Pulmonary Alveolar Stem Cell Senescence, Apoptosis, and Differentiation by p53-Dependent and -Independent Mechanisms in Telomerase-Deficient Mice

Pulmonary premature ageing and fibrogenesis as in idiopathic pulmonary fibrosis (IPF) occur with the DNA damage response in lungs deficient of telomerase. The molecular mechanism mediating pulmonary alveolar cell fates remains to be investigated. The present study shows that naturally occurring ageing is associated with the DNA damage response (DDR) and activation of the p53 signalling pathway. Telomerase deficiency induced by telomerase RNA component (TERC) knockout (KO) accelerates not only replicative senescence but also altered differentiation and apoptosis of the pulmonary alveolar stem cells (AEC2) in association with increased innate immune natural killer (NK) cells in TERC KO mice. TERC KO results in increased senescence-associated heterochromatin foci (SAHF) marker HP1γ, p21, p16, and apoptosis-associated cleaved caspase-3 in AEC2. However, additional deficiency of the tumour suppressor p53 in the Trp53−/− allele of the late generation of TERC KO mice attenuates the increased senescent and apoptotic markers significantly. Moreover, p53 deficiency has no significant effect on the increased gene expression of T1α (a marker of terminal differentiated AEC1) in AEC2 of the late generation of TERC KO mice. These findings demonstrate that, in natural ageing or premature ageing accelerated by telomere shortening, pulmonary senescence and IPF develop with alveolar stem cell p53-dependent premature replicative senescence, apoptosis, and p53-independent differentiation, resulting in pulmonary senescence-associated low-grade inflammation (SALI). Our studies indicate a natural ageing-associated molecular mechanism of telomerase deficiency-induced telomere DDR and SALI in pulmonary ageing and IPF.

Orthopedic Toxicities Among Adolescents and Young Adults Treated on DFCI ALL Consortium Trials

Adolescent and young adult patients with acute lymphoblastic leukemia (ALL) have superior outcomes when treated on pediatric regimens. Pediatric ALL regimens rely heavily on corticosteroids and asparaginase and are known to increase the risk of osteonecrosis (ON) and fractures in children, particularly adolescents. Orthopedic toxicity among young adults treated on pediatric-inspired regimens is not well described. Here, we report the symptomatic orthopedic toxicities of patients aged 15-50 years treated on sequential Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols. Among 367 patients with a median age of 23 years (range 15-50, 68% < 30 years), 60 patients were diagnosed with ON (5-year cumulative incidence (CI) 17%; [95% confidence interval 13-22]) and 40 patients experienced fracture (5-year CI 12% [95% CI 8-15]). Patients < 30 years were significantly more likely to be diagnosed with ON (5-year CI 21% vs. 8%, p=0.004). Patients treated more recently on pegaspargase-based protocols were significantly more likely to be diagnosed with ON compared to those treated on earlier trials with native E.coli asparaginase (5-year CI 24% vs 5%, p<0.001). Of the 54 ON events for which adequate information was available, surgery was performed in 25 (46%). Patients with ON had superior overall survival (OS) compared to those without (multivariable OS HR 0.15 [95% CI: 0.05-0.46], p=0.001; ON included as a time-varying exposure). Increased rates of orthopedic toxicity in late generation protocols may be driven by the pharmacokinetic drug interaction between pegaspargase and dexamethasone, leading to higher dexamethasone exposure.

Barrovian-type metamorphism in the western domain of the Cordillera Darwin Metamorphic Complex, Fuegian Andes

