An Ancient Harappan Genome Lacks Ancestry from Steppe Pastoralists or Iranian Farmers.

We report an ancient genome from the Indus Valley Civilization (IVC). The individual we sequenced fits as a mixture of people related to ancient Iranians (the largest component) and Southeast Asian hunter-gatherers, a unique profile that matches ancient DNA from 11 genetic outliers from sites in Iran and Turkmenistan in cultural communication with the IVC. These individuals had little if any Steppe pastoralist-derived ancestry, showing that it was not ubiquitous in northwest South Asia during the IVC as it is today. The Iranian-related ancestry in the IVC derives from a lineage leading to early Iranian farmers, herders, and hunter-gatherers before their ancestors separated, contradicting the hypothesis that the shared ancestry between early Iranians and South Asians reflects a large-scale spread of western Iranian farmers east. Instead, sampled ancient genomes from the Iranian plateau and IVC descend from different groups of hunter-gatherers who began farming without being connected by substantial movement of people.

The effect of large-scale anti-contagion policies on the COVID-19 pandemic.

Governments around the world are responding to the coronavirus disease 2019 (COVID-19) pandemic1, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with unprecedented policies designed to slow the growth rate of infections. Many policies, such as closing schools and restricting populations to their homes, impose large and visible costs on society; however, their benefits cannot be directly observed and are currently understood only through process-based simulations2-4. Here we compile data on 1,700 local, regional and national non-pharmaceutical interventions that were deployed in the ongoing pandemic across localities in China, South Korea, Italy, Iran, France and the United States. We then apply reduced-form econometric methods, commonly used to measure the effect of policies on economic growth5,6, to empirically evaluate the effect that these anti-contagion policies have had on the growth rate of infections. In the absence of policy actions, we estimate that early infections of COVID-19 exhibit exponential growth rates of approximately 38% per day. We find that anti-contagion policies have significantly and substantially slowed this growth. Some policies have different effects on different populations, but we obtain consistent evidence that the policy packages that were deployed to reduce the rate of transmission achieved large, beneficial and measurable health outcomes. We estimate that across these 6 countries, interventions prevented or delayed on the order of 61 million confirmed cases, corresponding to averting approximately 495 million total infections. These findings may help to inform decisions regarding whether or when these policies should be deployed, intensified or lifted, and they can support policy-making in the more than 180 other countries in which COVID-19 has been reported7.

Long divergent haplotypes introgressed from wild sheep are associated with distinct morphological and adaptive characteristics in domestic sheep.

The worldwide sheep population comprises more than 1000 breeds. Together, these exhibit a considerable morphological diversity, which has not been extensively investigated at the molecular level. Here, we analyze whole-genome sequencing individuals of 1,098 domestic sheep from 154 breeds, and 69 wild sheep from seven Ovis species. On average, we detected 6.8%, 1.0% and 0.2% introgressed sequence in domestic sheep originating from Iranian mouflon, urial and argali, respectively, with rare introgressions from other wild species. Interestingly, several introgressed haplotypes contributed to the morphological differentiations across sheep breeds, such as a RXFP2 haplotype from Iranian mouflon conferring the spiral horn trait, a MSRB3 haplotype from argali strongly associated with ear morphology, and a VPS13B haplotype probably originating from urial and mouflon possibly associated with facial traits. Our results reveal that introgression events from wild Ovis species contributed to the high rate of morphological differentiation in sheep breeds, but also to individual variation within breeds. We propose that long divergent haplotypes are a ubiquitous source of phenotypic variation that allows adaptation to a variable environment, and that these remain intact in the receiving population probably due to reduced recombination.

Zebrafish as a model to investigate a biallelic gain-of-function variant in MSGN1, associated with a novel skeletal dysplasia syndrome.

