bluuebunny/crossref_metadata_2025 huggingface dataset:
A Multifractal Vision of 5-Fluorouracil Release from Chitosan-Based Matrix
Authors: Paun Maria-Alexandra , Paun Vladimir-Alexandru , Paun Viorel-Puiu
Published: October 2022

A suite of four drug deliverance formulations grounded on 5-fluorouracil enclosed in a chitosan-founded intercellular substance was produced by 3,7-dimethyl-2,6-octadienal with in situ hydrogelation. The formulations have been examined from a morphological and structural point of view by Fourier transform infrared (FTIR) spectroscopy and microscopy with polarized light, respectively. The polarized optical microscopy (POM) pictures of the three representative formulations obtained were investigated by fractal analysis. The fractal dimension and lacunarity of each of them were thus calculated. In this paper, a novel theoretical method for mathematically describing medicament deliverance dynamics in the context of the polymeric medicament constitution limit has been advanced. Assuming that the polymeric drug motion unfolds only on the so-called non-differentiable curves (considered mathematically multifractal curves), it looks like in a one-dimensional hydrodynamic movement within a multifractal formalism, the drug-release physics models are provided by isochronous kinetics, but at a scale of resolution necessarily non-differentiable.
The Future of Public Health through Science Fiction
Authors: De Matas Jarrel Kristan Zakhary
Published: October 2022

This study investigates the ability of science fiction to address issues that emerge in public health. The issues that form the focus of this paper include the spread of misinformation and disinformation, dependence on technology, and competent public-private partnerships that serve the interests of society. Each of these issues is brought under the spotlight by Barbadian sociologist Karen Lord in ‘The Plague Doctors’ and American psychiatrist Justin C. Key in ‘The Algorithm Will See You Know’. The stories, although set in unrealized futures and describe as yet inconceivable advancements in technology, contain real-world problems involved in accessing healthcare. In doing so, both writers attend to the viability of literature, and the humanities in general, as a vehicle for encouraging reform to public health policies that face challenges such as inequities in healthcare and raising greater awareness of health concerns. My study bridges public health and literature, specifically science fiction, to get certain messages across. These messages include effectively communicating risks to people’s health, increasing understanding of social responsibility, and addressing uncertainty with transparency. The stories in question reveal futures where public health management has, for the most part, either got it right, in the case of ‘The Plague Doctors’, or not quite, in the case of ‘The Algorithm Will See You Now’. Because I consider the COVID-19 pandemic to be less of a disruptor to public health and more of a revealer of what public health needs to focus on, I foresee interdisciplinary projects such as mine as crucial to bridging the disconnect between people and public health policies.
Manual Physiotherapy Combined with Pelvic Floor Training in Women Suffering from Stress Urinary Incontinence and Chronic Nonspecific Low Back Pain: A Preliminary Study
Authors: Giordani Gianluca , De Angelis Sara , Parisi Annunziata Isabella , D’amico Andrea Cosimo , Di Re Moira , Liumbruno Chiara , Tamburella Federica , Lisi Danilo , Galeoto Giovanni , Tramontano Marco
Published: October 2022

Stress urinary incontinence (SUI) represents one of the most common subtypes of urinary incontinence (UI) reported by women. Studies have shown an association of SUI with nonspecific low back pain (NSLBP). The primary aim of the present study was to explore the long-term effects of a combined treatment of manual techniques and pelvic floor muscle (PFM) training in women suffering from SUI associated with NSLBP. The secondary aim was to evaluate which manual approach combined with PFM rehabilitation is more effective in improving symptoms related to SUI and in reducing pain perception related to NSLBP. Twenty-six patients suffering from SUI associated with chronic NSLBP were randomly assigned to one of two groups: the postural rehabilitation group (PRg) or the spinal mobilization group (SMg). Both groups performed a manual approach combined with PFM rehabilitation. All patients were evaluated before the treatment (T0), after 10 sessions (T1) and after 30 days from the end of the treatment (T2). The results showed an improvement in both groups in all of the investigated outcomes. Combining manual therapy and PFM training within the same therapy session may be useful for improving both SUI and NSLBP and increasing the quality of life of women suffering from SUI associated with NSLBP.
Benefits of Cardio-Pulmonary Rehabilitation in Moderate to Severe Forms of COVID-19 Infection
Authors: Douin Clara , Forton Kevin , Lamotte Michel , Gillet Alexis , Van de Borne Philippe
Published: October 2022

Our aim was to evaluate the benefits of cardio-pulmonary rehabilitation on severe to moderate COVID-19 patients. 25 discharged COVID-19 patients underwent a cardio-pulmonary test (CPET), a spirometry test and a measure of carbon monoxide lung diffusion capacity (DLCO) at the beginning of their rehabilitation program and after 23 ± 5 rehabilitation sessions. This rehabilitation program combined interval training exercises on a bike and resistance exercises for major muscle groups. We then compared their progress in rehabilitation to that obtained with cardiac patients. At the beginning of their rehabilitation program, COVID-19 patients presented a reduced physical capacity with a maximal aerobic capacity (VO2 max) at 71% of predicted value, a maximal workload at 70% of predicted value and an exercise hyperventilation measured by a higher VE/VCO2 slope. Exercise was mainly limited by muscle deconditioning. After rehabilitation, the VO2 max and maximal workload increased in COVID 19 patients by 18% and 26%, respectively. In patients with ischemic heart disease the post-rehabilitation gains in VO2 max and maximal workload were 22% and 25%, respectively. Moreover, exercise hyperventilation decreased by 10% in both groups. On the other hand, the intrinsic pulmonary function of COVID 19 patients improved following natural recovery. In conclusion, even if cardio-pulmonary rehabilitation is probably not the only parameter which explains the partial recovery of moderate to severe COVID-19 patients, it certainly helps to improve their physical capacity and reduce exercise hyperventilation.
Chitosan Soaking Improves Seed Germination of Platycodon Grandiflorus and Enhances Its Growth, Photosynthesis, Resistance, Yield, and Quality
Authors: Liu Hai , Zheng Zhihong , Han Xue , Zhang Cheng , Li Haitao , Wu Mingkai
Published: October 2022

