ACOD1 deficiency offers protection in a mouse model of diet-induced obesity by maintaining a healthy gut microbiota.

Aconitate decarboxylase 1 (ACOD1) is the enzyme synthesizing itaconate, an immuno-regulatory metabolite tuning host-pathogen interactions. Such functions are achieved by affecting metabolic pathways regulating inflammation and microbe survival. However, at the whole-body level, metabolic roles of itaconate remain largely unresolved. By using multiomics-integrated approaches, here we show that ACOD1 responds to high-fat diet consumption in mice by promoting gut microbiota alterations supporting metabolic disease. Genetic disruption of itaconate biosynthesis protects mice against obesity, alterations in glucose homeostasis and liver metabolic dysfunctions by decreasing meta-inflammatory responses to dietary lipid overload. Mechanistically, fecal metagenomics and microbiota transplantation experiments demonstrate such effects are dependent on an amelioration of the intestinal ecosystem composition, skewed by high-fat diet feeding towards obesogenic phenotype. In particular, unbiased fecal microbiota profiling and axenic culture experiments point towards a primary role for itaconate in inhibiting growth of Bacteroidaceae and Bacteroides, family and genus of Bacteroidetes phylum, the major gut microbial taxon associated with metabolic health. Specularly to the effects imposed by Acod1 deficiency on fecal microbiota, oral itaconate consumption enhances diet-induced gut dysbiosis and associated obesogenic responses in mice. Unveiling an unrecognized role of itaconate, either endogenously produced or exogenously administered, in supporting microbiota alterations underlying diet-induced obesity in mice, our study points ACOD1 as a target against inflammatory consequences of overnutrition.

Interferons reshape the 3D conformation and accessibility of macrophage chromatin.

Engagement of macrophages in innate immune responses is directed by type I and type II interferons (IFN-I and IFN-γ, respectively). IFN triggers drastic changes in cellular transcriptomes, executed by JAK-STAT signal transduction and the transcriptional control of interferon-stimulated genes (ISG) by STAT transcription factors. Here, we study the immediate-early nuclear response to IFN-I and IFN-γ in murine macrophages. We show that the mechanism of gene control by both cytokines includes a rapid increase of DNA accessibility and rearrangement of the 3D chromatin contacts particularly between open chromatin of ISG loci. IFN-stimulated gene factor 3 (ISGF3), the major transcriptional regulator of ISG, controlled homeostatic and, most notably, induced-state DNA accessibility at a subset of ISG. Increases in DNA accessibility correlated with the appearance of activating histone marks at surrounding nucleosomes. Collectively our data emphasize changes in the three-dimensional nuclear space and epigenome as an important facet of transcriptional control by the IFN-induced JAK-STAT pathway.

A model-based estimation of critical torques reduces the experimental effort compared to conventional testing.

PURPOSE: Critical torque (CT) is an important fatigue threshold in exercise physiology and can be used to analyze, predict, or optimize performance. The objective of this work is to reduce the experimental effort when estimating CTs for sustained and intermittent isometric contractions using a model-based approach. MATERIALS AND METHODS: We employ a phenomenological model of the time course of maximum voluntary isometric contraction (MVIC) torque and compute the highest sustainable torque output by solving an optimization problem. We then show that our results are consistent with the steady states obtained when simulating periodic maximum loading schemes. These simulations correspond to all-out tests, which are used to estimate CTs in practice. Based on these observations, the estimation of CTs can be formulated mathematically as a parameter estimation problem. To minimize the statistical uncertainty of the parameter estimates and consequently of the estimated CTs, we compute optimized testing sessions. This reduces the experimental effort even further. RESULTS: We estimate CTs of the elbow flexors for sustained isometric contractions to be 28% of baseline MVIC torque and for intermittent isometric contractions consisting of a 3 s contraction followed by 2 s rest to be 41% of baseline MVIC torque. We show that a single optimized testing session is sufficient when using our approach. CONCLUSIONS: Our approach reduces the experimental effort considerably when estimating CTs for sustained and intermittent isometric contractions.

Genetic and epigenetic variation in 5S ribosomal RNA genes reveals genome dynamics in Arabidopsis thaliana.

