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The effects of plant density and water stress on yield of Medicago sativa and Bromus tomentellus was studied. A greenhouse experiment was conducted at Isfahan University of Technology in 2013. The experiment included 18 treatments, three crop compositions (M.sativa, B. tomentellus or mixture of the two), two plant density levels, three watering regimes and four replicates, arranged in a completely randomized block design. Results showed that total yield of M. sativa mono-cropping was higher than mixed cropping and it was higher than B. tomentellus mono-cropping. Land Equivalent Ratio (LER) values were less than 1 for all mixed cropping treatments, indicated the interspecific competition in mixed cropping. The biomass production per plant decreased with increasing density, competition for resource utilization and water stress. Compare of above-ground and below-ground dry matter showed that M. sativa appeared to be more constrained by intraspecific than by interspecific competition, Conversely, B. tomentellus was more suppressed by interspecific competition exerted by M. sativa than by intraspecific competition. Relative competition intensity (RCI) values were positive for B. tomentellus and negative for M.sativa, implying that competitive ability of M.sativa was higher than B. tomentellus in mixed cropping .

Drylands occupied a large area of lands on Earth and a large percentage of the population are living in these areas. Land degradation or desertification is one of the biggest problems in arid zones. In general, little effort for mapping land degradation at regional to global scales has been made. Recent efforts to assess desertification in Iran led to devise the Iranian Model of Desertification Potential Assessment or IMDPA. In this article we intend to consider the concerns of international models of desertification, re-evaluate the Iranian Model of Desertification Potential Assessment in the East of Esfahan and Studies carried out on this model till now to review and to evaluate indicators of the soil, vegetation and erosion in the IMDPA. Our aim in this paper is to clarify many of the black spots of desertification in Iran, we're going to show where to start and what to expect on a study of desertification. In this study, water, soil and vegetation indicators and their indices in 172 homogeneous work units were assessed using the instruction of IMDPA, and the results were compared with a study done in the 90s. According to land degradation and desertification studies we propose a model as " Iranian Model of Desertification Status Assessment " or IMDSA be created in which the three indicators of land degradation, namely the degradation of soil, vegetation and water can be used on it. According to our study, to indicate soil degradation state, the four indices of Tillage Pan, Infiltration, Aggregate Size Distribution and Score of EC and to evaluate vegetation degradation status, the four indices of Alien Invasive or proliferous weed species, Biomass decline, Bare Spots, and proportion of useful species for use in the Iranian Model of Desertification Status Assessment were appropriate.

Background and Objectives: Injury by sharp instruments and needles are major occupational health hazard for healthcare workers. This study was conducted to determine the prevalence rate and causes of injuries due to needle stick in healthcare workers in Zahedan University of Medical Sciences. Methods: In a cross-sectional study, 231 healthcare workers of university hospitals of Zahedan University of Medical Sciences were selected at random in 2007. Data were collected through questionnaire and were analyzed by SPSS 13. Results: From all cases 77.1% were female 56.4% of them were expert, and 50.7% were nurses. Their mean age were 34±8.1 years. Needle stick prevalence was 64.9% during the whole history of career, and 57.2% of them had experiences of needle stick more than twice. Most cases of injuries were related to using needle 55.4%, and they were mostly prone to injury during injection and phlebotomy, 55.6%. The multivariate regression analysis showed that injury due to sharp instruments in university graduates was 60% less compared to those with high school or less, and the injury risk increases 5% in each year of increase in working experience. Conclusions: The findings of this study highlight the importance of training and preventive measures in healthcare centers particularly among high risk group.

Background and aims: Escherichia coli are one of the important causes of diarrhea in children, adult and immune compromised ones in developing country. The aim of this study was to investigate the antibiotic resistance of E. coli isolated from gastroenteritis cases in Shahrekord county, in order to obtain a rapid and suitable treatment. Methods: In this descriptive analytical study, 234 fecal samples were collected from diarrheic patients during 2011-2012. Bacteriological and biochemical tests were used to identify E. coli. Antibiotic resistance of the isolates was assessed by disk diffusion method. Results: The results showed that the minimal resistance was to Gentamycin (0%) and the maximal resistance was for Trimethoprim (79.8%). The resistance for Sulfametoxazole, Ampicillin, Ciprofloxacin, Cefotaxime, Chloramphenicol, and Tetracycline were 71%, 52.6%, 10.5%, 7%, 3.5%, 3.5% respectively. Also the results revealed that the single, double, triple and tetraple antibiotic resistance among the isolates were 17.5%, 39.5%, 38.6% and 4.4% respectively. Conclusion: According to the results of this study Ciprofloxacin and Cefotaxime are suitable antibiotics for treatment of E. coli enteric infections in this area. [ABSTRACT FROM AUTHOR]

Introduction: Cancer, the second most prominent factor of mortality, contributes to approximately one-sixth of global fatalities. Regrettably, present chemotherapeutic agents employed in oncology harm healthy cells. Therefore, more effective and non-toxic compounds isolated from natural sources, such as phytochemicals with anticancer activities, need further investigation. In addition, in many studies, mesenchymal stem cells or the supernatant obtained from the culture of these cells have shown anticancer effects. This study aimed to examine the impact of the supernatant derived from the close vicinity of mesenchymal stem cells, which were exposed to varying concentrations of crocetin, on the viability of B16F10 cancer cells in an in vitro environment., Methods and Materials: At first, the process of isolating mesenchymal stem cells from the bone marrow tissue of a mouse femur was carried out. Subsequently, these cells were then cultured, and their mesenchymal nature was confirmed. Subsequently, these cells were co-cultured with varying concentrations of crocetin plant extracts in distinct plates. Afterward, the resulting supernatant (conditioned media) acquired from this condition was used to treat B16F10 cancer cells cultured in separate plates. Finally, the survival rate of B16F9 cancer cells was assessed through the MTT test. The obtained data was evaluated with the aid of Prism and SPSS software., Results: For the first time, the results demonstrated that the administration of the conditioned media derived from the co-culture of mesenchymal stem cells with crocetin significantly reduces the viability of B16F10 cancer cells., Conclusion and Discussion: Our findings indicate that the conditioned media obtained from the co-culture of mesenchymal stem cells and the compound known as crocetin, in a concentration-dependent manner, can be considered a viable therapeutic adjunct to enhance the body's antitumor reactions in the treatment of patients suffering from B16F10 cancer.

