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Exosomes are one type of extracellular vesicles with size ranging from 30 to 150 nm, which are involved in intercellular communication by transporting specific proteins, nucleic acids, and low molecular weight metabolites. The size and competence of exosomes to transfer biological materials to recipient cells have made them suitable for biomedical use. Therefore, exosomes have been studied as drug delivery systems for various diseases due to low immunogenicity, preferred tumor homing, innate and acquired targetability, and stability. They are secreted by almost all cells from multivesicular endosomes and retrieved in all body fluids including bile, saliva, blood, lymph, urine, cerebrospinal fluid, milk, and etc . Plants' organs also secrete exosomes (Plant-derived exosome-like nanoparticles (PELNs)) which have been considered as an economical and affordable source of production. PELNs are pharmacologically rich in active molecules because of owning unique compositional and morphological features and they can be used as natural nano-carrier for transporting exogenous molecules. In this review, the bio-component and the applications of PELNs as drug delivery systems in neural disorders, tumor-targeted delivery, and gene delivery have been reviewed in different plants such as aloe, turmeric, ginger, lemon, grapefruit, grape, and strawberry.

Temperature-sensitive drug delivery systems (TSDDS) are one of the systems that have received more attention in medical science these days due to their advantages. As these systems are sensitive to temperature, drug delivery to the target becomes more specific. Temperature-sensitive nanogels have many applications, including microbial infections, cancer therapy, transdermal use, and tissue repair. These systems are characterized by minimal toxicity, improved therapeutic efficacy, and reduced exposure to normal cells. This mini-review is prepared with different types of temperature-sensitive nanogel formation, release mechanisms, and their different applications. Various systems reported under these categories for targeted and controlled delivery of different classes of drugs, such as anti-cancer and antibiotic drugs with special emphasis on anti-cancer drugs and tissue healing, are discussed in this mini-review.

Introduction: Recurrent aphthous stomatitis is a common lesion of the oral cavity, and many treatments have been introduced by researchers., Objective: This study aims to determine the effect of biosurfactant lipopeptide (Acinetobacter baumannii and Pseudomonas aeruginosa) adhesive mucus paste on the healing process of oral wounds., Materials and Methods: The studied population included 36 people (age range, 20-41 years). The volunteers had a history of oral ulcers and were randomly assigned to 3 groups: positive control (mouthwash chlorhexidine 0.2%), biosurfactant lipopeptide mucoadhesive (A baumannii and P aeruginosa), and base groups. In this analysis, the 2-paired sample t test, ANOVA, and Kruskal-Wallis test (Wilcoxon signed-rank test) were used., Results: On the second day of treatment, the efficacy index of the positive control group was higher than that of the mucoadhesive and the base groups (P = .04) and there was a significant difference between the mucoadhesive group and the positive control group compared with the base group (P = .001). On the sixth day of treatment, the positive control group was significantly different from the mucoadhesive and base groups in terms of wound size (P < .05)., Conclusions: This study showed that the use of mucoadhesive gel formation containing lipopeptide biosurfactant reduces pain and wound size compared to mucoadhesive without biosurfactant lipopeptide treatment, but it has less effect than routine treatment. Therefore, other studies should be done.

Wound healing refers to the complex process of restoring the forms and functions of damaged tissues. Multiple growth factors and released cytokines tightly regulate the wound site. Healing processes can be disrupted by any alteration that would aggravate the damage and lengthen the repair process. Some of the conditions that may impair wound healing include infections and inflammation. Surfactants are amphiphilic compounds widely used in various formulations including detergents, food, pharmaceuticals and cosmetics. Biosurfactants, therefore, are surface-active compounds produced by biological agents, particularly yeast or bacteria, and represent a safer and environmentally preferred alternative to chemical surfactants. Numerous studies have targeted surface-active molecules as wound healing agents for their anti-inflammatory, antioxidant and antibacterial potential. This review focuses on surface-active molecules used in wound healing activities and analyses their effectiveness and mechanisms of action.

Spinal intramedullary capillary hemangioma is a rare condition. Although most spinal/spinal cord hemangiomas are inborn in origin, perinatal presentation is uncommon. We present a neonate with an intramedullary hemangioma, born with communicating hydrocephalus and complete paraplegia. Spinal imagining showed an intradural mass with hemorrhagic foci, a low-lying conus medullaris, and scalloping of dorsal elements. Ventriculoperitoneal shunting was performed in an emergent setting, with cerebrospinal fluid showing a brownish appearance with high viscosity which implied a possible old hemorrhage. Tissue sample was taken from the spinal lesion in an elective setting. Histopathological examination revealed capillary lobules and extralobular large vessels resembling abnormal veins. The mentioned clues suggested that this congenital hemangioma had become symptomatic from the prenatal period. Though it is a are event, it should be kept in mind while evaluating a neonate with communicating hydrocephalus and weakness of extremities with or without cutaneous hemangiomatous stigmata.

Background: While of predominant abundance across vertebrate genomes and significant biological implications, the relevance of short tandem repeats (STRs) (also known as microsatellites) to speciation remains largely elusive and attributed to random coincidence for the most part. Here we collected data on the whole-genome abundance of mono-, di-, and trinucleotide STRs in nine species, encompassing rodents and primates, including rat, mouse, olive baboon, gelada, macaque, gorilla, chimpanzee, bonobo, and human. The collected data were used to analyze hierarchical clustering of the STR abundances in the selected species., Results: We found massive differential STR abundances between the rodent and primate orders. In addition, while numerous STRs had random abundance across the nine selected species, the global abundance conformed to three consistent &lt; clusters&gt;, as follows: &lt;rat, mouse&gt;, &lt;gelada, macaque, olive baboon&gt;, and &lt;gorilla, chimpanzee, bonobo, human&gt;, which coincided with the phylogenetic distances of the selected species (p &lt; 4E-05). Exceptionally, in the trinucleotide STR compartment, human was significantly distant from all other species., Conclusion: Based on hierarchical clustering, we propose that the global abundance of STRs is non-random in rodents and primates, and probably had a determining impact on the speciation of the two orders. We also propose the STRs and STR lengths, which predominantly conformed to the phylogeny of the selected species, exemplified by (t)10, (ct)6, and (taa4). Phylogenetic and experimental platforms are warranted to further examine the observed patterns and the biological mechanisms associated with those STRs., (© 2022. The Author(s).)

Background: One of the dermatologic problems in elderly people is skin aging, which is a natural and complex biological process. Morin is a flavonoid with high radical scavenging activity as well as antityrosinase effects but its low water solubility has restricted its application., Aims: This research aimed to develop, characterize, and optimize morin niosomes composed of non-ionic surfactants, and evaluate the in vitro UV protection and antiaging effectiveness., Methods: Niosomes were prepared by the film hydration method with sorbitan monostearate (Span® 40), polyoxyethylenesorbitan monopalmitate (Tween® 40), and cholesterol. The niosomes were characterized in terms of size, zeta potential, morphology, in vitro release behavior, and drug entrapment efficiency (EE). Afterward, antiaging activity, including antityrosinase, antioxidant, intracellular reactive oxygen species (ROS) scavenging, and sun protection factor (SPF) were evaluated., Results: The optimized niosomes appeared as unilamellar vesicles with a spherical shape, with size, zeta potential, and EE values of 6.13 ± 0.40 μm, -0.81 ± 0.32 mV, and 89.35% ± 2.80%, respectively. The noisome formulation remained stable at -4°C for 3 months. The release profiles of morin loaded in niosomes revealed the extended release over 8 h and followed zero-order release kinetics. Morin-loaded niosomes exhibited no significant toxicity toward the L929 cell line. The niosome loaded with morin showed anti skin aging activity, including antityrosinase effects (IC50 = 13.17 ± 1.58 μg/ml), antioxidant (IC50 = 28.49 ± 2.05 μg/ml), and ROS scavenging activity. For 1% and 5% (w/w) morin niosomes in eucerin base cream, the SPF was 39.03 ± 1.01 and 38.15 ± 0.82, respectively, whereas the noisome-free morin cream exhibited an SPF of 4.47 ± 0.56., Conclusion: Morin-loaded niosome has been shown to provide sun protection and antiaging effects, suggesting that it could be used in pharmaceutical and cosmetic products., (© 2022 Wiley Periodicals LLC.)