<p>The Cordillera de Darwin Metamorphic Complex (CDMC) comprise metamorphosed supracrustal rocks and metaplutonic suites which records a unique tectonic evolution among the metamorphic complexes of the southernmost Andes. The pressure (P) and temperature (T) conditions determined in garnet-bearing schists in the Central Domain of the CDMC indicate a clockwise P-T path of metamorphism reaching burial depth as high as 12 kbar at ca. 620°C. This metamorphic event has been related to the closure of a marginal back-arc basin (Rocas Verdes Basin) and collision of an ensialic magmatic arc with the continent in the late Cretaceous. We focus on garnet-biotite schists intercalated within a huge block consisting of repeated sequences of metabasalts and amphibolites (Rocas Verdes Ophiolites), located in the Western Domain of the CDMC, at Seno Martínez. The chemical zonation of small garnet porphyroblasts (diameter of ca. 300 um) record two stages of metamorphism. Garnet is almost almandine in composition with lesser amounts of Ca, Mn and Mg.  The concentric zonation is characterized by relatively lower contents of Fe-Mg and higher contents of Ca-Mn in the core. Garnet bear tiny inclusions of clinozoisite, which is also present as isolated grains in the foliated matrix. Laths of biotite define the main foliation and have a nearly constant composition characterized by X<sub>Fe</sub> of ca. 0.6. Two generations of phengitic white mica are identified on basis of Si content (a.pf.u.) varying between 3.20-3.30 (early generation) and of ca. 3.15 (late generation). To reconstruct the P-T conditions of metamorphism through thermodynamic modeling using the Perple_X software package, the bulk rock and mineral composition were considered. Using compositional isopleths of X<sub>Fe</sub>, X<sub>Mg</sub>, X<sub>Ca</sub> and X<sub>Mn</sub> in zoned garnet, Si content in white mica and X<sub>Fe</sub> in biotite allow the constrain two stages of metamorphism (M1 and M2). The P-T conditions of M1, represented by the composition of the garnet core, are restricted to ca. 8 kbar and 400°C. M2 is restricted to ca. 7.5 kbar at 480°C, determined with the composition of the garnet rim, X<sub>Fe</sub> in biotite and Si content in late phengitic white mica. Our preliminary results indicate that ophiolitic rocks and interleaved garnet-bearing schists were tectonically buried and metamorphosed in a relatively hot subduction interface characterized by a geothermal gradient of ca. 16°C/km, prior to the collision of the ensialic magmatic arc. Acknowledgements. This study was supported by the Fondecyt grant 1161818.</p>

Germ granule dysfunction is a hallmark and mirror of Piwi mutant sterility

In several species, Piwi/piRNA genome silencing defects cause immediate sterility that correlates with transposon expression and transposon-induced genomic instability. In C. elegans, mutations in the Piwi-related gene (prg-1) and other piRNA deficient mutants cause a transgenerational decline in fertility over a period of several generations. Here we show that the sterility of late generation piRNA mutants correlates poorly with increases in DNA damage signaling. Instead, sterile individuals consistently exhibit altered perinuclear germ granules. We show that disruption of germ granules does not activate transposon expression but induces multiple phenotypes found in sterile prg-1 pathway mutants. Furthermore, loss of the germ granule component pgl-1 enhances prg-1 mutant infertility. Environmental restoration of germ granule function for sterile pgl-1 mutants restores their fertility. We propose that Piwi mutant sterility is a reproductive arrest phenotype that is characterized by perturbed germ granule structure and is phenocopied by germ granule dysfunction, independent of genomic instability.

The North Pyrenean Frontal Thrust: structure, timing and late fluid circulation inferred from seismic and thermal-geochemical analyses of well data

During orogenesis, large-scale thrusts as orogenic fronts can act as conduits and/or barriers for fluid flow. Unravelling the timing and modes of tectonic activation of large-scale faults is crucial to understanding the relationship between fluid flow and deformation. The North Pyrenean Frontal Thrust (NPFT) corresponds to a major basement-involved thrust responsible for the northward overthrust of the pre-orogenic sediments on top of the Aquitaine Foreland Basin. This study questions the timing of activation of this thrust, its geometry, the nature of the last fluids, which circulated there, and its role on the circulation of fluids. The structural study confronted to published thermochronology data led to determine the timing of the two tectonic activations during the NPFT compression phase and to relate them to the fluid circulations. We constrain the first activation at Campanian times and link it to the leak of the deep gas reservoir present in depth, as the NPFT acted as a conduit. Then the NPFT acted as a barrier, probably due to the breccia consolidation during the Paleocene quiescence period. Finally, the Eocene-Oligocene reactivation led to fluid circulation of high salinity fluids from the Triassic evaporites leaching. This latter event is associated with a fracturing event and the late generation of calcite veins studied here. This is the first study in the Pyrenees directly applied to the NPFT which uses the association between fluid inclusions study, seismic and thermochronological data. It highlights that the NPFT may be an important structure responsible of the leakage of deep hydrocarbons reservoirs. It also shows the importance of the determination of the activation steps of large-scale faults to decipher the origin of fluid circulations in space and time.

