Whales originated from aquatic artiodactyls in the Eocene epoch of India

Although the first ten million years of whale evolution are documented by a remarkable series of fossil skeletons, the link to the ancestor of cetaceans has been missing. It was known that whales are related to even-toed ungulates (artiodactyls), but until now no artiodactyls were morphologically close to early whales. Here we show that the Eocene south Asian raoellid artiodactyls are the sister group to whales. The raoellid Indohyus is similar to whales, and unlike other artiodactyls, in the structure of its ears and premolars, in the density of its limb bones and in the stable-oxygen-isotope composition of its teeth. We also show that a major dietary change occurred during the transition from artiodactyls to whales and that raoellids were aquatic waders. This indicates that aquatic life in this lineage occurred before the origin of the order Cetacea

Gamma and beta frequency oscillations in response to novel auditory stimuli: A comparison of human electroencephalogram (EEG) data with in vitro models

Investigations using hippocampal slices maintained in vitro have demonstrated that bursts of oscillatory field potentials in the gamma frequency range (30-80 Hz) are followed by a slower oscillation in the beta 1 range (12-20 Hz). In this study, we demonstrate that a comparable gamma-to-beta transition is seen in the human electroencephalogram (EEG) in response to novel auditory stimuli. Correlations between gamma and beta 1 activity revealed a high degree of interdependence of synchronized oscillations in these bands in the human EEG. Evoked (stimulus-locked) gamma oscillations preceded beta 1 oscillations in response to novel stimuli, suggesting that this may be analogous to the gamma-to-beta shift observed in vitro. Beta 1 oscillations were the earliest discriminatory responses to show enhancement to novel stimuli, preceding changes in the broad-band event-related potential (mismatch negativity). Later peaks of induced beta activity over the parietal cortex were always accompanied by an underlying gamma frequency oscillation as seen in vitro. A further analogy between in vitro and human recordings was that both gamma and beta oscillations habituated markedly after the initial novel stimulus presentation

Preanalytical processing of archaeological mammal enamel apatite carbonates for stable isotope investigations: a comparative analysis of the effect of acid treatment on samples from Northwest Australia

Stable isotopic analysis of palaeontological and archaeological biogenic apatite carbonates from herbivorous mammalian species represents an important tool for worldwide palaeoecological research. Tooth enamel carbonates are more resistant to taphonomic processes than bone or dentine carbonates but are not invulnerable to diagenesis. As such, they require careful preanalytical processing that considers depositional environment and age. An established part of this process includes a weak acid treatment to remove soluble exogenous carbonates; however, published treatment times for isotopic studies of archaeological tooth enamel are variable and range from 15\ua0min to over 8\ua0hr. This study tests three different pretreatment protocols on modern and Pleistocene age archaeological kangaroo teeth (dating from contemporary to 46,000 bp) to assess the effect of acid treatment time on isotopic integrity. The results indicate that treatment time is a critical parameter for producing consistency across results and shorter pretreatments of 4\ua0hr or less are preferable for removing diagenetic carbonates while minimising alteration of the biological signal

Local gyrification index in probands with psychotic disorders and their first-degree relatives

BACKGROUND: Psychotic disorders are characterized by aberrant neural connectivity. Alterations in gyrification, the pattern and degree of cortical folding, may be related to the early development of connectivity. Past gyrification studies have relatively small sample sizes, yield mixed results for schizophrenia (SZ), and are scant for psychotic bipolar (BP) and schizoaffective (SZA) disorders and for relatives of these conditions. Here we examine gyrification in psychotic disorder patients and their first-degree relatives as a possible endophenotype. METHODS: Regional Local Gyrification Index (LGI) values, as measured by FreeSurfer software, were compared between 243 controls, 388 psychotic disorder probands, and 300 of their first-degree relatives. For patients, LGI values were examined grouped across psychotic diagnoses and then separately for SZ, SZA, and BP. Familiality (heritability) values and correlations with clinical measures were also calculated for regional LGI values. RESULTS: Probands exhibited significant hypogyria compared to controls in three brain regions and relatives with axis II cluster A disorders showed nearly significant hypogyria in these same regions. LGI values in these locations were significantly heritable and uncorrelated with any clinical measure. Observations of significant CONCLUSIONS: Psychotic disorders appear to be characterized by significant regionally localized hypogyria, particularly in cingulate cortex. This abnormality may be a structural endophenotype marking risk for psychotic illness and it may help elucidate etiological underpinnings of psychotic disorders

A Complete Pathway Model for Lipid A Biosynthesis in Escherichia coli.

Lipid A is a highly conserved component of lipopolysaccharide (LPS), itself a major component of the outer membrane of Gram-negative bacteria. Lipid A is essential to cells and elicits a strong immune response from humans and other animals. We developed a quantitative model of the nine enzyme-catalyzed steps of Escherichia coli lipid A biosynthesis, drawing parameters from the experimental literature. This model accounts for biosynthesis regulation, which occurs through regulated degradation of the LpxC and WaaA (also called KdtA) enzymes. The LpxC degradation signal appears to arise from the lipid A disaccharide concentration, which we deduced from prior results, model results, and new LpxK overexpression results. The model agrees reasonably well with many experimental findings, including the lipid A production rate, the behaviors of mutants with defective LpxA enzymes, correlations between LpxC half-lives and cell generation times, and the effects of LpxK overexpression on LpxC concentrations. Its predictions also differ from some experimental results, which suggest modifications to the current understanding of the lipid A pathway, such as the possibility that LpxD can replace LpxA and that there may be metabolic channeling between LpxH and LpxB. The model shows that WaaA regulation may serve to regulate the lipid A production rate when the 3-deoxy-D-manno-oct-2-ulosonic acid (KDO) concentration is low and/or to control the number of KDO residues that get attached to lipid A. Computation of flux control coefficients showed that LpxC is the rate-limiting enzyme if pathway regulation is ignored, but that LpxK is the rate-limiting enzyme if pathway regulation is present, as it is in real cells. Control also shifts to other enzymes if the pathway substrate concentrations are not in excess. Based on these results, we suggest that LpxK may be a much better drug target than LpxC, which has been pursued most often

