Spatiotemporal brain hierarchies of auditory memory recognition and predictive coding.

Our brain is constantly extracting, predicting, and recognising key spatiotemporal features of the physical world in order to survive. While neural processing of visuospatial patterns has been extensively studied, the hierarchical brain mechanisms underlying conscious recognition of auditory sequences and the associated prediction errors remain elusive. Using magnetoencephalography (MEG), we describe the brain functioning of 83 participants during recognition of previously memorised musical sequences and systematic variations. The results show feedforward connections originating from auditory cortices, and extending to the hippocampus, anterior cingulate gyrus, and medial cingulate gyrus. Simultaneously, we observe backward connections operating in the opposite direction. Throughout the sequences, the hippocampus and cingulate gyrus maintain the same hierarchical level, except for the final tone, where the cingulate gyrus assumes the top position within the hierarchy. The evoked responses of memorised sequences and variations engage the same hierarchical brain network but systematically differ in terms of temporal dynamics, strength, and polarity. Furthermore, induced-response analysis shows that alpha and beta power is stronger for the variations, while gamma power is enhanced for the memorised sequences. This study expands on the predictive coding theory by providing quantitative evidence of hierarchical brain mechanisms during conscious memory and predictive processing of auditory sequences.

Measurement of the

^{140}Ce(n,γ) is a key reaction for slow neutron-capture (s-process) nucleosynthesis due to being a bottleneck in the reaction flow. For this reason, it was measured with high accuracy (uncertainty ≈5%) at the n_TOF facility, with an unprecedented combination of a high purity sample and low neutron-sensitivity detectors. The measured Maxwellian averaged cross section is up to 40% higher than previously accepted values. Stellar model calculations indicate a reduction around 20% of the s-process contribution to the Galactic cerium abundance and smaller sizeable differences for most of the heavier elements. No variations are found in the nucleosynthesis from massive stars.

Molecular alterations and potential actionable mutations in peritoneal mesothelioma: a scoping review of high-throughput sequencing studies.

BACKGROUND: Peritoneal mesothelioma (PeM) is a rare malignancy with a poor prognosis. Currently there is a lack of effective systemic therapies. Due to the rarity of PeM, it is challenging to study new treatment options. Off-label use of targeted drugs could be an effective approach. This scoping review aims to explore the genomic landscape of PeM to identify potential therapeutic targets. MATERIALS AND METHODS: A systematic literature search of Embase, Medline, Web of Science, the Cochrane Library, and Google Scholar was carried out up to 1 November 2022. Studies that reported on molecular alterations in PeM detected by high-throughput sequencing techniques were included. Genes that were altered in ≥1% of PeMs were selected for the identification of potential targeted therapies. RESULTS: Thirteen articles were included, comprising 824 PeM patients. In total, 142 genes were altered in ≥1% of patients, of which 7 genes were altered in ≥10%. BAP1 was the most commonly altered gene (50%). Other commonly altered genes were NF2 (25%), CDKN2A (23%), CDKN2B (17%), PBRM1 (15%), TP53 (14%), and SETD2 (13%). In total, 17% of PeM patients were carriers of a germline mutation, mainly in BAP1 (7%). CONCLUSIONS: This scoping review provides an overview of the mutational landscape of PeM. Germline mutations might be a larger contributor to the incidence of PeM than previously thought. Currently available targeted therapy options are limited, but several targeted agents [such as poly (ADP-ribose) polymerase (PARP), enhancer of zeste homolog 2 (EZH2), and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors] were identified that might provide new targeted therapy options in the future.

Renal function in patients with significant tricuspid regurgitation: pathophysiological mechanisms and prognostic implications.

BACKGROUND: The pathophysiological mechanisms linking tricuspid regurgitation (TR) and chronic kidney disease (CKD) remain unknown. This study aimed to determine which pathophysiological mechanisms related to TR are independently associated with renal dysfunction and to evaluate the impact of renal impairment on long-term prognosis in patients with significant (≥ moderate) secondary TR. METHODS: A total of 1234 individuals (72 [IQR 63-78] years, 50% male) with significant secondary TR were followed up for the occurrence of all-cause mortality and the presence of significant renal impairment (eGFR of <60 mL min-1  1.73 m-2 ) at the time of baseline echocardiography. RESULTS: Multivariable analysis demonstrated that severe right ventricular (RV) dysfunction (TAPSE < 14 mm) was independently associated with the presence of significant renal impairment (OR 1.49, 95% CI 1.11 to 1.99, P = 0.008). Worse renal function was associated with a significant reduction in survival at 1 and 5 years (85% vs. 87% vs. 68% vs. 58% at 1 year, and 72% vs. 64% vs. 39% vs. 19% at 5 years, for stage 1, 2, 3 and 4-5 CKD groups, respectively, P < 0.001). The presence of severe RV dysfunction was associated with reduced overall survival in stage 1-3 CKD groups, but not in stage 4-5 CKD groups. CONCLUSIONS: Of the pathophysiological mechanisms identified by echocardiography that are associated with significant secondary TR, only severe RV dysfunction was independently associated with the presence of significant renal impairment. In addition, worse renal function according to CKD group was associated with a significant reduction in survival.

