分子与遗传医学

Five cases of Even-Plus syndrome have been reported, 2 in the year 19991 and 3 in the year 20152. We recently diagnosed another female patient with Even-Plus syndrome with a postural and gait abnormality. Left patellar dislocation was identified and corrected in order to limit patient’s disability.

Rheumatoid arthritis (RA) is characterized by citrullination of peptides and proteins mediated by calciumdependent peptidyl arginine deiminase enzymes (PADs). Various mechanisms of intracellular and extracellular protein citrullination have been elucidated so far. Here, we highlight one more important possible mechanism that could lead to intracellular citrullination due to dysregulated mitochondrial Ca2+ homeostasis i.e., inability of mitochondrial uptake of Ca2+ during physiological signaling and triggering the generation of autoimmune disease. Spontaneous secretion of intracellular PAD may be the result of high cytosolic Ca2+ due to a disturbance in mitochondrial calcium homeostasis secondary to oxidative damage without any compromise to the cell membrane. Various environmental triggers like air pollutants also induce oxidative stress (OS) which may compromise the mitochondrial integrity and disturb Ca2+ homeostasis. Adoption of simple lifestyle modification like yoga and meditation optimizes reactive oxygen species (ROS) levels and maintains mitochondrial integrity by increasing COX activity, thus may curb citrullination process and its sequelae.

Halalopathic, the proposed concept, is based on the compatibility between therapy and individual’s belief where the “power of word, tranquility and therapeutic agents” work cooperatively to induce more effective treatment. The healing approach may well affect non-genetic changes that human genome experiences as a result of interaction with the environment. To realize the concept, ingredients and processes need to be evaluated with regards to Halal standard. Halala-Tayyiba label on medicine will reveal to the patient that drug has been prepared under maximum hygiene, minimum contamination and the whole process is clean, pure and comply with Islamic principle. Halalopathic generate compatible system which will reflect on the chemistry of our bodies where disorder is decreased, and ultimately lower the entropy and increase the overall potential energy. The concept promotes personalized therapy and open new window for more effective treatment.

The frequency of chromosomal abnormalities is supposed to be elevated in infertile males as well as shown negative correlation of sperm concentration. Cytogenetic analysis, recommended by guidelines in infertile men, is expensive. Hence, it may be good for recognize riskiest men with chromosomal abnormalities, potentially by analyzing sperm concentration outside of the parameters. Aim to evaluate the frequency of chromosomal abnormalities in different subpopulations among Hakka population, we assessed several clinical parameters in infertile men. A total of 1291 azoospermic men and men apply for in-vitro fertilization (IVF) treatment, were analyzed for semen parameters, hormone levels, Y chromosome microdeletions and medical history, related to chromosomal abnormalities. Chromosomal abnormalities were detected 46 of 1291 men (3.6%) in our study. Correlation was no shown between chromosomal abnormalities and sperm parameters except for sperm volume (OR 0.76, P=0.029). Significantly, azoospermia was related to an increased frequency of chromosomal abnormalities (OR 32.24, P<0.001). Elevated gonadotropic hormone levels, meaningfully, was related to the risk of carrying a chromosome abnormality (OR 4.38, P<0.001). Lower rate of chromosomal abnormalities was observed in infertile males with positive andrologic history (OR 0.21, P=0.003). Previous miscarriages, related to an increased frequency of chromosomal abnormalities, were discovered in non-azoospermic men (OR 4.78, P=0.003). The results indicated that azoospermic men with hypergonadotrophic as well as an eventless andrologic history have frequently risk of chromosomal abnormalities.

We evaluated the clinical utility of high-throughput sequencing for fetal abnormalities detected with ultrasound examination. This study included pregnant women who were at risk for fetal aneuploidy with or without ultrasonography abnormalities, and who underwent invasive surgery. High-throughput sequencing was used for cell-free fetal DNA analysis, and some positive results were compared with conventional karyotyping. This study involved 971 pregnancies, cell-free fetal DNA identified 15 of 18 (83.33%) as fetal Down syndrome, 4 of 5 (80.00%) as trisomy 18, and 0 of 1 (0.00%) as trisomy 13. Comparing high-throughput sequencing results with conventional fetal karyotypes, we observed that sequencing revealed sub-chromosomal duplications or deletions, but results of karyotyping showed aberrations in chromosome structure or a normal karyotype. One chromosomal balanced translocation was inherited from the mother, another one chromosomal abnormalities was inherited from the father. When fetal chromosomal abnormalities were found by ultrasound abnormalities, non-invasive prenatal testing should not be recommended for the genetic evaluation. Invasive procedure should be first offered to the pregnant woman when abnormal nuchal translucency or other ultrasound abnormalities were found. During invasive prenatal diagnostic testing, fetal chromosomal anomalies should be evaluated by high-throughput sequencing combining with conventional karyotyping.

Betaine demonstrations antioxidative activity, enhances organic osmolytic activity and is an important cofactor in methylation. However, the main mechanisms betaine-induced autophagy in human dermal skin cells are not yet completely understood. Therefore, we hypothesized that betaine induces of autophagy. Thus, the autophagic effects exerted by betaine through activation of LKB1-AMPK signaling in human dermal fibroblasts (HDFs) and human epidermal keratinocytes (HEKs) were assessed. Betaine enhanced LKB1 and AMPK phosphorylation in HEKs, and LKB1, AMPK induced autophagy through mTOR downregulation. Beatine-induced autophagy was inhibited in cells transiently transfected with AMPK siRNA. Increased autophagosome activity was confirmed by LC3B-II formation and by increased perinuclear LC3B-II puncta in betaine-treated HEKs. according to our in vitro findings, and in vivo studies in HR-1 hairless mice demonstrated that betaine treatment significantly reduced the activity of the senescence-associated marker β-galactosidase (SA-β-gal) and increased p-LKB1 and p-AMPK levels compared with UVB-irradiated skin tissues. Collectively, our findings suggest that betaine-dependent autophagy diminishes mouse skin senescence and betaine may reduce HEK senescence through an LKB1-AMPK-dependent mechanism.

