Prime Type Research Articles

Crosstalk between three CRISPR-Cas types enables primed type VI-A adaptation in Listeria seeligeri.

CRISPR-Cas systems confer adaptive immunity to their prokaryotic hosts through the process of adaptation, where sequences are captured from foreign nucleic acids and integrated as spacers in the CRISPR array, and thereby enable crRNA-guided interference against new threats. While the Cas1-2 integrase is critical for adaptation, it is absent from many CRISPR-Cas loci, rendering the mechanism of spacer acquisition unclear for these systems. Here we show that the RNA-targeting type VI-A CRISPR system of Listeria seeligeri acquires spacers from DNA substrates through the action of a promiscuous Cas1-2 integrase encoded by a co-occurring type II-C system, in a transcription-independent manner. We further demonstrate that the type II-C integration complex is strongly stimulated by preexisting spacers in a third CRISPR system (type I-B) which imperfectly match phage targets and prime type VI-A adaptation. Altogether, our results reveal an unprecedented degree of communication among CRISPR-Cas loci encoded by a single organism.

Sanguineous cardiopulmonary bypass prime accelerates the inflammatory response during pediatric cardiac surgery.

The inflammatory response to cardiopulmonary bypass (CPB) in pediatric patients remains an unresolved challenge. Sanguineous CPB prime, composed of allogenic blood products, is one potentially important stimulus. This study aims to identify specific inflammatory mediators active in sanguineous CPB prime and their impact on the inflammatory response at CPB initiation. In a post-hoc analysis of a prospective observational cohort study (NCT05154864), where pediatric patients undergoing cardiac surgery with CPB were enrolled after informed consent, patients were grouped by CPB prime type (sanguineous vs crystalloid). Arterial samples were collected post-sternotomy as a baseline and again at CPB initiation from all patients. In the sanguineous group, CPB prime samples were also collected after buffered ultrafiltration but before CPB initiation. Luminex® measured concentrations of 24 inflammatory mediators for comparison between groups. Statistical analyses were by Mann-Whitney test and Wilcoxon signed-rank test. Data are presented as median [IQR]. Forty consecutive pediatric patients participated. The sanguineous group (n = 26) was younger (4.0 [0.2 - 6.0] vs 48.5 [39.0 - 69.5] months; p = 2.6 × 10-7) and smaller (4.9 [34 - 6.6] vs 17.2 [14.9 - 19.6] kg; p = 2.6 × 10-7) than the crystalloid group (n = 14). Despite this, baseline concentrations of 20 complement and cytokine concentrations were comparable between groups (p > 0.05) while four showed differences between groups (p < 0.05). The sanguineous prime contained supraphysiologic concentrations of complement mediators: C2, C3, C3a, C3b, and C5a. Correspondingly, upon CPB initiation, patients receiving sanguineous prime exhibited a significantly larger burden of C2, C3, C3b, C5, and C5a (p < 0.001) relative to the crystalloid group. Cytokine and chemokine mediators were present at trace levels in the sanguineous prime. Sanguineous prime contains activated complement that accelerates the inflammatory response at CPB initiation in neonates and infants. Immunomodulatory interventions targeting complement during CPB prime preparation could offer substantial benefits for these vulnerable patients.

The shear bond strength of orthodontic brackets after surface conditioning of Zirconia, Ceramic and E. max models

The current study aims to evaluate the shear bond strength (SBS) of metal orthodontic brackets after surface conditioning by hydrofluoric acid (HF) and aluminum oxide air abrasion (Al2O3) and using two prime types and to determines the adhesive remnant index (ARI). We compared the bond strength of different types of models (full glazed zirconia, ceramic faced zirconia and E. max faced zirconia) with different surface conditioning methods for attaching metal orthodontic brackets. The study used 60 models for each material, divided into subgroups based on the type of prime material and surface preparation method. The bond strength was measured using a universal testing machine and the results were analyzed using statistical software. Shear bond strength of the Aluminum oxide was statistically (p&lt;0.05) higher than the hydrofluoric acid and control groups in all groups (full glazed zirconia, ceramic faced zirconia and E. max faced zirconia). The Assure® Plus primer with Aluminum oxide surface treatment give rise to the highest shear bond strength than 3M™ Transbond™ XT, while there was no significant difference between Assure® Plus and 3M™ Transbond™ XT primer for both control and hydrofluoric acid groups. The highest shear bond strength was obtained with Aluminum oxide conditioning method for all types of ceramic materials used in this study.

