Zinc isotopes from archaeological bones provide reliable trophic level information for marine mammals

In marine ecology, dietary interpretations of faunal assemblages often rely on nitrogen isotopes as the main or only applicable trophic level tracer. We investigate the geographic variability and trophic level isotopic discrimination factors of bone zinc 66Zn/64Zn ratios (δ66Zn value) and compared it to collagen nitrogen and carbon stable isotope (δ15N and δ13C) values. Focusing on ringed seals (Pusa hispida) and polar bears (Ursus maritimus) from multiple Arctic archaeological sites, we investigate trophic interactions between predator and prey over a broad geographic area. All proxies show variability among sites, influenced by the regional food web baselines. However, δ66Zn shows a significantly higher homogeneity among different sites. We observe a clear trophic spacing for δ15N and δ66Zn values in all locations, yet δ66Zn analysis allows a more direct dietary comparability between spatially and temporally distinct locations than what is possible by δ15N and δ13C analysis alone. When combining all three proxies, a more detailed and refined dietary analysis is possible

Subarctic climate for the earliest Homo sapiens in Europe

Acknowledgments The re-excavation of Bacho Kiro Cave was jointly conducted by the National Institute of Archaeology with Museum, Bulgarian Academy of Sciences, Sofia and the Department of Human Evolution at the MPI-EVA. We would like to thank the National Museum of Natural History (Sofia), the Archaeology Department at the New Bulgarian University (Sofia), the Regional Museum of History in Gabrovo, and the History Museum in Dryanovo for assistance on this project and the opportunity to study the Bacho Kiro Cave faunal material. We would like to thank M. Trost, S. Hesse, M. Kaniecki, and P. Dittmann (MPI-EVA) for technical assistance during stable isotope sample preparation. S. Steinbrenner is thanked for technical assistance with TC/EA-IRMS maintenance. Thanks are also due to H. Temming and U. Schwarz (MPI-EVA) for the production of microCT scans and replicas of the sample materials. We would also like to acknowledge the assistance of to D. Veres with taking OSL samples. Last but not least we would like to thank the handling editor, S. Ortman, as well as three anonymous reviewers for their thoughtful comments that greatly improved this manuscript. Funding: The field work was financed by the Max Planck Society. The stable isotope work was funded by the Max Planck Society as part of S.P.’s doctoral project. S.P. was supported by the Max Planck Society and the University of Aberdeen. K.B. was supported by a Philip Leverhulme Prize from The Leverhulme Trust (PLP-2019-284). N.B.’s work was supported as part of a grant by the German Research Foundation (“PALÄODIET” Project 378496604). V.A. was supported by a grant from the Foundation for Science and Technology, Portugal (IF/01157/2015/CP1308/CT0002). Author contributions: The study was devised by S.P., K.B., S.P.M., J.-J.H., and T.T. Archaeological excavation was undertaken by N.S. and T.T. in collaboration with Z.R. and S.P.M. who all contributed contextual information. V.A. collected sedimentological data at the site and untertook micromorphological investigations that provided information on site formation for this study. Zooarchaeological and paleontological analyses were performed by G.M.S. and R.S. OSL dating was carried out by T.L. Radiocarbon dating and recalibration of radiocarbon dates were conducted by H.F. MC-ICPMS analysis was conducted by N.B. and S.P. Sampling, sample processing for oxygen and strontium stable isotope analysis, and TC/EA-IRMS analysis were carried out by S.P. Code and data analyses were written and conducted by S.P. N.-H.T. consulted on statistical analysis and coding. S.P. wrote the paper with input from all authors. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.Peer reviewedPublisher PD

Stability of schizophrenia diagnosis in a ten-year longitudinal study on first episode of non-affective psychosis: conclusions from the PAFIP cohort

