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Found 37443 matches. Displaying 2061-2070
Brenner S, Berger F, Rao L, Nicholas MP, Gennerich A
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Force production of human cytoplasmic dynein is limited by its processivity (opens in new window)

SCIENCE ADVANCES 2020 APR; 6(15):? Article eaaz4295
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Cytoplasmic dynein is a highly complex motor protein that generates forces toward the minus end of microtubules. Using optical tweezers, we demonstrate that the low processivity (ability to take multiple steps before dissociating) of human dynein limits its force generation due to premature microtubule dissociation. Using a high trap stiffness whereby the motor achieves greater force per step, we reveal that the motor's true maximal force ("stall force") is similar to 2 pN. Furthermore, an average force versus trap stiffness plot yields a hyperbolic curve that plateaus at the stall force. We derive an analytical equation that accurately describes this curve, predicting both stall force and zero-load processivity.This theoretical model describes the behavior of a kinesin motor under low-processivity conditions. Our work clarifies the true stall force and processivity of human dynein and provides a new paradigm for under-standing and analyzing molecular motor force generation for weakly processive motors.
Chang GQ, Collier AD, Karatayev O, Gulati G, Boorgu DSSK, Leibowitz SF
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Moderate Prenatal Ethanol Exposure Stimulates CXCL12/CXCR4 Chemokine System in Radial Glia Progenitor Cells in Hypothalamic Neuroepithelium and Peptide Neurons in Lateral Hypothalamus of the Embryo and Postnatal Offspring (opens in new window)

ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH 2020 APR; 44(4):866-879
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Background Prenatal exposure to ethanol (EtOH) has lasting effects on neuropeptide and neuroimmune systems in the brain alongside detrimental alcohol-related behaviors. At low-to-moderate doses, prenatal EtOH stimulates neurogenesis in lateral hypothalamus (LH) and increases neurons that express the orexigenic peptides hypocretin/orexin (Hcrt/OX) and melanin-concentrating hormone (MCH), and the proinflammatory chemokine CCL2, which through its receptor CCR2 stimulates cell differentiation and movement. Our recent studies demonstrated that CCL2 and CCR2 colocalize with MCH neurons and are involved in EtOH's stimulatory effect on their development but show no relation to Hcrt/OX. Here, we investigated another chemokine, CXCL12, and its receptor, CXCR4, which promote neurogenesis and neuroprogenitor cell proliferation, to determine if they also exhibit peptide specificity in their response to EtOH exposure. Methods Pregnant rats were intraorally administered a moderate dose of EtOH (2 g/kg/d) from embryonic day 10 (E10) to E15. Their embryos and postnatal offspring were examined using real-time quantitative PCR and immunofluorescence histochemistry, to determine if EtOH affects CXCL12 and CXCR4 and the colocalization of CXCR4 with Hcrt/OX and MCH neurons in the LH and with radial glia neuroprogenitor cells in the hypothalamic neuroepithelium (NEP). Results Prenatal EtOH strongly stimulated CXCL12 and CXCR4 in LH neurons of embryos and postnatal offspring. This stimulation was significantly stronger in Hcrt/OX than MCH neurons in LH and also occurred in radial glia neuroprogenitor cells dense in the NEP. These effects were sexually dimorphic, consistently stronger in females than males. Conclusions While showing prenatal EtOH exposure to have a sexually dimorphic, stimulatory effect on CXCL12 and CXCR4 in LH similar to CCL2 and its receptor, these results reveal their distinct relationship to the peptide neurons, with the former closely related to Hcrt/OX and the latter to MCH, and they link EtOH's actions in LH to a stimulatory effect on neuroprogenitor cells in the NEP.
Valenza M, Windisch KA, Butelman ER, Reed B, Kreek MJ
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Effects of Kappa opioid receptor blockade by LY2444296 HCl, a selective short-acting antagonist, during chronic extended access cocaine self-administration and re-exposure in rat (opens in new window)

