The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair

Baranes-Bachar, Keren,Levy-Barda, Adva,Oehler, Judith,Reid, Dylan A.,Soria-Bretones, Isabel,Voss, Ty C.,Chung, Dudley,Park, Yoon,Liu, Chao,Yoon, Jong-Bok,Li, Wei,Dellaire, Graham,Misteli, Tom,Huertas, Elsevier 2018 Molecular cell Vol.69 No.5

<P><B>Summary</B></P> <P>Double-strand breaks (DSBs) are critical DNA lesions that robustly activate the elaborate DNA damage response (DDR) network. We identified a critical player in DDR fine-tuning: the E3/E4 ubiquitin ligase UBE4A. UBE4A’s recruitment to sites of DNA damage is dependent on primary E3 ligases in the DDR and promotes enhancement and sustainment of K48- and K63-linked ubiquitin chains at these sites. This step is required for timely recruitment of the RAP80 and BRCA1 proteins and proper organization of RAP80- and BRCA1-associated protein complexes at DSB sites. This pathway is essential for optimal end resection at DSBs, and its abrogation leads to upregulation of the highly mutagenic alternative end-joining repair at the expense of error-free homologous recombination repair. Our data uncover a critical regulatory level in the DSB response and underscore the importance of fine-tuning the complex DDR network for accurate and balanced execution of DSB repair.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The E3/E4 ubiquitin ligase UBE4A is a new player in the DNA damage response </LI> <LI> UBE4A is required for optimal repair of DNA double-strand breaks </LI> <LI> After initial action of E3 ubiquitin ligases, UBE4A modulates ubiquitylation extent </LI> <LI> UBE4A’s activity is required for appropriate balance of repair pathways </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>

Energy-Aware Self-Stabilizing Distributed Clustering Protocol for Ad Hoc Networks: the case of WSNs

( Mandicou Ba ),( Olivier Flauzac ),( Bachar Salim Haggar ),( Rafik Makhloufi ),( Florent Nolot ),( Ibrahima Niang ) 한국인터넷정보학회 2013 KSII Transactions on Internet and Information Syst Vol.7 No.11

In this paper, we present an Energy-Aware Self-Stabilizing Distributed Clustering protocol based on message-passing model for Ad Hoc networks. The latter does not require any initialization. Starting from an arbitrary configuration, the network converges to a stable state in a finite time. Our contribution is twofold. We firstly give the formal proof that the stabilization is reached after at most transitions and requires at most n*log(2n+k+3) memory space, where n is the number of network nodes and k represents the maximum hops number in the clusters. Furthermore, using the OMNeT++ simulator, we perform an evaluation of our approach. Secondly, we propose an adaptation of our solution in the context of Wireless Sensor Networks (WSNs) with energy constraint. We notably show that our protocol can be easily used for constructing clusters according to multiple criteria in the election of cluster-heads, such as nodes` identity, residual energy or degree. We give a comparison under the different election metrics by evaluating their communication cost and energy consumption. Simulation results show that in terms of number of exchanged messages and energy consumption, it is better to use the Highest-ID metric for electing CHs.

Antihyperlipidemic activity of leaf and root extracts of $Premna$ $esculenta$ (Roxb.) in Poloxamer-407 induced hyperlipidemic mice and rats

Mahmud, Zobaer A.,Bachar, Sitesh C.,Qais, Nazmul 경희한의학연구센터 2011 Oriental Pharmacy and Experimental Medicine Vol.11 No.4

The ethanolic extracts of leaves and roots of $Premna$ $esculenta$ (Roxb.) were evaluated for antihyperlipidemic activity in poloxamer 407 induced hyperlipidemic rats and mice. The administration of the ethanolic extract of leaves induced a significant ($p$ <0.05) reduction in serum total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL) and very low density lipoprotein (VLDL) levels as well as the atherogenic index compared to the P-407 induced hyperlipidemic control mice after 24 h of treatment at a single dose of 500 mg/kg p.o. Both the leaf and root extracts significantly ($p$ <0.05) reduced the serum TC, TG, VLDL and LDL levels as well as the atherogenic index compared to P-407 induced hyperlipidemic control rats after 4 days of pretreatment at a dose of 250 mg/kg/day p.o. The lipid lowering effects were compared with standard drug atorvastatin (50 mg/kg p.o.). Furthermore, both extracts showed potential to moderate scavenging activity of superoxide, nitric oxide and DPPH free radicals. In DPPH radical scavenging assay the $IC_{50}$ values of the leaf and root extracts were found to be 425.79 and 20.26 ${\mu}g$/ml, respectively while ascorbic acid has the $IC_{50}$ value 16.34 ${\mu}g$/ml. The $IC_{50}$ values of the leaf and root extracts against superoxide radicals were found to be 109.57 and 366.2 ${\mu}g$/ml, respectively which were comparable to that of ascorbic acid (99.66 ${\mu}g$/ml). The findings of the investigation demonstrated both antihyperlipidemic and antioxidant activities of the leaf and root extracts of $P.$ $esculenta$ which could help in prevention of hyperlipidemia associated disorders.

