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Purpose: To analyze the conspicuity of pancreatic ductal adenocarcinoma (PDAC) in virtual monoenergetic images (VMI) on a novel photon-counting detector CT (PCD-CT) in comparison to energy-integrating CT (EID-CT). Methods: Inclusion criteria comprised initial diagnosis of PDAC (reference standard: histopathological analysis) and standardized contrast-enhanced CT imaging either on an EID-CT or a PCD-CT. Patients were excluded due to different histopathological diagnosis or missing tumor delineation on CT. On the PCD-CT, 40–190 keV VMI reconstructions were generated. Image noise, tumor-to-pancreas ratio (TPR) and contrast-to-noise ratio (CNR) were analyzed by ROI-based measurements in arterial and portal venous contrast phase. Two board-certified radiologist evaluated image quality and tumor delineation at both, EID-CT and PCD-CT (40 and 70 keV). Results: Thirty-eight patients (mean age 70.4 years ± 10.3 [range 45–91], 27 males; PCD-CT: n=19, EID-CT: n=19) were retrospectively included. On the PCD-CT, tumor conspicuity (reflected by low TPR and high CNR) was significantly improved at low-energy VMI series (≤ 70 keV compared to > 70 keV), both in arterial and in portal venous contrast phase (P < 0.001), reaching the maximum at 40 keV. Comparison between PCD-CT and EID-CT showed significantly higher CNR on the PCD-CT in portal venous contrast phase at < 70 keV (P < 0.016). On the PCD-CT, tumor conspicuity was improved in portal venous contrast phase compared to arterial contrast phase especially at the lower end of the VMI spectrum (≤ 70 keV). Qualitative analysis revealed that tumor delineation is improved in 40 keV reconstructions compared to 70 keV reconstructions on a PCD-CT. Conclusion: PCD-CT VMI reconstructions (≤ 70 keV) showed significantly improved conspicuity of PDAC in quantitative and qualitative analysis in both, arterial and portal venous contrast phase, compared to EID-CT, which may be important for early detection of tumor tissue in clinical routine. Tumor delineation was superior in portal venous contrast phase compared to arterial contrast phase. [ABSTRACT FROM AUTHOR]

Artificial intelligence is gaining increasing relevance in the field of radiology. This study retrospectively evaluates how a commercially available deep learning algorithm can detect pneumonia in chest radiographs (CR) in emergency departments. The chest radiographs of 948 patients with dyspnea between 3 February and 8 May 2020, as well as 15 October and 15 December 2020, were used. A deep learning algorithm was used to identify opacifications associated with pneumonia, and the performance was evaluated by using ROC analysis, sensitivity, specificity, PPV and NPV. Two radiologists assessed all enrolled images for pulmonal infection patterns as the reference standard. If consolidations or opacifications were present, the radiologists classified the pulmonal findings regarding a possible COVID-19 infection because of the ongoing pandemic. The AUROC value of the deep learning algorithm reached 0.923 when detecting pneumonia in chest radiographs with a sensitivity of 95.4%, specificity of 66.0%, PPV of 80.2% and NPV of 90.8%. The detection of COVID-19 pneumonia in CR by radiologists was achieved with a sensitivity of 50.6% and a specificity of 73%. The deep learning algorithm proved to be an excellent tool for detecting pneumonia in chest radiographs. Thus, the assessment of suspicious chest radiographs can be purposefully supported, shortening the turnaround time for reporting relevant findings and aiding early triage. [ABSTRACT FROM AUTHOR]

• Extremolytes protect extremophilic microbes from environmental stress. • They enable multiple applications in cosmetics, food, and health industry. • Ectoine is the industrial flagship among various extremolytes. • Heterologous workhorses emerge as extremolyte cell factories. Extremolytes are small organic molecules, which protect cells under extreme, virtually inhabitable conditions. Their exceptional properties can be translated into health-promoting and therapeutic activities, which open an avenue of opportunities for the cosmetic, medical, and food industries. Supported by powerful approaches from systems and synthetic biology and systems metabolic engineering, the bio-industry becomes more and more attracted to exploit this 'goldmine'. In addition to the well-established flagship ectoine, several novel extremolytes have emerged in the past years and high-efficiency cell factories have been created for bio-based extremolyte production. Here, we review recent prominent examples and success stories in the field. [ABSTRACT FROM AUTHOR]

Graphical abstract The quantification of intracellular fluxes via 13C metabolic flux analysis has become one of the major techniques to support systems-based metabolic engineering of industrial production hosts. Commonly, 13C studies are conducted using minimal media, however, a great variety of industrial processes rely on complex medium compounds. The use of parallel 13C tracer experiments as well as analytical multi-readout of labeling data together with model-based simulation offer a great starting point to tackle such complex systems. Prominent examples will highlight the recent progress made. [ABSTRACT FROM AUTHOR]

Abstract Corynebacterium glutamicum is a major workhorse in industrial biotechnology. For the past several decades, this soil bacterium has been used to produce the amino acids l -glutamate and l -lysine at a level of 6 million tons per year. Utilizing novel genome editing methods and advanced tools of systems and synthetic biology, the portfolio of C. glutamicum has exploded from classical food and feed products to the chemical industry, cosmetics and healthcare applications. Within the past five years, the number of industrial products has almost doubled to approximately 70 natural and non-natural compounds. This review summarizes the state-of-the-art regarding metabolically engineered cell factories of C. glutamicum , illustrates recent key technological developments and provides examples of the major industrial applications of this important microbe. Highlights • Genome-editing of the microbe allows for multiplexed genomic engineering. • Biosensors display a key innovation to drive strain development and screening. • Metabolically engineered Corynebacterium glutamicum is meanwhile applied to produce more than 70 products. • Novel substrate assimilation routes strongly expand the raw material basis for renewable bio-production. [ABSTRACT FROM AUTHOR]

