Life, Volume 12, Issue 7 (July 2022) – 178 articles

Synchronization between heart rate variability (HRV) in the low-frequency (LF) range (0.04–0.15 Hz) and 1-min variations in the components (X, Y, Z)and the total vector (F) of geomagnetic induction (nT) was studied in normotensive (blood pressure up to 140/90 mmHg) and hypertensive (blood pressure above 140/90 mmHg) individuals living in the Arkhangelsk region (60°51′52″ N 39°31′05″ E).The duration of registration of HRV for each person is 30 min in a sitting position. The most pronounced synchronization of the LF parameter, which reflects baroreflex activity, with variations in the GMF was found in normotensive individuals. The absence of a significant synchronization of the LF parameter with variations in the GMF components indicates a decrease in the sensitivity of the baroreflex mechanism and a risk of dysregulation of vascular tone, especially in people with arterial hypertension, under conditions of instability of the geomagnetic field. Full article

This work aimed at estimating narrow-sense heritability, defined as the proportion of the phenotypic variance explained by the sum of additive genetic effects, via Haseman–Elston regression for a subset of 56 plasma protein levels related to Multiple Sclerosis (MS). These were measured in 212 related individuals (with 69 MS cases and 143 healthy controls) obtained from 20 Sardinian families with MS history. Using pedigree information, we found seven statistically significant heritable plasma protein levels (after multiple testing correction), i.e., Gc ($h^2$ = 0.77; 95%CI: 0.36, 1.00), Plat ($h^2$ = 0.70; 95%CI: 0.27, 0.95), Anxa1 ($h^2$ = 0.68; 95%CI: 0.27, 1.00), Sod1 ($h^2$ = 0.58; 95%CI: 0.18, 0.96), Irf8 ($h^2$ = 0.56; 95%CI: 0.19, 0.99), Ptger4 ($h^2$ = 0.45; 95%CI: 0.10, 0.96), and Fadd ($h^2$ = 0.41; 95%CI: 0.06, 0.84). A subsequent analysis was performed on these statistically significant heritable plasma protein levels employing Immunochip genotyping data obtained in 155 healthy controls (92 related and 63 unrelated); we found a meaningful proportion of heritable plasma protein levels’ variability explained by a small set of SNPs. Overall, the results obtained, for these seven MS-related proteins, emphasized a high additive genetic variance component explaining plasma levels’ variability. Full article

Healthcare systems have been under immense pressure since the beginning of the COVID-19 pandemic; hence, studies on using machine learning (ML) methods for classifying ICU admissions and resource allocation are urgently needed. We investigated whether ML can propose a useful classification model for predicting the ICU admissions of COVID-19 patients. In this retrospective study, the clinical characteristics and laboratory findings of 100 patients with laboratory-confirmed COVID-19 tests were retrieved between May 2020 and January 2021. Based on patients’ demographic and clinical data, we analyzed the capability of the proposed weighted radial kernel support vector machine (SVM), coupled with (RFE). The proposed method is compared with other reference methods such as linear discriminant analysis (LDA) and kernel-based SVM variants including the linear, polynomial, and radial kernels coupled with REF for predicting ICU admissions of COVID-19 patients. An initial performance assessment indicated that the SVM with weighted radial kernels coupled with REF outperformed the other classification methods in discriminating between ICU and non-ICU admissions in COVID-19 patients. Furthermore, applying the Recursive Feature Elimination (RFE) with weighted radial kernel SVM identified a significant set of variables that can predict and statistically distinguish ICU from non-ICU COVID-19 patients. The patients’ weight, PCR Ct Value, CCL19, INF-β, BLC, INR, PT, PTT, CKMB, HB, platelets, RBC, urea, creatinine and albumin results were found to be the significant predicting features. We believe that weighted radial kernel SVM can be used as an assisting ML approach to guide hospital decision makers in resource allocation and mobilization between intensive care and isolation units. We model the data retrospectively on a selected subset of patient-derived variables based on previous knowledge of ICU admission and this needs to be trained in order to forecast prospectively. Full article

p53 is known as the guardian of the genome and plays various roles in DNA damage and cancer suppression. The p53 gene was found to express multiple p53 splice variants (isoforms) in a physiological, tissue-dependent manner. The various genes that up- and down-regulated p53 are involved in cell viability, senescence, inflammation, and carcinogenesis. Moreover, p53 affects the radioadaptive response. Given that several studies have already been published on p53, this review presents its role in the response to gamma irradiation by interacting with MDM2, NF-κB, and miRNA, as well as in the inflammation processes, senescence, carcinogenesis, and radiation adaptive responses. Finally, the potential of p53 as a biomarker is discussed. Full article

