Search

PIF1 is a 5′ to 3′ DNA helicase that can unwind double-stranded DNA and disrupt nucleic acid-protein complexes. In Saccharomyces cerevisiae, Pif1 plays important roles in mitochondrial and nuclear genome maintenance, telomere length regulation, unwinding of G-quadruplex structures, and DNA synthesis during break-induced replication. Some, but not all, of these functions are shared with other eukaryotes. To gain insight into the evolutionarily conserved functions of PIF1, we created pif1 null mutants in Drosophila melanogaster and assessed their phenotypes throughout development. We found that pif1 mutant larvae exposed to high concentrations of hydroxyurea, but not other DNA damaging agents, experience reduced survival to adulthood. Embryos lacking PIF1 fail to segregate their chromosomes efficiently during early nuclear divisions, consistent with a defect in DNA replication. Furthermore, loss of the BRCA2 protein, which is required for stabilization of stalled replication forks in metazoans, causes synthetic lethality in third instar larvae lacking either PIF1 or the polymerase delta subunit POL32. Interestingly, pif1 mutants have a reduced ability to synthesize DNA during repair of a double-stranded gap, but only in the absence of POL32. Together, these results support a model in which Drosophila PIF1 functions with POL32 during times of replication stress but acts independently of POL32 to promote synthesis during double-strand gap repair.

Prasentation, klinischer Verlauf und Outcome von Patienten mit primar biliarer Cholangitis (PBC) sind in Mitteleuropa nicht ausreichend beschrieben. Diese Arbeit untersucht demographische und klinische Daten und charakterisiert den Krankheitsverlauf der PBC am Patientenkollektiv am Universitatsklinikum Graz. Die Krankenakten von Patienten mit der Diagnose PBC, die im Zeitraum von 2004–2015 am Universitatsklinikum Graz in Betreuung waren, wurden retrospektiv untersucht. Erhoben wurden die Daten zum Zeitpunkt der Erstdiagnose und bei der letzten Kontrolle (Follow-up). Insgesamt wurden 95 Patienten (89 Frauen, 6 Manner) identifiziert. Das mediane Alter bei Erstdiagnose betrug 53 Jahre. Die alkalische Phosphatase (AP) war bei Erstdiagnose bei 60 % der Patienten um weniger als das 2‑Fache der Norm erhoht. 39 % der Patienten wiesen bei Erstdiagnose Symptome, wie Pruritus, Mudigkeit, Oberbauchbeschwerden oder eine Sicca-Symptomatik, auf. Eine Leberhistologie bei der Erstdiagnose lag bei 35 % aller Fallen vor (histologisches Stadium I nach Ludwig, n = 28; Stadium II, n = 5; Stadium III, n = 1; Stadium IV, n = 1). Das mediane Follow-up betrug 7 (1–21) Jahre. Die Mehrzahl der Patienten (69 %) hatte in der FibroScan®-Messung im Follow-up eine F0/F1-Fibrose. Eine Leberzirrhose lag in 10 Fallen (11 %) vor. Zwei mit der PBC assoziierte Todesfalle wurden verzeichnet. Ein inadaquates Ansprechen auf die Therapie mit Ursodesoxycholsaure lag in 30 % aller Falle vor. Zusammenfassend sind in unserem Kollektiv eine deutliche Erhohung der AP (>2- bis 4‑Fache der Norm) und ein schlechtes Outcome (Entwicklung einer Zirrhose, Tod, Transplantation) seltener als in der Literatur angegeben, wahrend demographische Daten durchaus mit denen aus anderen Arbeiten vergleichbar sind.

Recent evidence has shown that exposure to airborne particulate matter (PM) is associated with cognitive delay, depression, anxiety, autism, and neurodegenerative diseases; however, the role of PM in the etiology of these outcomes is not well-understood. Therefore, there is a need for controlled animal studies to better elucidate the causes and mechanisms by which PM impacts these health outcomes. We assessed the effects of gestational and early life exposure to traffic-related PM on social- and anxiety-related behaviors, cognition, inflammatory markers, and neural integrity in male rat juveniles. Gestating and lactating rats were exposed to PM from a Boston (MA, USA) traffic tunnel for 5 hours/day, 5 days/week for 6 weeks (3 weeks gestation, 3 weeks lactation). The target exposure concentration for the fine fraction of nebulized PM, measured as PM2.5, was 200 μg/m(3). To assess anxiety and cognitive function, F1 male juveniles underwent elevated platform, cricket predation, nest building, social behavior and marble burying tests at 32–60 days of age. Upon completion of behavioral testing, multiple cytokines and growth factors were measured in these animals and their brains were analyzed with diffusion tensor MRI to assess neural integrity. PM exposure had no effect on litter size or weight, or offspring growth; however, F1 litters developmentally exposed to PM exhibited significantly increased anxiety (p =0.04), decreased cognition reflected in poorer nest-organization (p =0.04), and decreased social play and allogrooming (p= 0.003). MRI analysis of ex vivo brains revealed decreased structural integrity of neural tissues in the anterior cingulate and hippocampus in F1 juveniles exposed to PM (p

