Response to trametinib, hydroxychloroquine, and bevacizumab in a young woman with NRAS-mutated metastatic intrahepatic cholangiocarcinoma: a case report.

Systemic chemotherapy is the main treatment option for patients with advanced intrahepatic cholangiocarcinoma (iCCA), however, its efficacy is limited. Herein, we report a young patient with NRAS-mutated chemoresistant metastatic iCCA, who received second-line therapy with a combination of trametinib (MEK1/2 inhibitor), hydroxychloroquine (autophagy inhibitor), and bevacizumab (angiogenesis inhibitor). A significant response was achieved during therapy, resulting in a 25% decrease in the size of tumor lesions after 2 months of treatment and an improvement in the patient's condition. The duration of this response was 4 months, but the patient died 10 months after the initiation of this triple therapy. This case report and the analysis of other available studies warrant further investigations on combined MEK and autophagy inhibition in RAS-mutated tumors.

First Insight into the Degradome of Aspergillus ochraceus: Novel Secreted Peptidases and Their Inhibitors.

Aspergillus fungi constitute a pivotal element within ecosystems, serving as both contributors of biologically active compounds and harboring the potential to cause various diseases across living organisms. The organism's proteolytic enzyme complex, termed the degradome, acts as an intermediary in its dynamic interaction with the surrounding environment. Using techniques such as genome and transcriptome sequencing, alongside protein prediction methodologies, we identified putative extracellular peptidases within Aspergillus ochraceus VKM-F4104D. Following manual annotation procedures, a total of 11 aspartic, 2 cysteine, 2 glutamic, 21 serine, 1 threonine, and 21 metallopeptidases were attributed to the extracellular degradome of A. ochraceus VKM-F4104D. Among them are enzymes with promising applications in biotechnology, potential targets and agents for antifungal therapy, and microbial antagonism factors. Thus, additional functionalities of the extracellular degradome, extending beyond mere protein substrate digestion for nutritional purposes, were demonstrated.

Comparing experience- and description-based economic preferences across 11 countries.

Recent evidence indicates that reward value encoding in humans is highly context dependent, leading to suboptimal decisions in some cases, but whether this computational constraint on valuation is a shared feature of human cognition remains unknown. Here we studied the behaviour of n = 561 individuals from 11 countries of markedly different socioeconomic and cultural makeup. Our findings show that context sensitivity was present in all 11 countries. Suboptimal decisions generated by context manipulation were not explained by risk aversion, as estimated through a separate description-based choice task (that is, lotteries) consisting of matched decision offers. Conversely, risk aversion significantly differed across countries. Overall, our findings suggest that context-dependent reward value encoding is a feature of human cognition that remains consistently present across different countries, as opposed to description-based decision-making, which is more permeable to cultural factors.

The relationship between charitable giving and emotional facial expressions: Results from affective computing.

This study investigated the relationship between emotional states (valence, arousal, and six basic emotions) and donation size in pet charities, and it compared the effectiveness of affective computing and emotion self-report methods in assessing attractiveness. Using FaceReader software and self-report, we measured the emotional states of participants (N = 45) during the donation task. The results showed that sadness, happiness, and anger were significantly related to donation size. Sadness and anger increased donations, whereas happiness decreased them. Arousal was not significantly correlated with the willingness to donate. These results are supported by both methods, whereas the self-reported data regarding the association of surprise, fear, and disgust with donation size are inconclusive. Thus, unpleasant emotions increase donation size, and combining affective computing with self-reported data improves the prediction of the effectiveness of a charity appeal. This study contributes to the understanding of the relationship between emotions and charitable behavior toward pet charities and evaluates the effectiveness of marketing mix elements using affective computing. The limitations include the laboratory setting for this experiment and the lack of measurement of prolonged and repeated exposure to unpleasant charity appeals.

Evaluating the Influence of Musical and Monetary Rewards on Decision Making through Computational Modelling.