Platycodon grandiflorus is a medical, ornamental, and edible traditional Chinese medicine whose seed germination and plant growth are frequently restricted by dormancy and stresses. In this study, we investigated how chitosan soaking affected seed germination, growth, photosynthesis, resistance, yield, and quality of P. grandiflorus. The results indicated that chitosan soaking had a preferable enhancing effect on seed germination of P. grandiflorus, which significantly (p < 0.05) promoted its germination rate, energy, and index, as well as cotyl and radicle length. Furthermore, 0.15–0.20% chitosan soaking effectively enhanced the leaf growth, height, stem diameter, and overground part dry weight of P. grandiflorus and reliably improved their leaves’ chlorophyll, photosynthetic rate, transpiration rate, and water use efficiency. Moreover, 0.15–0.20% chitosan soaking effectively enhanced the stress resistance and adaptability of P. grandiflorus via increasing its resistance substances and triggering its defense enzyme activity. Meanwhile, 0.15–0.20% chitosan soaking effectively improved the underground part growth and medical quality of P. grandiflorus. This study highlights that chitosan can be used as a favorable, efficient, and economical candidate or promoter for enhancing seed germination of P. grandiflorus and improving its growth, photosynthesis, resistance, yield, and quality; it also highlights that 0.15–0.20% chitosan is a suitable concentration.
Chemical Composition, Antioxidant, Antimicrobial, Antibiofilm and Anti-Insect Activities of Jasminum grandiflorum Essential Oil
Authors: Galovičová Lucia , Čmiková Natália , Vukovic Nenad , Vukic Milena , Kowalczewski Przemysław Łukasz , Bakay Ladislav , Kačániová Miroslava
Published: October 2022

The essential oil of Jasminum grandiflorum has very good biological activity. The present study aimed to analyze the chemical composition and biological activity of J. grandiflorum. The main constituents of J. grandiflorum essential oil were benzyl acetate (37%), benzyl benzoate (34.7%) and linalool (9.6%). The antioxidant activity was 58.47%, which corresponds to 220.93 TEAC. The antimicrobial activity was weak to moderate, with inhibition zones ranging from 2.33 to 5.33 mm. The lowest MIC value was against Candida glabrata. The antimicrobial activity of the vapor phase of the essential oil was significantly stronger than that of the contact application. Biofilm analysis using a MALDI-TOF MS Biotyper showed changes in the protein profile of Pseudomonas fluorescens that confirmed the inhibitory effect of J. grandiflorum. The insecticidal potential of the essential oil against Oxycarenus lavatera and Brassicogethes aeneus was also demonstrated. Due to the properties of J. grandiflorum essential oil, it could find application as a biofilm control agent for the shelf-life extension and storage of fruits and vegetables and as a possible insecticidal agent.
Effects of 1−MCP on Storage Quality and Enzyme Activity of Petals of Edible Rose Cultivar ‘Dianhong’ at Low Temperatures
Authors: Jin Pengcheng , Fu Jian , Du Wenwen , Li Hong , Cui Guangfen
Published: October 2022

To explore the effect of 1-methylcyclopropene (1−MCP) on the storage quality of edible roses, flowers of the edible rose variety ‘Dianhong’ were used as materials to study the effect of post-harvest 1−MCP fumigation (concentration of 30 μL/L). The measures included respiration intensity, water loss rate, antioxidant-related substance content (soluble sugar, crude fibre, AsA, anthocyanin, total phenols and MDA), enzyme activity (SOD, CAT, APX, PAL and PPO) and petal appearance quality in different storage periods, which could provide a theoretical reference for research and development on storage and preservation technology for edible rose petals. The results showed that, compared with the control, 1−MCP treatment reduced the initial respiration intensity of petals by more than 80%, slowed the water loss rate, increased the crude fibre content and effectively maintained the contents of soluble sugars, AsA, anthocyanins and total phenols. For the petals in the treatment group at the end of storage, the rate of water loss was 3.73%, the content of soluble sugar was only 17% (62.27 μg/g)—lower than that of fresh petals—and the content of AsA (0.33 mg/g) was the same as that of pre-storage (0.34 mg/g). The contents of total phenols and anthocyanins were 30.60% and 11.63% higher than those of the control group, respectively. In addition, 1−MCP treatment increased the activity of SOD, CAT, APX and PAL and inhibited the activity of PPO. The MDA content at the end of storage was 14.36% lower than that of the control, which reduced the rate of membrane lipid peroxidation. Correlation analysis showed that sensory quality of petals in the 1−MCP treatment group was positively correlated with respiratory intensity and soluble sugar content and negatively correlated with water loss rate, MDA and crude fibre content (p < 0.05) among the four antioxidant enzymes. APX and PAL were positively correlated with anthocyanin content and total phenols content, respectively. These results confirmed that 1−MCP could effectively maintain the storage quality of edible rose petals by increasing the antioxidant capacity of petals and prolong the storage period of fresh petals to 49 days.
The Effect of Harvest Date on Temporal Cannabinoid and Biomass Production in the Floral Hemp (Cannabis sativa L.) Cultivars BaOx and Cherry Wine
Authors: Linder Eric R. , Young Sierra , Li Xu , Henriquez Inoa Shannon , Suchoff David H
Published: October 2022