Purpose: The objective of this study is to validate a novel workflow for implementing patient-specific finite element (FE) simulations to virtually replicate the Transcatheter Aortic Valve Implantation (TAVI) procedure., Methods: Seven patients undergoing TAVI were enrolled. Patient-specific anatomical models were reconstructed from pre-operative computed tomography (CT) scans and subsequentially discretized, considering the native aortic leaflets and calcifications. Moreover, high-fidelity models of CoreValve Evolut R and Acurate Neo2 valves were built. To determine the most suitable material properties for the two stents, an accurate calibration process was undertaken. This involved conducting crimping simulations and fine-tuning Nitinol parameters to fit experimental force-diameter curves. Subsequently, FE simulations of TAVI procedures were conducted. To validate the reliability of the implemented implantation simulations, qualitative and quantitative comparisons with post-operative clinical data, such as angiographies and CT scans, were performed., Results: For both devices, the simulation curves closely matched the experimental data, indicating successful validation of the valves mechanical behaviour. An accurate qualitative superimposition with both angiographies and CTs was evident, proving the reliability of the simulated implantation. Furthermore, a mean percentage difference of 1,79 ± 0,93 % and 3,67 ± 2,73 % between the simulated and segmented final configurations of the stents was calculated in terms of orifice area and eccentricity, respectively., Conclusion: This study shows the successful validation of TAVI simulations in patient-specific anatomies, offering a valuable tool to optimize patients care through personalized pre-operative planning. A systematic approach for the validation is presented, laying the groundwork for enhanced predictive modeling in clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Central nervous system (CNS) disorders are one of the leading health problems today, accounting for a large proportion of global morbidity and mortality. Most these disorders are characterized by high levels of oxidative stress and intense inflammatory responses in degenerated neuronal tissues. While extensive research has been conducted on CNS diseases, but few breakthroughs have been made in treatment methods. To date, there are no disease-modifying drugs available for CNS treatment, underscoring the urgent need for finding effective medications. Bee venom (BV), which is produced by honeybee workers' stingers, has been a subject of interest and study across various cultures. Over the past few decades, extensive research has focused on BV and its therapeutic potentials. BV consists a variety of substances, mainly proteins and peptides like melittin and phospholipase A2 (PLA2). Research has proven that BV is effective in various medical conditions, including pain, arthritis and inflammation and CNS disorders such as Multiple sclerosis, Alzheimer's disease and Parkinson's disease. This review provides a comprehensive overview of the existing knowledge concerning the therapeutic effects of BV and its primary compounds on various CNS diseases. Additionally, we aim to shed light on the potential cellular and molecular mechanisms underlying these effects., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

SpikoGen® COVID-19 vaccine is based on the spike protein extracellular domain of the ancestral Wuhan-Hu-1 strain modified by removal of the furin cleavage site and addition of stabilising mutations expressed as a recombinant protein in insect cells. It is formulated with Advax-CpG55.2™ adjuvant to ensure optimal immunogenicity. In this study, data from several SpikoGen® clinical trials was retrospectively analysed to assess for any effect of gender or age on seroconversion, neutralizing antibody levels or the incidence of adverse events. Following the 1st dose, older age was associated with a reduced rate of fatigue (RR 0.97, p < 0.001), headache (RR 0.98, p = 0.034) and myalgia (RR 0.97, p=0.016), following the 2nd dose, the rate of fatigue (RR 0.98, p = 0.017) but following the 3rd dose no effect of age on adverse events was evident. Similarly, following the 1st dose, men reported a 19% lower incidence of fatigue, 36% lower incidence of headache and 28% lower incidence of myalgia when compared to women. Interestingly, there was no relationship between age or gender and serum neutralizing antibody levels, although after each vaccine dose there was a consistent trend to women having a higher seroconversion rate. There was no correlation between neutralizing antibody levels and adverse events. Unlike what is seen with mRNA vaccines, reactogenicity trended lower after each subsequent SpikoGen® dose. Overall, SpikoGen® exhibited positive immunogenicity and low reactogenicity, indicating that a low incidence of adverse events does not equate to poor immunogenicity. SpikoGen® remains a promising protein-based vaccine platform for COVID-19 protection., (© 2024. The Author(s).)

Background: Regarding adjustments to warfarin dosage, numerous studies have shown that computerized methods are superior to those based on personal experience., Objectives: To report the efficacy of a computer-based warfarin management system (WMS) in the Iranian population., Methods: By utilizing the existing dosing algorithms and obtaining expert opinions, we developed a computer-based WMS at a large tertiary cardiovascular center. The time in therapeutic range and the number of international normalized ratio (INR) tests of clinic patients were compared before and after the implementation of WMS., Results: Overall, 803 patients with 5407 INR tests were included in the before phase and 679 patients with 4189 INR tests in the after phase. The mean time in therapeutic range was 57.3% before and 59% after WMS implementation [mean difference, 1.64; 95% confidence interval (CI), -1.12-4.40]. In the before phase, the mean number of INR tests was 6.7, which dropped to 6.1 tests in the after phase (mean difference, -0.61; 95% CI, -0.97 to -0.24). Only 54.5% of the warfarin dosing prescriptions were consistent with the dosing recommendations of the WMS, and adherence to the WMS was poorest in the highest INR target range., Conclusions: For the first time in Iran, we demonstrated that a computerized system was as effective as a traditional experience-based method to monitor INR in VKA-anticoagulated patients. Furthermore, it could reduce both the number of INR tests and that of visits., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) with inflammation and immune dysfunction., Objectives: We compared the remyelination and immunomodulation properties of mesenchymal stem cells (MSCs) with their conditioned medium (CM) in the cuprizone model., Methods: Twenty-four C57BL/ 6 mice were divided into four groups. After cuprizone demyelination, MSCs and their CM were injected into the right lateral ventricle of mice. The expression level of IL-1β, TNF-α, and BDNF genes was evaluated using the qRT-PCR. APC antibody was used to assess the oligodendrocyte population using the immunofluorescent method. The remyelination and axonal repair were studied by specific staining of the LFB and electron microscopy techniques., Results: Transplantation of MSCs and CM increased the expression of the BDNF gene and decreased the expression of IL-1β and TNF-α genes compared to the cuprizone group, and these effects in the cell group were more than CM. Furthermore, cell transplantation resulted in a significant improvement in myelination and axonal repair, which was measured by luxol fast blue and transmission electron microscope images. The cell group had a higher number of oligodendrocytes than other groups., Conclusions: According to the findings, injecting MSCs intraventricularly versus cell-conditioned medium can be a more effective approach to improving chronic demyelination in degenerative diseases like MS., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by inflammation and demyelination of CNS neurons. Up to now, there are many therapeutic strategies for MS but they are only being able to reduce progression of diseases and have not got any effect on repair and remyelination. Stem cell therapy is an appropriate method for regeneration but has limitations and problems. So recently, researches were used of exosomes that facilitate intercellular communication and transfer cell-to-cell biological information. MicroRNAs (miRNAs) are a class of short non-coding RNAs that we can used to their dysregulation in order to diseases diagnosis. The miRNAs of microvesicles obtained stem cells may change the fate of transplanted cells based on received signals of injured regions. The miRNAs existing in MSCs may be displayed the cell type and their biological activities. Current studies show also that the miRNAs create communication between stem cells and tissue-injured cells. In the present review, firstly we discuss the role of miRNAs dysregulation in MS patients and miRNAs expression by stem cells. Finally, in this study was confirmed the relationship of microRNAs involved in MS and miRNAs expressed by stem cells and interaction between them in order to find appropriate treatment methods in future for limit to disability progression., (© 2024. The Author(s).)