The burden of COVID-19 remains unchanged for immunocompromised patients who do not respond to vaccines. Unfortunately, Omicron sublineages are resistant to monoclonal antibodies authorized in Europe so far, and small chemical antivirals have contraindications and toxicities that have not been studied in these patients. We report here the successful treatment of COVID-19 pneumonia lasting for 4 months after the transfusion of COVID-19 convalescent plasma (CCP) in a patient with severe immunosuppression due to both chronic lymphocytic leukemia and venetoclax treatment. The patient achieved a complete clinical, radiological and virological response after six transfusions (600 mL each) of high-titer CCP collected from triple-vaccinated and convalescent donors. This dramatic case adds to the mounting evidence of CCP efficacy in immunocompromised patients, provided that high-titer and large volumes are infused. Full article

Dementia is a neurological condition that primarily affects older adults and there is still no cure or therapy available to cure it. The symptoms of dementia can appear as early as 10 years before the beginning of actual diagnosed dementia. Hence, machine learning (ML) researchers have presented several methods for early detection of dementia based on symptoms. However, these techniques suffer from two major flaws. The first issue is the bias of ML models caused by imbalanced classes in the dataset. Past research did not address this issue well and did not take preventative precautions. Different ML models were developed to illustrate this bias. To alleviate the problem of bias, we deployed a synthetic minority oversampling technique (SMOTE) to balance the training process of the proposed ML model. The second issue is the poor classification accuracy of ML models, which leads to a limited clinical significance. To improve dementia prediction accuracy, we proposed an intelligent learning system that is a hybrid of an autoencoder and adaptive boost model. The autoencoder is used to extract relevant features from the feature space and the Adaboost model is deployed for the classification of dementia by using an extracted subset of features. The hyperparameters of the Adaboost model are fine-tuned using a grid search algorithm. Experimental findings reveal that the suggested learning system outperforms eleven similar systems which were proposed in the literature. Furthermore, it was also observed that the proposed learning system improves the strength of the conventional Adaboost model by 9.8% and reduces its time complexity. Lastly, the proposed learning system achieved classification accuracy of 90.23%, sensitivity of 98.00% and specificity of 96.65%. Full article

Diabetic hyperglycemia delays wound healing, leading to serious consequences. Topical antibiotics can reduce the risk of a wound infection during healing; nevertheless, the microbial fight against antibiotics brings about public health challenges. Anti-microbial peptides (AMPs) belong to a novel class of drug that is used to prevent and treat systemic and topical infections. The aim of the current work was to achieve better wound healing in diabetic rats by conjugating the anti-microbial peptide “apamin” (APA) with the broad-spectrum antibiotic “ceftriaxone” (CTX) to form a nanocomplex. The CTX–APA nanoconjugate formulation was optimized using a Box–Behnken design. The optimized CTX–APA nanoconjugate formulation was evaluated for its size and zeta potential, and was then examined using transmission electron microscopy (TEM). The CTX–APA nanoconjugate was loaded onto a hydroxypropyl methylcellulose (2% w/v)-based hydrogel. It was observed that the application of the CTX–APA nanocomplex on the wounded skin of diabetic rats accelerated the regeneration of the epithelium, granulation tissue formation, epidermal proliferation, and keratinization. The nanocomplex was capable of significantly reducing the expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), while increasing the expression of transforming growth factor beta-1 (TGF-β1) as well as the angiogenic markers: hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF). Conclusively, the application of an ion-paired CTX–APA nanocomplex enhances wound healing in diabetic rats. Full article

Plant leaves, which convert light energy into chemical energy, serve as a major food source on Earth. The decrease in crop yield and quality is caused by plant leaf premature senescence. It is important to detect senescence-associated genes. In this study, we collected 5853 genes from a leaf senescence database and developed a leaf-senescence-associated genes (SAGs) prediction model using the support vector machine (SVM) and XGBoost algorithms. This is the first computational approach for predicting SAGs with the sequence dataset. The SVM-PCA-Kmer-PC-PseAAC model achieved the best performance (F1score = 0.866, accuracy = 0.862 and receiver operating characteristic = 0.922), and based on this model, we developed a SAGs prediction tool called “SAGs_Anno”. We identified a total of 1,398,277 SAGs from 3,165,746 gene sequences from 83 species, including 12 lower plants and 71 higher plants. Interestingly, leafy species showed a higher percentage of SAGs, while leafless species showed a lower percentage of SAGs. Finally, we constructed the Leaf SAGs Annotation Platform using these available datasets and the SAGs_Anno tool, which helps users to easily predict, download, and search for plant leaf SAGs of all species. Our study will provide rich resources for plant leaf-senescence-associated genes research. Full article

