Homology and Specificity of Natural Sound-Encoding in Human and Monkey Auditory Cortex

Understanding homologies and differences in auditory cortical processing in human and nonhuman primates is an essential step in elucidating the neurobiology of speech and language. Using fMRI responses to natural sounds, we investigated the representation of multiple acoustic features in auditory cortex of awake macaques and humans. Comparative analyses revealed homologous large-scale topographies not only for frequency but also for temporal and spectral modulations. In both species, posterior regions preferably encoded relatively fast temporal and coarse spectral information, whereas anterior regions encoded slow temporal and fine spectral modulations. Conversely, we observed a striking interspecies difference in cortical sensitivity to temporal modulations: While decoding from macaque auditory cortex was most accurate at fast rates (> 30 Hz), humans had highest sensitivity to ~3 Hz, a relevant rate for speech analysis. These findings suggest that characteristic tuning of human auditory cortex to slow temporal modulations is unique and may have emerged as a critical step in the evolution of speech and language

Staphylococcus Aureus Infective Endocarditis: JACC Patient Pathways.

A 19-year-old female patient presented with Staphylococcus aureus infective endocarditis, with suspected subdural brain hemorrhage, disseminated intravascular coagulopathy, and septic renal as well as spleen infarcts. The patient had extensive vegetations on the mitral and tricuspid valves and underwent urgent mitral and tricuspid repair. This paper discusses the clinical case and current evidence regarding the management and treatment of Staphylococcus aureus endocarditis.S

Mitochondrial d-loop variation, coat colour and sex identification of Late Iron Age horses in Switzerland

In the Celtic world, horses enjoyed a prominent position as status symbols and objects of veneration, yet little is known about these Celtic horses except that they were rather small. The Late Iron Age was a time defined by increasing inter-cultural contact between Celtic peoples and the Romans. This is, amongst other features, observable in the phenotypes of domestic livestock such as horses. Amongst the usually small animals, larger ones are rarely but regularly encountered in the archaeological record. We have investigated mitochondrial (mt) DNA d-loop diversity, sex and coat colour using bones from 34 horses of different size from three Swiss sites (Mormont, Basel-Gasfabrik, Aventicum) most of them dating from 150 to 50 BCE. The aim was to characterise the diversity of matrilineages and coat colourations of Iron Age horses, and to identify molecular sex. We detected eleven mt haplotypes clustering into six haplogroups (B, D, F, I, X2, X3) in the ancient dataset (n = 19). Large individuals were all male, but smaller stallions were also identified; molecular sexing confirmed and augmented to morphological results. The horses were bay, chestnut and black in colour, and spottings or dilutions were absent in all animals. With a simplified primer system to detect premature greying, white coats can be excluded as well. The limited colour range proposes selection for monochrome animals. Additionally, ancient matrilineages were compared to modern horses from regions appertaining to the Late Roman Republic and to European pony breeds. Based on Principal Component Analysis (haplotype frequencies) and FST-values (genetic distances) the mtDNA variation of the Iron Age horses investigated here has survived in modern European breeds, particularly in northern European ponies