In this commentary, we discussed the new exciting progress in CRISPR based screening technology field and highlight recent developments in the area of CRISPR-based functional genomics. High-throughput functional genomics using CRISPR-Cas9 revolutionized our ability to decipher cellular function in health and disease. Despite its limitations, the simplicity and effectiveness of CRISPR/Cas9 based screening, makes an enormous impact on genomic screening and thus scientific discovery.

Objective: The aim of this study was to investigate in our area the clinical utility of QF-PCR, karyotyping and CMA for detecting chromosomal aberrations in fetuses with abnormal findings on first or second trimester ultrasound. Methods: We performed a retrospective analysis of 139 pregnancies with fetal structural anomaly or ultrasound markers. Results: Chromosomal abnormalities were identified in 28 patients (20.1% of all cases). Twenty-four of theses abnormalities (17.2% of total) were aneuploidies detected by QF-PCR. The remaining 4 chromosomal abnormalities (2.9% of cases) identified in this study were detected by CMA and/or by karyotyping, and only two genomic aberrations of 28 (1.4%) were identified by CMA but not by QF-PCR and conventional cytogenetics. Conclusion: QF-PCR must remain as the first-line test in prenatal diagnosis. Further studies with a bigger number of cases are desirable to corroborate the low additional detection rate of CMA analysis in our area.

Objectives: According to the cell language theory first proposed in 1997, living cells use a molecular language whose structure is similar to (or isomorphic) with the structures of the human language with respect to the 10 out of the 13 design features established by linguists. One of the predictions of the cell language theory is that there should exist in the living cell what is referred to as ‘hypermetabolic pathways’ that correspond to texts in human language deemed essential for reasoning and computing. A mathematical method known as the Planck-Shannon plot is described that can be employed to identify the predicted hypermetabolic pathways that underlie human breast cancer and hence can serve as potential anti-cancer drug targets. Data and analytic method: The gene expression profile data measured with microarrays were provided by Perez- Ortin’s group in Valencia, Spain and Perou and his coworkers at Stanford University. The mRNA data were transformed into histograms which were then fitted to the Planck Distribution Equation (PDE y = ((A / (x + B)5 ) / (eC/ ( x + B) – 1)) , to generate the numerical values for the parameters, A, B and C, that quantitatively characterize the shape of each histogram and hence the information contained in the original mRNA data set. The fitting of mRNA data to PDE was performed by the Sovler program available in Excel. Results: The hypermetabolic pathways, both intra-organismic, and inter-organismic, that are predicted by the cell language theory can be identified with the PDE-based analysis of mRNA data. The intra-organismic hypermetabolic pathway identified with PDE consists of 3 or more traditional metabolic pathways, while the interorganismic hypermetabolic pathway consists of one traditional metabolic pathway whose activity is correlated among 3 or more organisms exhibiting a common phenotype, e.g., breast cancer. Conclusion: Ribonoscopy, defined as the genome-wide study of mRNA levels within an organism or between different organisms, when combined with the quantitative method of analysis afforded by the Planck Distribution Equation (PDE), can identify a novel class of metabolic structures referred to as “intra-organismic hypermetabolic pathways” and “inter-organismic hypermetabolic pathways” that can serve as potential targets of cancer drug therapy.

Amyloid precursor protein (APP) gets cleaved by α, β, and γ secretases in both amyloidogenic and nonamyloidogenic processing. In amyloidogenic processing, Aβ40 and Aβ42 peptides result, leading to amyloid plaques in the brain, associated with various dementias, especially Alzheimer’s disease. Amyloid plaques also occur in the brains of children with autism spectrum disorder (ASD), while both elevated and diminished levels of soluble APP have been found in the serum of ASD patients. Treatment with mGluR5 inhibitors has successfully lowered APP and Aβ levels in vitro as well as ASD symptoms in a mouse model. Differences in ASD genotype and phenotype along with similarities to neurodegenerative dementias must be considered when investigating new biomarkers and treatments for ASD.

Human constitutional ring chromosomes are a rare type of chromosome structural abnormalities. The cytogenomic analysis of ring chromosome cases revealed different genomic imbalances and ring structures, variable levels of dynamic mosaicism, and selective karyotype evolution in different tissues. This cytogenomic heterogeneity is likely correlated with variable clinical manifestations of generalized features of ‘ring chromosome syndrome’, chromosome-specific and segmental aneuploidy related phenotypes, and risks of infertility and various types of cancers. Better understanding of the ‘biologic law’ governing ring chromosome formation and its mitotic segregation can contribute to the ‘diagnostic law’ guiding toward best practice in genetic analyses and the ‘therapeutic law’ for evidence-based treatment and management of ring chromosome disorders. Collaborative efforts are needed to study the biological processes involving ring chromosome formation, mitotic segregation and cell-autonomous correction, to develop cytogenomic diagnostic standards, and to generate registry of ring chromosome cases with defined genomic structures and dynamic mosaicism and detailed clinical manifestations. These efforts could provide more reliable karyotype-phenotype correlations for developing chromosome-specific guidelines and recommendations for genetic counseling and clinical treatment.