Cisplatin-induced peripheral neuropathy is associated with neuronal senescence-like response

Altres ajuts: Departament de Salut, programa CERCA SLT008/18/00028Cisplatin-induced peripheral neuropathy (CIPN) is a frequent serious dose-dependent adverse event that can determine dosage limitations for cancer treatment. CIPN severity correlates with the amount of platinum detected in sensory neurons of the dorsal root ganglia (DRG). However, the exact pathophysiology of CIPN is poorly understood, so the chance of developing neuroprotective treatment is reduced. The aim of this study was to determine the exact mechanisms involved in CIPN development. Methods: By single-cell RNA-sequencing (scRNAseq), we have studied the transcriptomic profile of DRG sensory neurons from a well-characterized neurophysiological mouse model of CIPN. Results :Gene Ontology analysis of the scRNAseq data indicated that cisplatin treatment induces the upregulation of biological pathways related to DNA damage response (DDR) in the DRG neuronal population. Moreover, DRG neurons also upregulated the Cdkn1a gene, confirmed later by the measurement of its protein product p21. While apoptosis activation pathways were not observed in DRG sensory neurons of cisplatin-treated mice, these neurons did express several senescence hallmarks, including senescence-associated β-galactosidase, phospho-H2AX, and nuclear factor kappa B (Nfkb)-p65 proteins. Conclusions:In this study, we determined that after cisplatin-induced DNA damage, p21 appears as the most relevant downstream factor of the DDR in DRG sensory neurons in vivo, which survive in a nonfunctional senescence-like state

The Ursinus Weekly, November 1, 1907

Phantom party at Olevian • Football • Historical Political meeting • The Schubert string quartette • Editorial: Smiles • Society • Personals • Seminary notes • College world • Alumni notes • Literary Supplement: The lack of appreciation of the beautiful; A defense of American poetry; The danger of hero worship in a democracy; Hallowe\u27en; The price of an experience; Hannibalhttps://digitalcommons.ursinus.edu/weekly/2882/thumbnail.jp

The Ursinus Weekly, June 7, 1907

Baccalaureate sermon • Alumni oration • Junior oratorical contest • Class Day exercises • Commencement day • Editorial: The seniors; Vacation • Society notes • Personals • Donation to Library • Alumni • Charmidean banquet • Spiritual conference • Literary Supplement: Farewell song to the Class of 1907; The power of music; Uses of literature; The heredity of the twentieth century; Greater love hath no man; The history and plan of agricultural education; Jerry; A plea for the better management of railroadshttps://digitalcommons.ursinus.edu/weekly/2948/thumbnail.jp

The Ursinus Weekly, May 21, 1909

Brotherhood of St. Paul fletcherizes • Buffalo Bill in Philadelphia • Malcolm Shackelford entertains audience • Glee club • Lecture • Baseball • Ursinus Union • Tennis tournament • Society notes • Alumni notes • Personals • Field house fund • Literary Supplement: A day in May; The power of sentiment; A generation of vipers; Literary criticism on Tolstoy; The power of ideas; Money and hypocrisyhttps://digitalcommons.ursinus.edu/weekly/2873/thumbnail.jp

Impact of Antimalarial Treatment and Chemoprevention on the Drug Sensitivity of Malaria Parasites Isolated from Ugandan Children

Changing treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterized ex vivo drug sensitivity and parasite polymorphisms associated with sensitivity in 459 Plasmodium falciparum samples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations between ex vivo drug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity with pfcrt 76T, as well as increased lumefantrine sensitivity with pfmdr1 86Y, Y184, and 1246Y. Over time, ex vivo sensitivity decreased for lumefantrine and piperaquine and increased for chloroquine, the prevalences of pfcrt K76 and pfmdr1 N86 and D1246 increased, and the prevalences of pfdhfr and pfdhps polymorphisms associated with antifolate resistance were unchanged. In recurrent infections, recent prior treatment with artemether-lumefantrine was associated with decreased ex vivo lumefantrine sensitivity and increased prevalence of pfcrt K76 and pfmdr1 N86, 184F, and D1246. In children assigned chemoprevention with monthly dihydroartemisinin-piperaquine with documented circulating piperaquine, breakthrough infections had increased the prevalence of pfmdr1 86Y and 1246Y compared to untreated controls. The noted impacts of therapy and chemoprevention on parasite polymorphisms remained significant in multivariate analysis correcting for calendar time. Overall, changes in parasite sensitivity were consistent with altered selective pressures due to changing treatment practices in Uganda. These changes may threaten the antimalarial treatment and preventive efficacies of artemether-lumefantrine and dihydroartemisinin-piperaquine, respectively

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Population Pharmacokinetics and Pharmacodynamics of Lumefantrine in Young Ugandan Children Treated With Artemether-Lumefantrine for Uncomplicated Malaria.