BACKGROUND/OBJECTIVES: Rare genetic disorders causing specific congenital developmental abnormalities often manifest in single families. Investigation of disease-causing molecular features are most times lacking, although these investigations may open novel therapeutic options for patients. In this study, we aimed to identify the genetic cause in an Iranian patient with severe skeletal dysplasia and to model its molecular function in zebrafish embryos. RESULTS: The proband displays short stature and multiple skeletal abnormalities, including mesomelic dysplasia of the arms with complete humero-radio-ulna synostosis, arched clavicles, pelvic dysplasia, short and thin fibulae, proportionally short vertebrae, hyperlordosis and mild kyphosis. Exome sequencing of the patient revealed a novel homozygous c.374G > T, p.(Arg125Leu) missense variant in MSGN1 (NM_001105569). MSGN1, a basic-Helix-Loop-Helix transcription factor, plays a crucial role in formation of presomitic mesoderm progenitor cells/mesodermal stem cells during early developmental processes in vertebrates. Initial in vitro experiments show protein stability and correct intracellular localization of the novel variant in the nucleus and imply retained transcription factor function. To test the pathogenicity of the detected variant, we overexpressed wild-type and mutant msgn1 mRNA in zebrafish embryos and analyzed tbxta (T/brachyury/ntl). Overexpression of wild-type or mutant msgn1 mRNA significantly reduces tbxta expression in the tailbud compared to control embryos. Mutant msgn1 mRNA injected embryos depict a more severe effect, implying a gain-of-function mechanism. In vivo analysis on embryonic development was performed by clonal msgn1 overexpression in zebrafish embryos further demonstrated altered cell compartments in the presomitic mesoderm, notochord and pectoral fin buds. Detection of ectopic tbx6 and bmp2 expression in these embryos hint to affected downstream signals due to Msgn1 gain-of-function. CONCLUSION: In contrast to loss-of-function effects described in animal knockdown models, gain-of-function of MSGN1 explains the only mildly affected axial skeleton of the proband and rather normal vertebrae. In this context we observed notochord bending and potentially disruption of pectoral fin buds/upper extremity after overexpression of msgn1 in zebrafish embryos. The latter might result from Msgn1 function on mesenchymal stem cells or on chondrogenesis in these regions. In addition, we detected ectopic tbx6 and bmp2a expression after gain of Msgn1 function in zebrafish, which are interconnected to short stature, congenital scoliosis, limb shortening and prominent skeletal malformations in patients. Our findings highlight a rare, so far undescribed skeletal dysplasia syndrome associated with a gain-of-function mutation in MSGN1 and hint to its molecular downstream effectors.

The genetic basis of early-onset hereditary ataxia in Iran: results of a national registry of a heterogeneous population.

BACKGROUND: To investigate the genetics of early-onset progressive cerebellar ataxia in Iran, we conducted a study at the Children's Medical Center (CMC), the primary referral center for pediatric disorders in the country, over a three-year period from 2019 to 2022. In this report, we provide the initial findings from the national registry. METHODS: We selected all early-onset patients with an autosomal recessive mode of inheritance to assess their phenotype, paraclinical tests, and genotypes. The clinical data encompassed clinical features, the Scale for the Assessment and Rating of Ataxia (SARA) scores, Magnetic Resonance Imaging (MRI) results, Electrodiagnostic exams (EDX), and biomarker features. Our genetic investigations included single-gene testing, Whole Exome Sequencing (WES), and Whole Genome Sequencing (WGS). RESULTS: Our study enrolled 162 patients from various geographic regions of our country. Among our subpopulations, we identified known and novel pathogenic variants in 42 genes in 97 families. The overall genetic diagnostic rate was 59.9%. Notably, we observed PLA2G6, ATM, SACS, and SCA variants in 19, 14, 12, and 10 families, respectively. Remarkably, more than 59% of the cases were attributed to pathogenic variants in these genes. CONCLUSIONS: Iran, being at the crossroad of the Middle East, exhibits a highly diverse genetic etiology for autosomal recessive hereditary ataxia. In light of this heterogeneity, the development of preventive strategies and targeted molecular therapeutics becomes crucial. A national guideline for the diagnosis and management of patients with these conditions could significantly aid in advancing healthcare approaches and improving patient outcomes.

Identifying the origins of obsidian artifacts in the Deh Luran Plain (Southwestern Iran) highlights community connections in the Neolithic Zagros.