Objective: Neuropsychological findings in obsessive-compulsive disorder (OCD) are mainly clustered around the role of memory and executive functions. However, outcomes vary across different OCD populations. In addition, the extent to which each of these factors can distinguish patients with OCD (PwOCD) from healthy individuals remains uncertain and attracts great attention. The present study aims to investigate the above issues., Method: This was a cross-sectional study of 182 individuals (90 PwOCD and 92 matched healthy controls). After screening for inclusion and exclusion criteria, the participants were administered neuropsychological tests including, the Wechsler Memory Scale-III (WMS-III), the Wisconsin Card Sorting Test (WCST), and the Stroop Color-Word Test (SCWT). Data were analyzed to test the study hypotheses using comparison of means and regression analysis methods., Results: The results showed that PwOCD had poorer performance than the control group in Immediate Memory, General Memory, and Working Memory and also according to response inhibition indexes. The results also showed that General Memory and Reaction Time2 from the SCWT index could be predictive variables for discriminating between PwOCD and controls., Conclusion: The findings of this study support the prior assumptions that PwOCD would have impaired memory dimensions and response inhibition, but did not support worse set-shifting performance. We also present an initial model for the predictive role of these neuropsychological variables in discriminating OCD from healthy individuals and increasing diagnostic accuracy., Competing Interests: No conflicts of interest declared concerning the publication of this article.

The human SBF1 (SET binding factor 1) gene, alternatively known as MTMR5, is predominantly expressed in the brain, and its epigenetic dysregulation is linked to late-onset neurocognitive disorders (NCDs), such as Alzheimer's disease. This gene contains a (GCC)-repeat at the interval between + 1 and + 60 of the transcription start site (SBF1-202 ENST00000380817.8). We sequenced the SBF1 (GCC)-repeat in a sample of 542 Iranian individuals, consisting of late-onset NCDs (N = 260) and controls (N = 282). While multiple alleles were detected at this locus, the 8 and 9 repeats were predominantly abundant, forming &gt; 95% of the allele pool across the two groups. Among a number of anomalies, the allele distribution was significantly different in the NCD group versus controls (Fisher's exact p = 0.006), primarily as a result of enrichment of the 8-repeat in the former. The genotype distribution departed from the Hardy-Weinberg principle in both groups (p &lt; 0.001), and was significantly different between the two groups (Fisher's exact p = 0.001). We detected significantly low frequency of the 8/9 genotype in both groups, higher frequency of this genotype in the NCD group, and reverse order of 8/8 versus 9/9 genotypes in the NCD group versus controls. Biased heterozygous/heterozygous ratios were also detected for the 6/8 versus 6/9 genotypes (in favor of 6/8) across the human samples studied (Fisher's exact p = 0.0001). Bioinformatics studies revealed that the number of (GCC)-repeats may change the RNA secondary structure and interaction sites at least across human exon 1. This STR was specifically expanded beyond 2-repeats in primates. In conclusion, we report indication of a novel biological phenomenon, in which there is selection against certain heterozygous genotypes at a STR locus in human. We also report different allele and genotype distribution at this STR locus in late-onset NCD versus controls. In view of the location of this STR in the 5' untranslated region, RNA/RNA or RNA/DNA heterodimer formation of the involved genotypes and alternative RNA processing and/or translation should be considered., (© 2022. The Author(s).)

Background: While the evolutionary divergence of cis-regulatory sequences impacts translation initiation sites (TISs), the implication of tandem repeats (TRs) in TIS selection remains largely elusive. Here, we employed the TIS homology concept to study a possible link between TRs of all core lengths and repeats with TISs., Methods: Human, as reference sequence, and 83 other species were selected, and data was extracted on the entire protein-coding genes (n = 1,611,368) and transcripts (n = 2,730,515) annotated for those species from Ensembl 102. Following TIS identification, two different weighing vectors were employed to assign TIS homology, and the co-occurrence pattern of TISs with the upstream flanking TRs was studied in the selected species. The results were assessed in 10-fold cross-validation., Results: On average, every TIS was flanked by 1.19 TRs of various categories within its 120 bp upstream sequence, per species. We detected statistically significant enrichment of non-homologous human TISs co-occurring with human-specific TRs. On the contrary, homologous human TISs co-occurred significantly with non-human-specific TRs. 2991 human genes had at least one transcript, TIS of which was flanked by a human-specific TR. Text mining of a number of the identified genes, such as CACNA1A, EIF5AL1, FOXK1, GABRB2, MYH2, SLC6A8, and TTN, yielded predominant expression and functions in the human brain and/or skeletal muscle., Conclusion: We conclude that TRs ubiquitously flank and contribute to TIS selection at the trans-species level. Future functional analyses, such as a combination of genome editing strategies and in vitro protein synthesis may be employed to further investigate the impact of TRs on TIS selection., (© 2022. The Author(s).)

Wound healing is a dynamic process that occurs in the tissue under the skin. During this process, oxidative stress biomarkers are excessively produced, which finally lead to inflammation and cellular damage. In this study, efforts have been made to evaluate the antioxidant effect and wound healing activity topical formulation containing Heliotropium bacciferum Forssk extract. The in vitro antioxidant properties were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activities and the ferric reducing antioxidant power (FRAP) assay. The herbal ointments (2.5% w/w and 5% w/w) were prepared from the hydroalcoholic extract of H. bacciferum Forssk and administrated on the induced wounds in Wistar rats. The chromatic assay, percentage of wound contraction, and histopathological studies were used for evaluating the wound healing activity. For the evaluation of reactive oxygen species (ROS), catalase (CAT) activity, superoxide dismutase (SOD), and glutathione (GSH) levels were examined. The DPPH method showed tremendous radical scavenging activities at the corresponding concentrations with EC 50 value of 80μg/mL. Topical application of the ointment (5% w/w) showed the highest wound contraction in comparison to the positive control (treated with CICALFATE™) and the control group (treated with normal saline). Similarly, the histological study of the group treated with the extract ointment (5% w/w) showed full collagen tissue deposition with a complete epidermal regeneration. The results of the assessment of GSH levels as well as CAT and SOD activities in the treated group (5% w/w) confirmed the scavenging property of the extract ointment. Our findings indicated the proper wound healing impact of the topical formulation of H. bacciferum Forssk due to its notable antioxidant capacity., (Copyright © 2021 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Biosurfactants are microbial-derived compounds with surface and emulsifying activities. Environmental and industrial applications make glycolipid biosurfactants particularly interesting among the several categories of biosurfactants. A potential glycolipid biosurfactant resource, Shewanella algae, was isolated from marine samples at the Persian Gulf. The glycolipid biosurfactant caused a reduction in water surface tension from 72 to 43 mN/m with a 0.25 mg/mL critical micelle concentration (CMC). Two-level factorial design was then applied for optimization of biosurfactant production, where a maximal reduction of culture broth surface tension (31 mN/m) acquired in the presence of crude oil (0.5%, v/v), NaNO 3 (0.2 g/L), NH 4 Cl (0.7 g/L), and peptone (0.5 g/L). GC-MS analysis of the culture broth showed when crude oil was used as the sole carbon source, S. algae was able to degrade most of its alkane components. Nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) spectroscopy revealed the glycolipid structure of biosurfactant. The glycolipid biosurfactant exhibited considerable growth inhibition of clinical bacterial pathogens and disrupted the preformed biofilms of Bacillus cereus (83%), Streptococcus pneumoniae (53%), Pseudomonas aeruginosa (92%), Escherichia coli (64%), Klebsiella pneumoniae (87%), and Acinetobacter sp. (72%). In conclusion, the glycolipid biosurfactant secreted by S. algae exhibited a wide range of functional properties and was evidenced as a promising candidate for biomedical application., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Across human protein-coding genes, the human neuron-specific genes, RIT2 and GPM6B, contain the two longest GA short tandem repeats (STRs) of 11 and 9-repeats, respectively, the length ranges of which are functional, and result in gene expression alteration. Here we sequenced the RIT2 and GPM6B STRs in 600 human subjects, consisting of late-onset neurocognitive disorder (n = 200), multiple sclerosis (n = 200), and controls (n = 200). Furthermore, we selected two large human databases, including the general-population-based gnomAD ( https://gnomad.broadinstitute.org ) and a mainly disease-phenotype-archiving database, TOPMed ( https://www.nhlbiwgs.org ), to compare allele frequencies in the general populations vs. the disease compartment. The RIT2 and GPM6B GA-repeats were monomorphic in the human subjects studied, at lengths of 11 and 9-repeats, respectively, and were predominantly human-specific in formula. Exception included a 9/11 genotype of the RIT2 GA-STR in an isolate case of female multiple sclerosis. Exceedingly rare alleles of the two GA repeats were significantly enriched in TOPMed vs. the gnomAD. We report prime instances of predominant monomorphism for specific lengths of STRs in human, and possible enrichment of rare divergent alleles in the disease phenotype compartment. While STRs are most attended because of their high polymorphic nature, STR monomorphism is an underappreciated feature, which may have a link with natural selection and disease., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

