Dynamic modulation of the processing of unpredicted technical errors by the posterior cingulate and the default mode network.

The pervasive use of information technologies (IT) has tremendously benefited our daily lives. However, unpredicted technical breakdowns and errors can lead to the experience of stress, which has been termed technostress. It remains poorly understood how people dynamically respond to unpredicted system runtime errors occurring while interacting with the IT systems on a behavioral and neuronal level. To elucidate the mechanisms underlying such processes, we conducted a functional magnetic resonance imaging (fMRI) study in which 15 young adults solved arithmetic problems of three difficulty levels (easy, medium and hard) while two types of system runtime errors (problem errors and feedback errors) occurred in an unexpected manner. The problem error condition consisted of apparently defective displays of the arithmetic problem and the feedback error condition involved erroneous feedback. We found that the problem errors positively influenced participants' problem-solving performance at the high difficulty level (i.e., hard tasks) at the initial stage of the session, while feedback errors disturbed their performance. These dynamic behavioral changes are mainly associated with brain activation changes in the posterior cingulate and the default mode network, including the posterior cingulate cortex, the mPFC, the retrosplenial cortex and the parahippocampal gyrus. Our study illustrates the regulatory role of the posterior cingulate in coping with unpredicted errors as well as with dynamic changes in the environment.

Automatic classification of experimental models in biomedical literature to support searching for alternative methods to animal experiments.

Current animal protection laws require replacement of animal experiments with alternative methods, whenever such methods are suitable to reach the intended scientific objective. However, searching for alternative methods in the scientific literature is a time-consuming task that requires careful screening of an enormously large number of experimental biomedical publications. The identification of potentially relevant methods, e.g. organ or cell culture models, or computer simulations, can be supported with text mining tools specifically built for this purpose. Such tools are trained (or fine tuned) on relevant data sets labeled by human experts. We developed the GoldHamster corpus, composed of 1,600 PubMed (Medline) articles (titles and abstracts), in which we manually identified the used experimental model according to a set of eight labels, namely: "in vivo", "organs", "primary cells", "immortal cell lines", "invertebrates", "humans", "in silico" and "other" (models). We recruited 13 annotators with expertise in the biomedical domain and assigned each article to two individuals. Four additional rounds of annotation aimed at improving the quality of the annotations with disagreements in the first round. Furthermore, we conducted various machine learning experiments based on supervised learning to evaluate the corpus for our classification task. We obtained more than 7,000 document-level annotations for the above labels. After the first round of annotation, the inter-annotator agreement (kappa coefficient) varied among labels, and ranged from 0.42 (for "others") to 0.82 (for "invertebrates"), with an overall score of 0.62. All disagreements were resolved in the subsequent rounds of annotation. The best-performing machine learning experiment used the PubMedBERT pre-trained model with fine-tuning to our corpus, which gained an overall f-score of 0.83. We obtained a corpus with high agreement for all labels, and our evaluation demonstrated that our corpus is suitable for training reliable predictive models for automatic classification of biomedical literature according to the used experimental models. Our SMAFIRA - "Smart feature-based interactive" - search tool ( https://smafira.bf3r.de ) will employ this classifier for supporting the retrieval of alternative methods to animal experiments. The corpus is available for download ( https://doi.org/10.5281/zenodo.7152295 ), as well as the source code ( https://github.com/mariananeves/goldhamster ) and the model ( https://huggingface.co/SMAFIRA/goldhamster ).

Protocol to conduct functional magnetic resonance spectroscopy in different age groups of human participants.

We present a protocol to conduct functional magnetic resonance spectroscopy (fMRS) in human participants before, during, and after training on a visual task. We describe steps for participant setup, volume-of-interest placement, fMRS measurement, and post-scan tests. We discuss the design, analysis, and interpretation of fMRS experiments. This protocol can be adapted to investigate the dynamics of chief excitatory and inhibitory neurotransmitters (glutamate and γ-aminobutyric acid, GABA, respectively) while participants perform or learn perceptual, motor, or cognitive tasks. For complete details on the use and execution of this protocol, please refer to Frank et al. (2022).1.

Vestibular and visual brain areas in the medial cortex of the human brain.

