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The detection of novel, low probability events in the environment is critical for survival. To perform this vital task, our brain is continuously building and updating a model of the outside world; an extensively studied phenomenon commonly referred to as predictive coding. Predictive coding posits that the brain is continuously extracting regularities from the environment to generate predictions. These predictions are then used to supress neuronal responses to redundant information, filtering those inputs, which then automatically enhances the remaining, unexpected inputs. We have recently described the ability of auditory neurons to generate predictions about expected sensory inputs by detecting their absence in an oddball paradigm using omitted tones as deviants. Here, we studied the responses of individual neurons to omitted tones by presenting individual sequences of repetitive pure tones, using both random and periodic omissions, presented at both fast and slow rates in the inferior colliculus and auditory cortex neurons of anesthetized rats. Our goal was to determine whether feature-specific dependence of these predictions exists. Results showed that omitted tones could be detected at both high (8 Hz) and slow repetition rates (2 Hz), with detection being more robust at the non-lemniscal auditory pathway.

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Polyhydroxyalkanoates (PHAs) are a well-known group of biodegradable and biocompatible bioplastics that are synthesised and stored by microorganisms as carbon and energy reservoirs. Extracellular PHA depolymerases (ePhaZs), secreted by a limited range of microorganisms, are the main hydrolytic enzymes responsible for their environmental degradation. Pseudomonas sp. GK13, initially identified as P. fluorescens GK13, produces PHA and a prototypic ePhaZ that specifically degrades mcl-PHA. In this study, a comprehensive characterization of strain GK13 was performed. The whole genomic sequence of GK13 was consolidated into one complete chromosome, leading to its reclassification as P. solani GK13. We conducted a detailed in silico examination of the bacteria genomic sequence, specifically targeting PHA metabolic functions. From the different growth conditions explored, PHA accumulation occurred only under carbon/nitrogen (C/N) imbalance, whereas ePhaZ production was induced even at balanced C/N ratios in mineral media. We extend our study to other bacteria belonging to the Pseudomonas genus revealing that the ePhaZ production capacity is closely associated with mcl-PHA synthesis capacity, as also suggested by metagenomic samples. This finding suggests that these types of microorganisms could contribute to the carbon economy of the microbial community, by storing PHA in carbon-rich times, and sharing it with the rest of the population during times of carbon scarcity through PHA hydrolysis. The conclusion pointed that carbon cycle metabolism performed by P. solani GK13 may contribute to the environmental circular economy at a microscopic scale.

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The neural mechanisms of novelty detection, especially in relation to behavior, are currently poorly understood. Here, we present a protocol for recording neuronal activity in macaque auditory cortex during novelty detection tasks. We describe steps for behavioral training, surgical headpost implantation, MRI-based electrode targeting, and electrophysiological recording. These steps allow direct assessment of the correlation between novelty detection behavior and neuronal activity. For complete details on the use and execution of this protocol, please refer to Gong et al.1.

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OBJECTIVES: This study compared the whitening effect, microhardness, and enamel surface alterations of over-the-counter (OTC) tooth bleaching products with those of a dentist-prescribed at-home bleaching agent. MATERIALS AND METHODS: The products available on a popular online marketplace were comprehensively searched and then rated using a specific formula. The effects of the lowest-rated OTC agent (LRA) and the highest-rated OTC agent (HRA) were compared with those of a dentist-prescribed bleaching agent (DPA) on the enamel of extracted human teeth. The bleaching efficacy, post-bleaching microhardness changes, and morphological alterations were assessed by spectrophotometric analysis, Vickers hardness testing, and scanning electron microscopy (SEM) respectively. Statistical analyses included one-way ANOVA and post hoc tests, maintaining a significance level of P < 0.05. RESULTS: The search of the online marketplace revealed 15 products. The LRA (Teeth Whitening Serum Gel, GEN, China) and the HRA (Bright White-Lovely Smile Premium Teeth Whitening strips, Ray of Smile, USA) were identified on the basis of their ranking. DPA resulted in significantly better tooth whitening than did LRA. The enamel microhardness was lower in the LRA treatment group (14.2%) than in the control and HRA treatment groups (8.84% and 7.26%, respectively). LRA also caused severe topographical alterations to the enamel. CONCLUSION: Compared with the poorly rated product, the dentist-prescribed tooth bleaching product resulted in greater colour improvement, less microhardness reduction, and surface changes. The highest-rated product was comparable with the dentist-prescribed agent in this study.

