Miracle-dz/UniFAR-FTUs huggingface dataset:
Preferential allelic deletion of RBSP3, LIMD1 and CDC25A in head and neck squamous cell carcinoma: Implication in cancer screening and early detection

ABSTRACT Head and neck squamous cell carcinoma is one of the leading cancers in terms of incidence and mortality. However, no reliable marker till date accurately predicts its progression when altered in healthy tissues. The study aims to identify alleles of microsatellites adjacent to important cell cycle regulatory, tumor suppressor genes altered in early head and neck lesions, viz. RBSP3, LIMD1 and CDC25A, which undergo frequent deletion and can be used for population screening and early detection. DNA for tumors and normal tissues was isolated from 143 patients in different stages of head and neck squamous cell carcinoma. The size of microsatellite present in normal tissues and their deletion in the corresponding tumor was identified, along with the correlation of expression in normal epithelium with respect to allele size. The results revealed a range of alleles (CA9 to CA32) for the different microsatellites of the genes in normal tissues. The larger alleles were significantly deleted with differential deletion of alleles observed in tumors, except for LIMD1, in which the smaller allele was significantly deleted. In normal tissues, some alleles represented as stable alleles with high prevalence, while in tumours, specific sizes showed greater propensity for deletion. However, similar expression of the proteins in normal epithelium adjacent to tumors was observed despite variations in allele size, possibly due to the location of the microsatellites. Thus, those alleles when present in normal tissues and undergoing persistent deletion in tumours could be used as markers for screening and early identification of populations at risk of developing head and neck lesions.
Attachment in Romantic Relationships and Somatization

Abstract Adult attachment representations have been considered to play a role in the development and treatment of somatizing behavior. In this study, the associations between the two attachment dimensions avoidance and anxiety and dimensions of psychopathology (somatization, depression, and general anxiety) were explored. The sample consists of 202 outpatients diagnosed with a somatoform disorder. Data were collected via self-report measures. A path analysis shows that the two attachment dimensions are not directly associated with somatization. There are, however, significant indirect associations between attachment and somatization mediated by depression and general anxiety, which are more pronounced for attachment anxiety than for attachment avoidance. The findings reveal that a low level of attachment security in romantic relationships, especially an anxious stance toward the partner, comes along with poor mental health, which in turn is related to a preoccupation with somatic complaints. Implications for the treatment of somatizing patients are discussed.
Characterization of fecal microbial communities in patients with liver cirrhosis

Liver cirrhosis is the pathologic end stage of chronic liver disease. Increasing evidence suggests that gut flora is implicated in the pathogenesis of liver cirrhosis complications. The aim of this study was to characterize the fecal microbial community in patients with liver cirrhosis in comparison with healthy individuals. We recruited 36 patients with liver cirrhosis and 24 healthy controls. The fecal microbial communities was analyzed by way of 454 pyrosequencing of the 16S ribosomal RNA V3 region followed by real‐time quantitative polymerase chain reaction. Community‐wide changes of fecal microbiota in liver cirrhosis were observed compared with healthy controls. The proportion of phylum Bacteroidetes was significantly reduced (P = 0.008), whereas Proteobacteria and Fusobacteria were highly enriched in the cirrhosis group (P = 0.001 and 0.002, respectively). Enterobacteriaceae (P = 0.001), Veillonellaceae (P = 0.046), and Streptococcaceae (P = 0.001) were prevalent in patients with cirrhosis at the family level. A positive correlation was observed between Child‐Turcotte‐Pugh (CTP) score and Streptococcaceae (R = 0.386, P = 0.02). Lachnospiraceae decreased significantly in patients with cirrhosis (P = 0.004) and correlated negatively with CTP score (R = −0.49, P = 0.002). Using partial least square discriminate analysis, we identified 149 operational taxonomic units (OTUs) as key phylotypes that responded to cirrhosis, most of which were Lachnospiraceae (65 OTUs), Streptococcaceae (23 OTUs), and Veillonellaceae (21 OTUs). Conclusion: Fecal microbial communities are distinct in patients with cirrhosis compared with healthy individuals. The prevalence of potentially pathogenic bacteria, such as Enterobacteriaceae and Streptococcaceae, with the reduction of beneficial populations such as Lachnospiraceae in patients with cirrhosis may affect prognosis. (HEPATOLOGY 2011;)
BCR-ABL inactivates cytosolic PTEN through Casein Kinase II mediated tail phosphorylation