Introduction: We aimed to investigate the association between cardiovascular disease (CVD) and various anthropometric indices, as well as the serum levels of copper (Cu) and zinc (Zn), copper-zinc ratio (Cu/Zn ratio) and zinc-copper ratio (Zn/Cu ratio), in a large population sample from northeastern Iranian., Method: 9704 individuals aged 35 to 65 were enrolled in the first phase of the study. After a 10-year follow-up, 7560 participants were enrolled into the second phase. The variables used in this study included demographic characteristics, such as gender and age; biochemical parameters including: serum Zn, Cu, Cu/Zn ratio, and Zn/Cu ratio; anthropometric parameters including: waist circumference (WC), body mass index (BMI), and waist-to-hip ratio (WHR). The relationship between the aforementioned indices and CVD was examined using decision tree (DT) and logistic regression (LR) models., Results: A total of 837 individuals were diagnosed with CVD among the 7560 participants. LR analysis showed that BMI, age, WH zinc-copper ratio (Zn/Cu ratio), and serum Zn/Cu ratio were significantly associated the development of CVD in men, and WHR, age, BMI, serum Cu, and Cu/Zn ratio in women. DT analysis showed that, age was the most important predictor of CVD in both genders. 71% of women, older than 49 years, with a WHR≥ 0.89, serum Cu< 75 (µg/dl), BMI≥ 22.93 (kg/m 2 ), and serum Cu≥ 14 (µg/dl), had the highest risk of CVD. In men, among those who were ≥ 53 years, with a WHR≥ 0.98, serum Zn/Cu ratio< 1.69, and BMI≥ 22.30, had the highest risk of CVD., Conclusion: Among Iranian adult population, BMI, age, and WHR were one of the predictors of CVD for both genders. The Zn/Cu ratio was CVD predictor for men while Cu/Zn ratio was CVD predictor for women., Competing Interests: Declaration of Competing Interest The authors confirm no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Exosomes are nano-sized membrane extracellular vesicles which can be released from various types of cells. Exosomes originating from inflammatory or injured cells can have detrimental effects on recipient cells, while exosomes derived from stem cells not only facilitate the repair and regeneration of damaged tissues but also inhibit inflammation and provide protective effects against various diseases, suggesting they may serve as an alternative strategy of stem cells transplantation. Exosomes have a fundamental role in communication between cells, through the transfer of proteins, bioactive lipids and nucleic acids (like miRNAs and mRNAs) between cells. This transfer significantly impacts both the physiological and pathological functions of recipient cells. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor, is able to mitigate damage caused by oxidative stress and inflammation through various signaling pathways. The positive effects resulting from the activation of the Nrf2 signaling pathway in different disorders have been documented in various types of literature. Studies have confirmed that exosomes derived from stem cells could act as Nrf2 effective agonists. However, limited studies have explored the Nrf2 role in the therapeutic effects of stem cell-derived exosomes. This review provides a comprehensive overview of the existing knowledge concerning the role of Nrf2 signaling pathways in the impact exerted by stem cell exosomes in some common diseases., (© 2024. The Author(s).)

One of the major causes of long-term disability and mortality is ischemic stroke that enjoys limited treatment approaches. On the one hand, oxidative stress, induced by excessive generation of reactive oxygen species (ROS), plays a critical role in post-stroke inflammatory response. Increased ROS generation is one of the basic factors in the progression of stroke-induced neuroinflammation. Moreover, intravenous (IV) thrombolysis using recombinant tissue plasminogen activator (rtPA) as the only medication approved for patients with acute ischemic stroke who suffer from some clinical restrictions it could not cover the complicated episodes that happen after stroke. Thus, identifying novel therapeutic targets is crucial for successful preparation of new medicines. Recent evidence indicates that the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) contributes significantly to regulating the antioxidant production in cytosol, which causes antiinflammatory effects on neurons. New findings have shown a relationship between activation of the Nrf2 and glial cells, nuclear factor kappa B (NF-κB) pathway, the nucleotide-binding domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling, and expression of inflammatory markers, suggesting induction of Nrf2 activation can represent a promising therapeutic alternative as the modulators of Nrf2 dependent pathways for targeting inflammatory responses in neural tissue. Hence, this review addresses the relationship of Nrf2 signaling with inflammation and Nrf2 activators' potential as therapeutic agents. This review helps to improve required knowledge for focused therapy and the creation of modern and improved treatment choices for patients with ischemic stroke., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: SpikoGen® is a recombinant subunit spike protein ectodomain vaccine manufactured in insect cells and formulated with the novel polysaccharide-based Advax-CpG55.2 adjuvant. This study aimed to compare the immunogenicity and safety of SpikoGen® vaccine in children, adolescents and young adults., Methods: This was a non-randomized, three-arm, open-label, parallel-group, immuno-bridging, non-inferiority trial to compare the immunogenicity and safety of a primary course of two intramuscular doses of SpikoGen® vaccine in children aged 5 to < 12 years, adolescents aged 12 to < 18 years and young adults aged 18 to 40 years. Children 5-12 years received a half dose of 12.5 μg spike protein, whereas the other groups received the full vaccine dose. Vaccine immunogenicity was evaluated via assessment of serum anti-spike and neutralizing antibodies 14 days after the second dose. Solicited adverse events were recorded for 7 days after each vaccination. Safety assessments including serious adverse events were continued through six months after the second dose in children and adolescents., Results: Two weeks after the second dose, seroconversion rates for neutralizing antibody levels were not significantly different for children (59.50 %), adolescents (52.06 %) and adults (56.01 %). The 95 % confidence interval of the difference in seroconversion rates between children and adults was within the prespecified non-inferiority margin of 10 % (-12 % to 5 %). SpikoGen® vaccine was well tolerated in all age groups with the most common solicited adverse events being injection site pain and fatigue which were generally transient and mild., Conclusion: SpikoGen® vaccine was shown to be safe, well tolerated and immunogenic in children as young as 5 years of age, with non-inferior responses to those seen in adults. The Iranian FDA authorisation of SpikoGen® vaccine is now extended down to 5 years of age., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Polycystic ovary syndrome is the most common cause of oligo-ovulation and anovulation among women of reproductive age, contributing to infertility. This study aimed to compare the effects of green tea tablets and metformin on ovulation, menstrual cycle regularity, and antioxidant biomarkers in women with polycystic ovary syndrome (PCOS). In this clinical trial study, 94 women with PCOS were randomly assigned to three groups: green tea ( n = 33), metformin ( n = 29), and control ( n = 32). Menstrual status and oxidative stress parameters, including total antioxidant capacity, thiol, and lipid peroxidation, were compared before and 3 months after the intervention among all three groups. Data analysis was conducted using SPSS software version 22 and employing the analysis of variance and paired t-tests. Following the intervention, the mean menstrual cycle duration in the green tea, metformin, and control groups was 32.22 ± 12.78, 48.72 ± 37.06, and 48.53 ± 31.04 days, respectively ( P = 0.040). There was no statistically significant difference between the three groups in terms of biochemical, hormonal, and antioxidant indices before and after the intervention ( P > 0.05). The intake of green tea tablets was associated with better outcomes in regulating the menstrual cycle in women with PCOS., Competing Interests: The authors declare no conflict of interest., (© 2024 by the authors.)