A Yonsei’s Heritage Language Learning Journey

This autoethnography chronicles my journey of learning Japanese as a heritage language (HL). Scholarship on Japanese HL learning has explored the challenges of HL learning for Japanese and Japanese Americans (JAs); however, little research was conducted on late-generation (third, fourth) JA learners, and particularly on “receptive learners.” 2 This autoethnography addresses these gaps by answering the question: what external (historical, societal) or internal (ethnic identity) factors influenced the loss or motivation to relearn my HL in the autoethnographer, a late-generation JA? Data were collected from my literacy narrative and pedagogical artifacts (e.g., journals, quizzes and assignments, etc.) from the Japanese as a Foreign Language (JFL) courses I took, and analyzed thematically for influential factors and motivation patterns. Findings reveal that (1) racism and internment (as the historical and societal factors) and shame and the aspiration to reconnect with the heritage culture (as the internal factors) influenced my longitudinal course of learning Japanese; and (2) what motivated a late-generation JA to study my HL is not for professional reasons, as claimed in previous research, but to heal from a conflicted legacy and the desire to communicate orally with members of the heritage culture. However, my effort to realize these goals was thwarted by the curricular design of the JFL courses, which focused primarily on orthographic practices and insufficiently on oral proficiency, raising legitimate questions about the pedagogical appropriateness of JFL courses for HL learners.

Kimberlite Metasomatism of the Lithosphere and the Evolution of Olivine in Carbonate-rich Melts — Evidence from the Kimberley Kimberlites (South Africa)

Olivine is the most abundant phase in kimberlites and is stable throughout most of the crystallization sequence, thus providing an extensive record of kimberlite petrogenesis. To better constrain the composition, evolution, and source of kimberlites we present a detailed petrographic and geochemical study of olivine from multiple dyke, sill, and root zone kimberlites in the Kimberley cluster (South Africa). Olivine grains in these kimberlites are zoned, with a central core, a rim overgrowth, and occasionally an external rind. Additional ‘internal’ and ‘transitional’ zones may occur between the core and rim, and some samples of root zone kimberlites contain a late generation of high-Mg olivine in cross-cutting veins. Olivine records widespread pre-ascent (proto-)kimberlite metasomatism in the mantle including the following features: (1) relatively Fe-rich (Mg# <89) olivine cores interpreted to derive from the disaggregation of kimberlite-related megacrysts (20 % of cores); (2) Mg–Ca-rich olivine cores (Mg# >89; >0·05 wt% CaO) suggested to be sourced from neoblasts in sheared peridotites (25 % of cores); (3) transitional zones between cores and rims probably formed by partial re-equilibration of xenocrysts (now cores) with a previous pulse of kimberlite melt (i.e. compositionally heterogeneous xenocrysts); (4) olivine from the Wesselton water tunnel sills, internal zones (I), and low-Mg# rims, which crystallized from a kimberlite melt that underwent olivine fractionation and stalled within the shallow lithospheric mantle. Magmatic crystallization begins with internal olivine zones (II), which are common but not ubiquitous in the Kimberley olivine. These zones are euhedral, contain rare inclusions of chromite, and have a higher Mg# (90·0 ± 0·5), NiO, and Cr2O3 contents, but are depleted in CaO compared with the rims. Internal olivine zones (II) are interpreted to crystallize from a primitive kimberlite melt during its ascent and transport of olivine toward the surface. Their compositions suggest assimilation of peridotitic material (particularly orthopyroxene) and potentially sulfides prior to or during crystallization. Comparison of internal zones (II) with liquidus olivine from other mantle-derived carbonate-bearing magmas (i.e. orangeites, ultramafic lamprophyres, melilitites) shows that low (100×) Mn/Fe (∼1·2), very low Ca/Fe (∼0·6), and moderate Ni/Mg ratios (∼1·1) appear to be the hallmarks of olivine in melts derived from carbonate-bearing garnet-peridotite sources. Olivine rims display features indicative of magmatic crystallization, which are typical of olivine rims in kimberlites worldwide; that is, primary inclusions of chromite, Mg-ilmenite and rutile, homogeneous Mg# (88·8 ± 0·3), decreasing Ni and Cr, and increasing Ca and Mn. Rinds and high-Mg olivine are characterized by extreme Mg–Ca–Mn enrichment and Ni depletion, and textural relationships indicate that these zones represent replacement of pre-existing olivine, with some new crystallization of rinds. These zones probably precipitated from evolved, oxidized, and relatively low-temperature kimberlite fluids after crustal emplacement. In summary, this study demonstrates the utility of combined petrography and olivine geochemistry to trace the evolution of kimberlite magmatic systems from early metasomatism of the lithospheric mantle by (proto-)kimberlite melts, to crystallization at different depths en route to surface, and finally late-stage deuteric or hydrothermal fluid alteration after crustal emplacement.