Polymorphisms in genes encoding receptors that modulate the activity of microglia and macrophages are attractive candidates for participation in genetic susceptibility to multiple sclerosis (MS). The aims of the study were to (1) investigate the association between Alzheimer’s disease-linked variant rs3865444:C>A in the CD33 gene and MS risk, (2) assess the effect of the strongest MS risk allele HLA-DRB1*15:01 on this association, and (3) analyze the correlation of rs3865444 with selected clinical phenotypes, i.e., age of onset and disease severity. CD33 rs3865444 was genotyped in a cohort of 579 patients and 1145 controls and its association with MS risk and clinical phenotypes was analyzed by logistic and linear regression analysis, respectively. Statistical evaluation revealed that rs3865444 reduces the risk of MS in the HLA-DRB1*15:01-positive subpopulation but not in the cohort negative for HLA-DRB1*15:01. A significant antagonistic epistasis between rs3865444 A and HLA-DRB1*15:01 alleles in the context of MS risk was detected by the interaction synergy factor analysis. Comparison of allele and genotype distribution between relapsing-remitting MS, secondary progressive MS, and control groups revealed that rs3865444 C to A substitution may also be associated with a decreased risk of transition of MS to its secondary progressive form, irrespective of the HLA-DRB1*15:01 carrier status. On the other hand, no correlation could be found between rs3865444 and the age of disease onset or MS severity score. Future studies are required to shed more light on the role of CD33 in MS pathogenesis. Full article

Gestation and the neonatal period are crucial periods in infant development. Many components of breast milk, including fatty acids, play an important role in strengthening the immune system. The aim of our research was to evaluate the fatty acid profiles of milk from 69 mothers, including subjects having a normal weight, obesity, or gestational diabetes. For the analyses, we used gas chromatography (GC) with flame ionization detection (FID) and GC coupled with mass spectrometry (GC/MS). The main fatty acids found in breast milk were palmitic acid (C16:0; 26–28%), linoleic acid (C18:2; 23–28%), and α-linolenic acid linoleic acid (C18:3; 15–17%), followed by myristic acid (C14:0; 5–8%), lauric acid (C12:0; 4–6%) and stearic acid (C18:0; 4–5%). The average breakdown of fatty acids was 50% saturated, 44% polyunsaturated, and 6% monounsaturated. Breast milk samples were classified using principal component analysis and linear discriminant analysis. Results showed that milk from the two major groups of obese and normal body mass index (BMI) could be distinguished with an accuracy of 89.66%. Breast milk samples of Hungarian and Ukrainian mothers showed significant differences based on the fatty acid composition, which variations are attributable to the mothers’ dietary habits. Full article

This study investigated the druggability, pharmacokinetics and ethyl acetate extract of Teucrium polium (EA T. polium), from Ha'il, and the protective effect against carbon tetrachloride (CCl₄) induced liver cirrhosis in rats. The total antioxidant capacity (TAC) and scavenging activity of the extract were examined. The in vivo protective study was based on the use of an animal model of CCl₄-induced liver cirrhosis. Four groups of rats have been used: Group I: control rats; Group II: received CCl₄ in olive oil (0.5 mL/kg); Group III: received the EA T. polium (25 mg/kg) of pretreatment for seven days by gavage then CCl₄ in olive oil by gavage for 15 days. Group IV: received the EA of T. polium for seven days (25 mg/kg). EA T. polium was found to possess significant antioxidant capacity. CCl₄ caused a hepatotoxicity associated increase in both levels of AST and ALT, which were reduced back to normal values following EA T. polium pretreatment. Hepatotoxicity associated structural modifications of liver tissues and increase in thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD) and carbonyl proteins (CP), associated decreases in several assessed antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT). The in vivo findings on the protective effect of T. polium were supported by its druggability, its pharmacokinetic properties and molecular docking assays. These results confirm the modulatory antioxidant and hepatoprotective potential of T. polium in this experimental liver cirrhosis model. T. polium phytochemicals are good candidates for further pharmaceutical explorations and drug design. Full article

Background: Medullary thyroid cancer (MTC) is a rare endocrine tumour that is sporadic in 75% of cases and occurs as a part of inherited cancer syndromes in approximately 25% of cases. The aim of this study was to determine the frequency and type of RET pathogenic variants (PVs) in the Slovenian MTC patient population diagnosed between 1995 and 2021 and to elucidate the full range of associated endocrinopathies. Methods: A retrospective analysis of medical records of 266 MTC patients and their relatives seen in a tertiary centre between 1995 and 2021 was performed. Sequence analysis of exons 10, 11, 13, 14, 15, and 16 of the RET gene was analysed in most patients using Sanger sequencing. From 2017, the entire sequence of RET gene was analysed in most patients using targeted next-generation sequencing. Results: Germline PVs in the RET proto-oncogene were identified in 21.6% probands from 21 different MTC families. Of their tested relatives, 65% (67/103) were RET-positive and 35% (36/103) were RET-negative. PVs were detected in codon 618 and codon 634 in 28.6%, and in codon 790 in 23.8%. The RET-positive group consisted of 52 MTC patients, 13 patients with C cell hyperplasia and 2 individuals with neither. Associated endocrinopathies were diagnosed in 8/21 families: primary hyperparathyroidism (PHPT) in six families and pheochromocytoma (PHEO) in five families. In 62% of RET-positive families (13/21), no associated endocrinopathies were diagnosed. PHEO was most commonly associated with C634R (6/13) and PHPT with C634R (4/7). Hirschsprung’s disease appeared in one patient with RET PV in codon 618. Based on data from the Cancer Registry of Republic of Slovenia, only individual cases of common cancers with well understood environmental risk factors were discovered; lung cancer in 2/21 of families, papillary thyroid cancer in 3/21 of families, cutaneous melanoma in 2/21 of families, cervical cancer in 1/21 families, and lymphoma in 1/21 families. Conclusions: Analysis of prospectively collected MTC cases during a 27-year period revealed that 21.6% of Slovenian patients are RET PV carriers. Sixty-two percent of families had none of the associated endocrinopathies, confirming the thesis that FMTC is the most common presentation. This could suggest using risk-stratified management approaches when screening for PHEO and PHPT in RET PV carriers. However, more studies are needed to evaluate potential genetic risk modifiers as well as safety, improved quality of life, and medical cost reduction in the case of a patient-oriented approach. Full article