Green routes are indispensable for a sustainable production of energy, chemicals and materials, and health and nutrition products from renewable resources. Naturally, microbes are capable to conduct many of the desired biochemical conversions involved, however, only at rather low efficiency. It is therefore essential to metabolically engineer them towards efficient cell factories, which enable a high product titer, yield and productivity, exhibit a good process robustness and a broad substrate spectrum, and are safe to be used, to name a few prominent points from the wish list for industrial bio-production. Such optimization of a microbial cell typically involves the implementation of several up to multiple traits into its genome, which then mediate the desired phenotype. While the genetic modification step itself is straightforward due to the much advanced genome editing methods, the selection of what exactly has to be optimized out of the manifold possibilities is still a challenge. Here we will discuss, how systems biology can offer guidance to orchestrate the hundreds to thousands of biochemical conversions of a microbe into a concert of desired performance. To this end, we will highlight recent success stories, where systems biology approaches have enabled next-level cell factories and bioprocesses. [ABSTRACT FROM AUTHOR]

The fungus Ashbya gossypii is an important industrial producer of riboflavin, i.e. vitamin B 2 . In order to meet the constantly increasing demands for improved production processes, it appears essential to better understand the underlying metabolic pathways of the vitamin. Here, we used a highly sophisticated set-up of parallel 13 C tracer studies with labeling analysis by GC/MS, LC/MS, 1D, and 2D NMR to resolve carbon fluxes in the overproducing strain A. gossypii B2 during growth and subsequent riboflavin production from vegetable oil as carbon source, yeast extract, and supplemented glycine. The studies provided a detailed picture of the underlying metabolism. Glycine was exclusively used as carbon-two donor of the vitamin’s pyrimidine ring, which is part of its isoalloxazine ring structure, but did not contribute to the carbon-one metabolism due to the proven absence of a functional glycine cleavage system. The pools of serine and glycine were closely connected due to a highly reversible serine hydroxymethyltransferase. Transmembrane formate flux simulations revealed that the one-carbon metabolism displayed a severe bottleneck during initial riboflavin production, which was overcome in later phases of the cultivation by intrinsic formate accumulation. The transiently limiting carbon-one pool was successfully replenished by time-resolved feeding of small amounts of formate and serine, respectively. This increased the intracellular availability of glycine, serine, and formate and resulted in a final riboflavin titer increase of 45%. [ABSTRACT FROM AUTHOR]

Succinic acid is a platform chemical of recognized industrial value and accordingly faces a continuous challenge to enable manufacturing from most attractive raw materials. It is mainly produced from glucose, using microbial fermentation. Here, we explore and optimize succinate production from sucrose, a globally applied substrate in biotechnology, using the rumen bacterium Basfia succiniciproducens DD1. As basis of the strain optimization, the yet unknown sucrose metabolism of the microbe was studied, using 13 C metabolic flux analyses. When grown in batch culture on sucrose, the bacterium exhibited a high succinate yield of 1 mol mol −1 and a by-product spectrum, which did not match the expected PTS-mediated sucrose catabolism. This led to the discovery of a fructokinase, involved in sucrose catabolism. The flux approach unraveled that the fructokinase and the fructose PTS both contribute to phosphorylation of the fructose part of sucrose. The contribution of the fructokinase reduces the undesired loss of the succinate precursor PEP into pyruvate and into pyruvate-derived by-products and enables increased succinate production, exclusively via the reductive TCA cycle branch. These findings were used to design superior producers. Mutants, which (i) overexpress the beneficial fructokinase, (II) lack the competing fructose PTS, and (iii) combine both traits, produce significantly more succinate. In a fed-batch process, B. succiniciproducens Δ fruA achieved a titer of 71 g L −1 succinate and a yield of 2.5 mol mol −1 from sucrose. [ABSTRACT FROM AUTHOR]

For more than fifty years, Escherichia coli has represented a remarkable success story in industrial biotechnology. Traditionally known as a producer of l -amino acids, E. coli has also entered the precious market of high-value molecules and is becoming a flexible, efficient production platform for various therapeutics, pre-biotics, nutraceuticals and pigments. This tremendous progress is enabled by systems metabolic engineering concepts that integrate systems biology and synthetic biology into the design and engineering of powerful E. coli cell factories. [ABSTRACT FROM AUTHOR]

While jail-based restoration to competency (RTC) programs are becoming more common, research on these programs and defendants who complete them is limited. The present study investigated characteristics of defendants who have completed a jail-based RTC program more than once to determine what factors differentiate them from those who completed the program only once. This study also investigated whether the use of psychological tests in competency to stand trial (CST) evaluations reduced the number of competency cases that are contested. Several predictors of RTC program repetitions were identified. However, no differences in number of contested cases were found in CST evaluations that used assessment instruments compared to evaluations where no assessment was used. [ABSTRACT FROM PUBLISHER]

Driven by the quest for sustainability, recent years have seen a tremendous progress in bio-based production routes from renewable raw materials to commercial goods. Particularly, the production of organic acids has crystallized as a competitive and fast-evolving field, related to the broad applicability of organic acids for direct use, as polymer building blocks, and as commodity chemicals. Here, we review recent advances in metabolic engineering and industrial market scenarios with focus on organic acids as top value products from biomass, accessible through fermentation and biotransformation. [ABSTRACT FROM AUTHOR]

Musical behaviours are universal across human populations and, at the same time, highly diverse in their structures, roles and cultural interpretations. Although laboratory studies of isolated listeners and music-makers have yielded important insights into sensorimotor and cognitive skills and their neural underpinnings, they have revealed little about the broader significance of music for individuals, peer groups and communities. This review presents a sampling of musical forms and coordinated musical activity across cultures, with the aim of highlighting key similarities and differences. The focus is on scholarly and everyday ideas about music--what it is and where it originates--as well the antiquity of music and the contribution of musical behaviour to ritual activity, social organization, caregiving and group cohesion. Synchronous arousal, action synchrony and imitative behaviours are among the means by which music facilitates social bonding. The commonalities and differences in musical forms and functions across cultures suggest new directions for ethnomusicology, music cognition and neuroscience, and a pivot away from the predominant scientific focus on instrumental music in the Western European tradition. [ABSTRACT FROM AUTHOR]