Harnessing immune priming: A double‐edged defence mechanism in insects

AbstractInsects are known to dominate adverse ecological conditions due to their diverse adaptations and resilient biological traits, with their immune systems playing a crucial role in this dominance. Traditionally, insects were thought to lack adaptive immune responses due to their inability to produce antibodies and transfer immunity across generations. However, recent research using insects as model organisms has challenged this notion, revealing that prior exposure to sublethal doses of pathogens or pathogen‐derived materials can protect against subsequent lethal exposures—a phenomenon known as ‘immune priming’. Evidence of bacterial, fungal and viral immune priming across different insect species highlights various types of priming, including trans‐stadial (across life stages) and trans‐generational (across generations) priming. Despite differing views on immune priming, its potential applications in agriculture are considerable, especially in biological control, the utilization of beneficial insects and sustainable pest management. This review explores the intricate dynamics of immune priming in insects, comparing it to vertebrate immunity and investigates its mechanisms, potential agricultural applications and future prospects.

Tracking the epidemiological trends of female breast cancer in Saudi Arabia since 1990 and forecasting future statistics using global burden of disease data, time-series analysis

BackgroundFemale breast cancer stands as the prime type of cancer in the Kingdom of Saudi Arabia (KSA), with a high incidence and mortality rates. This study assessed the burden of female breast cancer in KSA by analyzing and forecasting its incidence, mortality, and disability-adjusted life years (DALYs).MethodsWe retrieved data from the Global Burden of Disease (GBD) about female breast cancer from 1990 to 2021. Time-series analysis used the autoregressive integrated moving average (ARIMA) model to forecast female breast cancer statistics from 2022 to 2026.ResultsFrom 1990 to 2021, KSA reported 77,513 cases of female breast cancer. The age groups with the highest number of cases are 45–49 years, followed by 40–44 years, 50–54 years, and 35–39 years. The analysis also showed fewer cases in the younger age groups, with the lowest number in the less than 20-year-old age group. From 1990 to 2021, KSA reported 19,440 deaths due to breast cancer, increasing from 201 cases in 1990 to 1,190 cases in 2021. The age-standardized incidence rate/100,000 of breast cancer increased from 15.4 (95% confidence interval (CI) 11.2–21.0) in 1990 to 46.0 (95%CI 34.5–61.5) in 2021. The forecasted incidence rate of female breast cancer will be 46.5 (95%CI 45.8–46.5) in 2022 and 49.6 (95%CI 46.8–52.3) in 2026. The age-standardized death rate per 100,000 Saudi women with breast cancer increased from 6.73 (95%CI 6.73–9.03) in 1990 to 9.77 (95%CI 7.63–13.00) in 2021. The forecasted female breast cancer death rate will slightly decrease to 9.67 (95%CI 9.49–9.84) in 2022 and to 9.26 (95%CI 8.37–10.15) in 2026. DALYs increased from 229.2 (95%CI 165.7–313.6) in 1990 to 346.1 (95%CI 253.9–467.2) in 2021. The forecasted DALYs of female breast cancer will slightly decrease to 343.3 (95%CI 337.2–349.5) in 2022 reaching 332.1 (95%CI 301.2–363.1) in 2026.ConclusionsFemale breast cancer is still a significant public health burden that challenges the health system in KSA, current policies and interventions should be fashioned to alleviate the disease morbidity and mortality and mitigate its future burden.

Semantic versus perceptual priming: dissecting their impact on intuitive judgments of semantic coherence.

This research explores the mechanisms underlying the intuitive processing of semantic coherence, focusing on the effects of semantic and perceptual priming on semantic coherence detection. Two studies examined how these priming types influence individuals' abilities to discern semantic incoherence. In Study 1, we used solutions to semantically coherent triads as primes, finding that such priming significantly improves participants' accuracy and confidence in identifying incoherent elements within word tetrads. These results corroborate the hypothesis that intuitive judgments in linguistic tasks are closely tied to the processing fluency elicited by semantic connections. In Study 2, we show that perceptual priming does not significantly enhance accuracy, albeit it does increase the confidence with which individuals make their judgments. Distinct effects of semantic and perceptual priming on intuitive judgments highlight the complex interplay between processing fluency and affect in shaping intuitive judgments of semantic coherence. We discuss the nuanced roles of semantic and perceptual factors in influencing the accuracy and confidence of intuitive decisions.