The objectives of this study were to model the temporal accumulation of cannabidiol (CBD) and tetrahydrocannabinol (THC) in field-grown floral hemp in North Carolina and establish harvest timing recommendations to minimize non-compliant crop production. Field trials were conducted in 2020 and 2021 with BaOx and Cherry Wine cultivars. Harvest events started two weeks after floral initiation and occurred every two weeks for 12 weeks. Per-plant threshed biomass accumulation exhibited a linear plateau trend. The best fit model for temporal accumulation of THC was a beta growth curve. As harvest date was delayed, total THC concentrations increased until concentrations reached their maximum, then decreased as plants approached senescence. Logistic regression was the best fit model for temporal accumulation of CBD. CBD concentrations increased with later harvest dates. Unlike THC concentrations, there was no decline in total CBD concentrations. To minimize risk, growers should test their crop as early as possible within the USDA’s 30-day compliance window. We observed ‘BaOx’ and ‘Cherry Wine’ exceeding the compliance threshold 50 and 41 days after flower initiation, respectively.
Measuring Spatial Accessibility of Healthcare Facilities in Marinduque, Philippines
Authors: Salvacion Arnold R.
Published: October 2022

Sustainable development goal (SDG) 3 promotes well-being and healthy lives for people of all ages. However, based on the literature, one of the main challenges to achieving SDG 3 is inequality in access to health care. In order to support the efforts of the local government of the province to contribute to the achievement of SDG thru equitable access to health care, this study measured the spatial accessibility of healthcare facilities in Marinduque, Philippines. It used distance-based (i.e., travel-time) and area-based (i.e., enhanced two-step floating catchment analysis or E2SFCA) metrics. The distance from each healthcare facility to different villages in the province was established using QGIS and Google Maps. The distance traveled was measured using three (3) modes of transportation: tricycle, jeepney, and private vehicle. The E2SFCA scores were calculated for different population groups: the general population, women, children, and the elderly. Based on the results, island villages and those areas in the inner portion of the province lack physical access to healthcare facilities. Such a limitation was apparent in the distance- and area-based accessibility metrics. Among the population group considered in this study, the women population showed the lowest accessibility scores.
Research on Spatial Distribution Characteristics and Influencing Factors of Pension Resources in Shanghai Community-Life Circle
Authors: Huang Xiaoran , Gong Pixin , White Marcus , Zhang Bo
Published: October 2022

With population ageing being a notable demographic phenomenon, aging in place is an efficient model to accommodate the mounting aging needs. Based on the community scale, this study takes the 15-min community-life circle as the basic research unit to investigate the imbalanced distribution of pension resources and its influencing factors in downtown Shanghai. We obtained six types of elderly care facilities data from the Shanghai elderly care service platform and utilized the Gaussian 2-step Floating Catchment Area method to calculate the accessibility of 6-type elderly care facilities. Then, we used the Entropy Weight Method to calculate the comprehensive accessibility of elderly care facilities. The Getis–Ord Gi* method was adopted to analyze the overall distribution, identifying the well-developed and the under-developed areas. To explore the influencing factors of the distribution, this paper obtained multi-source data to construct a total of 17 indicators and established a Random Forest model to identify the feature importance. With the selected eight factors, the Geographically Weighted Regression (GWR) model was applied to study the spatial heterogeneity of influencing factors, and the model showed a good performance with the AdjR2 being 0.8364. The findings of this research reveal the following: (1) The distribution of six types of elderly care facilities is extremely uneven, with obvious spatial aggregation characteristics. Amongst the seven administrative regions, Huangpu District has the best accessibility to pension resources, while the resources in the other six regions are highly inadequate. (2) Essential influencing factors of the comprehensive accessibility of community-based elderly care facilities are accessibility of nursing institutions (positive), hotel density (positive), catering density (negative), education density (positive) and medical density (negative), while “rents”, “plot ratio” and “building density” have little impact on comprehensive accessibility. (3) The results of GWR revealed that the eight indicators are heterogeneous in space, all of which have bidirectional effects on comprehensive accessibility. By investigating the spatial distribution patterns and influencing factors of pension resources in Shanghai, this research could further contribute to establishing a sound community-based elderly care service system that improves older adults’ quality of life and promotes social fairness and justice.
Non-Canonical Functions of Myeloperoxidase in Immune Regulation, Tissue Inflammation and Cancer
Authors: Lockhart Joey S. , Sumagin Ronen
Published: October 2022

Myeloperoxidase (MPO) is one of the most abundantly expressed proteins in neutrophils. It serves as a critical component of the antimicrobial defense system, facilitating microbial killing via generation of reactive oxygen species (ROS). Interestingly, emerging evidence indicates that in addition to the well-recognized canonical antimicrobial function of MPO, it can directly or indirectly impact immune cells and tissue responses in homeostatic and disease states. Here, we highlight the emerging non-canonical functions of MPO, including its impact on neutrophil longevity, activation and trafficking in inflammation, its interactions with other immune cells, and how these interactions shape disease outcomes. We further discuss MPO interactions with barrier forming endothelial and epithelial cells, specialized cells of the central nervous system (CNS) and its involvement in cancer progression. Such diverse function and the MPO association with numerous inflammatory disorders make it an attractive target for therapies aimed at resolving inflammation and limiting inflammation-associated tissue damage. However, while considering MPO inhibition as a potential therapy, one must account for the diverse impact of MPO activity on various cellular compartments both in health and disease.
NAC1 Maintains Root Meristem Activity by Repressing the Transcription of E2Fa in Arabidopsis
Authors: Xie Chuantian , Ding Zhaojun
Published: October 2022