The circadian clock consists of a hierarchical multi-oscillator network of intracellular and intercellular mechanisms throughout the body that contributes to anticipating metabolic activity and maintaining system homeostasis in response to environmental cues and intrinsic stimuli. Over the past few years, genetic variations of core clock genes have been associated with cancer risk in several epidemiological studies. A growing number of epidemiological research studies have demonstrated a direct correlation between the disturbance of circadian rhythms and the growth of tumors, indicating that shift workers are more susceptible to malignancies of the colon, prostate, ovarian, breast, lung, and liver. One of the most related cancers with circadian rhythm is Gastrointestinal (GI) cancer, which is a leading cause of cancer-related mortality nowadays. The aim of this review was to demonstrate the effect of the clock gene network on the growth of GI cancer, providing molecular targets for GI cancer treatment, possible prognostic biomarkers, and guidance for treatment choices., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Loss of nervous system tissue after severe brain injury is a main determinant of poor functional recovery. Cell transplantation is a promising method to restore lost tissue and function, yet it remains unclear if transplanted neurons can demonstrate the population level dynamics important for movement control. Here we present a comprehensive approach for long-term single neuron monitoring and manipulation of transplanted embryonic cortical neurons after cortical injury in adult male mice performing a prehension task. The observed patterns of population activity in the transplanted network strongly resembled that of healthy networks. Specifically, the task-related spatiotemporal activity patterns of transplanted neurons could be represented by latent factors that evolve within a low dimensional manifold. We also demonstrate reliable modulation of the transplanted networks using minimally invasive epidural stimulation. Our approach may allow greater insight into how restoration of cell-type specific network dynamics in vivo can restore motor function., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Tocilizumab and baricitinib are considered standard treatments for hospitalized COVID-19 patients with an inflammatory status. However, the effects of co-administering these medications aiming for more rapid patient recovery are controversial among practitioners. The potential benefits include the rapid improvement of patients and regulation of the immune system, and the potential risks include the increased chance of serious adverse events, including infections. This study aimed to investigate the effects of co-administering these two medications on the 28-day mortality rate, other efficacy parameters, and safety issues. Methods: In this randomized open-label trial, 68 patients were recruited. The study was conducted at Dr. Masih Daneshvari Hospital during 6 months (from 21 March 2022 to 23 August 2022). Severely ill patients aged between 18 and 100 years old with confirmed COVID-19 were enrolled. The primary outcomes included the need for invasive mechanical ventilation and a 28-day mortality rate. Secondary outcomes included the need for non-invasive mechanical ventilation, the need for admission to the intensive care unit (ICU), the length of hospital stay, and the need for a second dose of tocilizumab. Safety assessments were also performed for 28 days. The data were collected from the patients' medical records, which included age, gender, and comorbidities. Results: The 28-day mortality rate or the need for mechanical ventilation was not statistically different among the two groups ( p -value = 0.49 for both outcomes). The need for non-invasive mechanical ventilation, the need for admission to the ICU, or the need for a second dose of tocilizumab and the length of hospital stay was not affected either ( p -value = 1; 0.1; 0.49 and 0.9, respectively). One patient developed thrombosis in the combination group. No adverse events related to infectious complications were recorded in any groups. Conclusion: This study showed no beneficial effects of combining tocilizumab and baricitinib in managing severe COVID-19 cases. However, the need for ICU admission was meaningfully lower in the combination group. Studies with larger sample sizes are needed to confirm these results. Clinical Trial Registration: Identifier: RCT20151227025726N30M., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dastan, Jamaati, Barati, Varmazyar, Yousefian, Niknami and Tabarsi.)

Background: Resistance to artemisinin has threatened major achievements in malaria control, more investigations is needed about resistant strains and related genes. We aimed to induce resistance to artesunate in the Plasmodium falciparum 3D7 strain using intermittent exposure method and comparing P.fk13 gene sequence between susceptible and resistance strains., Methods: P. falciparum 3D7 strain was cultured according to Trager & Jensen method with some modifications. Serial concentrations between 10 -2 mol/l, to 10 -7 mol/l were prepared, then P. falciparum 3D7 was exposed to each of the dilution to determine IC50 and lethal dose. Sensitivity reduction process was started from the concentration of 10 -7 mol/l and ended at 10 -2 mol/l. Exposed parasites were collected after at least 27 days after cultivation in each drug concentration. DNA extraction, PCR and sequencing process were performed to investigate any possible mutations in the P.fk13 gene sequence., Results: Effectiveness of 10-2mol/l concentration of artemisinin was found as a lethal dose. IC50 value was equal to 5×10 -4 mol/l. The resistant strain was provided in the lab, sequenced and registered in the gene bank as P.f Art -2 , (accession number MH796123. 1). Alignment of this registered sample showed no mutation in P.f kelch13 gene in comparison with standard strain submitted in the GenBank., Conclusion: Resistance to artesunate in malaria parasite may occur but with no mutation in the P.f kelch13 gene. Therefore, whole genome sequencing should be applied to determine mutations in resistant strains., Competing Interests: Conflict of interest All authors of this manuscript declare no conflict of interest., (© 2023 Barati et al. Published by Tehran University of Medical Sciences.)

SpikoGen® vaccine is a subunit COVID-19 vaccine expressed in insect cells comprising recombinant spike protein extracellular domain formulated with Advax-CpG55.2™ adjuvant. A Phase 2 trial was conducted in 400 adult participants randomised 3:1 to receive two intramuscular doses of SpikoGen® vaccine or saline placebo 3 weeks apart. Some Phase 2 trial participants later enrolled in a separate booster study and received a third dose of SpikoGen® vaccine. This stored serum was used to assess the ability of SpikoGen® vaccine to induce cross-neutralising antibodies against SARS-CoV-2 variants of concern. Sera taken at baseline and 2 weeks after the second vaccine dose from baseline seronegative Phase 2 subjects was evaluated using a panel of spike pseudotype lentivirus neutralisation assays for the ability to cross-neutralise a wide range of SARS-CoV-2 variants, including Omicron BA.1, BA.2 and BA.4/5. Stored samples of subjects who participated in both the 2-dose Phase 2 trial and a third dose booster trial 6 months later were also analysed for changes in cross-neutralising antibodies over time and dose. Two weeks after the second dose, sera broadly cross-neutralised most variants of concern, albeit with titres against Omicron variants being ~10-fold lower. While Omicron titres fell to low levels 6 months after the second vaccine dose in most subjects, they showed a ~20-fold rise after the third dose booster, after which there was only a ~2-3-fold difference in neutralisation of Omicron and the ancestral strains. Despite being based on the ancestral Wuhan sequence, after two doses, SpikoGen® vaccine induced broadly cross-neutralising serum antibodies. Titres then reduced over time but were rapidly restored by a third dose booster. This resulted in high neutralisation including against the Omicron variants. This data supports ongoing use of SpikoGen® vaccine for protection against recent SARS-CoV-2 Omicron variants., (© 2023 John Wiley & Sons Ltd.)