Multi-criteria evaluation of poly-generation system applied to commercial buildings with various prime movers and building types

The present study evaluates the performance of a poly-generation system applied to commercial buildings. An internal combustion engine (ICE) and solid oxide fuel cell (SOFC) used as prime movers represent different efficiency distributions according to part load ratio variation. Accordingly, discrete results are found in terms of energy, environment, and economy depending on the prime mover type applied to each building. A renewable energy system is combined with the poly-generation system, and the outputs produced from the energy generation units are transferred to the energy storage system and supplied to the demand sources. Through the parametric study and hybrid control method, the stored energy is optimally distributed to the cooling and heating system to maximize the primary energy saving ratio. The major components constituting the poly-generation system are modeled and validated based on experiments and literature to enhance the reliability of the dynamic simulation model. The monthly amounts of replenished and wasted energy are examined, and the magnitude of produced energy contribution to the building self-sufficiency ratio is also identified. When ICE- and SOFC-based poly-generations are applied to the hospital, 30.2% and 45.2% of the primary energy consumption is saved, respectively, compared with the conventional system. For the office, the corresponding systems reduce primary energy consumption by 1.8% and 37.2%, respectively. The economic feasibility of the poly-generation systems is examined considering the current energy project in South Korea.

Proteomic analysis and functional validation reveal distinct therapeutic capabilities related to priming of mesenchymal stromal/stem cells with IFN-γ and hypoxia: potential implications for their clinical use.

Mesenchymal stromal/stem cells (MSCs) are a heterogeneous population of multipotent cells that can be obtained from various tissues, such as dental pulp, adipose tissue, bone marrow and placenta. MSCs have gained importance in the field of regenerative medicine because of their promising role in cell therapy and their regulatory abilities in tissue repair and regeneration. However, a better characterization of these cells and their products is necessary to further potentiate their clinical application. In this study, we used unbiased high-resolution mass spectrometry-based proteomic analysis to investigate the impact of distinct priming strategies, such as hypoxia and IFN-γ treatment, on the composition and therapeutic functionality of the secretome produced by MSCs derived from the amniotic membrane of the human placenta (hAMSCs). Our investigation revealed that both types of priming improved the therapeutic efficacy of hAMSCs, and these improvements were related to the secretion of functional factors present in the conditioned medium (CM) and exosomes (EXOs), which play crucial roles in mediating the paracrine effects of MSCs. In particular, hypoxia was able to induce a pro-angiogenic, innate immune response-activating, and tissue-regenerative hAMSC phenotype, as highlighted by the elevated production of regulatory factors such as VEGFA, PDGFRB, ANGPTL4, ENG, GRO-γ, IL8, and GRO-α. IFN-γ priming, instead, led to an immunosuppressive profile in hAMSCs, as indicated by increased levels of TGFB1, ANXA1, THBS1, HOMER2, GRN, TOLLIP and MCP-1. Functional assays validated the increased angiogenic properties of hypoxic hAMSCs and the enhanced immunosuppressive activity of IFN-γ-treated hAMSCs. This study extends beyond the direct priming effects on hAMSCs, demonstrating that hypoxia and IFN-γ can influence the functional characteristics of hAMSC-derived secretomes, which, in turn, orchestrate the production of functional factors by peripheral blood cells. This research provides valuable insights into the optimization of MSC-based therapies by systematically assessing and comparing the priming type-specific functional features of hAMSCs. These findings highlight new strategies for enhancing the therapeutic efficacy of MSCs, particularly in the context of multifactorial diseases, paving the way for the use of hAMSC-derived products in clinical practice.

Betting on Your Feelings: The Interplay between Emotion and Cognition in Gambling Affective Task.