Root meristem is a reserve of undifferentiated cells which guide root development. To maintain root meristem identity and therefore continuous root growth, the rate of cell differentiation must coordinate with the rate of generation of new cells. The E2 promoter-binding factor a (E2Fa) has been shown to regulate root growth through controlling G1/S cell cycle transitions in Arabidopsis thaliana. Here, we found that NAC1, a member of the NAM/ATAF/CUC family of transcription factors, regulated root growth by directly repressing the transcription of E2Fa. Loss of NAC1 triggers an up-regulation of the E2Fa expression and causes a reduced meristem size and short-root phenotype, which are largely rescued by mutation of E2Fa. Further analysis showed that NAC1 was shown to regulate root meristem by controlling endopolyploidy levels in an E2Fa-dependent manner. This study provides evidence to show that NAC1 maintains root meristem size and root growth by directly repressing the transcription of E2Fa in Arabidopsis.
Non-Coding RNAs Are Implicit in Chronic Myeloid Leukemia Therapy Resistance
Authors: Rudich Alexander , Garzon Ramiro , Dorrance Adrienne
Published: October 2022

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm initiated by the presence of the fusion gene BCR::ABL1. The development of tyrosine kinase inhibitors (TKIs) highly specific to p210BCR-ABL1, the constitutively active tyrosine kinase encoded by BCR::ABL1, has greatly improved the prognosis for CML patients. Now, the survival rate of CML nearly parallels that of age matched controls. However, therapy resistance remains a persistent problem in the pursuit of a cure. TKI resistance can be attributed to both BCR::ABL1 dependent and independent mechanisms. Recently, the role of non-coding RNAs (ncRNAs) has been increasingly explored due to their frequent dysregulation in a variety of malignancies. Specifically, microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs) have been shown to contribute to the development and progression of therapy resistance in CML. Since each ncRNA exhibits multiple functions and is capable of controlling gene expression, they exert their effect on CML resistance through a diverse set of mechanisms and pathways. In most cases ncRNAs with tumor suppressing functions are silenced in CML, while those with oncogenic properties are overexpressed. Here, we discuss the relevance of many aberrantly expressed ncRNAs and their effect on therapy resistance in CML.
Altered Expression of AQP1 and AQP4 in Brain Barriers and Cerebrospinal Fluid May Affect Cerebral Water Balance during Chronic Hypertension
Authors: González-Marrero Ibrahim , Hernández-Abad Luis G. , González-Gómez Miriam , Soto-Viera María , Carmona-Calero Emilia M. , Castañeyra-Ruiz Leandro , Castañeyra-Perdomo Agustín
Published: October 2022

Hypertension is the leading cause of cardiovascular affection and premature death worldwide. The spontaneously hypertensive rat (SHR) is the most common animal model of hypertension, which is characterized by secondary ventricular dilation and hydrocephalus. Aquaporin (AQP) 1 and 4 are the main water channels responsible for the brain’s water balance. The present study focuses on defining the expression of AQPs through the time course of the development of spontaneous chronic hypertension. We performed immunofluorescence and ELISA to examine brain AQPs from 10 SHR, and 10 Wistar–Kyoto (WKY) rats studied at 6 and 12 months old. There was a significant decrease in AQP1 in the choroid plexus of the SHR-12-months group compared with the age-matched control (p < 0.05). In the ependyma, AQP4 was significantly decreased only in the SHR-12-months group compared with the control or SHR-6-months groups (p < 0.05). Per contra, AQP4 increased in astrocytes end-feet of 6 months and 12 months SHR rats (p < 0.05). CSF AQP detection was higher in the SHR-12-months group than in the age-matched control group. CSF findings were confirmed by Western blot. In SHR, ependymal and choroidal AQPs decreased over time, while CSF AQPs levels increased. In turn, astrocytes AQP4 increased in SHR rats. These AQP alterations may underlie hypertensive-dependent ventriculomegaly.
Neutrophil Gelatinase-Associated Lipocalin as Potential Predictive Biomarker of Melanoma and Non-Melanoma Skin Cancers in Psoriatic Patients: A Pilot Study
Authors: Verdelli Alice , Caproni Marzia , Coi Alessio , Corrà Alberto , Degl’Innocenti Donatella , Vasarri Marzia , Quintarelli Lavinia , Volpi Valter , Cipollini Emanuele Maria , Barletta Emanuela
Published: October 2022

Background: Studies have demonstrated a higher risk of nonmelanoma skin cancers (NMSC) and a modestly increased melanoma risk in patients with psoriasis. To date, no biomarkers predictive of evolution have been identified yet. Methods: The aim of this prospective case-control study was to investigate the potential role of neutrophil gelatinase-associated lipocalin (NGAL) as a predictive biomarker of skin cancers in psoriatic patients. Patients with a diagnosis of psoriasis were enrolled, as well as healthy subjects and patients with skin cancers as controls. Plasma protein expression of NGAL, metalloproteinases (MMP)-2, and MMP-9 was performed by an enzyme-linked immunosorbent assay (ELISA). In all the patients who developed skin cancer at follow-up, NGAL, MMP-2, and MMP-9 serum levels were dosed again. Results: Plasma NGAL levels were significantly higher in psoriatic patients with NMSC than without (182.3 ± 36.6 ng/mL vs. 139.9 ± 39.3 ng/mL) (p < 0.001). Plasma NGAL levels were significantly higher (p < 0.00001) in patients with psoriasis and NMSC than in patients with skin tumors without psoriasis (182.3 vs. 122.9). Patients with psoriasis who developed NMSC at follow-up showed increased plasma MMP-9 levels. Conclusion: NGAL seems to play a role in the pathogenesis of NMSC but not melanoma in patients with psoriasis.
The miR-182-5p/NDRG1 Axis Controls Endometrial Receptivity through the NF-κB/ZEB1/E-Cadherin Pathway
Authors: Yu Seong-Lan , Kang Yujin , Jeong Da-Un , Lee Dong Chul , Jeon Hye Jin , Kim Tae-Hyun , Lee Sung Ki , Han Ae Ra , Kang Jaeku , Park Seok-Rae
Published: October 2022

