Gossamer: Scaling Image Processing and Reconstruction to Whole Brains.

Neuronal reconstruction-a process that transforms image volumes into 3D geometries and skeletons of cells-bottlenecks the study of brain function, connectomics and pathology. Unlike artistic domains with similar challenges (e.g., hair modeling), scientists need exact and complete segmentations to study subtle topological differences. Existing methods are disk-bound, dense-access, coupled, single-threaded, algorithmically unscalable and require manual cropping of small windows and proofreading of skeletons due to low topological accuracy. Designing a data-intensive parallel solution suited to a neurons' shape, topology and far-ranging connectivity is particularly challenging due to I/O and load-balance, yet by abstracting vision tasks such as segmentation and skeletonization into strategically ordered specializations of search, we progressively lower memory by 4 orders of magnitude. This enables 1 mouse brain to be fully processed in-memory on a single server, at 67× the scale with 870× less memory while having 78% higher automated yield than the highest performing alternative methods.

Robust Resting-State Dynamics in a Large-Scale Spiking Neural Network Model of Area CA3 in the Mouse Hippocampus.

Hippocampal area CA3 performs the critical auto-associative function underlying pattern completion in episodic memory. Without external inputs, the electrical activity of this neural circuit reflects the spontaneous spiking interplay among glutamatergic pyramidal neurons and GABAergic interneurons. However, the network mechanisms underlying these resting-state firing patterns are poorly understood. Leveraging the Hippocampome.org knowledge base, we developed a data-driven, large-scale spiking neural network (SNN) model of mouse CA3 with 8 neuron types, 90,000 neurons, 51 neuron-type specific connections, and 250,000,000 synapses. We instantiated the SNN in the CARLsim4 multi-GPU simulation environment using the Izhikevich and Tsodyks-Markram formalisms for neuronal and synaptic dynamics, respectively. We analyzed the resultant population activity upon transient activation. The SNN settled into stable oscillations with a biologically plausible grand-average firing frequency, which was robust relative to a wide range of transient activation. The diverse firing patterns of individual neuron types were consistent with existing knowledge of cell type-specific activity in vivo. Altered network structures that lacked neuron- or connection-type specificity were neither stable nor robust, highlighting the importance of neuron type circuitry. Additionally, external inputs reflecting dentate mossy fibers shifted the observed rhythms to the gamma band. We freely released the CARLsim4-Hippocampome framework on GitHub to test hippocampal hypotheses. Our SNN may be useful to investigate the circuit mechanisms underlying the computational functions of CA3. Moreover, our approach can be scaled to the whole hippocampal formation, which may contribute to elucidating how the unique neuronal architecture of this system subserves its crucial cognitive roles.

Normalized unitary synaptic signaling of the hippocampus and entorhinal cortex predicted by deep learning of experimental recordings.

Biologically realistic computer simulations of neuronal circuits require systematic data-driven modeling of neuron type-specific synaptic activity. However, limited experimental yield, heterogeneous recordings conditions, and ambiguous neuronal identification have so far prevented the consistent characterization of synaptic signals for all connections of any neural system. We introduce a strategy to overcome these challenges and report a comprehensive synaptic quantification among all known neuron types of the hippocampal-entorhinal network. First, we reconstructed >2600 synaptic traces from ∼1200 publications into a unified computational representation of synaptic dynamics. We then trained a deep learning architecture with the resulting parameters, each annotated with detailed metadata such as recording method, solutions, and temperature. The model learned to predict the synaptic properties of all 3,120 circuit connections in arbitrary conditions with accuracy approaching the intrinsic experimental variability. Analysis of data normalized and completed with the deep learning model revealed that synaptic signals are controlled by few latent variables associated with specific molecular markers and interrelating conductance, decay time constant, and short-term plasticity. We freely release the tools and full dataset of unitary synaptic values in 32 covariate settings. Normalized synaptic data can be used in brain simulations, and to predict and test experimental hypothesis.

The pathogenicity classification of PAH gene variants in the Iranian population.

Till now not many studies have been conducted to classify PAH gene variants according to American College of Medical Genetics and Genomics (ACMG-AMP) guidelines. The aim of this study was to collect all PAH gene variants reported among Iranian population and investigate their pathogenicity based on ACMG-AMP guidelines. Systematic collection of PAH gene variants, verification of variants, in silico analysis, and application of ACMG-AMP guidelines were the main steps in performing the present study. A total of 267 unique variants were identified; according to ACMG-AMP guidelines, 90, 40, 71, 14, and 52 variants were classified as pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB), and benign (B), respectively. The need to pay more attention to synonymous and missense variants with low or no impact on protein function as well as intronic variants, whether they are deep or are close to intron/exon boundaries, was a highlight of this study. Due to the fact that few functional studies are performed on these variants, it is suggested that they be analyzed first using bioinformatics tools, and if positive results are obtained, then functional studies can be designed.

