The research and development of non-viral gene therapy has been extensive over the past decade and has received a big push thanks to the successful approval of non-viral gene therapy products in recent times. Despite these developments, gene therapy applications in cancer have been limited. One of the main causes of this has been the imbalance in development of delivery vectors as compared to nucleic acid payloads. This paper reviews non-viral vectors that can be used to deliver nucleic acids for cancer treatment. It discusses various types of vectors and highlights their current applications. Additionally, it also discusses perspective on regulatory landscape to facilitate commercial translation of gene therapy.

The tumor microenvironment (TME) surrounding tumor cells is a complex and highly dynamic system that promotes tumorigenesis. Cancer-associated fibroblasts (CAFs) are key elements in TME playing a pivotal role in cancer cells’ proliferation and metastatic spreading. Considering the high expression of the fibroblast activation protein (FAP) on cell membrane, CAFs emerged as appealing TME targets, namely for molecular imaging, leading to a pan-tumoral approach. Therefore, FAP inhibitors (FAPis) have been recently developed for PET imaging and radioligand therapy, exploring the clinical application in different tumor sub-types. The present review aimed to describe recent developments on radiolabeled FAP inhibitors and evaluate the possible translation of this pan-tumoral approach in clinical practice. At present, the application of FAPi-PET has been explored mainly in single-center studies, generally performed in small and heterogeneous cohorts of oncological patients. However, preliminary results were promising, in particular in low FDG-avid tumors such as primary liver and gastro-entero-pancreatic cancer, or in regions with unfavorable tumor-to-background ratio at FDG-PET/CT (i.e. brain), as well as in radiotherapy planning of head and neck tumors. Further promising results have been obtained in the detection of peritoneal carcinomatosis, especially in ovarian and gastric cancer. Data regarding the theranostics approach are still limited at presents, and definitive conclusion about its efficacy cannot be drawn at present. Nevertheless, the use of FAPi-based radio-ligand to treat the TME has been evaluated in first-in-human studies and appears feasible. Although the pan-tumoral approach in molecular imaging showed promising results, its real impact in day-to-day clinical practice has yet to be confirmed, and multi-center, prospective studies powered for efficacy are needed.

Though early-stage colorectal cancer has a high 5-year survival rate of 65-92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair proficient patients to immunotherapy.

The presence of mutated genes strongly correlates with the incidence of cancer. Decades of research, however, has not yielded any specific causative gene or set of genes for the vast majority of cancers. The Cancer Genome Atlas program was supposed to provide clarity but it only gave much more data without any accompanying insight into how the disease begins and progresses. It may be time to notice that epidemiological studies consistently show that the environment, not genes, has the principal role in causing cancer. Since carcinogenic chemicals in our food, drink, air and water are the primary culprits, we need to look at the biochemistry of cancer, with a focus on enzymes which invariably facilitate transformations in a cell. In particular, attention should be paid to the rate-limiting enzyme in DNA synthesis, ribonucleotide reductase (RnR) whose activity is tightly linked to tumor growth. Besides circumstantial evidence that cancer is induced at this enzyme’s vulnerable free-radical-containing active-site by various carcinogens, its role in initiating retinoblastoma and HPV-related cervical cancers is well documented. Blocking the activity of malignant RnR is a certain way to arrest cancer.

Cancer is one of the leading causes of death and morbidity with a complex pathophysiology. Traditional cancer therapies include chemotherapy, radiation therapy, targeted therapy, and immunotherapy. However, limitations such as lack of specificity, cytotoxicity, and multi-drug resistance pose a substantial challenge for favorable cancer treatment. The advent of nanotechnology has revolutionized the arena of cancer diagnosis and treatment. Nanoparticles (1-100nm) can be used in the treatment of cancer owing to their specific advantages such as biocompatibility, reduced toxicity, more excellent stability, enhanced permeability and retention effect, and precise targeting. Nanoparticles are classified into several main categories. The nanoparticle drug delivery system is particular and utilizes tumor and tumor environment characteristics. Nanoparticles not only solve the limitations of conventional cancer treatment but also overcome multidrug resistance. Additionally, as new multidrug resistance mechanisms are unraveled and studied, nanoparticles are being investigated more vigorously. Various therapeutic implications of nano-formulations have created brand new perspectives for cancer treatment. However, a majority of the research is limited to in vivo and in vitro studies, and the number of nano-drugs that are approved has not much amplified over the years. In this review, we discuss numerous types of nanoparticles, targeting mechanisms along with approved nanotherapeutics for oncological implications in cancer treatment. Further, we also summarize the current perspective, advantages, and challenges in clinical translation.

Cervical cancer (CC) is the most common cancer in women worldwide and is almost always associated with repeated infections by human papillomavirus (HPV). Screening by traditional tests combined with biomarker identification techniques for low- or high-grade injuries, are becoming increasingly important in diagnosis and prognosis, avoiding countless deaths. This article explores existing literature on the main serum biomarkers and the identification of biomarkers associated with the oncogenesis of HPV expression in the identification of pre-cancerous lesions and of CC for an effective treatment, with reduction of recurrence, as well as we explain strategies for the development of biomarkers based on DNA, proteins and other markers. We also describe how markers of chromosomal instability host DNA, promoting hypo- or hypermethylation of DNA, as well as polymorphisms and epigenetic events in the p53 gene. Finally, we discuss changes in gene expression using cDNA microarray techniques and changes in the expression of proteins and markers identified through mass spectrometry.

The emergence of three-dimensional human organoids has opened the door for development of patient-derived cancer organoid (PDO) models, which closely recapitulate parental tumor tissue. Mainstays of preclinical cancer modeling include in vitro cell lines and patient-derived xenografts, but these models lack the cellular heterogeneity seen in human tumors. Moreover, xenograft establishment is resource- and time-intensive, rendering these models difficult to use to inform clinical trials and decisions. PDOs, however, can be created efficiently and retain tumor-specific properties such as cellular heterogeneity, cell-cell and cell-stromal interactions, tumor microenvironment, and therapeutic responsiveness. PDO models and drug screening protocols have been described for several solid tumors and, more recently, for gliomas. Since PDOs can be developed in clinically relevant timeframes and share many characteristics of parent tumors, they may enhance the ability to provide precision oncologic care for patients. This review explores the current literature on cancer organoids, highlighting the history of PDO development, organoid models of glioma, and potential clinical applications of PDOs.

BTB domain and CNC homology 1 (BACH1) is a highly expressed transcription factor in tumors including breast and lung, relative to their non-tumor tissues. BACH1 is known to regulate multiple physiological processes including heme homeostasis, oxidative stress response, senescence, cell cycle, and mitosis. In a tumor, BACH1 promotes invasion and metastasis of cancer cells, and the expression of BACH1 presents a poor outcome for cancer patients including breast cancer patients. Recent studies identified novel functional roles of BACH1 in the regulation of metabolic pathways in cancer cells. BACH1 inhibits mitochondrial metabolism through transcriptional suppression of mitochondrial membrane genes. In addition, BACH1 suppresses activity of pyruvate dehydrogenase (PDH), a key enzyme that converts pyruvate to acetyl-CoA for the citric acid (TCA) cycle through transcriptional activation of pyruvate dehydrogenase kinase (PDK). Moreover, BACH1 increases glucose uptake and lactate secretion in aerobic glycolysis through the expression of metabolic enzymes involved such as hexokinase 2 (HK2) and glyceraldehyde 3- phosphate dehydrogenase (GAPDH). Pharmacological or genetic inhibition of BACH1 could reprogramme metabolic pathways, subsequently rendering metabolic vulnerability of cancer cells. Furthermore, inhibition of BACH1 decreased antioxidant-induced glycolysis rates as well as reduced migration and invasion of cancer cells, suggesting BACH1 as a potentially useful cancer therapeutic target.

Epidemiological studies on micronutrient consumption have reported protective associations in the incidence and/or progression of various cancer types. Supplementation with some of these micronutrients has been analyzed, showing chemoprotection, low toxicity, antiproliferation, and the ability to modify epigenetic signatures in various cancer models. The following review inves-tigates the reported effects of micronutrient intake or supplementation in breast cancer progres-sion. A PubMed search was conducted with the keywords “micronutrients breast cancer progres-sion,” and the results were analyzed. The selected micronutrients were: Vitamins (A, C, D, and E), Folic Acid, metals (Cu, Fe, Se, and Zn), fatty acids, polyphenols, and iodine. The majority of in vitro models showed antiproliferative, cell cycle arrest, and antimetastatic effects for almost all the micronutrients analyzed, but these effects do not reflect animal or human studies. Only one clinical trial with Vitamin D and one pilot study with molecular iodine showed favorable overall survival and disease-free interval.

For its microtubule-binding properties, the expression level of the neurodegeneration-associated protein Tau is pondered as a potential modifier of cancer resistance to chemotherapy since decades. Indeed, Tau binds microtubules at the same site as taxanes, a class of chemotherapeutic drugs designed to stabilize the microtubule network in order to stall cell division and to induce tumor cell death. Whilst independent studies report the association between low Tau expression and superior taxane response, the data were refused by a meta-analysis, suggesting interference of other parameters. Unpredictably, Tau expression level was identified as a prognostic cancer marker, whereby its positive or negative predictive value for survival depended on the cancer type. With recent experimental evidence linking Tau to P53 signaling, DNA stability and protection and to the implication of Tau in cancer is strengthened. The identification of a role of Tau at the interface between two major aging-related disorder families, neurodegeneration and cancer, offers clues for the epidemiological observation inversely correlating these disorders. Elucidating how Tau is mechanistically implicated in cellular pathways common to these devastating illnesses may extend the Tau-targeting therapeutic opportunities to cancer.

There is a major clinical need for accurate biomarkers for prostate cancer prognosis, to better inform treatment strategies and disease monitoring. Current clinically recognised prognostic factors, including prostate-specific antigen (PSA) levels, lack sensitivity and specificity in distinguishing aggressive from indolent disease, particularly in patients with localised intermediate grade prostate cancer. There has therefore been a major focus on identifying molecular biomarkers that can add prognostic value to existing markers, including investigation of DNA methylation, which has a known role in tumorigenesis. In this review, we will provide a comprehensive overview of the current state of DNA methylation biomarker studies in prostate cancer prognosis, and highlight the advances that have been made in this field. We cover the numerous studies into well-established candidate genes, and explore the technological transition that has enabled hypothesis-free genome-wide studies and the subsequent discovery of novel prognostic genes.

Breast Cancer diagnosis is one of the most studied problems in the medical domain. In the medical domain, cancer diagnosis has been studied extensively which instantiates the need of early prediction of cancer disease. For obtaining advance prediction, health records are exploited and given as input to an automated system. This paper focuses on constructing an automated system by employing deep learning based recurrent neural network models. A stacked GRU-LSTM-BRNN is proposed in this paper that accepts health records of a patient for determining possibility of being affected by breast cancer. Proposed model is compared against other baseline classifiers such as stacked Simple-RNN model, stacked LSTM-RNN model, stacked GRU-RNN model. Comparative results obtained in this study indicate that stacked GRU-LSTM-BRNN yield better classification performance for predictions related to breast cancer disease.

Circulating tumor DNA (ctDNA) in fluids has gained attention because ctDNA seems to identify tumor-specific abnormalities, which could be used for diagnosis, follow-up of treatment, and prognosis: the so-called liquid biopsy. Liquid biopsy is a minimally invasive approach and presents the sum of ctDNA from primary and secondary tumor sites. It has been possible not only to quantify the amount of ctDNA but also to identify (epi)genetic changes. Specific mutations in genes have been identified in the plasma of patients with several types of cancer, which highlights ctDNA as a possible cancer biomarker. However, achieving detectable concentrations of ctDNA in body fluids is not an easy task. ctDNA fragments present a short half-life, and there are no cut-off values to discriminate high and low ctDNA concentrations. Here, we discuss the use of ctDNA as a cancer biomarker, the main methodologies, the inherent difficulties, and the clinical predictive value of ctDNA.

We study a minimal model of the stress-driven p53 regulatory network that includes competition between active and mutant forms of the tumor-suppressor gene p53. Depending on the nature of the external stress signal, four distinct dynamical states are observed. These states can be distinguished by dierent dynamical properties and correspond to active, apoptotic, pre-malignant and cancer states. Transitions between any two of these states are found to be unidirectional and irreversible if the stress signal is either oscillatory or constant. When the signal decays exponentially, the apoptotic state vanishes, and for low stress the pre-malignant state is bounded by two critical points, allowing the system to transition reversibly from the active to the pre-malignant state. For signi cantly large stress, the range of the pre-malignant state expands and the system moves to the cancerous state which is a stable attractor. This suggests that identi fication of the pre-malignant state may be important both for therapeutic intervention as well as for drug discovery.

Coronavirus disease 2019 (COVID-19) has been declared a global pandemic by the World Health Organization on March 11, 2020. COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-Cov-2). Although primarily a respiratory disease, cardiovascular complications of COVID-19 have been increasingly recognized. In addition, higher fatality has been reported in COVID-19 patients with underlying cardiovascular diseases. Cancer survivors have a considerably increased risk for premature cardiovascular diseases, mainly due to cardiotoxic cancer treatments. Therefore, it is foreseeable that cancer survivors will be more vulnerable to cardiovascular complications caused by COVID-19. In this review, three scenarios for increased cardiovascular complications of COVID-19 in cancer patients are proposed. In the first scenario, cardiotoxic cancer treatment and COVID-19 synergize to exacerbate direct myocardial damage. In the second scenario, cardiotoxic cancer treatment leads to a reduced cardiac reserve in cancer survivors, making them more vulnerable to COVID-19 in a “two-hit” model. The third scenario suggests that several shared risk factors may aggravate cardiovascular complications caused by both cancer treatment and COVID-19. Taken together, cancer survivors may be more vulnerable to cardiovascular complications when challenged by the COVID-19, and special cardiovascular care should be given to these patients.

The PI3K/AKT pathway is a key target in oncology where most efforts are focussed on phenotypes such as cell proliferation and survival. Comparatively little attention has been paid to PI3K in stemness regulation, despite the emerging link between acquisition of stem cell-like features and therapeutic failure in cancer. The aim of this review is to summarise current known and unknowns of PI3K-dependent stemness regulation, by integrating knowledge from the fields of developmental, signalling and cancer biology. Particular attention is given to the role of the PI3K pathway in pluripotent stem cells (PSCs) and the emerging parallels to dedifferentiated cancer cells with stem cell-like features. Compelling evidence suggests that PI3K/AKT signalling forms part of a ‘core molecular stemness programme’ in both mouse and human PSCs. In cancer, the oncogenic PIK3CA^H1047R variant causes constitutive activation of the PI3K pathway and has recently been linked to increased stemness in a dose-dependent manner, similar to observations in mouse PSCs with heterozygous versus homozygous Pten loss. There is also evidence that the stemness phenotype may become ‘locked’ and thus independent of the original PI3K activation, posing limitations for the success of PI3K monotherapy in cancer.Ongoing therapeutic developments for PI3K-associated cancers may therefore benefit from a better understanding of the pathway’s two-layered and highly context-dependent regulation of cell growth versus stemness.