Endometrial receptivity is essential for successful pregnancy, and its impairment is a major cause of embryo-implantation failure. MicroRNAs (miRNAs) that regulate epigenetic modifications have been associated with endometrial receptivity. However, the molecular mechanisms whereby miRNAs regulate endometrial receptivity remain unclear. Therefore, we investigated whether miR-182 and its potential targets influence trophoblast cell attachment. miR-182 was expressed at lower levels in the secretory phase than in the proliferative phase of endometrium tissues from fertile donors. However, miR-182 expression was upregulated during the secretory phase in infertile women. Transfecting a synthetic miR-182-5p mimic decreased spheroid attachment of human JAr choriocarcinoma cells and E-cadherin expression (which is important for endometrial receptivity). miR-182-5p also downregulated N-Myc downstream regulated 1 (NDRG1), which was studied further. NDRG1 was upregulated in the secretory phase of the endometrium tissues and induced E-cadherin expression through the nuclear factor-κΒ (NF-κΒ)/zinc finger E-box binding homeobox 1 (ZEB1) signaling pathway. NDRG1-overexpressing or -depleted cells showed altered attachment rates of JAr spheroids. Collectively, our findings indicate that miR-182-5p-mediated NDRG1 downregulation impaired embryo implantation by upregulating the NF-κΒ/ZEB1/E-cadherin pathway. Hence, miR-182-5p is a potential biomarker for negative selection in endometrial receptivity and a therapeutic target for successful embryo implantation.
NLRP1 in Cutaneous SCCs: An Example of the Complex Roles of Inflammasomes in Cancer Development
Authors: Di Filippo Michela , Hennig Paulina , Karakaya Tugay , Slaufova Marta , Beer Hans-Dietmar
Published: October 2022

Protein complexes termed inflammasomes ensure tissue protection from pathogenic and sterile stressors by induction of inflammation. This is mediated by different caspase-1-induced downstream pathways, including activation of the pro-inflammatory cytokines proIL-1β and -18, induction of a lytic type of cell death, and regulation of the release of other pro-inflammatory molecules. Aberrant inflammasome activation underlies the pathology of numerous (auto)inflammatory diseases. Furthermore, inflammasomes support or suppress tumor development in a complex cell-type- and stage-dependent manner. In human keratinocytes and skin, NLRP1 is the central inflammasome sensor activated by cellular perturbation induced, for example, by UVB radiation. UVB represents the main inducer of skin cancer, which is the most common type of malignancy in humans. Recent evidence demonstrates that activation of NLRP1 in human skin supports the development of cutaneous squamous cell carcinomas (cSCCs) by inducing skin inflammation. In contrast, the NLRP1 inflammasome pathway is restrained in established cSCCs, suggesting that, at this stage, the protein complex has a tumor suppressor role. A better understanding of the complex functions of NLRP1 in the development of cSCCs and in general of inflammasomes in cancer might pave the way for novel strategies for cancer prevention and therapy. These strategies might include stage-specific modulation of inflammasome activation or its downstream pathways by mono- or combination therapy.
Asymmetric Dimethylarginine Is a Marker of Endothelial Dysfunction in Thrombotic Antiphospholipid Syndrome Patients
Authors: Stanisavljevic Natasa , Stojanovich Ljudmila , Djokovic Aleksandra , Todic Brankica , Dopsaj Violeta , Saponjski Jovica , Saponjski Dusan , Markovic Olivera , Belizna Cristina , Zdravkovic Marija , Marisavljevic Dragomir
Published: October 2022

Objective: The potential contribution of asymmetric dimethylarginine (ADMA) and high-sensitivity C reactive protein (hsCRP) to endothelial dysfunction in APS patients has not been studied in detail, until now. The study involved 105 APS patients (59 diagnosed with primary APS (PAPS) and 46 APS associated with systemic lupus erythematosus (SAPS)) who were compared to 40 controls. Endothelial dysfunction was assessed by measurement of flow-mediated dilatation (FMD) and glyceryl trinitrate dilatation (NMD) of the brachial artery. ADMA (micromol/L) was analyzed by ELISA. Results: FMD in patients with APS was significantly lower than that of the controls (p < 0.001), with no difference between the PAPS and the SAPS groups. ADMA and hsCRP concentrations were significantly higher in the patient cohort than in the control group (p < 0.001, p = 0.006, respectively), as was the case with the SAPS group as compared to the PAPS group (p < 0.001, p = 0.022, respectively). FMD impairment correlated to ADMA (ρ 0.472, p < 0.001) and to hsCRP (ρ 0.181, p = 0.033). In the regression model, the ADMA concentration confirmed the strength of its association (B 0.518, SE 0.183, Wald 8.041, p = 0.005, Exp(B) 1.679, 95% CI 1.174–2.402) to FMD impairment. The synergistic probability model of ADMA and hsCRP caused FMD impairment when the positivity of β2GPIIgG was added. ADMA may be used as a simple and low-cost tool for verifying the presence of endothelial dysfunction in APS patients. According to the results of the study, we could presume that hsCRP, together with aPL, has a preparatory effect on the endothelium in causing endothelial dysfunction.
Dynamic Regulation of Mitochondrial [Ca2+] in Hippocampal Neurons
Authors: Kushnireva Liliya , Basnayake Kanishka , Holcman David , Segal Menahem , Korkotian Eduard
Published: October 2022