Corynebacterium glutamicum, Escherichia coli, and Saccharomyces cerevisiae in particular, have become established as important industrial workhorses in biotechnology. Recent years have seen tremendous progress in their advance into tailor-made producers, driven by the upcoming demand for sustainable processes and renewable raw materials. Here, the diversity and complexity of nature is simultaneously a challenge and a benefit. Harnessing biodiversity in the right manner through synergistic progress in systems metabolic engineering and chemical synthesis promises a future innovative bio-economy. [ABSTRACT FROM AUTHOR]

Seit der Etablierung fermentativer Produktionsprozesse haben sich insbesondere Corynebacterium glutamicum, Escherichia coli und Saccharomyces cerevisiae als bedeutende Produktionsorganismen in der industriellen Biotechnologie durchgesetzt. Angetrieben von einem neu aufkommenden Interesse an Nachhaltigkeit und an der Verwendung nachwachsender Rohstoffe, wurden diese Mikroorganismen in den letzten Jahren zunehmend zu maßgeschneiderten Produktionsstämmen weiterentwickelt, wobei die Vielfalt und Komplexität ihrer natürlichen Syntheseleistung zugleich ein Gewinn und eine Herausforderung ist. Eine zielgerichtete Nutzbarmachung des großen metabolischen Potentials durch den synergistischen Einsatz des Systems Metabolic Engineering und der chemischen Synthese verspricht neue und innovative Konzepte für eine zukünftige Bio ‐ Ökonomie. Von der Zelle zur Zellfabrik: Die moderne Biotechnologie kombiniert systembiologische Analysen mit gentechnischen Hilfsmitteln, um Mikroorganismen für die Produktion natürlicher Wertprodukte nutzbar zu machen. Die Abbildung veranschaulicht die Umwandlung einer zellulären Blackbox in eine industrielle Zellfabrik. [ABSTRACT FROM AUTHOR]

Background: Pediocin PA-1 is a bacteriocin of recognized value with applications in food bio-preservation and the medical sector for the prevention of infection. To date, industrial manufacturing of pediocin PA-1 is limited by high cost and low-performance. The recent establishment of the biotechnological workhorse Corynebacterium glutamicum as recombinant host for pediocin PA-1 synthesis displays a promising starting point towards more efficient production. Results: Here, we optimized the fermentative production process. Following successful simplification of the production medium, we carefully investigated the impact of dissolved oxygen, pH value, and the presence of bivalent calcium ions on pediocin production. It turned out that the formation of the peptide was strongly supported by an acidic pH of 5.7 and microaerobic conditions at a dissolved oxygen level of 2.5%. Furthermore, elevated levels of CaCl2 boosted production. The IPTG-inducible producer C. glutamicum CR099 pXMJ19 Ptac pedACDCg provided 66 mg L−1 of pediocin PA-1 in a two-phase batch process using the optimized set-up. In addition, the novel constitutive strain Ptuf pedACDCg allowed successful production without the need for IPTG. Conclusions: The achieved pediocin titer surpasses previous efforts in various microbes up to almost seven-fold, providing a valuable step to further explore and develop this important bacteriocin. In addition to its high biosynthetic performance C. glutamicum proved to be highly robust under the demanding producing conditions, suggesting its further use as host for bacteriocin production. [ABSTRACT FROM AUTHOR]

ABSTRACT.Objectives:Sexting, defined as the transmission of sexually suggestive or explicit pictures or videos via mobile phone, has garnered considerable attention in both the public and research sectors. In popular culture, sexting has received considerable negative attention in regards to potential risk.Methods:The present study examined the prevalence of sexting behaviors among 287 volunteer students attending a university in the Southwest United States, as well as the extent to which concerns about sexting appear to be founded or unfounded.Results:Responses indicated that 38% of the participants had sent and/or received sexts during the past 6 months. Of those who engaged in sexting in the past 6 months, 84% had sent 1 to 10 sexts and 88% had received 1 to 10 sexts. Most respondents (64%) indicated that they had sent nude or seminude sexts for consensual sexual reasons. Of those individuals, 87% who reported sending sexts and 71% who reported receiving sexts indicated that the sexting occurred during a romantic relationship. Those who engaged in nude sexting had an earlier age of initiation into sexual behavior and had more sexual partners. Participants who had sent and received nude sexts also had some evidence of risky behavior including drug use and behavior problems in childhood. Additionally, participants who did not engage in sexting scored lower on measures of hostility toward women.Conclusions:Despite these findings, the overall study suggests that sexting may not be a cause for concern. Possible positive aspects of sexting and recommendations for future research are discussed. [ABSTRACT FROM AUTHOR]

Background The stabilizing and function-preserving effects of ectoines have attracted considerable biotechnological interest up to industrial scale processes for their production. These rely on the release of ectoines from high-salinity-cultivated microbial producer cells upon an osmotic down-shock in rather complex processor configurations. There is growing interest in uncoupling the production of ectoines from the typical conditions required for their synthesis, and instead design strains that naturally release ectoines into the medium without the need for osmotic changes, since the use of high-salinity media in the fermentation process imposes notable constraints on the costs, design, and durability of fermenter systems. Results Here, we used a Corynebacterium glutamicum strain as a cellular chassis to establish a microbial cell factory for the biotechnological production of ectoines. The implementation of a mutant aspartokinase enzyme ensured efficient supply of L-aspartate-beta-semialdehyde, the precursor for ectoine biosynthesis. We further engineered the genome of the basic C. glutamicum strain by integrating a codon-optimized synthetic ectABCD gene cluster under expressional control of the strong and constitutive C. glutamicum tuf promoter. The resulting recombinant strain produced ectoine and excreted it into the medium; however, lysine was still found as a by-product. Subsequent inactivation of the L-lysine exporter prevented the undesired excretion of lysine while ectoine was still exported. Using the streamlined cell factory, a fed-batch process was established that allowed the production of ectoine with an overall productivity of 6.7 g L-1 day-1 under growth conditions that did not rely on the use of high-salinity media. Conclusions The present study describes the construction of a stable microbial cell factory for recombinant production of ectoine. We successfully applied metabolic engineering strategies to optimize its synthetic production in the industrial workhorse C. glutamicum and thereby paved the way for further improvements in ectoine yield and biotechnological process optimization. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we demonstrate increased lysine production by flux coupling using the industrial work horse bacterium Corynebacterium glutamicum, which was mediated by the targeted interruption of the tricarboxylic acid (TCA) cycle at the level of succinyl-CoA synthetase. The succinylase branch of the lysine production pathway functions as the bridging reaction to convert succinyl-CoA to succinate in this aerobic bacterium. The mutant C. glutamicum ΔsucCD showed a 60% increase in the yield of lysine when compared to the advanced lysine producer which was used as parent strain. This mutant was highly vital and exhibited only a slightly reduced specific growth rate. Metabolic flux analysis with 13C isotope studies confirmed that the increase in lysine production was mediated by pathway coupling. The novel strain exhibited an exceptional flux profile, which was closer to the optimum performance predicted by in silico pathway analysis than to the large set of lysine-producing strains analyzed thus far. Fluxomics and transcriptomics were applied as further targets for next-level strain engineering to identify the back-up mechanisms that were activated upon deletion of the enzyme in the mutant strain. It seemed likely that the cells partly recruited the glyoxylate shunt as a by-pass route. Additionally, the α-ketoglutarate decarboxylase pathway emerged as the potential compensation mechanism. This novel strategy appears equally promising for Escherichia coli, which is used in the industrial production of lysine, wherein this bacterium synthesizes lysine exclusively by succinyl-CoA activation of pathway intermediates. The channeling of a high flux pathway into a production pathway by pathway coupling is an interesting metabolic engineering strategy that can be explored to optimize bio-production in the future. [Copyright &y& Elsevier]