Background: Gambling Disorder (GD) is a bio-psycho-social disorder resulting from the interaction of clinical, cognitive, and affective factors. Impulsivity is a crucial factor in addiction studies, as it is closely linked to cognitive distortions in GD by encompassing impulsive choices, motor responses, decision-making, and cognitive biases. Also, emotions, mood, temperament, and affective state are crucial in developing and maintaining GD. Gambling can be used as a maladaptive coping strategy to avoid or escape problems and distress. Methods: The aim of the present study is to explore differences in personality traits and emotion regulation of people suffering from GD, substance-dependent gamblers (SDGs), and healthy controls (HCs). Additionally, the study proposes a new experimental task: the "Gambling Affective Task" (GAT) to investigate the influence of affective priming on risk-taking behaviors. Results: Our findings indicate that participants placed lower bets following positive priming. Additionally, SDGs wagered significantly higher amounts than HCs, regardless of priming type. In general, participants exhibited longer response times after positive priming trials, compared to negative and neutral priming trials. These findings suggest that experiencing positive emotions can act as a protective factor by delaying and lengthening gambling behaviors. By comparing gamblers with and without substance comorbidity, we can gain insight into the exclusive factors of GD and improve our understanding of this disorder. Conclusions: By elucidating the impact of emotional states on risk-taking, the research also provides new insights into the prevention and treatment of GD.

A two-dose viral-vectored Plasmodium vivax multistage vaccine confers durable protection and transmission-blockade in a pre-clinical study.

Among Plasmodium spp. responsible for human malaria, Plasmodium vivax ranks as the second most prevalent and has the widest geographical range; however, vaccine development has lagged behind that of Plasmodium falciparum, the deadliest Plasmodium species. Recently, we developed a multistage vaccine for P. falciparum based on a heterologous prime-boost immunization regimen utilizing the attenuated vaccinia virus strain LC16m8Δ (m8Δ)-prime and adeno-associated virus type 1 (AAV1)-boost, and demonstrated 100% protection and more than 95% transmission-blocking (TB) activity in the mouse model. In this study, we report the feasibility and versatility of this vaccine platform as a P. vivax multistage vaccine, which can provide 100% sterile protection against sporozoite challenge and >95% TB efficacy in the mouse model. Our vaccine comprises m8Δ and AAV1 viral vectors, both harboring the gene encoding two P. vivax circumsporozoite (PvCSP) protein alleles (VK210; PvCSP-Sal and VK247; -PNG) and P25 (Pvs25) expressed as a Pvs25-PvCSP fusion protein. For protective efficacy, the heterologous m8Δ-prime/AAV1-boost immunization regimen showed 100% (short-term; Day 28) and 60% (long-term; Day 242) protection against PvCSP VK210 transgenic Plasmodium berghei sporozoites. For TB efficacy, mouse sera immunized with the vaccine formulation showed >75% TB activity and >95% transmission reduction activity by a direct membrane feeding assay using P. vivax isolates in blood from an infected patient from the Brazilian Amazon region. These findings provide proof-of-concept that the m8Δ/AAV1 vaccine platform is sufficiently versatile for P. vivax vaccine development. Future studies are needed to evaluate the safety, immunogenicity, vaccine efficacy, and synergistic effects on protection and transmission blockade in a non-human primate model for Phase I trials.

SynDesign: web-based prime editing guide RNA design and evaluation tool for saturation genome editing.

Saturation genome editing (SGE) enables in-depth functional evaluation of disease-associated genes and variants by generating all possible single nucleotide variants (SNVs) within a given coding region. Although prime editing can be employed for inducing these SNVs, designing efficient prime editing guide RNAs (pegRNAs) can be challenging and time-consuming. Here, we present SynDesign, an easy-to-use webtool for the design, evaluation, and construction precision pegRNA libraries for SGE with synonymous mutation markers. SynDesign offers a simple yet powerful interface that automates the generation of all feasible pegRNA designs for a target gene or variant of interest. The pegRNAs are selected using the state-of-the-art models to predict prime editing efficiencies for various prime editors and cell types. Top-scoring pegRNA designs are further enhanced using synonymous mutation markers which improve pegRNA efficiency by diffusing the cellular mismatch repair mechanism and serve as sequence markers for improved identification of intended edits following deep sequencing. SynDesign is expected to facilitate future research using SGE to investigate genes or variants of interest associated with human diseases. SynDesign is freely available at https://deepcrispr.info/SynDesign without a login process.