PRKACB (Protein Kinase CAMP-Activated Catalytic Subunit Beta) is predominantly expressed in the brain, and regulation of this gene links to neuroprotective effects against tau and Aβ-induced toxicity. Here we studied a (GCC)-repeat spanning the core promoter and 5' UTR of this gene in 300 human subjects, consisting of late-onset neurocognitive disorder (NCD) (N = 150) and controls (N = 150). We also implemented several models to study the impact of this repeat on the three-dimensional (3D) structure of DNA. While the PRKACB (GCC)-repeat was strictly monomorphic at 7-repeats, we detected two 7/8 genotypes only in the NCD group. In all examined models, the (GCC)7 and its periodicals had the least range of divergence variation on the 3D structure of DNA in comparison to the 8-repeat periodicals and several hypothetical repeat lengths. A similar inert effect on the 3D structure was not detected in other classes of short tandem repeats (STRs) such as GA and CA repeats. In conclusion, we report monomorphism of a long (GCC)-repeat in the PRKACB gene in human, its inert effect on DNA structure, and enriched divergence in late-onset NCD. This is the first indication of natural selection for a monomorphic (GCC)-repeat, which probably evolved to function as an "epigenetic knob", without changing the regional DNA structure., (© 2021. The Author(s).)

Expression dysregulation of the neuron-specific gene, RASGEF1C (RasGEF Domain Family Member 1C), occurs in late-onset neurocognitive disorders (NCDs), such as Alzheimer's disease. This gene contains a (GGC)13, spanning its core promoter and 5' untranslated region (RASGEF1C-201 ENST00000361132.9). Here we sequenced the (GGC)-repeat in a sample of human subjects (N = 269), consisting of late-onset NCDs (N = 115) and controls (N = 154). We also studied the status of this STR across various primate and non-primate species based on Ensembl 103. The 6-repeat allele was the predominant allele in the controls (frequency = 0.85) and NCD patients (frequency = 0.78). The NCD genotype compartment consisted of an excess of genotypes that lacked the 6-repeat (divergent genotypes) (Mid-P exact = 0.004). A number of those genotypes were not detected in the control group (Mid-P exact = 0.007). The RASGEF1C (GGC)-repeat expanded beyond 2-repeats specifically in primates, and was at maximum length in human. We conclude that there is natural selection for the 6-repeat allele of the RASGEF1C (GGC)-repeat in human, and significant divergence from that allele in late-onset NCDs. STR alleles that are predominantly abundant and genotypes that deviate from those alleles are underappreciated features, which may have deep evolutionary and pathological consequences., (© 2021. The Author(s).)

Objective: Application of vesicular drug delivery systems has made major progress in pharmaceutical science and technology. Niosomal drug delivery is potentially efficient to improve the pharmacokinetic and pharmacological properties of many compounds. Curcumin (CUR) has several documented anticancer activities; however, it has a low bioavailability that necessitates the development of efficient delivery systems. Accordingly, different niosomal preparations were prepared and evaluated in the present study to find a suitable delivery system., Materials and Methods: Span and Tween 20, 40, 60, and 80 were employed with various concentrations of cholesterol for studying the ability to form curcumin-loaded niosomes. Multiple characterization techniques including visual evaluation, particle size analysis, stability, encapsulation efficiency (EE), and release profile were studied. Cytotoxicity of curcumin niosomes on MCF-7 and 3T3 cell lines was determined using MTT assay., Results: Visual and particle size analysis indicated the formation of seven niosomal formulations in the micron size range, while the formulation consisted of Tween 40/cholesterol (50/50 M%) with 0.05% w/v CUR had an average diameter of 475 nm. The latter formulation was selected and it had EE of 78.5%. The CUR release profile showed 18.7% release over a period of 300 min. The MTT results showed that CUR incorporation significantly increased the cytotoxicity of niosomes and the extent of toxicity was higher in MCF-7 cells., Conclusion: In this study, a simple niosomal formulation was developed for CUR loading with favorable physicochemical properties. The presented niosomal curcumin had also considerable effects in cell toxicity studies, which can be suggested for future anticancer studies., Competing Interests: The authors have declared that there is no conflict of interest.

Aim: The aim of this study was to identify the minimal essential co-expression and physical interaction networks involved in the development of cognition impairment in human mid and late life., Methods: We searched the Online Mendelian Inheritance in Man (OMIM) database to extract the validated human genes annotated (until March 2020) for five major disorders of pathophysiological overlap and sequential chronological occurrence in human, including multiple sclerosis, type 2 diabetes mellitus, Alzheimer's disease, vascular dementia, and Lewy body dementia. Gene co-expression and physical interaction networks were subsequently constructed for the overlapping genes across the selected disorders., Results: Remarkably, each of the gene co-expression and physical interaction networks consisted of single clusters (P = 0.0005 and P = 1 × 10 -16 , respectively). APP was the major hub in the integrated and tissue-specific co-expression networks, whereas insulin was the major hub in the physical interaction network. Several other hubs were identified across the identified networks, including TNF, VEGFA, GAPDH, and NOTCH1., Conclusion: We propose the minimal co-expression and physical interaction networks and their single clustering in the development of cognition impairment in human mid and late life. This is a pilot study, warranting identification of more risk genes, using additional validated databases in the future.

There are many proteins and enzymes in the human body, and their dysfunction can lead to the emergence of a disease. The use of proteins as a drug is common in various diseases such as diabetes. Proteins are hydrophilic molecules whose spatial structure is critical to their correct function. There are different ways for the administration of proteins. Protein structures are degraded by gastric acid and enzymes in the gastrointestinal tract and have a slight ability to permeate from the gastrointestinal epithelium due to their large hydrophilic nature. Therefore, their oral use has limitations. Since the oral route for the administration of drugs is one of the best and easiest routes for patients, many studies have been done to increase the stability, penetration, and ultimately, the bioavailability of proteins through oral administration. One of the studied strategies for oral delivery of protein is the use of pH-sensitive polymer-based carriers. These carriers use different pH-sensitive polymers, such as eudragit®, chitosan, dextran, and alginate. The use of pH-sensitive polymer- based carriers by protecting the protein from stomach acid (low pH) and degrading enzymes, increasing permeability and maintaining the spatial structure of the protein, leads to increased bioavailability. In this review, we focus on the various polymers used to prepare pH-sensitive polymer- based carriers for the oral delivery of proteins., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The human X-linked zinc finger MYM-type protein 3 (ZMYM3) contains the longest GA-STR identified across protein-coding gene 5' UTR sequences, at 32-repeats. This exceptionally long GA-STR is located at a complex string of GA-STRs with a human-specific formula across the complex as follows: (GA)8-(GA)4-(GA)6-(GA)32 (ZMYM3-207 ENST00000373998.5). ZMYM3 was previously reported among the top three genes involved in the progression of late-onset Alzheimer's disease. Here we sequenced the ZMYM3 GA-STR complex in 750 human male subjects, consisting of late-onset neurocognitive disorder (NCD) as a clinical entity (n = 268) and matched controls (n = 482). We detected strict monomorphism of the GA-STR complex, except of the exceptionally long STR, which was architecturally skewed in respect of allele distribution between the NCD cases and controls [F (1, 50) = 12.283; p = 0.001]. Moreover, extreme alleles of this STR at 17, 20, 42, and 43 repeats were detected in seven NCD patients and not in the control group (Mid-P exact = 0.0003). A number of these alleles overlapped with alleles previously found in schizophrenia and bipolar disorder patients. In conclusion, we propose selective advantage for the exceptional length of the ZMYM3 GA-STR in human, and its link to a spectrum of diseases in which major cognition impairment is a predominant phenotype.

