Tuberculosis in Human Bones from 4000 Years Ago, Iran.

Background: Tuberculosis is caused by a bacterium called Mycobacterium tuberculosis, which is a contagious and infectious disease; in the first stage, it destroys the lungs and in the next stage other body organs, such as the spine and long bones. This disease is transmitted through an infected person and due to the weakness of the immune system, the infection intensifies. Tuberculosis has two stages: low activity and high activity. In this article, we have discussed the signs of tuberculosis destruction with high intensity on the bones of prehistory human remains. Methods: The examples of our research are related to human remains from the ancient cemetery of 4000 years ago from Sagezabad region of Qazvin Province of Iran. That period of history coincides with the Iron Age 2 and 3 in the region. People inside the Sagezabad cemetery were very near to early urban (the late rural) society. Results: By matching the form of bone destruction with international atlases for tuberculosis, we have reached a satisfactory result in this article. Due to the strong penetration of the infection into the bones, destruction in the remains was high, so it has simplified the diagnosis for us. Conclusion: We found tuberculosis among the bones. This common ancient disease existed even among Neanderthals.

Clinical Presentation and WES Analysis of a Large Iranian Pedigree in Five Successive Generation Affected to Sever Multiple Synostosis 2 (SYNS2, Farhud Type).

Background: Bone Morphogenetic Proteins and the related Growth and Differentiation Factors (GDFs) are much conserved signaling proteins. GDF5 is pivotal for skeletal development. Several skeletal dysplasia and malformation syndromes are known as a result of mutations in GDF5. Multiple Synostosis Syndrome2 (SYNS2) is characterized by tarsal-carpal coalition, humeroradial synostosis, brachydactyly, and proximal symphalangism. In this study, we analyzed a large Iranian pedigree affected with a new type of SYNS2 (Farhud Type) in five successive generations. Methods: In this family-based study (1982-2022), Genetic linkage analysis of the pedigree (58affected, 62healthy) excluded the locus on chromosome 17q21-q22 in our previous study. Thus, we focused on 20q11.22 locus and GDF5 gene. Genetic investigations were performed on 16 patients with SYNS2 and 40 healthy individuals. Results: Whole-exome-sequencing results identified a heterozygote missense mutation in exon2 of GDF5 (NG_008076.1:g.9239G>A, NM_000557.2:c.1424G>A, S475N, rs121909347). This mutation was found in all patients but not in the unaffected individuals. This missense mutation is notable because S475 is strictly conserved among different species, and it is located in a highly conserved and active mature domain of GDF5 (phyloP100way=7.64). The corresponding defect in GDF5 may have unknown interaction with normal active 3rd and 4th structure of the product. Further bioinformatics study (amino acid multiple alignments) showed that the S475 is a much-conserved residue in many different species. Conclusion: These results introduce a new role of GDF5 in pathogenesis of a SYNS2 (Farhud Type), considered in genetic counseling, prenatal diagnosis, and as a potential target for molecular therapy, if possible.

Tracking of Infectious Diseases and Deadly Injuries through Signs Observed in Excavated Human Skeletons of 2000 BC/Iron Age in Iran.

Background: Throughout history, many wars have occurred for various reasons, and many empires and kings have fallen or many people killed by wars. Wars were not always due to the conquest of the country. in the Iron Age, societies were governed by tribes at the head of the tribe, and war was only for to seize property, slaves, and food. Our research area is the same period as the Medes Kingdom, which included the union of small, large tribes, wars between tribes existed in that period, and their signs can be seen on the remains of the people of that period. Methods: Our research is related to human remains from Sagezabad cemetery, Qazvin plain, which dates back to 2000 BC (Iron Age 2 and 3) in Iran. Results: The blows on the remains were very serious and caused death. We have discussed how to kill by "considering the injured body". Conclusion: Our investigation of how people were killed in war based on injury marks and bullet holes in bones, and simulating those injuries to body tissues and organs also, people who had bone cuts from the war and survived and had bone repair and died due to lack of nutrients and infection were also discussed.

Oral Infections in Ancient Human Skulls in 2000 BC/Iron Age, Iran.

Background: Oral infections have been seen in humans since ancient times. Excessive penetration of this infection can cause human death. Most of these infections are gum cysts and abscesses. The cyst creates large hard lumps in the gums, which is causes loose, and protruding teeth and abscesses, causing cavities in the jawbone and teeth. In this article, we have discussed for this infectious disease in 4000 - year - old ancient humans from Qazvin Province, Iran. The bone remains of our research are related to Sagezabad ancient cemetery in Qazvin plain. Methods: We tried to use reliable international atlases to get detailed information about ancient oral infections. The bones were extracted from the 2019 excavation of the Ghara Tappe area of Sagezabad for the Iron Age 2nd and 3rd Qazvin plains of Iran. This cemetery belongs to the period of the Medes Kingdom (pre - Achaemenian kingdom) in Iran. Results: We have discussed one of the ancient cemeteries with a large number of ancient populations. In this cemetery, there are signs of war and infectious diseases on the bones, which can be clearly seen. We have specially mentioned the abscess as the cause of oral infection from Sagezabad cemetery. Conclusion: Oral infection existed in Iran since 2000 BC. Of course, this infection was common in ancient times and even Paleolithic period, like Homo Heidelbergensis.

