mitophagy enhancer to ameliorate Aβ-induced pathology. Together, these results supported the important role of mitophagy in AD pathogenesis and suggested that galangin may be used as a novel mitophagy enhancer to treat AD.
Circulating Cell-Free DNA Levels in Psychiatric Diseases: A Systematic Review and Meta-Analysis
Authors: Melamud Mark M. , Buneva Valentina N. , Ermakov Evgeny A.
Published: February 2023

The cell-free DNA (cfDNA) levels are known to increase in biological fluids in various pathological conditions. However, the data on circulating cfDNA in severe psychiatric disorders, including schizophrenia, bipolar disorder (BD), and depressive disorders (DDs), is contradictory. This meta-analysis aimed to analyze the concentrations of different cfDNA types in schizophrenia, BD, and DDs compared with healthy donors. The mitochondrial (cf-mtDNA), genomic (cf-gDNA), and total cfDNA concentrations were analyzed separately. The effect size was estimated using the standardized mean difference (SMD). Eight reports for schizophrenia, four for BD, and five for DDs were included in the meta-analysis. However, there were only enough data to analyze the total cfDNA and cf-gDNA in schizophrenia and cf-mtDNA in BD and DDs. It has been shown that the levels of total cfDNA and cf-gDNA in patients with schizophrenia are significantly higher than in healthy donors (SMD values of 0.61 and 0.6, respectively; p < 0.00001). Conversely, the levels of cf-mtDNA in BD and DDs do not differ compared with healthy individuals. Nevertheless, further research is needed in the case of BD and DDs due to the small sample sizes in the BD studies and the significant data heterogeneity in the DD studies. Additionally, further studies are needed on cf-mtDNA in schizophrenia or cf-gDNA and total cfDNA in BD and DDs due to insufficient data. In conclusion, this meta-analysis provides the first evidence of increases in total cfDNA and cf-gDNA in schizophrenia but shows no changes in cf-mtDNA in BD and DDs. Increased circulating cfDNA in schizophrenia may be associated with chronic systemic inflammation, as cfDNA has been found to trigger inflammatory responses.
Contributing to Biochemistry and Optoelectronics: Pyrrolo[1′,2′:2,3]imidazo[1,5-a]indoles and Cyclohepta[4,5]pyrrolo[1,2-c]pyrrolo[1,2-a]imidazoles via [3+2] Annulation of Acylethynylcycloalka[b]pyrroles with Δ1-Pyrrolines
Authors: Oparina Ludmila A. , Kolyvanov Nikita A. , Ushakov Igor A. , Nikitina Lina P. , Petrova Olga V. , Sobenina Lyubov N. , Petrushenko Konstantin B. , Trofimov Boris A.
Published: February 2023

Available pyrrolylalkynones with tetrahydroindolyl, cycloalkanopyrrolyl, and dihydrobenzo[g]indolyl moieties, acylethynylcycloalka[b]pyrroles, are readily annulated with Δ1-pyrrolines (MeCN/THF, 70 °C, 8 h) to afford a series of novel pyrrolo[1′,2′:2,3]imidazo[1,5-a]indoles and cyclohepta[4,5]pyrrolo[1,2-c]pyrrolo[1,2-a]imidazoles functionalized with an acylethenyl group in up to an 81% yield. This original synthetic approach contributes to the arsenal of chemical methods promoting drug discovery. Photophysical studies show that some of the synthesized compounds, e.g., benzo[g]pyrroloimidazoindoles, are prospective candidates for TADF emitters of OLED.
Ca2+- and Voltage-Activated K+ (BK) Channels in the Nervous System: One Gene, a Myriad of Physiological Functions
Authors: Ancatén-González Carlos , Segura Ignacio , Alvarado-Sánchez Rosangelina , Chávez Andrés E. , Latorre Ramon
Published: February 2023

