Aging-induced stem cell mutations as drivers for disease and cancer

Aging is characterized by a decrease in genome integrity, impaired organ maintenance, and an increased risk of cancer, which coincide with clonal dominance of expanded mutant stem and progenitor cell populations in aging tissues, such as the intestinal epithelium, the hematopoietic system, and the male germline. Here we discuss possible explanations for age-associated increases in the initiation and/or progression of mutant stem/progenitor clones and highlight the roles of stem cell quiescence, replication-associated DNA damage, telomere shortening, epigenetic alterations, and metabolic challenges as determinants of stem cell mutations and clonal dominance in aging

Slit/Robo Signaling Regulates Cell Fate Decisions in the Intestinal Stem Cell Lineage of Drosophila

SummaryIn order to maintain tissue homeostasis, cell fate decisions within stem cell lineages have to respond to the needs of the tissue. This coordination of lineage choices with regenerative demand remains poorly characterized. Here, we identify a signal from enteroendocrine cells (EEs) that controls lineage specification in the Drosophila intestine. We find that EEs secrete Slit, a ligand for the Robo2 receptor in intestinal stem cells (ISCs) that limits ISC commitment to the endocrine lineage, establishing negative feedback control of EE regeneration. Furthermore, we show that this lineage decision is made within ISCs and requires induction of the transcription factor Prospero in ISCs. Our work identifies a function for the conserved Slit/Robo pathway in the regulation of adult stem cells, establishing negative feedback control of ISC lineage specification as a critical strategy to preserve tissue homeostasis. Our results further amend the current understanding of cell fate commitment within the Drosophila ISC lineage

Dpp Signaling Determines Regional Stem Cell Identity in the Regenerating Adult Drosophila Gastrointestinal Tract

SummaryThe gastrointestinal tract is lined by a series of epithelia that share functional requirements but also have distinct, highly specialized roles. Distinct populations of somatic stem cells (SCs) regenerate these epithelia, yet the mechanisms that maintain regional identities of these SCs are not well understood. Here, we identify a role for the BMP-like Dpp signaling pathway in diversifying regenerative processes in the adult gastrointestinal tract of Drosophila. Dpp secreted from enterocytes at the boundary between the posterior midgut and the middle midgut (MM) sets up a morphogen gradient that selectively directs copper cell (CC) regeneration from gastric SCs in the MM and thus determines the size of the CC region. In vertebrates, deregulation of BMP signaling has been associated with Barrett’s metaplasia, wherein the squamous esophageal epithelium is replaced by a columnar epithelium, suggesting that the maintenance of regional SC identities by BMP is conserved

Provenance of Ordovician and Devonian sandstones from southern Peru and northern Bolivia - U-Pb and Lu-Hf isotope evidence of detrital zircons and its implications for the geodynamic evolution of the Western Gondwana margin (14° - 17° S)

In an attempt to trace the provenance of sedimentary detritus and to gain information on the crustal evolution of the Early Paleozoic western Gondwana margin (14°-17°S) we applied a combined in situ U-Pb and Lu-Hf LA-ICP-MS isotope analysis on detrital zircon from 12 Ordovician and Devonian sandstones in southern Peru and northern Bolivia. The sandstones are exposed in the Eastern Cordillera, the Altiplano and the Coastal Cordillera. The sedimentary basins are part of the Peru-Bolivia trough. Few intrusive and extrusive Early Paleozoic rocks indicate that the Ordovician basins developed in a back-arc position, with the arc on the Arequipa Massif in the west and the Amazonian craton in the east. This plate-tectonic setting appears to have changed into a passive margin in the Early Devonian. The U-Pb zircon age distribution of the Ordovician sandstones from the Eastern Cordillera has the most distinctive peak between 0.7 and 0.5 Ga (Brazilian interval). Contrastingly, the most prominent U-Pb zircon age peak of the Ordovician sandstones from the Altiplano is at 1.2-0.9 Ga (Grenvillian interval) with a smaller peak at 1.85-1.7 Ga. The Devonian sandstones from the same locality on the Altiplano contain zircons with a major age peak at 0.5-0.4 Ga (Famatinian interval). Smaller U-Pb age peaks can be connected to the Brazilian, Grenvillian and Transamazonian (2.2-1.8 Ga) intervals. Zircons of the Devonian sandstones from the Coastal Cordillera have a similar age distribution but the Grenvillian ages, in one case also the Transamazonian ages are significantly more pronounced than the Brazilian ages. Zircons formed during the Brazilian interval could have been derived from various eastern sources on the Amazonian craton, those with Grenvillian ages were derived either from the Sunsas belt to the east or from the Arequipa Massif to the west of the sedimentary basin. Zircons related to the Famatinan event most probably originated in the Arequipa Massif, the closest place where respective magmatic arc rocks were available. Thus, the Ordovician sandstones of the Eastern Cordillera and the Altiplano had an eastern source, while the Altiplano locality was fed from a very limited source area, probably the Sunsas belt. The Devonian siliciclastic strata instead were mainly influenced by the Arequipa Massif. Minor influences of eastern sources are documented by the presence of Brazilian zircon ages. The in situ Lu-Hf isotope signature provides information about crustal recycling. Together with the U-Pb zircon ages, crustal evolution paths can be reconstructed. εHf(t) values of the analysed zircons spread between –20 and +12. Zircons with a very juvenile signatures (less than 5 εHf-units below the respective depleted mantle composition) we detected only in the interval between 1.5 and 0.9 Ga. Hence, of the Brazilian and Famatinian events we only find zircons derived from an evolved crust. A striking feature is the common Hf model ages (c.1.5-1.2 Ga) of zircons formed during the Grenvillian, Brazilian and Famatinian orogenies. This indicates that Famatinian-aged crystalline rocks of the Arequipa Massif and the Brazilianaged crystalline rocks of the Amazonian craton have a similar crustal origin