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Experimenter bias compromises the integrity and advancement of science, especially when awarded as such. For example, the 2022 Nobel Prize in Physics awarded for the loophole-free experiments that tested physicist John S. Bell's inequality theorem. These experiments employed the logic of conducting local experiments to obtain local evidence that contradicted local realistic theories of nature, thereby validating quantum mechanics as a fundamental non-local theory. However, there was one loophole that was wittingly not tested by the Nobel laureates. The notable exception was Bell's "super-deterministic" loophole, which was validated (2000) (2001) (2002) (2003) (2004) (2005) (2006) (2007) (2008) (2009) (2010) (2011) (2012) non-locally, thus compromising the subsequent Nobel Prize. More importantly, the discovery of two mutually exclusive and jointly exhaustive non-local hidden variables revealed why local scientific methods obtain false-positive and false-negative results. With knowledge of this fundamental omission, the inclusion of the non-local hidden variables in the local methods used in science can then advance it to be a complete study of nature.

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AIMS: To evaluate patterns of recurrence and explore the prognostic differences between the 2018 FIGO staging system and the 2020 ESGO-ESTRO-ESP risk stratification system of endometrial cancer with an emphasis on early-stage disease. BACKGROUND: The incidence of endometrial cancer has risen by around 60% since the 90's. It is projected that by 2035 endometrial cancer will be the sixth most common cause of cancer-related death amongst females. METHODS: This was a retrospective cohort study which included patients treated between 2010 and 2017. Primary endpoints were overall survival (OS) and recurrence-free survival (RFS). Kaplan-Meyer survival analysis was used to assess OS and RFS across different risk groups. Cox proportional hazards regression was used to evaluate prognostic risk factors implicated in recurrence. Different recurrence patterns across the subgroups were analysed with Pearson's chi-square test. RESULTS: The study included 692 patients with a recurrence rate of 14.9%. The median time to recurrence was 17.1 months (IQR:8.8-28.4). The mean OS varied between 97.2 months in the low-risk group to 63.1 months in the high-risk group (p < 0.001). Mean RFS was 96.1 in the low-risk group and 58.9 in the high-risk group (p < 0.001). RFS was predicted by the following factors; high risk group (OR=3.87; p = 0.041), LVSI (OR=2.54, p = 0.005), carcinosarcoma (OR=2.20, p = 0.021) and serous subtype (OR=1.91, p = 0.01). Logistic regression was used to evaluate risk factors for loco-regional and distant recurrence. Patients in the low-risk group were less likely to have distant recurrence (OR=0.08, p = 0.004). Similarly, negative LVSI and Grade 1 cancers were associated with decreased risk of distant recurrence (OR=0.34, p = 0.006 and OR=0.33, p = 0.007, respectively). There were no significant risk factors for loco-regional recurrence. CONCLUSIONS: The 2020 ESGO-ESTRO-ESP risk stratification provides accurate estimates of recurrence risk and survival. Those treated in line with current guidance have significantly better outcomes.