Background: The novel approaches to psychiatric classification assume that disorders, contrary to what was previously thought, are not completely separate phenomena. In this regard, in addition to symptom-based criteria, disturbances are also considered on the basis of lower level components. With this viewpoint, identifying common biochemical markers would be beneficial in adopting a comprehensive strategy for prevention, diagnosis and treatment., Main Body: One of the problematic areas in clinical settings is the coexistence of both obsessive-compulsive disorder (OCD) and bipolar disorder (BD) that is challenging and difficult to manage. In this study, using a system biologic approach we aimed to assess the interconnectedness of OCD and BD at different levels. Gene Set Enrichment Analysis (GSEA) method was used to identify the shared biological network between the two disorders. The results of the analysis revealed 34 common genes between the two disorders, the most important of which were CACNA1C , GRIA1 , DRD2 , NOS1 , SLC18A1 , HTR2A and DRD1 . Dopaminergic synapse and cAMP signaling pathway as the pathways, dopamine binding and dopamine neurotransmitter receptor activity as the molecular functions, dendrite and axon part as the cellular component and cortex and striatum as the brain regions were the most significant commonalities., Short Conclusion: The results of this study highlight the role of multiple systems, especially the dopaminergic system in linking OCD and BD. The results can be used to estimate the disease course, prognosis, and treatment choice, particularly in the cases of comorbidity. Such perspectives, going beyond symptomatic level, help to identify common endophenotypes between the disorders and provide diagnostic and therapeutic approaches based on biological in addition to the symptomatic level., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: Microemulsions drug delivery systems (MDDS) have been known to increase the bioavailability of hydrophobic drugs. The main challenge of the MDDS is the development of an effective and safe system for drug carriage and delivery. Biosurfactants are preferred surface-active molecules because of their lower toxicity and safe characteristics when compared to synthetic surfactants. Glycolipid and lipopeptide are the most common biosurfactants that were tested for MDDS. The main goal of the present systematic review was to estimate the available evidence on the role of biosurfactant in the development of MDDS., Search Strategy: Literature searches involved the main scientific databases and were focused on the period from 2005 until 2017. The Search filter composed of two items: "Biosurfactant" and/or "Microemulsion.", Inclusion Criteria: Twenty-four studies evaluating the use of biosurfactant in MDDS were eligible for inclusion. Among these 14 were related to the use of glycolipid biosurfactants in the MDDS formulations, while four reported using lipopeptide biosurfactants and six other related review articles., Results: According to the output study parameters, biosurfactants acted as active stabilizers, hydrophilic or hydrophobic linkers and safety carriers in MDDS, and among them glycolipid biosurfactants had the most application in MDDS formulations., Conclusion: Synthetic surfactants could be replaced by biosurfactants as an effective bio-source for MDDS due to their excellent self-assembling and emulsifying activity properties., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Ohadi et al.)

Background: Approximately 2% of the human core promoter short tandem repeats (STRs) reach lengths of ≥6 repeats, which may in part be a result of adaptive evolutionary processes and natural selection. A single-exon transcript of the human nescient helix loop helix 2 (NHLH2) gene is flanked by the longest CA-repeat detected in a human protein-coding gene core promoter (Ensembl transcript ID: ENST00000369506.1). NHLH2 is involved in several biological and pathological pathways, such as motivated exercise, obesity, and diabetes., Methods: The allele and genotype distribution of the NHLH2 CA-repeat were investigated by sequencing in 655 Iranian subjects, consisting of late-onset neurocognitive disorder (NCD) as a clinical entity (n = 290) and matched controls (n = 365). The evolutionary trend of the CA-repeat was also studied across vertebrates., Results: The allele range was between 9 and 25 repeats in the NCD cases, and 12 and 24 repeats in the controls. At the frequency of 0.56, the 21-repeat allele was the predominant allele in the controls. While the 21-repeat was also the predominant allele in the NCD patients, we detected significant decline of the frequency (p < 0.0001) and homozygosity (p < 0.006) of this allele in this group. Furthermore, 12 genotypes were detected across 16 patients (5.5% of the entire NCD sample) and not in the controls (disease-only genotypes; p < 0.0003), consisting of at least one extreme allele. The extreme alleles were at 9, 12, 13, 18, and 19 repeats (extreme short end), and 23, 24, and 25 repeats (extreme long end), and their frequencies ranged between 0.001 and 0.04. The frequency of the 21-repeat allele significantly dropped to 0.09 in the disease-only genotype compartment (p < 0.0001). Evolutionarily, while the maximum length of the NHLH2 CA-repeat was 11 repeats in non-primates, this CA-repeat was ≥14 repeats in primates and reached maximum length in human., Conclusion: We propose a novel locus for late-onset NCD at the NHLH2 core promoter exceptionally long CA-STR and natural selection at this locus. Furthermore, there was indication of genotypes at this locus that unambiguously linked to late-onset NCD. This is the first instance of natural selection in favor of a predominantly abundant STR allele in human and its differential distribution in late-onset NCD., (© 2020 S. Karger AG, Basel.)

Lipopeptide biosurfactants (LPBs) are amphiphilic compounds produced by microorganisms exhibiting various biological activities. The main aim of the present study was to assess the in vitro antimicrobial, anti-biofilm, and cytotoxic effects of LPB produced by Acinetobacter junii (AjL). We determined AjL minimum inhibitory concentration (MIC) against both Gram-positive and Gram-negative bacteria as well as two fungal strains. Also, the anti-biofilm activity of AjL against the biofilm produced by clinically isolated bacterial strains was investigated. The AjL non-selectively showed activity against both Gram-positive and Gram-negative bacterial strains. The obtained results of the present study exhibited that the AjL in concentrations nearly below critical micelle concentration (CMC) has an effective antibacterial activity. It was found that the MIC values of AjL were lower than standard antifungal and it exhibited nearly 100% inhibition against Candida utilis. The attained results of the biofilm formation revealed that AjL disrupted the biofilm of Proteus mirabilis, Staphylococcus aureus, and Pseudomonas aeruginosa at 1250 μg/ml and 2500 μg/ml concentrations. The attained results of cytotoxic effect (determined by WST-1 assay) of the AjL revealed IC 50 of 7.8 ± 0.4 mg/ml, 2.4 ± 0.5 mg/ml, and 5.7 ± 0.1 mg/ml, against U87, KB, and HUVEC cell lines, respectively. The results indicated that AjL has a potential application in the relatively new field of biomedicine., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Machine learning can effectively nominate novel genes for various research purposes in the laboratory. On a genome-wide scale, we implemented multiple databases and algorithms to predict and prioritize the human aging genes (PPHAGE)., Results: We fused data from 11 databases, and used Naïve Bayes classifier and positive unlabeled learning (PUL) methods, NB, Spy, and Rocchio-SVM, to rank human genes in respect with their implication in aging. The PUL methods enabled us to identify a list of negative (non-aging) genes to use alongside the seed (known age-related) genes in the ranking process. Comparison of the PUL algorithms revealed that none of the methods for identifying a negative sample were advantageous over other methods, and their simultaneous use in a form of fusion was critical for obtaining optimal results (PPHAGE is publicly available at https://cbb.ut.ac.ir/pphage)., Conclusion: We predict and prioritize over 3,000 candidate age-related genes in human, based on significant ranking scores. The identified candidate genes are associated with pathways, ontologies, and diseases that are linked to aging, such as cancer and diabetes. Our data offer a platform for future experimental research on the genetic and biological aspects of aging. Additionally, we demonstrate that fusion of PUL methods and data sources can be successfully used for aging and disease candidate gene prioritization.

Peptides are the most abundant biological compounds in the cells that act as enzymes, hormones, structural element, and antibodies. Mostly, peptides have problems to move across the cells because of their size and poor cellular penetration. Therefore, a carrier that could transfer peptides into cells is ideal and would be effective for disease treatment. Until now, plenty of polymers, e.g., polysaccharides, polypeptides, and lipids were used in drug delivery. Hydrogels made from polysaccharides showed significant development in targeted delivery of peptide hormones because of their natural characteristics such as networks, pore sizes, sustainability, and response to external stimuli. The main aim of the present review was therefore, to gather the important usages of the hydrogels as a carrier in peptide hormone delivery and their application in tissue engineering and regenerative medicine., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Doostmohammadi et al.)

