Sphere Packing with Limited Overlap

The classical sphere packing problem asks for the best (infinite) arrangement of non-overlapping unit balls which cover as much space as possible. We define a generalized version of the problem, where we allow each ball a limited amount of overlap with other balls. We study two natural choices of overlap measures and obtain the optimal lattice packings in a parameterized family of lattices which contains the FCC, BCC, and integer lattice.Comment: 12 pages, 3 figures, submitted to SOCG 201

Cloning of CDP-Diacylglycerol Synthase from a Human Neuronal Cell Line

A critical step in the supply of substrate for the phosphoinositide signal transduction pathway is the formation of the liponucleotide intermediate, CDP-diacylglycerol, catalyzed by CDP-diacylglycerol synthase. Further insight into the regulation of phosphoinositide biosynthesis was sought by cloning of the gene for the vertebrate enzyme. Sequence of the corresponding gene from Drosophila was used to prepare a probe for screening of a human neuronal cell cDNA library. A cDNA was isolated with a predicted open reading frame of 1,332 bases, encoding a protein of 51 kDa. The amino acid sequence showed 50% identity (75% similarity) to that of Drosophila eye CDP-diacylglycerol synthase and substantial similarity to the Saccharomyces cerevisiae and Escherichia coli homologues. Northern blot analysis, with human cDNA riboprobes, suggested that the corresponding mRNA was expressed in all human tissues examined. Expression of the human cDNA in COS cells resulted in a more than fourfold increase in CDP-diacylglycerol synthase activity. Knowledge of the sequence of vertebrate CDP-diacylglycerol synthase should facilitate further investigations into its regulation and the possible existence of distinct isoforms.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65959/1/j.1471-4159.1996.67052200.x.pd

KCl-induced depolarization facilitates neuronal differentiation of P19 embryonic carcinoma cells

Articlehttp://deepblue.lib.umich.edu/bitstream/2027.42/96992/1/UMURF-Issue06_2009-TMYang.pd

Maximum Likelihood Estimation for Brownian Motion Tree Models Based on One Sample

We study the problem of maximum likelihood estimation given one data sample ($n=1$) over Brownian Motion Tree Models (BMTMs), a class of Gaussian models on trees. BMTMs are often used as a null model in phylogenetics, where the one-sample regime is common. Specifically, we show that, almost surely, the one-sample BMTM maximum likelihood estimator (MLE) exists, is unique, and corresponds to a fully observed tree. Moreover, we provide a polynomial time algorithm for its exact computation. We also consider the MLE over all possible BMTM tree structures in the one-sample case and show that it exists almost surely, that it coincides with the MLE over diagonally dominant M-matrices, and that it admits a unique closed-form solution that corresponds to a path graph. Finally, we explore statistical properties of the one-sample BMTM MLE through numerical experiments

Enhancement of cancer chemotherapy in vitro by intense ultrawideband electric field pulses

Experiments have been performed to enhance the Jurkat cell-killing effects of the cancer chemotherapy agent bleomycin using electric field pulses of 50–200 kV/cm50–200kV∕cm peak electric field strength, ∼ 150 ns∼150ns duration, and nanosecond rise time. Dramatic increases in cell killing (factors of ∼ 1000∼1000) were observed with a low dose of bleomycin after treatment with trains of ten or more pulses at all electric field strengths tested, compared to pulse-only or drug-only treatments. Cell death occurred within 24 h24h for treated cells, with some evidence of membrane phosphatidylserine externalization at 6 h6h postexposure but no significant increase in caspase activity, indicating that the primary mode of cell death was not caspase-mediated apoptosis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87477/2/094701_1.pd

Phosphatidylinositol 3‐kinase and Akt effectors mediate insulin‐like growth factor‐I neuroprotection in dorsal root ganglia neurons

Insulin‐like growth factor‐I (IGF‐I) protects neurons of the peripheral nervous system from apoptosis, but the underlying signaling pathways are not well understood. We studied IGF‐I mediated signaling in embryonic dorsal root ganglia (DRG) neurons. DRG neurons express IGF‐I receptors (IGF‐IR), and IGF‐I activates the phosphatidylinositol 3‐kinase (PI3K)/Akt pathway. High glucose exposure induces apoptosis, which is inhibited by IGF‐I through the PI3K/Akt pathway. IGF‐I stimulation of the PI3K/Akt pathway phosphorylates three known Akt effectors: the survival transcription factor cyclic AMP response element binding protein (CREB) and the pro‐apoptotic effector proteins glycogen synthase kinase‐3β (GSK‐3β) and forkhead (FKHR). IGF‐I regulates survival at the nuclear level through accumulation of phospho‐Akt in DRG neuronal nuclei, increased CREB‐mediated transcription, and nuclear exclusion of FKHR. High glucose increases expression of the pro‐apoptotic Bcl protein Bim (a transcriptional target of FKHR). However, IGF‐I does not regulate Bim or anti‐apoptotic Bcl‐xL protein expression levels, which suggests that IGF‐I neuroprotection is not through regulation of their expression. High glucose also induces loss of the initiator caspase‐9 and increases caspase‐3 cleavage, effects blocked by IGF‐I. These data suggest that IGF‐I prevents apoptosis in DRG neurons by regulating PI3K/Akt pathway effectors, including GSK‐3β, CREB, and FKHR, and by blocking caspase activation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154325/1/fsb2fj041581fje.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154325/2/fsb2fj041581fje-sup-0001.pd

Incorporating spatial dependence into a multicellular tumor spheroid growth model