Although there is a several array of diagnostic and therapeutic choices for pancreatic cancer in recent years, a crucial medical approach for the refractory disease is still needed. Oligonucleotide therapeutics, such as those based on antisense RNAs, RNA interference, aptamers and decoys, are promising agents against pancreatic cancer because they identify a specific nucleotide sequence or protein and interfere with gene expression as molecular-targeted agents. Within just the past quarter-century, the diversity and feasibility of these drugs as diagnostic or therapeutic tools have dramatically increased. Actually, there have been several clinical and preclinical studies of oligonucleotides for patients with pancreatic cancer so far. To support the discovery of effective diagnostic or therapeutic options by using oligonucleotide-based strategies in the absence of satisfactory therapies for long-term survival and the rising trend of diseases, we summarize the current clinical trials of oligonucleotide therapeutics for pancreatic cancer patients with underlying preclinical or scientific data and focus on the possibility of oligonucleotides to target pancreatic cancer in clinical implications.

It is estimated that pancreatic cancer will be the 2^nd leading cause of cancer-related deaths globally by 2030, highlighting the ongoing lack of effective treatment options in this devastating condition. There is a lack of reliable prognostic or predictive markers in pancreatic cancer to guide management decisions, whether for systemic chemotherapy, molecularly targeted therapies, or immunotherapies. To date, the results for targeted agents and immunotherapies in unselected populations of chemo-refractory pancreatic cancer have not met expectations. The reasons for this lack of efficacy of immunotherapy in pancreatic cancer are incompletely understood. The challenges in pancreatic cancer include the physical barrier created by the dense desmoplastic stroma surrounding the tumor, chemokine-mediated exclusion of T cells, poor antigenicity, paucity of infiltrating T cells within the tumor, ultimately leading to an immunosuppressive microenvironment. A better understanding of the role of inflammation in pancreatic cancer, its tumor microenvironment and individualized patient-related features, be they molecular, clinical or histopathological would enable a more effective tailored approach to the management of pancreatic cancer. In this review, the role of inflammation, the immune tumor microenvironment and potential immune biomarkers in pancreatic cancer are explored.

Carcinogenesis is the process whereby a normal cell is transformed into a neoplastic cell. This action involves several steps starting with initiation and followed by promotion and progression. Driving these stages are oxidative stress and inflammation, which in turn encompasses a myriad of aberrant gene expressions, both within the transforming cell population and the cells within the surrounding lesion. Chemoprevention of cancer with bioreactive foods or their extracted/purified components occurs via normalizing these inappropriate gene activities. Various foods/agents have been shown to affect different gene expressions. In this review we discuss whereby the chemoprevention activities of the red beetroot itself may disrupt carcinogenesis and the activities of the water soluble betalains extracted from the plant.

Neuroimmune semaphorin 4A (Sema4A), a member of semaphorin family of transmembrane and secreted proteins, is an important regulator of neuronal and immune functions. In the nervous system, Sema4A primarily regulates the functional activity of neurons serving as an axon guidance molecule. In the immune system, Sema4A regulates immune cell activation and function granting a fine tuning of immune response. Recent studies have shown a dysregulation of Sema4A expression in several types of cancer such as hepatocellular carcinoma, colorectal and breast cancers. Cancers have been associated with abnormal angiogenesis. The function of Sema4A in angiogenesis and cancer is not defined. Recent studies have demonstrated Sema4A expression and function in endothelial cells. However, the results of these studies are controversial as they report either pro – or anti-angiogenic Sema4A effects depending on the experimental settings. In this mini-review, we discuss these findings as well as our data on Sema4A regulation of inflammation and angiogenesis, which both are important pathologic processes underlining tumorigenesis and tumor metastasis. Understanding the role of Sema4A in those processes may guide the development of improved therapeutic treatments for cancer.

We are currently assisting at the explosion of the epitranscriptomics, which studies the functional role of chemical modifications into RNA molecules. Among more than 100 RNA modifications, the N6-methyladenosine (m6A), in particular, has attracted the interest of researchers all around the world. m6A is the most abundant internal chemical modification in mRNA and it can control any aspect of mRNA post-transcriptional regulation. m6A is installed by “writers”, removed by “erasers”, and recognized by “readers”, thus, it can be compared to the reversible and dynamic epigenetic modifications in histones and DNA. Given its fundamental role in determining the way mRNAs are expressed, it comes as no surprise that alterations to m6A modifications have a deep impact in cell differentiation, normal development and human diseases. Here, we review the proteins involved in m6A modification in mammals, m6A role in gene expression and its contribution to cancer development. In particular, we will focus on AML that, among first, has indicated how alteration in m6A modification can disrupt normal cellular differentiation and lead to cancer.

The latest scientific literature outlines a resilient interconnection between cancer modulation and dietary polyphenols by sphingolipid-mediated mechanisms, usually correlated with a modification of their metabolism. We aim to extensively survey this relation to show how it could be advantageous in cancer treatment or prevention by nutrients. Polyphenols, chemically characterized by polyhydroxylated phenolic structure, are well known for their pervasive pharmacological properties: anti-inflammatory, antibiotic, antiseptic, antitumor, antiallergic, cardioprotective and others. Pervasive is also their distribution in food products especially in plant foods as vegetables, cereals, legumes, fruits, nuts and beverages as wine, cider, beer, tea, cocoa. Recently, sphingolipids have been correlated with cancer by a dysregulation of their rheostat emerging as mediator of cell proliferation in cancer and modulator of chemotherapeutics.

The past decade has witnessed enormous progress, which has seen the noncoding RNAs (ncRNAs) turn from the so called dark matter RNA to critical functional molecules, influencing most physiological processes in development and disease contexts. Many ncRNAs interact with each other and are part of networks that influence the cell transcriptome and proteome and consequently the outcome of biological processes. The regulatory circuits controlled by ncRNAs have become increasingly more relevant in cancer. Further understanding of these complex network interactions and how ncRNAs are regulated, is paving the way for the identification of better therapeutic strategies in cancer.

Molecular imaging modalities are used for different type of cancers detection and diagnosis. In recent few years, there has been an increased focus on developing novel nanoparticles as new imaging contrast agents for early detection of cancer. The aim of this review article is to summarize molecular imaging technologies accompanying with using nanoparticles to improve potential imaging for cancer detection and hence valuable therapy in the future. Nanoprobes are rapidly becoming potentially transformative tools on cancer diagnostics for a wide range of imaging modalities such as CT, MRI, SPECT, PET, Ultrasound and Optical imaging. The study results seen in the recent literature are provided and discussed the diagnostic performance of imaging modalities for cancer diagnosis and their future directions. With knowledge of the correlation between the application of nanoparticles and molecular imaging modalities and with the development of targeted contrast agents or nanoprobes, they may provide better cancer diagnosis in the future.

The present investigation has been conducted on one hundred tissue fragments of breast cancer, collected and immediately cryopreserved following the surgical resection. The fragments were selected from patients with invasive ductal carcinoma of the breast, the most common and potentially aggressive type of mammary cancer, with the objective to increase the knowledge of breast cancer molecular markers, useful for diagnostic and prognostic categorization of patients, in assessing post-surgical therapeutic regimes. The proteomic screening, by 2D-IPG and mass spectrometry, allowed us to identify two main classes of protein clusters: proteins expressed ubiquitously at high levels in all patients, and proteins expressed sporadically among the same patients. Within the group of ubiquitous proteins, glycolytic enzymes and proteins with anti-apoptotic activity were predominant. Among the sporadic ones, proteins involved in cell motility, molecular chaperones and proteins involved in the detoxification appeared prevalent. The data of the present study indicates that the primary tumor growth is generally supported by two concurrent pathways: the inhibition of apoptosis and the stimulation of cellular proliferation. The second phase of the evolution of the tumor can be prematurely scheduled by the occasional presence of proteins involved in cell motility and in the defenses of the oxidative stress. To our knowledge this report on large-scales proteomics of breast cancer is currently a unique approach in the literature that offers the opportunity to evaluate the presence and recurrence of proteins to be used as prognostic indicators and susceptibility to metastasis in patients operated on for invasive ductal carcinoma of the breast.

Although mammography has been the gold standard for early detection of breast cancer, if a woman has dense breast tissue, a false negative diagnosis may occur. Breast ultrasound, whether hand-held or automated, is a useful adjunct to mammography but adds extra time and cost. The primary aim was to demonstrate that our second-generation Aceso system, which combines full-field digital mammography (FFDM) and automated breast ultrasound (ABUS) in a single platform, is able to produce improved quality images that provide clinically meaningful results. Aceso was first tested using two industry standards: a CDMAM phantom to assess the FFDM images; and the CIRS 054GS phantom to evaluate the ABUS images. In addition, 25 women participated in a clinical trial: 14 were healthy volunteers while 11 were patients referred by the breast clinic at Groote Schuur Hospital. The CDMAM phantom results showed the FFDM results were better than EUREF’s standard of “acceptable” and were approaching “achievable”. The ABUS results showed lateral and axial spatial resolution of 0.5 mm and adequate depth penetration of 80 mm. Our second-generation Aceso system, with its improved quality of clinical FFDM and ABUS images, has demonstrated its potential for early detection of breast cancer in a busy clinic.

The main aim of this study is to predict whether the type of breast cancer is “benign” or “malignant” by classical generalized linear model (GLM) approach and an extended family of GLM called generalized linear mixed model (GLMM) approach for binomially distributed response variable with binary link functions. In this study, an advanced statistical modeling approach based on the GLMM to the traditional statistical modeling approach based on the GLM for binomially distributed response variable with various binary link functions is proposed to investigate the relationships between the “malignant or benign diagnosis of the BC in patients” and “nine attributes” of 699 BC diagnosed patients. This study also focuses on the statistical significance of the accurate classification of the BC diagnosed patients in cancer studies in medicine in “benign” or “malignant” type based on the WBC dataset. In this study, the superiority of the GLMM approach over the GLM approach for the binary response variable especially belonging to the WBC dataset is emphasized in the field of cancer diagnosis in medicine. Also the importance and the power of the IC and performance metrics as the goodness-of-fit test statistics are strongly emphasized for accurate statistical inferences from the “best” fitted model. In this study, from the main findings, the best fitted model among the GLM and GLMM approaches for the binary response variable is determined as the GLMM under “logit” link function with “id” random effect with the most statistically significant odds of the occurance of the BC being “malignant” as 7.9104, 5.6888, 5.6643, 4.9842, 4.1212, 2.0679, 1.8755, and 1.3970 times more than being “benign” for every one-unit increase in the quantities of “clump thickness”, “bland chromatin”, “mitoses”, “bare nuclei”, “cell shape”, “marginal adhesion”, “epithelial cell size”, and “cell size”, respectively.

Background: The aim of the present study was to determine the correlation between obesity, serum levels of leptin and proximal gastric cancer. Methods: Sixty-four gastric cancer patients operated on with curative intent were included in the study. We determined the correlation between the preoperative serum levels of leptin and the tumor`s location. Results: Serum leptin levels were correlated significantly with the proximal third location (p = 0.04), gastric outlet obstructing tumors (p < 0.0001), CRP levels (p = 0.03) and BMI (p < 0.0001). Patients with high serum levels of leptin had significantly more intestinal types of gastric cancer (p = 0.033) and better differentiation compared to patients with low serum leptin levels (p = 0.009). The linear regression model determined the proximal tumor location (beta: 0.467; p = 0.045), BMI (beta: 0.657; p = 0.001), high preoperative serum albumin (beta: 0.563; p = 0.016) and the presence of pyloric stenosis (beta: 0.525; p = 0.006) as related significantly to serum leptin levels. The Cox proportional hazard model identified age (HR: 0.003; 95%CI: 0-0.794; p = 0.041), preoperative serum levels of leptin (HR: 0.125; 95%CI: 0.018-0.887; p = 0.037) and the number of extracted LNs (HR: 0.001; 95%CI: 0-0.677; p = 0.038) as independent prognostic factors. Conclusions: Serum levels of leptin were significantly elevated in patients with proximal gastric cancer, suggesting that the leptin`s effect might be due to its systemic secretion. This might explain the higher incidence of proximal gastric cancer in obese patients. Elevated serum leptin levels were an independent prognostic factor.

This study presents a detailed computational investigation aimed at identifying and evaluating potential small organic molecular scaffolds as inhibitors targeting the Pks13 protein, a critical enzyme in tuberculosis (TB) drug discovery. Our approach integrates multiple computational techniques, including quantitative structure-activity relationship (QSAR) modelling, compound library generation, molecular docking, biological activity prediction, re-evaluation of screened compounds, molecular dynamics (MD) analysis, and binding free energy estimation using the MM-GBSA approach. We developed a robust QSAR model using multiple linear regression (MLR) techniques, specifically tailored to predict the minimum inhibitory concentration (MIC) values of potential anti-TB agents. This model demonstrated excellent predictive performance, validated through rigorous internal and external validation procedures. Through molecular docking simulations, we identified five promising inhibitors Ethyl (R,Z)-2-(2-((2-chlorobenzyl) oxy)benzylidene)-5-(4-chlorophenyl)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine-6-carboxylate (PKD1), (7R,9aR)-7-(2-hydroxyphenyl)-4-(2-methoxyphenyl)-3-methyl-7,8,9,9a-tetrahydroisoxazolo[5,4-b]quinolin-5(6H)-one (PKD2), (7-(4-methoxy phenyl)-2-methyl-3-phenylpyrazolo[1,5-a]pyrimidin-5-yl)(4-(3-(trifluoromethyl)phenyl) piperazin-1-yl)methanone (PKD3), (8S,10S)-10-(((2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyl tetrahydro-2H-pyran-2-yl)oxy)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10-tetra-hydrotetracene-5,12-dione (PKD4), 3-(3,4-dimethylphenyl)-5-((2-(4-fluorophenyl)-2-oxoethyl) thio)-6-phenyl-2-thioxo-2,3,5,7a-tetrahydrothiazolo[4,5-d]pyrimidin-7(6H)-one (PKD5)with high binding affinities, prioritizing them based on their binding energies. These selected compounds were further assessed for their biological activity predictions, guiding the selection of candidates for experimental validation. Subsequent re-evaluation using absolute binding free energy estimation and MD simulations provided insights into the stability and dynamics of the protein-ligand complexes over time. Our findings highlighted the potential of identified compounds as stable binders within the Pks13-TE domain binding pocket, underscoring their viability as drug candidates. Additionally, binding free energy analysis using MM-GBSA reaffirmed the strong affinity of the proposed compounds towards Pks13. Our integrated computational approach offers a systematic and detailed framework for the identification and characterization of potential Pks13 inhibitors with specific relevance to TB drug discovery.