Atranorin (ATR) is a secondary metabolite of lichens. While previous studies investigated the effects of this substance predominantly in an in vitro environment, in our study we investigated the basic physicochemical properties, the binding affinity to human serum albumin (HSA), basic pharmacokinetics, and, mainly, on the systematic effects of ATR in vivo. Sporadic studies describe its effects during, predominantly, cancer. This project is original in terms of testing the efficacy of ATR on a healthy organism, where we can possibly attribute negative effects directly to ATR and not to the disease. For the experiment, 24 Sprague Dawley rats (Velaz, Únetice, Czech Republic) were used. The animals were divided into four groups. The first group (n = 6) included healthy males as control intact rats (♂INT) and the second group (n = 6) included healthy females as control intact rats (♀INT). Groups three and four (♂ATR/n = 6 and ♀ATR/n = 6) consisted of animals with daily administered ATR (10mg/kg body weight) in an ethanol–water solution per os for a one-month period. Our results demonstrate that ATR binds to HSA near the binding site TRP214 and acts on a systemic level. ATR caused mild anemia during the treatment. However, based on the levels of hepatic enzymes in the blood (ALT, ALP, or bilirubin levels), thiobarbituric acid reactive substances (TBARS), or liver histology, no impact on liver was recorded. Significantly increased creatinine and lactate dehydrogenase levels together with increased defecation activity during behavioral testing may indicate the anabolic effect of ATR in skeletal muscles. Interestingly, ATR changed some forms of behavior. ATR at a dose of 10 mg/kg body weight is non-toxic and, therefore, could be used in further research. Full article

Force-spectroscopy techniques have led to significant progress in studying the physicochemical properties of biomolecules that are not accessible in bulk assays. The application of piconewton forces with laser optical tweezers to single nucleic acids has permitted the characterization of molecular thermodynamics and kinetics with unprecedented accuracy. Some examples are the hybridization reaction between complementary strands in DNA and the folding of secondary, tertiary, and other heterogeneous structures, such as intermediate and misfolded states in RNA. Here we review the results obtained in our lab on deriving the nearest-neighbor free energy parameters in DNA and RNA duplexes from mechanical unzipping experiments. Remarkable nonequilibrium effects are also observed, such as the large irreversibility of RNA unzipping and the formation of non-specific secondary structures in single-stranded DNA. These features originate from forming stem-loop structures along the single strands of the nucleic acid. The recently introduced barrier energy landscape model quantifies kinetic trapping effects due to stem-loops being applicable to both RNA and DNA. The barrier energy landscape model contains the essential features to explain the many behaviors observed in heterogeneous nucleic-acid folding. Full article

Background: The use of various herbal therapists as part of traditional medicine in different parts of the world, including Bulgaria, is due to the knowledge accumulated over the centuries by people about their valuable biological activities. In this study, we investigate extracts from widely used Bulgarian medicinal plants for their ability to prevent the coronavirus infection of cells by testing different mechanisms of antiviral protection, their polyphenol content, and redox-modulating capacity. Methods: The influence on the stage of viral adsorption, the inhibition of extracellular virions, and the protective effect on uninfected cells of the plant’s extracts were reported by the end-point dilution method, and virus titer (in Δ lgs) was determined as compared to the untreated controls. The total content of polyphenols and flavonoids was also determined. We tested the antioxidant power of the extracts by their ability to inhibit the generation of superoxide anionic radicals and to scavenge DPPH radicals. We determined their iron-reducing, copper-reducing, and metal-chelating antioxidant powers. Results: Most of the extracts tested suppress the extracellular virions of HCov. They also inhibit the stage of viral adsorption to the host cell to varying degrees and have a protective effect on healthy cells before being subjected to viral invasion. The examined extracts contained significant levels of polyphenols and quercetin-like flavonoids and showed remarkable antioxidant, radical, and redox-modulating effects. Conclusions: All of these 13 extracts from Bulgarian medicinal plants tested can act as antioxidants and antiviral and symptomatic drugs for the management of coronavirus infection. Full article