Risk Factors for Cervical Cancer and CIN3 in Jewish Women in Israel - Two Case Control Studies

Bassal, Ravit,Schejter, Eduardo,Bachar, Rachel,Perri, Tamar,Korach, Jacob,Jakobson-Setton, Ariella,Ben-David, Liat Hogen,Cohen, Daniel,Keinan-Boker, Lital Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.4

Purpose: The aim of the study was to identify risk and protective factors/markers for cervical cancer and cervical intraepithelial neoplasia 3 (CIN3) in Israeli Jewish women in order to settle the discrepancy of low incidence rate of cervical cancer and relatively high incidence rate of CIN3. Materials and Methods: We conducted two case control studies, which examined the association between potential risk and protective factors/markers for cervical cancer or CIN3 using self administered detailed questionnaires. Results: For studying cervical cancer, 40 cases and 40 matched controls were interviewed. In the univariable and multivariable analyses older age, depression or anxiety and ever smoking seemed to act as independent risk factors/markers, while older age at first intercourse was protective. For studying CIN3, 99 cases and 79 controls were interviewed. Multivariable analysis has demonstrated that being born in Israel, depression or anxiety and ever smoking were independent risk factors/markers for CIN3. Conclusions: The risk factors/markers studied, that were associated with cervical cancer or CIN3 among Jewish women in Israel, are similar to those reported in other parts of the world, and do not explain the observed discrepancy of high in-situ cervical cancer rates and low invasive cervical cancer incidence in Israel.

Autophagy is a major regulator of beta cell insulin homeostasis

Riahi, Yael,Wikstrom, Jakob D.,Bachar-Wikstrom, Etty,Polin, Nava,Zucker, Hava,Lee, Myung-Shik,Quan, Wenying,Haataja, Leena,Liu, Ming,Arvan, Peter,Cerasi, Erol,Leibowitz, Gil Springer-Verlag 2016 Diabetologia Vol.59 No.7

<P>Aims/hypothesis We studied the role of protein degradation pathways in the regulation of insulin production and secretion and hypothesised that autophagy regulates proinsulin degradation, thereby modulating beta cell function. Methods Proinsulin localisation in autophagosomes was demonstrated by confocal and electron microscopy. Autophagy was inhibited by knockdown of autophagy-related (ATG) proteins and using the H+-ATPase inhibitor bafilomycin-A1. Proinsulin and insulin content and secretion were assessed in static incubations by ELISA and RIA. Results Confocal and electron microscopy showed proinsulin localised in autophagosomes and lysosomes. Beta-Atg7(-/-) mice had proinsulin-containing sequestosome 1 (p62 [also known as SQSTM1])(+) aggregates in beta cells, indicating proinsulin is regulated by autophagy in vivo. Short-term bafilomycin-A1 treatment and ATG5/7 knockdown increased steady-state proinsulin and hormone precursor chromogranin A content. ATG5/7 knockdown also increased glucose- and non-fuel-stimulated insulin secretion. Finally, mutated forms of proinsulin that are irreparably misfolded and trapped in the endoplasmic reticulum are more resistant to degradation by autophagy. Conclusions/interpretation In the beta cell, transport-competent secretory peptide precursors, including proinsulin, are regulated by autophagy, whereas efficient clearance of transport-incompetent mutated forms of proinsulin by alternative degradative pathways may be necessary to avoid beta cell proteotoxicity. Reduction of autophagic degradation of proinsulin increases its residency in the secretory pathway, followed by enhanced secretion in response to stimuli.</P>

Antihyperlipidemic activity of leaf and root extracts of Premna esculenta (Roxb.) in Poloxamer-407 induced hyperlipidemic mice and rats