To determine what actions to perform in each context, animals must learn how to execute motor programs in response to sensory cues. In rodents, the interface between sensory processing and motor planning occurs in the secondary motor cortex (M2). Here, we investigate dynamics in vasointestinal peptide (VIP) and somatostatin (SST) interneurons in M2 during acquisition of a cue-based, reach-to-grasp (RTG) task in mice. We observe the emergence of preparatory activity consisting of sensory responses and ramping activation in a subset of VIP interneurons during motor learning. We show that preparatory and movement activities in VIP neurons exhibit compartmentalized dynamics, with principal component 1 (PC1) and PC2 reflecting primarily movement and preparatory activity, respectively. In contrast, we observe later and more synchronous activation of SST neurons during the movement epoch with learning. Our results reveal how VIP population dynamics might support sensorimotor learning and compartmentalization of sensory processing and movement execution., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Microglia are the primary immune cells of the central nervous system (CNS) that comprise about 5-12% of all cells in the brain. These cells are the first line of defense that protects the CNS from damage and attacking pathogens. Microglia originate from yolk sac macrophages and migrate to the brain before the blood-brain barrier formation. Microglia show key roles in healthy CNS including promoting neurogenesis, synaptic sculpting, and maintaining homeostasis but in pathological conditions of CNS, microglial activation may exacerbate diseases. Thus, microglial depletion of the CNS is a novel approach that could be a useful tool to understand the microglial functions in neurodegenerative and neuroinflammatory diseases. There are methods for microglial ablation and reduction such as genetic tools and pharmacological inhibitors. In this study, we review recent studies that used different microglial ablation models for microglial reduction and repopulation after depletion in pathological states of CNS. Recently, studies showed that microglial depletion as a potential therapeutic application has benefits (such as inflammatory factors reduction, increase synaptogenesis, astrogliosis preventation) in CNS. For these reasons, the inhibition of microglia with these models was considered a therapeutic approach for neurodegenerative disease treatment., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with high mortality and morbidity rate affecting both upper and lower motor neurons (MN). Muscle force reduction, behavioral change, pseudobulbar affect, and cognitive impairments are the most common clinical manifestations of ALS. The main physiopathology of ALS is still unclear, though several studies have identified that oxidative stress, proteinopathies, glutamate-related excitotoxicity, microglial activation, and neuroinflammation may be involved in the pathogenesis of ALS. From 1995 until October 2022, only Riluzole, Dextromethorphan Hydrobromide (DH) with Quinidine sulfate (Q), Edaravone, and Sodium phenylbutyrate with Taurursodiol (PB/TUDCO) have achieved FDA approval for ALS treatment. Despite the use of these four approved agents, the survival rate and quality of life of ALS patients are still low. Thus, finding novel treatments for ALS patients is an urgent requirement. Masitinib, a tyrosine kinase inhibitor, emphasizes the neuro-inflammatory activity of ALS by targeting macrophages, mast cells, and microglia cells. Masitinib downregulates the proinflammatory cytokines, indirectly reduces inflammation, and induces neuroprotection. Also, it was effective in phase 2/3 and 3 clinical trials (CTs) by increasing overall survival and delaying motor, bulbar, and respiratory function deterioration. This review describes the pathophysiology of ALS, focusing on Masitinib's mechanism of action and explaining why Masitinib could be a promising actor in the treatment of ALS patients. In addition, Masitinib CTs and other competitor drugs in phase 3 CTs have been discussed., Competing Interests: Conflict of interest statement Authors declare no financial and non-financial conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: As February 2023, SARS-CoV-2 is still infecting people and children worldwide. Cough and dyspnea are annoying symptoms almost present in a large proportion of COVID-19 outpatients, and the duration of these symptoms might be long enough to affect the patients' quality of life. Studies have shown positive effects for noscapine plus licorice in the previous COVID-19 trials. This study aimed to assess the effects of the combination of noscapine and licorice-for relieving cough in outpatients with COVID-19. Methods: This randomized controlled trial was conducted on 124 patients at the Dr. Masih Daneshvari Hospital. Participants over 18 years of age with confirmed COVID-19 and cough were allowed to enter the study if the onset of symptoms was less than 5 days. The primary outcome was to assess the response to treatment over 5 days using the visual analogue scale. Secondary outcomes included the assessment of cough severity after 5 days using Cough Symptom Score, as well as the cough-related quality of life and dyspnea relieving. Patients in the noscapine plus licorice group received Noscough ® syrup 20 mL every 6 h for 5 days. The control group received diphenhydramine elixir 7 mL every 8 h. Results: By day five, 53 (85.48%) patients in the Noscough ® group and 49 (79.03%) patients in the diphenhydramine group had response to treatment. This difference was not statistically significant ( p -value = 0.34). The presence of dyspnea was significantly lower in the Noscough ® group versus diphenhydramine at day five (1.61% in the Noscough ® group vs. 12.9% in the diphenhydramine group; p -value = 0.03). The cough-related quality of life and severity also significantly favored Noscough ® syrup ( p -values <0.001). Conclusion: Noscapine plus licorice syrup was slightly superior to diphenhydramine in relieving cough symptoms and dyspnea in the COVID-19 outpatients. The severity of cough and cough-related quality of life were also significantly better in the noscapine plus licorice syrup. Noscapine plus licorice may be a valuable treatment in relieving cough in COVID-19 outpatients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Barati, Feizabadi, Khalaj, Sheikhzadeh, Jamaati, Farajidavar and Dastan.)

TP53 is the most frequently mutated gene in human cancer. It encodes the tumor suppressor protein p53, which suppresses tumorigenesis by acting as a critical transcription factor that can induce the expression of many genes controlling a plethora of fundamental cellular processes, including cell cycle progression, survival, apoptosis, and DNA repair. Missense mutations are the most frequent type of mutations in the TP53 gene. While these can have variable effects, they typically impair p53 function in a dominant-negative manner, thereby altering intra-cellular signaling pathways and promoting cancer development. Additionally, it is becoming increasingly apparent that p53 mutations also have non-cell autonomous effects that influence the tumor microenvironment (TME). The TME is a complex and heterogeneous milieu composed of both malignant and non-malignant cells, including cancer-associated fibroblasts (CAFs), adipocytes, pericytes, different immune cell types, such as tumor-associated macrophages (TAMs) and T and B lymphocytes, as well as lymphatic and blood vessels and extracellular matrix (ECM). Recently, a large body of evidence has demonstrated that various types of p53 mutations directly affect TME. They fine-tune the inflammatory TME and cell fate reprogramming, which affect cancer progression. Notably, re-educating the p53 signaling pathway in the TME may be an effective therapeutic strategy in combating cancer. Therefore, it is timely to here review the recent advances in our understanding of how TP53 mutations impact the fate of cancer cells by reshaping the TME., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The symptoms of pulmonary sarcoidosis may lead to fatigue, excessive daytime sleepiness, poor sleep quality, and a decrease in quality of life in these patients., Objectives: This study was designed to evaluate the effects of oral melatonin on sleep disorders of patients with pulmonary sarcoidosis., Methods: A randomized, single-blinded clinical trial was conducted on patients with pulmonary sarcoidosis. Eligible patients were randomly allocated into melatonin and control groups. Patients in the melatonin group were given 3 mg melatonin one hour before bedtime for three months. Sleep quality, daytime sleepiness, fatigue status, and quality of life were assessed applying General Sleep Disturbance Scale (GSDS), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Fatigue Assessment Scale (FAS), and the Patient-Reported Outcomes Measurement Information System (PROMIS), respectively, as well as the 12-item Short Form Survey (SF-12) scores at the baseline and three months after treatment., Results: There was a significant change in the GSDS (P < 0.001), PSQI (P < 0.001), ESS (P = 0.002), and FAS (P < 0.001) scores, which were decreased, compared to those of the control group. After intervention¸ global physical health and global mental health raw scores were improved comparing to the control group (P = 0.006, P = 0.02, respectively). The 12-item Short Form Survey evaluation showed that there was a significant difference between the melatonin (3.38 ± 4.61) and control (0.55 ± 7.25) groups in PCS-12 score after three months of therapy (P = 0.02)., Conclusions: Our findings showed that supplemental melatonin could significantly improve sleep problems, quality of life, and excessive daytime sleepiness in sarcoidosis patients., Competing Interests: Conflict of Interests: The authors have no conflict of interests., (Copyright © 2023, Author(s).)