Recent models for organism and tumor growth yield simple scaling laws based on conservation of energy. Here, we extend such a model to include spatial dependence to model necrotic core formation. We adopt the allometric equation for tumor volume with a reaction-diffusion equation for nutrient concentration. In addition, we assume that the total metabolic energy and average cellular metabolic rate depend on nutrient concentration in a Michaelis-Menten-like manner. From experimental results, we relate the necrotic volume to nutrient consumption and estimate both the time and nutrient concentration at necrotic core formation. Based on experimental results, we demand that the necrotic core radius varies linearly with tumor radius after core formation and extend the equations for tumor volume and nutrient concentration to the postnecrotic core regime. In particular, we obtain excellent agreement with experimental data and the final steady-state viable rim thickness.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87333/2/124701_1.pd

Fibroblast growth factor 2 regulates activity and gene expression of human postâ mitotic excitatory neurons

Many neuropsychiatric disorders are thought to result from subtle changes in neural circuit formation. We used human embryonic stem cells and induced pluripotent stem cells (hiPSCs) to model mature, postâ mitotic excitatory neurons and examine effects of fibroblast growth factor 2 (FGF2). FGF2 gene expression is known to be altered in brain regions of major depressive disorder (MDD) patients and FGF2 has antiâ depressive effects in animal models of depression. We generated stable inducible neurons (siNeurons) conditionally expressing human neurogeninâ 2 (NEUROG2) to generate a homogenous population of postâ mitotic excitatory neurons and study the functional as well as the transcriptional effects of FGF2. Upon induction of NEUROG2 with doxycycline, the vast majority of cells are postâ mitotic, and the gene expression profile recapitulates that of excitatory neurons within 6 days. Using hES cell lines that inducibly express NEUROG2 as well as GCaMP6f, we were able to characterize spontaneous calcium activity in these neurons and show that calcium transients increase in the presence of FGF2. The FGF2â responsive genes were determined by RNAâ Seq. FGF2â regulated genes previously identified in nonâ neuronal cell types were upâ regulated (EGR1, ETV4, SPRY4, and DUSP6) as a result of chronic FGF2 treatment of siNeurons. Novel neuronâ specific genes were also identified that may mediate FGF2â dependent increases in synaptic efficacy including NRXN3, SYT2, and GALR1. Since several of these genes have been implicated in MDD previously, these results will provide the basis for more mechanistic studies of the role of FGF2 in MDD.Alterations in fibroblast growth factor (FGF) signaling have been implicated in major depressive disorder (MDD). In this article, human stem cells are differentiated into glutamatergic neurons. FGF2 treatment of these neurons increases activity as determined using calcium imaging. RNAseq studies implicate a number of genes in this regulation of neuronal activity by FGF2 including SYT2, NRXN3, and GALR1.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143704/1/jnc14255-sup-0001-SupInfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143704/2/jnc14255-sup-0002-TableS1-S2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143704/3/jnc14255.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143704/4/jnc14255_am.pd

Combined mutation screening of NKX2-5, GATA4, and TBX5 in congenital heart disease: multiple heterozygosity and novel mutations

Background: Variants of several genes encoding transcription modulators, signal transduction, and structural proteins are known to cause Mendelian congenital heart disease (CHD). NKX2-5 and GATA4 were the first CHD-causing genes identified by linkage analysis in large affected families. Mutations of TBX5 cause Holt–Oram syndrome, which includes CHD as a clinical feature. All three genes have a well-established role in cardiac development. Design: In order to investigate the possible role of multiple mutations in CHD, a combined mutation screening was performed in NKX2-5, GATA4, and TBX5 in the same patient cohort. Samples from a cohort of 331 CHD patients were analyzed by polymerase chain reaction, double high-performance liquid chromatography and sequencing in order to identify changes in the NKX2-5, GATA4, and TBX5 genes. Results: Two cases of multiple heterozygosity of putative disease-causing mutations were identified. One patient was found with a novel L122P NKX2-5 mutation in combination with the private A1443D mutation of MYH6. A patient heterozygote for a D425N GATA4 mutation carries also a private mutation of the MYH6 gene (V700M). Conclusions: In addition to reporting two novel mutations of NKX2-5 in CHD, we describe families where multiple individual mutations seem to have an additive effect over the pathogenesis of CHD. Our findings highlight the usefulness of multiple gene mutational analysis of large CHD cohorts

lncRNAdb: a reference database for long noncoding RNAs

Large numbers of long RNAs with little or no protein-coding potential [long noncoding RNAs (lncRNAs)] are being identified in eukaryotes. In parallel, increasing data describing the expression profiles, molecular features and functions of individual lncRNAs in a variety of systems are accumulating. To enable the systematic compilation and updating of this information, we have developed a database (lncRNAdb) containing a comprehensive list of lncRNAs that have been shown to have, or to be associated with, biological functions in eukaryotes, as well as messenger RNAs that have regulatory roles. Each entry contains referenced information about the RNA, including sequences, structural information, genomic context, expression, subcellular localization, conservation, functional evidence and other relevant information. lncRNAdb can be searched by querying published RNA names and aliases, sequences, species and associated protein-coding genes, as well as terms contained in the annotations, such as the tissues in which the transcripts are expressed and associated diseases. In addition, lncRNAdb is linked to the UCSC Genome Browser for visualization and Noncoding RNA Expression Database (NRED) for expression information from a variety of sources. lncRNAdb provides a platform for the ongoing collation of the literature pertaining to lncRNAs and their association with other genomic elements. lncRNAdb can be accessed at: http://www.lncrnadb.org/