A central question in behavioural neuroscience is how different rewards modulate learning. While the role of monetary rewards is well-studied in decision-making research, the influence of abstract rewards like music remains poorly understood. This study investigated the dissociable effects of these two reward types on decision making. Forty participants completed two decision-making tasks, each characterised by probabilistic associations between stimuli and rewards, with probabilities changing over time to reflect environmental volatility. In each task, choices were reinforced either by monetary outcomes (win/lose) or by the endings of musical melodies (consonant/dissonant). We applied the Hierarchical Gaussian Filter, a validated hierarchical Bayesian framework, to model learning under these two conditions. Bayesian statistics provided evidence for similar learning patterns across both reward types, suggesting individuals' similar adaptability. However, within the musical task, individual preferences for consonance over dissonance explained some aspects of learning. Specifically, correlation analyses indicated that participants more tolerant of dissonance behaved more stochastically in their belief-to-response mappings and were less likely to choose the response associated with the current prediction for a consonant ending, driven by higher volatility estimates. By contrast, participants averse to dissonance showed increased tonic volatility, leading to larger updates in reward tendency beliefs.

Regionally specific cortical lateralization of abstract and concrete verb processing: Magnetic mismatch negativity study.

The neural underpinnings of processing concrete and abstract semantics remain poorly understood. Previous fMRI studies have shown that multimodal and amodal neural networks respond differentially to different semantic types; importantly, abstract semantics activates more left-lateralized networks, as opposed to more bilateral activity for concrete words. Due to the lack of temporal resolution, these fMRI results do not allow to easily separate language- and task-specific brain responses and to disentangle early processing stages from later post-comprehension phenomena. To tackle this, we used magnetoencephalography (MEG), a time-resolved neuroimaging technique, in combination with a task-free oddball mismatch negativity (MMN) paradigm, an established approach to tracking early automatic activation of word-specific memory traces in the brain. We recorded the magnetic MMN responses in 30 healthy adults to auditorily presented abstract and concrete action verbs to assess lateralization of word-specific lexico-semantic processing in a set of neocortical areas. We found that MMN responses to these stimuli showed different lateralization patterns of activity in the upper limb motor area (BA4) and parts of Broca's area (BA45/BA47) within ∼100-350 ms after the word disambiguation point. Importantly, the greater leftward response lateralization for abstract semantics was due to the lesser involvement of the right-hemispheric homologues, not increased left-hemispheric activity. These findings suggest differential region-specific involvement of bilateral sensorimotor systems already in the early automatic stages of processing abstract and concrete action semantics.

Transspinal Direct Current Electrical Stimulation Selectively Affects the Excitability of the Corticospinal System, Depending on the Intensity but Not Motor Skills.

Transspinal direct current stimulation (tsDCS) is a non-invasive technique used to modulate spinal cord activity. However, the effects and mechanisms of this stimulation are currently not comprehensively known. This study aimed to estimate the effect of different intensities of tsDCS applied at the level of cervical enlargement of the spinal cord (C7-Th1 segments) on the excitability of the corticospinal system (CSS) and the correction of motor skills in healthy subjects. The effect of tsDCS was estimated by the motor-evoked potentials (MEP) elicited by transcranial magnetic stimulation (TMS) in the primary motor cortex (M1). The study involved 54 healthy adults aged 22 ± 4 years. The application of 11 min anodal tsDCS at the level of the cervical spine C7-Th1 with a current intensity of 2.5 mA did not change the MEP amplitude of the upper limb muscles, in contrast to the data that we previously obtained with a current intensity of 1.5 mA. We also found no difference in the effect of 2.5 mA stimulation on motor skill correction in healthy subjects in the nine-hole peg test (9-HPT) and the serial reaction time task (SRT) as with 1.5 mA stimulation. Our data show that an increase in the intensity of stimulation does not lead to an increase in the effects but rather reduces the effects of stimulation. These results provide information about the optimally appropriate stimulation current intensities to induce CSS excitability and the ability of tsDCS to influence motor skills in healthy adults.

Correction: The Prediction of Market-level Food Choices by the Neural Valuation Signal.

[This corrects the article DOI: 10.1371/journal.pone.0286648.].

Molecular Analysis of Biliary Tract Cancers with the Custom 3' RACE-Based NGS Panel.