Quantification of neuron types in the rodent hippocampal formation by data mining and numerical optimization.

Quantifying the population sizes of distinct neuron types in different anatomical regions is an essential step towards establishing a brain cell census. Although estimates exist for the total neuronal populations in different species, the number and definition of each specific neuron type are still intensively investigated. Hippocampome.org is an open-source knowledge base with morphological, physiological and molecular information for 122 neuron types in the rodent hippocampal formation. While such framework identifies all known neuron types in this system, their relative abundances remain largely unknown. This work quantitatively estimates the counts of all Hippocampome.org neuron types by literature mining and numerical optimization. We report the number of neurons in each type identified by main neurotransmitter (glutamate or GABA) and axonal-dendritic patterns throughout 26 subregions and layers of the dentate gyrus, Ammon's horn, subiculum and entorhinal cortex. We produce by sensitivity analysis reliable numerical ranges for each type and summarize the amounts across broad neuronal families defined by biomarkers expression and firing dynamics. Study of density distributions indicates that the number of dendritic-targeting interneurons, but not of other neuronal classes, is independent of anatomical volumes. All extracted values, experimental evidence and related software code are released on Hippocampome.org.

α-Thalassemia Mutations in Ilam Province, West Iran.

Despite several studies performed in different provinces of Iran to identify the spectrum of α-globin gene mutations, no such study has so far been carried out in Ilam Province. A total of 274 individuals, including 201 α-thalassemia (α-thal) carriers and 73 normal subjects, originating from the northern counties of Ilam Province, participated in this study. Analysis of α-globin defects was performed using multiplex gap-polymerase chain reaction (gap-PCR), amplification refractory mutation system (ARMS)-PCR and direct sequencing, which revealed a total of 11 different mutations and 22 different genotypes. The -α3.7 (rightward) (NG_000006.1: g.34164_37967del3804), α-5 ntα (HBA2: c.95 + 2_95 + 6delTGAGG), and -α4.2 (leftward) deletions were the most prevalent mutations identified in our study, with frequencies of 66.23, 10.09 and 8.33%, respectively. In conclusion, the present study showed that the α-thal mutation spectrum in Ilam Province, at least in the northern part of the province, is different from that in other geographical regions of Iran. These results increase our knowledge about the spectrum and distribution of α-globin gene mutations in Iran.

CFTR gene mutation spectrum among 735 Iranian patients with cystic fibrosis: A comprehensive systematic review.

In this study, the spectrum and frequency of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations previously reported among Iranian cystic fibrosis (CF) patients have been reviewed and discussed. Using the keywords of Cystic Fibrosis, CF, CFTR, and Iran, along with their Persian equivalents, a comprehensive search was performed on the online databases. After applying the inclusion and exclusion criteria, 16 articles with an overall sample of 735 Iranian patients with CF, were included in this systematic review. A total of 101 different CFTR gene variants had been reported. The mutation of p.Phe508del (c.1521_1523delCTT) (21.22%) was the most frequent one among Iranian patients with CF. In conclusion, due to the fact that in many provinces of Iran no specific study has been done so far, it seems that the CFTR gene mutation spectrum in patients with CF from Iran is much wider.

Spectrum of PAH gene mutations in 1547 phenylketonuria patients from Iran: a comprehensive systematic review.