BK channels are large conductance potassium channels characterized by four pore-forming α subunits, often co-assembled with auxiliary β and γ subunits to regulate Ca2+ sensitivity, voltage dependence and gating properties. BK channels are abundantly expressed throughout the brain and in different compartments within a single neuron, including axons, synaptic terminals, dendritic arbors, and spines. Their activation produces a massive efflux of K+ ions that hyperpolarizes the cellular membrane. Together with their ability to detect changes in intracellular Ca2+ concentration, BK channels control neuronal excitability and synaptic communication through diverse mechanisms. Moreover, increasing evidence indicates that dysfunction of BK channel-mediated effects on neuronal excitability and synaptic function has been implicated in several neurological disorders, including epilepsy, fragile X syndrome, mental retardation, and autism, as well as in motor and cognitive behavior. Here, we discuss current evidence highlighting the physiological importance of this ubiquitous channel in regulating brain function and its role in the pathophysiology of different neurological disorders.
Increased Aquaporin-7 Expression Is Associated with Changes in Rat Brown Adipose Tissue Whitening in Obesity: Impact of Cold Exposure and Bariatric Surgery
Authors: Frühbeck Gema , Méndez-Giménez Leire , Becerril Sara , Ramírez Beatriz , Hernández-Pardos Ana Wenting , Cienfuegos Javier A. , Valentí Víctor , Moncada Rafael , Catalán Victoria , Gómez-Ambrosi Javier , da Silva Inês V. , Soveral Graça , Rodríguez Amaia
Published: February 2023

Glycerol is a key metabolite for lipid accumulation in insulin-sensitive tissues. We examined the role of aquaporin-7 (AQP7), the main glycerol channel in adipocytes, in the improvement of brown adipose tissue (BAT) whitening, a process whereby brown adipocytes differentiate into white-like unilocular cells, after cold exposure or bariatric surgery in male Wistar rats with diet-induced obesity (DIO) (n = 229). DIO promoted BAT whitening, evidenced by increased BAT hypertrophy, steatosis and upregulation of the lipogenic factors Pparg2, Mogat2 and Dgat1. AQP7 was detected in BAT capillary endothelial cells and brown adipocytes, and its expression was upregulated by DIO. Interestingly, AQP7 gene and protein expressions were downregulated after cold exposure (4 °C) for 1 week or one month after sleeve gastrectomy in parallel to the improvement of BAT whitening. Moreover, Aqp7 mRNA expression was positively associated with transcripts of the lipogenic factors Pparg2, Mogat2 and Dgat1 and regulated by lipogenic (ghrelin) and lipolytic (isoproterenol and leptin) signals. Together, the upregulation of AQP7 in DIO might contribute to glycerol influx used for triacylglycerol synthesis in brown adipocytes, and hence, BAT whitening. This process is reversible by cold exposure and bariatric surgery, thereby suggesting the potential of targeting BAT AQP7 as an anti-obesity therapy.
Advancing Stroke Research on Cerebral Thrombi with Omic Technologies
Authors: Costamagna Gianluca , Bonato Sara , Corti Stefania , Meneri Megi
Published: February 2023

Cerebrovascular diseases represent a leading cause of disability, morbidity, and death worldwide. In the last decade, the advances in endovascular procedures have not only improved acute ischemic stroke care but also conceded a thorough analysis of patients’ thrombi. Although early anatomopathological and immunohistochemical analyses have provided valuable insights into thrombus composition and its correlation with radiological features, response to reperfusion therapies, and stroke etiology, these results have been inconclusive so far. Recent studies applied single- or multi-omic approaches—such as proteomics, metabolomics, transcriptomics, or a combination of these—to investigate clot composition and stroke mechanisms, showing high predictive power. Particularly, one pilot studies showed that combined deep phenotyping of stroke thrombi may be superior to classic clinical predictors in defining stroke mechanisms. Small sample sizes, varying methodologies, and lack of adjustments for potential confounders still represent roadblocks to generalizing these findings. However, these techniques hold the potential to better investigate stroke-related thrombogenesis and select secondary prevention strategies, and to prompt the discovery of novel biomarkers and therapeutic targets. In this review, we summarize the most recent findings, overview current strengths and limitations, and present future perspectives in the field.
Viruses Binding to Host Receptors Interacts with Autophagy
Authors: Yang Jinsung
Published: February 2023