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first COVID-19 case was reported in Wuhan, China, in December 2019. In March 2020, the World Health Organization (WHO) declared COVID-19 a global pandemic. The first COVID-19 case in Nepal was reported in January 2020 in a Nepalese man who had returned from Wuhan to Nepal. This study aims to evaluate the government of Nepal’s (GoN) response to the COVID-19 pandemic and explore ways to prevent COVID-19 and other pandemic diseases in the future. As of May 2022, a total of 979,140 cases and 11,951 deaths associated with COVID-19 have been reported in Nepal. To prevent the spread of the virus, the GoN initiated various preventive and control measures, including lockdown strategies. The effects of COVID-19 are expected to persist for many years; the best strategies a resource-limited country such as Nepal can implement to control pandemic diseases such as COVID-19 in the pre-vaccine stage are to increase testing, tracing, and isolation capacity. Full article

Dry eye disease (DED) is most commonly caused by evaporative subtypes and mainly induced by meibomian gland dysfunction (MGD). Intense pulsed light (IPL) combined with meibomian gland expression (MGX) is a noninvasive treatment for improvement of ocular discomfort symptoms and MGD. In this prospective study between November 2020 and May 2022, the patients with MGD and abnormal meibomian expressibility that met the criteria of both ocular surface disease index (OSDI) ≥ 13 scores and standardized patient evaluation of eye dryness (SPEED) ≥ 8 scores were enrolled in Kaohsiung Veteran General Hospital. Three separate treatment sessions of IPL therapy combined with MGX were administered to the lower lids, with an interval of 28 days. Further tear film assessment included lipid layer thickness (LLT), tear meniscus height (TMH), noninvasive tear break-up time (NIBUT), and meibomian gland loss (MGL) either before or after first and third IPL therapy combined with MGX. In addition, lissamine green staining and pain scores were also recorded. We totally enrolled 37 patients of 74 eyes. Men accounted for 18.92% (7/37). The mean age was 54.51 ± 11.72 years. The mean OSDI scores were 58.12 ± 22, while the SPEED scores were 17.03 ± 5.98. The mean Schirmer’s test was 3.66 ± 2.43 mm. After three sessions of IPL treatment with MGX, the OSDI, SPEED, LLT, TMH, MGL, MGXS, and pain scores were significantly improved. For the MGX scores (MGXS) ≤ 20 group, lissamine green scores showed nearly significant improvements. For the MGXS > 20 group, TMH revealed statistical improvement. Noninvasive IPL therapy with MGX statistically improved not only dry eye symptoms, but also tear film assessments, including LLT, TMH, and MGL. Full article

The intricate relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the cardiovascular system is an extensively studied pandemic topic, as there is an ever-increasing amount of evidence that reports a high prevalence of acute cardiac injury in the context of viral infection. In patients with Coronavirus disease 2019, COVID-19, a significant increase in serum levels of cardiac troponin or other various biomarkers was observed, suggesting acute cardiac injury, thus predicting both a severe course of the disease and a poor outcome. Pathogenesis of acute cardiac injury is not yet completely elucidated, though several mechanisms are allegedly involved, such as a direct cardiomyocyte injury, oxygen supply-demand inequity caused by hypoxia, several active myocardial depressant factors during sepsis, and endothelial dysfunction due to the hyperinflammatory status. Moreover, the increased levels of plasma cytokines and catecholamines and a significantly enhanced prothrombotic environment may lead to the destabilization and rupture of atheroma plaques, subsequently triggering an acute coronary syndrome. In the present review, we focus on describing the epidemiology, pathogenesis, and role of biomarkers in the diagnosis and prognosis of patients with acute cardiac injury in the setting of the COVID-19 pandemic. We also explore some novel therapeutic strategies involving immunomodulatory therapy, as well as their role in preventing a severe form of the disease, with both the short-term outcome and the long-term cardiovascular sequelae being equally important in patients with SARS-CoV-2 induced acute cardiac injury. Full article

Brain tumors reduce life expectancy due to the lack of a cure. Moreover, their diagnosis involves complex and costly procedures such as magnetic resonance imaging (MRI) and lengthy, careful examination to determine their severity. However, the timely diagnosis of brain tumors in their early stages may save a patient’s life. Therefore, this work utilizes MRI with a machine learning approach to diagnose brain tumor severity (glioma, meningioma, no tumor, and pituitary) in a timely manner. MRI Gaussian and nonlinear scale features are extracted due to their robustness over rotation, scaling, and noise issues, which are common in image processing features such as texture, local binary patterns, histograms of oriented gradient, etc. For the features, each MRI is broken down into multiple small 8 × 8-pixel MR images to capture small details. To counter memory issues, the strongest features based on variance are selected and segmented into 400 Gaussian and 400 nonlinear scale features, and these features are hybridized against each MRI. Finally, classical machine learning classifiers are utilized to check the performance of the proposed hybrid feature vector. An available online brain MRI image dataset is utilized to validate the proposed approach. The results show that the support vector machine-trained model has the highest classification accuracy of 95.33%, with a low computational time. The results are also compared with the recent literature, which shows that the proposed model can be helpful for clinicians/doctors for the early diagnosis of brain tumors. Full article