The lack of application of management models that allow strategies to be converted into action and then measure their results in order to apply improvement actions to meet the objectives in small and medium-sized companies (SMEs); they generate problems in their management causing the closure of their operations unexpectedly; To mitigate the risks of closure and bankruptcy with the support of ICT, an alternative was presented considering that risk management is important in decision making at a strategic, tactical and operational level. The objective is to design a prototype to mitigate risks and prevent threats to avoid the closure of this type of company. Through the analysis of related articles, applying sequences of methodological steps; It was determined that the proposed results are aimed at how to identify and mitigate the risks and threats that cause their bankruptcy and closure. Prototypes resulted that allow mitigating risks, preventing threats and minimizing vulnerabilities in the management of SMEs. It was concluded that the proposed prototype to detect threats and vulnerabilities provides an optimal security model for small and medium-sized companies; As a result of the simulations, a security percentage of 77.92% was established, which means that the greater the number of risks and threats, the greater the probability that a small and medium-sized company will close.

Climate change is unpredictable and can change rapidly or over time; anthropogenic stressors work synergistically to strengthen their impact on vulnerable ecosystems and the fisheries sector. This study documented the past occurrence of extreme climate change impacts, such as supertyphoon Pablo (ST: Bopha), which severely affected Baganga, Davao Oriental, about ten years ago. A mixed-methods data collection was used, combining semi-structured interviews with small-scale fishers (N=120) in four fishing villages and focus group discussions (N=4, participated by about 4 focus groups) on assessing the impacts and their adaptation after climatic events occurred. Our findings indicate that the four selected fishing villages were exposed to common factors of climate change events that destroyed many lives and their livelihood. Including a decrease in catch per trip and the fishing operations disruption (98%). However, due to the impact of the supertyphoon, small-scale fishers in Baganga developed psychological distress (emotional 44% and physical 24%) due to the extreme event or disaster and economic losses (32%). In order to survive, their adaptation strategies relied on government and non-government-provided provisions and projects, e.g., planting trees, constructing a sea wall with wave breakers, cash for work, and tourism as an alternative livelihood. Despite this, our study revealed that the community had limited knowledge on the impacts of climate change, lack clear management goals especially for fishers, and the widespread use of illegal fishing gears. The local government must strongly implement rules, policies, and adaptation measures that will contribute to better and more resilient communities. This can help them to withstand future shocks and provide sustainable fisheries resources that will benefit all the fishers. The study will be useful to policymakers, disaster management group and organization that will help assist affected communities highly affected by climatic events.

Hepatic macrophages act as the liver’s first line of defense against injury. Their differentiation into pro-inflammatory or anti-inflammatory subpopulations is a critical event that maintains a delicate balance between liver injury and repair. In our investigation, we explored the influence of the small heterodimer partner (SHP), a nuclear receptor primarily associated with metabolism, on macrophage differentiation during the innate immune response. During macrophage differentiation, we observed significant alterations in Shp mRNA expression. Deletion of SHP promoted M1 differentiation while interfering with M2 polarization. Conversely, overexpression of SHP resulted in increased expression of peroxisome proliferator activated receptor gamma (Pparg), a master regulator of anti-inflammatory macrophage differentiation, thereby inhibiting M1 differentiation. Upon lipopolysaccharide (LPS) injection, there was a notable increase in the pro-inflammatory M1-like macrophages, accompanied by exacerbated infiltration of monocyte-derived macrophages (MDMs) into the livers of Shp myeloid cell specific knockout (Shp-MKO). Concurrently, we observed significant induction of tumor necrosis factor alpha (Tnfa) and chemokine (C-C motif) ligand 2 (Ccl2) expression in LPS-treated Shp-MKO livers. Additionally, the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kB) pathways were activated in LPS-treated Shp-MKO livers. Consistently, both pathways were hindered in SHP overexpression macrophages. Finally, we demonstrated that SHP interacts with p65, thereby influencing macrophage immune repones. In summary, our study uncovered a previously unrecognized role of SHP in promoting anti-inflammatory macrophage differentiation during the innate immune response. This was achieved by SHP acting as a regulator for the Pparg, MAPK and NF-kB pathways.

This article explores the Role and Contributions of Small and Medium Enterprises (SMEs) in a globalized and innovative economy, looking specifically at the challenges and opportunities. The establishment and expansion of new firms provides a sizable amount of net new jobs. While high-expectation entrepreneurial enterprises and gazelles are usually found among innovative and technology-based new organizations, it is also essential that there be a sizable supply for them to play a significant part in economic growth. In other words, encouraging all forms of en-trepreneurship is likely to increase the number of innovative, fast-growing enterprises as well as entrepreneurship. In many European countries, entrepreneurship needs to be encouraged. Findings show the crucial role the SME sector plays in the South African economy in tackling sustainable development. About 90% of all official firms in South Africa are thought to be small, medium, or micro-enterprises. The study concluded that one of the major contributions to the South African economy is the SME sector. The SME is not just viewed as a source of new jobs, but also as a sector that absorbs laid-off workers from both the private and public sectors.

Biomimetic foods are expected to have potential health benefits for the management and prevention of chronic diseases, such as diabetes and cardiovascular disease. In the current research, two commercially available and affordable plant proteins (soy protein isolate-SPI and pea protein isolate-PPI) at two levels (5%, 10%) were added to the Yangyu jiaotuan with an objective to develop a product with reduced glycemic properties and high protein content while maintaining its original taste and texture. The results showed that several important textural properties such as hardness and chewiness did not change significantly during the refrigerated storage. The storage modulus G′ increased with refrigerated storage time for different samples, there were significant differences among the five samples (with and without protein addition) with respect to frequency dependence during rheological measurements. The in vitro starch digestion experiments showed that the starch hydrolysis of Yangyu jiaotuan decreased considerably with the increase in PPI content and during refrigerated storage due to starch retrogradation. Protein has protected the microstructure and there was less damage when compared to samples without protein. The bimodal peaks of the particle size distribution curves showed that the newly developed Yangyu jiaotuan contains two different sizes of particles, the smaller particles (~30 μm) corresponded to PPI and starch granules, while the larger particles corresponded to the fragments of gel network of the starch matrix. Based on the above results, Yangyu jiaotuan mixed with pea protein is a convenient potato staple food product, which complies with the biomimetic potato food very well.

Alloys based on TiNi are widely used in various fields of technology and medicine. In the present work, we report on preparation of TiNi-alloy based wire with the shape memory effect, which was used for compression clips for surgery. Composition and structure of the wire, and its martensitic and physical-chemical properties were studied using SEM, TEM, optic microscopy, profilometry, mechanical tests, etc. The TiNi alloy was found to consist of B2 and B19' and secondary-phase particles of Ti2Ni, TiNi3 and Ti3Ni4. Its matrix was slightly enriched in Ni (50.3 at. % of Ni). Homogeneous grain structure was revealed (an average grain size of 19±0.3 μm) with equal quantities of grain boundaries of special and general types. Surface oxide layer provide improved biocompatibility and promote adhesion of protein molecules. Overall, the obtained TiNi wire was concluded to exhibit martensitic, physical and mechanical properties suitable for its use as an implant material. The wire was then used for manufacturing compression clips with the shape memory effect and applied in surgery. The medical experiment that involved 46 children demonstrated that the use of such clips in children with double-barreled enterostomies permitted to improve the results of surgical treatment.

Researchers have reported various impacts of the COVID-19 outbreak on small-scale fishers, such as stagnating market demands, reduction of market price and income, etc. While literature have heeded to these impacts in a relatively short time frame, scant evidence exists on the changing impacts over time and on the detailed processes of how fishers have been coping with the challenges in a longer time period. Furthermore, few studies have comprehensively analysed the impacts and strategies from multiple perspectives. This study aims to explore the perceived impacts of the COVID-19 outbreak on small-scale fishing communities and to highlight the coping strategies adopted by fishers over a year since the initial outbreak, through a case study in Trang Province, Thailand. Analysis of both qualitative and quantitative data obtained through semi-structured interviews indicated that fishers wisely utilised natural, financial and social capitals at the early stages of the outbreak, while human capitals were essential for recovering from the impacts in the later stages. Our findings suggest that the adaptive capacity to flexibly change livelihood strategies are crucial, while alternative income source may not necessarily help small-scale fishers under stagnating global economy.

During their complex life cycles, the Apicomplexan parasites, Plasmodium falciparum and Toxoplasma gondii employ several genetic switches to regulate their gene expression. One such switch is mediated at the level of translation through upstream Open Reading Frames (uORFs). As uORFs are found in the upstream regions of a majority of genes in both the parasites, it is essential that their roles in translational regulation be appreciated to a greater extent. This review provides a comprehensive summary of studies that show uORF-mediated gene regulation in these parasites and highlights examples of clinically and physiologically relevant proteins that exhibit uORF-mediated regulation. In addition to these examples, several studies that use bioinformatics, transcriptomics, proteomics, and ribosome profiling also indicate the possibility of widespread translational regulation by uORFs. Further analysis of genome-wide datasets will reveal novel genes involved in key biological pathways such as cell-cycle progression, stress-response, and pathogenicity. The cumulative evidence from studies presented in this review suggests that uORFs will play crucial roles in regulating gene expression during clinical disease caused by these important human pathogens.

This paper presents an optimal design for the inner current control loop of the continuous current conduction mode (CCM) power factor correction (PFC) stage, which it can be used as the front stage of the two stages alternating current-direct current (AC-DC) telecom power supply. Conventional single-phase CCM-PFC boost converter usually implemented with using of the proportional-integral (PI) controllers in both of the voltage and current control loops, to regulate the output DC voltage to the specified value, moreover to maintains the input current follows the input voltage which offers converter with high power factor (P.F) and low current total harmonic distortion (THD). However, due to the slow dynamic response of the PI controller at the zero-crossing point of the input supply current, input current can’t fully follow the input voltage which leads to high THD. Digitally controlled PFC converter with an optimal design of the inner current control loop using doubly control loops IP controller to reduce the THD and to offer input current with unity P.F was performed in this paper. Furthermore, for the economic design of the digitally control PFC converter, two isolated AC and DC voltage sensors are proposed and designed for the interfacing with the microcontroller unit (MCU). PSIM software was used to test the converter performance with using the proposed designed current controllers and isolated voltage sensors. High power density digitally controlled telecom PFC stage with P.F of about 99.93%, full load efficiency of about 98.70% and THD less 5.50% is achieved in this work.

Respiratory syncytial virus (RSV) is associated with adverse outcomes among immunocompromised patients. Inhaled ribavirin has been shown to improve mortality rates. The Small-Particle Aerosol Generator delivery system (SPAG-2) is the only FDA-cleared device to deliver inhaled ribavirin. However, it is difficult to set up and maintain. We developed a method for delivery of this medication using the vibrating mesh nebulizer (Aerogen®). We did not observe any adverse events with this method.

The failure to acknowledge and account for environmental externalities or spillovers in climate change adaptation policy, advocacy and programming spaces exercabates the risk of ecological degradation, more so, degradation of land. In particular use of unsuitable water sources for irrigation may increase salinisation risks. However, little if any policy assessments and research effort has been directed at investigating how farmer perceptions mediate spillovers from the ubiquitous irrigation adaptation strategy. In this study cognitive failure and/or bias construct is examined and proposed as an analytical lens in research, policy and learning and the convergence of disaster risk reduction and climate change adaptation discourses. The findings from small-scale farmers, Machakos and Kakamega counties, Kenya, suggest multifaceted biases and failures about the existence and importance of externalities in adaptation planning discourses. Among other dimensions, cognitive failure which encompasses fragmented approaches among institutions for use and management of resources, inadequate policy and information support, as well as, poor integration of actors in adaptation planning accounts for adaptation failure. The failures in such Human-Environment system interactions have the potential to exercabate existing vulnerability of farmer production systems in the long run. The findings further suggest that in absence of risk message information dissemination, education level, farming experience and information accumulation, as integral elements to human capital, do not seem to have significant effect on behaviour about mitigation of environmental spillovers. Implicitly, reversing the inherent adaptation failures calls for system approaches that enhance coordinated adaptation planning, prioritises proactive mitigation of slow onset disaster risks and broadens decision support systems, such as, risk information dissemination integration into the existing adaptation policy discourses and practice.

In this research, the computational fluid dynamic (CFD) approach that has been used in wind power generation field was applied for the solution of the problems of local strong wind areas in railway fields, and the mechanism of wind generation was discussed. At the same time, the affectivity of the application of computational fluid dynamic approach to railway field was discussed. The problem of local wind that occurs on the railway line in winter was taken up in this research. A computational simulation for the prediction of wind conditions by LES was implemented and it was clarified that the local strong wind area is mainly caused by separated flows originating from the small‐scale terrain positioned at its upstream (at approximately 180.0 m above sea level). Meanwhile, the effects of the size of calculation area and spatial grid resolution on the result of calculation and the effect of atmospheric stability were also discussed. It was clarified that when the air flow characteristic of the separated flow originating from the small‐scale terrain (at altitude of approximately 180.0 m) targeted in this research is reproduced at high accuracy by computational simulation of wind conditions, approximately 10.0 m of spatial resolution of computational grid in horizontal direction is required. As a result of the computational simulation of wind conditions of stably stratified flow (Fr = 1.0), lee waves were excited at the downstream of the terrain over time. As a result, the reverse‐flow region lying behind the terrain that had been observed at a neutral time was inhibited. Consequently, local strong wind area was generated at the downstream of the terrain and the strong wind area passing through the observation mast was observed. By investigating the speed increasing rate of local strong wind area induced at the time of stable stratification, it was found that the wind was approximately 1.2 times stronger than what was generated at a neutral time.

This paper presents a 612–1152 MHz Injection Locked Frequency Multiplier (ILFM). The proposed ILFM is only used for sending an input signal to the receiver in the I/Q mismatch calibration mode. Using the Phase-Locked Loop (PLL) to calibrate the receiver places a burden on this system due to the extra area required and power consumption. Instead of the PLL, to satisfy high frequency, low jitter, and low area, a Ring Oscillator is proposed. The free-running frequency of the ILFM is automatically digitally calibrated to reflect the frequency of the injected signal from the harmonics of the reference clock. To control the frequency of the ILFM, the load current is digitally tuned with 6-bit digital control signal. The proposed ILFM locks to the target frequency using a digitally controlled Frequency Locked Loop (FLL). This chip is fabricated using 1-poly 6-metal 0.18 µm CMOS and achieve the wide tuning range of 612–1152 MHz. The power consumption is 0.95 mW from a supply voltage of 1.8 V. The measured phase noise of the ILFM is −108 dBc/Hz at a 1 MHz offset.