Viruses must cross the plasma membrane to infect cells, making them eager to overcome this barrier in order to replicate in hosts. They bind to cell surface receptors as the first step of initiating entry. Viruses can use several surface molecules that allow them to evade defense mechanisms. Various mechanisms are stimulated to defend against viruses upon their entry into cells. Autophagy, one of the defense systems, degrades cellular components to maintain homeostasis. The presence of viruses in the cytosol regulates autophagy; however, the mechanisms by which viral binding to receptors regulates autophagy have not yet been fully established. This review discusses recent findings on autophagy induced by interactions between viruses and receptors. It provides novel perspectives on the mechanism of autophagy as regulated by viruses.
Spinal Cord Sensitization and Spinal Inflammation from an In Vivo Rat Endplate Injury Associated with Painful Intervertebral Disc Degeneration
Authors: Lai Alon , Iliff Denise , Zaheer Kashaf , Wang Dalin , Gansau Jennifer , Laudier Damien M. , Zachariou Venetia , Iatridis James C.
Published: February 2023

Intervertebral disc (IVD) degeneration with Modic-like changes is strongly associated with pain. Lack of effective disease-modifying treatments for IVDs with endplate (EP) defects means there is a need for an animal model to improve understanding of how EP-driven IVD degeneration can lead to spinal cord sensitization. This rat in vivo study determined whether EP injury results in spinal dorsal horn sensitization (substance P, SubP), microglia (Iba1) and astrocytes (GFAP), and evaluated their relationship with pain-related behaviors, IVD degeneration, and spinal macrophages (CD68). Fifteen male Sprague Dawley rats were assigned into sham or EP injury groups. At chronic time points, 8 weeks after injury, lumbar spines and spinal cords were isolated for immunohistochemical analyses of SubP, Iba1, GFAP, and CD68. EP injury most significantly increased SubP, demonstrating spinal cord sensitization. Spinal cord SubP-, Iba1- and GFAP-immunoreactivity were positively correlated with pain-related behaviors, indicating spinal cord sensitization and neuroinflammation play roles in pain responses. EP injury increased CD68 macrophages in the EP and vertebrae, and spinal cord SubP-, Iba1- and GFAP-ir were positively correlated with IVD degeneration and CD68-ir EP and vertebrae. We conclude that EP injuries result in broad spinal inflammation with crosstalk between spinal cord, vertebrae and IVD, suggesting that therapies must address neural pathologies, IVD degeneration, and chronic spinal inflammation.
Endothelin Receptor Antagonists in Kidney Disease
Authors: Martínez-Díaz Irene , Martos Nerea , Llorens-Cebrià Carmen , Álvarez Francisco J. , Bedard Patricia W. , Vergara Ander , Jacobs-Cachá Conxita , Soler Maria José
Published: February 2023