Exchange networks created by Neolithic pastoral transhumance have been central to explaining the distant transport of obsidian since chemical analysis was first used to attribute Near Eastern artifacts to their volcanic origins in the 1960s. Since then, critical reassessments of floral, faunal, and chronological data have upended long-held interpretations regarding the emergence of food production and have demonstrated that far-traveled, nomadic pastoralists were more myth than reality, at least during the Neolithic. Despite debates regarding their proposed conveyance mechanisms, obsidian artifacts' transport has received relatively little attention compared with zooarchaeological and archaeobotanical lines of investigation. The rise of nondestructive and portable instruments permits entire obsidian assemblages to be traced to their sources, renewing their significance in elucidating connections among early pastoral and agricultural communities. Here we share our findings about the obsidian artifacts excavated from the sites of Ali Kosh and Chagha Sefid in the southern Zagros. In the 1960s and 1970s, 28 obsidian artifacts from the sites were destructively tested, and the remainder were sorted by color. Our results emphasize a dynamic, accelerating connectivity among the Early and Late Neolithic communities. Here we propose and support an alternative model for obsidian distribution among more settled communities. In brief, diversity in the obsidian assemblage accelerated diachronically, an invisible trend in the earlier studies. Our model of increasing population densities is supported by archaeological data and computational simulations, offering insights regarding the Neolithic Demographic Transition in the Zagros, an equivalent of which is commonly thought to have occurred around the world.

Haplotype diversity of 17 Y-STR in the Iranian population.

The current study aimed to evaluate Y chromosome haplotypes obtained from 1353 unrelated Iranian males using the AmpFlSTRTM YfilerTM kit; 1353 out of the 1353 identified haplotypes were unique. The haplotype diversity (HD) and discriminating capacity (DC) values were 1.00000 and 0.997, respectively. Analysis of genetic distance was performed using molecular variance (AMOVA) and multidimensional scaling plots (MDS), revealing a statistically significant difference between the study population and previous data reported for other Iranian populations and other neighboring countries. The present findings are likely to be useful for forensic casework analyses and kinship investigations.

Crimean-Congo Hemorrhagic Fever Virus Kinetics in Serum, Saliva, and Urine, Iran, 2018.

Little is known about using noninvasive samples for diagnosing Crimean-Congo hemorrhagic fever (CCHF). We investigated detection of CCHF virus in serum, saliva, and urine samples. Our results indicate that serum is the best sample type for CCHF diagnosis; saliva can be used for noninvasive sampling.

Effect of Rodent Control Program on Incidence of Zoonotic Cutaneous Leishmaniasis, Iran.

We report the effect of a rodent control program on the incidence of zoonotic cutaneous leishmaniasis in an endemic region of Iran. A 1-year interruption in rodent control led to 2 years of increased incidence of zoonotic cutaneous leishmaniasis. Restarting rodent control led to a decline of zoonotic cutaneous leishmaniasis.

Translation and validation of a lifestyle questionnaire related to prostate cancer.

BACKGROUND: Valid and reliable instruments are needed to measure prostate cancer-related lifestyle changes, plan evidence-based interventions to modify lifestyle, and improve treatment outcomes. Due to the lack of appropriate instruments, this study was conducted to translate the Effects of Prostate Cancer upon Lifestyle Questionnaire (EPCLQ) into Persian and examine its psychometric properties in a sample of Iranian older adults with prostate cancer. METHODS: This methodological study was carried out between 2021 and 2022. Initially, the EPCLQ, comprising 36 items, was translated into Persian through a meticulous translation and back-translation procedure. Subsequent steps involved the assessment of face validity, qualitative content validity, content validity index, content validity ratio, construct validity via confirmatory factor analysis, and reliability testing of the Persian version of the EPCLQ. RESULTS: The psychometric evaluation led to the exclusion of 4 items from the EPCLQ. The refined model demonstrated satisfactory fit indices (PCFI = 0.732, PNFI = 0.696, CMIN/DF = 2.29, RMSEA = 0.072, IFI = 0.920, CFI = 0.919, and GFI = 0.971), indicating an appropriate fit of the final model. The internal consistency, as measured by Cronbach's alpha, was 0.67, and the intraclass correlation coefficient for the questionnaire was 0.938, reflecting high reliability. CONCLUSIONS: The Persian version of the EPCLQ, now consisting of 32 items, has been validated and is reliable for assessing the impact of prostate cancer on lifestyle among older adults. Its simplicity and the clarity of the items make it suitable for use in clinical settings or during home visits for follow-up assessments.