Objective: The X-linked ZMYM3 gene (also known as ZNF261) contains the longest STR, (GA)32, identified in a human protein-coding gene 5'UTR (ENST00000373998.5: ZMYM3-207). This STR reaches maximum length in human, and is located in a complex string of four consecutive GA-STRs with a human-specific formula across the complex. A previous study in Iranian male schizophrenia (SCZ) patients revealed co-occurrence of the extreme short and long alleles of the STR with SCZ. Here we studied the allelic distribution of this STR in bipolar disorder (BD) type I. The interval encompassing the human ZMYM3 STR complex was PCR-amplified and sequenced in 546 male subjects, consisting of 157 BD patients and 389 controls., Results: We found three alleles at the extreme short (17-repeat) and long (38- and 43-repeat) ends of the allele distribution curve in the BD cases (4.4% of the BD alleles) that were not detected in the controls (Mid p < 0.0001). These alleles overlapped with the extreme disease-only alleles detected previously in the SCZ patients. Domain reconstruction of the GA-STR complex revealed significant structural alteration as a result of various sequence repeats and nucleotide compositions at the inter and intraspecies levels., Conclusion: The ZMYM3 "exceptionally long" 5' UTR STR findings may alter our perspective of disease pathogenesis in psychiatric disorders, and set an example in which the low frequency alleles at the extreme short and long ends of the human STRs are, at least in part, a result of natural selection against these alleles and their unambiguous link to major human disorders., (Copyright © 2019. Published by Elsevier B.V.)

Background: Despite their vast biological implication, the relevance of short tandem repeats (STRs)/microsatellites to the protein-coding gene translation initiation sites (TISs) remains largely unknown., Methods: We performed an Ensembl-based comparative genomics study of all annotated orthologous TIS-flanking sequences in human and 46 other species across vertebrates, on the genomic DNA and cDNA platforms (755,956 TISs), aimed at identifying human-specific STRs in this interval. The collected data were used to examine the hypothesis of a link between STRs and TISs. BLAST was used to compare the initial five amino acids (excluding the initial methionine), codons of which were flanked by STRs in human, with the initial five amino acids of all annotated proteins for the orthologous genes in other vertebrates (total of 5,314,979 pair-wise TIS comparisons on the genomic DNA and cDNA platforms) in order to compare the number of events in which human-specific and non-specific STRs occurred with homologous and non-homologous TISs (i.e., ≥ 50% and < 50% similarity of the five amino acids)., Results: We detected differential distribution of the human-specific STRs in comparison to the overall distribution of STRs on the genomic DNA and cDNA platforms (Mann Whitney U test p = 1.4 × 10 -11 and p < 7.9 × 10 -11 , respectively). We also found excess occurrence of non-homologous TISs with human-specific STRs and excess occurrence of homologous TISs with non-specific STRs on both platforms (p < 0.00001)., Conclusion: We propose a link between STRs and TIS selection, based on the differential co-occurrence rate of human-specific STRs with non-homologous TISs and non-specific STRs with homologous TISs.

Differential expansion of a number of human short tandem repeats (STRs) at the critical core promoter and 5' untranslated region (UTR) support the hypothesis that at least some of these STRs may provide a selective advantage in human evolution. Following a genome-wide screen of all human protein-coding gene 5' UTRs based on the Ensembl database ( http://www.ensembl.org ), we previously reported that the longest STR in this interval is a (GA) 32 , which belongs to the X-linked zinc finger MYM-type containing 3 (ZMYM3) gene. In the present study, we analyzed the evolutionary implication of this region across evolution and examined the allele and genotype distribution of the "exceptionally long" STR by direct sequencing of 486 Iranian unrelated male subjects consisting of 196 cases of schizophrenia (SCZ) and 290 controls. We found that the ZMYM3 transcript containing the STR is human-specific (ENST00000373998.5). A significant allele variance difference was observed between the cases and controls (Levene's test for equality of variances F = 4.00, p < 0.03). In addition, six alleles were observed in the SCZ patients that were not detected in the control group ("disease-only" alleles) (mid p exact < 0.0003). Those alleles were at the extreme short and long ends of the allele distribution curve and composed 4% of the genotypes in the SCZ group. In conclusion, we found skewing of the genetic architecture at the ZMYM3 STR in SCZ. Further, we found a bell-shaped distribution of alleles and selection against alleles at the extreme ends of this STR. The ZMYM3 STR sets a prototype, the evolutionary course of which determines the range of alleles in a particular species. Extreme "disease-only" alleles and genotypes may change our perspective of adaptive evolution and complex disorders. The ZMYM3 gene "exceptionally long" STR should be sequenced in SCZ and other human-specific phenotypes/characteristics.

In the present study the produced biosurfactant of Acinetobacter junii B6 (recently isolated from Iranian oil excavation site) were partially purified and identified by high performance thin layer chromatography (HPTLC), Fourier transform infrared spectroscopy (FTIR), and proton nuclear magnetic resonance ( 1 H NMR). Elemental analysis of the biosurfactant by energy dispersive X-ray spectroscopy (EDS) revealed that the biosurfactant was anionic in nature. The physiochemical properties of the lipopeptide biosurfactant were evaluated by determination of its critical micelle concentration (CMC) and hydrophile-lipophile balance (HLB). The produced biosurfactant decreased the surface tension of water to 36mNm -1 with the CMC of approximately 300mg/l. Furthermore, the solubility properties of the biosurfactant (dissolved in phosphate-buffer saline solution, pH7.4) were investigated by turbidity examination, dynamic light scattering (DLS) measurements, and transmission electron microscopy (TEM) inspection. It could be concluded that the biosurfactant showed the spherical-shaped vesicles at a concentration higher than its CMC and the circular dichroism (CD) spectra showed that the secondary structure of the biosurfactant vesicles is dominated by the β sheet., (Copyright © 2018. Published by Elsevier B.V.)

Background: While there is an ongoing trend to identify single nucleotide substitutions (SNSs) that are linked to inter/intra-species differences and disease phenotypes, short tandem repeats (STRs)/microsatellites may be of equal (if not more) importance in the above processes. Genes that contain STRs in their promoters have higher expression divergence compared to genes with fixed or no STRs in the gene promoters. In line with the above, recent reports indicate a role of repetitive sequences in the rise of young transcription start sites (TSSs) in human evolution., Results: Following a comparative genomics study of all human protein-coding genes annotated in the GeneCards database, here we provide a genome-scale portrait of human-specific short- and medium-size (≥ 3-repeats) tri- and tetranucleotide STRs and STR motifs in the critical core promoter region between - 120 and + 1 to the TSS and evidence of skewing of this compartment in reference to the STRs that are not human-specific (Levene's test p < 0.001). Twenty-five percent and 26% enrichment of human-specific transcripts was detected in the tri and tetra human-specific compartments (mid-p < 0.00002 and mid-p < 0.002, respectively)., Conclusion: Our findings provide the first evidence of genome-scale skewing of STRs at a specific region of the human genome and a link between a number of these STRs and TSS selection/transcript specificity. The STRs and genes listed here may have a role in the evolution and development of characteristics and phenotypes that are unique to the human species.

Objective: Late-onset Alzheimer's disease (AD) is a genetically heterogeneous neurodegenerative disorder. Associations of the glutathione S-transferases (GSTs) polymorphisms with the risk factors for AD have not been definitely confirmed. We investigated the association of GSTM1 and GSTT1 null deletion and GSTP1 313 A/G polymorphisms and the risk of AD in an Iranian population., Methods: The case group consisted of 280 individuals with AD and the control group included 168 age-matched healthy individuals. The genotyping of the GSTP1 polymorphism was determined by PCR-RFLP and the GSTM1 and GSTT1 deletions were done by multiplex PCR method., Results: The GSTP1 AG genotype was significantly lower (p = 0.005; OR = 0.57, 95% CI: 0.38-0.84) in the patients (41.1%) than the control group (56.5%). The GSTM1 null genotype was significantly higher (p < 0.001) in the patients (40.5%) than the control group (15.8%). The GSTT1 null genotype was significantly higher (p < 0.038) in the patients (31.2%) than the control group (21.5%). The patients homozygous for the GSTM1 and GSTT1 null alleles showed a 3.5 and 1.5-fold increased risk of AD, respectively. There were interaction between GSTP1 AG genotype and absence of APOE e4 allele (p = 0.001), as well as presence of APOE ε4 and GSTM1 null genotype (p < 0.0001)., Conclusion: These findings suggested that GSTM1 and GSTT1 null deletions may be associated with susceptibility to AD and people with APOE e4 and GSTM1 null deletion have a higher increased risk for Late-onset AD in Iranian population.