Intra-cellular Staphylococcus aureus alone causes infection in vivo.

Chronic and recurrent bone infections occur frequently but have not been explained. Staphylococcus aureus (S. aureus) is often found among chronic and recurrent infections and may be responsible for such infections. One possible reason is that S. aureus can internalize and survive within host cells and by doing so, S. aureus can evade both host defense mechanisms and most conventional antibiotic treatments. In this study, we hypothesized that intra-cellular S. aureus could induce infections in vivo. Osteoblasts were infected with S. aureus and, after eliminating extra-cellular S. aureus, inoculated into an open fracture rat model. Bacterial cultures and radiographic observations at post-operative day 21 confirmed local bone infections in animals inoculated with intra-cellular S. aureus within osteoblasts alone. We present direct in vivo evidence that intra-cellular S. aureus could be sufficient to induce bone infection in animals; we found that intra-cellular S. aureus inoculation of as low as 102 colony forming units could induce severe bone infections. Our data may suggest that intra-cellular S. aureus can "hide" in host cells during symptom-free periods and, under certain conditions, they may escape and lead to infection recurrence. Intra-cellular S. aureus therefore could play an important role in the pathogenesis of S. aureus infections, especially those chronic and recurrent infections in which disease episodes may be separated by weeks, months, or even years.

Chloroma of the forearm: a case report of leukemia recurrence presenting with compression neuropathy and tenosynovitis.

Acute Myelogenous Leukemia (AML) typically involves intramedullary proliferation of myeloid precursor cells. Extramedullary manifestations of AML are exceedingly rare, but do occur. Granu-locytic sarcoma, or chloroma, is one example of extramedullary leukemia cells forming a tumorous mass. We report a case of Chloroma in the volar forearm compartment presenting with both median nerve compressive neuropathy and apparent tenosynovitis. Abscess was at the top of the early differential, and the patient was scheduled for operative debridement. However, further evaluation indicated that chloroma was present, thus obviating the need for emergent surgical intervention and necessitating the induction of chemotherapy. To our knowledge this is the first report of chloroma in this location and with these presenting symptoms.

Band erosion with gastric cancer.

Adjustable gastric banding is a well-established procedure for the treatment of morbid obesity. We present a 62-year-old female who experienced the rare complication of intragastric band perforation due to a gastric adenocarcinoma localized at the site of gastric banding, 10 years after insertion of the band.

[Occupational aziridine asthma in an engineer at a printing office]. / Aziridin-Asthma bei einem Druckerei-Ingenieur als Berufskrankheit.

We report on a case of an allergic bronchial asthma of an engineer in a printing office caused by polyfunctional aziridines. The causal relationship between exposure and symptoms could be demonstrated with a specific bronchoprovocation challenge testing. The consequences of the disease are discussed with respect to medical and legal aspects of the system of social security in Germany.

Time course and reversibility of changes in the gizzards of red knots alternately eating hard and soft food.

The ability to change organ size reversibly can be advantageous to birds that perform long migrations. During winter, red knots (Calidris canutus) feed on shellfish and carry a muscular gizzard that weighs 10% of their body mass. Gizzard size decreases when these birds eat soft foods, e.g. while breeding in the tundra. We studied the reversibility and time course of such changes using ultrasonography. Two groups of shellfish-adapted knots (N=9 and N=10) were fed alternately a hard and a soft food type. Diet switches elicited rapid reversible changes. Switches from hard to soft food induced decreases to 60% of initial gizzard mass within 8.5 days, while switches to hard food induced increases in gizzard mass to 147% within 6.2 days. A third group of knots (N=11), adapted to soft food for more than 1 year, initially had very small gizzards (25% of the mass of shellfish-adapted gizzards), but showed a similar capacity to increase gizzard size when fed shellfish. This is the first non-invasive study showing rapid digestive organ adjustments in non-domesticated birds.