With a world market of more than four million tons per year, l-amino acids are among the most important products in industrial biotechnology. The recent years have seen a tremendous progress in the development of tailor-made strains for such products, intensively driven from systems metabolic engineering, which upgrades strain engineering into a concept of optimization on a global scale. This concept seems especially valuable for efficient amino acid production, demanding for a global modification of pathway fluxes – a challenge with regard to the high complexity of the underlying metabolism, superimposed by various layers of metabolic and transcriptional control. [Copyright &y& Elsevier]

Since their discovery almost 60 years ago, Corynebacterium glutamicum and related subspecies are writing a remarkable success story in industrial biotechnology. Today, these gram-positive soil bacteria, traditionally well-known as excellent producers of l-amino acids are becoming flexible, efficient production platforms for various chemicals, materials and fuels. This development is intensively driven by systems metabolic engineering concepts integrating systems biology and synthetic biology into strain engineering. [Copyright &y& Elsevier]

Abstract: Dopamine, serotonin and glutamate play a role in the pathophysiology of schizophrenia. In the brain a functional crosstalk between the serotonin receptor 5-HT2A and the metabotropic glutamate receptor mGlu2 has been demonstrated. Such a crosstalk may be mediated indirectly through neuronal networks or directly by receptor oligomerization. A direct link of the 5-HT2A-mGlu2 heterocomplex formation to receptor function, i.e. to intracellular signaling, has not been fully demonstrated yet. Here we confirm the formation of 5-HT2A-mGlu2 heterocomplexes using quantitative Snap/Clip-tag based HTRF methods. Additionally, mGlu2 formed complexes with 5-HT2B and mGlu5 but not 5-HT2C indicating that complex formation is not specific to the 5-HT2A-mGlu2 pair. We studied the functional consequences of the 5-HT2A-mGlu2 heterocomplex addressing cellular signaling pathways. Co-expression of receptors in HEK-293 cells had no relevant effects on signaling mediated by the individual receptors when mGlu2 agonists, antagonists and PAMs, or 5-HT2A hallucinogenic and non-hallucinogenic agonists and antagonists were used. Hallucinogenic 5-HT2A agonists induced signaling through Gq/11, but not Gi and thus did not lead to modulation of intracellular cAMP levels. In membranes of the medial prefrontal cortex [3H]-LY341495 binding competition of mGlu2/3 agonist LY354740 was not influenced by 2,5-dimethoxy-4-iodoamphetamine (DOI). Taken together, the formation of GPCR heterocomplexes does not necessarily translate into second messenger effects. These results do not put into question the well-documented functional cross-talk of the two receptors in the brain, but do challenge the biological relevance of the 5-HT2A-mGlu2 heterocomplex. [Copyright &y& Elsevier]

Since their discovery many decades ago, Pseudomonas putida and related subspecies have been intensively studied with regard to their potential application in industrial biotechnology. Today, these Gram-negative soil bacteria, traditionally known as well-performing xenobiotic degraders, are becoming efficient cell factories for various products of industrial relevance including a full range of unnatural chemicals. This development is strongly driven by systems biotechnology, integrating systems metabolic engineering approaches with novel concepts from bioprocess engineering, including novel reactor designs and renewable feedstocks. [ABSTRACT FROM AUTHOR]

Background: In Escherichia coli phosphoenolpyruvate (PEP) is a key central metabolism intermediate that participates in glucose transport, as precursor in several biosynthetic pathways and it is involved in allosteric regulation of glycolytic enzymes. In this work we generated W3110 derivative strains that lack the main PEP consumers PEP:sugar phosphotransferase system (PTS-) and pyruvate kinase isozymes PykA and PykF (PTS- pykA- and PTS- pykF-). To characterize the effects of these modifications on cell physiology, carbon flux distribution and aromatics production capacity were determined. Results: When compared to reference strain W3110, strain VH33 (PTS-) displayed lower specific rates for growth, glucose consumption and acetate production as well as a higher biomass yield from glucose. These phenotypic effects were even more pronounced by the additional inactivation of PykA or PykF. Carbon flux analysis revealed that PTS inactivation causes a redirection of metabolic flux towards biomass formation. A cycle involving PEP carboxylase (Ppc) and PEP carboxykinase (Pck) was detected in all strains. In strains W3110, VH33 (PTS-) and VH35 (PTS-, pykF-), the net flux in this cycle was inversely correlated with the specific rate of glucose consumption and inactivation of Pck in these strains caused a reduction in growth rate. In the PTS- background, inactivation of PykA caused a reduction in Ppc and Pck cycling as well as a reduction in flux to TCA, whereas inactivation of PykF caused an increase in anaplerotic flux from PEP to OAA and an increased flux to TCA. The wild-type and mutant strains were modified to overproduce L-phenylalanine. In resting cells experiments, compared to reference strain, a 10, 4 and 7-fold higher aromatics yields from glucose were observed as consequence of PTS, PTS PykA and PTS PykF inactivation. Conclusions: Metabolic flux analysis performed on strains lacking the main activities generating pyruvate from PEP revealed the high degree of flexibility to perturbations of the central metabolic network in E. coli. The observed responses to reduced glucose uptake and PEP to pyruvate rate of conversion caused by PTS, PykA and PykF inactivation included flux rerouting in several central metabolism nodes towards anabolic biosynthetic reactions, thus compensating for carbon limitation in these mutant strains. The detected cycle involving Ppc and Pck was found to be required for maintaining the specific growth and glucose consumption rates in all studied strains. Strains VH33 (PTS-), VH34 (PTS- pykA-) and VH35 (PTS- pykF-) have useful properties for biotechnological processes, such as increased PEP availability and high biomass yields from glucose, making them useful for the production of aromatic compounds or recombinant proteins. [ABSTRACT FROM AUTHOR]

