The rockefeller university

Cytokinesis, the process by which cytoplasm is apportioned between dividing daughter cells, requires coordination of myosin II function, membrane trafficking, and central spindle organization. Most known regulators act during late cytokinesis; a few, including the myosin II-binding proteins anillin and supervillin, act earlier. Anillin's role in scaffolding the membrane cortex with the central spindle is well established, but the mechanism of supervillin action is relatively uncharacterized. We show here that two regions within supervillin affect cell division: residues 831-1281, which bind central spindle proteins, and residues 1-170, which bind the myosin II heavy chain (MHC) and the long form of myosin light-chain kinase. MHC binding is required to rescue supervillin deficiency, and mutagenesis of this site creates a dominant-negative phenotype. Supervillin concentrates activated and total myosin II at the furrow, and simultaneous knockdown of supervillin and anillin additively increases cell division failure. Knockdown of either protein causes mislocalization of the other, and endogenous anillin increases upon supervillin knockdown. Proteomic identification of interaction partners recovered using a high-affinity green fluorescent protein nanobody suggests that supervillin and anillin regulate the myosin II and actin cortical cytoskeletons through separate pathways. We conclude that supervillin and anillin play complementary roles during vertebrate cytokinesis.

We report a 17-year-old patient with inherited STAT1 deficiency, who was diagnosed with Mycobacterium szulgai chronic multifocal osteomyelitis and responded well to the therapy with ethambutol, rifampicin and azithromycin. Seven other reported cases of M. szulgai osteomyelitis are reviewed. This is the first description of M. szulgai osteomyelitis in an adolescent with a primary immunodeficiency.

All methicillin resistant S. aureus (MRSA) strains carry an acquired genetic determinant - mecA or mecC - which encode for a low affinity penicillin binding protein - PBP2A or PBP2A' - that can continue the catalysis of peptidoglycan transpeptidation in the presence of high concentrations of beta-lactam antibiotics which would inhibit the native PBPs normally involved with the synthesis of staphylococcal cell wall peptidoglycan. In contrast to this common genetic and biochemical mechanism carried by all MRSA strains, the level of beta-lactam antibiotic resistance shows a very wide strain to strain variation, the mechanism of which has remained poorly understood. The overwhelming majority of MRSA strains produce a unique - heterogeneous - phenotype in which the great majority of the bacteria exhibit very poor resistance often close to the MIC value of susceptible S. aureus strains. However, cultures of such heterogeneously resistant MRSA strains also contain subpopulations of bacteria with extremely high beta-lactam MIC values and the resistance level and frequency of the highly resistant cells in such strain is a characteristic of the particular MRSA clone. In the study described in this communication, we used a variety of experimental models to understand the mechanism of heterogeneous beta-lactam resistance. Methicillin-susceptible S. aureus (MSSA) that received the mecA determinant in the laboratory either on a plasmid or in the form of a chromosomal SCCmec cassette, generated heterogeneously resistant cultures and the highly resistant subpopulations that emerged in these models had increased levels of PBP2A and were composed of bacteria in which the stringent stress response was induced. Each of the major heterogeneously resistant clones of MRSA clinical isolates could be converted to express high level and homogeneous resistance if the growth medium contained an inducer of the stringent stress response.

Addictions are chronic relapsing brain diseases, with behavioral manifestations. Three main factors contribute to the development of an addiction: environment, including stress, the reinforcing effects of the drug, and genetics. In this review we will discuss the involvement of the dysregulation of the stress responsive hypothalamic-pituitary-adrenal (HPA) axis in the acquisition of, and persistence to drug addiction (Section B). Addictions to specific drugs such as cocaine/psychostimulants, alcohol, and mu-opioid receptor agonists (e. g., heroin) have some common direct or downstream effects, including modulation of dopaminergic systems. Through its action on the dopaminergic signaling pathways, cocaine affects the HPA axis, and brain nuclei responsible for movements, and rewarding effects. Several neurobiological systems have been implicated with cocaine addiction, including dopamine, serotonin and glutamate systems, opioid receptor and opioid neuropeptide gene systems, stress-responsive systems including CRF, vasopressin and orexin. The use of animal models (Sections C and D) has been essential for studying the individual vulnerabilities to the effects of drugs of abuse and the neural pathways and neurotransmitters affected by these drugs. Basic clinical research has revealed important relationship between cocaine use, HPA axis responsiveness, and gender (Section E). Finally, we will discuss gene polymorphisms that are associated with drug use (Section F). Results from animal models and basic clinical research have shown important interactions between the dopaminergic and the opioid systems. Hence, compounds modulating the opioid system may be beneficial in treating cocaine addiction.

