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Cellular proteins continuously undergo non-enzymatic covalent modifications (NECMs) that accumulate under normal physiological conditions and are stimulated by changes in the cellular microenvironment. Glycation, the hallmark of diabetes, is a prevalent NECM associated with an array of pathologies. Histone proteins are particularly susceptible to NECMs due to their long half-lives and nucleophilic disordered tails that undergo extensive regulatory modifications; however, histone NECMs remain poorly understood. Here we perform a detailed analysis of histone glycation in vitro and in vivo and find it has global ramifications on histone enzymatic PTMs, the assembly and stability of nucleosomes, and chromatin architecture. Importantly, we identify a physiologic regulation mechanism, the enzyme DJ-1, which functions as a potent histone deglycase. Finally, we detect intense histone glycation and DJ-1 overexpression in breast cancer tumors. Collectively, our results suggest an additional mechanism for cellular metabolic damage through epigenetic perturbation, with implications in pathogenesis.

Liposarcoma is the most common soft tissue sarcoma. Molecularly targeted therapeutics have had limited efficacy in liposarcomas, in part because of inadequate knowledge of the complex molecular alterations in these tumors. Our recent study revealed the tumor suppressive function of miR-193b in liposarcoma. Considering the biological and clinical heterogeneity of liposarcoma, here, we confirmed the under-expression of miR-193b in additional patient liposarcoma samples and cell lines. Based on STRING analysis of protein-protein interactions among the reported putative miR-193b targets, we validated three: PDGFR beta, SMAD4, and YAP1, belonging to strongly interacting pathways (focal adhesion, TGF beta, and Hippo, respectively). We show that all three are directly targeted by miR-193b in liposarcoma. Inhibition of PDGFR beta reduces liposarcoma cell viability and increases adipogenesis. Knockdown of SMAD4 promotes adipogenic differentiation. miR-193b targeting of the Hippo signaling effector YAP1 indirectly inhibits Wnt/beta-catenin signaling. Both a PDGFR inhibitor (CP-673451) and a Wnt/beta-catenin inhibitor (ICG-001) had potent inhibitory effects on liposarcoma cells, suggesting their potential application in liposarcoma treatment. In summary, we demonstrate that miR-193b controls cell growth and differentiation in liposarcoma by targeting multiple key components (PDGFR beta, SMAD4, and YAP1) in several oncogenic signaling pathways.

Background Nephrotic syndrome (NS), a chronic kidney disease, is characterized by significant loss of protein in the urine causing hypoalbuminemia and edema. In general, approximate to 15% of childhood-onset cases do not respond to steroid therapy and are classified as steroid-resistant NS (SRNS). In approximate to 30% of cases with SRNS, a causative mutation can be detected in one of 44 monogenic SRNS genes. The gene LAMA5 encodes laminin-5, an essential component of the glomerular basement membrane. Mice with a hypomorphic mutation in the orthologous gene Lama5 develop proteinuria and hematuria. Methods To identify additional monogenic causes of NS, we performed whole exome sequencing in 300 families with pediatric NS. In consanguineous families we applied homozygosity mapping to identify genomic candidate loci for the underlying recessive mutation. Results In three families, in whom mutations in known NS genes were excluded, but in whom a recessive, monogenic cause of NS was strongly suspected based on pedigree information, we identified homozygous variants of unknown significance (VUS) in the gene LAMA5. While all affected individuals had nonsyndromic NS with an early onset of disease, their clinical outcome and response to immunosuppressive therapy differed notably. Conclusion We here identify recessive VUS in the gene LAMA5 in patients with partially treatment-responsive NS. More data will be needed to determine the impact of these VUS in disease management. However, familial occurrence of disease, data from genetic mapping and a mouse model that recapitulates the NS phenotypes suggest that these genetic variants may be inherited factors that contribute to the development of NS in pediatric patients.

Taylor's law (TL), a commonly observed and applied pattern in ecology, describes variances of population densities as related to mean densities via log(variance) = log(a) + b*log(mean). Variations among datasets in the slope, b, have been associated with multiple factors of central importance in ecology, including strength of competitive interactions and demographic rates. But these associations are not transparent, and the relative importance of these and other factors for TL slope variation is poorly studied. TL is thus a ubiquitously used indicator in ecology, the understanding of which is still opaque. The goal of this study was to provide tools to help fill this gap in understanding by providing proximate determinants of TL slopes, statistical quantities that are correlated to TL slopes but are simpler than the slope itself and are more readily linked to ecological factors. Using numeric simulations and 82 multi-decadal population datasets, we here propose, test and apply two proximate statistical determinants of TL slopes which we argue can become key tools for understanding the nature and ecological causes of TL slope variation. We find that measures based on population skewness, coefficient of variation and synchrony are effective proximate determinants. We demonstrate their potential for application by using them to help explain covariation in slopes of spatial and temporal TL (two common types of TL). This study provides tools for understanding TL, and demonstrates their usefulness.