Vitamin E (Vit E) is an essential lipophilic antioxidant and anti-inflammatory agent that has potential as a neuroprotectant in newborn infants with brain injury. Vit E has shown promise in many in vitro studies, but success in translation to in vivo animal studies and the clinical setting has been mixed, with concern of adverse effects at high intravenous doses in preterm infants. However, a recent rise in knowledge of the beneficial effects of fat emulsions containing higher levels of Vit E, along with associated improved outcomes in some neonatal co-morbidities, has led many to reconsider Vit E administration as a potential therapeutic modality to improve neurological outcomes in the setting of neonatal brain injury. This narrative review discusses Vit E’s structure, mechanism(s) of action, evidence in animal models, and association with health outcomes in neonates, including both dietary and supplemental Vit E and their bioavailability and pharmacokinetics as it relates to the brain. Lastly, long-term neurodevelopmental outcomes along with gaps in current knowledge are critiqued, which to date suggests that additional translational studies in larger animal models and assessment of safety profiles of different routes and doses of administration should be explored prior to large clinical trials. Importantly, a greater understanding of the brain region(s) and cell type(s) affected by Vit E may help to target the use of Vit E as a beneficial neuroprotective agent to specific populations or types of injury seen in newborns. Full article

Background: BNCT (Boron Neutron Capture Therapy) is a tumor-selective particle radiotherapy that combines preferential boron accumulation in tumors and neutron irradiation. Although p-boronophenylalanine (BPA) has been clinically used, new boron compounds are needed for the advancement of BNCT. Based on previous studies in colon tumor-bearing mice, in this study, we evaluated MID:BSA (maleimide-functionalized closo-dodecaborate conjugated to bovine serum albumin) biodistribution and MID:BSA/BNCT therapeutic effect on tumors and associated radiotoxicity in the hamster cheek pouch oral cancer model. Methods: Biodistribution studies were performed at 30 mg B/kg and 15 mg B/kg (12 h and 19 h post-administration). MID:BSA/BNCT (15 mg B/kg, 19 h) was performed at three different absorbed doses to precancerous tissue. Results: MID:BSA 30 mg B/kg protocol induced high BSA toxicity. MID:BSA 15 mg B/kg injected at a slow rate was well-tolerated and reached therapeutically useful boron concentration values in the tumor and tumor/normal tissue ratios. The 19 h protocol exhibited significantly lower boron concentration values in blood. MID:BSA/BNCT exhibited a significant tumor response vs. the control group with no significant radiotoxicity. Conclusions: MID:BSA/BNCT would be therapeutically useful to treat oral cancer. BSA toxicity is a consideration when injecting a compound conjugated to BSA and depends on the animal model studied. Full article

Introduction: Cytomegalovirus (CMV) is the leading opportunistic infection in lung transplant (LTx) recipients. CMV is associated with graft failure and decreased survival. Recently, new antiviral therapies have been proposed. The present study aimed to investigate NK and T cell subsets of patients awaiting LTx. We analyzed the cellular populations between reactive and non-reactive QuantiFERON (QF) CMV patients for the prediction of immunological response to infection. Methods: Seventeen pre-LTx patients and 15 healthy controls (HC) have been enrolled. QF and IFN-γ ELISA assay detections were applied. NK cell subsets and T cell and proliferation assay were detected before and after stimulation with pp-65 and IE-1 CMV antigens after stratification as QF+ and QF−. Furthermore, we quantified the serum concentrations of NK− and T-related cytokines by bead-based multiplex analysis. Results: CD56^brCD16^lowNKG2A⁺KIR⁺ resulted in the best discriminatory cellular subsets between pre-LTx and HC. Discrepancies emerged between serology and QF assay. Better proliferative capability emerged from patients who were QF+, in particular in CD8 and CD25-activated cells. CD56^brCD16^low, adaptive/memory-like NK and CD8Teff were highly increased only in QF+ patients. Conclusions: QF more than serology is useful in the detection of patients able to respond to viral infection. This study provides new insights in terms of immunological responses to CMV in pre-LTX patients, particularly in NK and T cells biology. Full article

Background and aim: This study evaluates the upper airway flow characteristics, anatomical features and analyzes their correlations with AHI in patients with varied degrees of OSA severity seeking for discernments of the underlying pathophysiological profile. Materials and Methods: Patient-specific computational fluid dynamics models were reconstructed from high-resolution cone-beam computed tomography images for 4 OSA patients classified as minimal, mild, moderate, and severe according to AHI. Results: The parameters, minimal cross-sectional area (MCA), and the pharyngeal airway volume did not show clear correlations with the OSA severity defined according to AHI. No correlations were found between the classically defined resistance of the airway in terms of pressure drop and AHI. The flow analysis further showed that the fluid mechanisms likely to cause airway collapse are associated with the degree of narrowing in the pharyngeal airway rather than AHI. Results also suggested that some patients classified as severe OSA according to the AHI can show less susceptibility to airway collapse than patients with relatively lower AHI values and vice versa. Conclusions: The relative contribution of anatomical and non-anatomical causes to the OSA severity can significantly vary between patients. AHI alone is inadequate to be used as a marker of the pathophysiological profile of OSA. Combining airflow analysis with AHI in diagnosing OSA severity may provide additional details about the underlying pathophysiology, subsequently improving the individualized clinical outcomes. Full article