Self-motion perception involves an interaction between vestibular and visual brain regions. In the lateral brain, it includes the parietoinsular vestibular cortex and the posterior insular cortex. In the medial cortex, the cingulate sulcus visual (CSv) area is known to process visual-vestibular cues. Here, we show that the vestibular-visual network of the medial cortex extends beyond area CSv. We examined brain activations of 36 healthy right-handed participants by functional magnetic resonance imaging (fMRI) during stimulation with caloric vestibular, thermal, or visual motion cues. Consistent with previous research, we found that area CSv responded to both vestibular and visual cues but not to thermal cues. Moreover, the V6 complex and the precuneus motion (PcM) area responded primarily to (laminar-translational) visual motion cues. However, we also observed a region inferior to CSv within the pericallosal sulcus (vicinity of anterior retrosplenial) that primarily responded to vestibular cues. This vestibular pericallosal sulcus (vPCS) region did not respond to either visual or thermal cues. It was also distinct from a more posterior motion-sensitive region in the retrosplenial complex (mRSC) that responded to (radial) visual motion but not to vestibular and thermal cues. Together, our results suggest that the vestibular-visual network in the medial cortex not only includes areas CSv, PcM, and the V6 complex but also two additional brain regions adjacent to the callosum. These two brain regions exhibit similarities in terms of their locations and responses to vestibular and visual cues with self-motion-related brain regions recently described in nonhuman primates.NEW & NOTEWORTHY Self-motion perception involves several vestibular and visual cortical regions. Within the medial cortex, the cingulate sulcus visual (CSv) area, the precuneus motion (PcM) area, and the V6 complex respond selectively to self-motion cues. Here, we show that vestibular information is also processed in the pericallosal sulcus (vPCS), whereas (radial) visual motion information is associated with activation in the retrosplenial cortex (mRSC).

GPER1 links estrogens to centrosome amplification and chromosomal instability in human colon cells.

The role of the alternate G protein-coupled estrogen receptor 1 (GPER1) in colorectal cancer (CRC) development and progression is unclear, not least because of conflicting clinical and experimental evidence for pro- and anti-tumorigenic activities. Here, we show that low concentrations of the estrogenic GPER1 ligands, 17ß-estradiol, bisphenol A, and diethylstilbestrol cause the generation of lagging chromosomes in normal colon and CRC cell lines, which manifest in whole chromosomal instability and aneuploidy. Mechanistically, (xeno)estrogens triggered centrosome amplification by inducing centriole overduplication that leads to transient multipolar mitotic spindles, chromosome alignment defects, and mitotic laggards. Remarkably, we could demonstrate a significant role of estrogen-activated GPER1 in centrosome amplification and increased karyotype variability. Indeed, both gene-specific knockdown and inhibition of GPER1 effectively restored normal centrosome numbers and karyotype stability in cells exposed to 17ß-estradiol, bisphenol A, or diethylstilbestrol. Thus, our results reveal a novel link between estrogen-activated GPER1 and the induction of key CRC-prone lesions, supporting a pivotal role of the alternate estrogen receptor in colon neoplastic transformation and tumor progression.

Efficient learning in children with rapid GABA boosting during and after training.

It is generally thought that children learn more efficiently than adults. One way to accomplish this is to have learning rapidly stabilized such that it is not interfered with by subsequent learning. Although γ-aminobutyric acid (GABA) plays an important role in stabilization, it has been reported that GABAergic inhibitory processing is not fully matured yet in children compared with adults. Does this finding indicate that more efficient learning in children is not due to more rapid stabilization? Here, we measured the concentration of GABA in early visual cortical areas in a time-resolved fashion before, during, and after visual perceptual learning (VPL) within subjects using functional MRS (fMRS) and then compared the concentrations between children (8 to 11 years old) and adults (18 to 35 years old). We found that children exhibited a rapid boost of GABA during visual training that persisted after training ended, whereas the concentration of GABA in adults remained unchanged. Moreover, behavioral experiments showed that children exhibited rapid development of resilience to retrograde interference, which indicates that children stabilize VPL much faster than adults. These results together suggest that inhibitory processing in children's brains is more dynamic and adapts more quickly to stabilize learning than in adults, making learning more efficient in children.

