The rockefeller university

In studying how stem cells make and maintain tissues, nearly every chapter of a cell biology textbook takes on special interest. The field even allows us to venture where no chapters have yet been written. In studying this basic problem, we are continually bombarded by nature's surprises and challenges. Stem cell biology has captured my interest for nearly my entire scientific career. Below, I focus on my laboratory's contributions to this fascinating field, to which so many friends and colleagues have made seminal discoveries equally deserving of this award.

A search for gauge-mediated supersymmetry (SUSY) in final states with photons and large missing transverse momentum is presented. The data sample of pp collisions at root s= 13 TeV was collected with the CMS detector at the CERN LHC and corresponds to an integrated luminosity of 35.9 fb(-1). Data are compared with models in which the lightest neutralino has bino- or wino-like components, resulting in decays to photons and gravitinos, where the gravitinos escape detection. The event selection is optimized for both electroweak (EWK) and strong production SUSY scenarios. The observed data are consistent with standard model predictions, and limits are set in the context of a general gauge mediation model in which gaugino masses up to 980 GeV are excluded at 95% confidence level. Gaugino masses below 780 and 950 GeV are excluded in two simplified models with EWK production of mass-degenerate charginos and neutralinos. Stringent limits are set on simplified models based on gluino and squark pair production, excluding gluino (squark) masses up to 2100 (1750)GeV depending on the assumptions made for the decay modes and intermediate particle masses. This analysis sets the highest mass limits to date in the studied EWK models, and in the considered strong production models when the mass difference between the gauginos and the squarks or gluinos is small. (C) 2018 The Author. Published by Elsevier B.V.

CLC channels mediate passive Cl- conduction, while CLC transporters mediate active Cl- transport coupled to H+ transport in the opposite direction. The distinction between CLC-0/1/2 channels and CLC transporters seems undetectable by amino acid sequence. To understand why they are different functionally we determined the structure of the human CLC-1 channel. Its 'glutamate gate' residue, known to mediate proton transfer in CLC transporters, adopts a location in the structure that appears to preclude it from its transport function. Furthermore, smaller side chains produce a wider pore near the intracellular surface, potentially reducing a kinetic barrier for Cl- conduction. When the corresponding residues are mutated in a transporter, it is converted to a channel. Finally, Cl- at key sites in the pore appear to interact with reduced affinity compared to transporters. Thus, subtle differences in glutamate gate conformation, internal pore diameter and Cl- affinity distinguish CLC channels and transporters.

S-Fatty-acylation is the covalent attachment of long chain fatty acids, predominately palmitate (C16:0, S-palmitoylation),to cysteine (Cys) residues via a thioester linkage on proteins. This post-translational and reversible lipid modification regulates protein function and localization in eukaryotes and is important in mammalian physiology and human diseases. While chemical labeling methods have improved the detection and enrichment of S-fatty-acylated proteins, mapping sites of modification and characterizing the endogenously attached fatty acids are still challenging. Here, we describe the integration and optimization of fatty acid chemical reporter labeling with hydroxylamine-mediated enrichment of S-fatty-acylated proteins and direct tagging of modified Cys residues to selectively map lipid modification sites. This afforded improved enrichment and direct identification of many protein S-fatty-acylation sites compared to previously described methods. Notably, we directly identified the S-fatty-acylation sites of IFITM3, an important interferon-stimulated inhibitor of virus entry, and we further demonstrated that the highly conserved Cys residues are primarily modified by palmitic acid. The methods described here should facilitate the direct analysis of protein S-fatty-acylation sites and their endogenously attached fatty acids in diverse cell types and activation states important for mammalian physiology and diseases.

Lysine 2-hydroxyisobutyrylation (Khib) is an evolutionarily conserved and widespread histone mark like lysine acetylation (Kac). Here we report that EP300 functions as a lysine 2-hyroxyisobutyryltransferase to regulate glycolysis in response to nutritional cues. We discovered that EP300 differentially regulates Khib and Kac on distinct lysine sites, with only 6 of the 149 EP300-targeted Khib sites overlapping with the 693 EP300-targeted Kac sites. We demonstrate that diverse cellular proteins, particularly glycolytic enzymes, are targeted by EP300 for Khib, but not for Kac. Specifically, deletion of EP300 significantly reduces Khib levels on several EP300-dependent, Khib-specific sites on key glycolytic enzymes including ENO1, decreasing their catalytic activities. Consequently, EP300-deficient cells have impaired glycolysis and are hypersensitive to glucose-depletion-induced cell death. Our study reveals an EP300-catalyzed, Khib-specific molecular mechanism that regulates cellular glucose metabolism and further indicate that EP300 has an intrinsic ability to select short-chain acyl-CoA-dependent protein substrates.