As one of the highest prevalence rates in the world, the prevalence of Phenylketonuria (PKU) in Iran has been estimated at 16.5 per 100,000 neonates. The objective of this study was to evaluate the spectrum and frequency of mutations of the phenylalanine hydroxylase (PAH) gene in Iranian PKU patients. A systematic review was carried out on previous studies on PAH gene mutations in Iranian PKU patients. A complete search was carried out on the on-line databases of Scopus, Web of Science, PubMed/Medline, ProQuest, Science Direct, Magiran, SID and the search engine Google Scholar. The keywords of Phenylketonuria, PKU, Phenylalanine Hydroxylase, PAH, and Iran, as well as their Persian equivalents, in all possible combinations were used. Finally, a total of 21 eligible articles with a sample size of 1547 Iranian PKU patients, published between 2003 and 2020, were included in our systematic review. A total of 129 different PAH gene mutations including, IVS10-11G > A (c.1066-11G > A) (19.23%), p.R261Q (c.782G > A) (7.63%), p.P281L (c.842C > T) (6.24%), IVS2 + 5G > C (c.168 + 5G > C) (5.75%), p.R243* (c.727C > T) (3.59%), IVS9 + 5G > A (c.969 + 5G > A) (2.84%), p.R176* (c.526C > T) (2.42%), p.Lys363Nfs*37 (c.1089delG) (2.13%), IVS11 + 1G > C (c.1199 + 1G > C) (2.07%) and p.L48S (c.143 T > C) (2.04%) were identified. The spectrum and frequency of mutations observed in Iran were closer to those observed in the Mediterranean countries. Our results are valuable in planning panel-based studies in provinces with incomplete data on PAH gene mutations. This study is a good reference for genetic counselors and physicians who advise couples in making decisions to maintain or terminate a pregnancy.

Quantitative detection of SRY-Box 21 (SOX21) gene promoter methylation as a stool-based noninvasive biomarker for early diagnosis of colorectal cancer by MethyLight method.

BACKGROUND: In recent years, the study of potential epigenetic biomarkers in feces has been an attractive research approach for the noninvasive diagnosis of colorectal cancer (CRC). The aim of this study was to evaluate the stool-based DNA methylation potential of SRY-Box 21 (SOX21) gene promoter as an appropriate candidate biomarker for differentiating CRC patients and healthy individuals for the first time. METHODS: The MethyLight method was performed to analyze the methylation status of SOX21 gene promoter in fecal samples from 40 patients with CRC and 40 healthy controls. In addition, the diagnostic efficiency of measuring the hypermethylated SOX21 gene in the feces to the fecal occult blood test (FOBT) was compared. RESULTS: The percentage of methylated reference (PMR) values in the stool of CRC patients (median 1.44) was higher than those of healthy individuals (median 0.00) (P < 0.001). A sensitivity of 72.5% and specificity of 100% were obtained for SOX21 gene promoter methylation status and 29 of the patients were considered as positive in methylation status. There was no significant association between PMR values and demographic/clinicopathological features (P > 0.05). CONCLUSION: The results of the present study demonstrated that the stool-based assay of SOX21 gene promoter methylation has a relatively high sensitivity and specificity and it may serve as a noninvasive biomarker for early detection of CRC. However, more studies with a wide range of samples are required to further confirm the role of hypermethylation of SOX21 in the early CRC diagnosis.

Distribution of HBB Gene Mutations in the Kurdish Population of Ilam Province, West Iran.

ß-Thalassemia (ß-thal) is one of the most common diseases in Iran. Here, we report the spectrum of HBB gene mutations in 176 Kurdish ß-thal carriers from the northern part of Ilam Province, Iran. The amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique was used to identify common ß-globin gene mutations observed in Iran. Samples negative on ARMS-PCR were analyzed by direct sequencing of the ß-globin gene. In total, 12 different mutations were identified on the ß-globin gene. The mutations of IVS-II-1 (G>A) (HBB: c.315+1G>A), codons 8/9 (+G) (HBB: c.27_28insG), codons 36/37 (-T) (HBB: c.112delT) and IVS-I-110 (G>A) (HBB: c.93-21G>A), were the most prevalent mutations in our samples, with frequencies of 59.09, 10.80, 7.95 and 7.39%, respectively. In general, the mutation spectrum of the ß-globin gene in the northern part of Ilam Province is most similar to that in other western provinces of Iran. On the other hand, due to the high prevalence of carriers and ß-thal major (ß-TM) patients in this province, our results can be helpful in identifying carriers as well as at-risk fetuses through the prenatal diagnosis program.

Molecular Genetic Analysis of α-Thalassemia in Hamadan Province, West Iran.

Identifying couples who are carriers of thalassemia-causing mutations, followed by prenatal diagnosis (PND), is undoubtedly an effective way to prevent the birth of children with the disease. Our aim in this study was to report for the first time the spectrum of α-globin gene mutations in the population living in Hamadan Province, West Iran. Multiplex gap-polymerase chain reaction (gap-PCR), amplification refractory mutation system (ARMS)-PCR, and direct DNA sequencing of HBA1 and HBA2 genes were used to identify the α-thalassemia (α-thal)-causing mutations in a cohort of 389 individuals including 328 α-thal carriers and 61 normal subjects. A total of 17 different mutations and 25 different genotypes were detected. The -α3.7 (rightward) deletion (NG_000006.1: g.34164_37967del3804) was the most frequent mutation, accounting for more than half of all mutations (61.04%). This study revealed that there is a variety of α-thal mutations and α-thal genotypes in Hamadan Province, West Iran. This observation is probably due to the complexity of the Hamadan Province population that is composed of Persians (Fars), Turks, Kurds, and Lurs/Laks. In conclusion, our results demonstrated the spectrum of mutations in α-globin genes in Iran and increased our understanding of their distribution in this country.

