Lift-and-Round to Improve Weighted Completion Time on Unrelated Machines

We consider the problem of scheduling jobs on unrelated machines so as to minimize the sum of weighted completion times. Our main result is a $(3/2-c)$-approximation algorithm for some fixed $c>0$, improving upon the long-standing bound of 3/2 (independently due to Skutella, Journal of the ACM, 2001, and Sethuraman & Squillante, SODA, 1999). To do this, we first introduce a new lift-and-project based SDP relaxation for the problem. This is necessary as the previous convex programming relaxations have an integrality gap of $3/2$. Second, we give a new general bipartite-rounding procedure that produces an assignment with certain strong negative correlation properties.Comment: 21 pages, 4 figure

Late-onset retinal degeneration pathology de to mutations in CTRP5 is mediated through HTRA1

Late-onset retinal degeneration (L-ORD) is an autosomal dominant macular degeneration characterized by the formation of sub-retinal pigment epithelium (RPE) deposits and neuroretinal atrophy. L-ORD results from mutations in the C1q-tumor necrosis factor-5 protein (CTRP5), encoded by the CTRP5/C1QTNF5 gene. To understand the mechanism underlying L-ORD pathology, we used a human cDNA library yeast two-hybrid screen to identify interacting partners of CTRP5. Additionally, we analyzed the Bruch's membrane/choroid (BM-Ch) from wild-type (Wt), heterozygous S163R Ctrp5 mutation knock-in (Ctrp5S163R/wt ), and homozygous knock-in (Ctrp5S163R/S163R ) mice using mass spectrometry. Both approaches showed an association between CTRP5 and HTRA1 via its C-terminal PDZ-binding motif, stimulation of the HTRA1 protease activity by CTRP5, and CTRP5 serving as an HTRA1 substrate. The S163R-CTRP5 protein also binds to HTRA1 but is resistant to HTRA1-mediated cleavage. Immunohistochemistry and proteomic analysis showed significant accumulation of CTRP5 and HTRA1 in BM-Ch of Ctrp5S163R/S163R and Ctrp5S163R/wt mice compared with Wt. Additional extracellular matrix (ECM) components that are HTRA1 substrates also accumulated in these mice. These results implicate HTRA1 and its interaction with CTRP5 in L-ORD pathology

IFT88 mutations identified in individuals with non-syndromic recessive retinal degeneration result in abnormal ciliogenesis

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Lift-and-round to improve weighted completion time on unrelated machines

We consider the problem of scheduling jobs on unrelated machines so as to minimize the sum of weighted completion times. Our main result is a (3/2-c)-approximation algorithm for some fixed c > 0, improving upon the long-standing bound of 3/2. To do this, we first introduce a new lift-and-project based SDP relaxation for the problem. This is necessary as the previous convex programming relaxations have an integrality gap of 3/2. Second, we give a new general bipartite-rounding procedure that produces an assignment with certain strong negative correlation properties

A blood-brain barrier-penetrant AAV gene therapy improves neurological function in symptomatic mucolipidosis IV mice

Mucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits, and progressive vision loss. Using adeno-associated vector 9 (AAV9) and AAV-PHP.B as delivery vectors, we previously demonstrated the feasibility of modifying disease course in a mouse model of MLIV by the human MCOLN1 gene transfer. Here, using a primate-enabling capsid AAV.CPP.16 (CPP16), we constructed a new, clinic-oriented MCOLN1 gene expression vector and demonstrated its efficacy in the preclinical model of MLIV. Systemic administration of CPP16-MCOLN1 in adult symptomatic Mcoln1−/− mice at a dose of 1e12 vg per mouse resulted in MCOLN1 expression in the brain and peripheral tissues, alleviated brain pathology, rescued neuromotor function, and completely prevented paralysis. Notable expression of MCOLN1 transcripts was also detected in the retina of the mouse, which had exhibited significant degeneration at the time of the treatment. However, no increase in retinal thickness was observed after gene therapy treatment. Our results suggest a new AAV-based systemic gene replacement therapy for the treatment of MLIV that could be translated into clinical studies