Background and Aim: Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by the obstruction of the main pulmonary artery due to thrombosis and vascular remodeling. Regarding the need for anticoagulant therapy in CTEPH patients, this study aimed to compare rivaroxaban with warfarin in terms of its efficacy and safety in patients undergoing endarterectomy surgery., Methods: The study was a parallel clinical trial in patients who underwent endarterectomy following CTEPH. A total of 96 patients were randomly selected and assigned to two groups: warfarin-treated (control) and rivaroxaban-treated (intervention). Patients were clinically assessed for re-thrombosis, re-admission, bleeding, and mortality in the first, third, and sixth months after surgery., Results: There was no significant difference in the occurrence of thrombosis between the two groups within the first, third-, and sixth-months post-surgery (p=0.52, 1, 0.38 respectively). Moreover, the mortality rate (p=0.9), bleeding rate (p=0.06), and re-admission rate (p=0.15) showed no significant differences between the two groups., Conclusion: Rivaroxaban may be as effective as warfarin in treating CTEPH patients after endarterectomy in the short term and can be used as an anticoagulant in these patients. However, studies with long-term follow-ups are needed to consolidate the strategy of treating these patients with rivaroxaban., (Copyright © 2022 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objectives: We sought to investigate the efficacy and safety of SpikoGen®, a subunit coronavirus disease 2019 (COVID-19) vaccine composed of a recombinant severe acute respiratory syndrome coronavirus 2 spike protein with Advax-CpG55.2™ adjuvant., Methods: This randomized, placebo-controlled, double-blind, phase 3 trial was conducted on 16 876 participants randomized (3:1) to receive two intramuscular doses of SpikoGen® or a saline placebo 21 days apart. The primary outcome was to assess the efficacy of SpikoGen® in preventing symptomatic COVID-19. Secondary outcomes included safety assessments and evaluation of SpikoGen® vaccine's efficacy in preventing severe COVID-19. The study aimed for 147 COVID-19 symptomatic cases., Results: Overall, 12 657 and 4219 participants were randomized to the SpikoGen® and placebo group and followed for a median of 55 days (interquartile range, 48-60 days) and 51 days (interquartile range, 46-58 days) after 14 days of the second dose, respectively. In the final per-protocol analysis, the number of COVID-19 cases was 247 of 9998 (2.4%) in the SpikoGen® group and 119 of 3069 (3.8%) in the placebo group. This equated to a vaccine efficacy of 43.99% (95% CI, 30.3-55.0%). The efficacy was calculated to be 44.22% (95% CI, 31.13-54.82%) among all participants who received both doses. From 2 weeks after the second dose, 5 of 9998 (0.05%) participants in the SpikoGen® group and 6 of 3069 (0.19%) participants in the placebo group developed severe COVID-19, equating to a vaccine efficacy against severe disease of 77.51% (95% CI, 26.3-93.1%). The SpikoGen® vaccine was well tolerated., Discussion: A 2-dose regimen of SpikoGen® reduced the rate of COVID-19 and severe disease in the wave of the Delta variant., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Purpose: Obstructive sleep apnea (OSA) is a common serious sleep disorder. Melatonin-based drugs such as agomelatine may have beneficial effects on patients with sleep disorders. This study aimed to evaluate agomelatine effects on polysomnography parameters in patients with OSA., Methods: In this randomized, parallel, and single-blind study, seventy patients 18 years of age or older with obstructive sleep apnea who were referred to the sleep clinic were evaluated. The patients were randomly assigned into agomelatine and control groups. Patients in the agomelatine group received 50 mg agomelatine, one hour before sleep, for three consecutive nights prior to the polysomnography test, while the patients in the control group did not receive agomelatine. Sleep test parameters were compared between the two groups., Results: Three parameters in the agomelatine versus control group showed significant differences. They were the median and interquartile range of the total sleep time, 397 [326.5-437.4] vs. 287.5 [184-393.1; p, 0.004] minuets, sleep efficiency percentage, 75.6 [71-87.4] vs. 65.1 [50.8-80.1; p, 0.005] and the wakening percentage, 7.5 [12.01-27.6] vs. 8.8[18.3-49; p, 0.004] agomelatine vs. control group. Other polysomnography parameters revealed no significant differences between the two groups., Conclusions: Agomelatine administration in patients with OSA may improve total sleep time, sleep efficiency percentage and the percentage of patients' awakening.

Purpose: Studies have found that immunocompromised patients have suboptimal responses to COVID-19 vaccines, leading to approval of a need for booster doses in this population. SpikoGen® is a subunit recombinant spike protein vaccine combined with Advax-CpG55.2™ adjuvant to protect against COVID-19. Previous clinical trials found this vaccine to be tolerable, immunogenic, and efficacious in reducing the risk of COVID-19, including severe disease. However, the effects of this vaccine have not been assessed in immunocompromised patients. This study sought to assess the immunogenicity and safety of the SpikoGen vaccine as a third booster dose in patients undergoing kidney transplant who were receiving immunosuppressive therapy and had received their primary vaccination based on an inactivated whole virus platform (Sinopharm)., Methods: This single-arm trial was performed with 43 patients undergoing kidney transplant. The participants received a single booster dose of the SpikoGen vaccine 1 to 3 months after primary vaccination with 2 doses of the Sinopharm vaccine. Immunogenicity assessments were performed at baseline and 30 days after the booster dose. The primary outcomes were seroconversion rates of anti-S 1 and surrogate virus neutralizing antibodies. Safety outcomes included the incidence of solicited and unsolicited adverse events in the 7 days and 1 month after the booster dose, respectively., Findings: The SpikoGen vaccine induced positive humoral and cellular responses 30 days after the booster dose in those patients who were seropositive or seronegative after 2 primary doses of the Sinopharm vaccine. Thirty days after the SpikoGen vaccine booster, seroconversion rates were 35.29% (95% CI, 19.75%-53.51%) to anti-S 1 and 29.41% (95% CI, 13.27%-46.57%) to surrogate neutralizing antibodies. The most common local and systemic reported solicited adverse events were injection site pain and fatigue, which were largely mild and transient. No serious adverse events were reported., Implications: A single booster dose of SpikoGen vaccine given 1 to 3 months after primary vaccination with 2 doses of Sinopharm vaccine induced positive humoral and cellular immune responses in immunosuppressed patients undergoing renal transplant, thereby achieving spike antibody levels predictive of protection. This study was performed as a single-center study, and it will be important for future large multicenter studies to extend these results to other immunocompromised patient groups., Competing Interests: Declaration of Interest SB, NA, HK, RSH, MB, and SK are members of the Orchid Pharmed medical department which is in collaboration with CinnaGen company with respect to conducting clinical trials. The remaining authors have no other relevant affiliations., (Copyright © 2022 Elsevier Inc. All rights reserved.)