The technique 3' rapid amplification of cDNA ends (3' RACE) allows for detection of translocations with unknown gene partners located at the 3' end of the chimeric transcript. We composed a 3' RACE-based RNA sequencing panel for the analysis of FGFR1-4 gene rearrangements, detection of activating mutations located within FGFR1-4, IDH1/2, ERBB2 (HER2), KRAS, NRAS, BRAF, and PIK3CA genes, and measurement of the expression of ERBB2, PD-L1, and FGFR1-4 transcripts. This NGS panel was utilized for the molecular profiling of 168 biliary tract carcinomas (BTCs), including 83 intrahepatic cholangiocarcinomas (iCCAs), 44 extrahepatic cholangiocarcinomas (eCCAs), and 41 gallbladder adenocarcinomas (GBAs). The NGS failure rate was 3/168 (1.8%). iCCAs, but not other categories of BTCs, were characterized by frequent FGFR2 alterations (17/82, 20.7%) and IDH1/2 mutations (23/82, 28%). Other potentially druggable events included ERBB2 amplifications or mutations (7/165, 4.2% of all successfully analyzed BTCs) and BRAF p.V600E mutations (3/165, 1.8%). In addition to NGS, we analyzed microsatellite instability (MSI) using the standard five markers and revealed this event in 3/158 (1.9%) BTCs. There were no instances of ALK, ROS1, RET, and NTRK1-3 gene rearrangements or MET exon 14 skipping mutations. Parallel analysis of 47 iCCA samples with the Illumina TruSight Tumor 170 kit confirmed good performance of our NGS panel. In conclusion, targeted RNA sequencing coupled with the 3' RACE technology is an efficient tool for the molecular diagnostics of BTCs.

Screening of proteases produced by Aspergillus micromycetes active against proteins of the hemostasis system.

Background and Purpose: For these intents, proteases cardiovascular disease is the primary cause of death; hence, accurate diagnosis and treatment are urgently required are regarded as prospective agents . High substrate specificity is needed for an effective enzyme, which makes Aspergillus micromycetes, known for producing proteases with precise action, biotechnologically promising. This study mainly aimed to look at the possibilities of Aspergillus species, which had never been mentioned in terms of general proteolytics. Materials and Methods: Every species was cultivated in two-stage submerged conditions with two different nitrogen sources; whereupon, proteolytic activity in culture fluid was determined. Chromogenic peptide substrates and fibrin plates were used to evaluate the thrombin, plasmin, factor Xa, urokinase, protein C-like, activating activities towards hemostasis proteins, as well as fibrinolytic and plasminogen-activating activities of these species. Results: It was found that A. aureolatus and A. tennesseensis are active proteolytics exhibiting plasmin-like activities (116.17 and 87.09 U×10-3, respectively), factor Xa-like activity (76.27 and 77.92 U×10-3, respectively) and urokinase activity (85.99 and 59.91 U×10-3, respectively). The thrombin-like activity was found for A. tabacinus (50.37 U×10-3), and protein C-like activity was noticeable for A. creber, A. jensenii, A. protuberus, and A. ruber (62.90, 65.51, 73.37, and 111.85 U×10-3, respectively). Additionally, more than half of species had the ability to directly activate plasminogen or operate as fibrinolytics. Conclusion: New proteolytic strains were discovered, offering hope for the therapy of cardiovascular disorders. The high specificity and activity of fungal enzymes make them useful in a variety of fields, including medicine and diagnostics.

Cost-Efficient Detection of NTRK1/2/3 Gene Fusions: Single-Center Analysis of 8075 Tumor Samples.

The majority of NTRK1, NTRK2, and NTRK3 rearrangements result in increased expression of the kinase portion of the involved gene due to its fusion to an actively transcribed gene partner. Consequently, the analysis of 5'/3'-end expression imbalances is potentially capable of detecting the entire spectrum of NTRK gene fusions. Archival tumor specimens obtained from 8075 patients were subjected to manual dissection of tumor cells, DNA/RNA isolation, and cDNA synthesis. The 5'/3'-end expression imbalances in NTRK genes were analyzed by real-time PCR. Further identification of gene rearrangements was performed by variant-specific PCR for 44 common NTRK fusions, and, whenever necessary, by RNA-based next-generation sequencing (NGS). cDNA of sufficient quality was obtained in 7424/8075 (91.9%) tumors. NTRK rearrangements were detected in 7/6436 (0.1%) lung carcinomas, 11/137 (8.0%) pediatric tumors, and 13/851 (1.5%) adult non-lung malignancies. The highest incidence of NTRK translocations was observed in pediatric sarcomas (7/39, 17.9%). Increased frequency of NTRK fusions was seen in microsatellite-unstable colorectal tumors (6/48, 12.5%), salivary gland carcinomas (5/93, 5.4%), and sarcomas (7/143, 4.9%). None of the 1293 lung carcinomas with driver alterations in EGFR/ALK/ROS1/RET/MET oncogenes had NTRK 5'/3'-end expression imbalances. Variant-specific PCR was performed for 744 tumors with a normal 5'/3'-end expression ratio: there were no rearrangements in 172 EGFR/ALK/ROS1/RET/MET-negative lung cancers and 125 pediatric tumors, while NTRK3 fusions were detected in 2/447 (0.5%) non-lung adult malignancies. In conclusion, this study describes a diagnostic pipeline that can be used as a cost-efficient alternative to conventional methods of NTRK1-3 analysis.