A search for the pair production of heavy fermionic partners of the top quark with charge 5/3 (X-5/3) is performed in proton-proton collisions at a center-of-mass energy of 13 TeV with the CMS detector at the CERN LHC. The data sample analyzed corresponds to an integrated luminosity of 35.9 fb(-1). The X-5/3 quark is assumed always to decay into a top quark and a W boson. Both the right-handed and left-handed X-5/3 couplings to the W boson are considered. Final states with either a pair of same-sign leptons or a single lepton are studied. No significant excess of events is observed above the expected standard model background. Lower limits at 95% confidence level on the X-5/3 quark mass are set at 1.33 and 1.30 TeV respectively for the case of right-handed and left-handed couplings to W bosons in a combination of the same-sign dilepton and single-lepton final states.

Early-life stress modulates the development of cortico-limbic circuits and increases vulnerability to adult psychopathology. Given the important stress-buffering role of endocannabinoid (eCB) signaling, we performed a comprehensive investigation of the developmental trajectory of the eCB system and the impact of exposure to early life stress induced by repeated maternal separation (MS; 3 h/day) from postnatal day 2 (PND2) to PND12. Tissue levels of the eCB molecules anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured after MS exposures, as well under basal conditions at juvenile (PND14), adolescent (PND40) and adult (PND70) timepoints in the prefrontal cortex (PFC), amygdala and hippocampus. We also examined the effects of MS on CB1 receptor binding in these three brain regions at PND40 and PND70. AEA content was found to increase from PND2 into adulthood in a linear manner across all brain regions, while 2-AG was found to exhibit a transient spike during the juvenile period (PND12-14) within the amygdala and PFC, but increased in a linear manner across development in the hippocampus. Exposure to MS resulted in bidirectional changes in AEA and 2-AG tissue levels within the amygdala and hippocampus and produced a sustained reduction in eCB function in the hippocampus at adulthood. CB1 receptor densities across all brain regions were generally found to be downregulated later in life following exposure to MS. Collectively, these data demonstrate that early life stress can alter the normative ontogeny of the eCB system, resulting in a sustained deficit in eCB function, particularly within the hippocampus, in adulthood.

We report on a search for a spin-zero non-standard model particle in proton-antiproton collisions collected by the Collider Detector at Fermilab at a center-of-mass-energy of 1.96 TeV. This particle, the phi boson, is expected to decay into a bottom-antibottom quark pair and to be produced in association with at least one bottom quark. The data sample consists of events with three jets identified as initiated by bottom quarks and corresponds to 5.4 fb(-1) of integrated luminosity. In each event, the invariant mass of the two most energetic jets is studied by looking for deviations from the multijet background, which is modeled using data. No evidence is found for such a particle. Exclusion upper limits ranging from 20 to 2 pb are set for the product of production cross sections times branching fraction for the hypothetical phi boson with mass between 100 and 300 GeV/c(2). These are the most stringent constraints to date.

In daily life, in the operating room and in the laboratory, the operational way to assess wakefulness and consciousness is through responsiveness. A number of studies suggest that the awake, conscious state is not the default behavior of an assembly of neurons, but rather a very special state of activity that has to be actively maintained and curated to support its functional properties. Thus responsiveness is a feature that requires active maintenance, such as a homeostatic mechanism to balance excitation and inhibition. In this work we developed a method for monitoring such maintenance processes, focusing on a specific signature of their behavior derived from the theory of dynamical systems: stability analysis of dynamical modes. When such mechanisms are at work, their modes of activity are at marginal stability, neither damped (stable) nor exponentially growing (unstable) but rather hovering in between. We have previously shown that, conversely, under induction of anesthesia those modes become more stable and thus less responsive, then reversed upon emergence to wakefulness. We take advantage of this effect to build a single-trial classifier which detects whether a subject is awake or unconscious achieving high performance. We show that our approach can be developed into a means for intra-operative monitoring of the depth of anesthesia, an application of fundamental importance to modern clinical practice.

Real-time PCR targeting lytA (the major autolysin gene) and piaB (permease gene of the pia ABC transporter) are currently used as the gold-standard culture-independent assays for Streptococcus pneumoniae identification. We evaluated the performance of a new real-time PCR assay-targeting SP2020 (putative transcriptional regulator gene)-and compared its performance with the assays previously described. A collection of 150 pneumococci, 433 non-pneumococci and 240 polymicrobial samples (obtained from nasopharynx, oropharynx, and saliva; 80 from each site) was tested. SP2020 and lytA-CDC assays had the best performance (sensitivity of 100% for each compared to 95.3% for piaB). The specificity for lytA and piaB was 99.5% and for SP2020 was 99.8%. Misidentifications occurred for the three genes: lytA, piaB and SP2020 were found in non-pneumococcal strains; piaB was absent in some pneumococci including a serotype 6B strain. Combining lytA and SP2020 assays resulted in no misidentifications. Most polymicrobial samples (88.8%) yielded concordant results for the three molecular targets. The remaining samples seemed to contain non-typeable pneumococci (0.8%), and non-pneumococci positive for lytA (1.7%) or SP2020 (8.7%). We propose that combined detection of both lytA-CDC and SP2020 is a powerful strategy for the identification of pneumococcus either in pure cultures or in polymicrobial samples.