Adamant: a JSON schema-based metadata editor for research data management workflows.

The web tool Adamant has been developed to systematically collect research metadata as early as the conception of the experiment. Adamant enables a continuous, consistent, and transparent research data management (RDM) process, which is a key element of good scientific practice ensuring the path to Findable, Accessible, Interoperable, Reusable (FAIR) research data. It simplifies the creation of on-demand metadata schemas and the collection of metadata according to established or new standards. The approach is based on JavaScript Object Notation (JSON) schema, where any valid schema can be presented as an interactive web-form. Furthermore, Adamant eases the integration of numerous available RDM methods and software tools into the everyday research activities of especially small independent laboratories. A programming interface allows programmatic integration with other software tools such as electronic lab books or repositories. The user interface (UI) of Adamant is designed to be as user friendly as possible. Each UI element is self-explanatory and intuitive to use, which makes it accessible for users that have little to no experience with JSON format and programming in general. Several examples of research data management workflows that can be implemented using Adamant are introduced. Adamant (client-only version) is available from: https://plasma-mds.github.io/adamant.

Case Report: PsAPSASH syndrome: an alternative phenotype of syndromic hidradenitis suppurativa treated with the IL-17A inhibitor secukinumab.

Syndromic hidradenitis suppurativa (HS) is a form of symptom constellations, which differs from the familial and genetic form and comprises predominantly osteoarticular manifestations. Many forms include pyoderma gangrenosum and acne (PASH), pyogenic arthritis (PAPASH), spondyloarthritis (PASS) and psoriatic arthritis (PsaPASH) and are categorized in the autoinflammatory syndromes. anti-TNF-α and anti-IL-1a blockade are between the therapeutic approaches that improve skin symptoms and prevent permanent osteoarticular damage. This case report refers to the successful treatment of a mixed phenotype of the aforementioned symptoms using the IL-17A inhibitor secukinumab after initial treatment with adalimumab. The therapy improved both cutaneous and reported osteoarticular symptoms. Different approaches for these recalcitrant HS syndromes are essential in order to achieve long-term remission for those patients.

Plasma-MDS, a metadata schema for plasma science with examples from plasma technology.

A metadata schema, named Plasma-MDS, is introduced to support research data management in plasma science. Plasma-MDS is suitable to facilitate the publication of research data following the FAIR principles in domain-specific repositories and with this the reuse of research data for data driven plasma science. In accordance with common features in plasma science and technology, the metadata schema bases on the concept to separately describe the source generating the plasma, the medium in which the plasma is operated in, the target the plasma is acting on, and the diagnostics used for investigation of the process under consideration. These four basic schema elements are supplemented by a schema element with various attributes for description of the resources, i.e. the digital data obtained by the applied diagnostic procedures. The metadata schema is first applied for the annotation of datasets published in INPTDAT-the interdisciplinary data platform for plasma technology.

Biomedical Research Meets Toxicology: How In Vitro Chromosome Instability Methods Can Contribute to Carcinogenicity Prediction.

Cancer is a major health concern and a leading cause of mortality. The reliable identification of carcinogens and understanding of carcinogenicity has become a main focus of biomedical research and regulatory toxicology. While biomedical research applies cellular in vitro methods to uncover the underlying mechanisms causing cancer, regulatory toxicology relies on animal testing to predict carcinogenicity of chemicals, often with limited human relevance. Exemplified by chromosome instability-mediated carcinogenicity, we discuss the need to combine the strengths of both fields to develop highly predictive and mechanism-derived in vitro methods that facilitate risk assessment in respect to relevant human diseases.

Nuclear Localization of Robo is Associated with Better Survival in Bladder Cancer.