Endothelin (ET) is found to be increased in kidney disease secondary to hyperglycaemia, hypertension, acidosis, and the presence of insulin or proinflammatory cytokines. In this context, ET, via the endothelin receptor type A (ETA) activation, causes sustained vasoconstriction of the afferent arterioles that produces deleterious effects such as hyperfiltration, podocyte damage, proteinuria and, eventually, GFR decline. Therefore, endothelin receptor antagonists (ERAs) have been proposed as a therapeutic strategy to reduce proteinuria and slow the progression of kidney disease. Preclinical and clinical evidence has revealed that the administration of ERAs reduces kidney fibrosis, inflammation and proteinuria. Currently, the efficacy of many ERAs to treat kidney disease is being tested in randomized controlled trials; however, some of these, such as avosentan and atrasentan, were not commercialized due to the adverse events related to their use. Therefore, to take advantage of the protective properties of the ERAs, the use of ETA receptor-specific antagonists and/or combining them with sodium-glucose cotransporter 2 inhibitors (SGLT2i) has been proposed to prevent oedemas, the main ERAs-related deleterious effect. The use of a dual angiotensin-II type 1/endothelin receptor blocker (sparsentan) is also being evaluated to treat kidney disease. Here, we reviewed the main ERAs developed and the preclinical and clinical evidence of their kidney-protective effects. Additionally, we provided an overview of new strategies that have been proposed to integrate ERAs in kidney disease treatment.
Structure-Function Studies of Sponge-Derived Compounds on the Cardiac CaV3.1 Channel
Authors: Depuydt Anne-Sophie , Patel Piyush A. , Toplak Žan , Bhat Chinmaya , Voráčová Manuela , Eteläinen Irene , Vitulano Fiammetta , Bruun Tanja , Lempinen Antti , Hribernik Nives , Mäki-Lohiluoma Eero , Hendrickx Louise , Pinheiro-Junior Ernesto Lopes , Tomašič Tihomir , Mašič Lucija Peterlin , Yli-Kauhaluoma Jari , Kiuru Paula , Tytgat Jan , Peigneur Steve
Published: February 2023

T-type calcium (CaV3) channels are involved in cardiac automaticity, development, and excitation–contraction coupling in normal cardiac myocytes. Their functional role becomes more pronounced in the process of pathological cardiac hypertrophy and heart failure. Currently, no CaV3 channel inhibitors are used in clinical settings. To identify novel T-type calcium channel ligands, purpurealidin analogs were electrophysiologically investigated. These compounds are alkaloids produced as secondary metabolites by marine sponges, and they exhibit a broad range of biological activities. In this study, we identified the inhibitory effect of purpurealidin I (1) on the rat CaV3.1 channel and conducted structure–activity relationship studies by characterizing the interaction of 119 purpurealidin analogs. Next, the mechanism of action of the four most potent analogs was investigated. Analogs 74, 76, 79, and 99 showed a potent inhibition on the CaV3.1 channel with IC50’s at approximately 3 μM. No shift of the activation curve could be observed, suggesting that these compounds act like a pore blocker obstructing the ion flow by binding in the pore region of the CaV3.1 channel. A selectivity screening showed that these analogs are also active on hERG channels. Collectively, a new class of CaV3 channel inhibitors has been discovered and the structure–function studies provide new insights into the synthetic design of drugs and the mechanism of interaction with T-type CaV channels.
Inhibitors against Two PDZ Domains of MDA-9 Suppressed Migration of Breast Cancer Cells
Authors: Tang Heng , Wang Lei , Li Shuju , Wei Xiaoli , Lv Mengqi , Zhong Fumei , Liu Yaqian , Liu Jiuyang , Fu Bangguo , Zhu Qizhi , Wang Dan , Liu Jiajia , Ruan Ke , Gao Jia , Xu Weiping
Published: February 2023

Melanoma differentiation-associated gene 9 (MDA-9) is a small adaptor protein with tandem PDZ domains that promotes tumor progression and metastasis in various human cancers. However, it is difficult to develop drug-like small molecules with high affinity due to the narrow groove of the PDZ domains of MDA-9. Herein, we identified four novel hits targeting the PDZ1 and PDZ2 domains of MDA-9, namely PI1A, PI1B, PI2A, and PI2B, using a protein-observed nuclear magnetic resonance (NMR) fragment screening method. We also solved the crystal structure of the MDA-9 PDZ1 domain in complex with PI1B and characterized the binding poses of PDZ1-PI1A and PDZ2-PI2A, guided by transferred paramagnetic relaxation enhancement. The protein–ligand interaction modes were then cross-validated by the mutagenesis of the MDA-9 PDZ domains. Competitive fluorescence polarization experiments demonstrated that PI1A and PI2A blocked the binding of natural substrates to the PDZ1 and PDZ2 domains, respectively. Furthermore, these inhibitors exhibited low cellular toxicity, but suppressed the migration of MDA-MB-231 breast carcinoma cells, which recapitulated the phenotype of MDA-9 knockdown. Our work has paved the way for the development of potent inhibitors using structure-guided fragment ligation in the future.
Thymosin Beta 4 Inhibits LPS and ATP-Induced Hepatic Stellate Cells via the Regulation of Multiple Signaling Pathways
Authors: Choi Jihye , Cho Yunsang , Choi Hwal , Lee Sangmin , Han Hyeju , Lee Jeonghyeon , Kwon Jungkee
Published: February 2023