The tumor suppressive function of PTEN is exerted within 2 different cellular compartments. In the cytosol-membrane, it negatively regulates PI3K-AKT pathway through the de-phosphorylation of phosphatidylinositol (3,4,5)-triphosphate (PIP3), therefore blocking one of the major signaling transduction pathways in tumorigenesis. In the nucleus, PTEN controls genomic stability and cellular proliferation through phosphatase independent mechanisms. Importantly, impairments in PTEN cellular compartmentalization, changes in protein levels and post-transductional modifications affect PTEN tumor suppressive functions. Targeting mechanisms that inactivate PTEN promotes apoptosis induction of cancer cells, without affecting normal cells, with appealing therapeutic implications. Recently, we have shown that BCR-ABL promotes PTEN nuclear exclusion by favoring HAUSP mediated PTEN de-ubiquitination in Chronic Myeloid Leukemia. Here, we show that nuclear exclusion of PTEN is associated with PTEN inactivation in the cytoplasm of CML cells. In particular, BCR-ABL promotes Casein Kinase II-mediated PTEN tail phosphorylation with consequent inhibition of the phosphatase activity toward PIP3. Targeting Casein Kinase II promotes PTEN reactivation with apoptosis induction. We therefore propose a novel BCR-ABL/CKII/PTEN pathway as a potential target to achieve synthetic lethality with tyrosine kinase inhibitors.
RhoB is a component of the human cytomegalovirus assembly complex and is required for efficient viral production

Human Cytomegalovirus (HCMV), an ubiquitous β-herpesvirus, is a significant pathogen that causes medically severe diseases in immunocompromised individuals and in congenitally infected neonates. RhoB belongs to the family of Rho GTPases, which regulates diverse cellular processes. Rho proteins are implicated in the entry and egress from the host cell of mainly α- and γ-herpesviruses, whereas β-herpesviruses are the least studied in this regard. Here, we studied the role of RhoB GTPase during HCMV lytic infection. Microscopy analysis, both in fixed and live infected cells showed that RhoB was translocated to the assembly complex/compartment (AC) of HCMV, a cytoplasmic zone in infected cells where many viral structural proteins are known to accumulate and assembly of new virions takes place. Furthermore, RhoB was localized at the AC even when the expression of the late HCMV AC proteins was inhibited. At the very late stages of infection, cellular projections were formed containing RhoB and HCMV virions, potentially contributing to the successful viral spread. Interestingly, the knockdown of RhoB in HCMV-infected cells resulted in a significant reduction of the virus titer and could also affect the accumulation of AC viral proteins at this subcellular compartment. RhoB knockdown also affected actin fibers' structure. Actin reorganization was observed at late stages of infection originating from the viral AC and surrounding the cellular projections, implying a potential interplay between RhoB and actin during HCMV assembly and egress. In conclusion, our results demonstrate for the first time that RhoB is a constituent of the viral AC and is required for HCMV productive infection.
Structure of the HIV‐1 Rev response element alone and in complex with regulator of virion (Rev) studied by atomic force microscopy

The interaction of multiple HIV‐1 regulator of virion (Rev) proteins with the viral RNA target, the Rev response element (RRE), is critical for nuclear export of incompletely spliced and unspliced viral RNA, and for the onset of the late phase in the viral replication cycle. The heterogeneity of the Rev–RRE complex has made it difficult to study using conventional structural methods. In the present study, atomic force microscopy is applied to directly visualize the tertiary structure of the RRE RNA alone and in complex with Rev proteins. The appearance of the RRE is compatible with the earlier proposed RRE secondary structure in dimensions and overall shape, including a stalk and a head interpreted as stem I, and stem‐loops II–V in the secondary structure model, respectively. Atomic force microscopy imaging of the Rev–RRE complex revealed an increased height of the structure both in the stalk and head regions, which is in accordance with a binding model in which Rev binding to a high affinity site in stem IIB triggers oligomerization of Rev proteins through cooperative binding along stem I in RRE. The present study demonstrates that atomic force microscopy comprises a useful technique to study complex biological structures of nucleic acids at high resolution.
Nitric oxide in bone and joint disease