Both climate change and anthropogenic activities contribute to the deterioration of terrestrial water resources and ecosystems worldwide. Central Asian endorheic basins are among the most affected regions through both climate and human impacts. Here, we used a digital elevation model, digitized bathymetry maps and Landsat images to estimate the areal water cover extent and volumetric storage changes in small terminal lakes in Burabay National Nature Park (BNNP), located in Northern Central Asia (CA), for the period of 1986 to 2016. Based on the analysis of long-term climatic data from meteorological stations, short-term hydrometeorological network observations, gridded climate datasets (CRU) and global atmospheric reanalysis (ERA Interim), we have evaluated the impacts of historical climatic conditions on the water balance of BNNP lake catchments. We also discuss the future based on regional climate model projections. We attribute the overall decline of BNNP lakes to long-term deficit of water balance with lake evaporation loss exceeding precipitation inputs. Direct anthropogenic water abstraction has a minor importance in water balance. However, the changes in watersheds caused by the expansion of human settlements and roads disrupting water drainage may play a more significant role in lake water storage decline. More precise water resources assessment at the local scale will be facilitated by further development of freely available higher spatial resolution remote sensing products. In addition, the results of this work can be used for the development of lake/reservoir evaporation models driven by remote sensing and atmospheric reanalysis data without the direct use of ground observations.

Cholesterol homeostasis is pivotal for cellular function. Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1), also abbreviated as SOAT1, is an enzyme catalyzing the storage of excess cholesterol to cholesteryl esters. ACAT1 is an emerging target to treat diverse diseases including atherosclerosis, cancer, and neurodegenerative diseases. F12511 is a high affinity ACAT1 inhibitor. Previously, we developed a stealth liposome-based nanoparticle to encapsulate F12511 to enhance its delivery to the brain and showed its efficacy in treating a mouse model for Alzheimer’s disease (AD). In this study, we introduce F26, a close derivative of F12511 metabolite in rats. F26 was encapsulated in the same DSPE-PEG2000/phosphatidylcholine (PC) liposome-based nanoparticle system. We employed various in vitro and in vivo methodologies to assess F26's efficacy and toxicity compared to F12511. Results demonstrate that F26 is more effective and durable than F12511 in inhibiting ACAT1, in both mouse embryonic fibroblasts (MEFs) and in multiple mouse tissues including the brain tissues, without exhibiting any overt systemic or neurotoxic effects. This study demonstrates the superior pharmacokinetic and safety profile of F26 in wild-type mice, and suggests its therapeutic potential against various neurodegenerative diseases including AD.

The injury causes resistance in human gastric cancer (GC). This Adverse Outcome Pathway (AOP) entitled “Increases in cellular reactive oxygen species (ROS) and chronic ROS leading to human treatment-resistant gastric cancer (GC)” consists of molecular initiating event (MIE) as “Increases in cellular ROS” and “Chronic ROS”, followed by series of key events (KEs); “porcupine-induced Wnt secretion and Wnt signaling activation”, “beta-catenin activation”, “epithelial-mesenchymal transition (EMT), and adverse outcome (AO) as “human treatment-resistant GC” in the sequence. ROS has multiple roles in disease such as development and progression of cancer, or apoptotic induction causing anti-tumor effects. In this AOP, we focus on the role of sustained levels of chronic ROS to induce the therapy-resistance in human GC. EMT, which is cellular phenotypic change from epithelial to mesenchymal-like features, demonstrates cancer stem cell (CSC)-like characteristics in human GC. EMT is induced by Wnt/beta-catenin signaling, providing the rationale to have Wnt secretion and beta-catenin activation as KEs in the AOP.

Pancreatic cancer is one of the most fatal common cancers affecting both men and women, representing about 3 percent of all new cancer cases in the United States. In this study, we aimed to investigate the association of pancreatic cancer risk with alcohol consumption as well as folate intake. We performed a case-control study of 384 patients diagnosed with pancreatic cancer from May 2004 to December 2009 and 983 primary care healthy controls. Our findings showed no significant association between risk of pancreatic cancer and either overall alcohol consumption or type of alcohol consumed (drinks/day). Our study showed dietary folate intake was modestly but significantly inversely associated with pancreatic cancer (OR=0.99, P <.0001). The current study supports the hypothesis that pancreatic cancer risk is reduced with higher food-based folate intake.

Viral infections leading to inflammation have been implicated in several common diseases such as Alzheimer’s disease (AD) and type 1 diabetes (T1D). Of note, herpes simplex virus 1 (HSV-1) has been reported to be associated with AD. We sought to identify the transcriptomic changes due to HSV-1 infection and anti-viral drug (acyclovir, ACV) treatment of HSV-1 infection in dissoci-ated cells from human cerebral organoids (dcOrgs) versus stem cell-derived pancreatic islets (sc-islets) to gain potential biological insights into the relevance of HSV-1-induced inflammation in AD and T1D. We observed that differentially expressed genes (DEGs) in HSV-1-infected sc-islets were enriched for genes associated with several autoimmune diseases, most significantly T1D but also rheumatoid arthritis, psoriasis, Crohn’s disease, and multiple sclerosis, whereas DEGs in HSV-1-infected dcOrgs were exclusively enriched for genes associated with AD. ACV treatment of sc-islets did not rescue transcript expression of autoimmune disease-associated genes. Finally, we identified gene ontology categories that were enriched for DEGs that were in common across, or unique to, viral treatment of dcOrgs and sc-islets, such as categories involved in the transferase complex, mitochondrial and autophagy function. Collectively, this studies pro-vide insight to the molecular effects of inflammation in AD and T1D.

This study examined the patterns of epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) deposition in the small intestine and colon to evaluate the association between histopathological severity of EFEMP1 deposition and constipation and determine if amyloid transthyretin (ATTR) and EFEMP1 deposits can colocalize. In 40 older cases (≥80 years of age), EFEMP1 deposition in the small intestine initiated in the submucosal and subserous vessels, subserous interstitium, and serosa (early stage); progressing to the muscularis propria and peri-Auerbach plexus area (intermediate stage); and finally, spreading diffusely to areas, excluding the mucosa and muscularis mucosa (advanced stage). The colon had a similar pattern of progression. During the middle-to-advanced stages, amyloid formation was observed in some vascular and serous deposits. We identified a subgroup of cases in which EFEMP1 deposition was the only presumed cause of constipation. Additionally, we demonstrated the colocalization of ATTR and EFEMP1 deposition. Apple-green birefringence was detected under polarized light only in approximately one-half of the cases in the small intestine and one-third of the cases in the colon. These findings emphasize that EFEMP1 deposits may be associated with lower gastrointestinal pathological conditions. Given the challenges of histopathological diagnosis on Congo red-stained specimens, we recommend the combined use of elastic fiber staining and immunohistochemistry for EFEMP1 to prevent overlooking this deposition.

The principal function of science education is to introduce students to core scientific concepts and practices; nevertheless, it is now impossible, in such a complex world, to neglect the ethical issues involved. Placing school science in a broader context motivates students and equips them with valuable critical skills. A meaningful example was from palm oil production and pervasive use worldwide: plantations result in major deforestation occurring in species-rich tropical regions, making the palm oil issue global in scope and highly critical for several aspects related to sustainability. This paper reports a sequence of didactic activities starting from palm oil chemistry, gradually extended initially by a multidisciplinary approach, then by interdisciplinary-systemic maps and, ultimately, through a holistic vision - involving anthropological and cultural considerations about indigenous people of deforested territories. This progressive broadening corresponds to an ever-greater penetration into the personal sphere, a condition for a real ethical consciousness. The increased students’ awareness was tested by qualitative considerations, supporting the teaching dimension more than the learning one. Contrary to disciplinary contents, the emergence of moral feelings cannot be measured but only perceived. Therefore, chemistry provides key concepts essential for global competences development in order to deal with sustainability issues with an increased ethical awareness.

In this report, we present a study demonstrating how machine learning methods can reveal the interaction of different risk factors of post-transplant leukemic relapse and obtain robust predictions even with a modest clinical dataset. Using a cohort of 63 pediatric patients with acute lymphocytic leukemia (ALL) and 46 patients with acute myeloid leukemia (AML) who underwent stem cell transplant at a single institution, we built predictive models of leukemic relapse with both pretransplant and posttransplant patient variables (specifically lineage-specific chimerism) using the random forest classifier. The random forest classifier revealed different important predictive factors between ALL and AML in our relapse models consistent with previous knowledge. Furthermore, it also distinguished donor CD34 chimerism as most impactful in relapse prediction compare to donor chimerism of other cellular lineages in our dataset for ALL but CD3 for AML. Our models greatly improved sensitivity and specificity at predicting relapses in cross validation compared to a reference model based on our own institutional incidence of relapse and inferential statistical principles. Local Interpretable Model-Agnostic Explanations, an interpretable machine learning tool, confirmed our Random Forest Classification result and provided an intuitive explanation of how our machine learning models made the relapse prediction for each individual patient.

Proteases represent common targets in combating infectious diseases including COVID-19. The 3-chymotrypsin-like protease (3CLpro) is a validated molecular target for COVID-19 and it is key for developing potent and selective inhibitors for inhibiting viral replication of SARS-CoV-2. In this review, we discuss structural relationships and diverse subsites of 3CLpro, shedding light on the pivotal role of dimerization and active site architecture in substrate recognition and catalysis. Our analysis of bioinformatics and other published studies unveil a proposal of a novel catalytic mechanism for the SARS-CoV-2 polyprotein cleavage by 3CLpro, centering on the triad mechanism involving His41-Cys145-Asp187 and its indispensable role in viral replication. Recognizing Asp187 as a crucial component in the catalytic process underscores its significance as a fundamental pharmacophoric element in drug design. Next, we provide an overview of both covalent and non-covalent inhibitors, elucidating advancements in drug development observed in preclinical and clinical trials. By highlighting various chemical classes and their pharmacokinetic profiles, our review aims to guide future research directions toward the development of highly selective inhibitors, underscore the significance of 3CLpro as a validated therapeutic target, and propel the progression of drug candidates through preclinical and clinical phases.

Abstract: Kiwifruit, a perennial horticultural crop known for its nutritional value, faces significant challenges due to biotic and abiotic stresses, affecting its yield and quality. Leucine-rich repeat receptor-like proteins (LRR-RLPs), a major group of receptor-like proteins in plants, have diverse functions in plant physiology, including growth, development, signal transduction, and stress responses. Despite their importance, the specific roles of kiwifruit LRR-RLPs in response to biotic and abiotic stresses remain poorly understood. In this study, we investigated the expression patterns of kiwifruit LRR-RLPs under various stress conditions, including pathogen stress, heat stress, waterlogging stress, and copper stress. Through genome and transcriptome analyses, we identified a total of 101, 164, and 105 LRR-RLPs in Actinidia Chinensis 'Hongyang', Actinidia eriantha 'Huate', and Actinidia chinensis 'Red5' kiwifruit, respectively, classified into 9 subgroups based on phylogenetic relationships. Synteny analysis revealed that the expansion of kiwifruit LRR-RLPs was primarily attributed to segmental duplication events. Using RNA-seq data from pathogen-infected kiwifruits, we identified specific LRR-RLP genes potentially involved in different stages of pathogen infection. Additionally, we observed the potential involvement of kiwifruit LRR-RLPs in abiotic stress responses, with upstream transcription factors possibly regulating their expression. Furthermore, protein interaction network analysis unveiled the participation of kiwifruit LRR-RLP genes in the regulatory network of abiotic stress responses. These findings highlight the crucial roles of LRR-RLPs in mediating both biotic and abiotic stress responses in kiwifruit, offering valuable insights for the breeding of stress-resistant kiwifruit varieties.

The C-type lectin-like receptor 2 (CLEC-2) is expressed on platelets and mediates binding to podoplanin (PDPN) on various cell types. The binding to circulating tumor cells (CTCs) leads to platelet activation and promote metastatic spread. The increased level of soluble CLEC-2 (sCLEC-2), presumably, released from activated platelets was shown in patients with thromboinflammatory and malignant disease. However, the functional role of sCLEC-2 and the mechanism of sCLEC-2 release is not known. In this study, we focused on the effect of platelet activation on CLEC-2 expression and the sCLEC-2 plasma level in cancer patients. First, citrated blood from healthy volunteer donors (n=20) was used to measure the effect of platelet stimulation by classical agonists and PDPN on aggregation, CLEC-2 expression on platelets by flow cytometry, sCLEC-2 release to the plasma by ELISA and total CLEC-2 expression by Western blot analysis. Second, sCLEC-2 was determined in plasma samples from healthy donors (285) and patients with colorectal carcinoma (CRC; 194), melanoma (160), breast cancer (BC; 99) or glioblastoma (49). PDPN caused a significant increase of the aggregation response induced by classical agonists. ADP or PDPN stimulation of platelets caused a significant decrease of CLEC-2 on platelets and sCLEC-2 in the plasma, whereas, total CLEC-2 in platelet lysates remained the same. Thus, the increased plasma level of sCLEC-2 is not a suitable biomarker of platelet activation. In patients with CRC (median 0.9 ng/mL), melanoma (0.9 ng/mL) or BC (0.7 ng/mL) we found significantly lower sCLEC-2 levels (p&lt;0.0001), whereas, glioblastoma patients displayed higher levels (2.6 ng/mL; p=0.0233) compared to healthy controls (2.1 ng/mL). The low sCLEC-2 plasma level observed in most of the tumor entities of our study, presumably, results from the internalization of sCLEC-2 by activated platelets or binding of sCLEC-2 to CTC.

Bile acids (BAs) and their signalling pathways have been identified as therapeutic targets for liver and metabolic diseases. We generated Cyp2c70-/- (KO) mice that are not able to convert chenodeoxycholic acid into rodent-specific muricholic acids (MCAs) and, hence, possess a more hydrophobic, human-like BA pool. Recently, we have shown that KO mice display cholangiopathic features with development of liver fibrosis. The aim of this study was to determine whether BA sequestration modulates liver pathology in Western type-diet (WTD)-fed KO mice. The BA sequestrant colesevelam was mixed into the WTD (2% w/w) of male Cyp2c70+/+ (WT) and KO mice and the effects were evaluated after 3 weeks of treatment. Colesevelam increased fecal BA excretion in WT and KO mice and reduced the hydrophobicity of biliary BAs in KO mice. Colesevelam ameliorated diet-induced hepatic steatosis in WT mice, whereas KO mice were resistant to diet-induced steatosis and BA sequestration had no additional effects on liver fat content. Total cholesterol concentrations in livers of colesevelam-treated WT and KO mice were significantly lower than those of untreated controls. Of particular note, colesevelam treatment normalized plasma levels of liver damage markers in KO mice and markedly decreased hepatic mRNA levels of fibrogenesis-related genes in KO mice. Lastly, colesevelam did not affect glucose excursions and insulin sensitivity in WT or KO mice. Our data show that BA sequestration ameliorates liver pathology in Cyp2c70-/- mice with a human-like bile acid composition without affecting insulin sensitivity.