Risk signals are characteristic of many common inflammatory diseases and can function to activate nucleotide-binding oligomerization (NLR) family pyrin domain-containing 3 (NLRP3), the innate immune signal receptor in cytoplasm. The NLRP3 inflammasome plays an important role in the development of liver fibrosis. Activated NLRP3 nucleates the assembly of inflammasomes, leading to the secretion of interleukin (IL)-1β and IL-18, the activation of caspase-1, and the initiation of the inflammatory process. Therefore, it is essential to inhibit the activation of the NLRP3 inflammasome, which plays a vital role in the immune response and in initiating inflammation. RAW 264.7 and LX-2 cells were primed with lipopolysaccharide (LPS) for 4 h and subsequently stimulated for 30 min with 5 mM of adenosine 5′-triphosphate (ATP) to activate the NLRP3 inflammasome. Thymosin beta 4 (Tβ4) was supplemented to RAW264.7 and LX-2 cells 30 min before ATP was added. As a result, we investigated the effects of Tβ4 on the NLRP3 inflammasome. Tβ4 prevented LPS-induced NLRP3 priming by inhibiting NF-kB and JNK/p38 MAPK expression and the LPS and ATP-induced production of reactive oxygen species. Moreover, Tβ4 induced autophagy by controlling autophagy markers (LC3A/B and p62) through the inhibition of the PI3K/AKT/mTOR pathway. LPS combined with ATP significantly increased thee protein expression of inflammatory mediators and NLRP3 inflammasome markers. These events were remarkably suppressed by Tβ4. In conclusion, Tβ4 attenuated NLRP3 inflammasomes by inhibiting NLRP3 inflammasome-related proteins (NLRP3, ASC, IL-1β, and caspase-1). Our results indicate that Tβ4 attenuated the NLRP3 inflammasome through multiple signaling pathway regulations in macrophage and hepatic stellate cells. Therefore, based on the above findings, it is hypothesized that Tβ4 could be a potential inflammatory therapeutic agent targeting the NLRP3 inflammasome in hepatic fibrosis regulation.
Unusual Square Pyramidal Chalcogenide Mo5 Cluster with Bridging Pyrazolate-Ligands
Authors: Savina Iulia V. , Ivanov Anton A. , Evtushok Darya V. , Gayfulin Yakov M. , Komarovskikh Andrey Y. , Syrokvashin Mikhail M. , Ivanova Mariia N. , Asanov Igor P. , Eltsov Ilia V. , Kuratieva Natalia V. , Mironov Yuri V. , Shestopalov Michael A.
Published: February 2023

The family of chalcogenide molybdenum clusters is well presented in the literature by a series of compounds of nuclearity ranging from binuclear to multinuclear articulating octahedral fragments. Clusters actively studied in the last decades were shown to be promising as components of superconducting, magnetic, and catalytic systems. Here, we report the synthesis and detailed characterization of new and unusual representatives of chalcogenide clusters: square pyramidal complexes [{Mo5(μ3-Se)i4(μ4-Se)i(μ-pz)i4}(pzH)t5]1+/2+ (pzH = pyrazole, i = inner, t = terminal). Individually obtained oxidized (2+) and reduced (1+) forms have very close geometry (proven by single-crystal X-ray diffraction analysis) and are able to reversibly transform into each other, which was confirmed by cyclic voltammetry. Comprehensive characterization of the complexes, both in solid and in solution, confirms the different charge state of molybdenum in clusters (XPS), magnetic properties (EPR), and so on. DFT calculations complement the diverse study of new complexes, expanding the chemistry of molybdenum chalcogenide clusters.
Antibacterial Activity of Nanostructured Zinc Oxide Tetrapods
Authors: Büter Aike , Maschkowitz Gregor , Baum Martina , Mishra Yogendra Kumar , Siebert Leonard , Adelung Rainer , Fickenscher Helmut
Published: February 2023