Hotspots of land use change in Europe

Die Zweitveröffentlichung der Publikation wurde durch Studierende des Projektseminars "Open Access Publizieren an der HU" im Sommersemester 2017 betreut. Nachgenutzt gemäß den CC-Bestimmungen des Lizenzgebers bzw. einer im Dokument selbst enthaltenen CC-Lizenz.Assessing changes in the extent and management intensity of land use is crucial to understanding land-system dynamics and their environmental and social outcomes. Yet, changes in the spatial patterns of land management intensity, and thus how they might relate to changes in the extent of land uses, remains unclear for many world regions.Wecompiled and analyzed high-resolution, spatiallyexplicit land-use change indicators capturing changes in both the extent and management intensity of cropland, grazing land, forests, and urban areas for all of Europe for the period 1990–2006. Based on these indicators, we identified hotspots of change and explored the spatial concordance of area versus intensity changes.Wefound a clear East–West divide with regard to agriculture, with stronger cropland declines and lower management intensity in the East compared to the West. Yet, these patterns were not uniform and diverging patterns of intensification in areas highly suitable for farming, and disintensification and cropland contraction in more marginal areas emerged. Despite the moderate overall rates of change, many regions in Europe fell into at least one land-use change hotspot during 1990–2006, often related to a spatial reorganization of land use (i.e., co-occurring area decline and intensification or co-occurring area increase and disintensification). Our analyses highlighted the diverse spatial patterns and heterogeneity of land-use changes in Europe, and the importance of jointly considering changes in the extent and management intensity of land use, as well as feedbacks among land-use sectors. Given this spatial differentiation of land-use change, and thus its environmental impacts, spatially-explicit assessments of land-use dynamics are important for context-specific, regionalized land-use policy making.Peer Reviewe

Phase II study (KAMELEON) of single-agent T-DM1 in patients with HER2-positive advanced urothelial bladder cancer or pancreatic cancer/cholangiocarcinoma

The antibody-drug conjugate trastuzumab emtansine (T-DM1) is approved for human epidermal growth factor receptor 2 (HER2/ERBB2)-positive breast cancer. We aimed to study tumor HER2 expression and its effects on T-DM1 responses in patients with HER2-positive urothelial bladder cancer (UBC) or pancreatic cancer (PC)/cholangiocarcinoma (CC). In the phase II KAMELEON study (NCT02999672), HER2 status was centrally assessed by immunohistochemistry, with positivity defined as non-focal homogeneous or heterogeneous overexpression of HER2 in ≥30% of stained cells. We also performed exploratory biomarker analyses (e.g., gene-protein assay) on tissue samples collected from study participants and consenting patients who failed screening. Of the 284 patients successfully screened for HER2 status (UBC, n = 69; PC/CC, n = 215), 13 with UBC, four with PC, and three with CC fulfilled eligibility criteria. Due to recruitment difficulty, the sponsor terminated KAMELEON prematurely. Of the five responders in the UBC cohort (overall response rate, 38.5%), HER2 expression was heterogeneous in two and homogeneous in three. The one responder in the PC/CC cohort had PC, and the tumor displayed homogeneous expression. In the biomarker-evaluable population, composed of screen-failed and enrolled patients, 24.3% (9/37), 1.5% (1/66), and 8.2% (4/49) of those with UBC, PC, or CC, respectively, had HER2-positive tumors. In a gene-protein assay combining in situ hybridization with immunohistochemistry, greater HER2 homogeneity was associated with increased ERBB2 amplification ratio. In conclusion, KAMELEON showed that some patients with HER2-positive UBC or PC can respond to T-DM1 and provided insight into the prevalence of HER2 positivity and expression patterns in three non-breast tumor types.</p

Metabolite Profiling Uncovers Plasmid-Induced Cobalt Limitation under Methylotrophic Growth Conditions

BACKGROUND:The introduction and maintenance of plasmids in cells is often associated with a reduction of growth rate. The reason for this growth reduction is unclear in many cases. METHODOLOGY/PRINCIPAL FINDINGS:We observed a surprisingly large reduction in growth rate of about 50% of Methylobacterium extorquens AM1 during methylotrophic growth in the presence of a plasmid, pCM80 expressing the tetA gene, relative to the wild-type. A less pronounced growth delay during growth under non-methylotrophic growth conditions was observed; this suggested an inhibition of one-carbon metabolism rather than a general growth inhibition or metabolic burden. Metabolome analyses revealed an increase in pool sizes of ethylmalonyl-CoA and methylmalonyl-CoA of more than 6- and 35-fold, respectively, relative to wild type, suggesting a strongly reduced conversion of these central intermediates, which are essential for glyoxylate regeneration in this model methylotroph. Similar results were found for M. extorquens AM1 pCM160 which confers kanamycin resistance. These intermediates of the ethylmalonyl-CoA pathway have in common their conversion by coenzyme B(12)-dependent mutases, which have cobalt as a central ligand. The one-carbon metabolism-related growth delay was restored by providing higher cobalt concentrations, by heterologous expression of isocitrate lyase as an alternative path for glyoxylate regeneration, or by identification and overproduction of proteins involved in cobalt import. CONCLUSIONS/SIGNIFICANCE:This study demonstrates that the introduction of the plasmids leads to an apparent inhibition of the cobalt-dependent enzymes of the ethylmalonyl-CoA pathway. Possible explanations are presented and point to a limited cobalt concentration in the cell as a consequence of the antibiotic stress