While neuronal mitochondria have been studied extensively in their role in health and disease, the rules that govern calcium regulation in mitochondria remain somewhat vague. In the present study using cultured rat hippocampal neurons transfected with the mtRCaMP mitochondrial calcium sensor, we investigated the effects of cytosolic calcium surges on the dynamics of mitochondrial calcium ([Ca2+]m). Cytosolic calcium ([Ca2+]c) was measured using the high affinity sensor Fluo-2. We recorded two types of calcium events: local and global ones. Local events were limited to a small, 2–5 µm section of the dendrite, presumably caused by local synaptic activity, while global events were associated with network bursts and extended throughout the imaged dendrite. In both cases, cytosolic surges were followed by a delayed rise in [Ca2+]m. In global events, the rise lasted longer and was observed in all mitochondrial clusters. At the end of the descending part of the global event, [Ca2+]m was still high. Global events were accompanied by short and rather high [Ca2+]m surges which we called spikelets, and were present until the complete decay of the cytosolic event. In the case of local events, selective short-term responses were limited to the part of the mitochondrial cluster that was located directly in the center of [Ca2+]c activity, and faded quickly, while responses in the neighboring regions were rarely observed. Caffeine (which recruits ryanodine receptors to supply calcium to the mitochondria), and carbonyl cyanide m-chlorophenyl hydrazine (CCCP, a mitochondrial uncoupler) could affect [Ca2+]m in both global and local events. We constructed a computational model to simulate the fundamental role of mitochondria in restricting calcium signals within a narrow range under synapses, preventing diffusion into adjacent regions of the dendrite. Our results indicate that local cytoplasmic and mitochondrial calcium concentrations are highly correlated. This reflects a key role of signaling pathways that connect the postsynaptic membrane to local mitochondrial clusters.
Glucocorticoid-Regulated Kinase CAMKIγ in the Central Amygdala Controls Anxiety-like Behavior in Mice
Authors: Piechota Marcin , Skupio Urszula , Borczyk Małgorzata , Ziółkowska Barbara , Gołda Sławomir , Szumiec Łukasz , Szklarczyk-Smolana Klaudia , Bilecki Wiktor , Rodriguez Parkitna Jan Manuel , Korostyński Michał
Published: October 2022

The expression of the Calcium/Calmodulin-Dependent Protein Kinase I gamma (encoded by the Camk1g gene) depends on the activation of glucocorticoid receptors (GR) and is strongly regulated by stress. Since Camk1g is primarily expressed in neuronal cells of the limbic system in the brain, we hypothesized that it could be involved in signaling mechanisms that underlie the adaptive or maladaptive responses to stress. Here, we find that restraint-induced stress and the GR agonist dexamethasone robustly increase the expression of Camk1g in neurons of the amygdalar nuclei in the mouse brain. To assess the functional role of Camk1g expression, we performed a virally induced knock-down of the transcript. Mice with bilateral amygdala-specific Camk1g knock-down showed increased anxiety-like behaviors in the light-dark box, and an increase in freezing behavior after fear-conditioning, but normal spatial working memory during exploration of a Y-maze. Thus, we confirm that Camk1g is a neuron-specific GR-regulated transcript, and show that it is specifically involved in behaviors related to anxiety, as well as responses conditioned by aversive stimuli.
Assessing T-Cell Immunity in Kidney Transplant Recipients with Absent Antibody Production after a 3rd Dose of the mRNA-1273 Vaccine
Authors: Infantino Maria , Tsalouchos Aris , Russo Edda , Laudicina Selene , Grossi Valentina , Lari Barbara , Benucci Maurizio , Stacchini Lorenzo , Amedei Amedeo , Casprini Patrizia , Villalta Danilo , Dattolo Pietro Claudio , Manfredi Mariangela
Published: October 2022

The vulnerable population of kidney transplant recipients (KTRs) are low responders to COVID-19 vaccines, so specific immune surveillance is needed. The interferon-gamma (IFN-γ) release assay (IGRA) is effective in assessing T cell-mediated immunity. We assessed SARS-CoV-2-directed T cell responses in KTRs with absent antibody production after a third dose of the mRNA-1273 vaccine, using two different IGRAs. A cohort of 57 KTRs, who were actively followed up, received a third dose of the mRNA-1273 vaccine. After the evaluation of humoral immunity to SARS-CoV-2, 14 seronegative patients were tested with two commercial IGRAs (SD Biosensor and Euroimmun). Out of 14 patients, one and three samples were positive by IGRAs with Euroimmun and SD Biosensor, respectively. The overall agreement between the two assays was 85.7% (κ = 0.444). In addition, multivariate linear regression analysis showed no statistically significant association between the IFN-γ concentration, and the independent variables analyzed (age, gender, years since transplant, total lymphocytes cells/mcl, CD3+ cells/mcl, CD3+ CD4+ cells/mcl, CD3+ CD8+ cells/mcl, CD19+ cells/mcl, CD3-CD16+CD56+ cells/mcl) (p > 0.01). In a vulnerable setting, assessing cellular immune response to complement the humoral response may be advantageous. Since the two commercial IGRAs showed a good agreement on negative samples, the three discordant samples highlight the need for further investigations.
Proteomic and miRNA Profiles of Exosomes Derived from Myometrial Tissue in Laboring Women
Authors: Deng Wenfeng , Wang Xiaodi , Chen Lina , Wen Bolun , Chen Yunshan , Ji Kaiyuan , Liu Huishu
Published: October 2022