Rapid and Cost-Efficient Detection of RET Rearrangements in a Large Consecutive Series of Lung Carcinomas.

RET-kinase-activating gene rearrangements occur in approximately 1-2% of non-small-cell lung carcinomas (NSCLCs). Their reliable detection requires next-generation sequencing (NGS), while conventional methods, such as immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) or variant-specific PCR, have significant limitations. We developed an assay that compares the level of RNA transcripts corresponding to 5'- and 3'-end portions of the RET gene; this test relies on the fact that RET translocations result in the upregulation of the kinase domain of the gene and, therefore, the 5'/3'-end expression imbalance. The present study included 16,106 consecutive NSCLC patients, 14,449 (89.7%) of whom passed cDNA quality control. The 5'/3'-end unbalanced RET expression was observed in 184 (1.3%) tumors, 169 of which had a sufficient amount of material for the identification of translocation variants. Variant-specific PCR revealed RET rearrangements in 155/169 (91.7%) tumors. RNA quality was sufficient for RNA-based NGS in 10 cases, 8 of which carried exceptionally rare or novel (HOOK1::RET and ZC3H7A::RET) RET translocations. We also applied variant-specific PCR for eight common RET rearrangements in 4680 tumors, which emerged negative upon the 5'/3'-end unbalanced expression test; 33 (0.7%) of these NSCLCs showed RET fusion. While the combination of the analysis of 5'/3'-end RET expression imbalance and variant-specific PCR allowed identification of RET translocations in approximately 2% of consecutive NSCLCs, this estimate approached 120/2361 (5.1%) in EGFR/KRAS/ALK/ROS1/BRAF/MET-negative carcinomas. RET-rearranged tumors obtained from females, but not males, had a decreased level of expression of thymidylate synthase (p < 0.00001), which is a known predictive marker of the efficacy of pemetrexed. The results of our study provide a viable alternative for RET testing in facilities that do not have access to NGS due to cost or technical limitations.

Neurochronometry of choice-induced preference changes: when do preferences actually change?

According to cognitive dissonance theory, a discrepancy between preferences and actions may lead to the revaluation of preferences, increasing preference for the chosen options and decreasing for the rejected options. This phenomenon is known as the spreading of alternatives (SoA), which results in a choice-induced preference change (CIPC). Previous neuroimaging studies have identified several brain regions that play a role in cognitive dissonance. However, the neurochronometry of the cognitive mechanisms underlying CIPC is a topic of debate. In other words, does it occur during the difficult choice, immediately after the choice, or when people encounter the options again? Furthermore, it remains unclear what is the exact time point, relative to the onset of facing options, either within the choice or after it, when the attitudes start to be revised. We argue that applying online protocols of transcranial magnetic stimulation (TMS), during or immediately after the choice process, could be the most efficient way to better understand the temporal dynamics of the SoA effect. TMS allows for achieving high temporal and spatial resolution, modulating the activity of areas of interest, and examining the causal relationships. Besides, unlike the offline TMS, the online instrument allows tracking of the neurochronometry of attitude change, by varying stimulation onsets and durations with respect to the option stimuli. Based on scrupulous analysis of previous findings, employing online TMS studies of conflict monitoring, cognitive control, and CIPC neuroimaging results, we conclude that the use of online TMS is critical to examine the neurochronometry of CIPC.

The prediction of market-level food choices by the neural valuation signal.