Stem cells (SCs) govern tissue homeostasis and wound repair. They reside within niches, the special microenvironments within tissues that control SC lineage outputs. Upon injury or stress, new signals emanating from damaged tissue can divert nearby cells into adopting behaviours that are not part of their homeostatic repertoire. This behaviour, known as SC plasticity, typically resolves as wounds heal. However, in cancer, it can endure. Recent studies have yielded insights into the orchestrators of maintenance and lineage commitment for SCs belonging to three mammalian tissues: the haematopoietic system, the skin epithelium and the intestinal epithelium. We delineate the multifactorial determinants and general principles underlying the remarkable facets of SC plasticity, which lend promise for regenerative medicine and cancer therapeutics.

Acquisition of mutations is central to evolution; however, the detrimental effects of most mutations on protein folding and stability limit protein evolvability. Molecular chaperones, which suppress aggregation and facilitate polypeptide folding, may alleviate the effects of destabilizing mutations thus promoting sequence diversification. To illuminate how chaperones can influence protein evolution, we examined the effect of reduced activity of the chaperone Hsp90 on poliovirus evolution. We find that Hsp90 offsets evolutionary trade-offs between protein stability and aggregation. Lower chaperone levels favor variants of reduced hydrophobicity and protein aggregation propensity but at a cost to protein stability. Notably, reducing Hsp90 activity also promotes clusters of codon-deoptimized synonymous mutations at inter-domain boundaries, likely to facilitate cotranslational domain folding. Our results reveal how a chaperone can shape the sequence landscape at both the protein and RNA levels to harmonize competing constraints posed by protein stability, aggregation propensity, and translation rate on successful protein biogenesis.

Plaque psoriasis is one of the most common autoimmune skin diseases and is characterized by erythematous, scaly plaques. Many highly effective, targeted therapies have been developed as a result of an improved understanding of the pathogenesis of psoriasis. Using agents that target the central interleukin (IL)-23/IL-17 immune axis, this once difficult-to-treat disease is now among the most effectively treated autoimmune diseases with major clinical improvements possible in around 90% of patients. In this article, we outline the immune mechanisms responsible for the development of psoriasis and provide an overview of the novel IL-23 antagonists being used to manage this chronic skin disease.

A search for resonancelike structures in the B-s(0)pi(+/-) invariant mass spectrum is performed using proton-proton collision data collected by the CMS experiment at the LHC at root s = 8 TeV, corresponding to an integrated luminosity of 19.7 fb(-1). The B-s(0) mesons are reconstructed in the decay chain B-s(0) -> J/Psi phi, with J/Psi -> mu(+) mu(-) and phi -> K+K-. The B-s(0)pi(+/-) invariant mass distribution shows no statistically significant peaks for different selection requirements on the reconstructed B-s(0) and pi(+/-) candidates. Upper limits are set on the relative production rates of the X(5568) and B-s(0) states times the branching fraction of the decay X(5568)(+/-) -> B-s(0)pi(+/-). In addition, upper limits are obtained as a function of the mass and the natural width of possible exotic states decaying into B-s(0)pi(+/-).

A search for supersymmetry (SUSY) is performed in final states comprising one or more jets and missing transverse momentum using data from proton-proton collisions at a centre-of-mass energy of 13 TeV. The data were recorded with the CMS detector at the CERN LHC in 2016 and correspond to an integrated luminosity of 35.9 fb(-1). The number of signal events is found to agree with the expected background yields from standard model processes. The results are interpreted in the context of simplified models of SUSY that assume the production of gluino or squark pairs and their prompt decay to quarks and the lightest neutralino. The masses of bottom, top, and mass-degenerate light-flavour squarks are probed up to 1050, 1000, and 1325 GeV, respectively. The gluino mass is probed up to 1900, 1650, and 1650 GeV when the gluino decays via virtual states of the aforementioned squarks. The strongest mass bounds on the neutralinos from gluino and squark decays are 1150 and 575 GeV, respectively. The search also provides sensitivity to simplified models inspired by split SUSY that involve the production and decay of long-lived gluinos. Values of the proper decay length CT0 from 10(-3) to 10(5) mm are considered, as well as a metastable gluino scenario. Gluino masses up to 1750 and 900 GeV are probed for CT0 = 1mm and for the metastable state, respectively. The sensitivity is moderately dependent on model assumptions for CT0 greater than or similar to 1 m. The search provides coverage of the CT0 parameter space for models involving long-lived gluinos that is complementary to existing techniques at the LHC.