Flavorful Supersymmetry

Weak scale supersymmetry provides elegant solutions to many of the problems of the standard model, but it also generically gives rise to excessive flavor and CP violation. We show that if the mechanism that suppresses the Yukawa couplings also suppresses flavor changing interactions in the supersymmetry breaking parameters, essentially all the low energy flavor and CP constraints can be satisfied. The standard assumption of flavor universality in the supersymmetry breaking sector is not necessary. We study signatures of this framework at the LHC. The mass splitting among different generations of squarks and sleptons can be much larger than in conventional scenarios, and even the mass ordering can be changed. We find that there is a plausible scenario in which the NLSP is a long-lived right-handed selectron or smuon decaying into the LSP gravitino. This leads to the spectacular signature of monochromatic electrons or muons in a stopper detector, providing strong evidence for the framework.Comment: 20 pages; typos corrected, comments added, to appear in PR

Unexpected transformation of dissolved phenols to toxic dicarbonyls by hydroxyl radicals and UV light.

Water treatment systems frequently use strong oxidants or UV light to degrade chemicals that pose human health risks. Unfortunately, these treatments can result in the unintended transformation of organic contaminants into toxic products. We report an unexpected reaction through which exposure of phenolic compounds to hydroxyl radicals (•OH) or UV light results in the formation of toxic α,β-unsaturated enedials and oxoenals. We show that these transformation products damage proteins by reacting with lysine and cysteine moieties. We demonstrate that phenolic compounds react with •OH produced by the increasingly popular UV/hydrogen peroxide (H2O2) water treatment process or UV light to form toxic enedials and oxoenals. In addition to raising concerns about potential health risks of oxidative water treatment, our findings suggest the potential for formation of these toxic compounds in sunlit surface waters, atmospheric water, and living cells. For the latter, our findings may be particularly relevant to efforts to understand cellular damage caused by in vivo production of reactive oxygen species. In particular, we demonstrate that exposure of the amino acid tyrosine to •OH yields an electrophilic enedial product that undergoes cross-linking reaction with both lysine and cysteine residues

Increased tolerance to humans among disturbed wildlife.

Human disturbance drives the decline of many species, both directly and indirectly. Nonetheless, some species do particularly well around humans. One mechanism that may explain coexistence is the degree to which a species tolerates human disturbance. Here we provide a comprehensive meta-analysis of birds, mammals and lizards to investigate species tolerance of human disturbance and explore the drivers of this tolerance in birds. We find that, overall, disturbed populations of the three major taxa are more tolerant of human disturbance than less disturbed populations. The best predictors of the direction and magnitude of bird tolerance of human disturbance are the type of disturbed area (urbanized birds are more tolerant than rural or suburban populations) and body mass (large birds are more tolerant than small birds). By identifying specific features associated with tolerance, these results guide evidence-based conservation strategies to predict and manage the impacts of increasing human disturbance on birds

Revision of the East Asian Plagiophorus hispidus species group (Coleoptera: Staphylinidae, Pselaphinae, Cyathigerini)

The hispidus species group is formed for four new species from East Asia of the genus Plagiophorus Motschulsky: P. hispidus sp. nov., P. hlavaci sp. nov., P. serratus sp. nov., and P. grandoculatus sp. nov. Uncoated specimens were examined using field-emission scanning electron microscopy, and micrographs of the holotypes are presented. Keys to the species groups of the genus occurring in East Asia and to the species of the hispidus group are given. The hispidus group is probably monophyletic, having peculiar spinous setae on the male metasternum. The chaetotaxy of the labrum and clypeus is useful for distinguishing species of Plagiophoru

A Metabolic Dependency for Host Isoprenoids in the Obligate Intracellular Pathogen Rickettsia parkeri Underlies a Sensitivity to the Statin Class of Host-Targeted Therapeutics.

Gram-negative bacteria in the order Rickettsiales have an obligate intracellular growth requirement, and some species cause human diseases such as typhus and spotted fever. The bacteria have evolved a dependence on essential nutrients and metabolites from the host cell as a consequence of extensive genome reduction. However, it remains largely unknown which nutrients they acquire and whether their metabolic dependency can be exploited therapeutically. Here, we describe a genetic rewiring of bacterial isoprenoid biosynthetic pathways in the Rickettsiales that has resulted from reductive genome evolution. Furthermore, we investigated whether the spotted fever group Rickettsia species Rickettsia parkeri scavenges isoprenoid precursors directly from the host. Using targeted mass spectrometry, we found that infection caused decreases in host isoprenoid products and concomitant increases in bacterial isoprenoid metabolites. Additionally, we report that treatment of infected cells with statins, which inhibit host isoprenoid synthesis, prohibited bacterial growth. We show that growth inhibition correlates with changes in bacterial size and shape that mimic those caused by antibiotics that inhibit peptidoglycan biosynthesis, suggesting that statins lead to an inhibition of cell wall synthesis. Altogether, our results describe a potential Achilles' heel of obligate intracellular pathogens that can potentially be exploited with host-targeted therapeutics that interfere with metabolic pathways required for bacterial growth.IMPORTANCE Obligate intracellular pathogens, which include viruses as well as certain bacteria and eukaryotes, are a subset of infectious microbes that are metabolically dependent on and unable to grow outside an infected host cell because they have lost or lack essential biosynthetic pathways. In this study, we describe a metabolic dependency of the bacterial pathogen Rickettsia parkeri on host isoprenoid molecules that are used in the biosynthesis of downstream products, including cholesterol, steroid hormones, and heme. Bacteria make products from isoprenoids, such as an essential lipid carrier for making the bacterial cell wall. We show that bacterial metabolic dependency can represent a potential Achilles' heel and that inhibiting host isoprenoid biosynthesis with the FDA-approved statin class of drugs inhibits bacterial growth by interfering with the integrity of the cell wall. This work supports the potential to treat infections by obligate intracellular pathogens through inhibition of host biosynthetic pathways that are susceptible to parasitism

