Telomere maintenance through recruitment of internal genomic regions

Cells surviving crisis are often tumorigenic and their telomeres are commonly maintained through the reactivation of telomerase. However, surviving cells occasionally activate a recombination-based mechanism called alternative lengthening of telomeres (ALT). Here we establish stably maintained survivors in telomerase-deleted Caenorhabditis elegans that escape from sterility by activating ALT. ALT survivors trans-duplicate an internal genomic region, which is already cis-duplicated to chromosome ends, across the telomeres of all chromosomes. These 'Template for ALT' (TALT) regions consist of a block of genomic DNA flanked by telomere-like sequences, and are different between two genetic background. We establish a model that an ancestral duplication of a donor TALT region to a proximal telomere region forms a genomic reservoir ready to be incorporated into telomeres on ALT activation.

The genetic basis of natural variation in C. elegans telomere length [preprint]

Telomeres are involved in the maintenance of chromosomes and the prevention of genome instability. Despite this central importance, significant variation in telomere length has been observed in a variety of organisms. The genetic determinants of telomere-length variation and their effects on organismal fitness are largely unexplored. Here, we describe natural variation in telomere length across the Caenorhabditis elegans species. We identify a large-effect variant that contributes to differences in telomere length. The variant alters the conserved oligosaccharide/oligonucleotide-binding fold of POT-2, a homolog of a human telomere-capping shelterin complex subunit. Mutations within this domain likely reduce the ability of POT-2 to bind telomeric DNA, thereby increasing telomere length. We find that telomere-length variation does not correlate with offspring production or longevity in C. elegans wild isolates, suggesting that naturally long telomeres play a limited role in modifying fitness phenotypes in C. elegans

The Genetic Basis of Natural Variation in Caenorhabditis elegans Telomere Length

Telomeres are involved in the maintenance of chromosomes and the prevention of genome instability. Despite this central importance, significant variation in telomere length has been observed in a variety of organisms. The genetic determinants of telomere-length variation and their effects on organismal fitness are largely unexplored. Here, we describe natural variation in telomere length across the Caenorhabditis elegans species. We identify a large-effect variant that contributes to differences in telomere length. The variant alters the conserved oligonucleotide/oligosaccharide-binding fold of protection of telomeres 2 (POT-2), a homolog of a human telomere-capping shelterin complex subunit. Mutations within this domain likely reduce the ability of POT-2 to bind telomeric DNA, thereby increasing telomere length. We find that telomere-length variation does not correlate with offspring production or longevity in C. elegans wild isolates, suggesting that naturally long telomeres play a limited role in modifying fitness phenotypes in C. elegans

clfB-tree: Cacheline friendly persistent B-tree for NVRAM

Emerging byte-addressable non-volatile memory (NVRAM) is expected to replace block device storages as an alternative low-latency persistent storage device. If NVRAM is used as a persistent storage device, a cache line instead of a disk page will be the unit of data transfer, consistency, and durability. In this work, we design and develop clfB-tree—a B-tree structure whose tree node fits in a single cache line. We employ existing write combining store buffer and restricted transactional memory to provide a failure-atomic cache line write operation. Using the failure-atomic cache line write operations, we atomically update a clfB-tree node via a single cache line flush instruction without major changes in hardware. However, there exist many processors that do not provide SW interface for transactional memory. For those processors, our proposed clfB-tree achieves atomicity and consistency via in-place update, which requires maximum four cache line flushes. We evaluate the performance of clfB-tree on an NVRAM emulation board with ARM Cortex A-9 processor and a workstation that has Intel Xeon E7-4809 v3 processor. Our experimental results show clfB-tree outperforms wB-tree and CDDS B-tree by a large margin in terms of both insertion and search performance

Failure-Atomic Slotted Paging for Persistent Memory

The slotted-page structure is a database page format commonly used for managing variable-length records. In this work, we develop a novel "failure-atomic slotted page structure" for persistent memory that leverages byte addressability and durability of persistent memory to minimize redundant write operations used to maintain consistency in traditional database systems. Failure-atomic slotted paging consists of two key elements: (i) in-place commit per page using hardware transactional memory and (ii) slot header logging that logs the commit mark of each page. The proposed scheme is implemented in SQLite and compared against NVWAL, the current state-of-the-art scheme. Our performance study shows that our failure-atomic slotted paging shows optimal performance for database transactions that insert a single record. For transactions that touch more than one database page, our proposed slot-header logging scheme minimizes the logging overhead by avoiding duplicating pages and logging only the metadata of the dirty pages. Overall, we find that our failure-atomic slotted-page management scheme reduces database logging overhead to 1/6 and improves query response time by up to 33% compared to NVWAL