The author offers a response to the article "Consilience Revisited: Musical and Scientific Approaches to Chinese Performance" by Francesca R. Sborgi Lawson published in this issue. The author comments on the scientific approach to the study of music evidenced by the books "The Singing Neanderthals: The Origins of Music, Language, Mind and Body" by Steven Mithen and "Music, Language, and the Brain" by Aniruddh Patel. The collaboration between neuroscience and ethnomusicology is discussed.

Abstract: Individuals with serious and persistent mental illness who have also engaged in illegal sexual behavior present a unique challenge for our legal and clinical systems. Frequently, these individuals may engage in problematic sexual behaviors which result in hospitalization rather than incarceration, and an overburdened and resource-deficient public community mental health system is ill-equipped to address the seriousness of these sexual behaviors. We have a rather limited understanding of how prevention programs, intervention strategies, and risk assessment would work with this population. Here we evaluate data from a sample of 245 inpatient psychiatric sexual offenders in a forensic mental health setting and compare these with what information has already been presented in some of the literature. Through an examination of seriously mentally ill sexual offenders and their clinical presentation, legal history, and risk management concerns, we illustrate a variety of tertiary prevention needs. Future directions in the area of prevention and risk management for seriously mentally ill sexual offenders are also discussed. [Copyright &y& Elsevier]

This article proceeds from the widely accepted assumption that Reformed refugee churches developed a particular exile theology. The distinctive characteristics of this theology are in the areas of ecclesiology, predestination doctrine, the relationship to civil powers and to Judaism, along with an emphasis on social concerns. The article tries to trace this theology in Western European confessions of faith, those of immigrant churches and of the churches that were much affected by religious persecution and migration, such as the French and Dutch ones. Many refugee and Strangers, Churches published their confessions. Yet, the confessions varied considerably regarding their structure and also their content. Some of the abovementioned topics were not mentioned at all, while others were referred to in a rather general way. It is ecciesiology that stands out as the chief and remarkably well-treated subject. The study argues, therefore, for an 'ecclesiology of religious exiles' rather than to speak of their 'theology'. [ABSTRACT FROM AUTHOR]

Abstract: Here, we describe the development of a genetically defined strain of l-lysine hyperproducing Corynebacterium glutamicum by systems metabolic engineering of the wild type. Implementation of only 12 defined genome-based changes in genes encoding central metabolic enzymes redirected major carbon fluxes as desired towards the optimal pathway usage predicted by in silico modeling. The final engineered C. glutamicum strain was able to produce lysine with a high yield of 0.55g per gram of glucose, a titer of 120gL−1 lysine and a productivity of 4.0gL−1 h−1 in fed-batch culture. The specific glucose uptake rate of the wild type could be completely maintained during the engineering process, providing a highly viable producer. For these key criteria, the genetically defined strain created in this study lies at the maximum limit of classically derived producers developed over the last fifty years. This is the first report of a rationally derived lysine production strain that may be competitive with industrial applications. The design-based strategy for metabolic engineering reported here could serve as general concept for the rational development of microorganisms as efficient cellular factories for bio-production. [Copyright &y& Elsevier]

The recent years have seen tremendous progress towards the understanding of microbial metabolism on a higher level of the entire functional system. Hereby, huge achievements including the sequencing of complete genomes and efficient post-genomic approaches provide the basis for a new, fascinating era of research-analysis of metabolic and regulatory properties on a global scale. Metabolic flux (fluxome) analysis displays the first systems oriented approach to unravel the physiology of microorganisms since it combines experimental data with metabolic network models and allows determining absolute fluxes through larger networks of central carbon metabolism. Hereby, fluxes are of central importance for systems level understanding because they fundamentally represent the cellular phenotype as integrated output of the cellular components, i.e. genes, transcripts, proteins, and metabolites. A currently emerging and promising area of research in systems biology and systems metabolic engineering is therefore the integration of fluxome data in multi-omics studies to unravel the multiple layers of control that superimpose the flux network and enable its optimal operation under different environmental conditions. [ABSTRACT FROM AUTHOR]

In the present work, lysine production by Corynebacterium glutamicum was improved by metabolic engineering of the tricarboxylic acid (TCA) cycle. The 70% decreased activity of isocitrate dehydrogenase, achieved by start codon exchange, resulted in a >40% improved lysine production. By flux analysis, this could be correlated to a flux shift from the TCA cycle toward anaplerotic carboxylation. [ABSTRACT FROM AUTHOR]

Social values and status cause diverse obstacles for escaping abuse (e.g., belief in the sanctity of marriage vs. financial necessity to stay for survival). India provides a unique opportunity to explore the interplay of status and corresponding patriarchal values in relation to the incidence of domestic violence and how it is viewed, coped with, and psychologically impacting native women. Sixty-four women of Tamil Nadu, India were surveyed. Women of higher status were found to be less likely to acknowledge abuse as a societal problem, accurately identify abuse events, and seek help or report abuse. Women who had more realistic conceptions of abuse were more likely to seek help but also likely to experience more severe psychological distress. All of the women surveyed had symptoms of post-traumatic stress disorder that were exacerbated by unsuspected variables. The implications of these findings are discussed in light of public health strategies. [ABSTRACT FROM AUTHOR]

The article presents a study on the psychological relationship between religious ecstatics and secular deep listeners and responses to music. It notes that both the Pentecostal Ecstatics and Deep Listeners have strong arousal, based on the galvanic skin response (GSR) Index, in listening to their preferred music. It also cites enabling strategies classification that can be used to overcome sciences and humanities interdisciplinary boundaries such as enabling attitudes, languages and models.