No wonder you activities are, reading will be always needed. It is not only to fulfil the duties that you need to finish in deadline time. Reading will encourage your mind and thoughts. Of course, reading will greatly develop your experiences about everything. Reading nitric oxide in bone and joint disease is also a way as one of the collective books that gives many advantages. The advantages are not only for you, but for the other peoples with those meaningful benefits.
Essential role of the C‐terminus in Melanocarpus  albomyces laccase for enzyme production, catalytic properties and structure

The C‐terminus of the fungal laccase from Melanocarpus albomyces (MaL) is processed during secretion at a processing site conserved among the ascomycete laccases. The three‐dimensional structure of MaL has been solved as one of the first complete laccase structures. According to the crystal structure of MaL, the four C‐terminal amino acids of the mature protein penetrate into a tunnel leading towards the trinuclear site. The C‐terminal carboxylate group forms a hydrogen bond with a side chain of His140, which also coordinates to the type 3 copper. In order to analyze the role of the processed C‐terminus, site‐directed mutagenesis of the MaL cDNA was performed, and the mutated proteins were expressed in Trichoderma reesei and Saccharomyces cerevisiae. Changes in the C‐terminus of MaL caused major defects in protein production in both expression hosts. The deletion of the last four amino acids dramatically affected the activity of the enzyme, as the deletion mutant delDSGL559 was practically inactive. Detailed characterization of the purified L559A mutant expressed in S. cerevisiae showed the importance of the C‐terminal plug for laccase activity, stability, and kinetics. Moreover, the crystal structure of the L559A mutant expressed in S. cerevisiae showed that the C‐terminal mutation had clearly affected the trinuclear site geometry. The results in this study clearly confirm the critical role of the last amino acids in the C‐terminus of MaL.
Colorectal Cancer Incidence: Does Iran Follow the West?

Context Colorectal cancer (CRC) is the third most prevalent cancer worldwide which is less common in the Middle East. It is also the second leading cause of cancer-related mortality and represents a major public health problem in developed countries. Objectives The present review aimed to explore the differences among the reports on number and age standardized incidences of CRC in both sexes in different areas of Iran to find the incidence trend of this cancer. Data Sources All the published reports citing the incidence of CRC in Iran were collected by conducting a literature search in international databases. Study Selection English articles were included where there was a clear definition of the population of patients under study and where the criteria for diagnosing CRC were well described. Data Extraction One author read each paper and extracted several studies and then the studies suitable for inclusion were reported in three categories. Results We identified 181 independent studies dating back to 2003; 168 full text articles were assessed for eligibility. However, 136 full text articles were excluded due to different reasons. Finally, 26 studies were suitable for inclusion in the analysis. The highest and lowest (age standardized rates) ASRs were respectively 3.4 and 2.6 in males and 11.42 and 10.56 in females. Time showed a slightly increasing trend in recent years. Conclusions Although Iran was expected to have a low incidence rate of CRC, recent studies revealed a slightly increasing trend for the incidence rate of CRC. This finding shows the necessity to consider CRC screening as an important issue in health policy priorities.
Centriolin, a centriole-appendage protein, regulates peripheral spindle migration and asymmetric division in mouse meiotic oocytes

