Decreased hippocampal noradrenaline does not affect corticosterone release following electrical stimulation of CA1 pyramidal cells

Bipolar electrodes were implanted into the CA1 pyramidal cells of the dorsal hippocampus and the effect of electrical stimulation of these cells on corticosterone secretion was investigated in freely moving rats. Histology showed that the electrodes were positioned in close proximity to the CA1 pyramidal cells. Rats that were subjected to high intensity electrical stimulation (1, 10, and 100A) behaved differently when compared to their sham stimulated controls. They were more active and displayed wet dog shakes. Plasma corticosterone levels increased dose-dependently in rats subjected to different electrical stimulation intensities. Although prior treatment (24 hours) of rats with DSP₄ (60 mg/kg, i.p.) significantly reduced hippocampal noradrenaline content by 46%, it did not bring about any behavioural changes. DSP₄ treatment also had no effect on electrically stimulated corticosterone release. These data suggested that stimulation of CA1 pyramidal cells may lead to increased corticosterone release and that a decrease in hippocampal noradrenaline concentration was unable to alter this corticosterone response.     

Serpin-6 expression protects embryonic stem cells from lysis by antigen-specific CTL

The immune response to embryonic stem (ES) cells is still poorly understood. In this study, we addressed the adaptive cellular immune response to undifferentiated and differentiated ES cells infected with lymphocytic choriomeningitis virus (LCMV), a vertically transmitted pathogen in mice and humans. In contrast to the prevailing view, we found that undifferentiated and differentiated murine ES cells express MHC class I molecules, although at low levels. When cocultured with LCMV-infected ES cells, syngeneic but not allogeneic LCMV-specific CTL secrete IFN-gamma. Strikingly, LCMV-specific CTL do not efficiently kill LCMV-infected ES cells. ES cells showed high-level expression of the serine protease inhibitor 6, an endogenous inhibitor of the CTL-derived cytotoxic effector molecule granzyme B. Down-regulation of serpin-6 by RNA interference sensitized ES cells for CTL-induced cell death. The results of this study suggest that LCMV-infected murine ES cells present viral Ags and are recognized by LCMV-specific CTL in a MHC class I-restricted manner, yet resist CTL-mediated lysis through high-level expression of serine protease inhibitor 6.     

Adolescents' perceived weight associated with depression in young adulthood: a longitudinal study

Objective: The objective of this study is to examine whether adolescents’ measured BMI and self‐ or mother's perception of weight status at age 14 are associated with depression at age 21. Research Methods and Procedures: The study participants were a subsample of 2017 participants of the Mater–University of Queensland Study of Pregnancy and Its Outcomes, a population‐based birth cohort study, which commenced in 1981 in Brisbane, Australia, for whom measured BMI at ages 14 and 21 and information on self‐reported mental health problems were available at the age 21 follow‐up. A total of 1802 individuals had measured BMI and reported weight perception in a supplementary questionnaire at 14 years, and their self‐reported mental health problems were reported at 21 years. Mental health was measured using Center for Epidemiology Studies Depression Scale and Young Adults Self‐Reported depression/anxiety at 21 years of age. Results: We found that both young adult males and females who perceived themselves as overweight at age 14 had more mental health problems compared with those who perceived themselves as the right weight. When we combined adolescents’ weight perception with their measured BMI categories, weight perception but not measured overweight was associated with mental health problems for males and females at age 21. This association remained after adjusting for potential confounders, including adolescents’ behavioral problems, family meals, diet, physical activity, and television watching. Conclusions: This study suggests that the perception of being overweight during adolescence is a significant risk factor for depression in young adult men and women. The perception of being overweight during adolescence should be considered a possible target for a prevention intervention.     

Structural insights into the inhibitor binding and new inhibitor design to Polo-like kinase-1 Polo-box domain using computational studies

Polo box domain (PBD) from Polo-Like Kinase-1 (PLK-1) a cell cycle regulator is one of the important non-kinase targets implicated in various cancers. The crystal structure of PLK-1 PBD bound to phosphopeptide inhibitor is available and acylthiourea derivatives have been reported as potent PBD inhibitors. In this work, structure and ligand-based pharmacophore methods have been used to identify new PBD inhibitors. The binding of acylthiourea analogs and new inhibitors to PBD were assessed using molecular docking and molecular dynamics simulations to understand their binding interactions, investigate the complex stability and reveal the molecular basis for inhibition. This study provides the binding free energies and residue-wise contributions to decipher the essential interactions in the protein-inhibitor complementarity for complex formation and the design of new PBD inhibitors with better binding.

Communicated by Ramaswamy H. Sarma     

Measures,Gaps, and Mitigation Strategies in Bangladesh’s COVID-19 Response

EcoHealth - The Coronavirus Disease 2019 (COVID-19) spread rapidly from China to most other countries around the world in early 2020 killing millions of people. To prevent virus spread, world...     

FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway

The Fanconi anemia (FA) core complex plays a central role in the DNA damage response network involving breast cancer susceptibility gene products, BRCA1 and BRCA2. The complex consists of eight FA proteins, including a ubiquitin ligase (FANCL) and a DNA translocase (FANCM), and is essential for monoubiquitination of FANCD2 in response to DNA damage. Here, we report a novel component of this complex, termed FAAP100, which is essential for the stability of the core complex and directly interacts with FANCB and FANCL to form a stable subcomplex. Formation of this subcomplex protects each component from proteolytic degradation and also allows their coregulation by FANCA and FANCM during nuclear localization. Using siRNA depletion and gene knockout techniques, we show that FAAP100-deficient cells display hallmark features of FA cells, including defective FANCD2 monoubiquitination, hypersensitivity to DNA crosslinking agents, and genomic instability. Our study identifies FAAP100 as a new critical component of the FA-BRCA DNA damage response network.     