Abstract: The field of sexual victimization prevention has been greatly shaped by societal movements of the past forty years. The social forces that have driven the study of sexual victimization have led to major research gaps which may be viewed as opportunities for new focuses. This paper will: (1) review these social movements in light of the opportunities that have arisen, (2) re-evaluate the information that has been collected in light of the research purpose, preventing harm to potential victims through providing tailored prevention messages, victim sensitive avenues of reporting, and individualized intervention tactics based on personality characteristics, and (3) provide a framework with which to conceptualize normative personality in relation to the process of victimization-related trauma. Although research has provided many insights into the basic principles of prevention, much remains to be explored. [Copyright &y& Elsevier]

Abstract: A NMR method based on the combination of selective pulses with Zero-Quantum Filtered TOCSY magnetization transfer was used to measure the specific 13C-enrichment of labelled molecules. The analysis of a labelled lysine sample showed that DANTE-Z schemes give accurate measurements; meanwhile, DPFGSE schemes resulted in the underestimation of 13C-enrichments. The former method can be applied to overcome signal overlap problems that are often encountered in the analysis of labelled molecules. [Copyright &y& Elsevier]

Background: Pyruvate kinase is an important element in flux control of the intermediate metabolism. It catalyzes the irreversible conversion of phosphoenolpyruvate into pyruvate and is under allosteric control. In Corynebacterium glutamicum, this enzyme was regarded as promising target for improved production of lysine, one of the major amino acids in animal nutrition. In pyruvate kinase deficient strains the required equimolar ratio of the two lysine precursors oxaloacetate and pyruvate can be achieved through concerted action of the phosphotransferase system (PTS) and phosphoenolpyruvate carboxylase (PEPC), whereby a reduced amount of carbon may be lost as CO2 due to reduced flux into the tricarboxylic acid (TCA) cycle. In previous studies, deletion of pyruvate kinase in lysine-producing C. glutamicum, however, did not yield a clear picture and the exact metabolic consequences are not fully understood. Results: In this work, deletion of the pyk gene, encoding pyruvate kinase, was carried out in the lysine-producing strain C. glutamicum lysCfbr, expressing a feedback resistant aspartokinase, to investigate the cellular response to deletion of this central glycolytic enzyme. Pyk deletion was achieved by allelic replacement, verified by PCR analysis and the lack of in vitro enzyme activity. The deletion mutant showed an overall growth behavior (specific growth rate, glucose uptake rate, biomass yield) which was very similar to that of the parent strain, but differed in slightly reduced lysine formation, increased formation of the overflow metabolites dihydroxyacetone and glycerol and in metabolic fluxes around the pyruvate node. The latter involved a flux shift from pyruvate carboxylase (PC) to PEPC, by which the cell maintained anaplerotic supply of the TCA cycle. This created a metabolic by-pass from PEP to pyruvate via malic enzyme demonstrating its contribution to metabolic flexibility of C. glutamicum on glucose. Conclusion: The metabolic flux analysis performed illustrates the high flexibility of the metabolic network of C. glutamicum to compensate for external perturbation. The organism could almost maintain its growth and production performance through a local redirection of the metabolic flux, thereby fulfilling all anabolic and catabolic needs. The formation of the undesired overflow metabolites dihydroxyacetone and glycerol, in the deletion mutant, however, indicates a limiting capacity of the metabolism down-stream of their common precursor glyceraldehyde 3-phosphate and opens possibilities for further strain engineering. [ABSTRACT FROM AUTHOR]

Abstract: While both psychopaths and sexual sadists engage in acts of predatory violence, little empirical work has examined the relationship between the two disorders. This paper outlines the constructs of psychopathy and sexual sadism and reviews the literature investigating the emotional lives of individuals with these disorders, paying particular attention to how emotional deficits might facilitate instrumental violence. Specifically, it is hypothesized that the emotion recognition and emotional experience deficits found among psychopaths, and perhaps present in sexual sadists, may lead to deficits in their ability to empathize with others, resulting in an increased likelihood for perpetrating instrumental violence. The relationship between empathy and aggression in psychopaths and sexual sadists is discussed, and distinctions are drawn between the two disorders with respect to their capacities to experience cognitive and affective empathy on a global level. Gaps in the literature are identified and additional areas of inquiry are suggested. [Copyright &y& Elsevier]

Abstract: In the present work, metabolic flux engineering of Corynebacterium glutamicum was carried out to increase lysine production. The strategy focused on engineering of the pentose phosphate pathway (PPP) flux by different genetic modifications. Over expression of the zwf gene, encoding G6P dehydrogenase, in the feedback-deregulated lysine-producing strain C. glutamicum ATCC 13032 lysCfbr resulted in increased lysine production on different carbon sources including the two major industrial sugars, glucose and sucrose. The additional introduction of the A243T mutation into the zwf gene and the over expression of fructose 1,6-bisphosphatase resulted in a further successive improvement of lysine production. Hereby the point mutation resulted in higher affinity of G6P dehydrogenase towards NADP and reduced sensitivity against inhibition by ATP, PEP and FBP. Overall, the lysine yield increased up to 70% through the combination of the different genetic modifications. Through strain engineering formation of trehalose was reduced by up to 70% due to reduced availability of its precursor G6P. Metabolic flux analysis revealed a 15% increase of PPP flux in response to over expression of the zwf gene. Overall a strong apparent NADPH excess resulted. Redox balancing indicated that this excess is completely oxidized by malic enzyme. [Copyright &y& Elsevier]

This article examines the issue of sexual violence in prisons and what options are available to reduce the risk. The authors build upon the work of Nancy Wolff and combine research with inmate interviews and suggestions to address the problem. One issue addressed is the reluctance of victims to report the abuse. According to the article, fear of retaliation from the perpetrator and other inmates is the central reason for this. The authors suggest creating an anonymous method of reporting as well as training staff to recognize the early signs of impending assault.