The Sry-related HMG-box (Sox) family is a group of transcriptional regulators that play a critical role in many important developmental processes in both vertebrates and invertebrates. In aquatic animals, the function of Sox genes on sexual development has been gained particular attentions. The present study reported the molecular characterization of a Sox member (PtSoxE) in the swimming crab, Portunus trituberculatus, and tissue distribution analysis showed it was male-specific. Since the most highly expression of PtSoxE was found in the androgenic gland (AG), its relation to the insulin-like androgenic gland hormone (IAG) was further investigated. The PtSoxE siRNA caused a significant decrease in IAG expression in both AG and testis, whereas PtSoxE expression could be induced by treating with AG homogenate and rIAG. The result suggested a transcriptional interaction between PtSoxE and IAG. In addition, PtSoxE expression showed a closely positive correlation with several reported spermatogenesis-related genes, suggesting its involvement in testicular development of P. trituberculatus.

Berberis vulgaris L. is currently widely studied for its antioxidant and chemopreventive proper-ties, especially given the beneficial properties of its fruits in this regard. Although the bark and roots have been well known and used in traditional medicine since ancient times, little is known about the other parts of this plant. The aim of the research was to determine the antioxidant and LOX inhibitory activity effects of extracts obtained from leaves, fruits, and stems. Another aim of the work was to carry out the quantitative and qualitative analysis of phenolic acids, flavonoid aglycones, and flavonoid glycosides. Extracts were obtained with the use of ASE (accelerated solvent extraction). The total content of polyphenols was determined and was found to vary de-pending on the organ, with the highest amount of polyphenols found in the leaves extract. The free radical scavenging activity of the extracts was determined spectrophotometrically in relation to the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical, with results ranging from 63.88 mgTE/g for leaves to 65.25 mgTE/g for the stem. Antioxidant activity was also assessed using the ABTS test. The lowest value was recorded for the barberry fruit (117.93 mg TE/g) and the highest level was found for the barberry leaves (140.49 mgTE/g). The oxygen radical absorption capacity test (ORAC) showed the lowest value for the stem (167.70 mgTE/g) and the highest level for the leaves (267.81 mgTE/g). The range of percentage inhibition of LOX was determined as well. The percentage inhibition of the enzyme was positively correlated with the sum of flavonoids, TPC, TFC, and the content of selected flavonoids. For the first time, phenolic acids, flavonoid agly-cones, and flavonoid glycosides were determined qualitatively and quantitatively in individual parts of Berberis vulgaris L. The content of phenolic acids, flavonoid aglycones, and flavonoid glycosides was determined with the LC-MS/MS method. For the first time, the following phenol-ic acids were quantitatively and qualitatively identified in individual parts of Berberis vulgaris: 3-caffeoylquinic acid, protocatechuic acid, 5-caffeoylquinic acid, flavonoid glycosides: eleuthero-side E, rutin, isoquercitin, luteoloside, nar-cissoside, naringenin-7-glucoside, isorhamnetin-3-glucoside, afzeline, and quercitrin. Flavonoid aglycones: catechin, luteolin, and eriodictyol were determined qualitatively and quantitatively for the first time as well.

The authors present a novel sensing platform for a disposable electrochemical, non-enzymatic glucose sensor strip at physiological pH. The sensing material is based on dendritic gold nanostructures (AuNs) resembling feather branches, which are electrodeposited onto a Laser-scribed 3D-Graphene electrode (LSGE). The LSGEs were fabricated via a one-step laser scribing process on a commercially available polyimide sheet. This study investigates several parameters that influence the morphology of the deposited Au nanostructures and the catalytic activity towards glucose electro-oxidation. The electrocatalytic activity of AuNs-LSGE was evaluated using Cyclic Voltammetry (CV), Linear Sweep Voltammetry (LSV), and Amperometry, and was compared to commercially available carbon electrodes prepared under the same electrodeposition conditions. The sensor demonstrated good stability and high selectivity of the amperometric response in the presence of interfering agents, such as ascorbic acid, when a Nafion membrane was applied over the electrode surface. The proposed sensing strategy offers a wide linear detection range, from 0.5 to 20 mM, which covers normal and elevated levels of glucose in the blood, with a detection limit of 0.21 mM. The AuNs-LSGE platform exhibits great potential for use as a disposable glucose sensor strip for point-of-care applications, including self-monitoring and food management. Its non-enzymatic features reduce dependence on enzymes, making it suitable for practical and cost-effective biosensing solutions.

The genus Amphichorda has been recently re-erected as an independent linage from Beauveria, circumscribed within Cordycipitaceae. However, its phylogenetic relationships with other members of this family remain obscure. In our on-going efforts to expand the knowledge on the diversity of culturable ascomycetes from the Mediterranean Sea, we isolated several specimens of Amphichorda. Preliminary sequence analyses revealed great phylogenetic distance with accepted Amphichorda species and a close relation to Onychophora coprophila. Onychophora is a monotypic genus of enteroblastic conidiogenous cells, presumably related to Acremonium (Bionectriaceae); while Amphichorda exhibits holoblastic conidiogenesis. Here, we examine representative strains of Amphichorda species to resolve the taxonomy of the genus and the above-mentioned fungi combining morphological, ultrastructure and multi-locus phylogenetic analyses (ITS, LSU, tef1, BenA). The results revealed Amphichorda as a member of the Bionectriaceae, where its asexual morphs represent a transition between enteroblastic and holoblastic conidiogenesis for this group of fungi. We also describe and illustrate Amphichorda littoralis sp. nov., and propose the new combination Amphichorda coprophila. In addition, we stablish key phenotypic features to distinguish Amphichorda species and demonstrate the higher salt tolerance degree of A. littoralis, consistent with its marine origin. This work provides a comprehensive framework for future studies in the genus.

Bacterial nanocellulose (BNC) surface has a negative charge that allows the adsorption of calcium ions to initiate the nucleation of different calcium phosphate phases. The aim of this study was to investigate different methods of mineralization on three-dimensional microporous bacterial nanocellulose, to mimetize the composition, structure, and biomechanical properties of natural bone. To generate 3D microporous biomaterial, the porogen particles were incorporated during the BNC fermentation with the strain Komagataeibacter medellinensis. Calcium phosphates (CPs) were deposited on BNC scaffolds by five alternating immersing cycles with calcium and phosphate solutions. Scanning electron microscopy micrograph showed that the scaffolds have different pore sizes, between 70 and 350 µm, but the porous interconnectivity was affected by the biomineralization method and time. The crystals on the BNC surface are shown to be rod-shaped with a calcium phosphate ratio similar to that of immature bone, increasing from 1.13 to 1.6 with cycle numbers. The main mineral phases obtained by X-ray diffraction were Octacalcium Dihydrogen Hexakis (phosphate (V)) Pentahydrate (OCP). In vitro cell studies showed good cellular adhesion and higher cell viability to 95% in all the scaffolds. Osteogenic differentiation of human bone marrow mesenchymal stem cells on the scaffolds was evaluated by bone expression markers like alkaline phosphatase, osteocalcin, and osteopontin. In conclusion, it is possible to prepare 3D BNC scaffolds with controlled microporosity, which could allow osteoblast adhesion, proliferation, and differentiation.

BACKGROUND: Ficus thonningii extracts exhibit hypoglycaemic, hypolipidaemic and antioxidant activities. We investigated the potential of methanolic F. thonningii stem-bark extracts (MEFT) to protect growing Sprague-Dawley (SD) against high-fructose diet-induced metabolic derangements (MD) in a model mimicking children fed obesogenic diets. METHODS: Eighty (40 males; 40 females) 21-days old SD rat pups were randomly allocat-ed to and administered, for 8 weeks, five treatment regimens: 1 - standard rat chow (SC) + water (PW), 2 - SC + 20% (w/v) fructose solution (FS), 3 - SC + FS + fenofibrate at 100 mg/kg bwt/day, 4 - SC + FS + low dose MEFT (LD; 50 mg/kg bwt/day) and 5 - SC + FS + high dose MEFT (HD; 500 mg/kg bwt/day). Body weight, glucose load tolerance, fasting blood glucose and triglyceride, plasma insulin concentration, sensitivity to insulin, liver mass and fat content, steatosis and inflammation were determined. RESULTS: Fructose had no effect on the rats’ growth, glucose and insulin concentration, glucose tolerance and insulin sensitivity (P>0.05) but increased triglycerides in females; in-duced hepatic microsteatosis and inflammation in both sexes but macrosteatosis in females (P<0.05). In females, MEFT prevented fructose-induced plasma triglyceride increase. Low dose MEFT increased liver lipid content in females (P<0.05). The MEFT protected the rats against hepatic steatosis and inflammation but fenofibrate protected against hepatic mi-crosteatosis. CONCLUSION: MEFT can be used as prophylaxis against dietary fructose-induced ele-ments of MD but caution must be taken as low dose MEFT increases hepatic lipid accretion in females predisposing to fatty liver disease.

Mesenchymal stem cells (MSCs) showed in vitro mesoderm-lineage differentiation and self-renew capacity. However, no comparative study was reported on the biological characteristics of stem cells derived from skeletal muscle (SM-MSCs), dermal skin (DS-MSCs), and adipose tissues (A-MSCs) from a single donor in camels. The present study aimed to evaluate the influence of MSCs source on stem cell characteristics. We evaluated proliferation capacity and mesoderm-lineage differentiation potential from SM-MSCs, DS-MSCs, and A-MSCs. They showed spindle-like morphology after homogenization. The proliferation ability was no significant difference in all groups. Furthermore, the portion of the cell cycle and expression of pluripotent markers (Oct4, Sox2, and Nanog) were similar in all cell lines at passage 3. The differentiation capacity of A-MSCs into adipocytes was significantly higher than that of SM-MSCs and DS-MSCs. However, the osteoblast differentiation capacity of A-MSCs was significantly lower than that of SM-MSCs and DS-MSCs. Additionally, after osteoblast differentiation, the ALP activity and calcium content was significantly decreased in A-MSCs as compared to SM-MSCs and DS-MSCs. To the best of our knowledge, we primally established MSCs from the single camel and demonstrated their comparative characteristics including expression of pluripotent factors and proliferation, and in vitro differentiation capacity into adipocytes and osteoblasts.

Hydroa vacciniforme (HV) is a rare form of photosensitivity disorders in children and is frequently associated with Epstein-Barr virus (EBV) infection, whereas HV-like lymphoproliferative disorders (HVLPD) describe a spectrum of EBV-associated T-cell or NK-cell lymphoproliferations with HV-like cutaneous manifestations, including EBV-positive HV, atypical HV, and HV-like lymphoma. Classic HV occurs in childhood with vesiculopapules on sun-exposed areas, which is usually induced by sunlight and ultraviolet irradiation, and mostly resolves by early adult life. Unlike classic HV, atypical or severe HV manifests itself as recurrent papulovesicular eruptions in sun-exposed and sun-protected areas associated occasionally with facial edema, fever, lymphadenopathy, oculomucosal lesions, gastrointestinal involvement, and hepatosplenomegaly. Notably, atypical or severe HV may progress to EBV-associated systemic T-cell or natural killer (NK)-cell lymphoma after a chronic course. Although rare in the United States and Europe, atypical or severe HV and HV-like lymphoma are predominantly reported in children from Asia and Latin America with high EBV DNA levels, low numbers of NK cells, and T cell clones in the blood. In comparison with the conservative treatment used for patients with classic HV, systemic therapy such as immunomodulatory therapy is recommended as the first-line therapy for patients with atypical or severe HV. This review aims to provide an integrated, overview of current evidence and knowledge of HV and HVLPD to elucidate the pathophysiology, practical issues, environmental factors, and the impact of EBV infection.

Purpose: Myelodysplastic syndromes (MDS) are caused by a stem cell failure, but the relationship between immune dysregulation and the course of disease has not yet been analyzed in detail. Experimental design: To get insights into the pathophysiologic and clinical relevance of the histotopography of immune cell subpopulations in this process, the immune cell infiltrate with focus on its spatial distribution was determined by multispectral imaging (MSI) in 147 bone marrow biopsies from MDS or secondary acute myeloid leukemia (sAML) patients and healthy controls (HC). In addition, the data were correlated to genetic alterations and clinical features of these patients including therapy response. Results: A high inter-tumoral heterogeneity in the frequency and spatial distribution of CD3⁺CD8⁺, CD3⁺CD8^-, CD3⁺FOXP3⁺ T cell subsets, MUM1p⁺CD3^- post-germinal B/plasma cells and CD34⁺ blasts was found in MDS and sAML samples. In HC only few B cells/plasma cells, but no T cell subpopulations were detected in the proximity to CD34⁺ blasts. In contrast, the frequency of these lymphocytes was increased in proximity to CD34⁺ blasts in both MDS and sAML independent of the karyotype, genetic alterations frequently detected in MDS, clinical risk stratification systems or treatment response to hypomethylating agents. Furthermore, an increased frequency of CD3⁺CD8⁺ T cells and MUM1p⁺ CD3^- B cells was found in responders to epigenetic drugs. Conclusions: Thus, we conclude that (i) T cell subsets do not belong to the normal stem cell niche, (ii) the presence of T and B cell subpopulations not directly affect the course of MDS, (iii) lymphocytes in the proximity to CD34⁺ blasts might indicate defective stem cell properties and (iv) the number of lymphocytes is a predictor of therapy response to hypomethylating agents.

Hyperbaric oxygen (HBO) treatment has been proven to attenuate neuroinflammation in rats. This study aimed to determine the potential mechanism underlying the anti-inflammatory effects of HBO treatment on burn-induced neuroinflammation in rats. Thirty-six adult male Sprague–Dawley (SD) rats were randomly assigned to the following six groups (n = 6 per group): (1) sham burn with sham HBO treatment, (2) sham burn with HBO treatment, (3) burn with 1-week sham HBO treatment, (4) burn with 2-week sham HBO treatment, (5) burn with 1-week HBO treatment, and (6) burn with 2-week HBO treatment. SD rats that received third-degree burn injury were used as a full-thickness burn injury model. Subsequently, we analyzed the expression of proteins involved in the galectin-3 (Gal-3)-dependent Toll-like receptor-4 (TLR-4) pathway through enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC) analysis, and Western blotting, and a behavior test was also conducted. The behavior test revealed that HBO treatment significantly suppressed mechanical hypersensitivity in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). ELISA results showed that tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) levels in the dorsal horn of the spinal cord and the skin were significantly decreased in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). Western blotting results demonstrated that HBO treatment significantly reduced the expression of Gal-3 and TLR-4 in the dorsal horn of the spinal cord in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). IHC analysis results showed that the expression of Gal-3, TLR-4, CD68, and CD45 in the dorsal horn of the spinal cord was significantly lower in the burn with HBO treatment group than in the burn with sham HBO treatment group (p < 0.05), and the expression of CD68 and macrophage migration inhibitory factor (MIF) in the right hind paw skin was significantly lower. The expression of vimentin and fibroblast growth factor (FGF) in the right hind paw skin was significantly higher after HBO treatment (p < 0.05). This study proved that early HBO treatment relieves neuropathic pain, inhibits the Gal-3-dependent TLR-4 pathway, and suppresses microglia/macrophage activation in a rat model.

