Merger Policy and Innovation: Must Enforcement Change to Account for Technological Change?

Merger policy is the most active area of U.S. antitrust policy. It is now widely believed that merger policy must move beyond its traditional focus on static efficiency to account for innovation and address dynamic efficiency. Innovation can fundamentally affect merger analysis in two ways. First, innovation can dramatically affect the relationship between the pre-merger marketplace and what is likely to happen if a proposed merger is consummated. Thus, innovation can fundamentally influence the appropriate analysis for addressing traditional, static efficiency concerns. Second, innovation can itself be an important dimension of market performance that is potentially affected by a merger. We explore how merger policy is meeting the challenges posed by innovation.

Mergers and Innovation

Merger review is the most active area of U.S. antitrust policy. It is now widely believed that merger policy must move beyond its traditional focus on short-run, price and output effects to account for longer-run effects on technological innovation. The question is, how should merger policy adapt to technological change? Some have argued that the right response is for antitrust authorities to reduce merger enforcement to prevent unintended harm to innovation. Others have suggested that the enforcement agencies analyze a merger’s effects on innovation using the same framework they use to analyze a transaction’s effects on prices and output levels. We argue that merger authorities should neither treat innovation like price and output under the existing framework nor retreat from enforcement in the name of innovation. We examine how merger policy should change both to accommodate the influence of innovation on traditional, static efficiency concerns and to recognize that innovation can itself be an important dimension of market performance affected by a merger

MICROTUBULE PROTEIN : Identification in and Transport to Nerve Endings

The subunit protein of microtubules, tubulin, has been demonstrated to be present in isolated nerve endings by gel electrophoresis, amino acid composition, and peptide mapping. The tubulin constitutes approximately 28% of the soluble protein of the nerve endings. The transport of tubulin to the nerve endings has been demonstrated and its relationship to slow transport is discussed

Abnormal microtubule packing in processes of SF9 cells expressing the FTDP-17 V337M tau mutation

AbstractMutations in the gene for the microtubule associated protein, tau have been identified for fronto-temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). In vitro data have shown that FTDP-17 mutant tau proteins have a reduced ability to bind microtubules and to promote microtubule assembly. Using the baculovirus system we have examined the effect of the V337M mutation on the organization of the microtubules at the ultrastructural level. Our results show that the organization of the microtubules is disrupted in the presence of V337M tau with greater distances between the microtubules and fewer microtubules per process

Apolipoprotein E and Alzheimer's Disease: Ethnic Variation in Genotypic Risks

The presence of the apolipoprotein E4 (apo €4) allele significantly increases the risk of Alzheimer's disease. Whether this is due to biological effects of the apo E4 protein or reflects linkage disequilibrium with an as yet unidentified Alzheimer's disease susceptibility gene is of critical importance. In a community study in northern Manhattan we found a fivefold increase in the risk of Alzheimer's disease among African-Americans, Hispanics, and whites homozygous for apo ~4. Overall, the risk between Alzheimer's disease and apo ~4 heterozygosity was also increased by twofold, but the association was somewhat weaker for African-Americans than for Hispanics and whites. In contrast, the apo e2/~3 genotype was associated with an eightfold increased risk of Alzheimer's disease in African-Americans but it was associated with reduced risk in whites. Variability in the strength and type of association between Alzheimer's disease and the apo E polymorphisms in the three ethnic groups could not be fully explained by age differences. The allelic frequency of apoe"4 was significantly higher in patients than control subjects in all ethnic groups at age 70 or younger, reflecting the higher proportion of apo E4 homozygotes, but this difference diminished with increasing age. The allelic frequency of apoe'2 for African-Americans and Hispanics, but not whites, was significantly higher in patients than control subjects, but only after age 70. Though these findings need confirmation, they suggest that modifier genes or environmenral factors may interact selectively with apo E4 in African-Americans to weaken the association with Alzheimer's disease or that the apo E allelic system is in linkage disequilibrium with a nearby, as yet unidentified Alzheimer's disease susceptibility locus

Assembly and Interrogation of Alzheimer’s Disease Genetic Networks Reveal Novel Regulators of Progression

