Pliocene mixed-layer oceanography for Site 1241, using combined Mg/Ca and δ¹⁸O analyses of Globigerinoides sacculifer

To reconstruct changes in tropical Pacific surface hydrography, we used samples from Site 1241 (5°50′N, 86°26′W; 2027-m water depth) to establish high-resolution records of Mg/Ca and δ18O for the mixed-layer dwelling planktonic foraminifer Globigerinoides sacculifer for the Pliocene time interval from 4.8 to 2.4 Ma. An increase in average seasurface temperatures (SSTs) (24.5°–25.5°C) between 4.8 and 3.7 Ma can probably be explained by a southward shift of the Intertropical Convergence Zone, thereby increasing the influence of the warmer North Equatorial Countercurrent. The general global cooling trend, a response to intensification of Northern Hemisphere glaciation (NHG), started at ~3.2 Ma (shown by the δ18Obenthic record) and is paralleled by tropical east Pacific cooling (indicated by SSTMg/Ca). Tropical east Pacific cooling, however, had already commenced by ~3.7 Ma, suggesting that global cooling, probably related to decreasing atmospheric CO2 concentrations, might have started well before intensification of NHG. Relative changes in local sea-surface salinity (indicated by δ18Osalinity) show a decoupling from global high-latitude processes (shown by the δ18Obenthic record). Long-term regional freshening started with decreasing SSTMg/Ca at ~3.7 Ma, suggesting that changes in the tropical wind field combined with latitudinal shifts of the tropical rainbelt were related to general decreases in tropical east Pacific SST-controlled δ18Osalinity. The similarity of Pliocene SSTMg/Ca for G. sacculifer with modern SSTs in the east Pacific, in combination with the early development of a shallow thermocline at Site 1241, gives no direct support to the idea that a permanent El Niño-like Pliocene climate might have existed during the early Pliocene

Astronomically calibrated timescales from 6 to 2.5 Ma and Benthic Isotope Stratigraphies, sites 1236, 1237, 1239, and 1241

We present benthic isotope stratigraphies for Sites 1236, 1237, 1239, and 1241 that span the late Miocene–Pliocene time interval from 6 to 2.4 Ma. Orbitally tuned timescales were generated for Sites 1237 and 1241 by correlating the high-frequency variations in gamma ray attenuation density, percent sand of the carbonate fraction, and benthic δ¹³C to variations in Earth’s orbital parameters. The astronomical timescales for Sites 1237 and 1241 are in agreement with the one from Atlantic Site 925/926 (Ocean Drilling Program Leg 154). The comparison of benthic δ¹⁸O and δ¹³C records from the east Pacific sites and Atlantic Site 925/926 revealed a surprising clarity of the “41-k.y. signal” in δ¹³C records and a remarkably good correlation between their δ¹³C records. This suggests that the late Miocene–Pliocene amplitudes of obliquityrelated δ¹³C cycles reflect a magnitude of global response often larger than that provided by obliquity-related δ¹⁸O cycles. At Site 1237, the orbitally derived ages of Pliocene magnetic reversal boundaries between the base of Réunion and the top of Thvera confirm astronomical datings of the generally accepted ATNTS2004 timescale, except for the top of Kaena and the base of Sidufjall. Our astronomical age for the top of Kaena is about one obliquity cycle older. The base of Sidufjall appears to be about one precession cycle younger. The age models of Sites 1236 and 1239 were established by correlating their benthic δ¹⁸O and δ¹³C records directly to the orbitally tuned isotope record of Site 1241

Community engagement and data quality: best practices and lessons learned from a citizen science project on birdsong