Glioblastoma (GBL) is one of the more malignant primary brain tumors, currently treated by a multimodality strategy including surgery, radio- and chemotherapy, mainly consisting of Temozolomide(TMZ)-based chemotherapy. Tumor relapse often occurs due to the establishment of TMZ resistance, with a patient median survival

Photoreceptor degeneration is a major cause of untreatable blindness worldwide and has recently been targeted by emerging technologies, including cell- and gene-based therapies. Cell types of neural lineage have shown promise for replacing either photoreceptors or retinal pigment epithelial cells following delivery to the subretinal space, while cells of bone marrow lineage have been tested for retinal trophic effects following delivery to the vitreous cavity. Here we explore an alternate approach in which cells from the immature neural retinal are delivered to the vitreous cavity with the goal of providing trophic support for degenerating photoreceptors. Rat and human retinal progenitor cells were transplanted to the vitreous of rats with a well-studied photoreceptor dystrophy, resulting in substantial anatomical preservation and functional rescue of vision. This work provides scientific proof-of-principle for a novel therapeutic approach to photoreceptor degeneration that is currently being evaluated in clinical trials.

To elucidate mesenchymal stromal cells (MSC)-tumor intricate and ambiguous interactions, the reliable cell labeling and tracking techniques are imperative. Traditional methods of cell labelling have limitations mostly relevant to need for genetic modification what demands the exploration for alternative strategies. Here, we propose using fluorescent photoconvertible microcapsules containing Rhodamine B (RhB) to study mMSC migration in brain tumors. These 3 μm sized microcapsules are readily internalised by cells and undergo photoconversion under 561 nm laser exposure with fluorescence blue shift on demand. Optimal photoconversion was achieved with a laser irradiation duration of 0.4 ms, which provide a maximal brightness of photoconverted label without an excessive laser exposure on cells. Capsules modified with polyallylamine hydrochloride demonstrated the best potential for intracellular uptake without significantly affecting cell viability, motility, or proliferation. The optimal ratio of 20 capsules per mMSC was determined for labeling. Moreover, migration of individual mMSCs within 2D and 3D glioblastoma cell (EPNT-5) colonies over 2 days and in vivo tumor settings over 7 days was tracked. Our study unveils a robust platform for investigating MSC-tumor dynamics, offering insights into therapeutic strategies. Photoconvertible microcapsules could also become an indispensable tool for studying complex fundamental processes of cell-cell interactions for a wide range of problems in biology and medicine.

In this research work, we describe the preparation process, characterization, and photo-physical studies of an ionic liquid (IL) based semiconductor Zinc Oxide (ZnO) nanoparticles synthesized by an economical wet chemical precipitation method. For the first time, an IL was synthesized with the help of a chemical reaction between triethylamine (TEA) and bromoacetic acid (BAA). A polyamide dye was prepared by a reaction between two monomers, ethylenediamine (EDA) and trimesoylchloride (TMC), under room temperature conditions. The polyamide dye was capped on ZnO nanoparticles, and the final product was divided into three different samples, A, B, and C, according to level of concentrations of IL and Polyamide dye. These samples were characterized with X-Ray Diffraction (XRD), Field Emission Scanning Electron Microscopy (FESEM), Dynamic Light Scattering (DLS) spectra, Ultraviolet-Visible (UV-Vis), and Fluorescence spectroscopies. The formation of polyamide linkages in the ionic liquid has been confirmed by a spectroscopic method using Fourier Transform Infrared (FTIR) spectroscopy. The capping of polyamide dye molecules on the surface of ZnO nanoparticles revealed two things: (i) improved UV absorption spectra and (ii) enhanced luminescence in the photoluminescence spectra. Hence, during investigations, broad absorption bands were observed at peaks 263 nm, 278 nm, and 276 nm respectively for samples A, B, and C. Further, IL was used as an electrolyte or redox mediator and polyamide as a dye material in the fabrication of ZnO Dye-Sensitized Solar Cells (DSSCs). The samples A, B, and C were used in the fabrication of photo-anode assemblies for ZnO DSSCs. The ZnO DSSCs were tested under strong simulated light at Air Mass (AM) 1.5 solar irradiations. The observed photovoltaic results shown that solar cell SCB generated a maximum power conversion efficiency (η) of 5.65%, higher than the power conversion efficiencies of solar cells SCA (3.99%) and SCC (4.46%) respectively. The Incident Photon to Current Conversion Efficiency (IPCE) spectra values of ZnO DSSCs shown a significant improvement in the incident photon to current conversion efficiency of solar cell SCB (IPCE=61%) as compared to SCC (enhanced by 6%) and SCA (enhanced by 4%). Such solar cell assemblies can be suitable for green and clean energy applications.

Cerebral cavernous malformations (CCM) or familial cavernomatosis is a rare, autosomal dominant, inherited disease characterized by the presence of vascular malformations consisting of blood vessels with an abnormal structure in the form of clusters. Based on the altered gene (CCM1/Krit1, CCM2, CCM3) and its origin (spontaneous or familial), different types of this dis-ease can be found. In this work we have isolated and cultivated primary endothelial cells (ECs) from peripheral blood of a type 1 CCM patient. Differential functional and gene expression pro-file of these cells were analyzed and compared to primary ECs from a healthy donor. The muta-tion of the familial index case consisted of a heterozygous point mutation in the position +1 splicing consensus between exons 15 and 16, causing failure in RNA processing and in the final protein. Furthermore, gene expression analysis by quantitative PCR revealed a decreased ex-pression of genes involved in intercellular junction formation, angiogenesis, and vascular ho-meostasis. Cell biology analysis showed that CCM1 ECs were impaired in angiogenesis and cell migration. Taken together, the results obtained suggest that the alterations found in CCM1 ECs are already present in the heterozygous condition, suffering from vascular impairment and someway predisposed to vascular damage.

The expression of non-coding RNAs varies greatly depending on the cell type and physiological state. Changes in expression affect the regulatory properties of these molecules. We investigated RNA-seq data from sorted blood cells of healthy control donors and severe COVID-19 patients. Our aim was to display a distinguishable piRNA differential expression portrait for each type of cell and to study the behavior of piRNA in the blood cells of COVID-19 patients. Overall piRNA expression in sorted control cells (erythrocytes, monocytes, lymphocytes, eosinophils, basophils, neutrophils) differs depending on cell type. Four of the most abundant piRNA were expressed relatively equally in all cell types, they included piR-49145, piR-49144, piR-49143 and piR-33151. By reviewing piRNA expression in each group of sorted cells from severe COVID-19 patients we observed 3 upregulated and 10 downregulated piRNAs in erythrocytes. Monocytes were presented with a larger amount of statistically significant piRNA, 4 upregulated and 35 downregulated. In lymphocytes, all 19 piRNAs were upregulated.

Glioblastoma is a central nervous system cancer type with a poor prognosis. One of its main features is the constant change of metabolism phenotype to support its development and progression. Mitochondria play a critical role in cellular metabolism. Acetylation on lysine residues of mitochondrial enzymes is a mechanism for regulating protein function. This modification negatively affects the mitochondrial proteome function and is counteracted by the enzyme sirtuin 3 (SIRT3). To better understand how SIRT3 regulates mitochondrial metabolism, we inhibited SIRT3 and examined by high-resolution mass spectrometry analysis the proteome and acetylome of two glioblastoma cell lines with different metabolic preferences. Our results indicate that protein synthesis machinery is regulated by lysine acetylation and plays a role in the metabolic phenotype. We also identified new SIRT3 targets not previously associated with specific functions, highlighting their potential as future targets for further study. This study shed light on the role of SIRT3 in mitochondria and its implication for cellular metabolism. We have generated knowledge at the proteome and acetylome levels on the dynamics between two glioblastoma cell lines with opposing metabolic phenotypes. Our results might guide in searching for biomarkers at both proteome and acetylome levels in glioblastoma.

Purpose of Review Multipotent Mesenchymal stromal cells (MSCs) have recently risen to prominence in regenerative medicine for their powerful intrinsic properties of self-regeneration, immunomodulation, and multi-potency. They exhibited an excellent safety profile in early-phase clinical trials. Nevertheless, MSCs-based therapy suffers reduced efficacy in randomized clinical trials due to a poor understanding of their proper delivery modalities. Here, we intend to explore the current application of MSCs after tissue injuries. We specifically focus on tissue source, delivery routes, metabolic fitness, and cell dose. We further discuss potential approaches to optimize in vivo engraftment. Recent findings MSCs therapeutic effect mediates by paracrine and contact factors, which are cells' intrinsic physiological processes. The cell culture expansion process does not destroy MSCs' intrinsic properties. In vivo persistence of administered MSCs determines their therapeutic potency. Cell viability, fitness, immune match, and delivery route meticulously regulate their in vivo persistency. Different genetic or chemical modification strategies are currently applied to extend their in vivo lifespan and boost their pharmaceutical effect. Summary Improving the in vivo persistence of implanted MSCs could facilitate its clinical translation. This review highlights the pros and cons of different MSCs’ delivery strategies used in clinical or preclinical studies, emphasizing various modification approaches. These can promote prolonged graft cell survival.

TMEM16A is a Ca2+-activated Cl- channel expressed in various species and tissues. In mammalian skeletal muscle precursors, the activity of these channels is still poorly investigated. Here, we characterized TMEM16A channels and investigated if the pharmacological activation of Piezo1 channels could modulate the TMEM16A currents in mouse myogenic precursors. Whole-cell patch-clamp recordings combined with the pharmacological agents Ani9, T16inh-A01 and Yoda1 were used to characterize TMEM16A-mediated currents and the possible modulatory effect of Piezo1 activity on TMEM16A channels. Western blot analysis was also carried out to confirm the expression of TMEM16A and Piezo1 channel proteins. We found that TMEM16A channels were functionally expressed in fusion-competent mouse myogenic precursors. The pharmacological blockage of TMEM16A inhibited myocyte fusion into myotubes. Moreover, the specific Piezo1 antagonist Yoda1 positively regulated TMEM16A currents. The findings demonstrate, for the first time, a sarcolemmal TMEM16A channel activity and its involvement at the early stage of mammalian skeletal muscle differentiation. In addition, the results suggest a possible role of mechanosensitive Piezo1 channels in the modulation of TMEM16A currents.

Lymphoma is the most prevalent type of cancer in cats, and the search for alternative treatments is of utmost importance given the significant number of animals that exhibit tumor recurrence or are unresponsive to conventional chemotherapy treatment. Oncolytic viruses possess a unique ability to target and eliminate cancer cells while simultaneously stimulating an immune response against these malignant cells. The present study aimed to explore the oncolytic potential of Newcastle Disease Virus expressing green fluorescent protein (NDV-GFP) in a feline leukemia virus (FeLV)-positive lymphoma cell line. Our research suggests that NDV-GFP has a propensity to selectively target, infiltrate, and replicate with-in feline lymphoma cells, resulting in the induction of apoptosis in these cells, as opposed to non-tumor cells. Therefore, our research provides evidence supporting the development of novel oncolytic therapies based on NDV for the treatment of feline lymphomas.

Recent works identified ClpXP, mitochondrial caseinolytic protease, as the only target of imipridones - new class of antitumor agents. Our study of the mechanism of imipridone derivative TR-57 action in SUM159 human breast cancer cells demonstrated mitochondrial fragmentation, degradation of mitochondrial mtDNA and mitochondrial dysfunction, due to inhibition of Complex I and Complex II activity. Complete inhibition of oxidative phosphorylation accom-panied with 90, 94, 88 and 87% decrease in the content of Complex I, II, III and IV proteins, respectively. The content of the FOF1-ATPase subunits decreased sharply by approximately 35% after 24 hours and remained unchanged up to 72 hours of incubation with TR-57. At the same time, a disappearance of the ATPIF1, natural inhibitor of mitochondrial FOF1-ATPase observed after 24 h exposure to TR-57. ATPase inhibitor oligomycin had no effect on the mitochondrial membrane potential in intact SUM159, whereas it caused a 65% decrease in TR-57-treated cells. SUM159 cells incubated with TR57 up to 72 hours retained the level of proteins facilitating the ATP transfer across the mitochondrial membranes: VDAC1 expression was not affected, while expression of ANT-1/2 and APC2 increased by 20% and 40%, respectively. Thus, our results suggest that alt-hough TR-57 treatment lead to complete inhibition of respiratory chain activity of SUM159 cells, hydrolysis of cytoplasmic ATP by reversal activity of FOF1-ATPase supports mitochondrial polarization.

In this paper, the overall performance of Cu-(In,Ga)-Se₂ (CIGSe) solar cells was improved in the ultraviolet (UV)–visible wavelength region by two-segment process. In which, adjusting DC sputtering powers (20–40 W) for absorbers (segment I), and metal-alloy compositions (CdS, ZnO/CdS, ZnMgO/CdS and ZnMgO) for buffers (segment II) were explored and characterized. Upon choosing the optimal-30-W CIGSe-absorber (with 0.95-CGI ratio) sputtered by the segment-I process, the Cu-rich film can distinctly boost grain growth, thus reducing the trap state density. After segment-II process as the toxic-CdS alternative, the optimal Zn_0.9Mg_0.1O-alloy buffer can reach the best conversion efficiency (η = 8.70%) was attained for the environmental protection. Meanwhile, and the overall internal/external quantum efficiencies (IQE/EQE) were improved by 13.15%, respectively for the 2.48–3.62-eV bandgap (short wavelength) range. The developed photovoltaic (PV) module (with 9 optimum-CIGSe cells) exhibits acceptable stability with a variance within ±5% over the 60-day experiment. This discovery in PV-device research contributes to a new scientific understanding of renewable energy. Furthermore, this study undeniably enhances the progress of practical applications for PV-modules in alignment with sustainable development goals. It also actively supports the development of eco-friendly communities.