Objective: The role of short tandem repeats (STRs) in the control of gene expression among species is being increasingly understood following the identification of several instances in which certain STRs occur identically, or expand differentially, in primates versus nonprimates. These STRs may regulate genes that participate in characteristics that are associated with the divergence of primates from sibling orders (e.g., brain higher order functions). The CYTH4 gene contains the longest tetranucleotide STR in its core promoter, at 7-repeats, and links to the evolution of human and nonhuman primates. Allele and genotype distribution of this STR were studied in patients affected by schizophrenia (SCZ) and controls., Methods: High-resolution data were obtained on the allele and genotype distribution of the CYTH4 STR and a novel C > T single-nucleotide polymorphism (SNP) at its immediate upstream sequence in 255 patients with SCZ and 249 controls. Each sample was sequenced twice using the fluorescent dye termination method., Results: Novel alleles were detected at the long extreme of the GTTT-repeat, at 10- and 11-repeats, in the SCZ cases and controls. Excess of homozygosity was observed for the entire range of alleles across the GTTT-repeat and the C > T SNP in the SCZ patients in comparison with the controls (Yates corrected p < 0.011). Three genotypes consisting of the 11-repeat allele (i.e., 11/11, 10/11, and 7/11) were detected only in the SCZ patients (i.e., disease-only genotypes), and contributed to 2.3% of the SCZ genotypes (Mid p exact <0.007). The frequency of the 11-repeat allele was estimated at 0.02 and 0.006 in the SCZ patients and controls, respectively (Mid p exact <0.006)., Conclusion: This indicates that STR genotypes that are absent in the control group may be risk factors for SCZ. Future studies are warranted to test the significance of our findings.

Evolutionary analyses of the critical core promoter interval support a selective advantage for expanding the length of certain short tandem repeats (STRs) in humans. We recently reported genome-wide data on human core promoter STRs that are "exceptionally long" (≥6-repeats). Near the top of the list, the neuron-specific gene, RIT2, contains one of the longest GA-STRs at 11-repeats. In the present study, we analyzed the evolutionary implications of this STR across species. We also studied this STR in a sample of 2,143 Iranian human subjects that encompassed a number of neuropsychiatric disorders and controls. We report that this GA repeat is functional and different lengths of the repeat result in significant alteration in gene expression activity. The 11-repeat allele was human specific and the sole allele detected in 110 unrelated Iranian individuals randomly selected and sequenced from our control pool. Remarkably, homozygosity for a 5-repeat allele was detected in a consanguineous, hospitalized case of schizophrenia, which significantly decreased gene expression activity (p < 5 × 10 -6 ). The frequency of the 5-repeat allele in the Iranian population was calculated at <0.0001, putting this allele in the deleterious mutations category based on allele frequency. The 5-repeat allele is annotated in the Ensembl database in the heterozygous status (5/11) in one of four indigenous hunter-gatherer men sequenced from southern Africa (BUSHMAN KB1: rs113265205). The present findings indicate for the first time, selective advantage for a human-specific allele at an STR locus, and a phenomenon in which genotypes and alleles at the extreme length of STRs occur with disease only. This is a pilot study that warrants large-scale sequencing of the RIT2 core promoter STR in diseases and characteristics that are linked to the brain function.

Multiple sclerosis (MS) is a chronic autoimmune disease, and the most common cause of nontraumatic disability in young people. The etiology of this disease is not well defined yet. Cytokines play an important role in differentiation, maturation and survival of a wide range of cells, including cells of the immune system. Suppressor of cytokine signaling (SOCS) proteins are the most important regulators of this cytokine signaling pathway. The aim of present study was to compare the expression levels of SOCS1, SOCS2, SOCS3 and SOCS5 genes in the blood of 50 relapsing-remitting MS (RR-MS) patients and 50 healthy controls by Taqman Quantitative Real-Time PCR in patients and healthy control group. We observed that SOCS1 and SOCS5 expression was significantly down-regulated (P=0.045 and P=0.044, respectively); whereas, no significant difference was observed between MS patients and controls for SOCS2 and SOCS3 gene expression (P=0.747 and P=0.439, respectively). In addition, there was no significant correlation between the expression of SOCS1, SOCS2, SOCS3 and SOCS5 genes and clinical findings, such as the level of physical disability in the MS patients according to the Kurtzke Expanded Disability Status Scale (EDSS) criterion and disease duration. However, a significant positive correlation was observed between expression levels of SOCS genes. This study shows that loss of balance among various members of the SOCS family proteins may contribute to pathophysiology of multiple sclerosis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: The NRG1-ERBB4 neurotransmitter signaling pathway plays a key role in the pathogenesis of schizophrenia (SZ). The intronic single-nucleotide polymorphism rs707284 in ERBB4 links to PI3K-AKT suppression in SZ. Another protein indirectly affecting NRG1-ERBB4 signaling is β-secretase, which is encoded by the BACE1 gene, and activates NRG1 by proteolytic cleavage. In this study, we aimed to investigate the association of ERBB4 rs707284 and BACE1 rs490460 with the risk of SZ in an Iranian population., Subjects and Methods: A total of 973 subjects, including 480 SZ patients and 493 healthy controls, matched by ethnicity, age, and gender, were recruited in a case-control study. Genomic DNA was extracted from peripheral blood of all subjects and genotyping of rs707284 and rs490460 was performed using polymerase chain reaction (PCR)-restriction fragment length polymorphism and tetra-primer amplification refractory mutation system (tetra-ARMS) PCR genotyping assays, respectively., Results: A significant association was observed between the rs490460 T allele and SZ (p = 0.0002, odds ratio 0.69, 95% confidence interval 0.57-0.84). There was no association between the risk of SZ and rs707284., Conclusion: Our data indicate that rs490460 is associated with the risk of SZ. In silico analysis indicates that rs490460 may be a potential splicing site, which affects protein structure. Replication studies are needed to confirm our data.

Neurological disorders include a wide variety of mostly multifactorial diseases related to the development, survival, and function of the neuron cells. Single-nucleotide polymorphisms (SNPs) have been extensively studied in neurological disorders, and in a number of instances have been reproducibly linked to disease as risk factors. The RIT2 gene has been recently shown to be associated with a number of neurological disorders, such as Parkinson's disease (PD) and autism. In the study reported here, we investigated the association of the rs12456492 and rs16976358 SNPs of the RIT2 gene with PD, essential tremor (ET), autism, schizophrenia (SCZ), and bipolar disorder (BPD; total of 2290 patients), and 1000 controls, by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Significant association was observed between rs12456492 and two disorders, PD and ET, whereas rs16976358 was found to be associated with autism, SCZ, and BPD. Our findings are indicative of differential association between the RIT2 SNPs and different neurological disorders.

