Iron causes lipid oxidation and inhibits proteasome function in multiple myeloma cells: A proof of concept for novel combination therapies

Adaptation to import iron for proliferation makes cancer cells potentially sensitive to iron toxicity. Iron loading impairs multiple myeloma (MM) cell proliferation and increases the efficacy of the proteasome inhibitor bortezomib. Here, we defined the mechanisms of iron toxicity in MM.1S, U266, H929, and OPM-2 MM cell lines, and validated this strategy in preclinical studies using Vk*MYC mice as MM model. High-dose ferric ammonium citrate triggered cell death in all cell lines tested, increasing malondialdehyde levels, the by-product of lipid peroxidation and index of ferroptosis. In addition, iron exposure caused dose-dependent accumulation of polyubiquitinated proteins in highly iron-sensitive MM.1S and H929 cells, suggesting that proteasome workload contributes to iron sensitivity. Accordingly, high iron concentrations inhibited the proteasomal chymotrypsin-like activity of 26S particles and of MM cellular extracts in vitro. In all MM cells, bortezomib-iron combination induced persistent lipid damage, exacerbated bortezomib-induced polyubiquitinated proteins accumulation, and triggered cell death more efficiently than individual treatments. In Vk*MYC mice, addition of iron dextran or ferric carboxymaltose to the bortezomib-melphalan-prednisone (VMP) regimen increased the therapeutic response and prolonged remission without causing evident toxicity. We conclude that iron loading interferes both with redox and protein homeostasis, a property that can be exploited to design novel combination strategies including iron supplementation, to increase the efficacy of current MM therapies

Human Amniocytes Are Receptive to Chemically Induced Reprogramming to Pluripotency

Restoring pluripotency using chemical compounds alone would be a major step forward in developing clinical-grade pluripotent stem cells, but this has not yet been reported in human cells. We previously demonstrated that VPA_ AFS cells, human amniocytes cultivated with valproic acid (VPA) acquired functional pluripotency while remaining distinct from human embryonic stem cells (hESCs), questioning the relationship between the modulation of cell fate and molecular regulation of the pluripotency network. Here, we used single-cell analysis and functional assays to reveal that VPA treatment resulted in a homogeneous population of self-renewing non-transformed cells that fulfill the hallmarks of pluripotency, i.e., a short G1 phase, a dependence on glycolytic metabolism, expression of epigenetic modifications on histones 3 and 4, and reactivation of endogenous OCT4 and downstream targets at a lower level than that observed in hESCs. Mechanistic insights into the process of VPA-induced reprogramming revealed that it was dependent on OCT4 promoter activation, which was achieved independently of the PI3K (phosphatidylinositol 3-kinase)/ AKT/ mTOR (mammalian target of rapamycin) pathway or GSK3 beta inhibition but was concomitant with the presence of acetylated histones H3K9 and H3K56, which promote pluripotency. Our data identify, for the first time, the pluripotent transcriptional and molecular signature and metabolic status of human chemically induced pluripotent stem cells

Contingent infrastructure and the dilution of ‘Chineseness’: Reframing roads and rail in Kampala and Addis Ababa

Amid growing interest in China’s role in financing and building infrastructure in Africa, there is still little research on how Chinese-financed infrastructures are negotiated and realised at the city and metropolitan scale. We compare the Light Rail Transit in Addis Ababa, Ethiopia with the expressway linking Kampala to Entebbe airport in Uganda, examining the processes of bargaining behind these transport infrastructures and their emergent effects on urban land use and city-dwellers’ mobility. We find that both projects were designed and implemented through opaque negotiations between African national elites and Chinese agencies, with little or no engagement from city authorities, leading to haphazard outcomes that are poorly integrated with broader planning. Yet we also suggest that despite being enabled and mediated by Chinese agencies, such projects do not embody a Chinese global vision. They instead reflect the entrepreneurial activities of Chinese contractors and the varying ways in which these connect with African national governments’ shifting priorities. Moreover, as they are subsumed into the urban context, these transposed infrastructures have been rapidly repurposed and their ‘Chineseness’ diluted, with one morphing into an infrastructure for the poor and the other into a site of private value extraction. We thus argue that, far from representing a domineering or neo-colonial influence, Chinese-financed infrastructures that land in institutionally complex African city-regions can be rapidly swallowed up into the political-economic landscape, producing contingent benefits and disbenefits that are far removed from the visions of any planners – Chinese or African, past or present