Regulated deficit irrigation (RDI) strategies aim to improve water usage without reducing yield. Generally, irrigation strategy effectiveness is measured as fruit yield, with little consideration of fruit quality. As water deficit and increased plant cell sclerification often associated, this study explores the effect of RDI on pear fruit stone cells, a crucial factor affecting flesh texture. The presence, distribution and development of pear fruit stone cells under RDI and full irrigation are compared using Pyrus communis L. cv. Barlett trees, employing recently developed microscope image analysis technology. The Control treatment was maintained under non-stress conditions, while the RDI treatment received an average of 15% of Control water during the latter part of Stage I fruit development. Observations at the end of Stage I and at harvest showed no effect on stone cell presence under the tested RDI strategy. Relative area of stone cells within the flesh was greater at Stage I than at harvest, as stone cell expansion occurred early in development while the (unsclerified) parenchyma cells, dominant component of the fruit flesh, expanded until harvest. Stone cell cluster density was higher near the fruit core than in the cortex center and exterior. These initial results suggest that well-planned RDI strategies will generally not affect pear fruit stone cell content and thus, textural quality. Microscope image analysis supported results from previously used analytical techniques, principally chemical, while providing a tool for better understanding the process and timing of stone cell differentiation and thus testing the factors involved.

This paper presents a comprehensive evaluation of metal foam employment within polymer electrolyte fuel cells (PEFCs) and compares it with conventional serpentine channels from both experiment viewpoints and computational fluid dynamics simulation. The experiments are designed to study the effects of material, area density, compression ratio, and final thickness of metal foam. Additionally, the influence of housing plate material and relative humidity (RH) is also tested for the first time. The results reveal that at RH=75-100%, the best distributor design is nickel foam with a compression ratio of 70%, a final thickness of 0.5mm, and SS-304 housing plate, which delivers 3110 mA cm^-2 as limiting current density that is scarce in the literature. The PEFC with this foam distributor shows a 10% improvement in maximum power density and 45% in limiting current density compared to the serpentine channel case. While at RH=30%, the same foam flow field with a final thickness of 1mm is a superior option. The experiments also indicate that maximum power density increases by 23% as the compression ratio rises from 0 to 70%, while reducing final thickness from 1 to 0.5 mm causes a 19% enhancement in cell performance. Simulation results reveal that metal foam is more successful in evenly reactant distribution so that the average oxygen mass fraction at the cathode catalyst layer is increased by 38% in the metal foam case compared to the serpentine channel.

This study proposes a redesign of asymmetric single-chamber microbial fuel cells (a-SCMFC) with the goal of optimizing energy production. The new approach is based on the introduction of an Intermediate Microfluidic Septum (IMS) as a relatively simple and inexpensive method to opti-mize both electrolyte flow and species transfer inside the devices. SCMFCs with the novel IMS, operated with sodium acetate as the carbon source, demonstrate to enhance the energy recovery (Erec) factor, defined as the ratio between the energy yield and the inner volume of electrolyte. In standard operative conditions, cells with IMS exhibit Erec value of (37±1) J/m3, with respect to (3.0±0.3) J/m3 of control cells. Furthermore, changing sodium acetate concentration the Erec values change accordingly. By monitoring the activity of a-SCMFCs for over one-year, beneficial impact of the IMS on both the initial inoculation phase and the long-term stability of electrical perfor-mance were observed. These improvements suggest the effectiveness of IMS to allow the de-velopment of efficient biofilms, likely due to the reduction in oxygen diffusion towards the anode. Electrochemical characterizations confirm that the presence of the IMS impacts the diffusion processes inside the electrolytic chamber, supporting the hypothesis of a beneficial effect on oxygen diffusion.

Andrographis paniculata leaves have been widely used in traditional medicine due to their rich content of phenolic compounds. In this study, we evaluated the total phenolic and flavonoid content of Andrographis paniculata leaf extracts (ALE), as well as its antioxidant activities against DPPH, ABTS, and hydrogen peroxide radicals. Additionally, we conducted cell viability assays, RT-PCR, and western blot analysis to investigate the biochemical effects of ALE on UVB-induced HaCaT cells. Our results revealed that ALE exhibited a high concentration of polyphenols and flavonoids, which were associated with potent abiotic antioxidant properties. Furthermore, ALE treatment effectively abrogated the damage caused by UVB radiation on key molecules such as hyaluronan synthase 1, Aquaporin 3, and loricrin in HaCaT cells. ALE also demonstrated the ability to reduce the overactivation of mitogen-activated protein kinases (MAPKs) and the expression of pro-inflammatory cytokines, including interleukin-6 and interleukin-1β in UVB-induced HaCaT cells. Additionally, ALE positively influenced the peroxisome proliferator-activated receptor alpha in these cells. Overall, our findings highlight the antioxidant and anti-inflammatory effects of ALE, as well as its significant role in modulating skin barrier functions. These results contribute to the growing body of evidence supporting the therapeutic potential of ALE in skincare and dermatological applications.

Currently, efficient utilization of low-grade thermal energy is a great challenge. Thermoelectricity is an extremely promising method of generating electrical energy from temperature differences. As a promising energy conversion technology, thermo-electrochemical cells (TECs) have attracted much attention in recent years for their ability to convert thermal energy directly into electricity with high thermal power. Within TECs, anions and cations gain and lose electrons, respectively at the electrodes using the potential difference between the hot and cold terminals of the electrodes by redox couples. Additionally, the anions and cations therein are constantly circulating and mobile via concentration diffusion and thermal diffusion, providing an uninterrupted supply of power to the exterior. This review article focuses mainly on the operation of TECs, recent ad-vances in redox couples, electrolytes, and electrodes. The outlook for optimization strategies re-garding TECs is also presented in this paper.

Ferruginol is a promising abietane-type antitumor diterpene able to induce apoptosis in SK-Mel-28 human malignant melanoma. We here aim to increase this activity by testing the effect of a small library of ferruginol analogues. After an screening of their antiproliferative activity (SRB staining) on SK-Mel-28 cells the analogue 18-aminoferruginol (GI50=10 µM) was further selected for mechanistic studies including effects on mitochondrial viability (MTT assay, IC50=10 µM p<0.0001), induction of apoptosis (DAPI staining, p<0.001), changes in cell morphology associated with the treatment (cell shrinkage and membrane blebbing), induction of caspase-3/7 activity (2.5x at 48h, 6.5x at 72h; p<0.0001), changes in the mitochondrial membrane potential (not significant), and effects on 2D cell migration and 3D cell invasion (modified Boyden assay, not significant). The results were compared to those of the parent molecule (ferruginol, GI50»50 µM) and paclitaxel (GI50=10 nM) as a reference drug. In conclusion, we demonstrate here that derivatization of ferruginol into 18-aminoferruginol increases its antiproliferative activity 5 times in SK-MEL-28 cells as well as changing the apoptotic mechanism of its parent molecule ferruginol from activation of caspases without depolarization of mitochondrial membrane.

Being the major cellular component of highly dynamic tissue endometrial stromal cells (EnSC) are exposed to cycles of proliferation upon hormonal stimulation what might pose risks for mutations accumulation and malignization. However, endometrial stromal tumors are rare and unusual types of tumor. The present study aimed to uncover defense mechanisms that might underlie resistance of EnSC against oncogenic transformation. All experiments were performed in vitro using the following methods: FACS, WB, RT-PCR, IF, molecular cloning, lentiviral transduction, and CRISPR/Cas9 genome editing. We revealed that expression of the mutant HRASG12V results in senescence of EnSC. We experimentally confirmed inability of HRASG12V-expressing EnSC to bypass senescence and resume proliferation even upon oestrogen stimulation. At the molecular level, induction of oncogene-induced senescence (OIS) was accompanied by the activation of MEK/ERK, PI3K/AKT, p53/p21WAF/CIP/Rb and p38/p16INK4a/Rb pathways, however inhibiting either pathway did not prevent cell cycle arrest. PTEN loss was established as the additional feature of HRASG12V-induced senescence of EnSC. By using CRISPR-Cas9 mediated PTEN knockout, we distinguished PTEN loss-induced senescence as a reserve molecular mechanism to prevent transformation of HRASG12V-expressing EnSC. The present study highlights oncogene-induced senescence as an antitumor defense mechanism of EnSC controlled by multiple backup molecular pathways.

Triatoma infestans (Klug) is an insect recognized as not only an important vector of South-American trypanosomiasis (Chagas disease) but also a model of specific cellular morphofunctional organization and epigenetic characteristics. The purpose of the present review is to highlight certain cellular processes that are particularly unveiled in T. infestans, such as 1) somatic polyploidy involving nuclear and cell fusions that generate giant nuclei; 2) diversification of nuclear phenotypes in the Malpighian tubules during insect development; 3) heterochromatin compartmentalization into large bodies with specific spatial distribution and presumed mobility in the cell nuclei; 4) chromatin remodeling and co-occurrence of necrosis and apoptosis in the Malpighian tubules under stress conditions; 5) epigenetic markers; 6) unexplained response of heterochromatin to valproic acid, an epidrug that inhibits histone deacetylases and induces DNA demethylation in other cell systems. These cellular processes and epigenetic characteristics emphasize the role of T. infestans as an attractive model for cellular research.

Background. Intravenous iron therapy is used in treatment of anemia in uremic pa-tients. In patients treated with peritoneal dialysis iv. infused iron diffuses into the peritoneal cavity and may cause injury to the mesothelial cell. Methods. We studied effect of Iron Isomaltoside (IIS) in presence of NF-κβ inhibitor dehydroxymethyepoxyquinmicin (DHMEQ) on function of the peritoneal mesothelial cells. Experiments were performed on human peritoneal mesothelial cells in in vitro culture ex-posed to IIS 15 ug/dL ± DHMEQ 1 ug/mL. Intracellular oxidative stress, secretory activity and collagen synthesis in the cells were studied. Results. IIS induced oxidative stress in the mesothelial cells and that effect was weaker in presence of DHMEQ (-52%,p<0.001). In cells exposed to IIS increased expression of genes for IL6 (+74%,p<0.001), PAI-1 (+43%, p<0.01) and TGFβ (+53%,p<0.001) was observed and reduced for tPA (-36%,p<0.01). In presence of IIS increased secretion of IL6 (+56%, p<0.001), TGFβ (+49%,p<0.001) and PAI-1 (+51%, p<0.001) was observed whereas secretion of tPA was reduced (-25%, p0.001). DHMEQ reduced changes in genes and secre-tory activity caused by IIS. In presence of IIS synthesis of collagen in mesothelial cells was increased (+45%,p<0.001) and that effect was weaker (-25% vs. IIS, p<0001) when simulta-neously DHMEQ was used. Discussion. IIS induces proinflammatory changes in mesothelial cells, deteriorates their fibrinolytic activity and stimulates synthesis of collagen. All these effects are reduced when simultaneously NF-κβ inhibitor – DHMEQ is used.

Considering tumors from an evolucionary perspective, successive tumor cells undergo turnover in response to stressful conditions which pressures tumor cells to adapt to a new environment. Tumor cells uses parts of themselves to communicate and share biological information, known as extracellular vesicles (EV) secretion to promote their survival and “survive to each and every metabolic cost”. Tumor microenvironment (TME) is a miscellaneous of cells, factors, extracellular matrix proteins and EVs. EVs include smalls (<160nm, exosomes) and larger (100-1,000nm, microvesicles) lipid bilayer enclosed packages of biomolecules that are shed by tumors to TME. Tumor-derived extracellular vesicles transfer adaptative stress signaling to recipient cells, reprograming these cells. Heat Shock Proteins (HSP) are more prominent stress response regulators found in exosomes. HSP-loaded exosomes actively reprogram tumor and TME cells to acquire mechanisms that contribute to tumor progression and therapy resistance. The intercellular communication mediated by HSP-loaded EVs favors the escape of tumor cells from, endoplasmic reticulum (ER) stress, hypoxia, apoptosis and anti-cancer therapies. Extracellular HSPs activate and deactivate immune response, induce cell differentiation, changes vascular homeostasis, and help to augment the pre-metastatic niche formation. Here we will explore the EV mechanism of HSP transmission among TME cells and the relevance of these intercellular communications for resistance to therapies in cancer.

Liquid biopsy has been developed to diagnose and monitor cancer. Despite the recent advances in investigating early cancer detection and diagnosis strategies, there is still a lack of improvements in capturing (CTCs). To archive this, we developed an efficient CTC detection system by integrating gold nanoparticles and a microfluidic platform, which can achieve CTC capture within 120 min. The microdevice was functionalized by immobilizing antibodies specific to the target cells. The method was tested with spiked tumor cells in whole human blood with three pancreatic cancer cell lines and compared with purified cancer cells suspended in a phosphate buffer solution. Our results captured pancreatic cancer cells spiked in blood samples with efficiency (90±3.2)% and were used to isolate CTCs from patients with metastatic pancreatic cancer. This methodology will enable the production of functionalized, patterned surfaces that interact with tumor cells, enhancing the selective capture of CTCs from biological assays.

A sixty-six-year-old woman with a strong family history of breast cancer noted gradual onset of axillary lymph node enlargement in 2019. Axillary lymph node biopsies disclosed Lymph node involvement by Chronic Lymphocytic Leukemia (CLL/SLL). Immunophenotype analysis of nodal tissue and of bloodstream leukemic cells in immunohistochemistry and flow cytometry and next generation molecular diagnostics confirmed CLL/SLL. Replicate absolute peripheral blood lymphocyte counts in excess of 5.0 x 10e3/microliter confirmed the numerical threshold for diagnosis of Chronic Lymphocytic Leukemia in the bloodstream. FISH studies disclosed an immunoglobulin “mutation negative” CLL/SLL genotype without a light chain restriction pattern. No translocations or germline mutations were present. Borrelia spirochetes in the bloodstream were detected with simultaneous high spirochetemia of both borrelia miyamotoi and borrelia burgdorferi. FISH hybridization of leukemic lymphocytes disclosed extensive borrelia invasion of the cytoplasm and of the nucleus compartments of CLL/SLL tumor cells. Retrospective studies of the patient’s archival stored blood smears obtained three years prior in 2016 at age 63 disclosed no evidence of CLL/SLL but confirmed asymptomatic bloodstream borrelia miyamotoi and borrelia burgdorferi borrelia infection. Lyme serology had been reported as negative in 2016. Additionally, retrospective FISH DNA hybridizations focused on preleukemic bloodstream Lymphocytes disclosed rare borrelia spirochetal adherence to benign blood lymphocytes in the year 2016 in the preleukemic blood smears. This case report is the very first to describe precursor chronic asymptomatic Lyme borreliosis and Miyamotoi borrelia bloodstream infections three years prior to the diagnosis of Rai Stage 1 Chronic Lymphocytic leukemia.