OBJECTIVE: To evaluate the ten-year stability of schizophrenia diagnosis in a cohort of first-episode psychosis (FEP) patients and the factors associated with it. METHODS: Changes in diagnosis of 209 FEP patients were described during ten years of follow-up. Related factors with maintenance or change of schizophrenia diagnosis were evaluated in prospective and retrospective approaches through Binary Logistic Regressions, ROC and survival curves. RESULTS: Out of the 209 patients, 126 were diagnosed of schizophrenia six months after their inclusion in the clinical program. Prospective analyses showed that eight of those 126 schizophrenia patients had changed to a different diagnosis after ten years, and predictors of change were better childhood premorbid adjustment, less severity of clinical global impression at baseline, and diagnosis of comorbid personality disorder during follow-up. Retrospectively, out of the 154 patients with schizophrenia in the ten-year assessment, 36 had a different diagnosis at baseline, and those factors related with a different prior diagnosis than schizophrenia were better socioeconomic status and shorter duration of untreated psychosis (DUP). A survival analysis on the timing of schizophrenia diagnosis showed that male gender and longer DUP were predictors of earlier definite diagnosis. CONCLUSIONS: Diagnostic stability of schizophrenia in our FEP sample is high, especially prospective stability, and the group of patients with diagnostic change corresponded to a milder psychopathological profile before and at the onset of disease. Moreover, we observed a cautious attitude in the diagnosis of schizophrenia in patients with shorter DUP who had schizophrenia diagnosis after ten years

A multi-proxy approach to exploring Homo sapiens’ arrival, environments and adaptations in Southeast Asia

The capability of Pleistocene hominins to successfully adapt to different types of tropical forested environments has long been debated. In order to investigate environmental changes in Southeast Asia during a critical period for the turnover of hominin species, we analysed palaeoenvironmental proxies from five late Middle to Late Pleistocene faunas. Human teeth discoveries have been reported at Duoi U’Oi, Vietnam (70–60 ka) and Nam Lot, Laos (86–72 ka). However, the use of palaeoproteomics allowed us to discard the latter, and, to date, no human remains older than ~ 70 ka are documented in the area. Our findings indicate that tropical rainforests were highly sensitive to climatic changes over that period, with significant fluctuations of the canopy forests. Locally, large-bodied faunas were resilient to these fluctuations until the cooling period of the Marine Isotope Stage 4 (MIS 4; 74–59 ka) that transformed the overall biotope. Then, under strong selective pressures, populations with new phenotypic characteristics emerged while some other species disappeared. We argue that this climate-driven shift offered new foraging opportunities for hominins in a novel rainforest environment and was most likely a key factor in the settlement and dispersal of our species during MIS 4 in SE Asia

Cognitive performance at first episode of psychosis and the relationship with future treatment resistance: Evidence from an international prospective cohort study