A comprehensive review of HVS-I mitochondrial DNA variation of 19 Iranian populations.

Iran is located along the Central Asian corridor, a natural artery that has served as a cross-continental route since the first anatomically modern human populations migrated out of Africa. We compiled and reanalyzed the HVS-I (hypervariable segment-I) of 3840 mitochondrial DNA (mtDNA) sequences from 19 Iranian populations and from 26 groups from adjacent countries to give a comprehensive review of the maternal genetic variation and investigate the impact of historical events and cultural factors on the maternal genetic structure of modern Iranians. We conclude that Iranians have a high level of genetic diversity. Thirty-six haplogroups were observed in Iran's populations, and most of them belong to widespread West-Eurasian haplogroups, such as H, HV, J, N, T, and U. In contrast, the predominant haplogroups observed in most of the adjacent countries studied here are H, M, D, R, U, and C haplogroups. Using principal component analysis, clustering, and genetic distance-based calculations, we estimated moderate genetic relationships between Iranian and other Eurasian groups. Further, analyses of molecular variance and comparing geographic and genetic structures indicate that mtDNA HVS-I sequence diversity does not exhibit any sharp geographic structure in the country. Barring a few from some culturally distinct and naturally separated minorities, most Iranian populations have a homogenous maternal genetic structure.

Interstitial lung diseases (ILD) in common variable immunodeficiency (CVID) patients: a study from Iran.

INTRODUCTION: Interstitial lung disease (ILD) is a prevalent complication in patients with common variable immunodeficiency (CVID) and is often related to other characteristics such as bronchiectasis and autoimmunity. Because the term ILD encompasses a variety of acute and chronic pulmonary conditions, diagnosis is usually based on imaging features. Histopathology is less available. This study was conducted with the aim of investigating the ILD in patients with CVID. MATERIALS AND METHODS: In this retrospective cross-sectional study, sixty CVID patients who referred to the pulmonology and immunodeficiency clinics of Mofid Children's Hospital between 2013 and 2022 were included. The diagnosis of ILD were based on transbronchial lung biopsy (TBB) or clinical and radiological symptoms. The prevalence of ILD in CVID patients was determined. Also, the CVID patients with and without ILD were compared in terms of demographic characteristics, clinical, laboratory and radiologic findings. RESULTS: Among all patients, ten patients had ILD (16.6%). In terms of laboratory parameters, there was a significant difference between platelets in the two groups of CVID patients with and without ILD, and the level of platelets was higher in the group of patients with ILD. Moreover, in terms of clinical symptoms, pneumonia, diarrhea and hepatomegaly were significantly different between the two groups and were statistically higher in the group of patients with ILD (P < 0.05). Autoimmunity and malignancy were not significantly different in two groups. There was a significant difference in, hyperinflation between the two groups of CVID patients with and without ILD, and the frequency of, hyperinflation was higher in the patients without ILD (P = 0.040). CONCLUSION: Understanding the pathogenesis of ILD plays an essential role in revealing non-infectious pulmonary complications that occur in CVID patients. Increasing efforts to understand ILD not only shed light on its hidden pathogenesis and clinical features, but also enhance our understanding of CVID in a broader sense.

The effects of killer cell immunoglobulin-like receptor (KIR) genes on susceptibility to severe COVID-19 in the Iranian population.

BACKGROUND: Variations in the innate and adaptive immune response systems are linked to variations in the severity of COVID-19. Natural killer cell (NK) function is regulated by sophisticated receptor system including Killer-cell immunoglobulin-like receptor (KIR) family. We aimed to investigate the impact of possessing certain KIR genes and genotypes on COVID19 severity in Iranians. KIR genotyping was performed on 394 age/sex matched Iranians with no underlying conditions who developed mild and severe COVID- 19. The presence and/or absence of 11 KIR genes were determined using the PCR with sequence specific primers (PCR-SSP). RESULTS: Patients with mild symptoms had higher frequency ofKIR2DS1 (p = 0.004) and KIR2DS2 (p = 0.017) genes compared to those with severe disease. While KIR3DL3 and deleted variant of KIR2DS4 occurred more frequently in patients who developed a severe form of the disease. In this study, a significant increase of and B haplotype was observed in the Mild group compared to the Severe group (respectively, p = 0.002 and p = 0.02). Also, the prevalence of haplotype A was significantly higher in the Severe group than in the Mild group (p = 0.02). CONCLUSIONS: These results suggest that the KIR2DS1, KIR2DS, and B haplotype maybe have a protective effect against COVID-19 severity. The results also suggest the inhibitory gene KIR2DL3 and haplotype A are risk factors for the severity of COVID-19.