Citizen Science (CS) is a research approach that has become popular in recent years and offers innovative potential for dialect research in ornithology. As the scepticism about CS data is still widespread, we analysed the development of a 3-year CS project based on the song of the Common Nightingale (Luscinia megarhynchos) to share best practices and lessons learned. We focused on the data scope, individual engagement, spatial distribution and species misidentifications from recordings generated before (2018, 2019) and during the COVID-19 outbreak (2020) with a smartphone using the ‘Naturblick’ app. The number of nightingale song recordings and individual engagement increased steadily and peaked in the season during the pandemic. 13,991 nightingale song recordings were generated by anonymous (64%) and non-anonymous participants (36%). As the project developed, the spatial distribution of recordings expanded (from Berlin based to nationwide). The rates of species misidentifications were low, decreased in the course of the project (10–1%) and were mainly affected by vocal similarities with other bird species. This study further showed that community engagement and data quality were not directly affected by dissemination activities, but that the former was influenced by external factors and the latter benefited from the app. We conclude that CS projects using smartphone apps with an integrated pattern recognition algorithm are well suited to support bioacoustic research in ornithology. Based on our findings, we recommend setting up CS projects over the long term to build an engaged community which generates high data quality for robust scientific conclusions.Gesellschaftliches Engagement und Datenqualität: Bewährte Praktiken und Erfahrungen aus einem bürgerwissenschaftlichen Projekt zum Vogelgesang Citizen Science (CS) ist eine Forschungsmethode, die in den letzten Jahren an Bedeutung gewonnen hat und innovatives Potenzial für die Dialektforschung in der Ornithologie bietet. Da die Vorbehalte gegenüber CS-Daten immer noch weit verbreitet sind, haben wir die Entwicklung eines dreijährigen CS-Projekts zum Gesang der Nachtigall (Luscinia megarhynchos) analysiert, um bewährte Praktiken und gewonnene Erfahrungen darzustellen. Wir fokussierten uns auf den Datenumfang, das individuelle Engagement von Teilnehmenden, die räumliche Verteilung und die Fehlbestimmungen von Arten aus Aufnahmen, die vor (2018, 2019) und während des COVID-19-Ausbruchs (2020) mit einem Smartphone unter Verwendung der "Naturblick" App erstellt wurden. Die Anzahl der Aufnahmen von Nachtigallgesängen und das individuelle Engagement stiegen stetig an und erreichten ihren Höhepunkt in der Saison während der Pandemie. 13.991 Aufnahmen von Nachtigallgesängen wurden von anonymen (64%) und nicht-anonymen Teilnehmenden (36%) erstellt. Im Laufe des Projekts weitete sich die räumliche Verteilung der Aufnahmen aus (von Berlin auf bundesweit). Die Rate der Fehlbestimmungen war gering, ging im Laufe des Projekts zurück (von 10% auf 1%) und wurde hauptsächlich von gesanglichen Ähnlichkeiten mit anderen Vogelarten beeinflusst. Unsere Studie zeigte außerdem, dass das gesellschaftliche Engagement und die Datenqualität nicht direkt von den durchgeführten Disseminationsaktivitäten beeinflusst wurden, sondern dass erstere von externen Faktoren abhingen und letztere von der App profitierte. Wir schließen daraus, dass CS-Projekte, die Smartphone-Apps mit einem integrierten Mustererkennungsalgorithmus verwenden, gut geeignet sind, um die bioakustische Forschung in der Ornithologie zu unterstützen. Auf der Grundlage unserer Ergebnisse empfehlen wir, CS-Projekte langfristig zu etablieren, um eine aktive Teilnehmergemeinschaft (Community) aufzubauen, die qualitativ hochwertige Daten für fundierte wissenschaftliche Schlussfolgerungen generiert

Pineal anlage tumor: clinical and diagnostic features, and rationales for treatment

Purpose To provide a treatment-focused review and develop basic treatment guidelines for patients diagnosed with pineal anlage tumor (PAT). Methods Prospectively collected data of three patients with pineal anlage tumor from Germany was combined with clinical details and treatment information from 17 published cases. Results Overall, 20 cases of PAT were identified (3 not previously reported German cases, 17 cases from published reports). Age at diagnosis ranged from 0.3 to 35.0 (median: 3.2 ± 7.8) years. All but three cases were diagnosed before the age of three years. For three cases, metastatic disease at initial staging was described. All patients underwent tumor surgery (gross-total resection: 9, subtotal resection/biopsy: 9, extent of resection unknown: 2). 15/20 patients were alive at last follow-up. Median follow-up for 10/15 surviving patients with available follow-up and treatment data was 2.4 years (0.3–6.5). Relapse was reported for 3 patients within 0.8 years after diagnosis. Five patients died, 3 after relapse and 2 from early postoperative complications. Two-year-progression-free- and -overall survival were 65.2 ± 12.7% and 49.2 ± 18.2%, respectively. All 4 patients who received intensive chemotherapy including high-dose chemotherapy combined with radiotherapy (2 focal, 2 craniospinal [CSI]) had no recurrence. Focal radiotherapy- and CSI-free survival rates in 13 evaluable patients were 46.2% (6/13) and 61.5% (8/13), respectively. Conclusion PAT is an aggressive disease mostly affecting young children. Therefore, adjuvant therapy using intensive chemotherapy and considering radiotherapy appears to comprise an appropriate treatment strategy. Reporting further cases is crucial to evaluate distinct treatment strategies

Myeloid cell subpopulations compensate each other for Ccr2-deficiency in glioblastoma