Myometrial contraction is essential for successful delivery. Recent studies have highlighted the vital roles of tissue-derived exosomes in disease diagnostic, prognostic, and therapeutic applications; however, the characteristics of uterine myometrium-derived exosomes are unclear. Here, we successfully isolated exosomes from myometrial tissues, human myometrial smooth muscle cells (HMSMCs), and human umbilical vein endothelial cells (HUVECs), then performed quantitative liquid chromatography-tandem mass spectrometry and miRNA sequencing to investigate the cargo of the exosomes. Fifty-two proteins and five miRNAs were differentially expressed (DE) in term non-labor and term labor myometrium-derived exosomes. Among them, seven proteins (SERPINE1, THBS1, MGAT1, VIM, FGB, FGG, and VWF) were differentially expressed both in the myometrial exosomes and tissues, three miRNAs (miR-363-3p, miR-203a-3p, and miR-205-5p) target 13 DE genes. The top three miRNA derived from HMSMCs (miR-125b-1-3p, miR-337-5p, and miR-503-5p) and HUVECs (miR-663a, miR-4463, and miR-3622a-5p) were identified. Two proteins, GJA1 and SLC39A14, exist in female blood exosomes and are highly expressed in HMSMCs exosomes, are also upregulated in the laboring myometrium, which verified increased in laboring blood samples, might be novel potential biomarkers for myometrial activation. The proteomic and miRNA profile of exosomes derived from laboring myometrium revealed some molecules in the exosomes that affect the intercellular communication and the function of the myometrium.
Immunomodulatory Effect of Human Lactoferrin on Toll-like Receptors 2 Expression as Therapeutic Approach for Keratoconus
Authors: Regueiro Uxía , López-López Maite , Varela-Fernández Rubén , Sobrino Tomás , Diez-Feijoo Elio , Lema Isabel
Published: October 2022

Keratoconus (KC) is a corneal disorder whose etiology shares a close relationship with Lactoferrin (LTF) dysregulation and Toll-like Receptors 2 (TLR2) overexpression. This study shows how these two important biomarkers are clinically and molecularly interrelated, increasing knowledge about KC pathophysiology, and opening the door to future therapies. In this prospective clinical study, serum and tear LTF concentrations were quantified in 90 KC patients and 60 controls. A correlation analysis with multiple blood and tear immunoinflammatory mediators, and KC-associated tomographic parameters, was performed. An in vitro study using HEK-BlueTMhTLR2 cell cultures was also conducted to determine the expression and functionality of TLR2 under the influence of LTF treatment. As a result, a LTF decreased was observed in KC patients compared to controls (p < 0.0001), evidencing the strong correlation with TLR2 overexpression at systemic and ocular surface level, with inflammatory mediator upregulation and with KC severity. In stimulated cell cultures, TLR2 expression was decreased using 2 mg/mL of LTF. The levels of secreted embryonic alkaline phosphatase (SEAP) and interleukin-8 (IL-8) were also reduced in supernatants after LTF treatment. As conclusions, the dysregulation of LTF and TLR2 in the ocular surface of KC patients contributes to KC severity by maintaining a detrimental chronic immune–inflammatory state. The immunomodulatory properties of LTF on TLR2 expression suggest its potential as a therapeutic approach for KC.
Differential Cytotoxicity of Curcumin-Loaded Micelles on Human Tumor and Stromal Cells
Authors: Do Xuan-Hai , Hoang My Hanh Thi , Vu Anh-Tuan , Nguyen Lai-Thanh , Bui Dung Thi Thuy , Dinh Duy-Thanh , Nguyen Xuan-Hung , Than Uyen Thi Trang , Mai Hien Thi , To Thuy Thanh , Nguyen Tra Ngoc Huong , Hoang Nhung Thi My
Published: October 2022

Although curcumin in the form of nanoparticles has been demonstrated as a potential anti-tumor compound, the impact of curcumin and nanocurcumin in vitro on normal cells and in vivo in animal models is largely unknown. This study evaluated the toxicity of curcumin-loaded micelles in vitro and in vivo on several tumor cell lines, primary stromal cells, and zebrafish embryos. Breast tumor cell line (MCF7) and stromal cells (human umbilical cord vein endothelial cells, human fibroblasts, and human umbilical cord-derived mesenchymal stem cells) were used in this study. A zebrafish embryotoxicity (FET) assay was conducted following the Organisation for Economic Co-operation and Development (OECD) Test 236. Compared to free curcumin, curcumin PM showed higher cytotoxicity to MCF7 cells in both monolayer culture and multicellular tumor spheroids. The curcumin-loaded micelles efficiently penetrated the MCF7 spheroids and induced apoptosis. The nanocurcumin reduced the viability and disturbed the function of stromal cells by suppressing cell migration and tube formation. The micelles demonstrated toxicity to the development of zebrafish embryos. Curcumin-loaded micelles demonstrated toxicity to both tumor and normal primary stromal cells and zebrafish embryos, indicating that the use of nanocurcumin in cancer treatment should be carefully investigated and controlled.
Discovery of Simple Diacylhydrazine-Functionalized Cinnamic Acid Derivatives as Potential Microtubule Stabilizers
Authors: Zhou Xiang , Fu Yi-Hong , Zou Ya-Yu , Meng Jiao , Ou-Yang Gui-Ping , Ge Qiang-Sheng , Wang Zhen-Chao
Published: October 2022