Effects of Lexical Priming on Priming Type and Presence of Distractors in Persons with Mild Cognitive Impairment

Objectives: The purpose of the study is to examine if the lexical priming effect is valid in persons with mild cognitive impairment (MCI). In addition, this study attempted to examine the correlation between working memory and sentence production ability for MCI and healthy adults (HA).Methods: Fifteen individuals with MCI and sixteen HA described action pictures in sentences following lexical (agent or theme) primes. Priming effect was analyzed in terms of priming type and presence of distractor.Results: 1) Persons with MCI did show significantly lower proportion of passive sentences compared to HA. Overall, the proportion of passives were significantly higher in the theme primed condition versus the agent primed condition. 2) The difference in the presence of distractor stimuli in the agent primed condition was significantly larger than in the theme primed condition. 3) It was observed that the better the working memory ability of MCI participants, the higher the production of active sentences when compared with passive sentences in the theme primed condition.Conclusion: Persons with MCI used word-driven information as a strategy of sentence production like HA did. In addition, MCI participants showed difficulty in production of complex structures such as passive sentences. In previous research, most of the studies examined the priming effect through structural priming tasks for HA and aphasia patients. The results of this study also showed the effect of lexical priming in persons with MCI, and the finding of lower production of passive sentences in persons with MCI compared to HA emphasized the linguistic deficits that may appear in individuals with MCI.

Optimization of cardiopulmonary bypass prime fluid to preserve microcirculatory perfusion during on-pump coronary artery bypass graft surgery: PRIME study protocol for a double-blind randomized trial

BackgroundAcute microcirculatory perfusion disturbances and organ edema are important factors leading to organ dysfunction during cardiac surgery with cardiopulmonary bypass (CPB). Priming of the CPB system with crystalloid or colloid fluids, which inevitably leads to hemodilution, could contribute to this effect. However, there is yet no optimal evidence-based strategy for this type of priming. Hence, we will investigate different priming strategies to reduce hemodilution and preserve microcirculatory perfusion.MethodsThe PRIME study is a single-center double-blind randomized trial. Patients undergoing elective coronary artery bypass graft surgery with CPB will be randomized into three groups of prime fluid strategy: (1) gelofusine with crystalloid, (2) albumin with crystalloid, or (3) crystalloid and retrograde autologous priming. We aim to include 30 patients, 10 patients in each arm. The primary outcome is the change in microcirculatory perfusion. Secondary outcomes include colloid oncotic pressure; albumin; hematocrit; electrolytes; fluid balance and requirements; transfusion rates; and endothelial-, glycocalyx-, inflammatory- and renal injury markers. Sublingual microcirculatory perfusion will be measured using non-invasive sidestream dark field video microscopy. Microcirculatory and blood measurements will be performed at five consecutive time points during surgery up to 24 h after admission to the intensive care unit.DiscussionPRIME is the first study to assess the effect of different prime fluid strategies on microcirculatory perfusion in cardiac surgery with CPB. If the results suggest that a specific crystalloid or colloid prime fluid strategy better preserves microcirculatory perfusion during on-pump cardiac surgery, the current study may help to find the optimal pump priming in cardiac surgery.Trial registrationClinicalTrials.gov NCT05647057. Registered on 04/25/2023. ClinicalTrials.gov PRS: Record Summary NCT05647057, all items can be found in the protocol.

Investigating implicit emotion processing in autism spectrum disorder across age groups: A cross-modal emotional priming study.

Cumulating evidence suggests that atypical emotion processing in autism may generalize across different stimulus domains. However, this evidence comes from studies examining explicit emotion recognition. It remains unclear whether domain-general atypicality also applies to implicit emotion processing in autism and its implication for real-world social communication. To investigate this, we employed a novel cross-modal emotional priming task to assess implicit emotion processing of spoken/sung words (primes) through their influence on subsequent emotional judgment of faces/face-like objects (targets). We assessed whether implicit emotional priming differed between 38 autistic and 38 neurotypical individuals across age groups as a function of prime and target type. Results indicated no overall group differences across age groups, prime types, and target types. However, differential, domain-specific developmental patterns emerged for the autism and neurotypical groups. For neurotypical individuals, speech but not song primed the emotional judgment of faces across ages. This speech-orienting tendency was not observed across ages in the autism group, as priming of speech on faces was not seen in autistic adults. These results outline the importance of the delicate weighting between speech- versus song-orientation in implicit emotion processing throughout development, providing more nuanced insights into the emotion processing profile of autistic individuals.