Effect of lisinopril on rat liver tissues in L-NAME induced hypertension model

N ^G-Nitro-l-arginine methyl ester hydrochloride (L-NAME) is a non-specific nitric oxide (NO) inhibitor and it has been used to eliminate the role of NO in many studies like animal models for hypertension. In this study, we aimed to investigate whether lisinopril treatment has any biochemical and/or histopathological effect on rat liver tissue in a L-NAME-induced hypertension model. Forty-eight 6-weeks-old male Spraque–Dawley rats were used in the study. The animals used in the study were randomly divided into four equal groups. To induce hypertension, L-NAME was added to drinking water at a concentration of 600 mg/l and each rat was given 75 mg/kg/day of L-NAME for 6 weeks. Tail cuff systolic blood pressure (SBP) was measured at first, third, and sixth weeks. There was a significant difference between the experiment groups and controls. In only lisinopril given and L-NAME plus lisinopril administered groups, each rat was given 10 mg/kg of lisinopril for 6 weeks. At the end of the study, the animals were sacrificed. Blood and tissue samples were collected for biochemical and histopathological analysis. It has been observed that mean NO level was significantly decreased in L-NAME given group (p<0.05). Mean ALT levels were significantly increased in lisinopril and L-NAME plus lisinopril given groups, when compared with the control group (p<0.05). AST levels were in normal range in all groups (p>0.05). Hepatocyte degeneration was prominent in lisinopril given group, whereas mononuclear cell infiltration was significant in L-NAME given groups. Although the beneficial effects in L-NAME-induced hypertension treatment, lisinopril can lead to some unexpected results like hepatocyte degeneration, serum enzyme level elevation, and slight mononuclear cell infiltration.     

Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome

Intragenic homozygous deletions in the Large gene are associated with a severe neuromuscular phenotype in the myodystrophy (myd) mouse. These mutations result in a virtual lack of glycosylation of α-dystroglycan. Compound heterozygous LARGE mutations have been reported in a single human patient, manifesting with mild congenital muscular dystrophy (CMD) and severe mental retardation. These mutations are likely to retain some residual LARGE glycosyltransferase activity as indicated by residual α-dystroglycan glycosylation in patient cells. We hypothesized that more severe LARGE mutations are associated with a more severe CMD phenotype in humans. Here we report a 63-kb intragenic LARGE deletion in a family with Walker-Warburg syndrome (WWS), which is characterized by CMD, and severe structural brain and eye malformations. This finding demonstrates that LARGE gene mutations can give rise to a wide clinical spectrum, similar as for other genes that have a role in the post-translational modification of the α-dystroglycan protein. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Otoferlin Deficiency in Zebrafish Results in Defects in Balance and Hearing: Rescue of the Balance and Hearing Phenotype with Full-Length and Truncated Forms of Mouse Otoferlin

Sensory hair cells convert mechanical motion into chemical signals. Otoferlin, a six-C2 domain transmembrane protein linked to deafness in humans, is hypothesized to play a role in exocytosis at hair cell ribbon synapses. To date, however, otoferlin has been studied almost exclusively in mouse models, and no rescue experiments have been reported. Here we describe the phenotype associated with morpholino-induced otoferlin knockdown in zebrafish and report the results of rescue experiments conducted with full-length and truncated forms of otoferlin. We found that expression of otoferlin occurs early in development and is restricted to hair cells and the midbrain. Immunofluorescence microscopy revealed localization to both apical and basolateral regions of hair cells. Knockdown of otoferlin resulted in hearing and balance defects, as well as locomotion deficiencies. Further, otoferlin morphants had uninflated swim bladders. Rescue experiments conducted with mouse otoferlin restored hearing, balance, and inflation of the swim bladder. Remarkably, truncated forms of otoferlin retaining the C-terminal C2F domain also rescued the otoferlin knockdown phenotype, while the individual N-terminal C2A domain did not. We conclude that otoferlin plays an evolutionarily conserved role in vertebrate hearing and that truncated forms of otoferlin can rescue hearing and balance.     

Flavonoids isolated from Tridax procumbens (TPF) inhibit osteoclasts differentiation and bone resorption

Background

The Tridax procumbens flavonoids (TPF), are well known for their medicinal properties among local natives. The TPF are traditionally used for dropsy, anaemia, arthritis, gout, asthma, ulcer, piles, and urinary problems. It also used in treating gastric problems, body pain, and rheumatic pains of joints. The TPF have been reported to increase osteogenic functioning in mesenchymal stem cells. However, their effects on osteoclastogenesis remain unclear. The TPF isolated from T. procumbens and investigated the effects of the TPF inhibit on osteoclast differentiation and bone resorption activities using primary osteoclastic cells. Osteoclast formation was assessed by counting the number of tartrate resistant acid phosphatase (TRAP) positive multinucleated cells and by measuring both TRAP activities.

Results

The TPF significantly suppressed the RANKL-induced differentiation of osteoclasts and the formation of pits in primary osteoclastic cells. The TPF also decreased the expression of mRNAs related to osteoclast differentiation, including Trap, Cathepsin K, Mmp-9, and Mmp-13 in primary osteoclastic cells. The treatment of primary osteoclastic cells with the TPF decreased Cathepsin K, Mmp-9, and Mmp-13 proteins expression in primary osteoclastic cells.

Conclusion

These results indicated that TPF inhibit osteoclastogenesis and pits formation activities. Our results suggest that the TPF could be a potential anti-bone resorptic agent to treat patients with bone loss-associated diseases such as osteoporosis.