MD ( Medical Doctor ) Student, An Najah National University & An Najah National University Teaching Hospital
To investigate relatives’ attitudes towards informing patients with Alzheimer about their disgnosis
Alzheimer's disease ( AD ) is a chronic neurodegenerative disease that destroys memory and other important mental functions. It starts slowly with mild confusion and difficulty remembering, then it gets worse over time as the patients may forget important people in their lives and undergo dramatic personality changes. Alzheimer's disease is the most common cause of dementia, accounts for 60 - 80 % of all cases of dementia - a group of brain disorders that cause loss of intellectual and social skills. Because there's no cure for Alzheimer's disease, it's important to seek supportive services and support networks as early as possible.
Objectives : To evaluate & investigate relatives’ attitudes towards informing patients with Alzheimer’s disease (AD) about their diagnosis.
Setting : An Najah National University Teaching Hospital & Al-Watani Hospital in Palestine
Methods : The closest relatives of each of 61 subjects diagnosed for the first time as having AD will be interviewed, using a semistructured questionnaire. Spontaneous requests by the relatives to not inform the patients concerning the diagnosis will be also recorded. Why relatives choose to not fully inform the patient about his/her current condition and the degree of relationship between the patient and his/her caregiver will also be evaluated. In AD patients, dementia severity is measured using Global Deterioration Scale (GDS) and Minimental State Examination (MMSE) Before having the interview, AD clinical course is described with respect to progressive deterioration of mental functions and irreversibility of the process. The interview is based on specific questions concerning the following issues :
Abstract: During lytic infection, herpes simplex virus (HSV) DNA is replicated by a mechanism involving DNA recombination. For instance, replication of the HSV-1 genome produces X- and Y-branched structures, reminiscent of recombination intermediates. HSV-1's replication machinery includes a trimeric helicase/primase is composed of helicase (UL5) and primase (UL52) subunits and a third subunit, UL8. UL8 has been reported to stimulate the helicase and primase activities of the complex in the presence of ICP8, an HSV-1 protein that functions as an annealase, a protein that binds complementary single-stranded (ss)DNA and facilitates its annealing to duplex DNA. UL8 also influences the intracellular localization of the UL5/UL52 subunits, but UL8`s catalytic activities are not known. In this study, we used a combination of biochemical techniques and transmission electron microscopy. First, we report that UL8 alone forms protein filaments in solution. Moreover, we also found that, UL8 binds to ssDNAs >50 nt long and promotes the annealing of complementary ssDNA to generate highly branched duplex DNA structures. Finally, UL8 has a very high affinity for replication fork structures containing a gap in the lagging strand as short as 15 nt, suggesting that UL8 may aid in directing or loading the trimeric complex onto a replication fork. The properties of UL8 uncovered here suggest that UL8 may be involved in the generation of the X- and Y-branched structures that are the hallmarks of HSV replication.
Pub.: 27 Jul '17, Pinned: 31 Jul '17
Abstract: Yatakemycin (YTM) is an extraordinarily toxic DNA alkylating agent with potent antimicrobial and antitumor properties and is the most recent addition to the CC-1065 and duocarmycin family of natural products. Though bulky DNA lesions the size of those produced by YTM are normally removed from the genome by the nucleotide-excision repair (NER) pathway, YTM adducts are also a substrate for the bacterial DNA glycosylases AlkD and YtkR2, unexpectedly implicating base-excision repair (BER) in their elimination. The reason for the extreme toxicity of these lesions and the molecular basis for the way they are eliminated by BER have been unclear. Here, we describe the structural and biochemical properties of YTM adducts that are responsible for their toxicity, and define the mechanism by which they are excised by AlkD. These findings delineate an alternative strategy for repair of bulky DNA damage and establish the cellular utility of this pathway relative to that of NER.