The Slit-Robo pathway has shown to be altered in several malignant diseases. However, its role in bladder cancer is poorly understood. Therefore, we aimed to assess the tissue expression of Robo1 and Robo4 as well as their ligand Slit2 in different stages of bladder cancer to explore possible changes of Slit-Robo signalling during the progression of bladder cancer. Robo1, Robo4 and Slit2 gene expressions were analyzed in 92 frozen bladder cancer tissue samples by using reverse transcription quantitative real-time PCR. Immunohistochemical analyses were performed on 149 formalin-fixed and paraffin-embedded bladder cancer tissue samples. Results were correlated with the clinical and follow-up data by performing both univariable and multivariable analyses. Robo1 and Robo4 nuclear staining intensitiy was significantly higher in low stage and low grade bladder cancer. Elevated Robo1 nuclear staining was associated with better disease-specific survival (DSS) (p = 0.045). Similarly, stronger Robo4 nuclear staining tended to be associated with longer DSS (p = 0.061). We found higher Robo1 and Slit2 gene expression levels in advanced stages of bladder cancer (p = 0.007 and p < 0.001). High Slit2 gene expression was correlated with significantly shorter DSS (p < 0.005), while Robo1 and Robo4 gene expressions were not associated with patients' prognosis. Our results demonstrate that the nuclear expression of Robo1 and Robo4 is associated with a favourable prognosis suggesting that its translocation into the nucleus represent a posttranslational regulation process which may exhibit an antitumor effect in bladder cancer.

Multimodal Clinical Imaging Assessment of the Outcome in Mild-to-Moderate Acne: A Prospective Study.

BACKGROUND: The quality of outcome assessment in acne studies has been either subjective/insufficient or time consuming through the ordinary lesion counting. OBJECTIVE: To evaluate the application of multimodal clinical imaging (MCI), a combination of imaging technology and computation, in the assessment of acne lesions in a clinical study setting. METHODS: A prospective, monocentric, single-group open study designed to evaluate the efficacy and tolerance of a cosmetic product (IP/SG) in subjects with mild-to-moderate facial acne by classical clinical counting (CCC) - change in the total/inflammatory/noninflammatory acne lesion number compared with baseline (D0) - Investigator Global Assessment (IGA) and self-reported outcomes. Concomitantly, MCI was administered. The study was performed for 12 weeks (D84) with a 4-week follow-up (D112). RESULTS: Mean age of patients (n = 49) was 18.2 ± 3.7 years (range 13-25). The mean acne duration was 3.8 ± 2.8 years. The total number of lesions did not differ significantly between D0/D84 by both CCC and MCI. However, the Cardiff Acne Disability Index (CADI) and uncomfortable feeling improved at D28/D0, the perception of oily skin improved at D14/D0, and the perception of sticky skin improved from D28/D0 to D56/D0. Deterioration was detected between D84/D0 and D112/D0, namely after product discontinuation. Interestingly, a change in trend was recorded for acne lesions at D14/D0 by MCI but not by CCC. CONCLUSION: MCI, applied for the first time in a small clinical study setting, is at least as reliable as CCC and may allow for a sensitive longitudinal evaluation of single acne lesions and their response to products, especially in conditions where clinical evaluation reaches its limits.

Hyperspectral imaging of tissue perfusion and oxygenation in wounds: assessing the impact of a micro capillary dressing.

OBJECTIVE: Experimental tests of non-invasive multi- or hyperspectral imaging (HSI) systems reveal the high potential of support for medical diagnostic purposes and scientific biomedical analysis. Until now the use of HSI technologies for medical applications was limited by complex and overly sophisticated systems. We present a new and compact HSI-camera that could be used in normal clinical practice. METHOD: We assessed the use of the HSI system on the hands of 10 healthy volunteers, looking at control parameters, and those following venous occlusion, arterial occlusion and reperfusion, including tissue oxygenation, tissue haemoglobin index, perfusion in 4-6mm depth=near infrared spectroscopy (NIR), and tissue water index. Pseudo colours used ranged from 0% (blue) to 100% (red). We also assessed differences in the wounds of three patients. RESULTS: The results show good potential in all parameters in the healthy volunteers, which had high conformity with validated reference oximetry measurements. In three wounds, different levels of oxygenation were identified in the wound area, although interpretation of these results is complex. In Cases 2 and 3, following the application of a micro capillary dressing, improvements were seen in perfusion and reduction of the tissue water index (TWI). CONCLUSION: The camera system proved to be quick, flexible and yielded data with high spatial and spectral resolution. These data will be used to perform a power analysis for a randomised controlled study.

Objective assessment of acne.