CRF1-R Activation of the Dynorphin/Kappa Opioid System in the Mouse Basolateral Amygdala Mediates Anxiety-Like Behavior

Stress is a complex human experience and having both rewarding and aversive motivational properties. The adverse effects of stress are well documented, yet many of underlying mechanisms remain unclear and controversial. Here we report that the anxiogenic properties of stress are encoded by the endogenous opioid peptide dynorphin acting in the basolateral amygdala. Using pharmacological and genetic approaches, we found that the anxiogenic-like effects of Corticotropin Releasing Factor (CRF) were triggered by CRF1-R activation of the dynorphin/kappa opioid receptor (KOR) system. Central CRF administration significantly reduced the percent open-arm time in the elevated plus maze (EPM). The reduction in open-arm time was blocked by pretreatment with the KOR antagonist norbinaltorphimine (norBNI), and was not evident in mice lacking the endogenous KOR ligand dynorphin. The CRF1-R agonist stressin 1 also significantly reduced open-arm time in the EPM, and this decrease was blocked by norBNI. In contrast, the selective CRF2-R agonist urocortin III did not affect open arm time, and mice lacking CRF2-R still showed an increase in anxiety-like behavior in response to CRF injection. However, CRF2-R knockout animals did not develop CRF conditioned place aversion, suggesting that CRF1-R activation may mediate anxiety and CRF2-R may encode aversion. Using a phosphoselective antibody (KORp) to identify sites of dynorphin action, we found that CRF increased KORp-immunoreactivity in the basolateral amygdala (BLA) of wildtype, but not in mice pretreated with the selective CRF1-R antagonist, antalarmin. Consistent with the concept that acute stress or CRF injection-induced anxiety was mediated by dynorphin release in the BLA, local injection of norBNI blocked the stress or CRF-induced increase in anxiety-like behavior; whereas norBNI injection in a nearby thalamic nucleus did not. The intersection of stress-induced CRF and the dynorphin/KOR system in the BLA was surprising, and these results suggest that CRF and dynorphin/KOR systems may coordinate stress-induced anxiety behaviors and aversive behaviors via different mechanisms

Executive functions and borderline personality features in adolescents with major depressive disorder

BackgroundExecutive functions (EF) consolidate during adolescence and are impaired in various emerging psychiatric disorders, such as pediatric Major Depressive Disorder (pMDD) and Borderline Personality Disorder. Previous studies point to a marked heterogeneity of deficits in EF in pMDD. We examined the hypothesis that deficits in EF in adolescents with pMDD might be related to comorbid Borderline Personality features (BPF).MethodsWe examined a sample of 144 adolescents (15.86 ± 1.32) diagnosed with pMDD. Parents rated their child’s EF in everyday life with the Behavior Rating Inventory of Executive Function (BRIEF) and BPF with the Impulsivity and Emotion Dysregulation Scale (IED-27). The adolescents completed equivalent self-rating measures. Self- and parent-ratings of the BRIEF scores were compared with paired t-Tests. Correlation and parallel mediation analyses, ICC, and multiple regression analyses were used to assess symptom overlap, parent-child agreement, and the influence of depression severity.ResultsOver the whole sample, none of the self- or parent-rated BRIEF scales reached a mean score above T &gt; 65, which would indicate clinically impaired functioning. Adolescents tended to report higher impairment in EF than their parents. Depression severity was the strongest predictor for BPF scores, with Emotional Control predicting parent-rated BPF and Inhibit predicting self-rated BPF. Furthermore, the Behavioral Regulation Index, which includes EF closely related to behavioral control, significantly mediated the relationship between depression severity and IED-27 factors emotional dysregulation and relationship difficulties but not non-suicidal self-injuries.ConclusionOn average, adolescents with depression show only subtle deficits in executive functioning. However, increased EF deficits are associated with the occurrence of comorbid borderline personality features, contributing to a more severe overall psychopathology. Therefore, training of executive functioning might have a positive effect on psychosocial functioning in severely depressed adolescents, as it might also improve comorbid BPF.Clinical trial registrationwww.ClinicalTrials.gov, identifier NCT03167307