SpikoGen® is a subunit recombinant spike protein vaccine combined with Advax-CpG55.2™ adjuvant. This COVID-19 vaccine was shown to be safe, immunogenic and efficacious in previous clinical trials. This study aimed to assess the safety and immunogenicity of SpikoGen® vaccine as a homologous and heterologous booster vaccination. This double-blind and randomized placebo-controlled (5:1) trial was performed on 300 already vaccinated participants. SpikoGen® or saline placebo was administered as a booster dose to participants who had received a full two-dose COVID-19 vaccination course. Immunogenicity assessments were done 14 days after the booster dose with the primary immunogenicity outcome seroconversion rate of neutralizing antibodies. Safety outcomes included the incidence of solicited adverse events up to 7 days after the booster dose. SpikoGen® vaccine induced a robust humoral response both as a homologous and heterologous booster, when compared to the placebo. At Day 14, seroconversion of neutralizing antibodies was 76% (95% confidence interval [CI]: 69%-82%) in the SpikoGen® group versus 3% (95% CI: 0%-13%) in the placebo group. The most common local and systemic reported adverse events were injection site pain and fatigue. No serious adverse events were reported. The SpikoGen®-booster induced cross-neutralization of other SARS-CoV-2 variants. Irrespective of the primary vaccine course received, SpikoGen® vaccine showed promising effects as both a homologous and heterologous booster dose. This vaccine also had a good safety profile with no vaccine-associated serious adverse events. On the basis of these results, SpikoGen® vaccine has been approved as a booster dose., (© 2022 John Wiley & Sons Ltd.)

Objective: We aimed to investigate the immunogenicity and safety of SpikoGen®, a subunit COVID-19 vaccine composed of a recombinant prefusion-stabilized SARS-CoV-2 spike protein combined with the Advax-CpG55.2™ adjuvant, in seronegative and seropositive populations as primary vaccination., Methods: This randomized, placebo-controlled, double-blind phase 2 trial was conducted on 400 participants randomized 3:1 to receive two doses of 25 μg of SpikoGen® 3 weeks apart or the placebo. The primary safety outcomes were the incidence of solicited adverse events up to 7 days after each dose and unsolicited adverse events up to 28 days after the second dose. The primary immunogenicity outcomes were seroconversion against the S 1 protein and the geometric mean concentration of S 1 antibodies by days 21 and 35., Results: The SpikoGen® vaccine was well tolerated and no serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, largely graded as mild and transient. By day 35 (2 weeks post second dose), the seroconversion rate against S 1 was 63.55 (95% CI: 57.81-69.01) in the SpikoGen® group versus 7.23 (95% CI: 2.7-15.07) in the placebo group. The geometric mean concentration of S 1 antibodies was 29.12 (95% CI: 24.32-34.87) in the SpikoGen® group versus 5.53 (95% CI: 4.39-6.97) in the placebo group. Previously infected seropositive volunteers showed a large SARS-CoV-2 humoral response after a single SpikoGen® dose., Discussion: SpikoGen® had an acceptable safety profile and induced promising humoral and cellular immune responses against SARS-CoV-2., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Spinal cord injury (SCI) is a traumatic injury with sensory and motor deficits that more than 1 million patients worldwide suffer from disability due to it. Many pharmacological therapies help reduce SCI-related injury and protect CNS from more damage but no current therapy could improve the axonal repair. In this regard, stem cell therapy is considered a regenerative method for SCI patient treatment. The neurotrophic and immunomodulatory factor secretion, differentiation, neuroprotecting, and remyelinating properties have made mesenchymal stem cells (MSCs) principally useful in this field. There are studies on the role of MSCs in patients suffering from SCI. However, low number of SCI patients and the lack of control groups in these studies, the cell transplantation appropriate methods, including cell source, dose, route of delivery, and transplantation timing, are various in trials. This study reviews the beneficial effects of MSC transplantation in SCI clinical studies with a special focus on the MSC properties and limitations of MSC transplantation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In the present review, the main features involved in the susceptibility and progression of neurodegenerative disorders (NDDs) have been discussed, with the purpose of highlighting their potential application for promoting the management and treatment of patients with NDDs. In particular, the impact of genetic and epigenetic factors, nutrients, and lifestyle will be presented, with particular emphasis on Alzheimer's disease (AD) and Parkinson's disease (PD). Metabolism, dietary habits, physical exercise and microbiota are part of a complex network that is crucial for brain function and preservation. This complex equilibrium can be disrupted by genetic, epigenetic, and environmental factors causing perturbations in central nervous system homeostasis, contributing thereby to neuroinflammation and neurodegeneration. Diet and physical activity can directly act on epigenetic modifications, which, in turn, alter the expression of specific genes involved in NDDs onset and progression. On this subject, the introduction of nutrigenomics shed light on the main molecular players involved in the modulation of health and disease status. In particular, the review presents data concerning the impact of ADH1B , CYP1A2, and MTHFR on the susceptibility and progression of NDDs (especially AD and PD) and how they may be exploited for developing precision medicine strategies for the disease treatment and management., Competing Interests: The author declares no conflicts of interest.