Background: Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia, with recent research finding systematic biological differences between antipsychotic resistant and responsive patients. Our aim was to determine whether cognitive impairment at first episode significantly differs between future antipsychotic responders and resistant cases. Methods: Analysis of data from seven international cohorts of first-episode psychosis (FEP) with cognitive data at baseline (N = 683) and follow-up data on antipsychotic treatment response: 605 treatment responsive and 78 treatment resistant cases. Cognitive measures were grouped into seven cognitive domains based on the preexisting literature. We ran multiple imputation for missing data and used logistic regression to test for associations between cognitive performance at FEP and treatment resistant status at follow-up. Results: On average patients who were future classified as treatment resistant reported poorer performance across most cognitive domains at baseline. Univariate logistic regressions showed that antipsychotic treatment resistance cases had significantly poorer IQ/general cognitive functioning at FEP (OR = 0.70, p = .003). These findings remained significant after adjusting for additional variables in multivariable analyses (OR = 0.76, p = .049). Conclusions: Although replication in larger studies is required, it appears that deficits in IQ/general cognitive functioning at first episode are associated with future treatment resistance. Cognitive variables may be able to provide further insight into neurodevelopmental factors associated with treatment resistance or act as early predictors of treatment resistance, which could allow prompt identification of refractory illness and timely interventions.Funding: This work was supported by a Stratified Medicine Programme grant to J.H.M from the Medical Research Council (grant number MR/L011794/1 which funded the research and supported S.E.S., A.F.P., R.M.M., J.T.R.W. & J.H.M.) E.M’s PhD is funded by the MRC-doctoral training partnership studentship in Biomedical Sciences at King’s College London. J.H.M, E.K, R.M.M are part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. A.P.K. is funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. O.A. is further funded by an NIHR Post-Doctoral Fellowship (PDF2018-11-ST2-020). The views expressed are those of the authors and not necessarily those of the NHS, the MRC, the NIHR or the Department of Health. E.M.J. is supported by the UCL/UCLH Biomedical Research Centre. The AESOP (London, UK) cohort was funded by the UK Medical Research Council (Ref: G0500817). The Bologna (Italy) cohort was funded by the European Community’s Seventh Framework Program under grant agreement (agreement No. HEALTH-F2-2010–241909, Project EU-GEI). The GAP (London, UK) cohort was funded by the UK National Institute of Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health, South London and Maudsley NHS Mental Health Foundation Trust (SLaM) and the Institute of Psychiatry, Psychology, and Neuroscience at King’s College London; Psychiatry Research Trust; Maudsley Charity Research Fund; and the European Community’s Seventh Framework Program grant (agreement No. HEALTH-F2-2009-241909, Project EU-GEI). The Oslo (Norway) cohort was funded by the Stiftelsen KG Jebsen, Research Council of Norway (#223273, under the Centers of Excellence funding scheme, and #300309, #283798) and the South-Eastern Norway Regional Health Authority (#2006233, #2006258, #2011085, #2014102, #2015088, #2017-112). The Paris (France) cohort was funded by European Community’s Seventh Framework Program grant (agreement No. HEALTHF2-2010–241909, Project EU-GEI). The Santander (Spain) cohort was funded by the following grants (to B.C.F): Instituto de Salud Carlos III, FIS 00/3095, PI020499, PI050427, PI060507, Plan Nacional de Drogas Research Grant 2005-Orden sco/3246/2004, and SENY Fundatio Research Grant CI 2005-0308007, Fundacion Marques de Valdecilla A/02/07 and API07/011. SAF2016-76046-R and SAF2013-46292-R (MINECO and FEDER). The West London (UK) cohort was funded The Wellcome Trust (Grant Numbers: 042025; 052247; 064607)

Bullet-Shaped Magnetite Biomineralization Within a Magnetotactic Deltaproteobacterium: Implications for Magnetofossil Identification

Magnetite produced by magnetotactic bacteria (MTB) provides stable paleomagnetic signals because it occurs as natural single‐domain magnetic nanocrystals. MTB can also provide useful paleoenvironmental information because their crystal morphologies are associated with particular bacterial groups and the environments in which they live. However, identification of the fossil remains of MTB (i.e., magnetofossils) from ancient sediments or rocks is challenging because of their generally small sizes and because the growth, morphology, and chain assembly of magnetite within MTB are not well understood. Nanoscale characterization is, therefore, needed to understand magnetite biomineralization and to develop magnetofossils as biogeochemical proxies for paleoenvironmental reconstructions. Using advanced transmission electron microscopy, we investigated magnetite growth and chain arrangements within magnetotactic Deltaproteobacteria strain WYHR‐1, which reveals how the magnetite grows to form elongated, bullet‐shaped nanocrystals. Three crystal growth stages are recognized: (i) initial isotropic growth to produce nearly round ~20 nm particles, (ii) subsequent anisotropic growth along the [001] crystallographic direction to ~75 nm lengths and ~30-40 nm widths, and (iii) unidirectional growth along the [001] direction to ~180 nm lengths, with some growing to ~280 nm. Crystal growth and habit differ from that of magnetite produced by other known MTB strains, which indicates species‐specific biomineralization. These findings suggest that magnetite biomineralization might be much more diverse among MTB than previously thought. When characterized adequately at species level, magnetofossil crystallography, and apomorphic features are, therefore, likely to become useful proxies for ancient MTB taxonomic groups or species and for interpreting the environments in which they lived.This study was supported financially by the National Natural Science Foundation of China (grants no. 41920104009, 41890843, and 41621004), The Senior User Project of RVKEXUE2019GZ06 (Center for Ocean Me Mega‐Science, Chinese Academy of Sciences), and the Australian Research Council (grant DP160100805