The negative regulator Opi1 of phospholipid biosynthesis in yeast contacts the pleiotropic repressor Sin3 and the transcriptional activator Ino2.

Structural genes of phospholipid biosynthesis in the yeast Saccharomyces cerevisiae are transcriptionally co-regulated by ICRE (inositol/choline-responsive element) promoter motifs. Gene activation by an ICRE is mediated by binding of the Ino2/Ino4 transcription factor, whereas repression in the presence of high concentrations of inositol and choline (IC) requires an intact Opi1 repressor. However, the mechanism of specific repression and the functional interplay among these regulators remained unclear from previous work. Using in vivo as well as in vitro interaction assays, we show binding of the pleiotropic repressor Sin3 to the pathway-specific regulator Opi1. The paired amphipathic helix 1 (PAH1) within Sin3 and OSID (Opi1-Sin3 interaction domain) in the N-terminus of Opi1 were mapped as contact sites. The regulatory significance of the Opi1-Sin3 interaction was shown by the obvious deregulation of an ICRE-dependent reporter gene in a sin3 mutant. Opi1 also interacts with a newly identified functional domain of the transcriptional activator Ino2 (RID, repressor interaction domain). These results define the molecular composition of the transcription complex mediating control of ICRE-dependent genes and allow a hypothesis on the flow of regulatory information in response to phospholipid precursors.

Levodopa pharmacokinetic-pharmacodynamic modeling and 6-[18F]levodopa positron emission tomography in patients with Parkinson's disease.

OBJECTIVE: Parameters of a pharmacokinetic-pharmacodynamic (PK-PD) model of levodopa have been claimed to reflect the magnitude of the dopaminergic deficit in patients with Parkinson's disease. The aim of this study was to correlate such parameters with positron emission tomography (PET) with levodopa tagged with 6-fluorine 18, an established imaging method for striatal dopaminergic neurons. METHODS: Twenty-three patients in different disease stages (Hoehm and Yahr stage 2.5-5 [Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;4:427-42]; median duration, 12 years) were studied. PK-PD modeling followed a single oral dose of levodopa/benserazide. The sum score of the Columbia Rating Scale (CURSSigma) was used for clinical assessments. A nonparametric effect compartment approach assuming a sigmoidal E(max) model was applied to the PK-PD analysis of plasma levodopa concentrations and corresponding CURSSigma. Thereafter 6-[18F]levodopa PET was performed, and the influx rate constants (k(c)) for the putamen and the caudatus region were correlated with the median effective concentration (EC(50)) and the equilibrium half-life (T(eq)) of the PK-PD model. RESULTS: (1) A significant correlation was observed between PK-PD parameters or with k(c) putamen as the dependent variable and the duration of the disease as the independent variable, which explains 33% of the variability of the EC(50), 42% of the variability of T(eq), and 36% of the variability of k(c). (2) Significant correlations were observed between k(c) and either EC(50) or T(eq), yielding the closest correlation for the putamen region (r = -0.47, P <.05; and r = 0.55, P <.01; respectively). CONCLUSIONS: Our findings show that key parameters of a PK-PD model of levodopa were in fairly close agreement with imaging of dopaminergic neurons by 6-[18F]levodopa PET. However, although PK-PD modeling of levodopa has been proven as a useful investigation of approaches aimed to restore dopaminergic deficits or to monitor disease progression, this modeling cannot serve as a pathomorphologic surrogate for the loss of striatal dopaminergic neurons.

2-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)- and 2-(2,2-dioxo-1,4-dihydro-2H-2lambda6-benzo[1,2,6]thiadiazin-3-yl)-N-hydroxy-acetamides as potent and selective peptide deformylase inhibitors.

Potent, selective, and structurally new inhibitors of the Fe(II) enzyme Escherichia coli peptide deformylase (PDF) were obtained by rational optimization of the weakly binding screening hit (5-chloro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid hydrazide (1). Three-dimensional structural information, gathered from Ni-PDF complexed with 1, suggested the preparation of two series of related hydroxamic acid analogues, 2-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-N-hydroxy-acetamides (A) and 2-(2,2-dioxo-1,4-dihydro-2H-2lambda(6)-benzo[1,2,6]thiadiazin-3-yl)-N-hydroxy-acetamides (B), among which potent PDF inhibitors (37, 42, and 48) were identified. Moreover, two selected compounds, one from each series, 36 and 41, showed good selectivity for PDF over several endoproteases including matrix metalloproteases. However, these compounds showed only weak antibacterial activity.