Doubleheader logging: Eliminating journal write overhead for mobile DBMS

Various transactional systems use out-of-place up-dates such as logging or copy-on-write mechanisms to update data in a failure-atomic manner. Such out-of-place update methods double the I/O traffic due to back-up copies in the database layer and quadruple the I/O traffic due to the file system journaling. In mobile systems, transaction sizes of mobile apps are known to be tiny and transactions run at low concurrency. For such mobile transactions, legacy out-of-place update methods such as WAL are sub-optimal. In this work, we propose a crash consistent in-place update logging method - doubleheader logging (DHL) for SQLite. DHL prevents previous consistent records from being lost by performing a copy-on-write inside the database page and co-locating the metadata-only journal information within the page. This is done, in turn, with minimal sacrifice to page utilization. DHL is similar to when journaling is disabled, in the sense that it incurs almost no additional overhead in terms of both I/O and computation. Our experimental results show that DHL outperforms other logging methods such as out-of-place update write-ahead logging (WAL) and in-place update multi-version B-tree (MVBT)

Inhibitory effect of traditional oriental medicine-derived monoamine oxidase B inhibitor on radioresistance of non-small cell lung cancer

Increased survival of cancer cells mediated by high levels of ionizing radiation (IR) reduces the effectiveness of radiation therapy for non-small cell lung cancer (NSCLC). In the present study, danshensu which is a selected component of traditional oriental medicine (TOM) compound was found to reduce the radioresistance of NSCLC by inhibiting the nuclear factor-κB (NF-κB) pathway. Of the various TOM compounds reported to inhibit the IR activation of NF-κB, danshensu was chosen as a final candidate based on the results of structural comparisons with human metabolites and monoamine oxidase B (MAOB) was identified as the putative target enzyme. Danshensu decreased the activation of NF-κB by inhibiting MAOB activity in A549 and NCI-H1299 NSCLC cells. Moreover, it suppressed IR-induced epithelial-to-mesenchymal transition, expressions of NF-κB-regulated prosurvival and proinflammatory genes, and in vivo radioresistance of mouse xenograft models. Taken together, this study shows that danshensu significantly reduces MAOB activity and attenuates NF-κB signaling to elicit the radiosensitization of NSCLC

B-3-Tree: Byte-Addressable Binary B-Tree for Persistent Memory

In this work, we propose B-3-tree, a hybrid index for persistent memory that leverages the byte-addressability of the in-memory index and the page locality of B-trees. As in the byte-addressable in-memory index, B-3-tree is updated by 8-byte store instructions. Also, as in disk-based index, B-3-tree is failure-atomic since it makes every 8-byte store instruction transform a consistent index into another consistent index without the help of expensive logging. Since expensive logging becomes unnecessary, the number of cacheline flush instructions required for B-3-tree is significantly reduced. Our performance study shows that B-3-tree outperforms other state-of-the-art persistent indexes in terms of insert and delete performance. While B-3-tree shows slightly worse performance for point query performance, the range query performance of B-3-tree is 2x faster than FAST and FAIR B-tree because the leaf page size of B-3-tree can be set to 8x larger than that of FAST and FAIR B-tree without degrading insertion performance. We also show that read transactions can access B-3- tree without acquiring a shared lock because B-3-tree remains always consistent while a sequence of 8-byte write operations are making changes to it. As a result, B-3-tree provides high concurrency level comparable to FAST and FAIR B-tree

The Genetic Basis of Natural Variation in Caenorhabditis elegans Telomere Length.

Telomeres are involved in the maintenance of chromosomes and the prevention of genome instability. Despite this central importance, significant variation in telomere length has been observed in a variety of organisms. The genetic determinants of telomere-length variation and their effects on organismal fitness are largely unexplored. Here, we describe natural variation in telomere length across the Caenorhabditis elegans species. We identify a large-effect variant that contributes to differences in telomere length. The variant alters the conserved oligonucleotide/oligosaccharide-binding fold of protection of telomeres 2 (POT-2), a homolog of a human telomere-capping shelterin complex subunit. Mutations within this domain likely reduce the ability of POT-2 to bind telomeric DNA, thereby increasing telomere length. We find that telomere-length variation does not correlate with offspring production or longevity in C. elegans wild isolates, suggesting that naturally long telomeres play a limited role in modifying fitness phenotypes in C. elegans