Organized in tandem repeat arrays in most eukaryotes and transcribed by RNA polymerase III, expression of 5S rRNA genes is under epigenetic control. To unveil mechanisms of transcriptional regulation, we obtained here in depth sequence information on 5S rRNA genes from the Arabidopsis thaliana genome and identified differential enrichment in epigenetic marks between the three 5S rDNA loci situated on chromosomes 3, 4 and 5. We reveal the chromosome 5 locus as the major source of an atypical, long 5S rRNA transcript characteristic of an open chromatin structure. 5S rRNA genes from this locus translocated in the Landsberg erecta ecotype as shown by linkage mapping and chromosome-specific FISH analysis. These variations in 5S rDNA locus organization cause changes in the spatial arrangement of chromosomes in the nucleus. Furthermore, 5S rRNA gene arrangements are highly dynamic with alterations in chromosomal positions through translocations in certain mutants of the RNA-directed DNA methylation pathway and important copy number variations among ecotypes. Finally, variations in 5S rRNA gene sequence, chromatin organization and transcripts indicate differential usage of 5S rDNA loci in distinct ecotypes. We suggest that both the usage of existing and new 5S rDNA loci resulting from translocations may impact neighboring chromatin organization.

Lateral cephalometric analysis for treatment planning in orthodontics based on MRI compared with radiographs: A feasibility study in children and adolescents.

OBJECTIVE: The objective of this prospective study was to evaluate whether magnetic resonance imaging (MRI) is equivalent to lateral cephalometric radiographs (LCR, "gold standard") in cephalometric analysis. METHODS: The applied MRI technique was optimized for short scanning time, high resolution, high contrast and geometric accuracy. Prior to orthodontic treatment, 20 patients (mean age ± SD, 13.95 years ± 5.34) received MRI and LCR. MRI datasets were postprocessed into lateral cephalograms. Cephalometric analysis was performed twice by two independent observers for both modalities with an interval of 4 weeks. Eight bilateral and 10 midsagittal landmarks were identified, and 24 widely used measurements (14 angles, 10 distances) were calculated. Statistical analysis was performed by using intraclass correlation coefficient (ICC), Bland-Altman analysis and two one-sided tests (TOST) within the predefined equivalence margin of ± 2°/mm. RESULTS: Geometric accuracy of the MRI technique was confirmed by phantom measurements. Mean intraobserver ICC were 0.977/0.975 for MRI and 0.975/0.961 for LCR. Average interobserver ICC were 0.980 for MRI and 0.929 for LCR. Bland-Altman analysis showed high levels of agreement between the two modalities, bias range (mean ± SD) was -0.66 to 0.61 mm (0.06 ± 0.44) for distances and -1.33 to 1.14° (0.06 ± 0.71) for angles. Except for the interincisal angle (p = 0.17) all measurements were statistically equivalent (p < 0.05). CONCLUSIONS: This study demonstrates feasibility of orthodontic treatment planning without radiation exposure based on MRI. High-resolution isotropic MRI datasets can be transformed into lateral cephalograms allowing reliable measurements as applied in orthodontic routine with high concordance to the corresponding measurements on LCR.

Restrictive influence of SAMHD1 on Hepatitis B Virus life cycle.

Deoxynucleotide triphosphates (dNTPs) are essential for efficient hepatitis B virus (HBV) replication. Here, we investigated the influence of the restriction factor SAMHD1, a dNTP hydrolase (dNTPase) and RNase, on HBV replication. We demonstrated that silencing of SAMHD1 in hepatic cells increased HBV replication, while overexpression had the opposite effect. SAMHD1 significantly affected the levels of extracellular viral DNA as well as intracellular reverse transcription products, without affecting HBV RNAs or cccDNA. SAMHD1 mutations that interfere with the dNTPase activity (D137N) or in the catalytic center of the histidine-aspartate (HD) domain (D311A), and a phospho-mimetic mutation (T592E), abrogated the inhibitory activity. In contrast, a mutation diminishing the potential RNase but not dNTPase activity (Q548A) and a mutation disabling phosphorylation (T592A) did not affect antiviral activity. Moreover, HBV restriction by SAMHD1 was rescued by addition of deoxynucleosides. Although HBV infection did not directly affect protein level or phosphorylation of SAMHD1, the virus upregulated intracellular dATPs. Interestingly, SAMHD1 was dephosphorylated, thus in a potentially antiviral-active state, in primary human hepatocytes. Furthermore, SAMHD1 was upregulated by type I and II interferons in hepatic cells. These results suggest that SAMHD1 is a relevant restriction factor for HBV and restricts reverse transcription through its dNTPase activity.

Are you afraid of the dark? Notes on the psychology of belief in histories of science and the occult.