Is long-distance bird flight equivalent to a high-energy fast? Body composition changes in freely migrating and captive fasting great knots.

We studied changes in body composition in great knots, Calidris tenuirostris, before and after a migratory flight of 5,400 km from northwest Australia to eastern China. We also took premigratory birds into captivity and fasted them down to their equivalent arrival mass after migration to compare organ changes and nutrient use in a low-energy-turnover fast with a high-energy-turnover fast (migratory flight). Migrated birds were as economical as any fasting animal measured yet at conserving protein: their estimated relative protein contribution (RPC) to the energy used was 4.0%. Fasted birds had an estimated RPC of 6.8% and, consequently, a much lower lean mass and higher fat content for an equivalent body mass than migrated birds. Lean tissue was catabolized from most organs in both groups, except the brain. Furthermore, a principal components biplot showed that individuals were grouped primarily on the basis of overall organ fat or lean tissue content rather than by the size of specific organs. This indicates that organ changes during migratory flight are similar to those of a low-energy fast, although the length of the fast in this study probably accentuated organ reductions in some functional groups. Whether the metabolic characteristics of a flying migratory fast follow the three-phase model described in many inactive fasting animals is unclear. We have some evidence for skeletal fat being catabolized without phase 3 of a fast having been reached.

Intervention study on acquired color vision deficiencies in styrene-exposed workers.

The main aim of the study was to examine the possible effects of occupational exposure to styrene on color vision function and the course after reduction of exposure. Color vision function was examined in 22 styrene-exposed laminators and 11 control subjects at a boat manufacturing plant. The Lanthony D-15 desaturated panel was used to test acquired dyschromatopsia. In all, six examinations were performed: Monday morning and Thursday afternoon of the same week, before and immediately after a vacation of 4 weeks (altogether, phase 1), and approximately 10 months later (phase 2), after the exposure level of styrene had been reduced. Styrene uptake was objectified by biological monitoring measuring the metabolites mandelic acid and phenylglyoxcylic acid in urine samples taken on Thursday afternoon. In both Thursday examinations, styrene-exposed workers had higher color confusion index (CCI) values compared with controls, which indicated quantitative color vision loss. After an exposure-free period of 4 weeks, a significant decrease of CCI values to normal range was found in laminators. Reexamination 10 months later showed also lower CCI values in exposed workers, indicating a dose-effect relationship. Abnormal CCI values occurred primarily in subjects with an excretion of approximately 500 to 600 mg mandelic acid plus phenylglyoxcylic acid per gram creatinine or more. We concluded that styrene-induced color vision dysfunction is reversible after an exposure-free interval of 4 weeks. The current Biological Tolerance Value of 600 mg mandelic acid plus phenylglyoxcylic acid per gram creatinine, as used in Germany, protects styrene-exposed workers from this subclinical effect.

Bootstrap methods for sex determination from the os coxae using the ID3 algorithm.

This study presents a method for identifying small subsets of morphological attributes of the skeletal pelvis that have consistently high reliability in assigning the sex of unknown individuals. An inductive computer algorithm (ID3) was applied to a bootstrapped training set/test set design in which the model was developed from 70% of the sample and tested on the remaining 30%. Relative accuracy of sex classification was evaluated for seven subsets of 31 morphological features of the adult os coxae. Using 115 ossa coxarum selected from the Terry Collection, a selected suite of the three most consistently diagnostic attributes averaged 93.1% correct classification of individuals by sex over ten trials. Attribute suites developed collaboratively with three well known skeletal experts averaged 87.8, 91.3, and 89.6% correct. The full set of 31 attributes averaged 90.0% accuracy. We demonstrate a small set of three criteria, selected and ordered by ID3, that is more accurate than other combinations, and suggest that ID3 is a useful approach for developing identification systems.

Results of magnetic resonance imaging in long-term manganese dioxide-exposed workers.