Background: Glutamate receptor 4, metabotropic (GRM4) expression is increased in the brain of patients with depression. The poorly conserved miR-1202 is downregulated in depression and is negatively correlated with GRM4. A variation located at the 3' UTR of the GRM4 gene may influence the interaction between miR-1202 and GRM4. The aim of this study was to determine the possible association between GRM4 3' UTR variant (rs2229901) and major depressive disorder (MDD)., Methods: A total of 500 subjects comprising 250 patients with MDD and 250 healthy controls were included in our study. The single nucleotide polymorphism rs2229901 was genotyped using PCR-RFLP method. Allele and genotype frequencies were compared between the two groups using chi-square test and logistic regression models. The impact of rs2229901 on GRM4/miR-1202 hybrid stability and local GRM4-3' UTR secondary structure were assessed using RNAsnp program., Results: Genotype and allele frequency of rs2229901were significantly different in patients with MDD comparing to the control group (p=0.018 and p=0.007, respectively). The G-allele was more prevalent among patients with MDD. The rs2229901 variant was predicted to be structure-disruptive., Limitations: The relatively small sample size and lack of functional experiments are the major limitations of this study., Conclusion: Our results suggest that rs2229901 is associated with MDD risk. This variant probably impacts the interaction between GRM4 and miR-1202. Functional studies are needed to clarify the possible mechanisms by which rs2229901 influences MDD risk., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Recently, the development of a safe bioactive material with antioxidant properties, which can improve healing activity are focusing. Biosurfactants are very famous for their antimicrobial and free radical scavenging activities. Thereof, the main aim of the present study was to investigate the antioxidant and wound healing activity of the lipopeptide biosurfactant (LBS) produced by Acinetobacter junii B6. DPPH radical scavenging activities and FRAP assays were used to measure the antioxidant properties., Methods: For evaluation of the wound healing activity, 36 rats (previously wounded in depilated thoracic region) were randomly distributed into six groups and chromatic, wound contraction, and histopathological feature were examined. The assessment levels of reactive oxygen species (ROS) after LBS exposure were determined using malondialdehyde (MDA), hydrogen peroxide (H2O2), and glutathione (GSH) assay kits., Results: DPPH assay showed notable scavenging activities at the corresponding concentrations with IC50 value of 0.7 mg/ml. The reductive potency of the LBS showed lower performance at low concentration, while exhibited a remarkable increase at higher concentration. The best histopathological remission was achieved following treatment by 5 mg/ml of the LBS. Scar wounds at day 13 showed the lowest lesion sizes, increased re-epithelialization, hair follicle detection, and decreased amounts of neutrophilic inflammation, immaturity of the wound bed, erythema, edema, capillary, and retention of necrotic tissue., Conclusion: Results from MDA, H2O2, and GSH levels of the treated sample confirmed the scavenging property of the bacterial derived LBS through ROS. It could be concluded that the pharmaceutical formula encourages the wound healing because of its notable antioxidant capacity., Highlights: • DPPH and FRAP assays showed notable scavenging activity. • MDA, H2O2, and GSH; confirmed the scavenging property of the derived biosurfactant through ROS. • Synthesized formula encourages the healing of the wound because of its antioxidant capacity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Recent reports of a link between human- and primate-specific genetic factors and human/primate-specific characteristics and diseases necessitate genome-wide identification of those factors. We have previously reported core promoter short tandem repeats (STRs) of extreme length (≥6-repeats) that have expanded exceptionally in primates vs. non-primates, and may have a function in adaptive evolution. In the study reported here, we extended our study to the human STRs of ≥3-repeats in the category of penta and hexaucleotide STRs, across the entire human protein coding gene core promoters, and analyzed their status in several superorders and orders of vertebrates, using the Ensembl database. The ConSite software was used to identify the transcription factor (TF) sets binding to those STRs. STR specificity was observed at different levels of human and non-human primate (NHP) evolution. 73% of the pentanucleotide STRs and 68% of the hexanucleotide STRs were found to be specific to human and NHPs. AP-2alpha, Sp1, and MZF were the predominantly selected TFs (90%) binding to the human-specific STRs. Furthermore, the number of TF sets binding to a given STR was found to be a selection factor for that STR. Our findings indicate that selected STRs, the cognate binding TFs, and the number of TF set binding to those STRs function as switch codes at different levels of human and NHP evolution and speciation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Accumulating evidence of population association studies support the hypothesis that the high heritability of major psychiatric disorders is a combination of relatively common alleles of modest effect, and rare alleles some with relatively larger effects. We have previously reported low frequency mutations in the proximal promoter of the human calreticulin (CALR) gene that co-occur with the spectrum of major psychiatric disorders. One of those mutations at -205C>T (rs556992558) was detected in an isolate case of schizoaffective disorder. In the current study, the functional implication of mutation -205T is studied in the human neuronal cell lines LAN-5, BE(2)-C and HEK-293. In contrast with other mutations in the promoter region which increase gene expression activity, the -205T mutation significantly decreased gene expression in those cell lines in comparison with the wild-type -205C nucleotide (p < 0.000001, p < 0.0005, and p < 0.017, respectively). Treatment of the cell lines with the mood-stabilizing drug, valproic acid (VPA) resulted in differential gene expression activity in the mutant -205T versus the wild-type -205C construct. VPA increased gene expression activity in both constructs, while a significantly higher expression activity was observed in the mutant construct (p < 0.01), indicative of the creation of a positive effector binding site for VPA as a result of the -205T mutation. We conclude that deviation from normalcy in the level of CALR in either direction is associated with major psychiatric disorders.

Non-syndromic autosomal recessive intellectual disability (ID) is a genetically heterogeneous disorder with more than 50 mutated genes to date. ID is characterized by deficits in memory skills and language development with difficulty in learning, problem solving, and adaptive behaviors, and affects ∼ 1% of the population. For detection of disease-causing mutations in such a heterogeneous disorder, homozygosity mapping together with exome sequencing is a powerful approach, as almost all known genes can be assessed simultaneously in a high-throughput manner. In this study, a hemizygous c.786C>G:p.Ile262Met in the testis specific protein Y-encoded-like 2 (TSPYL2) gene and a homozygous c.11335G>A:p.Asp3779Asn in the low-density lipoprotein receptor-related protein 2 (LRP2) gene were detected after genome-wide genotyping and exome sequencing in a consanguineous Pakistani family with two boys with mild ID. Mutations in the LRP2 gene have previously been reported in patients with Donnai-Barrow and Stickler syndromes. LRP2 has also been associated with a 2q locus for autism (AUTS5). The TSPYL2 variant is not listed in any single-nucleotide polymorphism databases, and the LRP2 variant was absent in 400 ethnically matched healthy control chromosomes, and is not listed in single-nucleotide polymorphism databases as a common polymorphism. The LRP2 mutation identified here is located in one of the low-density lipoprotein-receptor class A domains, which is a cysteine-rich repeat that plays a central role in mammalian cholesterol metabolism, suggesting that alteration of cholesterol processing pathway can contribute to ID.

A recent large-scale study have reported that rs1063843, a single nucleotide polymorphism located in the CAMKK2 gene is highly associated with schizophrenia in European and Han Chinese populations. Increasing evidences show that schizophrenia and bipolar disorder have some common genetic variance. Here, we evaluated the association of this variant with schizophrenia and bipolar disorder in Iranian population. Genomic DNA was extracted from peripheral blood of 500 schizophrenic patients, 500 bipolar patients and 500 normal controls and all were genotyped for the rs1063843 using a PCR-RFLP method. The allele frequency of rs1063843 was significantly different in both schizophrenia and bipolar patients comparing to control group. For the first time, we showed that rs1063843 is highly associated with bipolar disorder, although more replication studies are needed to confirm our findings. Our results also support the findings of previous studies suggesting a significant association between rs1063843 and schizophrenia.

We have recently reported a genome-scale catalog of human protein-coding genes that contain "exceptionally long" STRs (≥6-repeats) in their core promoter, which may be of selective advantage in this species. At the top of that list, SCGB2B2 (also known as SCGBL), contains one of the longest CA-repeat STRs identified in a human gene core promoter, at 25-repeats. In the study reported here, we analyzed the conservation status of this CA-STR across evolution. The functional implication of this STR to alter gene expression activity was also analyzed in the HEK-293 cell line. We report that the SCGB2B2 core promoter CA-repeat reaches exceptional lengths, ranging from 9- to 25-repeats, across Apes (Hominoids) and the Old World monkeys (CA>2-repeats were not detected in any other species). The longest CA-repeats and highest identity in the SCGB2B2 protein sequence were observed between human and bonobo. A trend for increased gene expression activity was observed from the shorter to the longer CA-repeats (p<0.009), and the CA-repeat increased gene expression activity, per se (p<0.02). We propose that the SCGB2B2 gene core promoter CA-repeat functions as an expression code for the evolution of Apes and the Old World monkeys., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Recent emerging evidence indicates that changes in gene expression levels are linked to human evolution. We have previously reported a human-specific nucleotide in the promoter sequence of the calreticulin (CALR) gene at position -220C, which is the site of action of valproic acid. Reversion of this nucleotide to the ancestral A-allele has been detected in patients with degrees of deficit in higher brain cognitive functions. This mutation has since been reported in the 1000 genomes database at an approximate frequency of <0.0004 in humans (rs138452745). In the study reported here, we present update on the status of rs138452745 across evolution, based on the Ensembl and NCBI databases. The DNA pulldown assay was also used to identify the proteins binding to the C- and A-alleles, using two cell lines, SK-N-BE and HeLa. Consistent with our previous findings, the C-allele is human-specific, and the A-allele is the rule across all other species (N=38). This nucleotide resides in a block of 12-nucleotides that is strictly conserved across evolution. The DNA pulldown experiments revealed that in both SK-N-BE and HeLa cells, the transcription repressor BEN domain containing 3 (BEND3) binds to the human-specific C-allele, whereas the nuclear factor I (NFI) family members, NF1A, B, C, and X, specifically bind to the ancestral A-allele. This binding pattern is consistent with a previously reported decreased promoter activity of the C-allele vs. the A-allele. We propose that there is a link between binding of BEND3 to the CALR rs138452745 C-allele and removal of NFI binding site from this nucleotide, and the evolution of human-specific higher brain functions. To our knowledge, CALR rs138452745 is the first instance of enormous nucleotide conservation across evolution, except in the human species., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The membrane epithelial mucin MUC1 is expressed at the luminal surface of most simple epithelial cells, but expression is greatly increased in most breast cancers. The aims of present study were to investigate expression of the MUC1 gene and interactive affects in metastases. Whole cell RNA isolation from 50 sentinel lymph nodes (SNLs) of breast cancer patients was performed using reverse transcription and real-time PCR. All patients were diagnosed with breast cancer and without metastasis, confirmed by IHC staining. The evaluation of tumor and normal samples for expression of MUC1 gene, the results were 49.1% non-expressive and 45.3% expression (Student t, p = 0.03). Also in comparison of normal breast tissue and breast cancer SLN for MUC1 gene, MUC1 negative SLNs were 75.0% (18 samples) and MUC1 positive samples were 25.0% (6 samples). Over-expression of MUC1 gene may offer a target for therapy related to progression and metastasis in women with breast cancer.