In this study, novel biomarkers in Blood Mononuclear Cells (PBMCs) of Hepatocellular Carcinoma (HCC) patients were identified through microarray data analysis. The problem that prompted the study was the lack of reliable biomarkers for early diagnosis and monitoring of HCC. The purpose of this study was to discover potential biomarkers in PBMCs of HCC patients that can be used for early diagnosis and monitoring of the disease. The main hypothesis was that there are genes that are overexpressed in PBMC of HCC patients compared to healthy individuals. The results showed that genes HBB, WBP2, HBA2, and HBA1 were overexpressed in PBMCs of HCC patients. Additionally, nine genes were found to be upregulated in HCC patients and had a relation between KEGG pathways of RA, suggesting a link between the two diseases. These genes are TLR4, IL1B, CXCL5, IL11, HLA-DQA1, HLA-DRA, LBT, ATP6V1B2 and ATP6V1C1. The Gene ontology analysis revealed biological processes used in the process of how these genes play a role in development of HCC. In conclusion, this study identified potential biomarkers in PBMC of HCC patients that can aid in early diagnosis and monitoring of the disease. The findings of this study have important implications for improving the clinical management of HCC patients.

In this research, assume a SuperHyperGraph. Then a neutrosophic SuperHyperMatching $\mathcal{C}(NSHG)$ for a neutrosophic SuperHyperGraph $NSHG:(V,E)$ is the maximum neutrosophic cardinality of a neutrosophic SuperHyperSet $S$ of high neutrosophic cardinality neutrosophic SuperHyperEdges such that there's no neutrosophic SuperHyperVertex not to in a neutrosophic SuperHyperEdge and there's no neutrosophic SuperHyperEdge to have a neutrosophic SuperHyperVertex in a neutrosophic SuperHyperEdge; a neutrosophic SuperHyperMatching SuperHyperPolynomial $\mathcal{C}(NSHG)$ for a neutrosophic SuperHyperGraph $NSHG:(V,E)$ is the neutrosophic SuperHyperPolynomial contains the neutrosophic coefficients defined as the neutrosophic number of the maximum neutrosophic cardinality of a neutrosophic SuperHyperSet $S$ of high neutrosophic cardinality neutrosophic SuperHyperEdges such that there's no neutrosophic SuperHyperVertex not to in a neutrosophic SuperHyperEdge and there's no neutrosophic SuperHyperEdge to have a neutrosophic SuperHyperVertex in a neutrosophic SuperHyperEdge and the neutrosophic power is neutrosophicly corresponded to its neutrosophic coefficient; a neutrosophic R-SuperHyperMatching $\mathcal{C}(NSHG)$ for a neutrosophic SuperHyperGraph $NSHG:(V,E)$ is the maximum neutrosophic cardinality of a neutrosophic SuperHyperSet $S$ of high neutrosophic cardinality neutrosophic SuperHyperVertices such that there's no neutrosophic SuperHyperVertex not to in a neutrosophic SuperHyperEdge and there's no neutrosophic SuperHyperEdge to have a neutrosophic SuperHyperVertex in a neutrosophic SuperHyperEdge; a neutrosophic R-SuperHyperMatching SuperHyperPolynomial $\mathcal{C}(NSHG)$ for a neutrosophic SuperHyperGraph $NSHG:(V,E)$ is the neutrosophic SuperHyperPolynomial contains the neutrosophic coefficients defined as the neutrosophic number of the maximum neutrosophic cardinality of a neutrosophic SuperHyperSet $S$ of high neutrosophic cardinality neutrosophic SuperHyperVertices such that there's no neutrosophic SuperHyperVertex not to in a neutrosophic SuperHyperEdge and there's no neutrosophic SuperHyperEdge to have a neutrosophic SuperHyperVertex in a neutrosophic SuperHyperEdge and the neutrosophic power is neutrosophicly corresponded to its neutrosophic coefficient. It's useful to define a ``neutrosophic'' version of a SuperHyperMatching . Since there's more ways to get type-results to make a SuperHyperMatching more understandable. For the sake of having neutrosophic SuperHyperMatching, there's a need to ``redefine'' the notion of a ``SuperHyperMatching ''. A basic familiarity with neutrosophic SuperHyperMatching theory, SuperHyperGraphs theory, and neutrosophic SuperHyperGraphs theory are proposed.

Gene electrotransfer is one of the main non-viral methods for intracellular delivery of plasmid DNA, wherein pulsed electric fields are used to transiently permeabilize the cell membrane allowing enhanced transmembrane transport. By localizing the electric field over small portions of the cell membrane using nanostructured substrates, it is possible to increase considerably the gene electrotransfer efficiency while preserving cell viability. In this study, we design an electrotransfer approach based on commercially available cell culture inserts with polyethylene-terephthalate (PET) porous substrate. We first use multiscale numerical modelling to determine the pulse parameters, substrate pore size, and other factors that are expected to result in successful gene electrotransfer. Based on numerical results we design a simple device combining an insert with substrates containing pores with 0.4 um and 1.0 um diameter, a multiwell plate, and a pair of wire electrodes. We test the device in three mammalian cell lines and obtain transfection efficiencies similar to those achieved with bulk electroporation, but with low-voltage pulses that do not require the use of expensive electroporators. Our combined theoretical and experimental analysis calls for further systematic studies that will investigate the influence of substrate pore size and porosity on gene electrotransfer efficiency and cell viability.

This study develops into the application of a combined MFC unit with chemical coagulation for total treatment of inert contaminants in complex substrates. Microbial Fuel Cell (MFC) technology converts chemical energy in the form of organic matter, into bioelectricity in an environmentally friendly and effi-cient manner, reducing carbon emissions and increasing bioenergy production. An evaluation of a la-boratory scale chemical coagulation using an aluminum and poly-based coagulant on how effective it can remove bulk impurities such as particulate COD and turbidity to obtain the purest and most cost-effectively treated wastewater using a jar test is being conducted in this current study. This study aims to find the most effective treatment technologies for wastewater recovery in breweries in order to achieve zero liquid effluent discharge (ZLED). The preliminary results showed that adding a modest amount of poly and a 50 % alum alone treatment improved COD, color, and turbidity reduction. The turbidity removal efficiency achieved after chemical coagulation treatment was 90.50 % and 59.36 % COD removal, demonstrating the benefits of adopting an alum/poly based technique. To determine ZLED, this study clearly advised a combined treatment technique, specifically the MFC-flocculator unit for efficient organics and inorganics removal.

The power conversion efficiency (PCE) of polymer solar cells (PSCs) are strongly depended on the bulk-heterojunction active layer. Here, the 1,8-diiodooctane (DIO) additives have been added into the PCDTBT: PC70BM blend PSCs. Based on the higher boiling point than host solvent ODB and better solubility of PC71BM, the device photovoltaic properties with DIO additive were changed obviously. The investigations of EQE indicate that the DIO can influence the charge recombination and transportation process, and absorption studies demonstrate that the charge carriers generation process can also be affected by DIO. The overall impact reflected on the decreased equivalent resistant. With 3% v/v DIO, the Jsc, Voc and FF are both increased. Correspondingly, a highest PCE is achieved of 6.15%, while the reference device without DIO only has a PCE of 5.23%. Hence, adding DIO solvent additive is a effective method for the photovoltaic properties improving of PCDTBT: PC70BM blend PSCs.

The naturally occurring dipeptide carnosine (β alanyl L histidine) specifically attenuates tumor growth. Here, we asked whether other small imidazole containing compounds also affect viability of tumor cells without affecting non-malignant cells, and whether formation of histamine is involved. Patient-derived fibroblasts and glioblastoma cells were treated with carnosine, L alanyl L histidine (LA-LH), ß alanyl L alanine, L histidine, histamine, imidazole, β alanine and L alanine. Cell viability was assessed by cell-based assays and microscopy. The intracellular release of L histidine and formation of histamine was investigated by High Performance Liquid Chromatography coupled Mass Spectrometry. Whereas carnosine and LA LH inhibited tumor cell growth with minor effects on fibroblasts, L-histidine, histamine and imidazole affected viability in both cell types. Compounds without imidazole moiety did not diminish viability. In the presence of LA LH but not in the presence of carnosine a significant rise of intracellular amounts of histidine was detected in all cells. Formation of histamine was not detectable in the presence of carnosine, LA LH or histidine. In conclusion, the imidazole moiety of carnosine contributes to its anti-neoplastic effect, which is also seen in the presence of histidine and LA LH. Despite histamine had a strong effect on cell viability, formation of histamine is not responsible for the effects on cell viability of carnosine, LA LH and histidine.

Due to increased energy intensive human activities resulting accelerated demand for electric power coupled with occurrence of natural disasters with increased frequency, intensity, and duration, it becomes essential to explore and advance renewable energy technology for sustainability of the society. Addressing the stated problem and providing a radical solution has been attempted in this study. To harvest the renewable energy, among variety of solar cells reported, a composite a-Si/CZTS photovoltaic devices has not yet been investigated. The calculated parameters for solar cell based on the new array of layers consisting of a-Si/CZTS are reported in this study. The variation of i) solar cell efficiency as a function of CZTS layer thickness, temperature, acceptor, and donor defect concentration; ii) variation of the open circuit current density as a function of temperature, open circuit voltage; iii) variation of open circuit voltage as a function of the thickness of the CZTS layer has been determined. There has been no reported study on a-Si/CZTS configuration-based solar cell, analysis of the parameters, and study to address the challenges imped efficiency of the photovoltaic device and the same has been discussed in this work. The value of the SnO2/a-Si/CZTS solar cells obtained from the simulation is 23.9 %.

Dielectric spectroscopy (DS) is a promising cell screening method that can be used for diagnostic and drug discovery purposes. The primary challenge of using DS in physiological buffers is the electrode polarization (EP) that overwhelms the impedance signal within a large frequency range. These effects further amplify with miniaturization of the measurement electrodes. In this study, we present a microfluidic system and the associated equivalent circuit models for real-time measurements of cell membrane capacitance and cytoplasm resistance in physiological buffers with 10s increments. The current device captures several hundreds of biological cells in individual microwells through gravitational settling and measures the system’s impedance using microelectrodes covered with dendritic gold nanostructures. Using PC-3 cells (a highly metastatic prostate cancer cell line) suspended in cell growth media (CGM), we demonstrate stable measurements of cell membrane capacitance and cytoplasm resistance in the device for over 15 minutes. We also describe a consistent application of the equivalent circuit model, starting from the reference measurements used to determine the system parameters. The circuit model is tested using devices with varying dimensions, and the obtained cell parameters between different devices are nearly identical. Further analyses of the impedance data have shown that accurate cell membrane capacitance and cytoplasm resistance can be extracted using a limited number of measurements in the 5 MHz to 10 MHz range. This will potentially reduce the timescale required for real-time DS measurements below 1s. Overall the new microfluidic device can be used for dielectric characterization of biological cells in physiological buffers for various cell screening applications.

The aim was to evaluate the influence of model (alcohol, sugar, salt, protein and acid) and real foods and beverages on the viability of probiotics during incubation and artificial digestion. Viability of monocultures Lactobacillus acidophilus CCM4833 and Bifidobacterium breve CCM7825T and commercial mixture of 9 probiotic bacterial strains were tested by cultivation assay and flow cytometry. In model foods, the best viability was determined in the presence of 0.2 g/L glucose, 10% albumin and 10% ethanol. As the most suitable real food for probiotic survival complex protein and carbohydrate substrates were found, such as beef broth, potato salad with pork, chicken with rice, chocolate spread, porridge and yoghurt. The best liquid was milk and meat broth, followed by coca-cola, beer and coffee. Viability of probiotics was higher when consumed with meals than with beverages only. Addition of prebiotics increased the viability of probiotics especially in presence of instant and fast foods. Generally, the highest viability of probiotics during artificial digestion was observed in mixed culture in presence of protein, sugar and fat or their combination. The increase of cell viability observed in such foods during model digestion may further contribute to the positive effect of probiotics on human health.

Most hair relaxers or straighteners used for Afro-textured hair have a pH above 11. This pH, according to international occupational health and safety guidelines, is corrosive to the skin. Further, relaxers are associated with a 3-6 times increased risk of alopecia. The skin also gets into contact with these hair straightening products during application resulting in skin irritation. Using animals as test subjects to determine these products' potential risk and safety margin is standard practice; however, with the European Union (EU) ban on animal testing, the testing method needs to be replaced by newer in vitro laboratory technologies. This study used previously and newly established in vitro cell-based technologies and human-skin derived cells as laboratory models to evaluate relaxer-induced cytotoxicity. These technologies include endpoint (MTT, CCK-8 and flow cytometry) and real-time assays (real-time cell analysis (RTCA) and extracellular flux analysis). Cellular toxicity was evident following treatment of keratinocytes and fibroblasts with acceptable concentrations of thioglycolic acid (TGA, HSCH2COOH), ammonium bisulphite (NH4HSO3), lithium hydroxide (LiOH) and sodium hydroxide (NaOH) based relaxers. Real-time assays showed significant reductions (P<0.001) in cell index and ATP production following treatment of keratinocytes with as little as one-tenth of the acceptable concentrations. Increased apoptosis (47.9%, 58.0%, 76.7% and 80.3%) also occurred in cells after treatment with TGA, NH4HSO3, NaOH and LiOH, respectively. In conclusion, this study demonstrated that using skin cells in conjunction with advanced cell-based technologies could serve as alternatives to laboratory animals for accessing the toxicity margin of hair relaxers, straighteners and other cosmetics.

Surface passivation, which has been intensively studied recently, is essential for the perovskite solar cells (PSCs), due to the intrinsic defects in perovskite crystal. A series of chemical or physical methods have been published for passivating the defects of perovskite, which effectively suppressed the charge recombination and enhanced the photovoltaic performance. In this study, the n-type semiconductor of [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) is dissolved in chlorobenzene (CB) for the surface passivation during the spin-coating process for depositing the two-dimensional (2D) perovskite film. This approach simplifies the fabrication process of 2D PSCs and benefits the film quality. As a result, the defects of perovskite film are effectively passivated by this method. A better perovskite/PCBM heterojunction is generated, exhibiting an increased film coverage and improved film morphology of PCBM. It is found that this technology results in an improved electron transporting performance as well as suppressed charge recombination for electron transport layer. As a result, PSCs based on the one-step formed perovskite/PCBM heterojunctions exhibit the optimized power conversion efficiency of 15.69% which is about 37% higher than that of regular perovskite devices. The device environmental stability is also enhanced due to the quality-improved electron transport layer.

Apoptosis, the programmed and intentional death of senescent, damaged, or otherwise superfluous cells, is the natural end-point for most cells within multicellular organisms. Apoptotic cells are not inherently damaging, but if left unattended they can lyse through secondary necrosis. The resulting release of intracellular contents drives inflammation in the surrounding tissue and can lead to autoimmunity. These negative consequences of secondary necrosis are avoided by efferocytosis—the phagocytic clearance of apoptotic cells. Efferocytosis is a product of both apoptotic cell and efferocyte mechanisms, which cooperate to ensure the rapid and complete removal of apoptotic cells. Herein, the processes used by apoptotic cells to ensure their timely removal, and the receptors, signaling, and cellular processes used by efferocytes to identify, remove, and process the apoptotic cells, are reviewed.