CDON Mutation Related to Nose Deformity with Variable Expression in Holoprosencephaly in an Iranian Family: A Case Report.

Holoprosencephaly, a complicated brain abnormality arising from incomplete prosencephalon cleavage, affects both the forebrain and the face. Holoprosencephaly Type 11, with variable expression or partial penetrance, is caused by CDON pathogenic variants associated with the disrupted Sonic Hedgehog (SHH)-pathway. Herein, we aimed to describe a family with genetic nose problems. After counselling and drawing pedigree in Farhud's Genetic Clinic, Tehran, Iran in 2021, DNA extraction of a proband and a few members of his family (patient and control) was conducted. Whole exome sequencing was utilized for detecting the gene and its variant in the proband with a nose deformity. The results were confirmed with Sanger sequencing. This variant was checked in other members by Sanger sequencing. Analysis of the Exome data showed a heterozygous splicing variant in the CDON gene (NM_016952; c.3276+1G>T) in the proband who had a nose deformity and then the results were confirmed with Sanger sequencing. Such a variant was observed in Proband's brother with a nose deformity and was not observed in Proband's cousin with no abnormal phenotype. Recent investigations, in an Iranian family, with a heterozygous splicing CDON mutation as a human candidate gene are discussed for the first time in relation to the likely pathogenesis of facial deformities, particularly nose deformity, in Holoprosencephaly.

Investigation of rs8106922 and rs157580 of TOMM40 Gene in Individuals with Late-Onset Alzheimer's Disease in Iran.

Background: We aimed to investigate two polymorphisms, rs8106922 and rs157580 of TOMM40 in Alzheimer's disease (AD). Methods: In the present case-control research, we collected blood samples from 117 AD patients and 130 controls from Alzheimer's Hospital, residents of Tehran, Iran during the winter 2020 to autumn 2022. Following extraction of DNA, Genotyping of TOMM40 polymorphisms rs8106922 and rs157580 were examined by sequencing and ARMS/PCR approaches. We compared distributions of genotypes in both patient and healthy groups using the Chi-Square test. Results: Regarding rs157580, a statistically significant difference was observed in the GA genotype frequency between patient and healthy groups, in both univariate and multivariate modes with these results that have come respectively, and it can be regarded as a protection factor P<0.05).. No significant difference was observed in the frequency of A and G alleles between patient and healthy groups. Besides, concerning rs8106922, the AG genotype frequency in research groups in both univariate and multivariate cases, with these results that have come respectively was significantly different (P=0.003) & (P=0.009). Regarding GG genotype, a statistically significant difference was observed between the patient and healthy groups in both univariate and multivariate cases, respectively (P=0.419) & (P=0.425). Significant differences were observed in the G allele frequency for rs8106922 in the healthy and patient groups (P=0.007), it can be regarded as a potential protective factor. Conclusion: It is possible to consider the TOMM40 gene as one of the potential genes concerning Alzheimer's disease.

Executive Functions and Public Health: A Narrative Review.

Executive functions (EFs) skills are necessary for regulating the thoughts, emotions, and actions which are associated with many aspects of daily functioning. Executive dysfunction (EDFs) is present in a wide range of mental disorders. New study indicates that EFs may predict health behavior and make it easier to engage in a variety of healthy activities. In this narrative review, EFs and public health are briefly discussed. In general, 133 articles met the inclusion criteria (published 2018-2023) which were reviewed. EFs affect the mental and physical health. Besides individual problems, people with mental problems have heavy costs to society. Mental health cannot be considered separately from general health. Consequently, preventive and therapeutic approaches to mental health should be considered not only at the level of the whole society, but also at the global level.

CRISPR/Cas9 RET Gene Knockout in Medullary Thyroid Carcinoma Cell-lines: Optimization and Validation.

Background: Medullary Thyroid Cancer (MTC) is a very aggressive type of thyroid carcinoma. Mutation in RET proto-oncogene is demonstrated in MTC development. We aimed to knock-out of RET-oncogene using CRISPR/Cas9 genome editing method in MTC cell-lines. Methods: This research was conducted in Shahid Beheshti University of Medical Sciences, Tehran, Iran during 2019-2020. Four different sgRNAs were designed to target exons one, two, and four of RET-oncogene in TT and MZ-CRC-1 cell-lines using bioinformatics tools, then the CRISPR/Cas9 constructs was made. About 72-hours after cell transfection, T7EI method and DNA sequencing were used to confirm the knock-out of RET-oncogene. Expression of RET, Calcitonin genes and RET protein were evaluated by Real-time PCR and ELISA, respectively. Results: The results of T7E1, and DNA sequencing of transfected cells confirmed RET gene knock-out by CRISPR/Cas9. There was a significant decrease in RET gene expression and RET protein in transfected TT and MZ cells compared to controls. The rate of cell apoptosis in transfected cells was significantly increased. Calcitonin gene expression was also significantly reduced in transfected cells. p-RET, p-PI3K, p-AKT, p-MEK, p-ERK protein levels were significantly reduced in TT and MZ transfected cells. Conclusion: For the first time, knock-out of RET gene was performed and confirmed using CRISPR/Cas9. Inhibition of this gene leads to inhibition of the tyrosine kinase RET signal transduction pathway. Therefore, it can be one of the most effective and specific therapeutic goals in the field of Personalized Medicine in the treatment of diseases caused by over activity of RET molecular pathway.