PSYCHOPHARMACOLOGY 2020 APR; 237(4):1147-1160
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Rationale Cocaine addiction is a chronic brain disease characterized by compulsive drug intake and dysregulation of brain reward systems. Few preclinical studies have modeled the natural longitudinal course of cocaine addiction. Extended access self-administration protocols are powerful tools for modeling the advanced stages of addiction; however, few studies have duration of drug access longer than 12 h/session, potentially limiting their construct validity. Identification of changes in cocaine intake patterns during the development of addictive-like states may allow better treatments for vulnerable subjects. The kappa opioid receptor (KOPr) system has been implicated in the neurobiological regulation of addictive states as well as mood and stress disorders, with selective KOPr antagonists proposed as possible pharmacotherapeutic agents. Chronic cocaine exposure increases the expression of KOPr and its endogenous agonists, the dynorphins, in several brain areas in rodents. Objectives To examine the behavioral pattern of intake during chronic (14 days) 18 h intravenous cocaine self-administration (0.5 mg/kg/infusion) and the effect of a novel short-acting KOPr antagonist LY2444296 HCl (3 mg/kg) administered during sessions 8 to 14 of chronic 18 h/day cocaine self-administration and prior to a single re-exposure session after 2 cocaine-free withdrawal days. Results Both daily and hourly cocaine intake patterns changed over 14 days of 18 h self-administration. LY pretreatment affected the pattern of self-administration across the second week of extended access cocaine self-administration and prevented the increase in cocaine intake during re-exposure. Conclusions Overall, the KOPr antagonist attenuated escalated cocaine consumption in a rat model of extended access cocaine self-administration.
Zhang ZD, Zhou CL, Li XL, Barnes SD, Deng S, Hoover E, Chen CC, Lee YS, Zhang YX, Wang CS, Metang LA, Wu C, Tirado CR, Johnson NA, Wongvipat J, Navrazhina K, Cao Z, Choi D, Huang CH, Linton E, Chen XP, Liang YP, Mason CE, de Stanchina E, Abida W, Lujambio A, Li S, Lowe SW, Mendell JT, Malladi VS, Sawyers CL, Mu P
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Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation (opens in new window)

CANCER CELL 2020 APR 13; 37(4):584-598.e11
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Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms.
Oksenhendler E, Spaan AN, Neven B, Stolzenberg MC, Fusaro M, Casanova JL, Rieux-Laucat F, Boisson B, Mag?rus A
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Autoimmune Lymphoproliferative Syndrome Presenting with Invasive Streptococcus pneumoniae Infection (opens in new window)

JOURNAL OF CLINICAL IMMUNOLOGY 2020 APR; 40(3):543-546
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Frew JW
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Putting nodule counts behind us: hidradenitis suppurativa outcome measures independent of descriptive semantics (opens in new window)

BRITISH JOURNAL OF DERMATOLOGY 2020 APR; 182(4):829-830
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Abt I, Adamczyk L, Aggarwal R, Aushev V, Behnke O, Behrens U, Bertolin A, Bloch I, Brock I, Brook NH, Brugnera R, Bruni A, Bussey PJ, Caldwell A, Capua M, Catterall CD, Chwastowski J, Ciborowski J, Ciesielski R, Cooper-Sarkar AM, Corradi M, Dementiev RK, Dusini S, Ferrando J, Floerchinger S, Foster B, Gallo E, Gangadharan D, Garfagnini A, Geiser A, Gladilin LK, Golubkov YA, Grzelak G, Gwenlan C, Hochman D, Jomhari NZ, Kadenko I, Kananov S, Karshon U, Kaur P, Klanner R, Klein U, Korzhavina IA, Kovalchuk N, Kowalski H, Kuprash O, Kuze M, Levchenko BB, Levy A, Lohr B, Lohrmann E, Longhin A, Lukina OY, Makarenko I, Malka J, Masciocchi S, Nagano K, Nam JD, Onderwaater J, Onishchuk Y, Paul E, Pidhurskyi I, Polini A, Przybycien M, Quintero A, Ruspa M, Saxon DH, Schneekloth U, Schorner-Sadenius T, Selyuzhenkov I, Shchedrolosiev M, Shcheglova LM, Skillicorn IO, Slominski W, Solano A, Stanco L, Stefaniuk N, Stopa P, Surrow B, Sztuk-Dambietz J, Tassi E, Tokushuku K, Turcato M, Turkot O, Tymieniecka T, Verbytskyi A, Abdullah WATW, Wichmann K, Wing M, Yamada S, Yamazaki Y, Zarnecki AF, Zawiejski L, Zenaiev O
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Two-particle azimuthal correlations as a probe of collective behaviour in deep inelastic ep scattering at HERA (opens in new window)