Background and Objective: Transcatheter aortic valve implantation (TAVI) has become the standard treatment for a wide range of patients with aortic stenosis. Although some of the TAVI post-operative complications are addressed in newer designs, other complications and lack of long-term and durability data on the performance of these prostheses are limiting this procedure from becoming the standard for heart valve replacements. The design optimization of these devices with the finite element and optimization techniques can help increase their performance quality and reduce the risk of malfunctioning. Most performance metrics of these prostheses are morphology-dependent, and the design and the selection of the device before implantation should be planned for each individual patient., Methods: In this study, a patient-specific aortic root geometry was utilized for the crimping and implantation simulation of 50 stent samples. The results of simulations were then evaluated and used for developing regression models. The strut width and thickness, the number of cells and patterns, the size of stent cells, and the diameter profile of the stent were optimized with two sets of optimization processes. The objective functions included the maximum crimping strain, radial strength, anchorage area, and the eccentricity of the stent., Results: The optimization process was successful in finding optimal models with up to 40% decrease in the maximum crimping strain, 261% increase in the radial strength, 67% reduction in the eccentricity, and about an eightfold increase in the anchorage area compared to the reference device., Conclusions: The stents with larger distal diameters perform better in the selected objective functions. They provide better anchorage in the aortic root resulting in a smaller gap between the device and the surrounding tissue and smaller contact pressure. This framework can be used in designing patient-specific stents and improving the performance of these devices and the outcome of the implantation process., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Although SARS-CoV-2 infects the upper respiratory tract, we know little about the amount, type, and kinetics of antibodies (Ab) generated in the oral cavity in response to COVID-19 vaccination. We collected serum and saliva samples from participants receiving two doses of mRNA COVID-19 vaccines and measured the level of anti-SARS-CoV-2 Ab. We detected anti-Spike and anti-Receptor Binding Domain (RBD) IgG and IgA, as well as anti-Spike/RBD associated secretory component in the saliva of most participants after dose 1. Administration of a second dose of mRNA boosted the IgG but not the IgA response, with only 30% of participants remaining positive for IgA at this timepoint. At 6 months post-dose 2, these participants exhibited diminished anti-Spike/RBD IgG levels, although secretory component-associated anti-Spike Ab were more stable. Examining two prospective cohorts we found that participants who experienced breakthrough infections with SARS-CoV-2 variants had lower levels of vaccine-induced serum anti-Spike/RBD IgA at 2-4 weeks post-dose 2 compared to participants who did not experience an infection, whereas IgG levels were comparable between groups. These data suggest that COVID-19 vaccines that elicit a durable IgA response may have utility in preventing infection. Our study finds that a local secretory component-associated IgA response is induced by COVID-19 mRNA vaccination that persists in some, but not all participants. The serum and saliva IgA response modestly correlate at 2-4 weeks post-dose 2. Of note, levels of anti-Spike serum IgA (but not IgG) at this timepoint are lower in participants who subsequently become infected with SARS-CoV-2. As new surges of SARS-CoV-2 variants arise, developing COVID-19 booster shots that provoke high levels of IgA has the potential to reduce person-to-person transmission., (© 2022. The Author(s), under exclusive licence to Society for Mucosal Immunology.)

Motor neuron diseases such as spinal cord injuries and amyotrophic lateral sclerosis are known as the most common disorders worldwide. Using stem cells (e.g., human umbilical cord blood mesenchymal stem cells) is currently a potent medical approach for modulating the impact of neural damages and regeneration of spinal cord injuries. MicroRNAs (miRNA) are taken into account as principal regulators during differentiation. The miRNAs play a significant role in stem cell self-renewal and fate determination. There are few studies on how miRNAs regulate neural differentiation in stem cells. The purpose of this study is to explore miRNA profiles of CB-MSCs during differentiation into motor neuron-like cells. Human CB-MSCs were isolated and characterized using flow cytometry. Cell differentiation has been induced by combining retinoic acid (RA) and sonic hedgehog (Shh) in a two-step protocol for 14 days. Then, cell differentiation was confirmed by immunocytochemistry and flow cytometry. The miRNA was analyzed using Illumina/Solexa sequencing platform. In this regard, three libraries were prepared to investigate the effect of these two biological morphogens on the miRNA profile of the differentiating cells. These libraries were Control (non-treated CB-MSCs), Test 1 (RA + /Shh +), and Test 2 (RA-/Shh-). Quantitative RT-PCR was employed to verify miRNA expression. CB-MSCs were spindle-shaped in morphology, and they did not express hematopoietic markers. After differentiation, the cells expressed motor neuron markers (i.e., Islet-1, SMI-32, and ChAT) at the protein level after 14 days. The analysis of miRNA sequencing demonstrated a significant up-regulation of miR-9-5p and miR-324-5p in Test 1 (RA + /Shh +). Also, there is a considerable down-regulation of mir-137 and let-7b in Test 2 (RA-/Shh-). These results have been obtained by comparing them with the Control library. Indeed, they were responsible for neuron and motor neuron differentiation and suppression of proliferation in neural progenitor cells. Furthermore, significant up-regulation was detected in some novel microRNAs involved in cholinergic, JAK-STAT, and Hedgehog and MAPK signaling pathways. CB-MSCs are potent to express motor neuron markers. This procedure has been performed by developing a two-week protocol and employing Shh and RA. The miRNA profile analysis showed a significant up-regulation in the expression of some miRs involved in neuron differentiation and motor neuron maturation. MiR-9-5p and miR-324-5p were up-regulated at the early stage of differentiation. Also, miR-137 and miR-let-7b were downregulated in the absence of RA and Shh. Furthermore, several novel miRNAs involved in cholinergic, Hedgehog, MAPK, and JAK-STAT signaling pathways have been detected. However, further studies are still necessary to validate their functions during motor neuron generation and maturation., (© 2022. The Author(s).)

Multiple sclerosis (MS), which is an autoimmune disease, is characterized by symptoms such as demyelination, axonal damage, and astrogliosis. As the most abundant type of glial cells, astrocytes play an important role in MS pathogenesis. Mesenchymal stem cells (MSCs) are a subset of stromal cells that have the potential for migration, immune-modulation, differentiation, remyelination, and neuroregeneration. Therefore, the present study evaluates the effects of MSC transplantation on A1 reactive astrocytes and the remyelination process in the cuprizone mouse model. The study used 30 male C57BL/6 mice, which were randomly distributed into three subgroups (n = 10), i.e., control, cuprizone, and transplanted MSCs groups. In order to generate a chronic demyelination model, the mice in the cuprizone group received food mixed with 0.2% cuprizone powder for 12 weeks. Then, 2 μl of DMEM containing approximately 3 × 10 5 DiI labeled cells was injected with a 4-min interval into the right lateral ventricle using a 10-μl Hamilton syringe. After 2 weeks of cell transplantation, we used the rotarod test to evaluate the behavioral deficits, while the remyelination process was assessed by transmission electron microscopy (TEM) and Luxol Fast Blue (LFB) staining. We assessed the population of A1 astrocytes and oligodendrocytes using specific markers, such as C3, GFAP, and Olig2, using the immunefleurocent method. The pro-inflammatory and trophic factors were assessed by a real-time polymerase chain reaction. According to our data, the specific marker of A1 astrocytes (C3) decreased in the MSCs group, while the number of oligodendrocytes significantly increased in this group compared to the cuprizone mice. Additionally, MSC was able to enhance the remyelination process after cuprizone usage, as shown by LFB and TEM images. The molecular results showed that MSCs could reduce pro-inflammatory factors, such as IL-1 and TNF-α, through the secretion of BDNF and TGF-β as trophic factors. The obtained results indicated that MSC could reduce demyelination and inflammation by decreasing A1 neurotoxic reactive astrocytes and neurotrophic and immunomodulatory factors secretion in the chronic cuprizone demyelination model., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)