SARS-COV-2 Notable Mutations and Variants: A Review Article.

SARS-COV-2 (COVID-19) the virus that caused an epidemic of sever acute respiratory syndrome is what the world has been dealing with since Dec 2019. As the pandemic continues different variants that emerge during mutations have become the latest concern, with notable examples detected in South Africa, Brazil, and UK. Variants are complicated and each one is a collection of several mutations, all of which have the potential to change the virus in unexpected ways. Studying variants is imperative as they can lead the epidemic to the increase of population immunity. In the present study, we reviewed key mutations and concerning variants according to the WHO tracking Sars-Cov-2 program. Databases were searched through Feb to Mar 2022. Overall, 477 studies were extracted from databases, among them 165 studies included mutations, 239 included COVID-19 variants and 43 included both mutations and variants. At the final step of data screening 24 studies associated to mutations, 31 studies with the highlighted information on COVID-19 variants and 31 studies related to both mutations and variants were extracted for this review article. In conclusion, analyses of the genomic sequence of SARS-CoV-2 indicate that structural proteins are key molecules in the assembly of virus while NSPs can have different biochemical properties and possibly cellular functions.

In-Vitro Fertilization Impact on the Risk of Breast Cancer: A Review Article.

BACKGROUND: Due to the increasing prevalence of infertility, the number of referrals to infertility treatment centers has also increased. Nowadays, assisted reproductive technology (ART), including in vitro fertilization (IVF), is a treatment for infertility or genetic problems. Considering the possible consequences of this method among women undergoing in vitro fertilization (IVF) and kids conceived by IVF, extensive research has been conducted in this regard. METHODS: Overall, 100 articles were entered into the study, and relevant articles were searched and extracted from PubMed, Springer, and Google Scholar databases. In IVF procedure, medications such as Clomiphene citrate and gonadotropins are used to stimulate and mature follicles and thus increase ovulation. RESULTS: There are conflicting opinions on this issue. Some findings report a slight increase in cancer risk for hormone-sensitive cancers including breast cancer. The long-term use of IVF medications can increase estrogen hormones and cause excessive expression of genes, resulting in an increased risk of breast cancer, which is one of the most frequent cancers among women. CONCLUSION: There are some risks to be aware of, which followed the hypothesis that long IVF treatment process may lead to breast cancer among IVF candidates. Furthermore, the risk of breast cancer may be increased in those women with a positive family history and related inherited genes. Therefore, women candidates for IVF should be informed of the probable implications of the reproductive therapy techniques.

A Homozygote Mutation in S-Antigen Visual Arrestin SAG Gene in an Iranian Patient with Oguchi Type One: A Case Report.

Oguchi disease is a rare autosomal recessive form of congenital stationary night blindness (CSNB) characterized by specific features such as golden-brown discoloration of the fundus called Mizuo-Nakamura phenomenon which is distinguishable by fundoscopy, and retinography. Clinical diagnosis is confirmed through genetic test. Two known genes in pathogenesis of Oguchi disease are SAG and GRK1. A 35-year-old Iranian male exhibiting the clinical features of congenital stationary night blindness, was referred to the genetic clinic of Dr. Farhud, Tehran, Iran in 2012 and examined. Ophthalmic examination including slit-lamp biomicroscopy, perimetry and funduscopy was performed. Additionally, the full-field electroretinography and molecular testing for congenital stationary night blindness were performed. Molecular genetic tests, including the analysis of GSK1 and SAG genes exon-intron boundaries were performed for this patient and his family. According to the sequencing results, we did not find any mutation in GSK1 gene. However, a new homozygote mutation at location chr2:233320735, c.517delC, p.P96LfsX28 was identified in exon four of SAG gene. This deletion causes a frame shift mutation, and premature stop codon that results in deletion of about 281 amino acid residues of S-antigen visual arrestin protein (from entire C-terminal). This mutation was also found in patient's parents and one of his sister as heterozygote form. This is the first molecular evidence for SAG gene mutation in an Iranian family affected with Oguchi disease type 1. The identification of the new c.517delC, p.P96LfsX28 mutation in this family with Oguchi disease can confirm the pathogenicity of this variant.