The popular view of the inherent conflict between science and the occult has been rendered obsolete by recent advances in the history of science. Yet, these historiographical revisions have gone unnoticed in the public understanding of science and public education at large. Particularly, reconstructions of the formation of modern psychology and its links to psychical research can show that the standard view of the latter as motivated by metaphysical bias fails to stand up to scrutiny. After highlighting certain basic methodological maxims shared by psychotherapists and historians, I will try to counterbalance simplistic claims of a 'need to believe' as a precondition of scientific open-mindedness regarding the occurrence of parapsychological phenomena by discussing instances revealing a presumably widespread 'will to disbelieve' in the occult. I shall argue that generalized psychological explanations are only helpful in our understanding of history if we apply them in a symmetrical manner.

La visión popular del conflicto inherente entre la ciencia y lo oculto, ha quedado obsoleta debido a los avances recientes en la historia de la ciencia. Sin embargo, estas revisiones historiográficas han pasado casi desapercibidas en la comprensión pública de la ciencia y la educación. Particularmente las reconstrucciones de la formación de la psicología moderna y sus conexiones con la investigación psíquica, nos muestran que la visión común de esta última, motivada por sesgos metafísicos no pasa la prueba de la realidad. En este artículo discuto ejemplos de una ''voluntad de incredulidad'' para contrabalancear las demandas simplistas de una ''necesidad de creer'' como precondición de una apertura científica de la mente en relación con la incidencia de fenómenos parapsicológicos, y sugiero que las explicaciones psicológicas generalizadas son útiles solamente en nuestra comprensión de la historia si las aplicamos de manera simétrica.

L'opinion populaire concernant le conflit intrinsèque entre la science et l'occulte a été rendue obsolète par les récentes avancées de l'histoire des sciences. Pourtant ces révisions historiographiques sont passées inaperçues de la compréhension publique de la science et de l'éducation publique dans son ensemble. Les reconstructions de l'évolution de la psychologie moderne et de ses liens avec la recherche psychique peuvent montrer en particulier que la vision standard de cette dernière en tant que motivée par un bais métaphysique échoue à résister à son examen. Pour contrebalancer l'argument simpliste d'un 'besoin de croire' comme précondition à l'ouverture d'esprit scientifique concernant l'occurrence des phénomènes parapsychologiques, des exemples sont ici discutés de 'volonté de ne pas croire' et il est suggéré que des explications psychologiques généralisées sont seulement utiles pour nous aider à comprendre l'histoire à condition de les appliquer de manière symétrique.

Comprehensive genome and epigenome characterization of CHO cells in response to evolutionary pressures and over time.

The most striking characteristic of CHO cells is their adaptability, which enables efficient production of proteins as well as growth under a variety of culture conditions, but also results in genomic and phenotypic instability. To investigate the relative contribution of genomic and epigenetic modifications towards phenotype evolution, comprehensive genome and epigenome data are presented for six related CHO cell lines, both in response to perturbations (different culture conditions and media as well as selection of a specific phenotype with increased transient productivity) and in steady state (prolonged time in culture under constant conditions). Clear transitions were observed in DNA-methylation patterns upon each perturbation, while few changes occurred over time under constant conditions. Only minor DNA-methylation changes were observed between exponential and stationary growth phase; however, throughout a batch culture the histone modification pattern underwent continuous adaptation. Variation in genome sequence between the six cell lines on the level of SNPs, InDels, and structural variants is high, both upon perturbation and under constant conditions over time. The here presented comprehensive resource may open the door to improved control and manipulation of gene expression during industrial bioprocesses based on epigenetic mechanisms. Biotechnol. Bioeng. 2016;113: 2241-2253. © 2016 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.

Efficiency of powered systems for interproximal enamel reduction (IER) and enamel roughness before and after polishing-an in vitro study.

OBJECTIVE: This aims to evaluate the efficiency of three different powered interproximal enamel reduction (IER) systems and to assess enamel roughness before and after polishing using different polishing times. MATERIAL AND METHODS: Four metal strips of the G5 ProLign Set (swissdentacare, SDC, Grancia, Switzerland), four segmental discs of the ASR-Set 4594 and two sonic tips of the SonicLine Set (both Gebr. Basseler GmbH & Co. KG, Komet, Lemgo, Germany) were evaluated. Human extracted incisors served as the medium. Enamel reduction was determined in five intervals of 15 s each. Polishing was performed for 15 and 30 s using the manufacturers' recommended polishing systems. Enamel roughness (Ra) was quantitatively assessed by confocal laser scanning microscopy (CLSM). RESULTS: Significant differences in terms of enamel reduction were found among the working ends of all tested systems. The time needed to remove 0.1, 0.2 and 0.3 mm of enamel was determined. Surface analysis showed significantly higher mean Ra values for nine out of ten working ends before polishing. This was still the case for five working ends after 15 s and for two after 30 s of polishing. CONCLUSION: The graining and the system used have a significant influence on enamel reduction. The time needed for polishing depends on the last working end used; a polishing time of 30 s is not always appropriate. CLINICAL RELEVANCE: Knowledge about the cutting efficiency of powered IER working ends might help the clinician to estimate better the amount of enamel reduction during the stripping process.