Suppression of artifacts and barcode bias in high-throughput transcriptome analyses utilizing template switching

Template switching (TS) has been an inherent mechanism of reverse transcriptase, which has been exploited in several transcriptome analysis methods, such as CAGE, RNA-Seq and short RNA sequencing. TS is an attractive option, given the simplicity of the protocol, which does not require an adaptor mediated step and thus minimizes sample loss. As such, it has been used in several studies that deal with limited amounts of RNA, such as in single cell studies. Additionally, TS has also been used to introduce DNA barcodes or indexes into different samples, cells or molecules. This labeling allows one to pool several samples into one sequencing flow cell, increasing the data throughput of sequencing and takes advantage of the increasing throughput of current sequences. Here, we report TS artifacts that form owing to a process called strand invasion. Due to the way in which barcodes/indexes are introduced by TS, strand invasion becomes more problematic by introducing unsystematic biases. We describe a strategy that eliminates these artifacts in silico and propose an experimental solution that suppresses biases from TS

The Pharmacogenetics of Symptom Response to Antipsychotic Drugs

Antipsychotic drugs are limited in their efficacy by the relatively poor response of negative and cognitive symptoms of schizophrenia as well as by the substantial variability in response between patients. Pharmacogenetic studies have sought to identify the genetic factors that underlie the individual variability in response to treatment, with a past emphasis on dopamine and serotonin receptors as candidate genes. Few studies have separated effects on positive and negative symptoms, despite the established differences in response to drug treatment between these syndromes. Where this has been done most findings are consistent with the conclusion that dopamine receptor polymorphisms relate to positive symptom response, while negative symptom improvement is influenced by polymorphisms of genes involved in 5-HT neurotransmission. A wide range of polymorphisms in other candidate genes have been investigated, with some positive findings in those genes associated with glutamatergic transmission and/or risk factors for schizophrenia. However, there remains a lack of good replicated findings; furthermore there is little evidence to support drug-specific genetic associations with treatment response. While most past studies focused on single candidate genes, technology now permits genome-wide association studies with response to antipsychotics. Although not without major limitations, these "hypothesis-free" approaches are beginning to identify further important risk factors for treatment response. Again there is little consistency between various studies, although some of the polymorphisms identified are in genes involved in neurodevelopment, which is increasingly being recognized as important in the pathophysiology of schizophrenia

Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics

© The Author(s) 2019.A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.This work was supported by: SAF2016-76046-R and SAF2013-46292-R (MINECO and FEDER) to B.C.F., PI16/00156 (isciii and FEDER) to J.P.V., LUCHAMOS POR LA VIDA project to F.R.J. and J.P.V., SAF2017-83702-R (MINECO and FEDER), Red TERCEL RD12/0019/0024 (ISCIII) and GVA-PROMETEO 2018/041 (Generalitat Valenciana) to S.M. J.P.V. is supported by the RyC research programme (RYC-2013-14097) and F.R.J. by the predoctoral research programme (BES-2014-070615), from MINECO and FEDER

Analysis of gene expression data from non-small celllung carcinoma cell lines reveals distinct sub-classesfrom those identified at the phenotype level

Microarray data from cell lines of Non-Small Cell Lung Carcinoma (NSCLC) can be used to look for differences in gene expression between the cell lines derived from different tumour samples, and to investigate if these differences can be used to cluster the cell lines into distinct groups. Dividing the cell lines into classes can help to improve diagnosis and the development of screens for new drug candidates. The micro-array data is first subjected to quality control analysis and then subsequently normalised using three alternate methods to reduce the chances of differences being artefacts resulting from the normalisation process. The final clustering into sub-classes was carried out in a conservative manner such that subclasses were consistent across all three normalisation methods. If there is structure in the cell line population it was expected that this would agree with histological classifications, but this was not found to be the case. To check the biological consistency of the sub-classes the set of most strongly differentially expressed genes was be identified for each pair of clusters to check if the genes that most strongly define sub-classes have biological functions consistent with NSCLC