Abstract: The accurate and appropriate assessment and treatment of juvenile sex offenders is necessary for public safety and for the juvenile''s own development. A growing body of literature has reported on specialized assessment instruments and treatment strategies for use with juvenile sex offenders. The current article reviews the evidence regarding the reliability and validity of various assessment instruments and outcome research regarding treatments with this population. With regard to assessment, the authors conclude that the most promising area of specialized assessment is risk assessment. With regard to intervention, the authors argue that despite methodological limitations, research on the treatment of juvenile sex offenders suggests that treatments are successful in creating change. Specifically, cognitive behavioral treatment and mulitsystemic therapy have demonstrated decreased recidivism compared to a control group. Recommendations regarding future research for the area and implications with respect to uniqueness of this population are considered. [Copyright &y& Elsevier]

Abstract: This paper focuses on the empirical literature concerning the development, maintenance, and treatment of sexual offending and disparities between this research, current theory, and practice in the field of sex offender treatment. We contend that treatment programs result in only modest reductions in sexual recidivism for two main reasons: flaws in the etiological theory of sexual offending upon which they are established (theory of problem), and flaws in the theory of treatment delivery with respect to the methods undertaken to reduce sexual reoffending (theory of change). These flaws arise from aspects of ‘theory of problem’ and ‘theory of change’ which lack empirical investigation or are contrary to research findings in relevant areas. Specifically, we discuss components of accepted etiological theories which do not yet demonstrate evidence of a causal relationship with sexual recidivism, as well as argue for more research differentiating developmental from maintaining factors in sexual offending. We also discuss specific treatment methods that lack empirical evidence justifying their use, are undertaken despite evidence of contraindication, or require further validation of their effectiveness or necessity. Implications of the above limitations are discussed and recommendations for enhancing treatment effectiveness are offered. [Copyright &y& Elsevier]

The overexpression of fructose 1,6-bisphosphatase (FBPase) in Corynebacterium glutamicum leads to significant improvement of lysine production on different sugars. Amplified expression of FBPase via the promoter of the gene encoding elongation factor TU (EFTU) increased the lysine yield in the feedback-deregulated lysine-producing strain C. glutamicum lysCfbr by 40% on glucose and 30% on fructose or sucrose. Additionally formation of the by-products glycerol and dihydroxyacetone was significantly reduced in the PEFTUfbp mutant. As revealed by 13C metabolic flux analysis on glucose the overexpression of FBPase causes a redirection of carbon flux from glycolysis toward the pentose phosphate pathway (PPP) and thus leads to increased NADPH supply. Normalized to an uptake flux of glucose of 100%, the relative flux into the PPP was 56% for C. glutamicum lysCfbr PEFTUfbp and 46% for C. glutamicum lysCfbr. The flux for NADPH supply was 180% in the PEFTUfbp strain and only 146% in the parent strain. Amplification of FBPase increases the production of lysine via an increased supply of NADPH. Comparative studies with another mutant containing the sod promoter upstream of the fbp gene indicate that the expression level of FBPase relates to the extent of the metabolic effects. The overexpression of FBPase seems useful for starch- and molasses-based industrial lysine production with C. glutamicum. The redirection of flux toward the PPP should also be interesting for the production of other NADPH-demanding compounds as well as for products directly stemming from the PPP. [ABSTRACT FROM AUTHOR]

Abstract: The construct of psychopathy has often been considered mutually exclusive to the presence of genuine depressive or anxiety symptomotology. This article addresses the hypothesized reasons for this dichotomous relationship. In this study, 68 civilly committed adult male sex offenders were evaluated using a variety of psychological measures to determine if psychopathic individuals in this group would demonstrate clinically significant affective symptoms. Results indicate that the men in this sample endorsed high rates of psychopathy on the PCL-R, with 42% of these expressing concurrent symptoms of depression and 26% manifesting symptoms of an anxiety disorder. Relationships between affective symptoms and PCL-R factor scores and qualitative differences between these constructs in child molesters and rapists are also discussed. [Copyright &y& Elsevier]

Examines the factors for the completion in a correctional sex offender treatment program. Participants of the treatment program; Examination of archival records; Sources of demographic information; Factors influencing treatment completion based on logistic regression; Implications of the study for offender recovery.

Examines the characteristics and treatment of adolescents who have committed sexual offenses. Presumed etiologies for the behavior; Treatment programs; Critical questions that remained unanswered; Reports issued by the National Task Force on Juvenile Sex Offending.

Assesses the test-retest reliability and validity of sexual interest self-report instrument for juvenile sexual offenders. Questions on the validity of Adolescent Sexual Interest Card Sort (ASIC); Determining the consistency of ASIC items; Correlation of clients' sexual interests with phallometric response; Vulnerability of self-report measures to dissimulation.

Little is known about parents' pragmatic input and the ways it contributes to preschoolers' acquisition of pragmatic competence. In order to address this issue, five families with preschoolers were asked to audiotape everyday family interactions over the course of one year. Parents provided a great deal of input about 15 different behaviors that included both pragmatic phrases and more abstract discourse skills. Input fell into 13 different categories. It typically addressed children's errors and omissions and was indirect. The results replicate and extend previous research and offer insights into preschoolers' acquisition of pragmatic competence. It is suggested that parental input provides rich information about pragmatic behaviors and conventions, that indirectness forces children to generate appropriate responses, and that children play an active role in the acquisition process. [ABSTRACT FROM AUTHOR]