Léon Marillier and the veridical hallucination in late-nineteenth- and early-twentieth-century French psychology and psychopathology.

Recent research on the professionalization of psychology at the end of the nineteenth century shows how objects of knowledge which appear illegitimate to us today shaped the institutionalization of disciplines. The veridical or telepathic hallucination was one of these objects, constituting a field both of division and exchange between nascent psychology and disciplines known as 'psychic sciences' in France, and 'psychical research' in the Anglo-American context. In France, Leon Marillier (1862-1901) was the main protagonist in discussions concerning the concept of the veridical hallucination, which gave rise to criticisms by mental specialists and psychopathologists. After all, not only were these hallucinations supposed to occur in healthy subjects, but they also failed to correspond to the Esquirolian definition of hallucinations through being corroborated by their representation of external, objective events.

Psychical research in the history and philosophy of science. An introduction and review.

As a prelude to articles published in this special issue, I sketch changing historiographical conventions regarding the 'occult' in recent history of science and medicine scholarship. Next, a review of standard claims regarding psychical research and parapsychology in philosophical discussions of the demarcation problem reveals that these have tended to disregard basic primary sources and instead rely heavily on problematic popular accounts, simplistic notions of scientific practice, and outdated teleological historiographies of progress. I conclude by suggesting that rigorous and sensitively contextualized case studies of past elite heterodox scientists may be potentially useful to enrich historical and philosophical scholarship by highlighting epistemologies that have fallen through the crude meshes of triumphalist and postmodernist historiographical generalizations alike.

Normalizing the supernormal: the formation of the "Gesellschaft für Psychologische Forschung" ("Society for Psychological Research"), C. 1886-1890.

This paper traces the formation of the German "Gesellschaft für psychologische Forschung" ("Society for Psychological Research"), whose constitutive branches in Munich and Berlin were originally founded as inlets for alternatives to Wundtian experimental psychology from France and England, that is, experimental researches into hypnotism and alleged supernormal phenomena. By utilizing the career trajectories of Max Dessoir and Albert von Schrenck-Notzing as founding members of the "Gesellschaft," this paper aims to open up novel perspectives regarding extra-scientific factors involved in historically determining the epistemological and methodological boundaries of nascent psychology in Germany.

Policing epistemic deviance: Albert Von Schrenck-Notzing and Albert Moll(1).

Shortly after the death of Albert von Schrenck-Notzing (1862-1929), the doyen of early twentieth century German para psychology, his former colleague in hypnotism and sexology Albert Moll (1862-1939) published a treatise on the psychology and pathology of parapsychologists, with Schrenck-Notzing serving as a prototype of a scientist suffering from an 'occult complex'. Moll's analysis concluded that parapsychologists vouching for the reality of supernormal phenomena, such as telepathy, clairvoyance, telekinesis and materialisations, suffered from a morbid will to believe, which paralysed their critical faculties and made them cover obvious mediumistic fraud. Using Moll's treatment of Schrenck-Notzing as an historical case study of boundary disputes in science and medicine, this essay traces the career of Schrenck-Notzing as a researcher in hypnotism, sexology and parapsychology; discusses the relationship between Moll and Schrenck-Notzing; and problematises the pathologisation and defamation strategies of deviant epistemologies by authors such as Moll.

The B-cell identity factor Pax5 regulates distinct transcriptional programmes in early and late B lymphopoiesis.

Pax5 controls the identity and development of B cells by repressing lineage-inappropriate genes and activating B-cell-specific genes. Here, we used genome-wide approaches to identify Pax5 target genes in pro-B and mature B cells. In these cell types, Pax5 bound to 40% of the cis-regulatory elements defined by mapping DNase I hypersensitive (DHS) sites, transcription start sites and histone modifications. Although Pax5 bound to 8000 target genes, it regulated only 4% of them in pro-B and mature B cells by inducing enhancers at activated genes and eliminating DHS sites at repressed genes. Pax5-regulated genes in pro-B cells account for 23% of all expression changes occurring between common lymphoid progenitors and committed pro-B cells, which identifies Pax5 as an important regulator of this developmental transition. Regulated Pax5 target genes minimally overlap in pro-B and mature B cells, which reflects massive expression changes between these cell types. Hence, Pax5 controls B-cell identity and function by regulating distinct target genes in early and late B lymphopoiesis.

Psychical research and the origins of American psychology: Hugo Münsterberg, William James and Eusapia Palladino.