The Spectrum of α-Thalassemia Mutations in Kurdistan Province, West Iran.

In order to identify the α-thalassemia (α-thal) mutation spectrum in Kurdistan Province, West Iran, a total of 217 individuals, including 154 α-thal carriers and 63 normal subjects were investigated in this study. Molecular analysis of α1- and α2-globin genes using multiplex gap-polymerase chain reaction (gap-PCR), amplification refractory mutation system (ARMS)-PCR or direct DNA sequencing, showed 11 different α-globin variants. The -α3.7 (rightward) deletion (NG_000006.1: g.34164_37967del3804) (70.32%), polyadenylation signal (polyA2) site (AATAAA>AATGAA) (αpolyA2α) (HBA2: c.*92A>G) (7.74%), -α4.2 (leftward) deletion (6.45%) and codon 59 (or Hb Adana) (G>A) (ααcodon 59) (HBA1: c.179G>A) (4.52%) were the most frequent mutations in the present study. In conclusion, the spectrum of α-thal mutations in Kurdistan Province is closest to that in western provinces of Iran (Kurdish and Laki populations). In addition, it was revealed that the codon 59 mutation is common in the Kurdish population. On the other hand, despite the same ethnic background of Kurds in Iran and Iraq, the - -MED I double gene deletion and polyA2 point mutation have different distributions in these two populations. Therefore, further studies are needed to identify the cause of these differences.

Severe α-Thalassemia Due to Compound Heterozygosity for Hb Adana (α59 Gly>Asp) (HBA1: c.179G > A) and Codon 127 (A > T) (HBA2: c.382A > T) in an Iranian Family.

We describe a novel compound heterozygous genotype which consists of two point mutations named Hb Adana (HBA1: c.179G>A) and codon 127 (HBA2: c.382A>T) in a Kurdish family with two girls affected with severe α-thalassemia (α-thal). Both patients (the proband and her sister) had a history of splenectomy during childhood. Although the proband had no blood transfusion history, her affected sister has had two blood transfusions so far. In conclusion, diagnosing and reporting new genotypes on the α-globin genes will improve our knowledge about complicated genotype-phenotype correlations in α-thal disorder.

High potential of SOX21 gene promoter methylation as an epigenetic biomarker for early detection of colorectal cancer.

BACKGROUND: Despite the advances in screening during the past decades, colorectal cancer (CRC) still is a leading cause of cancer deaths worldwide. Therefore, the development of new diagnostic methods is necessary. AIM: The aim of this study was to compare methylation changes of SRY-Box 21 (SOX21) gene promoter in tumor tissues and their normal adjacent mucosa in patients with CRC and to examine the relationship between the methylation levels and demographic/clinicopathological factors. MATERIALS AND METHODS: A total of 41 CRC patients participated in the present study. After the extraction of DNA and bisulfite treatment of the samples, the methylation levels were determined by using the MethyLight method. STATISTICAL ANALYSIS: Two-sided Mann-Whitney U test was used to compare the median level of methylation in tumor tissues and their adjacent normal mucosa. RESULTS: The methylation rates in tumor tissue samples were significantly higher compared to their adjacent normal mucosa (P < 0.0001). No association between demographic/clinicopathological factors and methylation status observed in tumor tissues. A receiver operating characteristics curve was constructed and tissue samples exhibited a sensitivity of 80.5% and specificity of 97.6% for SOX21 promoter methylation. CONCLUSION: The results of this study indicated the high potential of SOX21 gene promoter methylation as a candidate noninvasive diagnostic biomarker in stool and plasma of colorectal cancer patients. However, further studies with larger sample sizes are required to evaluate the specific role of SOX21 methylation as a biomarker for early detection of CRC.

A comprehensive knowledge base of synaptic electrophysiology in the rodent hippocampal formation.