Thermal energy storage in a confined aquifer: Second cycle

This is the published version. Copyright 1981 American Geophysical UnionDuring the first 6-month injection-storage-recovery cycle of the Auburn University Aquifer Thermal Energy Storage Project, water pumped from an upper supply aquifer was heated to an average temperature of 55°C with an oil-fired boiler and then injected into a lower storage aquifer. Injection and recovery temperatures, flow rates, and temperatures at six depths in 10 observation wells and hydraulic heads in seven wells were recorded twice daily. The second-cycle injection, which was performed in a manner similar to the first, began on September 23, 1978, and continued until November 25, 1978, when 58,010 m3 of water had been pumped into the storage aquifer. The major problem experienced during the first cycle, a clogging injection well, was reduced by regular backwashing. This was done 8 times during injection and resulted in a 24% average injection rate increase compared to the first cycle. A 63-day storage period ended on January 27, 1979, and production of hot water began with an initial temperature of 54°C. By March 23 this temperature had dropped to 33°C, with 66,400 m3 of water and 76% of the injected thermal energy recovered. This compares to 66% recovery during the first cycle over the same drop in production temperature. Production of hot water continued until April 20, at which time 100,100 m3 of water and 89% of the injected thermal energy was recovered at a final production temperature of 27.5°C. During the second cycle, measurements were made of relative land subsidence and rebound to a precision approaching 0.1 mm. The surface elevation near the injection well rose 4 mm during injection, fell during storage, and fell more rapidly toward its original elevation during production. This movement was due to thermal expansion and contraction rather than to effects caused by head changes in the storage aquifer

Mapeo litológico y mineralógico del batolito devónico Cerro Áspero, usando imágenes ASTER, Sierras Pampeanas Orientales, Argentina

The present study evaluates ASTER image processing as a technique to assist the lithological and mineralogical mapping oflarge granitic bodies and associated hydrothermal alteration assemblages related to the Cerro Áspero batholith, in Sierra de Comechingones, Argentina. This batholith was formed by the successive emplacement of several sub circular, high-level crust plutons that intruded, in the Upper Devonian, to metamorphic sequences of high to medium grade reworked by shear zones. Each of these plutons developed internal, external and roof units, and dyke swarms. Internal units are composed by porphyritic biotite monzogranites and external, roof units and dyke swarms are dominated by two-mica and muscovite leucocratic monzogranites to quarz-rich alkali-feldspar granites. The main associated mineralizations are W-Mo magmatic-hydrothermaldeposits and postbatholith epithemal fluorite deposits of cretaceous age. Supervised classification, principal component analyses and emissivity calculations were made to identify lithological composition and variations within the different plutons that comprise the Cerro Áspero batholith. This methodology allowed us to have a better and precise mapping of the study area as well as the contacts between the different plutons that comprise the Cerro Áspero batholith. The classification with spectral angle mapper methods allowed to identify the different sectors with hydrothermal alteration (argillic and silicification). The argillic alteration is mainly associated with epithermal fluorite deposits74339440

Dynamics of trimming the content of face representations for categorization in the brain

To understand visual cognition, it is imperative to determine when, how and with what information the human brain categorizes the visual input. Visual categorization consistently involves at least an early and a late stage: the occipito-temporal N170 event related potential related to stimulus encoding and the parietal P300 involved in perceptual decisions. Here we sought to understand how the brain globally transforms its representations of face categories from their early encoding to the later decision stage over the 400 ms time window encompassing the N170 and P300 brain events. We applied classification image techniques to the behavioral and electroencephalographic data of three observers who categorized seven facial expressions of emotion and report two main findings: (1) Over the 400 ms time course, processing of facial features initially spreads bilaterally across the left and right occipito-temporal regions to dynamically converge onto the centro-parietal region; (2) Concurrently, information processing gradually shifts from encoding common face features across all spatial scales (e.g. the eyes) to representing only the finer scales of the diagnostic features that are richer in useful information for behavior (e.g. the wide opened eyes in 'fear'; the detailed mouth in 'happy'). Our findings suggest that the brain refines its diagnostic representations of visual categories over the first 400 ms of processing by trimming a thorough encoding of features over the N170, to leave only the detailed information important for perceptual decisions over the P300

AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1

Damaged mitochondria are eliminated by mitophagy, a selective form of autophagy whose dysfunction associates with neurodegenerative diseases. PINK1, PARKIN and p62/SQTMS1 have been shown to regulate mitophagy, leaving hitherto ill-defined the contribution by key players in 'general' autophagy. In basal conditions, a pool of AMBRA1 - an upstream autophagy regulator and a PARKIN interactor - is present at the mitochondria, where its pro-autophagic activity is inhibited by Bcl-2. Here we show that, upon mitophagy induction, AMBRA1 binds the autophagosome adapter LC3 through a LIR (LC3 interacting region) motif, this interaction being crucial for regulating both canonical PARKIN-dependent and -independent mitochondrial clearance. Moreover, forcing AMBRA1 localization to the outer mitochondrial membrane unleashes a massive PARKIN- and p62-independent but LC3-dependent mitophagy. These results highlight a novel role for AMBRA1 as a powerful mitophagy regulator, through both canonical or noncanonical pathways

Water in HD 209458b's atmosphere from 3.6 - 8 microns IRAC photometric observations in primary transit

The hot Jupiter HD 209458b was observed during primary transit at 3.6, 4.5, 5.8 and 8.0 microns using the Infrared Array Camera (IRAC) on the Spitzer Space Telescope. We detail here the procedures we adopted to correct for the systematic trends present in the IRAC data. The light curves were fitted including limb darkening effects and fitted using Markov Chain Monte Carlo and prayer-bead Monte Carlo techniques, finding almost identical results. The final depth measurements obtained by a combined Markov Chain Monte Carlo fit are at 3.6 microns, 1.469 +- 0.013 % and 1.448 +- 0.013 %; at 4.5 microns, 1.478 +- 0.017 % ; at 5.8 microns, 1.549 +- 0.015 % and at 8.0 microns 1.535 +- 0.011 %. Our results clearly indicate the presence of water in the planetary atmosphere. Our broad band photometric measurements with IRAC prevent us from determining the additional presence of other other molecules such as CO, CO2 and methane for which spectroscopy is needed. While water vapour with a mixing ratio of 10^-4-10^-3 combined with thermal profiles retrieved from the day-side may provide a very good fit to our observations, this data set alone is unable to resolve completely the degeneracy between water abundance and atmospheric thermal profile.Comment: 14 pages, 6 tables, 10 figures, Accepted for publication in MNRA

Traffic Instabilities in Self-Organized Pedestrian Crowds

In human crowds as well as in many animal societies, local interactions among individuals often give rise to self-organized collective organizations that offer functional benefits to the group. For instance, flows of pedestrians moving in opposite directions spontaneously segregate into lanes of uniform walking directions. This phenomenon is often referred to as a smart collective pattern, as it increases the traffic efficiency with no need of external control. However, the functional benefits of this emergent organization have never been experimentally measured, and the underlying behavioral mechanisms are poorly understood. In this work, we have studied this phenomenon under controlled laboratory conditions. We found that the traffic segregation exhibits structural instabilities characterized by the alternation of organized and disorganized states, where the lifetime of well-organized clusters of pedestrians follow a stretched exponential relaxation process. Further analysis show that the inter-pedestrian variability of comfortable walking speeds is a key variable at the origin of the observed traffic perturbations. We show that the collective benefit of the emerging pattern is maximized when all pedestrians walk at the average speed of the group. In practice, however, local interactions between slow- and fast-walking pedestrians trigger global breakdowns of organization, which reduce the collective and the individual payoff provided by the traffic segregation. This work is a step ahead toward the understanding of traffic self-organization in crowds, which turns out to be modulated by complex behavioral mechanisms that do not always maximize the group's benefits. The quantitative understanding of crowd behaviors opens the way for designing bottom-up management strategies bound to promote the emergence of efficient collective behaviors in crowds.Comment: Article published in PLoS Computational biology. Freely available here: http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.100244

Evidence for non-exponential elastic proton-proton differential cross-section at low |t| and sqrt(s) = 8 TeV by TOTEM

The TOTEM experiment has made a precise measurement of the elastic proton-proton differential cross-section at the centre-of-mass energy sqrt(s) = 8 TeV based on a high-statistics data sample obtained with the beta* = 90 optics. Both the statistical and systematic uncertainties remain below 1%, except for the t-independent contribution from the overall normalisation. This unprecedented precision allows to exclude a purely exponential differential cross-section in the range of four-momentum transfer squared 0.027 < |t| < 0.2 GeV^2 with a significance greater than 7 sigma. Two extended parametrisations, with quadratic and cubic polynomials in the exponent, are shown to be well compatible with the data. Using them for the differential cross-section extrapolation to t = 0, and further applying the optical theorem, yields total cross-section estimates of (101.5 +- 2.1) mb and (101.9 +- 2.1) mb, respectively, in agreement with previous TOTEM measurements.Comment: Final version published in Nuclear Physics