Implicature priming, salience, and context adaptation

Recent experimental research has observed two kinds of priming effects on quantity implicatures. One is the Strong–Weak contrast, where more quantity implicatures are observed after prime trials forcing interpretations with quantity implicatures (‘Strong primes’) than after prime trials forcing interpretations without quantity implicatures (‘Weak primes’). The other effect is the Alternative-Weak contrast, where prime trials mentioning alternative expressions (‘Alternative primes’) similarly lead to more quantity implicatures. It has been claimed that both of these effects should be understood in terms of increased salience of alternative expressions used to compute quantity implicatures. We present experimental evidence that speaks against this hypothesis. With the help of novel baseline conditions, which were absent in previous studies on implicature priming, we observe that the results in the priming paradigm commonly used in the literature are inverse preference effects in the sense that robust priming effects are observed towards interpretations that are normally unexpected, and depending on the baseline expectation, each of the three prime types mentioned above may have priming effects. We furthermore investigated different types of alternative priming for so-called ad hoc implicatures and found that for these implicatures, presenting an alternative expression in a simple sentence does not have a priming effect on the implicature of a similarly simple sentence, but presenting it in a more complex conjunctive construction does. Our results also show that conjunctions of similar but irrelevant expressions have a similarly robust priming effect and that conjunctive sentences with two conjuncts do not give rise to priming effects on the interpretation of sentences of the same syntactic complexity, but those with three conjuncts do. To make sense of these observations, we propose that what crucially matters for priming implicatures is incremental change in one’s probabilistic expectations about the current conversational context brought about by a process we call context adaptation.

The frequency and cueing mechanisms of involuntary autobiographical memories while driving

ABSTRACT Involuntary autobiographical memories (IAMs) have been typically studied with paper diaries, kept for a week or longer. However, such studies are unable to capture the true frequency of IAMs, nor the level of detail that would give new insights into the mechanisms of IAMs. To address this gap, a new audio-recording method was developed and tested on the first author who recorded 674 IAMs while driving a car on a 30–40-minute-long habitual route on 20 occasions. Results revealed very high frequency of IAMs (almost 34 per journey) that were reported more often in response to dynamic (one-off) than static cues. Moreover, a substantial number of memory chains and long-term priming of IAMs by previously encountered incidental stimuli were also recorded. Based on these results, a new theoretical model is proposed in which the occurrence of IAMs is determined by an interplay of factors at the time of the IAM, such as the type of ongoing activity and internal or external triggers, as well as different types of long-term priming. The results also have practical implications for studying mind-wandering and safety issues in driving and aircraft-flying, where periods of concentration are followed by monotony and less demanding tasks.

A Novel Irreversible TEAD Inhibitor, SWTX-143, Blocks Hippo Pathway Transcriptional Output and Causes Tumor Regression in Preclinical Mesothelioma Models.

The Hippo pathway and its downstream effectors, the YAP and TAZ transcriptional coactivators, are deregulated in multiple different types of human cancer and are required for cancer cell phenotypes in vitro and in vivo, while largely dispensable for tissue homeostasis in adult mice. YAP/TAZ and their main partner transcription factors, the TEAD1-4 factors, are therefore promising anticancer targets. Because of frequent YAP/TAZ hyperactivation caused by mutations in the Hippo pathway components NF2 and LATS2, mesothelioma is one of the prime cancer types predicted to be responsive to YAP/TAZ-TEAD inhibitor treatment. Mesothelioma is a devastating disease for which currently no effective treatment options exist. Here, we describe a novel covalent YAP/TAZ-TEAD inhibitor, SWTX-143, that binds to the palmitoylation pocket of all four TEAD isoforms. SWTX-143 caused irreversible and specific inhibition of the transcriptional activity of YAP/TAZ-TEAD in Hippo-mutant tumor cell lines. More importantly, YAP/TAZ-TEAD inhibitor treatment caused strong mesothelioma regression in subcutaneous xenograft models with human cells and in an orthotopic mesothelioma mouse model. Finally, SWTX-143 also selectively impaired the growth of NF2-mutant kidney cancer cell lines, suggesting that the sensitivity of mesothelioma models to these YAP/TAZ-TEAD inhibitors can be extended to other tumor types with aberrations in Hippo signaling. In brief, we describe a novel and specific YAP/TAZ-TEAD inhibitor that has potential to treat multiple Hippo-mutant solid tumor types.