Hypoxia is an abiotic stress in plants. Flooding resulting from climate change is a major crop threat that increases the risk of hypoxic stress. The molecular mechanisms underlying hypoxia in plants were elucidated in recent years, but new genes related to this stress remain to be discovered. Thus, we aimed to perform a meta-analysis of the RNA sequencing (RNA-Seq) data of Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) under hypoxia. We collected 29 (Arabidopsis) and 26 (rice) pairs of RNA-Seq data involving hypoxic (including submergence) and normoxic (control) treatments and extracted the genes that were commonly upregulated or downregulated in the majority of the experiments. The meta-analysis revealed 40 and 19 commonly upregulated and downregulated genes, respectively, in the two species. Several WRKY transcription factors and cinnamate-4-hydroxylase were commonly upregulated, but their involvement in hypoxia remains unclear. Our meta-analysis identified candidate genes for novel molecular mechanisms in plants under hypoxia. Full article

Purpose: The treatment efficacy of the transarterial approach to lung cancer is evaluated. Materials and Methods: A total of 98 patients with advanced lung cancer or recurrent lung cancer after the standard therapies were enrolled retrospectively. The bronchial arteries and mediastinal branches from the subclavian artery were selected by a microcatheter. Immediately after the selective arterial infusion of anti-neoplastic agents, embolization with a spherical embolic material was carried out. Local tumor effects and overall survival were evaluated. Result: The mean reduction rate was 17.9%, with 24.2% for partial remission and with 2.1% for progression disease. The rate of stable disease was 72.6%. The response rate was 25.3%, and the disease control rate was 97.9%. The median survival time (MST) was 11.4 months, the 1-year survival rate was 45.2%, and the 2-year survival rate was 35.6%. Although it is insignificant, the MST for 51 adenocarcinomas was higher than that of 29 squamous cell carcinomas (18.6 months and 9.4 months, respectively). The local extension of tumors related to a better prognosis, though it was not significant. Lymph node metastases and distant metastases were poor prognostic factors. No major complications nor treatment-related mortalities were found in this study. Conclusion: The transarterial treatment for lung cancer should be considered as a treatment option when the other treatments were not indicated both in initial cases and in recurrent cases. Full article

Fetal programming is the concept that maternal stressors during critical periods of fetal development can alter offspring phenotypes postnatally. Excess glucocorticoids can interact with the fetus to effect genetic and epigenetic changes implicated in adverse developmental outcomes. The present study investigates how chronic exposure to the synthetic glucocorticoid dexamethasone during late gestation alters the expression of genes related to behavior in brain areas relevant to the regulation and function of the hypothalamic–pituitary–adrenal axis. Pregnant Wistar Kyoto rats received subcutaneous injections of dexamethasone (100 μg/kg) daily from gestational day 15–21 or vehicle only as sham controls. The amygdala and paraventricular nucleus (PVN) were micro-punched to extract mRNA for reverse transcription and quantitative polymerase chain reaction for the analysis of the expression of specific genes. In the PVN, the expression of the glucocorticoid receptor NR3C1 was downregulated in female rats in response to programming. The expression of CACNA1C encoding the Ca_v1.2 pore subunit of L-type voltage-gated calcium channels was downregulated in male and female rats prenatally exposed to dexamethasone. Collectively, the results suggest that prenatal exposure to elevated levels of glucocorticoids plays a role in the dysregulation of the hypothalamic–pituitary–adrenal axis and potentially learning and memory by altering the expression of specific genes within the amygdala and PVN. Full article