Pub.: 24 Jul '17, Pinned: 31 Jul '17
Abstract: The eukaryotic B-family DNA polymerases include four members, Polα, Polδ, Polϵ, and Polζ, which share common architectural features, such as the exonuclease/polymerase and C-terminal domains (CTDs) of catalytic subunits bound to indispensable B-subunits, which serve as scaffolds that mediate interactions with other components of the replication machinery. Crystal structures for the B-subunits of Polα and Polδ/Polζ have been reported; the former within the primosome and separately with CTD, and the latter with the N-terminal domain (NTD) of the C-subunit. Here we present the crystal structure of the human Polϵ B-subunit (p59) in complex with CTD of the catalytic subunit (p261C). The structure revealed a well-defined electron density for p261C and the phosphodiesterase (PDE) and oligonucleotide/oligosaccharide-binding domains of p59. However, electron density was missing for the p59 NTD and for the linker connecting it to the PDE domain. Similar to Polα, p261C contains a three-helix bundle in the middle and zinc-binding modules (Zn1 and Zn2) on each side. Intersubunit interactions involving 11 hydrogen bonds and numerous hydrophobic contacts account for stable complex formation with a buried surface area of 3094 Å(2) Comparative structural analysis of p59-p261C with the corresponding Polα complex revealed significant differences between the B-subunits and CTDs as well as their interaction interfaces. The B-subunit of Polδ/Polζ also substantially differs from B-subunits of either Polα or Polϵ. This work provides a structural basis to explain biochemical and genetic data on the importance of B-subunit integrity in replisome function in vivo.
Pub.: 28 Jul '17, Pinned: 31 Jul '17
Abstract: DNA repair enzymes recognize and remove damaged bases that are embedded in the duplex. To gain access, most enzymes use nucleotide flipping , whereby the target nucleotide is rotated 180 degree into the active site. In human alkyladenine DNA glycosylase (AAG), the enzyme that initiates base excision repair of alkylated bases, the flipped-out nucleotide is stabilized by intercalation of the side chain of tyrosine 162 that replaces the lesion nucleobase. Previous kinetic studies provided evidence for the formation of a transient complex that precedes the stable flipped-out complex, but it is not clear how this complex differs from nonspecific complexes. We used site-directed mutagenesis and transient-kinetic approaches to investigate the timing of Y162 intercalation for AAG. The tryptophan substitution (Y162W) appeared to be conservative, because the mutant protein retained a highly favorable equilibrium constant for flipping the 1,N6-ethenoadenine (εA) lesion and the rate of N-glycosidic bond cleavage was identical to that of the wild-type enzyme. We assigned the tryptophan fluorescence signal from Y162W by removing two native tryptophan residues (W270A/W284A). Stopped-flow experiments then demonstrated that the change in tryptophan fluorescence of the Y162W mutant is extremely rapid upon binding to either damaged or undamaged DNA, much faster than the lesion-recognition and nucleotide-flipping steps that were independently determined by monitoring the εA fluorescence. These observations suggest that intercalation by this aromatic residue is one of the earliest steps in the search for DNA damage, and that this interaction is important for the progression of AAG from nonspecific searching to specific-recognition complexes.
Pub.: 28 Jul '17, Pinned: 31 Jul '17
Abstract: Humans have three genes encoding DNA ligases with conserved structural features and activities, but they also have notable differences. The LIG3 gene encodes a ubiquitous isoform in all tissues (LIG3α) and a germ line-specific splicing isoform (LIG3β) that differ in the C-terminal domain. Both isoforms are found in the nucleus and the mitochondria. Here, we determined the kinetics and thermodynamics of single-strand break ligation by LIG3α and LIG3β, and compared this framework to that of LIG1, the nuclear replicative ligase. The kinetic parameters of the LIG3 isoforms are nearly identical under all tested conditions, indicating the BRCT domain specific to LIG3α does not alter ligation kinetics. Although LIG3 is only 22% identical to LIG1 across their conserved domains, the two enzymes had very similar maximal ligation rates. Comparison of the rate and equilibrium constants for LIG3 and LIG1 nevertheless revealed important differences. The LIG3 isoforms were 7 times more efficient than LIG1 at ligating nicked DNA under optimal conditions, mainly because of their lower KM value for the DNA substrate. This could explain why LIG3 is less prone to abortive ligation than LIG1. Surprisingly, the affinity of LIG3 for Mg2+ was 10 times weaker than that of LIG1, suggesting that Mg2+ availability regulates DNA ligation in vivo, as Mg2+ levels are higher in the mitochondria than in the nucleus. The biochemical differences between the LIG3 isoforms and LIG1 identified here will guide the understanding of both unique and overlapping biological roles of these critical enzymes.
Pub.: 29 Jul '17, Pinned: 31 Jul '17
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