Aims Glioblastomas are high-grade brain tumours that are characterised by the accumulation of brain-resident microglia and peripheral macrophages. Recruitment of these myeloid cells can be facilitated by CCR2/CCL2 signalling. Besides the well-known CCR2+ macrophages, we have identified microglia expressing CCR2 in glioma tissues. Thus, we investigated how Ccr2-deficiency of one of the myeloid cell populations affects the other population and tumour biology. Methods We generated four chimeric groups to analyse single and combined Ccr2-deficiency of microglia and macrophages. On day 21 after tumour cell implantation (GL261), we conducted flow cytometry, immunofluorescence and real-time polymerase chain reaction analyses. Tumour volume and metabolism were determined by magnetic resonance imaging and magnetic resonance spectroscopy. Moreover, in vitro studies were performed with primary microglia and bone marrow-derived macrophages. Results We demonstrated reduced infiltration of macrophages and microglia depending on the lack of Ccr2. However, the total number of myeloid cells remained constant except for the animals with dual Ccr2-knockout. Both microglia and macrophages with Ccr2-deficiency showed impaired expression of proinflammatory molecules and altered phagocytic activity. Despite the altered immunologic phenotype caused by Ccr2-deficiency, glioma progression and metabolism were hardly affected. Alterations were detected solely in apoptosis and proliferation of tumours from animals with specific Ccr2-deficient microglia, whereas vessel stability was increased in mice with Ccr2-knockout in both cell populations. Conclusion These results indicate that microglia and macrophages provide a homoeostatic balance within glioma tissue and compensate for the lack of the corresponding counterpart. Moreover, we identified that the CCR2/CCL2 axis is involved in the immunologic function of microglia and macrophages beyond its relevance for migration

Sucrose protects cell wall invertase but not vacuolar invertase against proteinaceous inhibitors

AbstractVacuolar (VI) and cell wall invertases (CWI) of higher plants can be inactivated in vitro and, possibly, in vivo by proteinaceous inhibitors. The respective mechanisms have not yet been compared. Therefore, partially purified CWI from transformed tobacco cells and VI from tomato fruit were preincubated with invertase-inhibitor fractions isolated from the same tissues. Both inhibitors were able to inhibit both invertases. However, VI was fully inhibited within less than 1 min by both inhibitors, whereas inactivation of CWI was much slower. Furthermore, CWI, but not VI, was strongly protected against inhibition by sucrose. A polyclonal antiserum directed against the tobacco inhibitor (INT) cross-reacted with a 19 kDa polypeptide in the partially purified tomato inhibitor (ILE) fraction. The results indicate that INT and ILE have similar structural properties, whereas the mechanism of inactivation is clearly different for CWI and VI

Apoptosis signaling proteins as prognostic biomarkers in colorectal cancer: a review.

Colorectal cancer is a leading cause of cancer related mortality in the Western world. In recent years, combination 5-fluorouracil based adjuvant chemotherapy as first line treatment of this disease has led to improved disease free and overall survival. However drug resistance, both innate and acquired, remains an obstacle in the effective treatment of this disease. Apoptotic pathways are frequently altered in both tumor progression and drug resistance; therefore proteins associated with this pathway may have potential as prognostic biomarkers for this disease. Identification of clinical biomarkers that are able to identify patients who are more likely to respond to specific chemotherapy will lead to more personalized, effective, and less toxic therapy. This review focuses on the current status of apoptosis related proteins as biomarkers for colorectal cancer and discusses the possible application of systems approaches in this context

RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses

Background: Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease. // Methods: We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case–control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities. // Findings: Between June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38–96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15–87·23; p=0·0055; I2=99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31–81, n=16), and two-thirds had a family history of parkinsonism. RAB32 Ser71Arg heterozygotes shared a common haplotype, although penetrance was incomplete. Findings in one individual at autopsy showed sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In functional studies, RAB32 Arg71 activated LRRK2 kinase to a level greater than RAB32 Ser71. // Interpretation: RAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling. // Funding: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council

Citizen science’s transformative impact on science, citizen empowerment and socio-political processes

Citizen science (CS) can foster transformative impact for science, citizen empowerment and socio-political processes. To unleash this impact, a clearer understanding of its current status and challenges for its development is needed. Using quantitative indicators developed in a collaborative stakeholder process, our study provides a comprehensive overview of the current status of CS in Germany, Austria and Switzerland. Our online survey with 340 responses focused on CS impact through (1) scientific practices, (2) participant learning and empowerment, and (3) socio-political processes. With regard to scientific impact, we found that data quality control is an established component of CS practice, while publication of CS data and results has not yet been achieved by all project coordinators (55%). Key benefits for citizen scientists were the experience of collective impact (“making a difference together with others”) as well as gaining new knowledge. For the citizen scientists’ learning outcomes, different forms of social learning, such as systematic feedback or personal mentoring, were essential. While the majority of respondents attributed an important value to CS for decision-making, only few were confident that CS data were indeed utilized as evidence by decision-makers. Based on these results, we recommend (1) that project coordinators and researchers strengthen scientific impact by fostering data management and publications, (2) that project coordinators and citizen scientists enhance participant impact by promoting social learning opportunities and (3) that project initiators and CS networks foster socio-political impact through early engagement with decision-makers and alignment with ongoing policy processes. In this way, CS can evolve its transformative impact