Objectives: Rodents used in scientific research are typically housed in cages containing natural bedding materials. Despite extensive evidence of biological harm from inhaled particulate matter (PM), relatively little work has been performed to measure bedding-generated PM exposure in caged animals used in basic science research. Our objectives were to determine whether bedding-generated PM was present in significant concentrations in rodent cages and to identify the main factors affecting the accumulation and attenuation of bedding-generated PM inside cages. Materials and Methods: We measured PM2.5 concentrations in cages containing common bedding materials (pine, aspen, paper, and corncob) with filter top isolator absent or present on the cages. PM2.5 concentrations were monitored with rats inside cages as well as during artificial manipulation of the bedding (designed to simulate rodent activity). Results and Discussion: Upon rodent digging or mechanical/manual stirring, all four bedding materials produced significant increases in PM2.5 concentrations (as much as 100–200 µg/m3 PM2.5, 50- to 100-fold higher than during periods of no rodent activity), and concentrations in cages fitted with filter tops were an order of magnitude higher than in cages without filter tops. Elevated concentrations were sustained for longer durations in cages with filter tops (5–10 minutes) compared to cages with only bar lids (0–2 minutes). Conclusions: These results indicate that standard laboratory housing conditions can expose rodents to substantial levels of PM2.5. Bedding-generated PM has potential implications as an environmental agent in rodent studies.

PIF1 is a 5′ to 3′ DNA helicase that can unwind double-stranded DNA and disrupt nucleic acid-protein complexes. In Saccharomyces cerevisiae, Pif1 plays important roles in mitochondrial and nuclear genome maintenance, telomere length regulation, unwinding of G-quadruplex structures, and DNA synthesis during break-induced replication. Some, but not all, of these functions are shared with other eukaryotes. To gain insight into the evolutionarily conserved functions of PIF1, we created pif1 null mutants in Drosophila melanogaster and assessed their phenotypes throughout development. We found that pif1 mutant larvae exposed to high concentrations of hydroxyurea, but not other DNA damaging agents, experience reduced survival to adulthood. Embryos lacking PIF1 fail to segregate their chromosomes efficiently during early nuclear divisions, consistent with a defect in DNA replication. Furthermore, loss of the BRCA2 protein, which is required for stabilization of stalled replication forks in metazoans, causes synthetic lethality in third instar larvae lacking either PIF1 or the polymerase delta subunit POL32. Interestingly, pif1 mutants have a reduced ability to synthesize DNA during repair of a double-stranded gap, but only in the absence of POL32. Together, these results support a model in which Drosophila PIF1 functions with POL32 during times of replication stress but acts independently of POL32 to promote synthesis during double-strand gap repair.

Reservoirs represent a specific environmental component in many parts of the Earth, especially where water supply is limited. As is the case of the Moldavian hilly area, due to its dryness, the inhabitants created an extensive network of reservoirs since the medieval period, in the proximity of the settlement network. Over time, many dams were abandoned, while others have been relocated with impressive dynamics at a historical scale. In this paper, by analyzing old maps, LiDAR high-res DEMs, ERT surveys, and sediments, we have reconstructed the reservoir network's expansion in the last century at a regional scale and investigated the main geomorphologic characteristics of dams and associated landforms. In Jijia catchment (3386 km2) we found a total number of 1351 dams, of which 832 abandoned. 495 reservoirs were recognized on different topo maps dating from the 20th century, while 337 have been identified on DEMs. Two reservoirs were investigated in detail by field surveys, ERT surveys, profile digging, sediment analysis, and micro-sedimentological study, confirming lacustrine deposits according to the topographic reconstructions based on high-resolution LiDAR DEMs. These sedimentary lacustrine archives can substantially contribute to detailed paleoclimatic, paleohydrologic, and paleovegetation reconstruction in the study area.

There is convincing evidence that living close to major roadways and highways is associated with increased morbidity and mortality. Data indicate that traffic-related air pollution (TRAP) contribut...