Alzheimer’s disease (AD) is a complex multifactorial disorder with poorly characterized pathogenesis. Our understanding of this disease would thus benefit from an approach that addresses this complexity by elucidating the regulatory networks that are dysregulated in the neural compartment of AD patients, across distinct brain regions. Here, we use a Systems Biology (SB) approach, which has been highly successful in the dissection of cancer related phenotypes, to reverse engineer the transcriptional regulation layer of human neuronal cells and interrogate it to infer candidate Master Regulators (MRs) responsible for disease progression. Analysis of gene expression profiles from laser-captured neurons from AD and controls subjects, using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe), yielded an interactome consisting of 488,353 transcription-factor/ target interactions. Interrogation of this interactome, using the Master Regulator INference algorithm (MARINa), identified an unbiased set of candidate MRs causally responsible for regulating the transcriptional signature of AD progression. Experimental assays in autopsyderived human brain tissue showed that three of the top candidate MRs (YY1, p300 and ZMYM3) are indeed biochemically and histopathologically dysregulated in AD brains compared to controls. Our results additionally implicate p53 and loss of acetylation homeostasis in the neurodegenerative process. This study suggests that an integrative, SB approach can be applied to AD and other neurodegenerative diseases, and provide significant novel insight on the disease progression

Generation of iPSC lines from archived non-cryoprotected biobanked dura mater

Background: Induced pluripotent stem cells (iPSCs) derived from patients with neurodegenerative disease generally lack neuropathological confirmation, the gold standard for disease classification and grading of severity. The use of tissue with a definitive neuropathological diagnosis would be an ideal source for iPSCs. The challenge to this approach is that the majority of biobanked brain tissue was not meant for growing live cells, and thus was not frozen in the presence of cryoprotectants such as DMSO. Results: We report the generation of iPSCs from frozen non-cryoprotected dural tissue stored at −80°C for up to 11 years. This autopsy cohort included subjects with Alzheimer’s disease and four other neurodegenerative diseases. Conclusions: Disease-specific iPSCs can be generated from readily available, archival biobanked tissue. This allows for rapid expansion of generating iPSCs with confirmed pathology as well as allowing access to rare patient variants that have been banked

Gene-Wise Association of Variants in Four Lysosomal Storage Disorder Genes in Neuropathologically Confirmed Lewy Body Disease

Objective Variants in GBA are associated with Lewy Body (LB) pathology. We investigated whether variants in other lysosomal storage disorder (LSD) genes also contribute to disease pathogenesis. Methods We performed a genetic analysis of four LSD genes including GBA, HEXA, SMPD1, and MCOLN1 in 231 brain autopsies. Brain autopsies included neuropathologically defined LBD without Alzheimer Disease (AD) changes (n = 59), AD without significant LB pathology (n = 71), Alzheimer disease and lewy body variant (ADLBV) (n = 68), and control brains without LB or AD neuropathology (n = 33). Sequencing of HEXA, SMPD1, MCOLN1 and GBA followed by ‘gene wise’ genetic association analysis was performed. To determine the functional effect, a biochemical analysis of GBA in a subset of brains was also performed. GCase activity was measured in a subset of brain samples (n = 64) that included LBD brains, with or without GBA mutations, and control brains. A lipidomic analysis was also performed in brain autopsies (n = 67) which included LBD (n = 34), ADLBV (n = 3), AD (n = 4), PD (n = 9) and control brains (n = 17), comparing GBA mutation carriers to non-carriers. Results In a ‘gene-wise’ analysis, variants in GBA, SMPD1 and MCOLN1 were significantly associated with LB pathology (p range: 0.03–4.14 x10-5). Overall, the mean levels of GCase activity were significantly lower in GBA mutation carriers compared to non-carriers (p<0.001). A significant increase and accumulation of several species for the lipid classes, ceramides and sphingolipids, was observed in LBD brains carrying GBA mutations compared to controls (p range: p<0.05-p<0.01). Interpretation Our study indicates that variants in GBA, SMPD1 and MCOLN1 are associated with LB pathology. Biochemical data comparing GBA mutation carrier to non-carriers support these findings, which have important implications for biomarker development and therapeutic strategies