Within a cross-sectional study, the neurotoxic effects of occupational exposure to manganese were examined. From a group of 90 (58 male and 32 female) workers, 11 men with long-term and high exposure to manganese dioxide (MnO2) dust were defined as exposed workers. Eleven age-matched workers of similar socioeconomic status were used as a reference group. Ambient air and biological monitoring (blood, urine, hair), clinical (Webster Rating Scale, WRS), neurophysiological (visual evoked potentials (VEP), nerve conduction velocity (NCV), electroencephalography (EEG)), and motor performance (Wiener Testsystem) examinations were performed. The pallidal index (PI), the ratio of globus pallidus to subcortical frontal white-matter signal intensity in T1-weighted magnetic resonance imaging (MRI) planes multiplied by 100, was used. For the individual body burden, manganese in blood was the most reliable biomarker. A "job-exposure matrix" for the cumulative Mn-exposure index (CEI) was calculated for each worker. The results of WRS, VEP, NCV, EEG, and motor performance tests showed no significant group differences. However, the pallidal index was increased in Mn-exposed persons. Furthermore, a statistically significant positive correlation was found between CEI and pallidal index. The results of other studies are discussed. The meaning of MRI findings for health status as well as gender-specific differences should be examined in further follow-up studies.

Evaluation of a modified German version of the Q16 questionnaire for neurotoxic symptoms in workers exposed to solvents.

OBJECTIVES: To assess sensitivity and specificity of a questionnaire designed to detect neurotoxic symptoms in workers exposed to solvents and in patients with a psycho-organic syndrome. METHODS: The Swedish Q16 is a self administered questionnaire for neurotoxic symptoms. The modified German version consists of 18 questions. The results were analysed from 1166 questionnaires which were completed by adults belonging to the following groups; 483 workers with occupational exposure to solvents and 193 non-exposed controls, 25 patients with a psycho-organic syndrome, 25 sex and age matched patients with a lung disease, and a sample of 440 people from the general population. RESULTS: The German Q18 was easy to handle and quick to perform. Workers exposed to solvents reported significantly more complaints than controls (2.9 v 2.5). All patients with a psycho-organic syndrome had five or more complaints. This was true for only 32% of patients with lung disease. These comparisons showed that chronic exposure to solvents was associated with subjective complaints related particularly to cognitive functions. In the sample of the general population, age, education level, smoking habits, and time of performance showed no significant influence on the Q18 result. Women had significantly more complaints than men (3.2 v 2.3). People who reported drinking alcohol occasionally or moderately had significantly fewer complaints than teetotalers. CONCLUSIONS: The German Q18 has an acceptable sensitivity and reliability, a reasonable specificity, and a good practicability. It is a useful instrument for screening workers exposed to solvents. A cut off point of 5 for men is recommended, and a cut off point of 6 for women is proposed.

Ion-exchange as a mode of cation transfer into room-temperature ionic liquids containing crown ethers: implications for the 'greenness' of ionic liquids as diluents in liquid-liquid extraction.

The transfer of strontium ion from acidic nitrate media into a series of 1-alkyl-3-methylimidazolium-based room-temperature ionic liquids containing dicyclohexano-18-crown-6 is shown to proceed via cation-exchange, in contrast to conventional solvents such as alkan-1-ols, in which extraction of a strontium nitrato-crown ether complex is observed.

An improved extraction chromatographic resin for the separation of uranium from acidic nitrate media.

The preparation and characterization of a new extraction chromatographic resin exhibiting extraordinarily strong retention of hexavalent uranyl ion over a wide range of nitric acid concentrations and very high selectivity for U(VI) over Fe(III) and numerous other cations is described. This new material (designated U/TEVA-2) comprises a novel liquid stationary phase consisting of an equimolar mixture of diamyl amylphosphonate (DA[AP]) and Cyanex 923((R)) (a commercially available trialkyl-phosphine oxide, TRPO) sorbed on silanized silica or Amberchrom CG-71. Cyanex 923 is shown to be preferable to a related TRPO, Cyanex 925((R)), due to its lower viscosity and higher selectivity for U(VI) over Fe(III). The retention of uranyl nitrate by the U/TEVA-2 resin, as measured by the k' values (number of free column values to peak maximum) is >5000 from approximately 0.1 to 8 M HNO(3). The ability of the new resin to strongly and selectively retain U(VI) from such a wide range of acid concentrations, along with its favorable physical properties, make it a good candidate for application in the separation and preconcentration of U(VI) from complex environmental, biological, and nuclear waste samples for subsequent determination.

Functional MRI of language-related activation in left frontal schizencephaly.

Brain activation associated with covert verb generation was studied in a right-handed patient with an asymptomatic left frontal schizencephaly by functional magnetic resonance imaging. Activation of the dysplastic neuronal tissue lining the cleft and the adjacent cortex was found, indicating participation of the malformed region in physiologic cerebral functions. This finding may have clinical impact in patients with medically intractable seizures due to malformations of the cortical development prior to epilepsy surgery.