Cytokines play important roles in the inflammation pathways. Alzheimer's disease (AD) is an inflammatory disease, and it is suggested that cytokines are able to influence AD. We investigated the association between IL16 polymorphisms and risk of AD in an Iranian population. The case group consisted of 144 individuals with AD and the control group included 173 healthy individuals. Genotyping of the IL16 rs4072111 C>T and rs1131445 T>C polymorphisms was determined using PCR-RFLP method. The frequency of rs4072111 CT genotype was significantly lower (P=0.007; OR=0.5, 95% CI: 0.3-0.8) in the patients (17.3%) than the control group (30%). The rs4072111 T allele was significantly lower (P=0.008; OR=0.5, 95% CI: 0.3-0.9) in the cases (8.6%) compared with the control group (15.6%). The IL16 rs4072111 polymorphism may be associated with susceptibility to AD and the T allele may have a protective role in the progression of AD in an Iranian population., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Primate-specific genes and regulatory mechanisms could provide insight into human brain functioning and disease. In a genome-scale analysis of the entire protein-coding genes listed in the GeneCards database, we have recently reported human genes that contain "exceptionally long" short tandem repeats (STRs) in their core promoter, which may be of adaptive/selective evolutionary advantage in this species. The longest tetra-nucleotide repeat identified in a human gene core promoter belongs to the CYTH4 gene. This GTTT-repeat is specific to Hominidae and Old World monkeys, and the shortest allele of this repeat, (GTTT)6, is linked with neural dysfunction and type I bipolar disorder in human. In the present study, we sought a possibly broader role for the CYTH4 gene core promoter GTTT-repeat in neural functioning and investigated its allelic distribution in a total of 949 human subjects, consisting of two neurodegenerative disorders, multiple sclerosis (MS) (n = 272) and Alzheimer's disease (AD) (n = 257), and controls (n = 420). The range of the alleles of this GTTT-repeat in the human sample studied was between 6- and 9-repeats. The shortest allele, (GTTT)6, was significantly in excess in the MS and AD patients in comparison with the controls (p < 0.004). The 6/6, 6/7, and 7/7 genotypes were in excess in the MS and AD patients, whereas the overall frequency of all other genotypes (consisting of at least one longer allele, i.e., 8- or 9-repeat) was higher in the controls (p < 0.005), indicating a dominant and protective effect for the longer alleles against neurodegeneration. This is the first indication of the involvement of a primate-specific STR in neurodegeneration in humans. We propose an adaptive evolutionary role for the expansion of the CYTH4 gene core promoter GTTT-repeat in the human brain, which is supported by a link between the shortest allele of this repeat with neuropsychiatric disorders.

Evidence of primate-specific genes and gene regulatory mechanisms linked to bipolar disorder (BD) lend support to evolutionary/adaptive processes in the pathogenesis of this disorder. Following a genome-scale analysis of the entire protein coding genes annotated in the GeneCards database, we have recently reported that cytohesin-4 (CYTH4) contains the longest tetra-nucleotide short tandem repeat (STR) identified in a human protein-coding gene core promoter, which may be of adaptive advantage to this species. In the current study, we analyzed the evolutionary trend of this STR across evolution. We also analyzed the functional implication and distribution of this STR in a group of patients with type 1 BD (n=233) and controls (n=262). We found that this STR is exceptionally expanded in primates (Fisher exact p<0.00003). Association was observed between type I BD and the 6-repeat allele of this STR, (GTTT)₆ (Yates corrected Χ(2)=12.68, p<0.0001, OR: 1.68). This allele is the shortest length of the GTTT-repeat identified in the human subjects studied. Consistent with that finding, excess homozygosity was observed for the shorter alleles, (GTTT)₆ and (GTTT)₇, vs. the longer alleles, (GTTT)₈ and (GTTT)₉ in the BD group (Yates corrected Χ(2)=5.18, p<0.01, 1 df, OR: 1.96). Using Dual Glo luciferase system in HEK-293 cells, a trend for gene expression repression was observed from the 6- to the 9-repeat allele (p<0.003), and the GTTT-repeat significantly down-regulated gene expression, per se (p<0.0006). This is the first evidence of a link between a primate-specific STR and a major psychiatric disorder in human. It may be speculated that the CYTH4 GTTT-repeat in primates may have conferred selective advantage to this order, reflected in neural function and neurophenotypes. The role of the CYTH4 gene in the pathogenesis of type I BD remains to be clarified in the future studies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Alteration in gene expression levels underlies many of the phenotypic differences across species. Because of their highly mutable nature, proximity to the +1 transcription start site (TSS), and the emerging evidence of functional impact on gene expression, core promoter short tandem repeats (STRs) may be considered an ideal source of variation across species. In a genome-scale analysis of the entire Homo sapiens protein-coding genes, we have previously identified core promoters with at least one STR of ≥ 6-repeats, with possible selective advantage in this species. In the current study, we performed reverse analysis of the entire Homo sapiens orthologous genes in mouse in the Ensembl database, in order to identify conserved STRs that have shrunk as an evolutionary advantage to humans. Two protocols were used to minimize ascertainment bias. Firstly, two species sharing a more recent ancestor with Homo sapiens (i.e. Pan troglodytes and Gorilla gorilla gorilla) were also included in the study. Secondly, four non-primate species encompassing the major orders across Mammals, including Scandentia, Laurasiatheria, Afrotheria, and Xenarthra were analyzed as out-groups. We introduce STR evolutionary events specifically identical in primates (i.e. Homo sapiens, Pan troglodytes, and Gorilla gorilla gorilla) vs. non-primate out-groups. The average frequency of the identically shared STR motifs across those primates ranged between 0.00005 and 0.06. The identified genes are involved in important evolutionary and developmental processes, such as normal craniofacial development (TFAP2B), regulation of cell shape (PALMD), learning and long-term memory (RGS14), nervous system development (GFRA2), embryonic limb morphogenesis (PBX2), and forebrain development (APAF1). We provide evidence of core promoter STRs as evolutionary switch codes for primate speciation, and the first instance of identity-by-descent for those motifs at the interspecies level., (© 2014 Wiley Periodicals, Inc.)

Mirror movements (MRMV) are involuntary movements on one side of the body that mirror voluntary movements on the opposite side. Congenital mirror movement disorder is a rare, typically autosomal-dominant disorder, although it has been suspected that some sporadic cases may be due to recessive inheritance. Using a linkage analysis and a candidate gene approach, two genes have been implicated in congenital MRMV disorder to date: DCC on 18q21.2 (MRMV1), which encodes a netrin receptor, and RAD51 on 15q15.1 (MRMV2), which is involved in the maintenance of genomic integrity. Here, we describe a large consanguineous Pakistani family with 11 cases of congenital MRMV disorder reported across five generations, with autosomal recessive inheritance likely. Sanger sequencing of DCC and RAD51 did not identify a mutation. We then employed microarray genotyping and autozygosity mapping to identify a shared region of homozygosity-by-descent among the affected individuals. We identified a large autozygous region of ~3.3 Mb on chromosome 22q13.1 (Chr22:36605976-39904648). We used Sanger sequencing to exclude several candidate genes within this region, including DMC1 and NPTXR. Whole exome sequencing was employed, and identified a splice site mutation in the dynein axonemal light chain 4 gene, DNAL4. This splice site change leads to skipping of exon 3, and omission of 28 amino acids from DNAL4 protein. Linkage analysis using Simwalk2 gives a maximum Lod score of 6.197 at this locus. Whether or how DNAL4 function may relate to the function of DCC or RAD51 is not known. Also, there is no suggestion of primary ciliary dyskinesis, situs inversus, or defective sperm in affected family members, which might be anticipated given a putative role for DNAL4 in axonemal-based dynein complexes. We suggest that DNAL4 plays a role in the cytoplasmic dynein complex for netrin-1-directed retrograde transport, and in commissural neurons of the corpus callosum in particular. This, in turn, could lead to faulty cross-brain wiring, resulting in MRMV.