Determining reference ranges for lymphocyte proliferation responses to phytohemagglutinin and Bacillus Calmette-Guérin in Iranian children.

PURPOSE: To establish reference ranges (RRs) for stimulation index of T cell proliferation triggered by phytohemagglutinin (PHA-SI) and Bacillus Calmette-Guérin (BCG-SI). METHODS: This study investigated data from 359 healthy children and 35 patients with cellular immunodeficiency as positive controls (2010-2021). We applied a colorimetric-based method (BrdU) to measure proliferation and determine the RRs at the 2.5th and 97.5th percentiles (95% confidence intervals). A cross-validation approach was performed. RESULTS: In healthy controls, the RRs for PHA-SI and BCG-SI ranged between 3 and 5.2 and 2.52 to 5.2, respectively. PHA-SI and BCG-SI were in Severe Combined Immunodeficiency (SCID) patients from 1.2 to 2.5 and 0 to 2, while in Mendelian susceptibility to mycobacterial diseases (MSMD) patients, 2.53 to 4.5 and 0.74 to 2.2, respectively. The thresholds' accuracy was checked for testing reference intervals with diagnostic effects. CONCLUSION: This study establishes PHA-SI and BCG-SI reference ranges to aid in diagnosing and treating congenital immunodeficiency diseases.

Determination of HLA class II risk alleles and prediction of self/non-self-epitopes contributing Hashimoto's thyroiditis in a group of Iranian patients.

One of the probable hypotheses for the onset of autoimmunity is molecular mimicry. This study aimed to determine the HLA-II risk alleles for developing Hashimoto's thyroiditis (HT) in order to analyze the molecular homology between candidate pathogen-derived epitopes and potentially self-antigens (thyroid peroxidase, TPO) based on the presence of HLA risk alleles. HLA-DRB1/-DQB1 genotyping was performed in 100 HT patients and 330 ethnically matched healthy controls to determine the predisposing/protective alleles for HT disease. Then, in silico analysis was conducted to examine the sequence homology between epitopes derived from autoantigens and four potentially relevant pathogens and their binding capacities to HLA risk alleles based on peptide docking analysis. We identified HLA-DRB1*03:01, *04:02, *04:05, and *11:04 as predisposing alleles and DRB1*13:01 as a potentially predictive allele for HT disease. Also, DRB1*11:04 ~ DQB1*03:01 (Pc = 0.002; OR, 3.97) and DRB1*03:01 ~ DQB1*02:01 (Pc = 0.004; OR, 2.24) haplotypes conferred a predisposing role for HT. Based on logistic regression analysis, carrying risk alleles increased the risk of HT development 4.5 times in our population (P = 7.09E-10). Also, ROC curve analysis revealed a high predictive power of those risk alleles for discrimination of the susceptible from healthy individuals (AUC, 0.70; P = 6.6E-10). Analysis of peptide sequence homology between epitopes of TPO and epitopes derived from four candidate microorganisms revealed a homology between envelop glycoprotein D of herpes virus and sequence 151-199 of TPO with remarkable binding capacity to HLA-DRB1*03:01 allele. Our findings indicate the increased risk of developing HT in those individuals carrying HLA risk alleles which can also be related to herpes virus infection.

Co-overexpression of chitinase and ß-1,3-glucanase significantly enhanced the resistance of Iranian wheat cultivars to Fusarium.