A precise and reliable assessment of acne severity is unarguably the most essential clinical method when it comes to monitoring and choosing optimal treatment in the daily practice. Since the early 1960s, different severity assessment systems have been described in the literature. The two commonly used concepts are global gradings and lesion counting. Both systems have been controversially discussed as to which is more reliable and providing an objective outcome measurement tool; however, both have some subjectivity involved. More objective methods for assessing the severity of acne vulgaris include photography, fluorescence photography, polarized light photography, video microscopy, and multispectral imaging. Such techniques have limitations such as high cost, complex and sophisticated apparatus, and a sometimes time-consuming imaging process. There are newly developed technologies that could avoid the problems of inter- and intrarater subjectivity.

Formation of hybrid ABX3 perovskite compounds for solar cell application: first-principles calculations of effective ionic radii and determination of tolerance factors.

The development of hybrid organic-inorganic perovskite solar cells is one of the most rapidly growing fields in the photovoltaic community and is on its way to challenge polycrystalline silicon and thin film technologies. High power conversion efficiencies can be achieved by simple processing with low cost. However, due to the limited long-term stability and environmental toxicity of lead in the prototypic CH3NH3PbI3, there is a need to find alternative ABX3 constitutional combinations in order to promote commercialization. The Goldschmidt tolerance factor and the octahedral factor were found to be necessary geometrical concepts to evaluate which perovskite compounds can be formed. It was figured out that the main challenge lies in estimating an effective ionic radius for the molecular cation. We calculated tolerance factors and octahedral factors for 486 ABX3 monoammonium-metal-halide combinations, where the steric size of the molecular cation in the A-position was estimated concerning the total charge density. A thorough inquiry about existing mixed organic-inorganic perovskites was undertaken. Our results are in excellent agreement with the reported hybrid compounds and indicate the potential existence of 106 ABX3 combinations hitherto not discussed in the literature, giving hints for more intense research on prospective individual candidates.

A diagnostic predicament: activated sarcoidosis or pulmonary histoplasmosis. A case report.

We report a case of a 41-year-old man presenting with persisting fevers over 2 weeks. The patient had spent 4 weeks in Central America. He was in control of a stable stage II sarcoidosis. Laboratory and various microbiological tests as well as chest radiography led to no diagnosis. Activated sarcoidosis was hypothesized as the most likely diagnosis. However, we considered an infectious process as a differential diagnosis, in detail, the travel history imposed histoplasmosis. Chest-CT documented localized interstitial consolidations. Bronchoscopy with bronchoalveolar lavage (BAL) and biopsy was performed. Results of BAL fluid, biopsy, distinct sarcoidosis serum markers and a borderline positive histoplasmosis-serology yielded in a diagnostic dilemma as no distinct diagnosis was drawable. After the patient was already started on a prednisolone trial, the final diagnosis - pulmonary histoplasmosis - could be achieved via positive culture and PCR out of the BAL fluid. This case shows the difficult differentiation between an acute exacerbation of a chronic pulmonary disease and a concomitant infection, which was especially aggravated in this case as the histoplasmosis masqueraded an acute picture of sarcoidosis.

Analysis of putative protomer crosstalk in the trimeric transporter BetP: The heterotrimer approach.

The homotrimeric, secondary active betaine carrier BetP from Corynebacterium glutamicum is a model system for stress-regulated transport in bacteria. Its activity responds to hyperosmotic stress and it harbors two different functions, transport catalysis (betaine uptake) and stimulus sensing, resp. activity regulation. Structural information from 2D and 3D crystals as well as functional analysis of monomerized BetP suggested the presence of conformational crosstalk between the individual protomers. To study whether the oligomeric state is functionally significant on a mechanistic level we generated heterooligomeric complexes of BetP in which single protomers within the trimer can be addressed. By testing dominant negative effects in a trimer of one active protomer combined with two protomers in which transport and regulation were abolished, we provide experimental evidence for the absence of functionally significant conformational crosstalk between the protomers on the level of both transport and regulation. This is supported by experiments using mutant forms of putative interacting signal donor and acceptor domains of individual BetP protomers. This result has important consequences for oligomeric transport proteins in general and BetP in particular.

