Faculty Bibliography

Aplasia cutis congenita (ACC) in a symmetric, stellate pattern on the trunk or extremities is classically associated with a fetus papyraceus. We report symmetric truncal ACC in a neonate born of a sextuplet pregnancy that had been reduced to twins. This case highlights truncal ACC as a consequence of modern reproductive medicine

Hybrid systems are dynamical systems with the ability to describe mixed discrete-continuous evolution of a wide range of systems. Consequently, at first glance, hybrid systems appear powerful but recalcitrant, neither yielding to analysis and reasoning through a purely continuous-time modeling as with systems of differential equations, nor open to inferential processes commonly used for discrete state-transition systems such as finite state automata. A convenient and popular model, called hybrid automata, was introduced to model them and has spurred much interest on its tractability as a tool for inference and model checking in a general setting. Intuitively, a hybrid automaton is simply a 'finite-state' automaton with each state augmented by continuous variables, which evolve according to a set of well-defined continuous laws, each specified separately for each state. This article investigates both the notion of hybrid automaton and the model checking problem over such a structure. In particular, it relates first-order theories and analysis results on multivalued maps and reduces the bounded reachability problem for hybrid automata whose continuous laws are expressed by inclusions (x' is an element of f (x,t)) to a decidability problem for first-order formula? over the reals. Furthermore, the paper introduces a class of hybrid automata for which the reachability problem can be decided and shows that the problem of deciding whether a hybrid automaton belongs to this class can be again decided using first-order formulae over the reals. Despite the fact that the bisimulation quotient for this class of hybrid automata can be infinite, we show that our techniques permit effective model checking for a nontrivial fragment of CTL. (C) 2008 Elsevier Inc. All rights reserved

Members of the Nodal family regulate left-right asymmetry during vertebrate organogenesis, but it is unclear how Nodal signaling controls asymmetric morphogenesis at the cellular level. We used high-resolution time-lapse imaging in zebrafish to compare the movements of cardiomyocytes in the presence or absence of Nodal signaling. Loss of Nodal signaling in late-zygotic mutants for the Nodal co-receptor one-eyed pinhead (LZoep) abolished the leftward movement of cardiomyocytes. Global heart rotation was blocked but cardiomyocyte neighbor relationships were maintained as in wild type. Cardiomyocytes in LZoep mutants moved more slowly and less directionally than their wild-type counterparts. The phenotypes observed in the absence of Nodal signaling strongly resemble abnormalities found in BMP signaling mutants. These results indicate that a Nodal-BMP signaling cascade drives left-right heart morphogenesis by regulating the speed and direction of cardiomyocyte movement.

KvLm is a prokaryotic voltage-gated K(+) (Kv) channel from Listeria monocytogenes. The sequence of the voltage-sensing module (transmembrane segments S1-S4) of KvLm is atypical in that it contains only three of the eight conserved charged residues known to be deterministic for voltage sensing in eukaryotic Kv's. In contrast, the pore module (PM), including the S4-S5 linker and cytoplasmic tail (linker-S5-P-S6-C-terminus) of KvLm, is highly conserved. Here, the full-length (FL)-KvLm and the KvLm-PM only proteins were expressed, purified, and reconstituted into giant liposomes. The properties of the reconstituted FL-KvLm mirror well the characteristics of the heterologously expressed channel in Escherichia coli spheroplasts: a right-shifted voltage of activation, micromolar tetrabutylammonium-blocking affinity, and a single-channel conductance comparable to that of eukaryotic Kv's. Conversely, ionic currents through the PM recapitulate both the conductance and blocking properties of the FL-KvLm, yet the KvLm-PM exhibits only rudimentary voltage dependence. Given that the KvLm-PM displays many of the conduction properties of FL-KvLm and of other eukaryotic Kv's, including strict ion selectivity, we conclude that self-assembly of the PM subunits in lipid bilayers, in the absence of the voltage-sensing module, generates a conductive oligomer akin to that of the native KvLm, and that the structural independence of voltage sensing and PMs observed in eukaryotic Kv channels was initially implemented by nature in the design of prokaryotic Kv channels. Collectively, the results indicate that this robust functional module will prove valuable as a molecular template for coupling new sensors and to elucidate PM residue-specific contributions to Kv conduction properties.

BACKGROUND: Human metapneumovirus is a recently discovered RNA virus that typically causes respiratory disease in children. It has been linked to severe lower airway disease in hematopoietic stem cell and solid-organ transplant recipients. hMPV infection in a large population of patients with underlying cancer and varying degrees of immunosuppression has not been reported. We sought to characterize hMPV infection in patients with cancer. METHODS: Review of all cases of hMPV infection from two seasons (2005-6 and 2006-7) detected by DFA and/or real-time PCR at MSKCC, a tertiary cancer center in New York City. RESULTS: Among MSKCC patients with cancer, 51 (2.7%) of 1899 patients were positive for hMPV, including 3.2% with hematologic neoplasm and 1.7% with solid tumors. More children (4.5%) were positive than adults (2.2%). PCR detected twice as many cases as DFA. Cough and fever were common complaints. The longest shedding period was 80 days. 40 patients received radiographic evaluation; of these, 22 showed abnormalities including patchy (11), ground glass (5), and interstitial infiltrates (4). CONCLUSIONS: hMPV causes a nonspecific respiratory illness and was found in more than 2% of all tested persons with cancer. PCR detected substantially more cases than DFA. Unlike previous reports, we observed no fatalities due to hMPV, including 22 HSCT recipients with the infection.