The COVID-19 era has prompted several researchers to search for a linkage between COVID-19 and its associated neurological manifestation. Toll-like receptor 4 (TLR-4) acts as one such connecting link. spike protein of SARS-CoV-2 can bind either to ACE-2 receptors or to TLR-4 receptors, leading to aggregation of α-synuclein and neurodegeneration via the activation of various cascades in neurons. Recently, dithymoquinone has been reported as a potent multi-targeting candidate against SARS-CoV-2. Thus, in the present study, dithymoquinone and its six analogues were explored to target 3CL^pro (main protease of SARS-CoV-2), TLR4 and PREP (Prolyl Oligopeptidases) by using the molecular docking and dynamics approach. Dithymoquinone (DTQ) analogues were designed in order to investigate the effect of different chemical groups on its bioactivity. It is noteworthy to mention that attention was given to the feasibility of synthesizing these analogues by a simple photo-dimerisation reaction. The DTQ analogue containing the 4-fluoroaniline moiety [Compound (4)] was selected for further analysis by molecular dynamics after screening via docking-interaction analyses. A YASARA structure tool built on the AMBER14 force field was used to analyze the 100 ns trajectory by taking 400 snapshots after every 250 ps. Moreover, RMSD, RoG, potential energy plots were successfully obtained for each interaction. Molecular docking results indicated strong interaction of compound (4) with 3CL^pro, TLR4 and PREP with a binding energy of −8.5 kcal/mol, −10.8 kcal/mol and −9.5 kcal/mol, respectively, which is better than other DTQ-analogues and control compounds. In addition, compound (4) did not violate Lipinski’s rule and showed no toxicity. Moreover, molecular dynamic analyses revealed that the complex of compound (4) with target proteins was stable during the 100 ns trajectory. Overall, the results predicted that compound (4) could be developed into a potent anti-COVID agent with the ability to mitigate neurological manifestations associated with COVID-19. Full article

Kefir, a symbiotic consortium of diverse bacteria and yeasts, is one of the most popular probiotic foods on the market. Its consumption has been referred to as beneficial in human skin health, namely in the reinforcement of skin’s barrier function. This benefit likely results from the productive activity of lactic acid bacteria during kefir fermentation. Lactic acid is naturally present in the skin, and actively contributes to epidermal water dynamics and “barrier.” Few studies have been conducted regarding the impact of probiotic consumption in human epidermal water homeostasis. Therefore, this study was designed to explore the impact of the regular consumption of kefir on the skin water dynamics in a group of participants with healthy skin. Participants (n = 27) were healthy female volunteers from whom twelve consumed 100 mL of kefir every day for eight weeks as part of their diet. The remaining (untreated) participants served as the control group. Epidermal water balance was assessed by measuring transepidermal water loss (TEWL) and stratum corneum (SC) hydration on three different occasions—at baseline (T0), after four weeks (T4) and after eight weeks (T8) of interventive kefir consumption. Our study revealed a significant reduction in TEWL (p = 0.043) in the kefir group after eight weeks of regular consumption. In the same period, no differences were found for TEWL in the control group (p = 0.997). Regarding hydration, skin dryness was progressive in the control group, with a significant reduction in SC hydration (p = 0.002) at T8 in comparison to T0. In the kefir group, SC hydration was preserved between T0 and T8 (p = 0.997), which we believe to be related to epidermal “barrier” reinforcement. Our study seems to confirm that the regular consumption of kefir does improve cutaneous water balance even in healthy skin. Full article

Distal symmetrical polyneuropathy (DSPN) is a serious complication of diabetes associated with significant disability and mortality. Although more than 50% of people with diabetes develop DSPN, its pathogenesis is still relatively unknown. This lack of understanding has limited the development of novel disease-modifying therapies and left the reasons for failed therapies uncertain, which is critical given that current management strategies often fail to achieve long-term efficacy. In this article, the pathogenesis of DSPN is reviewed, covering pathogenic changes in the peripheral nervous system, microvasculature and central nervous system (CNS). Furthermore, the successes and limitations of current therapies are discussed, and potential therapeutic targets are proposed. Recent findings on its pathogenesis have called the definition of DSPN into question and transformed the disease model, paving the way for new research prospects. Full article

Patients with incomplete spinal cord injury have decreased mobility, and many do not recover walking ability. The purpose of this study was to investigate rectus femoris muscle thickness and echo intensity on ultrasound and functional outcomes in these patients. This was a prospective cohort study in an inpatient rehabilitation center, which recruited 40 consecutive patients with incomplete spinal cord injury. The patients underwent an ultrasound assessment at 6 weeks post-injury. Ultrasound measurements were performed using B-mode ultrasound scanning and standardized protocols. Functional outcomes on discharge, including Lower Extremity Muscle Score (LEMS), Functional Independence Measure (FIM), and Walking Index for Spinal Cord Injury II (WISCI II), were measured. Rectus femoris muscle thickness was significantly correlated with discharge LEMS (Spearman’s rho = 0.448; p = 0.004), FIM motor subscale (Spearman’s rho = 0.595; p < 0.001), FIM walk subscale (Spearman’s rho = 0.621; p < 0.001) and WISCI II (Spearman’s rho = 0.531; p < 0.001). The rectus femoris echo intensity was also significantly correlated with discharge LEMS (Spearman’s rho = −0.345; p = 0.029), FIM motor subscale (Spearman’s rho = −0.413; p = 0.008), FIM walk subscale (Spearman’s rho = −0.352; p = 0.026), and WISCI II (Spearman’s rho = −0.355; p = 0.025). We report that a relationship exists between rectus femoris muscle ultrasonographic characteristics and muscle function and ambulatory outcomes after inpatient rehabilitation. Ultrasound muscle measurements are potentially useful in assessing muscle wasting and function in patients with spinal cord injury. Full article