ABSTRACT Unlike somatic cells mitosis, germ cell meiosis consists of 2 consecutive rounds of division that segregate homologous chromosomes and sister chromatids, respectively. The meiotic oocyte is characterized by an absence of centrioles and asymmetric division. Centriolin is a relatively novel centriolar protein that functions in mitotic cell cycle progression and cytokinesis. Here, we explored the function of centriolin in meiosis and showed that it is localized to meiotic spindles and concentrated at the spindle poles and midbody during oocyte meiotic maturation. Unexpectedly, knockdown of centriolin in oocytes with either siRNA or Morpholino micro-injection, did not affect meiotic spindle organization, cell cycle progression, or cytokinesis (as indicated by polar body emission), but led to a failure of peripheral meiotic spindle migration, large polar body emission, and 2-cell like oocytes. These data suggest that, unlike in mitotic cells, the centriolar protein centriolin does not regulate cytokinesis, but plays an important role in regulating asymmetric division of meiotic oocytes.
Probe the function of histone lysine 36 methylation using histone H3 lysine 36 to methionine mutant transgene in mammalian cells

ABSTRACT Chondroblastoma is a cartilaginous tumor that typically arises under 25 y of age (80%). Recent studies have identified a somatic and heterozygous mutation at the H3F3B gene in over 90% chondroblastoma cases, leading to a lysine 36 to methionine replacement (H3.3K36M). In human cells, H3F3B gene is one of 2 genes that encode identical H3.3 proteins. It is not known how H3.3K36M mutant proteins promote tumorigenesis. We and others have shown that, the levels of H3K36 di- and tri-methylation (H3K36me2/me3) are reduced dramatically in chondroblastomas and chondrocytes bearing the H3.3K36M mutation. Mechanistically, H3.3K36M mutant proteins inhibit enzymatic activity of some, but not all H3K36 methyltransferases. Chondrocytes harboring the same H3F3B mutation exhibited the cancer cell associated phenotypes. Here, we discuss the potential effects of H3.3K36M mutation on epigenomes including H3K36 and H3K27 methylation and cellular phenotypes. We suggest that H3.3K36M mutant proteins alter epigenomes of specific progenitor cells, which in turn lead to cellular transformation and tumorigenesis.
Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation

No specific drugs are currently available against hepatitis delta virus (HDV), a defective virus leading to the most severe form of chronic viral hepatitis in man. The lack of convenient HDV infection models has hampered the development of effective therapeutics. In this study, naïve and hepatitis B virus (HBV) chronically infected humanized uPA/SCID mice were employed to establish a small animal model of HBV/HDV coinfection and superinfection. For preclinical antiviral drug evaluation, the GMP version of the myristoylated preS‐peptide (Myrcludex‐B), a lipopeptide derived from the pre‐S1 domain of the HBV envelope, was applied to prevent de novo HBV/HDV coinfection in vivo. Virological parameters were determined at serological and intrahepatic level both by real‐time polymerase chain reaction (PCR) and by immunohistochemistry. Establishment of HDV infection was highly efficient in both HBV‐infected and naïve chimeric mice with HDV titers rising up to 1 × 10E9 copies/mL. Notably, HDV superinfection led to a median 0.6log reduction of HBV viremia, which although not statistically significant suggests that HDV may hinder HBV replication. In the setting of HBV/HDV simultaneous infection, a majority of human hepatocytes stained HDAg‐positive long before HBV spreading was completed, confirming that HDV can replicate intrahepatically also in the absence of HBV infection. Furthermore, the increase of HBV viremia and intrahepatic cccDNA loads was significantly slower than in HBV mono‐infected mice. Treatment with the HBV entry inhibitor Myrcludex‐B, efficiently hindered the establishment of HDV infection in vivo. Conclusion: We established an efficient model of HBV/HDV infection to exploit mechanisms of viral interference in human hepatocytes and to test the efficacy of an HDV‐entry inhibitor in vivo. (HEPATOLOGY 2011)
Hepatic macrophage migration and differentiation critical for liver fibrosis is mediated by the chemokine receptor C‐C motif chemokine receptor 8 in mice