Flavorful Supersymmetry from Higher Dimensions

We present models of flavorful supersymmetry in higher dimensions. The Higgs fields and the supersymmetry breaking field are localized in the same place in the extra dimension(s). The Yukawa couplings and operators generating the supersymmetry breaking parameters then receive the same suppression factors from the wavefunction profiles of the matter fields, leading to a specific correlation between these two classes of interactions. The resulting phenomenology is very rich, while stringent experimental constraints from the low-energy flavor and CP violating processes can all be satisfied. We construct both unified and non-unified models in this framework, which can be either strongly or weakly coupled at the cutoff scale. We analyze one version in detail, a strongly coupled unified model, which addresses various issues of supersymmetric grand unification. The models presented here provide an explicit example in which the supersymmetry breaking spectrum can be a direct window into the physics of flavor at a very high energy scale.Comment: 31 pages, 2 figures; references and comments adde

The glucocorticoid-Angptl4-ceramide axis induces insulin resistance through PP2A and PKCζ.

Chronic glucocorticoid exposure is associated with the development of insulin resistance. We showed that glucocorticoid-induced insulin resistance was attenuated upon ablation of Angptl4, a glucocorticoid target gene encoding the secreted protein angiopoietin-like 4, which mediates glucocorticoid-induced lipolysis in white adipose tissue. Through metabolomic profiling, we revealed that glucocorticoid treatment increased hepatic ceramide concentrations by inducing enzymes in the ceramide synthetic pathway in an Angptl4-dependent manner. Angptl4 was also required for glucocorticoids to stimulate the activities of the downstream effectors of ceramide, protein phosphatase 2A (PP2A) and protein kinase Cζ (PKCζ). We further showed that knockdown of PP2A or inhibition of PKCζ or ceramide synthesis prevented glucocorticoid-induced glucose intolerance in wild-type mice. Moreover, the inhibition of PKCζ or ceramide synthesis did not further improve glucose tolerance in Angptl4-/- mice, suggesting that these molecules were major downstream effectors of Angptl4. Overall, our study demonstrates the key role of Angptl4 in glucocorticoid-augmented hepatic ceramide production that induces whole-body insulin resistance

Software for non-parametric image registration of 2-photon imaging data

Functional 2-photon microscopy is a key technology for imaging neuronal activity. The recorded image sequences, however, can contain non-rigid movement artifacts which requires high-accuracy movement correction. Variational optical flow (OF) estimation is a group of methods for motion analysis with established performance in many computer vision areas. However, it has yet to be adapted to the statistics of 2-photon neuroimaging data. In this work, we present the motion compensation method Flow-Registration that outperforms previous alignment tools and allows to align and reconstruct even low signal-to-noise ratio 2-photon imaging data and is able to compensate high-divergence displacements during local drug injections. The method is based on statistics of such data and integrates previous advances in variational OF estimation. Our method is available as an easy-to-use ImageJ/FIJI plugin as well as a MATLAB toolbox with modular, object oriented file IO, native multi-channel support and compatibility with existing 2-photon

Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition.

Autophagy is a lysosomal degradation pathway that eliminates aggregated proteins and damaged organelles to maintain cellular homeostasis. A major route for activating autophagy involves inhibition of the mTORC1 kinase, but current mTORC1-targeting compounds do not allow complete and selective mTORC1 blockade. Here, we have coupled screening of a covalent ligand library with activity-based protein profiling to discover EN6, a small-molecule in vivo activator of autophagy that covalently targets cysteine 277 in the ATP6V1A subunit of the lysosomal v-ATPase, which activates mTORC1 via the Rag guanosine triphosphatases. EN6-mediated ATP6V1A modification decouples the v-ATPase from the Rags, leading to inhibition of mTORC1 signaling, increased lysosomal acidification and activation of autophagy. Consistently, EN6 clears TDP-43 aggregates, a causative agent in frontotemporal dementia, in a lysosome-dependent manner. Our results provide insight into how the v-ATPase regulates mTORC1, and reveal a unique approach for enhancing cellular clearance based on covalent inhibition of lysosomal mTORC1 signaling