Fusarium head blight (FHB) is a devastating fungal disease affecting different cereals, particularly wheat, and poses a serious threat to global wheat production. Chitinases and ß-glucanases are two important proteins involved in lysing fungal cell walls by targeting essential macromolecular components, including chitin and ß-glucan micro fibrils. In our experiment, a transgenic wheat (Triticum aestivum) was generated by introducing chitinase and glucanase genes using Biolistic technique and Recombinant pBI121 plasmid (pBI-ChiGlu (-)). This plasmid contained chitinase and glucanase genes as well as nptII gene as a selectable marker. The expression of chitinase and glucanase was individually controlled by CaMV35S promoter and Nos terminator. Immature embryo explants from five Iranian cultivars (Arta, Moghan, Sisun, Gascogen and A-Line) were excised from seeds and cultured on callus induction medium to generate embryonic calluses. Embryogenic calluses with light cream color and brittle texture were selected and bombarded using gold nanoparticles coated with the recombinant pBI-ChiGlu plasmid. Bombarded calluses initially were transferred to selective callus induction medium, and later, they were transfferd to selective regeneration medium. The selective agent was kanamycin at a concentration of 25 mg/l in both media. Among five studied cultivars, A-Line showed the highest transformation percentage (4.8%), followed by the Sisun, Gascogen and Arta in descending order. PCR and Southern blot analysis confirmed the integration of genes into the genome of wheat cultivars. Furthermore, in an in-vitro assay, the growth of Fusarium graminearum was significantly inhibited by using 200 µg of leaf protein extract from transgenic plants. According to our results, the transgenic plants (T1) showed the resistance against Fusarium when were compared to the non-transgenic plants. All transgenic plants showed normal fertility and no abnormal response was observed in their growth and development.

Predicting the quality attributes related to geographical growing regions in red-fleshed kiwifruit by data fusion of electronic nose and computer vision systems.

The ability of a data fusion system composed of a computer vision system (CVS) and an electronic nose (e-nose) was evaluated to predict key physiochemical attributes and distinguish red-fleshed kiwifruit produced in three distinct regions in northern Iran. Color and morphological features from whole and middle-cut kiwifruits, along with the maximum responses of the 13 metal oxide semiconductor (MOS) sensors of an e-nose system, were used as inputs to the data fusion system. Principal component analysis (PCA) revealed that the first two principal components (PCs) extracted from the e-nose features could effectively differentiate kiwifruit samples from different regions. The PCA-SVM algorithm achieved a 93.33% classification rate for kiwifruits from three regions based on data from individual e-nose and CVS. Data fusion increased the classification rate of the SVM model to 100% and improved the performance of Support Vector Regression (SVR) for predicting physiochemical indices of kiwifruits compared to individual systems. The data fusion-based PCA-SVR models achieved validation R2 values ranging from 90.17% for the Brix-Acid Ratio (BAR) to 98.57% for pH prediction. These results demonstrate the high potential of fusing artificial visual and olfactory systems for quality monitoring and identifying the geographical growing regions of kiwifruits.

The influence of climate change on the future distribution of two Thymus species in Iran: MaxEnt model-based prediction.

Within a few decades, the species habitat was reshaped at an alarming rate followed by climate change, leading to mass extinction, especially for sensitive species. Species distribution models (SDMs), which estimate both present and future species distribution, have been extensively developed to investigate the impacts of climate change on species distribution and assess habitat suitability. In the West Asia essential oils of T. daenensis and T. kotschyanus include high amounts of thymol and carvacrol and are commonly used as herbal tea, spice, flavoring agents and medicinal plants. Therefore, this study aimed to model these Thymus species in Iran using the MaxEnt model under two representative concentration pathways (RCP 4.5 and RCP 8.5) for the years 2050 and 2070. The findings revealed that the mean temperature of the warmest quarter (bio10) was the most significant variable affecting the distribution of T. daenensis. In the case of T. kotschyanus, slope percentage was the primary influencing factor. The MaxEnt modeling also demonstrated excellent performance, as indicated by all the Area Under the Curve (AUC) values exceeding 0.9. Moreover, based on the projections, the two mentioned species are expected to undergo negative area changes in the coming years. These results can serve as a valuable achievement for developing adaptive management strategies aimed at enhancing protection and sustainable utilization in the context of global climate change.