Largely unacknowledged by historians of the human sciences, late-19th-century psychical researchers were actively involved in the making of fledgling academic psychology. Moreover, with few exceptions historians have failed to discuss the wider implications of the fact that the founder of academic psychology in America, William James, considered himself a psychical researcher and sought to integrate the scientific study of mediumship, telepathy and other controversial topics into the nascent discipline. Analysing the celebrated exposure of the medium Eusapia Palladino by German-born Harvard psychologist Hugo Münsterberg as a representative example, this article discusses strategies employed by psychologists in the United States to expel psychical research from the agenda of scientific psychology. It is argued that the traditional historiography of psychical research, dominated by accounts deeply averse to its very subject matter, has been part of an ongoing form of 'boundary-work' to bolster the scientific status of psychology.

SAMHD1-deficient CD14+ cells from individuals with Aicardi-Goutières syndrome are highly susceptible to HIV-1 infection.

Myeloid blood cells are largely resistant to infection with human immunodeficiency virus type 1 (HIV-1). Recently, it was reported that Vpx from HIV-2/SIVsm facilitates infection of these cells by counteracting the host restriction factor SAMHD1. Here, we independently confirmed that Vpx interacts with SAMHD1 and targets it for ubiquitin-mediated degradation. We found that Vpx-mediated SAMHD1 degradation rendered primary monocytes highly susceptible to HIV-1 infection; Vpx with a T17A mutation, defective for SAMHD1 binding and degradation, did not show this activity. Several single nucleotide polymorphisms in the SAMHD1 gene have been associated with Aicardi-Goutières syndrome (AGS), a very rare and severe autoimmune disease. Primary peripheral blood mononuclear cells (PBMC) from AGS patients homozygous for a nonsense mutation in SAMHD1 (R164X) lacked endogenous SAMHD1 expression and support HIV-1 replication in the absence of exogenous activation. Our results indicate that within PBMC from AGS patients, CD14+ cells were the subpopulation susceptible to HIV-1 infection, whereas cells from healthy donors did not support infection. The monocytic lineage of the infected SAMHD1 -/- cells, in conjunction with mostly undetectable levels of cytokines, chemokines and type I interferon measured prior to infection, indicate that aberrant cellular activation is not the cause for the observed phenotype. Taken together, we propose that SAMHD1 protects primary CD14+ monocytes from HIV-1 infection confirming SAMHD1 as a potent lentiviral restriction factor.

An RNA-Seq strategy to detect the complete coding and non-coding transcriptome including full-length imprinted macro ncRNAs.

Imprinted macro non-protein-coding (nc) RNAs are cis-repressor transcripts that silence multiple genes in at least three imprinted gene clusters in the mouse genome. Similar macro or long ncRNAs are abundant in the mammalian genome. Here we present the full coding and non-coding transcriptome of two mouse tissues: differentiated ES cells and fetal head using an optimized RNA-Seq strategy. The data produced is highly reproducible in different sequencing locations and is able to detect the full length of imprinted macro ncRNAs such as Airn and Kcnq1ot1, whose length ranges between 80-118 kb. Transcripts show a more uniform read coverage when RNA is fragmented with RNA hydrolysis compared with cDNA fragmentation by shearing. Irrespective of the fragmentation method, all coding and non-coding transcripts longer than 8 kb show a gradual loss of sequencing tags towards the 3' end. Comparisons to published RNA-Seq datasets show that the strategy presented here is more efficient in detecting known functional imprinted macro ncRNAs and also indicate that standardization of RNA preparation protocols would increase the comparability of the transcriptome between different RNA-Seq datasets.

Systems-biology approaches to discover anti-viral effectors of the human innate immune response.

Virus infections elicit an immediate innate response involving antiviral factors. The activities of some of these factors are, in turn, blocked by viral countermeasures. The ensuing battle between the host and the viruses is crucial for determining whether the virus establishes a foothold and/or induces adaptive immune responses. A comprehensive systems-level understanding of the repertoire of anti-viral effectors in the context of these immediate virus-host responses would provide significant advantages in devising novel strategies to interfere with the initial establishment of infections. Recent efforts to identify cellular factors in a comprehensive and unbiased manner, using genome-wide siRNA screens and other systems biology "omics" methodologies, have revealed several potential anti-viral effectors for viruses like Human immunodeficiency virus type 1 (HIV-1), Hepatitis C virus (HCV), West Nile virus (WNV), and influenza virus. This review describes the discovery of novel viral restriction factors and discusses how the integration of different methods in systems biology can be used to more comprehensively identify the intimate interactions of viruses and the cellular innate resistance.