The cellular and synaptic architecture of the rodent hippocampus has been described in thousands of peer-reviewed publications. However, no human- or machine-readable public catalog of synaptic electrophysiology data exists for this or any other neural system. Harnessing state-of-the-art information technology, we have developed a cloud-based toolset for identifying empirical evidence from the scientific literature pertaining to synaptic electrophysiology, for extracting the experimental data of interest, and for linking each entry to relevant text or figure excerpts. Mining more than 1,200 published journal articles, we have identified eight different signal modalities quantified by 90 different methods to measure synaptic amplitude, kinetics, and plasticity in hippocampal neurons. We have designed a data structure that both reflects the differences and maintains the existing relations among experimental modalities. Moreover, we mapped every annotated experiment to identified potential connections, that is, specific pairs of presynaptic and postsynaptic neuron types. To this aim, we leveraged Hippocampome.org, an open-access knowledge base of morphologically, electrophysiologically, and molecularly characterized neuron types in the rodent hippocampal formation. Specifically, we have implemented a computational pipeline to systematically translate neuron type properties into formal queries in order to find all compatible potential connections. With this system, we have collected nearly 40,000 synaptic data entities covering 88% of the 3,120 potential connections in Hippocampome.org. Correcting membrane potentials with respect to liquid junction potentials significantly reduced the difference between theoretical and experimental reversal potentials, thereby enabling the accurate conversion of all synaptic amplitudes to conductance. This data set allows for large-scale hypothesis testing of the general rules governing synaptic signals. To illustrate these applications, we confirmed several expected correlations between synaptic measurements and their covariates while suggesting previously unreported ones. We release all data open-source at Hippocampome.org in order to further research across disciplines.

The status of PAH gene-VNTR alleles and mini-haplotypes associations with PAH gene mutations in Iranian Kurdish PKU patients.

Background: The analysis of haplotypes/mini-haplotypes in the PAH gene has been used as an informative tool in several genetic anthropology studies. Considering the notion that Iranian population is one of the most heterogeneous i the world, this study was conducted to evaluate the association of VNTR-STR mini-haplotypes with the PAH gene mutations in PKU patients in Kermanshah province. Methods: A total of 24 unrelated Kurdish PKU patients with the known PAH gene causing mutations and 72 healthy controls were selected. The DNA fragments containing VNTR and STR systems were amplified by polymerase chain reaction (PCR). For VNTR system, PCR products were separated using electrophoresis on 2.5% agarose gel. For STR system, the samples were analyzed using DNA sequencing analysis version 5.2 software. Results: Overall, 5 PAH-VNTR-alleles, including VNTR3, 7, 8, 9, 12, and 3 PAH-STR-alleles, including STR238, 242, and 250, were detected in this study. VNTR3 and 8 alleles had the most frequency among healthy controls. Also, 6 different mini-haplotype alleles were found to be associated with PKU chromosomes. The 2 most prevalent mutations in Kermanshah province, IVS2+5G>C and IVS9+5G>A, were strongly linked to mini-haplotypes 9/242 and 8/238, respectively. Conclusion: The distributions and frequencies of VNTR alleles in Kurdish population have the most similarity to alleles previously described in European Caucasian families. Moreover, since the most common mutations in Kermanshah PKU chromosomes are rare and this was the first study on mini-haplotypes VNTR/STR among Iranian Kurdish PKU patients, given that this study was the first of its kind, it was not possible to compare its results with that of other studies on Iranian and non-Iranian populations.

The Spectrum of α-Thalassemia Mutations in the Lak Population of Iran.

α-Thalassemia (α-thal) is one of the most common genetic disorders worldwide. The aim of this study was to investigate for the first time the α-thal mutation spectrum in the Lak population living in Lorestan Province, Iran. One hundred and seventy-six α-thal carriers participated in the study. Multiplex gap-polymerase chain reaction (gap-PCR), amplification refractory mutation system (ARMS)-PCR and direct sequencing were used for the detection of different mutations on the α-globin (HBA1 and HBA2) genes. A total of 11 different mutations was identified. The -α3.7 (rightward; NG_000006.1: g.34164_37967del3804) deletion was observed most frequently (56.35%), followed by α-5 ntα (HBA2: c.95+2_95+6delTGAGG), αpolyA2α (HBA2: c.*92A>G) and - -MED I (NG_000006.1: g.24664_41064del16401), with frequencies of 15.47, 9.39, and 6.08%, respectively. These four mutations accounted for more than 87.0% of the total mutated alleles. Moreover, 19 different genotypes were identified. The types and distribution pattern of the mutations identified in this study, in comparison with other studies conducted in Iran, was most similar to the Kurdish population of Kermanshah Province, Iran. Due to the lack of information on α-thal in Lorestan Province, it was not possible to compare the mutation spectrum in the Lur and Lak populations. In conclusion, our results may help in setting up a strategy for an α-thal screening program and genetic counseling in the Lak people.