Correlations Between Brain Structure and Symptom Dimensions of Psychosis in Schizophrenia, Schizoaffective, and Psychotic Bipolar I Disorders

Introduction: Structural alterations may correlate with symptom severity in psychotic disorders, but the existing literature on this issue is heterogeneous. In addition, it is not known how cortical thickness and cortical surface area correlate with symptom dimensions of psychosis. Methods: Subjects included 455 individuals with schizophrenia, schizoaffective, or bipolar I disorders. Data were obtained as part of the Bipolar Schizophrenia Network for Intermediate Phenotypes study. Diagnosis was made through the Structured Clinical Interview for DSM-IV. Positive and negative symptom subscales were assessed using the Positive and Negative Syndrome Scale. Structural brain measurements were extracted from T1-weight structural MRIs using FreeSurfer v5.1 and were correlated with symptom subscales using partial correlations. Exploratory factor analysis was also used to identify factors among those regions correlating with symptom subscales. Results: The positive symptom subscale correlated inversely with gray matter volume (GMV) and cortical thickness in frontal and temporal regions, whereas the negative symptom subscale correlated inversely with right frontal cortical surface area. Among regions correlating with the positive subscale, factor analysis identified four factors, including a temporal cortical thickness factor and frontal GMV factor. Among regions correlating with the negative subscale, factor analysis identified a frontal GMV-cortical surface area factor. There was no significant diagnosis by structure interactions with symptom severity. Conclusions: Structural measures correlate with positive and negative symptom severity in psychotic disorders. Cortical thickness demonstrated more associations with psychopathology than cortical surface area

Coronavirus Papain-like Proteases Negatively Regulate Antiviral Innate Immune Response through Disruption of STING-Mediated Signaling

Viruses have evolved elaborate mechanisms to evade or inactivate the complex system of sensors and signaling molecules that make up the host innate immune response. Here we show that human coronavirus (HCoV) NL63 and severe acute respiratory syndrome (SARS) CoV papain-like proteases (PLP) antagonize innate immune signaling mediated by STING (stimulator of interferon genes, also known as MITA/ERIS/MYPS). STING resides in the endoplasmic reticulum and upon activation, forms dimers which assemble with MAVS, TBK-1 and IKKε, leading to IRF-3 activation and subsequent induction of interferon (IFN). We found that expression of the membrane anchored PLP domain from human HCoV-NL63 (PLP2-TM) or SARS-CoV (PLpro-TM) inhibits STING-mediated activation of IRF-3 nuclear translocation and induction of IRF-3 dependent promoters. Both catalytically active and inactive forms of CoV PLPs co-immunoprecipitated with STING, and viral replicase proteins co-localize with STING in HCoV-NL63-infected cells. Ectopic expression of catalytically active PLP2-TM blocks STING dimer formation and negatively regulates assembly of STING-MAVS-TBK1/IKKε complexes required for activation of IRF-3. STING dimerization was also substantially reduced in cells infected with SARS-CoV. Furthermore, the level of ubiquitinated forms of STING, RIG-I, TBK1 and IRF-3 are reduced in cells expressing wild type or catalytic mutants of PLP2-TM, likely contributing to disruption of signaling required for IFN induction. These results describe a new mechanism used by CoVs in which CoV PLPs negatively regulate antiviral defenses by disrupting the STING-mediated IFN induction

Association Analysis of 94 Candidate Genes and Schizophrenia-Related Endophenotypes

While it is clear that schizophrenia is highly heritable, the genetic basis of this heritability is complex. Human genetic, brain imaging, and model organism studies have met with only modest gains. A complementary research tactic is to evaluate the genetic substrates of quantitative endophenotypes with demonstrated deficits in schizophrenia patients. We used an Illumina custom 1,536-SNP array to interrogate 94 functionally relevant candidate genes for schizophrenia and evaluate association with both the qualitative diagnosis of schizophrenia and quantitative endophenotypes for schizophrenia. Subjects included 219 schizophrenia patients and normal comparison subjects of European ancestry and 76 schizophrenia patients and normal comparison subjects of African ancestry, all ascertained by the UCSD Schizophrenia Research Program. Six neurophysiological and neurocognitive endophenotype test paradigms were assessed: prepulse inhibition (PPI), P50 suppression, the antisaccade oculomotor task, the Letter-Number Span Test, the California Verbal Learning Test-II, and the Wisconsin Card Sorting Test-64 Card Version. These endophenotype test paradigms yielded six primary endophenotypes with prior evidence of heritability and demonstrated schizophrenia-related impairments, as well as eight secondary measures investigated as candidate endophenotypes. Schizophrenia patients showed significant deficits on ten of the endophenotypic measures, replicating prior studies and facilitating genetic analyses of these phenotypes. A total of 38 genes were found to be associated with at least one endophenotypic measure or schizophrenia with an empirical p-value<0.01. Many of these genes have been shown to interact on a molecular level, and eleven genes displayed evidence for pleiotropy, revealing associations with three or more endophenotypic measures. Among these genes were ERBB4 and NRG1, providing further support for a role of these genes in schizophrenia susceptibility. The observation of extensive pleiotropy for some genes and singular associations for others in our data may suggest both converging and independent genetic (and neural) pathways mediating schizophrenia risk and pathogenesis