Endometriosis is a common gynecological disease that affects approximately 10% of women of childbearing age. It is characterized by endometrial growth outside the uterus and often results in inflamed lesions, pain, and reduced fertility. Although heightened estrogenic activity and/or reduced progesterone responsiveness are considered to be involved in the etiology of endometriosis, neither the extent of their participation nor the underlying mechanisms are clearly understood. Heterogeneous uterine cell types differentially respond to estrogen and progesterone (P(4)). P(4), primarily acting via its nuclear receptor (PR), activates gene transcription and impacts many reproductive processes. Deletion of Fkbp52, an immunophilin cochaperone for PR, results in uterine-specific P(4) resistance in mice, creating an opportunity to study the unique aspects of P(4) signaling in endometriosis. Here we explored the roles of FKBP52 in this disease using Fkbp52(-/-) mice. We found that the loss of FKBP52 encourages the growth of endometriotic lesions with increased inflammation, cell proliferation, and angiogenesis. We also found remarkable down-regulation of FKBP52 in cases of human endometriosis. Our results provide the first evidence corroborated by genetic studies in mice for a potential role of an immunophilin cochaperone in the etiology of human endometriosis. This investigation is highly relevant for clinical application, particularly because P(4) resistance is favorably indicated in endometriosis and other gynecological diseases.

Forkhead transcription factor FoxO3a, also known as DAF-16 in Caenorhabditis elegans, is a key regulator of the insulin receptor (IR)/insulin-like growth factor-I signaling pathway mediated extension of life span in worms and yeast. In this study, we report that calorie restriction (CR)-mediated activation of the IR signaling pathway leads to hyperphosphorylation of FoxO3a transcription factor and, consequently, its exclusion from the nucleus. This inactivation of FoxO3a activity is correlated with attenuation of Alzheimer's disease (AD)-type amyloid neuropathology and with preservation of spatial reference memory in the Tg2576 mouse model of AD. Further, in vitro studies reveal that exogenous expression of viral, triple-mutant, constitutively active FoxO3a resulting in increased nuclear FoxO3a activity in primary neuron cultures derived from Tg2576 mouse embryos, causally promotes AD amyloid-beta peptide (Abeta) levels by inhibiting nonamyloidogenic alpha-secretase activity, indicating the existence of an inverse correlation between FoxO3a activity and cerebral Abeta amyloidosis. Moreover, we report for the first time that the exclusion of the FoxO3a transcription factor from the nucleus in combination with inhibition of nuclear FoxO3a activity by SIRT1-mediated deacetylation in response to CR is a mechanism resulting in the repression of Rho-associated protein kinase-1 gene expression, thereby activating nonamyloidogenic alpha-secretase processing of the amyloid precursor protein and lowering Abeta generation. This study provides a novel metabolic pathway for prevention and/or treatment of AD

Retina differentiation involves the acquisition of a precise layered arrangement, with RPE cells in the first layer in intimate contact with photoreceptors in the second layer. Here, we developed an in vitro coculture model, to test the hypothesis that RPE cells play a pivotal role in organizing the spatial structure of the retina. We cocultured rat retinal neurons with ARPE-19 epithelial cells under various experimental conditions. Strikingly, when seeded over RPE cells, photoreceptors attached to their apical surfaces and proceeded with their development, including the increased synthesis of rhodopsin. Conversely, when we seeded RPE cells over neurons, the RPE cells rapidly detached photoreceptors from their substrata and positioned themselves underneath, thus restoring the normal in vivo arrangement. Treatment with the metalloproteinase inhibitor TIMP-1 blocked this reorganization, suggesting the involvement of metalloproteinases in this process. Reorganization was highly selective for photoreceptors because 98% of photoreceptors but very few amacrine neurons were found to redistribute on top of RPE cells. Interestingly, RPE cells were much more efficient than other epithelial or nonepithelial cells in promoting this reorganization. RPE cells also promoted the growth of photoreceptor axons away from them. An additional factor that contributed to the distal arrangement of photoreceptor axons was the migration of photoreceptor cell bodies along their own neurites toward the RPE cells. Our results demonstrate that RPE and photoreceptor cells interact in vitro in very specific ways. They also show that in vitro studies may provide important insights into the process of pattern formation in the retina.

Directed indels, insertions or deletions within paralogous genes, have the potential to root the tree of life. Here we apply the top-down rooting algorithm to indels found in PyrD (dihydroorotate dehydrogenase), a key enzyme involved in the de novo biosynthesis of pyrimidines, and HisA (P-ribosylformimino-AICAR-P-isomerase), an essential enzyme in the histidine biosynthesis pathway. Through the comparison of each indel with its two paralogous outgroups, we exclude the root of the tree of life from the clade that encompasses the Actinobacteria, the double-membrane prokaryotes, and their last common ancestor. In combination with previous indel rooting studies excluding the root from a clade consisting of the Firmicutes, the Archaea, and their last common ancestor, this provides evidence for a unique eubacterial root for the tree of life located between the actinobacterial-double-membrane clade and the archaeal-firmicute clade. Mapping the phylogenetic distributions of genes involved in peptidoglycan and lipid synthesis onto this rooted tree parsimoniously implies that the cenancestral prokaryotic population consisted of organisms enclosed by a single, ester-linked lipid membrane, covered by a peptidoglycan layer.