Chemokines critically control the infiltration of immune cells upon liver injury, thereby promoting hepatic inflammation and fibrosis. The chemokine receptor CCR8 can affect trafficking of monocytes/macrophages, monocyte‐derived dendritic cells (DCs) and T‐helper cell (Th) subsets, but its role in liver diseases is currently unknown. To investigate the functional role of CCR8 in liver diseases, ccr8−/− and wild‐type (WT) mice were subjected to chronic experimental injury models of carbon tetrachloride (CCl4) administration and surgical bile duct ligation (BDL). CCR8 was strongly up‐regulated in the injured liver. Ccr8−/− mice displayed attenuated liver damage (e.g., ALT, histology, and TUNEL) compared to WT mice and were also protected from liver fibrosis in two independent injury models. Flow cytometry revealed reduced infiltrates of liver macrophages, neutrophils and natural killer cells, whereas hepatic CD4+ T cells increased. The main CCR8‐expressing cells in the liver were hepatic macrophages, and CCR8 was functionally necessary for CCL1‐directed migration of inflammatory but not for nonclassical monocytes into the liver. Moreover, the phenotype of liver macrophages from injured ccr8−/− animals was altered with increased expression of DC markers and enhanced expression of T‐cell‐attracting chemokine macrophage inflammatory protein 1‐alpha (MIP‐1α/CCL3). Correspondingly, hepatic CD4+ T cells showed increased Th1 polarization and reduced Th2 cells in CCR8‐deficient animals. Liver fibrosis progression, but also subsequent T‐cell alterations, could be restored by adoptively transferring CCR8‐expressing monocytes/macrophages into ccr8−/− mice during experimental injury. Conclusions: CCR8 critically mediates hepatic macrophage recruitment upon injury, which subsequently shapes the inflammatory response in the injured liver, affecting macrophage/DC and Th differentiation. CCR8 deficiency protects the liver against injury, ameliorating initial inflammatory responses and hepatic fibrogenesis. Inhibition of CCR8 or its ligand, CCL1, might represent a successful therapeutic target to limit liver inflammation and fibrosis progression. (Hepatology 2012)
Recent insights into cerebral cavernous malformations: a complex jigsaw puzzle under construction

Cerebral cavernous malformations (CCM) are common vascular malformations with an unpredictable risk of hemorrhage, the consequences of which range from headache to stroke or death. Three genes, CCM1, CCM2 and CCM3, have been linked to the disease. The encoded CCM proteins interact with each other within a large protein complex. Within the past 2 years, a plethora of new data has emerged on the signaling pathways in which CCM proteins are involved. CCM proteins regulate diverse aspects of endothelial cell morphogenesis and blood vessel stability such as cell–cell junctions, cell shape and polarity, or cell adhesion to the extracellular matrix. Although fascinating, a global picture is hard to depict because little is known about how these pathways coordinate to orchestrate angiogenesis. Here we present what is known about the structural domain organization of CCM proteins, their association as a ternary complex and their subcellular localization. Numerous CCM partners have been identified using two‐hybrid screens, genetic analyses or proteomic studies. We focus on the best‐characterized partners and review data on the signaling pathways they regulate as a step towards a better understanding of the etiology of CCM disease.
A biophysical view of the interplay between mechanical forces and signaling pathways during transendothelial cell migration

The vascular endothelium is exposed to an array of physical forces, including shear stress via blood flow, contact with other cells such as neighboring endothelial cells and leukocytes, and contact with the basement membrane. Endothelial cell morphology, protein expression, stiffness and cytoskeletal arrangement are all influenced by these mechanochemical forces. There are many biophysical tools that are useful in studying how forces are transmitted in endothelial cells, and these tools are also beginning to be used to investigate biophysical aspects of leukocyte transmigration, which is a ubiquitous mechanosensitive process. In particular, the stiffness of the substrate has been shown to have a significant impact on cellular behavior, and this is true for both endothelial cells and leukocytes. Thus, the stiffness of the basement membrane as an endothelial substrate, as well as the stiffness of the endothelium as a leukocyte substrate, is relevant to the process of transmigration. In this review, we discuss recent work that has related the biophysical aspects of endothelial cell interactions and leukocyte transmigration to the biochemical pathways and molecular interactions that take place during this process. Further use of biophysical tools to investigate the biological process of leukocyte transmigration will have implications for tissue engineering, as well as atherosclerosis, stroke and immune system disease research.