Zinc oxide (ZnO) tetrapods as microparticles with nanostructured surfaces show peculiar physical properties and anti-infective activities. The aim of this study was to investigate the antibacterial and bactericidal properties of ZnO tetrapods in comparison to spherical, unstructured ZnO particles. Additionally, killing rates of either methylene blue-treated or untreated tetrapods and spherical ZnO particles for Gram-negative and Gram-positive bacteria species were determined. ZnO tetrapods showed considerable bactericidal activity against Staphylococcus aureus, and Klebsiella pneumoniae isolates, including multi-resistant strains, while Pseudomonas aeruginosa and Enterococcus faecalis remained unaffected. Almost complete elimination was reached after 24 h for Staphylococcus aureus at 0.5 mg/mL and Klebsiella pneumoniae at 0.25 mg/mL. Surface modifications of spherical ZnO particles by treatment with methylene blue even improved the antibacterial activity against Staphylococcus aureus. Nanostructured surfaces of ZnO particles provide active and modifiable interfaces for the contact with and killing of bacteria. The application of solid state chemistry, i.e., the direct matter-to-matter interaction between active agent and bacterium, in the form of ZnO tetrapods and non-soluble ZnO particles, can add an additional principle to the spectrum of antibacterial mechanisms, which is, in contrast to soluble antibiotics, depending on the direct local contact with the microorganisms on tissue or material surfaces.
Core-Shell Magnetic Imprinted Polymers for the Recognition of FLAG-Tagpeptide
Authors: Lafuente-González Elsa , Guadaño-Sánchez Miriam , Urriza-Arsuaga Idoia , Urraca Javier Lucas
Published: February 2023

FLAG® tag (DYKDDDDK) is a small epitope peptide employed for the purification of recombinant proteins such as immunoglobulins, cytokines, and gene regulatory proteins. It provides superior purity and recoveries of fused target proteins when compared to the commonly used His-tag. Nevertheless, the immunoaffinity-based adsorbents required for their isolation are far more expensive than the ligand-based affinity resin used in combination with the His-tag. In order to overcome this limitation we report herein the development of molecularly imprinted polymers (MIPs) selective to the FLAG® tag. The polymers were prepared by the epitope imprinting approach using a four amino acids peptide, DYKD, including part of the FLAG® sequence as template molecule. Different kinds of magnetic polymers were synthesised in aqueous and organic media also using different sizes of magnetite core nanoparticles. The synthesised polymers were used as solid phase extraction materials with excellent recoveries and high specificity for both peptides. The magnetic properties of the polymers confer a new, effective, simple, and fast method in the purification using FLAG® tag.
A Comparative Review of Pregnancy and Cancer and Their Association with Endoplasmic Reticulum Aminopeptidase 1 and 2
Authors: Hur Brian , Wong Veronica , Lee Eun D.
Published: February 2023

The fundamental basis of pregnancy and cancer is to determine the fate of the survival or the death of humanity. However, the development of fetuses and tumors share many similarities and differences, making them two sides of the same coin. This review presents an overview of the similarities and differences between pregnancy and cancer. In addition, we will also discuss the critical roles that Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and 2 may play in the immune system, cell migration, and angiogenesis, all of which are essential for fetal and tumor development. Even though the comprehensive understanding of ERAP2 lags that of ERAP1 due to the lack of an animal model, recent studies have shown that both enzymes are associated with an increased risk of several diseases, including pregnancy disorder pre-eclampsia (PE), recurrent miscarriages, and cancer. The exact mechanisms in both pregnancy and cancer need to be elucidated. Therefore, a deeper understanding of ERAP’s role in diseases can make it a potential therapeutic target for pregnancy complications and cancer and offer greater insight into its impact on the immune system.