To develop novel microtubule-binding agents for cancer therapy, an array of N-cinnamoyl-N’-(substituted)acryloyl hydrazide derivatives were facilely synthesized through a two-step process. Initially, the antiproliferative activity of these title compounds was explored against A549, 98 PC-3 and HepG2 cancer cell lines. Notably, compound I23 exhibited the best antiproliferative activity against three cancer lines with IC50 values ranging from 3.36 to 5.99 μM and concurrently afforded a lower cytotoxicity towards the NRK-52E cells. Anticancer mechanism investigations suggested that the highly bioactive compound I23 could potentially promote the protofilament assembly of tubulin, thus eventually leading to the stagnation of the G2/M phase cell cycle of HepG2 cells. Moreover, compound I23 also disrupted cancer cell migration and significantly induced HepG2 cells apoptosis in a dosage-dependent manner. Additionally, the in silico analysis indicated that compound I23 exhibited an acceptable pharmacokinetic profile. Overall, these easily prepared N-cinnamoyl-N’-(substituted)acryloyl hydrazide derivatives could serve as potential microtubule-interacting agents, probably as novel microtubule-stabilizers.
Diagnostic Odyssey in an Adult Patient with Ophthalmologic Abnormalities and Hearing Loss: Contribution of RNA-Seq to the Diagnosis of a PEX1 Deficiency
Authors: Muñoz-Pujol Gerard , Alforja-Castiella Socorro , Casaroli-Marano Ricardo , Morales-Romero Blai , García-Villoria Judit , Yépez Vicente A. , Gagneur Julien , Gusic Mirjana , Prokisch Holger , Tort Frederic , Ribes Antonia
Published: October 2022

Peroxisomal biogenesis disorders (PBDs) are a heterogeneous group of genetic diseases. Multiple peroxisomal pathways are impaired, and very long chain fatty acids (VLCFA) are the first line biomarkers for the diagnosis. The clinical presentation of PBDs may range from severe, lethal multisystemic disorders to milder, late-onset disease. The vast majority of PBDs belong to Zellweger Spectrum Disordes (ZSDs) and represents a continuum of overlapping clinical symptoms, with Zellweger syndrome being the most severe and Heimler syndrome the less severe disease. Mild clinical conditions frequently present normal or slight biochemical alterations, making the diagnosis of these patients challenging. In the present study we used a combined WES and RNA-seq strategy to diagnose a patient presenting with retinal dystrophy as the main clinical symptom. Results showed the patient was compound heterozygous for mutations in PEX1. VLCFA were normal, but retrospective analysis of lysosphosphatidylcholines (LPC) containing C22:0–C26:0 species was altered. This simple test could avoid the diagnostic odyssey of patients with mild phenotype, such as the individual described here, who was diagnosed very late in adult life. We provide functional data in cell line models that may explain the mild phenotype of the patient by demonstrating the hypomorphic nature of a deep intronic variant altering PEX1 mRNA processing.
The Implications of Noncoding RNAs in the Evolution and Progression of Nonalcoholic Fatty Liver Disease (NAFLD)-Related HCC
Authors: Rusu Ioana , Pirlog Radu , Chiroi Paul , Nutu Andreea , Puia Vlad Radu , Fetti Alin Cornel , Rusu Daniel Radu , Berindan-Neagoe Ioana , Al Hajjar Nadim
Published: October 2022

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide. Meanwhile, liver cancer represents the sixth most common malignancy, with hepatocellular carcinoma (HCC) as the primary, most prevalent subtype. Due to the rising incidence of metabolic disorders, NAFLD has become one of the main contributing factors to HCC development. However, although NAFLD might account for about a fourth of HCC cases, there is currently a significant gap in HCC surveillance protocols regarding noncirrhotic NAFLD patients, so the majority of NAFLD-related HCC cases were diagnosed in late stages when survival chances are minimal. However, in the past decade, the focus in cancer genomics has shifted towards the noncoding part of the genome, especially on the microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which have proved to be involved in the regulation of several malignant processes. This review aims to summarize the current knowledge regarding some of the main dysregulated, noncoding RNAs (ncRNAs) and their implications for NAFLD and HCC development. A central focus of the review is on miRNA and lncRNAs that can influence the progression of NAFLD towards HCC and how they can be used as potential screening tools and future therapeutic targets.
Clot Morphology in Acute Ischemic Stroke Decision Making
Authors: Huang Joanna C. , Bhaskar Sonu M. M.
Published: October 2022

Stroke is a leading cause of death and disability in the world, and the provision of reperfusion therapy and endovascular therapy, in particular, have revolutionized the treatment of patients with stroke and opened opportunities to look at brain clots retrieved after the procedure. The use of histopathology and molecular profiling of clots is of growing research and clinical interest. However, its clinical implications and incorporation within stroke workflows remain suboptimal. Recent studies have indicated that the study of brain clots may inform the mechanism of stroke and hence guide treatment decision-making in select groups of patients, especially patients without a defined cause or known mechanism. This article provides a comprehensive overview of various clot histopathological examinations in acute stroke-care settings, their clinical utility, and existing gaps and opportunities for further research. We also provide targeted recommendations to improve clot analysis workflow, hence standardizing its incorporation into clinical practice.