Neuroimaging studies have demonstrated the ability to use the brain activity of a group of individuals to forecast the behavior of an independent group. In the current study, we attempted to forecast aggregate choices in a popular restaurant chain. During our functional magnetic resonance imaging (fMRI) study, 22 participants were exposed to 78 photos of dishes from a new menu of a popular restaurant chain. In addition to self-reported preferences, fMRI data was extracted from an a priori domain-general and task-specific region of interest-the ventral striatum. We investigated the relationship between the neural activity and real one-year sales provided by the restaurant chain. Activity in the ventral striatum, which was defined using the task-specific region of interest, significantly correlated (r = 0.28, p = 0.01) with one-year sales. A regression analysis, which included ventral striatum activity together with the objective characteristics of the products (price and weight), behavioral, and survey data, showed R2 values of 0.33. Overall, our results confirm prior studies, which have suggested, that brain activity in the reward system of a relatively small number of individuals can forecast the aggregate choice of a larger independent group of people.

New approach to soil management focusing on soil health and air quality: one earth one life (critical review).

Soil plays a key role in ecosphere and air quality regulation. Obsolete environmental technologies lead to soil quality loss, air, water, and land systems pollution. Pedosphere and plants are intertwined with the air quality. Ionized O2 is capable to intensify atmosphere turbulence, providing particulate matter (PM2.5) coalescence and dry deposition. Addressing environmental quality, a Biogeosystem Technique (BGT*) heuristic transcendental (nonstandard and not direct imitation of nature) methodology has been developed. A BGT* main focus is an enrichment of Earth's biogeochemical cycles through land use and air cleaning. An intra-soil processing, which provides the soil multilevel architecture, is one of the BGT* ingredients. A next BGT* implementation is intra-soil pulse continuously discrete watering for optimal soil water regime and freshwater saving up to 10-20 times. The BGT* comprises intra-soil dispersed environmentally safe recycling of the PM sediments, heavy metals (HMs) and other pollutants, controlling biofilm-mediated microbial community interactions in the soil. This provides abundant biogeochemical cycle formation and better functioning of the humic substances, biological preparation, and microbial biofilms as a soil-biological starter, ensuring priority plants and trees nutrition, growth and resistance to phytopathogens. A higher underground and aboveground soil biological product increases a reversible C biological sequestration from the atmosphere. An additional light O2 ions photosynthetic production ensures a PM2.5 and PM0.1 coalescence and strengthens an intra-soil transformation of PM sediments into nutrients and improves atmosphere quality. The BGT* provides PM and HMs intra-soil passivation, increases soil biological productivity, stabilizes a climate system of the earth and promotes a green circular economy.

KRAS, NRAS, BRAF, HER2 and MSI Status in a Large Consecutive Series of Colorectal Carcinomas.

This study aimed to analyze clinical and regional factors influencing the distribution of actionable genetic alterations in a large consecutive series of colorectal carcinomas (CRCs). KRAS, NRAS and BRAF mutations, HER2 amplification and overexpression, and microsatellite instability (MSI) were tested in 8355 CRC samples. KRAS mutations were detected in 4137/8355 (49.5%) CRCs, with 3913 belonging to 10 common substitutions affecting codons 12/13/61/146, 174 being represented by 21 rare hot-spot variants, and 35 located outside the "hot" codons. KRAS Q61K substitution, which leads to the aberrant splicing of the gene, was accompanied by the second function-rescuing mutation in all 19 tumors analyzed. NRAS mutations were detected in 389/8355 (4.7%) CRCs (379 hot-spot and 10 non-hot-spot substitutions). BRAF mutations were identified in 556/8355 (6.7%) CRCs (codon 600: 510; codons 594-596: 38; codons 597-602: 8). The frequency of HER2 activation and MSI was 99/8008 (1.2%) and 432/8355 (5.2%), respectively. Some of the above events demonstrated differences in distribution according to patients' age and gender. In contrast to other genetic alterations, BRAF mutation frequencies were subject to geographic variation, with a relatively low incidence in areas with an apparently warmer climate (83/1726 (4.8%) in Southern Russia and North Caucasus vs. 473/6629 (7.1%) in other regions of Russia, p = 0.0007). The simultaneous presence of two drug targets, BRAF mutation and MSI, was observed in 117/8355 cases (1.4%). Combined alterations of two driver genes were detected in 28/8355 (0.3%) tumors (KRAS/NRAS: 8; KRAS/BRAF: 4; KRAS/HER2: 12; NRAS/HER2: 4). This study demonstrates that a substantial portion of RAS alterations is represented by atypical mutations, KRAS Q61K substitution is always accompanied by the second gene-rescuing mutation, BRAF mutation frequency is a subject to geographical variations, and a small fraction of CRCs has simultaneous alterations in more than one driver gene.