JNK Signaling Confers Tolerance to Oxidative Stress and Extends Lifespan in Drosophila

AbstractChanges in the genetic makeup of an organism can extend lifespan significantly if they promote tolerance to environmental insults and thus prevent the general deterioration of cellular function that is associated with aging. Here, we introduce the Jun N-terminal kinase (JNK) signaling pathway as a genetic determinant of aging in Drosophila melanogaster. Based on expression profiling experiments, we demonstrate that JNK functions at the center of a signal transduction network that coordinates the induction of protective genes in response to oxidative challenge. JNK signaling activity thus alleviates the toxic effects of reactive oxygen species (ROS). In addition, we show that flies with mutations that augment JNK signaling accumulate less oxidative damage and live dramatically longer than wild-type flies. Our work thus identifies the evolutionarily conserved JNK signaling pathway as a major genetic factor in the control of longevity

Trophic Factors in Inflammation and Regeneration: The Role of MANF and CDNF

Regeneration is an important process in multicellular organisms, responsible for homeostatic renewal and repair of different organs after injury. Immune cell activation is observed at early stages of the regenerative response and its regulation is essential for regenerative success. Thus, immune regulators play central roles in optimizing regenerative responses. Neurotrophic factors (NTFs) are secreted molecules, defined by their ability to support neuronal cell types. However, emerging evidence suggests that they can also play important functions in the regulation of immune cell activation and tissue repair. Here we discuss the literature supporting a role of NTFs in the regulation of inflammation and regeneration. We will focus, in particular, in the emerging roles of mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) in the regulation of immune cell function and in the central role that immune modulation plays in their biological activity in vivo. Finally, we will discuss the potential use of these factors to optimize regenerative success in vivo, both within and beyond the nervous system

The missing link of Rodinia break up in western South America: A petrographical, geochemical, and zircon Pb-Hf isotope study of the volcanosedimentary Chilla beds (Altiplano, Bolivia)

The assembly of Rodinia involved the collision of eastern Laurentia with southwestern Amazonia at ca. 1 Ga. The tectonostratigraphic record of the central Andes records a gap of ∼300 m.y. between 1000 Ma and 700 Ma, i.e., from the beginning of the Neoproterozoic Era to the youngest part of the Cryogenian Period. This gap encompasses the time of final assembly and breakup of the Rodinia supercontinent in this region. We present new petrographic and whole-rock geochemical data and U-Pb ages combined with Hf isotope data of detrital zircons from the volcanosedimentary Chilla beds exposed on the Altiplano southwest of La Paz, Bolivia. The presence of basalt to andesite lavas and tuffs of continental tholeiitic affinity provides evidence of a rift setting for the volcanics and, by implication, the associated sedimentary rocks. U-Pb ages of detrital zircons (n = 124) from immature, quartz-intermediate sandstones have a limited range between 1737 and 925 Ma. A youngest age cluster (n = 3) defines the maximum depositional age of 925 ± 12 Ma. This is considered to coincide with the age of deposition because Cryogenian and younger ages so typical of Phanerozoic units of this region are absent from the data. The zircon age distribution shows maxima between 1300 and 1200 Ma (37% of all ages), the time of the Rondônia–San Ignacio and early Sunsás (Grenville) orogenies in southwestern Amazonia. A provenance mixing model considering the Chilla beds, Paleozoic Andean units, and data from eastern Laurentia Grenville sources shows that >90% of the clastic input was likely derived from Amazonia. This is also borne out by multidimensional scaling (MDS) analysis of the data. We also applied MDS analysis to combinations of U-Pb age and Hf isotope data, namely εHf(t) and 176Hf/177Hf values, and demonstrate again a very close affinity of the Chilla beds detritus to Amazonian sources. We conclude that the Chilla beds represent the first and hitherto only evidence of Rodinia breakup in Tonian time in Andean South America.publishedVersio

Unsupervised parallel machines scheduling with tool switches

This paper addresses the problem of scheduling jobs on identical parallel machines with tool switches in a high-mix, low-volume manufacturing environment. Inspired by the initiatives on “lights-out factory” at our industry partner, our problem setting involves several complex features. For example, we consider unsupervised production hours (e.g., night shifts where operators are not available) in which tool switches cannot occur. Moreover, motivated by current practice, tool switches in our problem setting cause costs instead of delays. Also, a subset of jobs is prioritized to be completed within a scheduling horizon, and a job may consist of ordered operations due to reentry to machines. The objective is to maximize the profit generated by the manufacturing system, which is composed of revenue generated by the finished operations minus tool switching costs and penalty costs of unfinished priority jobs. The decisions involve assigning operations to machines, sequencing these operations, and determining a tool-switching plan. A mix-integer linear programming model is first formulated. We then propose a genetic algorithm to solve industry-size problem instances, in which tailored crossover and mutation mechanisms are introduced. We illustrate the performance of the proposed GA with industry case studies using real-world data. We also make the anonymized data set publicly available. Computational experiments reveal that approximately 26% profit improvement can be achieved by using the proposed GA instead of the current way of scheduling at our industry partner. Moreover, we find that the proposed GA brings higher benefits when the duration of the unsupervised shifts gets longer, and there is high pressure on prioritizing jobs in the schedule