Previous research and theory suggest that effective use of specific pragmatic behaviors is important to social competence in children. The present study is the first attempt to examine the impact four pragmatic skills have on likeability using expe rimental methodology. Ninety-one popular and less popular 10-year-old girls listened to one of five audiotaped scenarios in which a girl used four different pragmatic skills (requesting, turn taking, responding promptly when spoken to, and maintaining th e logic of the conversation) either appropriately or inappropriately in a conversation with a school librarian. Subjects rated how much they would like to play with the girl and also described her in terms of attractiveness, school ability, and popularit y. Subjects saw the girl as more like able when she displayed pragmatic competence than when she requested inappropriately, F(1, 33) = 47,86, p<.001; interrupted, F(1, 33) = 13.56, p<.001; and failed to maintain the logic of the conversation, F(1, 31' = 5.90, p<.05. They also described her more positively when she displayed pragmatic competence. Subjects' responses did not vary as a function of their own popularity level. These results demonstrate the importance of pragmatic skills for populari ty and the paradigm offers a methodology for identifying pragmatic skills of relevance to various populations. [ABSTRACT FROM AUTHOR]

Children's pragmatic development can be revealed in both their use of pragmatic skills and their metapragmatic comments. Six families with preschoolers (mean age: 3 years, 3 months) were observed in unstructured, conversational interactions for about a year. Conversations were transcribed, and 65 instances of spontaneous metapragmatic comments were identified. Five types of comments were observed: comments about other people's pragmatic errors, comments and questions about pragmatic rules, comments to regulate and maintain the conversation, self-promptings of pragmatic behaviors, and accounts for pragmatic errors by reference to conflicting pragmatic rules. These comments make it clear that preschoolers can not only work to make conversations smoother and more effective, but also take an active role in testing and expanding their pragmatic understanding. The comments also reflect more sophisticated pragmatic knowledge than laboratory studies have revealed. [ABSTRACT FROM AUTHOR]

Background: Cyanobacteria receive huge interest as green catalysts. While exploiting energy from sunlight, they co-utilize sugar and CO2. This photomixotrophic mode enables fast growth and high cell densities, opening perspectives for sustainable biomanufacturing. The model cyanobacterium Synechocystis sp. PCC 6803 possesses a complex architecture of glycolytic routes for glucose breakdown that are intertwined with the CO2-fixing Calvin-Benson-Bassham (CBB) cycle. To date, the contribution of these pathways to photomixotrophic metabolism has remained unclear. Results: Here, we developed a comprehensive approach for 13C metabolic flux analysis of Synechocystis sp. PCC 6803 during steady state photomixotrophic growth. Under these conditions, the Entner-Doudoroff (ED) and phosphoketolase (PK) pathways were found inactive but the microbe used the phosphoglucoisomerase (PGI) (63.1%) and the oxidative pentose phosphate pathway (OPP) shunts (9.3%) to fuel the CBB cycle. Mutants that lacked the ED pathway, the PK pathway, or phosphofructokinases were not affected in growth under metabolic steady-state. An ED pathway-deficient mutant (Δeda) exhibited an enhanced CBB cycle flux and increased glycogen formation, while the OPP shunt was almost inactive (1.3%). Under fluctuating light, ∆eda showed a growth defect, different to wild type and the other deletion strains. Conclusions: The developed approach, based on parallel 13C tracer studies with GC–MS analysis of amino acids, sugars, and sugar derivatives, optionally adding NMR data from amino acids, is valuable to study fluxes in photomixotrophic microbes to detail. In photomixotrophic cells, PGI and OPP form glycolytic shunts that merge at switch points and result in synergistic fueling of the CBB cycle for maximized CO2 fixation. However, redirected fluxes in an ED shunt-deficient mutant and the impossibility to delete this shunt in a GAPDH2 knockout mutant, indicate that either minor fluxes (below the resolution limit of 13C flux analysis) might exist that could provide catalytic amounts of regulatory intermediates or alternatively, that EDA possesses additional so far unknown functions. These ideas require further experiments. [ABSTRACT FROM AUTHOR]

Lignin is one of the most abundant renewable resources on earth and is readily produced as a sidestream during biomass fractioning. So far, these large quantities of lignin have been severely underutilized, thereby wasting this valuable renewable. Recent technological advances in lignin recovery, breakdown, and conversion have now started forming the first sustainable value chains to take advantage of lignin. Microbial cell factories, inspired by nature's miscellaneous set of lignin-degrading microbes, are at the heart of these novel processes. Recent success stories in which the enzymes and pathways of these microbes were harnessed for biobased production from lignin hold great promise for a sustainable upgrading of this renewable polymer into value-added compounds. [ABSTRACT FROM AUTHOR]

In the early diagnostic workup of acute pancreatitis (AP), the role of contrast-enhanced CT is to establish the diagnosis in uncertain cases, assess severity, and detect potential complications like necrosis, fluid collections, bleeding or portal vein thrombosis. The value of texture analysis/radiomics of medical images has rapidly increased during the past decade, and the main focus has been on oncological imaging and tumor classification. Previous studies assessed the value of radiomics for differentiating between malignancies and inflammatory diseases of the pancreas as well as for prediction of AP severity. The aim of our study was to evaluate an automatic machine learning model for AP detection using radiomics analysis. Patients with abdominal pain and contrast-enhanced CT of the abdomen in an emergency setting were retrospectively included in this single-center study. The pancreas was automatically segmented using TotalSegmentator and radiomics features were extracted using PyRadiomics. We performed unsupervised hierarchical clustering and applied the random-forest based Boruta model to select the most important radiomics features. Important features and lipase levels were included in a logistic regression model with AP as the dependent variable. The model was established in a training cohort using fivefold cross-validation and applied to the test cohort (80/20 split). From a total of 1012 patients, 137 patients with AP and 138 patients without AP were included in the final study cohort. Feature selection confirmed 28 important features (mainly shape and first-order features) for the differentiation between AP and controls. The logistic regression model showed excellent diagnostic accuracy of radiomics features for the detection of AP, with an area under the curve (AUC) of 0.932. Using lipase levels only, an AUC of 0.946 was observed. Using both radiomics features and lipase levels, we showed an excellent AUC of 0.933 for the detection of AP. Automated segmentation of the pancreas and consecutive radiomics analysis almost achieved the high diagnostic accuracy of lipase levels, a well-established predictor of AP, and might be considered an additional diagnostic tool in unclear cases. This study provides scientific evidence that automated image analysis of the pancreas achieves comparable diagnostic accuracy to lipase levels and might therefore be used in the future in the rapidly growing era of AI-based image analysis. [ABSTRACT FROM AUTHOR]