Outcome context-dependence is not WEIRD: Comparing reinforcement- and description-based economic preferences worldwide.

Recent evidence indicates that reward value encoding in humans is highly context-dependent, leading to suboptimal decisions in some cases. But whether this computational constraint on valuation is a shared feature of human cognition remains unknown. To address this question, we studied the behavior of individuals from across 11 countries of markedly different socioeconomic and cultural makeup using an experimental approach that reliably captures context effects in reinforcement learning. Our findings show that all samples presented evidence of similar sensitivity to context. Crucially, suboptimal decisions generated by context manipulation were not explained by risk aversion, as estimated through a separate description-based choice task (i.e., lotteries) consisting of matched decision offers. Conversely, risk aversion significantly differed across countries. Overall, our findings suggest that context-dependent reward value encoding is a hardcoded feature of human cognition, while description-based decision-making is significantly sensitive to cultural factors.

High-grade B-cell lymphoma with concurrent MYC rearrangement and 11q aberrations: clinicopathologic, cytogenetic, and molecular characterization of 4 cases.

High-grade B-cell lymphoma with 11q aberrations (LBL-11q) resembles Burkitt lymphoma (BL), is negative for MYC rearrangement, and harbors chromosome 11q aberrations. Rare cases of high-grade B-cell lymphoma with concurrent MYC rearrangement and 11q aberrations (HGBCL-MYC-11q) have been described. In this study, we report the clinicopathologic, cytogenetic, and molecular findings in 4 such cases. Diagnoses were made on tissue or bone marrow biopsies. Karyotype, fluorescence in situ hybridization, genomic microarray analyses, and next-generation sequencing were performed. All patients were male (median age, 39 years). Three cases were diagnosed as BL, while one was diagnosed as diffuse large B-cell lymphoma. Karyotypes (available in 2 patients) were complex. In 1 patient, copy number analysis showed gains at 1q21.1-q44 and 13q31.3 and loss of 13q34, abnormalities typically seen in BL. All of our cases showed 2 or more mutations that are recurrent in BL, including ID3, TP53, DDX3X, CCND3, FBXO1, and MYC. Two cases showed a GNA13 mutation, commonly seen in LBL-11q. Cases of HGBCL-MYC-11q display overlapping morphologic and immunophenotypic, as well as cytogenetic and molecular features between BL and LBL-11q, with a mutational landscape enriched for mutations recurrent in BL. Concurrent MYC rearrangement with 11q abnormalities is important to recognize, especially as it has implications for their classification.

Neural mechanisms of expert persuasion on willingness to pay for sugar.

Introduction: Sugar consumption is associated with many negative health consequences. It is, therefore, important to understand what can effectively influence individuals to consume less sugar. We recently showed that a healthy eating call by a health expert can significantly decrease the willingness to pay (WTP) for sugar-containing food. Here, we investigate which aspects of neural responses to the same healthy eating call can predict the efficacy of expert persuasion. Methods: Forty-five healthy participants performed two blocks of a bidding task, in which they had to bid on sugar-containing, sugar-free and non-edible products, while their electroencephalography (EEG) was recorded. In between the two blocks, they listened to a healthy eating call by a nutritionist emphasizing the risks of sugar consumption. Results: We found that after listening to the healthy eating call, participants significantly decreased their WTP for sugar-containing products. Moreover, a higher intersubject correlation of EEG (a measure of engagement) during listening to the healthy eating call resulted in a larger decrease in WTP for sugar-containing food. Whether or not a participant's valuation of a product was highly influenced by the healthy eating call could also be predicted by spatiotemporal patterns of EEG responses to the healthy eating call, using a machine learning classification model. Finally, the healthy eating call increased the amplitude of the P300 component of the visual event-related potential in response to sugar-containing food. Disussion: Overall, our results shed light on the neural basis of expert persuasion and demonstrate that EEG is a powerful tool to design and assess health-related advertisements before they are released to the public.