JOURNAL OF HIGH ENERGY PHYSICS 2020 APR 14; ?(4):? Article 070
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Two-particle azimuthal correlations have been measured in neutral current deep inelastic ep scattering with virtuality Q(2)> 5 GeV2 at a centre-of-mass energy root s = 318 GeV recorded with the ZEUS detector at HERA. The correlations of charged particles have been measured in the range of laboratory pseudorapidity -1.5 < eta < 2.0 and transverse momentum 0.1 < p(T)< 5.0 GeV and event multiplicities N-ch up to six times larger than the average < N-ch >approximate to 5. The two-particle correlations have been measured in terms of the angular observables c(n{2})=<< cosn Delta phi >>, where n is between 1 and 4 and phi is the relative azimuthal angle between the two particles. Comparisons with available models of deep inelastic scattering, which are tuned to reproduce inclusive particle production, suggest that the measured two-particle correlations are dominated by contributions from multijet production. The correlations observed here do not indicate the kind of collective behaviour recently observed at the highest RHIC and LHC energies in high-multiplicity hadronic collisions.
Thi VLD, Wu XF, Belote RL, Andreo U, Takacs CN, Fernandez JP, Vale-Silva LA, Prallet S, Decker CC, Fu RM, Qu BQ, Uryu K, Molina H, Saeed M, Steinmann E, Urban S, Singaraja RR, Schneider WM, Simon SM, Rice CM
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Stem cell-derived polarized hepatocytes (opens in new window)

NATURE COMMUNICATIONS 2020 APR 3; 11(1):? Article 1677
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Human stem cell-derived hepatocyte-like cells (HLCs) offer an attractive platform to study liver biology. Despite their numerous advantages, HLCs lack critical in vivo characteristics, including cell polarity. Here, we report a stem cell differentiation protocol that uses trans-well filters to generate columnar polarized HLCs with clearly defined basolateral and apical membranes separated by tight junctions. We show that polarized HLCs secrete cargo directionally: Albumin, urea, and lipoproteins are secreted basolaterally, whereas bile acids are secreted apically. Further, we show that enterically transmitted hepatitis E virus (HEV) progeny particles are secreted basolaterally as quasi-enveloped particles and apically as naked virions, recapitulating essential steps of the natural infectious cycle in vivo. We also provide proof-of-concept that polarized HLCs can be used for pharmacokinetic and drug-drug interaction studies. This novel system provides a powerful tool to study hepatocyte biology, disease mechanisms, genetic variation, and drug metabolism in a more physiologically relevant setting.
Hsieh A, Morton SU, Willcox JAL, Gorham JM, Tai AC, Qi HJ, DePalma S, McKean D, Griffin E, Manheimer KB, Bernstein D, Kim RW, Newburger JW, Porter GA, Srivastava D, Tristani-Firouzi M, Brueckner M, Lifton RP, Goldmuntz E, Gelb BD, Chung WK, Seidman CE, Seidman JG, Shen YF
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EM-mosaic detects mosaic point mutations that contribute to congenital heart disease (opens in new window)

GENOME MEDICINE 2020 APR 29; 12(1):? Article 42
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Background The contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined. Methods We developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available. Results EM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction. Conclusions We estimate that similar to 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed similar to 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses.
Ge YJ, Miao YX, Gur-Cohen S, Gomez N, Yang H, Nikolova M, Polak L, Hu Y, Verma A, Elemento O, Krueger JG, Fuchs E
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The aging skin microenvironment dictates stem cell behavior (opens in new window)

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2020 MAR 10; 117(10):5339-5350
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Aging manifests with architectural alteration and functional decline of multiple organs throughout an organism. In mammals, aged skin is accompanied by a marked reduction in hair cycling and appearance of bald patches, leading researchers to propose that hair follicle stem cells (HFSCs) are either lost, differentiate, or change to an epidermal fate during aging. Here, we employed single-cell RNA-sequencing to interrogate aging-related changes in the HFSCs. Surprisingly, although numbers declined, aging HFSCs were present, maintained their identity, and showed no overt signs of shifting to an epidermal fate. However, they did exhibit prevalent transcriptional changes particularly in extracellular matrix genes, and this was accompanied by profound structural perturbations in the aging SC niche. Moreover, marked age-related changes occurred in many nonepithelial cell types, including resident immune cells, sensory neurons, and arrector pili muscles. Each of these SC niche components has been shown to influence HF regeneration. When we performed skin injuries that are known to mobilize young HFSCs to exit their niche and regenerate HFs, we discovered that aged skin is defective at doing so. Interestingly, however, in transplantation assays in vivo, aged HFSCs regenerated HFs when supported with young dermis, while young HFSCs failed to regenerate HFs when combined with aged dermis. Together, our findings highlight the importance of SC:niche interactions and favor a model where youthfulness of the niche microenvironment plays a dominant role in dictating the properties of its SCs and tissue health and fitness.