Zobaer A. Mahmud,Sitesh C. Bachar,Nazmul Qais 경희대학교 융합한의과학연구소 2011 Oriental Pharmacy and Experimental Medicine Vol.11 No.4

The ethanolic extracts of leaves and roots of Premna esculenta (Roxb.) were evaluated for antihyperlipidemic activity in poloxamer 407 induced hyperlipidemic rats and mice. The administration of the ethanolic extract of leaves induced a significant (p<0.05) reduction in serum total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL) and very low density lipoprotein (VLDL)levels as well as the atherogenic index compared to the P-407induced hyperlipidemic control mice after 24 h of treatment at a single dose of 500 mg/kg p.o. Both the leaf and root extracts significantly (p<0.05) reduced the serum TC, TG, VLDL and LDL levels as well as the atherogenic index compared to P-407 induced hyperlipidemic control rats after 4 days of pretreatment at a dose of 250 mg/kg/day p.o. The lipid lowering effects were compared with standard drug atorvastatin (50 mg/kg p.o.). Furthermore, both extracts showed potential to moderate scavenging activity of superoxide,nitric oxide and DPPH free radicals. In DPPH radical scavenging assay the IC_(50) values of the leaf and root extracts were found to be 425.79 and 20.26 μg/ml, respectively while ascorbic acid has the IC_(50) value 16.34 μg/ml. The IC_(50)values of the leaf and root extracts against superoxide radicals were found to be 109.57 and 366.2 μg/ml,respectively which were comparable to that of ascorbic acid (99.66 μg/ml). The findings of the investigation demonstrated both antihyperlipidemic and antioxidant activities of the leaf and root extracts of P. esculenta which could help in prevention of hyperlipidemia associated disorders.

Omalizumab as a Succesfull Therapy in Normocomplementemic Urticarial Vasculitis: A Series of Four Patients and Review of the Literature

( Ece Nur Degirmentepe ),( Kubra Kızıltac ),( Pırıl Etikan ),( Ralfi Singer ),( Bachar Memet ),( Emek Kocaturk ) 대한피부과학회 2019 Annals of Dermatology Vol.31 No.3

Urticarial vasculitis is an eruption characterized by inflamed itchy or painful red papules or plaques that resemble urticaria but last longer than 24 hours and heal with residual pigmentation or purpura. Histopathologically, urticarial vasculitis presents as leukocytoclastic vasculitis with perivascular infiltrate and fibrin deposits. The treatment options are oral antihistamines, oral corticosteroids, dapsone, colchicine and hydroxychloroquine. We report four cases with normocomplementemic urticarial vasculitis who were treated with omalizumab and a brief review of the literature on the use of omalizumab in normocomplementemic urticarial vasculitis. (Ann Dermatol 31(3) 335∼338, 2019)

Methanol Extract of Flacourtia indica Aerial Parts Induces Apoptosis via Generation of ROS and Activation of Caspases in Human Colon Cancer HCT116 Cells

Park, Ki-Woong,Kundu, Juthika,Chae, In Gyeong,Bachar, Sitesh Chandra,Bae, Jung-Woo,Chun, Kyung-Soo Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.17

Different plant parts of Flacourtia indica have long been used in Ayurvedic medicine. Previous studies have demonstrated that the methanolic extract of F. indica possess anti-inflammatory properties. The present study was aimed at investigating the anticancer effects of methanol extract of Flacourtia indica (FIM) aerial parts in human colon cancer (HCT116) cells. Treatment of cells with FIM at a concentration of $500{\mu}g/ml$ for 24 hours significantly reduced cell viability and induced apoptosis, which was associated with the increased cytoplasmic expression of cytochrome c, activation of caspase-3, and the cleavage of poly-(ADP-ribose) polymerase. Incubation with FIM also inhibited the levels of Bcl-2, Bcl-xl and survivin, which are the markers of cell proliferation, whereas the expression of Bax remained unchanged. Treatment with FIM led to the generation of reactive oxygen species (ROS) in a concentration-dependent manner. Pharmacological inhibition of ROS generation by pretreatment of cells with N-acetyl cysteine abrogated FIM-induced apoptosis in HCT116 cells. Thus, these results demonstrate that FIM has anti-proliferative and pro-apoptotic effects in HCT116 cells and the effects are, at least in part, due to the ROS dependent activation of caspases.