Trimethylated histone H3 lysine 4 (H3K4) and H3K27 generally mark transcriptionally active and repressive chromatins, respectively. In most cell types, these two modifications are mutually exclusive, and this segregation is crucial for the regulation of gene expression. However, how this anticorrelation is achieved has not been fully understood. Here, we show that removal of the H3K27 trimethyl mark facilitates recruitment of SET1-like H3K4 methyltransferase complexes to their target genes by eliciting a novel interaction between histone H3 and two common subunits, WDR5 and RBBP5, of SET1-like complexes. Consistent with this result, H3K27 trimethylation destabilizes interactions of H3 with SET1-like complexes and antagonizes their ability to carry out H3K4 trimethylation of peptide (H3 residues 1 to 36), histone octamer, and mononucleosome substrates. Altogether, our studies reveal that H3K27 trimethylation of histone H3 represses a previously unrecognized interaction between H3 and SET1like complexes. This provides an important mechanism that directs the anticorrelation between H3K4 and H3K27 trimethylation.

Endocannabinoid (eCB) signaling has been identified as a modulator of adaptation to stress, and is integral to basal and stress-induced glucocorticoid regulation. Furthermore, interactions between eCBs and glucocorticoids have been shown to be necessary for the regulation of emotional memories, suggesting that eCB function may relate to the development of post-traumatic stress disorder (PTSD). To examine this, plasma eCBs were measured in a sample (n = 46) drawn from a population-based cohort selected for physical proximity to the World Trade Center (WTC) at the time of the 9/11 attacks. Participants received a structured diagnostic interview and were grouped according to whether they met diagnostic criteria for PTSD (no PTSD, n = 22; lifetime diagnosis of PTSD = 24). eCB content (2-arachidonoylglycerol (2-AG) and anandamide (AEA)) and cortisol were measured from 8 a.m. plasma samples. Circulating 2-AG content was significantly reduced among individuals meeting diagnostic criteria for PTSD. The effect of reduced 2-AG content in PTSD remained significant after controlling for the stress of exposure to the WTC collapse, gender, depression and alcohol abuse. There were no significant group differences for AEA or cortisol levels; however, across the whole sample AEA levels positively correlated with circulating cortisol, and AEA levels exhibited a negative relationship with the degree of intrusive symptoms within the PTSD sample. This report shows that PTSD is associated with a reduction in circulating levels of the eCB 2-AG. Given the role of 2-AG in the regulation of the stress response, these data support the hypothesis that deficient eCB signaling may be a component of the glucocorticoid dysregulation associated with PTSD. The negative association between AEA levels and intrusive symptoms is consistent with animal data indicating that reductions in AEA promote retention of aversive emotional memories. Future work will aim to replicate these findings and extend their relevance to clinical pathophysiology, as well as to neuroendocrine and molecular markers of PTSD. (C) 2013 Elsevier Ltd. All rights reserved.

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) resets their identity back to an embryonic age and, thus, presents a significant hurdle for modeling late-onset disorders. In this study, we describe a strategy for inducing aging-related features in human iPSC-derived lineages and apply it to the modeling of Parkinson's disease (PD). Our approach involves expression of progerin, a truncated form of lamin A associated with premature aging. We found that expression of progerin in iPSC-derived fibroblasts and neurons induces multiple aging-related markers and characteristics, including dopamine-specific phenotypes such as neuromelanin accumulation. Induced aging in PD iPSC-derived dopamine neurons revealed disease phenotypes that require both aging and genetic susceptibility, such as pronounced dendrite degeneration, progressive loss of tyrosine hydroxylase (TH) expression, and enlarged mitochondria or Lewy-body-precursor inclusions. Thus, our study suggests that progerin-induced aging can be used to reveal late-onset age-related disease features in hiPSC-based disease models.

During development, the establishment of proper tissue architecture depends upon the coordinated control of cell divisions not only in space and time, but also direction. Execution of an oriented cell division requires establishment of an axis of polarity and alignment of the mitotic spindle along this axis. Frequently, the cleavage plane also segregates fate determinants, either unequally or equally between daughter cells, the outcome of which is either an asymmetric or symmetric division, respectively. The last few years have witnessed tremendous growth in understanding both the extrinsic and intrinsic cues that position the mitotic spindle, the varied mechanisms in which the spindle orientation machinery is controlled in diverse organisms and organ systems, and the manner in which the division axis influences the signaling pathways that direct cell fate choices.

Rapidity distributions are presented for events containing either a Z boson or a photon with a single jet in proton-proton collisions produced at the CERN LHC. The data, collected with the CMS detector at root s = 7 TeV, correspond to an integrated luminosity of 5.0 fb(-1). The individual rapidity distributions of the boson and the jet are consistent within 5% with expectations from perturbative QCD. However, QCD predictions for the sum and the difference in rapidities of the two final-state objects show discrepancies with CMS data. In particular, next-to-leading-order QCD calculations, and two common Monte Carlo event generators using different methods to match matrix-element partons with parton showers, appear inconsistent with the data as well as with each other.