Direct identification of bacteria in urine samples by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and relevance of defensins as interfering factors.

Standard methods for the identification of uropathogens that are based on the determination of metabolic activity require cultivation on agar plates, which often takes more than 1 day. If microbial growth on agar plates is slow, or if metabolic activity is impaired by adverse interactions resulting from the patient's condition or from medical treatment, the application of standard methods may lead to delayed or erroneous identification of bacteria. In recent studies, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has proven to be able to rapidly identify bacteria obtained from cultures. We tested the applicability of this analytical technique for the rapid identification of bacteria collected directly from urine samples and compared the results with those of conventional identification methods, such as the Vitek system, the MicroScan WalkAway system and the API system, and in some cases with the gas chromatographic determination of the bacterial long-chain fatty acid pattern. We analysed a total of 107 urine samples with bacterial counts ranging from 10(2) to ≥10(5) c.f.u. ml(-1). Mass spectrometric identification of bacteria was accomplished for 62 of these samples. In the mass spectra obtained from 40 of the 45 urine samples for which no identification result was achieved, a triplet of very intense peaks corresponding to the human α-defensins 1, 2 and 3 occurred at m/z values of around 3440 Da. This signal suppressed the intensity of the bacterial protein peaks and thus impaired database matching. Our results show that MALDI-TOF MS allows the reliable direct identification of bacteria in urine samples at concentrations as low as 10(3) c.f.u. ml(-1). In a subset of samples, human defensins may occur and impair the mass spectrometric identification of bacteria.

Osmotic stress response in C. glutamicum: impact of channel- and transporter-mediated potassium accumulation.

Potassium accumulation is an essential aspect of bacterial response to diverse stress situations; consequently its uptake plays a pivotal role. Here, we show that the Gram-positive soil bacterium Corynebacterium glutamicum which is employed for the large-scale industrial production of amino acids requires potassium under conditions of ionic and non-ionic osmotic stress. Besides the accumulation of high concentrations of potassium contributing significantly to the osmotic potential of the cytoplasm, we demonstrate that glutamate is not the counter ion for potassium under these conditions. Interestingly, potassium is required for the activation of osmotic stress-dependent expression of the genes betP and proP. The Kup-type potassium transport system which is present in C. glutamicum in addition to the potassium channel CglK does not contribute to potassium uptake at conditions of hyperosmotic stress. Furthermore, we established a secondary carrier of the KtrAB type from C. jeikeium in C. glutamicum thus providing an experimental comparison of channel- and carrier-mediated potassium uptake under osmotic stress. While at low potassium availability, the presence of the KtrAB transporter improves both potassium accumulation and growth of C. glutamicum upon osmotic stress, at proper potassium supply, the channel CglK is sufficient.

PSA quo vadis? It is reasonable to start with prostate-specific antigen testing at the age of 40!

BACKGROUND: It is common to start with PSA (prostate-specific antigen)-testing at the age of 50. If patients with a PSA value greater than 4 ng/mL should be considered for prostate biopsy, approximately 20% of all men undergoing test are considered for biopsy at the time of first early-detection examination. METHODS: We have screened 2,592 asymptomatic men younger than 45 years. With a short questionnaire, we assessed age, body mass index (BMI), concomitant diseases, last sexual intercourse, and last bicycle riding. We compared this cohort with a group of 11,656 men aged 45-75 years from a nationwide prostate cancer screening trial. RESULTS: In this cohort, only 4 men with a PSA value greater than 4 ng/mL and 10 with a PSA greater than 3 ng/mL were identified. More than 99% of all men younger than 45 years had a PSA lesser than 4 ng/mL. Sexual intercourse, bicycle riding, or BMI had a significant but minimal influence on the PSA value. CONCLUSIONS: It is reasonable to start with PSA testing at the age of 40 years. The advantage of screening younger patients is that almost no one should be considered for biopsy at the time of first early-detection examination. We identified a baseline value at which only a minimal influence was exerted by benign prostatic hypertrophy. In comparison with many current guidelines, we gained a lead time of 10 years for observation of PSA dynamics. IMPACT: The importance of PSA velocity for stratification of patients at risk for development of significant prostate cancer will grow.