The early negative bias of social semantics: evidence from behavioral and ERP studies

BackgroundCompared to nonsocial information, the human brain is more highly sensitive to social information. As a kind of typical social semantic information, the words describing person traits differ from the nonsocial semantic information describing inanimate objects in many ways. It remains to be seen whether the processing of trait words has a valence asymmetric and whether it differs from the processing of nonsocial semantic information in terms of behavioral responses and neural temporal processes.MethodTaking person and object names as priming stimuli and adjective words only used for describing humans or objects as target stimuli, the present study aimed to investigate the processing characteristics of social and nonsocial semantic information by recording both behavioral and ERP data.ResultsBehavioral results showed that the response times for negative words were significantly slower than those for positive words whether for social or nonsocial semantic information. The accuracy rates of negative words were significantly lower than those of positive words when the targets were social words which is contrary to the nonsocial words. The ERP results indicated that there was a negative bias effect on the processing of both types of information during the whole time course of brain neural activity; that is, the P2, N400, and LPP amplitudes elicited by negative words were larger than those elicited by positive words; However, the negative bias effect of social semantic information started at the early perceptual stage which was significantly earlier than the onset of negative bias of nonsocial semantic information, and was significantly affected by the prime type. In addition, there was a significant semantic conflict N400 effect only for nonsocial semantic information.ConclusionsOverall, the present study revealed the existence of an early negative bias of social information and provided evidence for the specificity of social information.

Reverse Transcription Can Critically Impact the Diagnostic Outcome of BCR::ABL1 Quantitative Real-Time RT-PCR.

Reverse transcriptases (RT) are essential tools in BCR::ABL1 fusion transcript monitoring in chronic myeloid leukemia (CML). The RT type and cDNA priming method may impair the stoichiometry of cDNA synthesis, thereby potentially introducing a bias in BCR::ABL1 qRT-PCR data. Using the Acrometrix™ BCR::ABL1 reference panel and 37 clinical specimens, we have comparatively investigated the performance of the RTs MLV and SuperScript IV with random hexamer vs. target-specific priming. Quantitative RT-PCR results identified the priming type and RT type as major factors for diagnostic data variation, mainly due to the different efficacies of processing BCR::ABL1 low-copy-numbers (<50) compared to GUSB or ABL1 high-copy targets. The impairment of SuperScript IV in processing low- and high-copy-number RNA targets equally was not reflected by the diagnostically relevant Log (BCR::ABL1/GUSB%) values. Therefore, the correct representation of housekeeping and BCR::ABL1 target genes should have priority when aiming at as high a number of housekeeping gene copies as possible. Our data suggest that for improving BCR::ABL1 assay sensitivity, increased RNA/cDNA amounts and the use of distinct RT/priming combinations are advantageous. However, for inter-laboratory harmonization, the proper conversion factor according to the CML international standard (IS) has to be reevaluated each time the grade of RT is changed.

3D Culture and Interferon-γ Priming Modulates Characteristics of Mesenchymal Stromal/Stem Cells by Modifying the Expression of Both Intracellular and Exosomal microRNAs.

Mesenchymal stromal/stem cells (MSCs) have emerged as a therapeutic tool in regenerative medicine. Recent studies have shown that exosome (EXO)-derived microRNAs (miRNAs) play a crucial role in mediating MSC functions. Additionally, intracellular miRNAs have been found to regulate MSC therapeutic capacities. However, the molecular mechanisms underlying miRNA-mediated MSC effects are not fully understood. We used 3D culture and IFN-γ to prime/enhance the MSC therapeutic effects in terms of functional miRNAs. After priming, our analysis revealed stable variations in intracellular miRNA among the MSC biological replicates. Conversely, a significant variability of miRNA was observed among EXOs released from biological replicates of the priming treatment. For each priming, we observed distinct miRNA expression profiles between the MSCs and their EXOs. Moreover, in both types of priming, gene ontology (GO) analysis of deregulated miRNAs highlighted their involvement in tissue repair/regeneration pathways. In particular, the 3D culture enhanced angiogenic properties in both MSCs and EXOs, while IFN-γ treatment enriched miRNAs associated with immunomodulatory pathways. These findings suggest that 3D culture and IFN-γ treatment are promising strategies for enhancing the therapeutic potential of MSCs by modulating miRNA expression. Additionally, the identified miRNAs may contribute to understanding the molecular mechanisms underlying the miRNA-mediated therapeutic effects of MSCs.