Fast Growth Increases the Selective Advantage of a Mutation Arising Recurrently during Evolution under Metal Limitation

Understanding the evolution of biological systems requires untangling the molecular mechanisms that connect genetic and environmental variations to their physiological consequences. Metal limitation across many environments, ranging from pathogens in the human body to phytoplankton in the oceans, imposes strong selection for improved metal acquisition systems. In this study, we uncovered the genetic and physiological basis of adaptation to metal limitation using experimental populations of Methylobacterium extorquens AM1 evolved in metal-deficient growth media. We identified a transposition mutation arising recurrently in 30 of 32 independent populations that utilized methanol as a carbon source, but not in any of the 8 that utilized only succinate. These parallel insertion events increased expression of a novel transporter system that enhanced cobalt uptake. Such ability ensured the production of vitamin B12, a cobalt-containing cofactor, to sustain two vitamin B12–dependent enzymatic reactions essential to methanol, but not succinate, metabolism. Interestingly, this mutation provided higher selective advantages under genetic backgrounds or incubation temperatures that permit faster growth, indicating growth-rate–dependent epistatic and genotype-by-environment interactions. Our results link beneficial mutations emerging in a metal-limiting environment to their physiological basis in carbon metabolism, suggest that certain molecular features may promote the emergence of parallel mutations, and indicate that the selective advantages of some mutations depend generically upon changes in growth rate that can stem from either genetic or environmental influences

The Airway Microbiota in Cystic Fibrosis: A Complex Fungal and Bacterial Community—Implications for Therapeutic Management

International audienceBackground Given the polymicrobial nature of pulmonary infections in patients with cystic fibrosis (CF), it is essential to enhance our knowledge on the composition of the microbial community to improve patient management. In this study, we developed a pyrosequencing approach to extensively explore the diversity and dynamics of fungal and prokaryotic populations in CF lower airways. Methodology and Principal Findings Fungi and bacteria diversity in eight sputum samples collected from four adult CF patients was investigated using conventional microbiological culturing and high-throughput pyrosequencing approach targeting the ITS2 locus and the 16S rDNA gene. The unveiled microbial community structure was compared to the clinical profile of the CF patients. Pyrosequencing confirmed recently reported bacterial diversity and observed complex fungal communities, in which more than 60% of the species or genera were not detected by cultures. Strikingly, the diversity and species richness of fungal and bacterial communities was significantly lower in patients with decreased lung function and poor clinical status. Values of Chao1 richness estimator were statistically correlated with values of the Shwachman-Kulczycki score, body mass index, forced vital capacity, and forced expiratory volume in 1 s (p = 0.046, 0.047, 0.004, and 0.001, respectively for fungal Chao1 indices, and p = 0.010, 0.047, 0.002, and 0.0003, respectively for bacterial Chao1 values). Phylogenetic analysis showed high molecular diversities at the sub-species level for the main fungal and bacterial taxa identified in the present study. Anaerobes were isolated with Pseudomonas aeruginosa, which was more likely to be observed in association with Candida albicans than with Aspergillus fumigatus