BACKGROUND: The pharmacokinetics and pharmacodynamics of lumefantrine, a component of the most widely used treatment for malaria, artemether-lumefantrine, has not been adequately characterized in young children. METHODS: Capillary whole-blood lumefantrine concentration and treatment outcomes were determined in 105 Ugandan children, ages 6 months to 2 years, who were treated for 249 episodes of Plasmodium falciparum malaria with artemether-lumefantrine. RESULTS: Population pharmacokinetics for lumefantrine used a 2-compartment open model with first-order absorption. Age had a significant positive correlation with bioavailability in a model that included allometric scaling. Children not receiving trimethoprim-sulfamethoxazole with capillary whole blood concentrations 200 ng/mL (P = .0007). However, for children receiving trimethoprim-sulfamethoxazole, the risk of recurrent parasitemia did not differ significantly on the basis of this threshold. Day 3 concentrations were a stronger predictor of 28-day recurrence than day 7 concentrations. CONCLUSIONS: We demonstrate that age, in addition to weight, is a determinant of lumefantrine exposure, and in the absence of trimethoprim-sulfamethoxazole, lumefantrine exposure is a determinant of recurrent parasitemia. Exposure levels in children aged 6 months to 2 years was generally lower than levels published for older children and adults. Further refinement of artemether-lumefantrine dosing to improve exposure in infants and very young children may be warranted

Diversity and carbon storage across the tropical forest biome

Tropical forests are global centres of biodiversity and carbon storage. Many tropical countries aspire to protect forest to fulfil biodiversity and climate mitigation policy targets, but the conservation strategies needed to achieve these two functions depend critically on the tropical forest tree diversity-carbon storage relationship. Assessing this relationship is challenging due to the scarcity of inventories where carbon stocks in aboveground biomass and species identifications have been simultaneously and robustly quantified. Here, we compile a unique pan-tropical dataset of 360 plots located in structurally intact old-growth closed-canopy forest, surveyed using standardised methods, allowing a multi-scale evaluation of diversity-carbon relationships in tropical forests. Diversity-carbon relationships among all plots at 1 ha scale across the tropics are absent, and within continents are either weak (Asia) or absent (Amazonia, Africa). A weak positive relationship is detectable within 1 ha plots, indicating that diversity effects in tropical forests may be scale dependent. The absence of clear diversity-carbon relationships at scales relevant to conservation planning means that carbon-centred conservation strategies will inevitably miss many high diversity ecosystems. As tropical forests can have any combination of tree diversity and carbon stocks both require explicit consideration when optimising policies to manage tropical carbon and biodiversity.Additional co-authors: Kofi Affum-Baffoe, Shin-ichiro Aiba, Everton Cristo de Almeida, Edmar Almeida de Oliveira, Patricia Alvarez-Loayza, Esteban Álvarez Dávila, Ana Andrade, Luiz E. O. C. Aragão, Peter Ashton, Gerardo A. Aymard C., Timothy R. Baker, Michael Balinga, Lindsay F. Banin, Christopher Baraloto, Jean-Francois Bastin, Nicholas Berry, Jan Bogaert, Damien Bonal, Frans Bongers, Roel Brienen, José Luís C. Camargo, Carlos Cerón, Victor Chama Moscoso, Eric Chezeaux, Connie J. Clark, Álvaro Cogollo Pacheco, James A. Comiskey, Fernando Cornejo Valverde, Eurídice N. Honorio Coronado, Greta Dargie, Stuart J. Davies, Charles De Canniere, Marie Noel Djuikouo K., Jean-Louis Doucet, Terry L. Erwin, Javier Silva Espejo, Corneille E. N. Ewango, Sophie Fauset, Ted R. Feldpausch, Rafael Herrera, Martin Gilpin, Emanuel Gloor, Jefferson S. Hall, David J. Harris, Terese B. Hart, Kuswata Kartawinata, Lip Khoon Kho, Kanehiro Kitayama, Susan G. W. Laurance, William F. Laurance, Miguel E. Leal, Thomas Lovejoy, Jon C. Lovett, Faustin Mpanya Lukasu, Jean-Remy Makana, Yadvinder Malhi, Leandro Maracahipes, Beatriz S. Marimon, Ben Hur Marimon Junior, Andrew R. Marshall, Paulo S. Morandi, John Tshibamba Mukendi, Jaques Mukinzi, Reuben Nilus, Percy Núñez Vargas, Nadir C. Pallqui Camacho, Guido Pardo, Marielos Peña-Claros, Pascal Pétronelli, Georgia C. Pickavance, Axel Dalberg Poulsen, John R. Poulsen, Richard B. Primack, Hari Priyadi, Carlos A. Quesada, Jan Reitsma, Maxime Réjou-Méchain, Zorayda Restrepo, Ervan Rutishauser, Kamariah Abu Salim, Rafael P. Salomão, Ismayadi Samsoedin, Douglas Sheil, Rodrigo Sierra, Marcos Silveira, J. W. Ferry Slik, Lisa Steel, Hermann Taedoumg, Sylvester Tan, John W. Terborgh, Sean C. Thomas, Marisol Toledo, Peter M. Umunay, Luis Valenzuela Gamarra, Ima Célia Guimarães Vieira, Vincent A. Vos, Ophelia Wang, Simon Willcock & Lise Zemagh

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal alpha-toxin

The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor kappa B signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor alpha-toxin. Naturally elicited antibodies against alpha-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to alpha-toxin in nonleukocytic cells.Peer reviewe

Report of the Topical Group on Top quark physics and heavy flavor production for Snowmass 2021

This report summarizes the work of the Energy Frontier Topical Group on EW Physics: Heavy flavor and top quark physics (EF03) of the 2021 Community Summer Study (Snowmass). It aims to highlight the physics potential of top-quark studies and heavy-flavor production processes (bottom and charm) at the HL-LHC and possible future hadron and lepton colliders and running scenarios