The Spectrum of ß-Thalassemia Mutations in Hamadan Province, West Iran.

ß-Thalassemia (ß-thal) is one of the most common hemoglobinopathies worldwide and is caused by mutations on the ß-globin (HBB) gene. The aim of the present study was to determine the mutation spectrum of the ß-globin gene in ß-thal carriers who were originally from Hamadan Province, Western Iran. Two hundred and eighty-two ß-thal carriers participated in the study. Amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and direct sequencing were used for detection of different mutations. A total of 25 different mutations, including 21 ß-thal mutations and four other hemoglobin (Hb) variants, in 280 ß-thal carriers (99.3%) were detected in the present study. Three types of mutations including IVS-II-1 (G>A) (HBB: c.315+1G>A) (26.24%), codons 8/9 (+G) (HBB: c.27_28insG) (14.54%) and codons 36/37 (-T) (HBB: c.112delT) (12.76%) accounted for more than 50.0% of the identified mutations. Moreover, IVS-I-110 (G>A) (HBB: c.93-21G>A), codon 44 (-C) (HBB: c.135delC) and IVS-I (25 bp deletion) (HBB: c.93-21_del), had frequencies of 7.09, 7.09 and 5.67%, respectively. Allele frequencies of the remaining 19 mutations were less than 5.0%. This study is the first comprehensive study on a large sample size in Hamadan Province, Iran. In conclusion, the present study significantly increased the spectrum of HBB gene mutations in Hamadan Province compared with previous studies. Therefore, these results can be helpful in identifying ß-thal carriers and at-risk fetuses through prenatal diagnosis (PND).

Spectrum of Phenylalanine Hydroxylase Gene Mutations in Hamadan and Lorestan Provinces of Iran and Their Associations with Variable Number of Tandem Repeat Alleles.

Phenylketonuria (PKU) is one of the most common known inherited metabolic diseases. The present study aimed to investigate the status of molecular defects in phenylalanine hydroxylase (PAH) gene in western Iranian PKU patients (predominantly from Kermanshah, Hamadan, and Lorestan provinces) during 2014-2016. Additionally, the results were compared with similar studies in Iran. Nucleotide sequence analysis of all 13 exons and their flanking intronic regions of the PAH gene was performed in 18 western Iranian PKU patients. Moreover, a variable number of tandem repeat (VNTR) located in the PAH gene was studied. The results revealed a mutational spectrum encompassing 11 distinct mutations distributed along the PAH gene sequence on 34 of the 36 mutant alleles (diagnostic efficiency of 94.4%). Also, four PAH VNTR alleles (with repeats of 3, 7, 8 and 9) were detected. The three most frequent mutations were IVS9+5G>A, IVS7-5T>C, and p.P281L with the frequency of 27.8%, 11%, and 11%, respectively. The results showed that there is not only a consanguineous relation, but also a difference in PAH characters of mutations between Kermanshah and the other two parts of western Iran (Hamadan and Lorestan). Also, it seems that the spectrum of mutations in western Iran is relatively distinct from other parts of the country, suggesting that this region might be a special PAH gene distribution region. Moreover, our findings can be useful in the identification of genotype to phenotype relationship in patients, and provide future abilities for confirmatory diagnostic testing, prognosis, and predict the severity of PKU patients.

Weighing the Evidence in Peters' Rule: Does Neuronal Morphology Predict Connectivity?

Although the importance of network connectivity is increasingly recognized, identifying synapses remains challenging relative to the routine characterization of neuronal morphology. Thus, researchers frequently employ axon-dendrite colocations as proxies of potential connections. This putative equivalence, commonly referred to as Peters' rule, has been recently studied at multiple levels and scales, fueling passionate debates regarding its validity. Our critical literature review identifies three conceptually distinct but often confused applications: inferring neuron type circuitry, predicting synaptic contacts among individual cells, and estimating synapse numbers within neuron pairs. Paradoxically, at the originally proposed cell-type level, Peters' rule remains largely untested. Leveraging Hippocampome.org, we validate and refine the relationship between axonal-dendritic colocations and synaptic circuits, clarifying the interpretation of existing and forthcoming data.