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INTRODUCTION: This study systematically reviewed literature regarding the effect of different concentrations of sodium hypochlorite (NaOCl) used during root canal treatment (RCT) on postendodontic pain (PEP) and rescue analgesia. METHODS: Following registration with PROSPERO (CRD42023388916), a search was conducted using PubMed, Scopus, Web of Science, and Embase databases. Randomized controlled trials of patients receiving RCT which assessed PEP at different time intervals were included. Following data extraction and Cochrane risk of bias assessment 2, meta-analyses were performed to evaluate PEP during the first 48 hours along with rescue analgesic intake. The certainty of the evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: Five randomized controlled trials with 674 patients were included. One study exhibited a low risk of bias, while 4 raised some concerns. Patients treated with low concentrations of NaOCl (≤3%) were significantly less likely to report PEP at 24 hours (OR = 2.32; [95% CI, 1.63-3.31]; P < .05) and 48 hours (OR = 2.49; [95% CI, 1.73-3.59]; P < .05) as compared with high concentrations of NaOCl (≥5%). Furthermore, with low concentrations of NaOCl, significantly lesser moderate-severe PEP was reported at 24 hours (OR = 2.32; [95% CI, 1.47-3.62]; P < .05) and 48 hours (OR = 2.35; [95% CI, 1.32-4.16]; P < .05) and lesser analgesia was needed (OR = 2.43; [95% CI, 1.48-4.00]; P < .05). CONCLUSIONS: While PEP can be influenced by several factors, low certainty evidence suggests that when NaOCl is used as an irrigant during RCT, PEP may be less likely with lower concentrations of NaOCl. Moderate certainty evidence indicates that lesser analgesia may be required with lower concentrations of NaOCl. These results should be cautiously interpreted.

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Understanding the apical pressure and irrigant flow patterns in root canals is crucial for safe and effective irrigation. Therefore, this study aimed to assess the flow characteristics of irrigants in root canal models with varying tapers during final irrigation by employing various needle designs, including a back-to-back double-side-vented needle, through computational fluid dynamics. The root canal model was configured as a closed geometrical cone with a simulated apical zone (size 30) and features tapers of 4%, 6%, and 8%. Three needle types-open-ended needle (OEN), single side-vented needle (SSVN), and double side-vented needle (DSVN)-were investigated. The results indicated that for the 4% taper models, the open-ended needle generated the maximum apical pressure, followed by the double side-vented needle and the single side-vented needle. However, in the 6% and 8% tapering root canal models, the double-side-vented needle applied the lowest maximum apical pressure. Consequently, the DSVN can pose a risk for irrigant extrusion in minimally prepared canals due to heightened apical pressure. In wider canals, the DSVN exhibited lower apical pressure. The maximum irrigant replacement was observed with OEN compared to that of the closed-ended group for both flow rates. Additionally, compared with OENs, closed-ended needles exhibited nonuniform and lower shear wall stress.

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This study aimed to determine if greater perceived social support was directly associated with better Type 2 diabetes (T2D) treatment adherence and if better T2D treatment adherence was related to lower HbA1c levels in Chilean adults with T2D. For this purpose, 200 adults were recruited from the Chilean Diabetic Association. Participants were asked to complete self-report instruments and provide a capillary blood sample to measure HbA1c. Structural equation model analyses were performed to determine direct associations. The study's results indicate that greater perceived social support was associated with healthier dietary habits, regular foot care, more frequent physical activity, and lower medication intake. Likewise, blood sugar testing and physical activity were related to HbA1c. These findings provide evidence of how perceived social support relates to T2D treatment adherence behaviors in Latino patients from South America and could be used for interventions to enhance social support from patients' families, partners, and friends.

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Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding to a ubiquitin ligase. More generally referred to as bifunctional degraders, PROTACs have led the way in the field of targeted protein degradation (TPD), with several compounds currently undergoing clinical testing. Alongside bifunctional degraders, single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered as a viable approach for development of therapeutics, driven by advances in rational discovery approaches. This review focuses on drug discovery with respect to bifunctional and molecular glue degraders within the ubiquitin proteasome system, including analysis of mechanistic concepts and discovery approaches, with an overview of current clinical and pre-clinical degrader status in oncology, neurodegenerative and inflammatory disease.

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According to the predictive processing framework, perception emerges from the reciprocal exchange of predictions and prediction errors (PEs) between hierarchically organized neural circuits. The nonlemniscal division of the inferior colliculus (IC) is the earliest source of auditory PE signals, but their neuronal generators, properties, and functional relevance have remained mostly undefined. We recorded single-unit mismatch responses to auditory oddball stimulation at different intensities, together with activity evoked by two sequences of alternating tones to control frequency-specific effects. Our results reveal a differential treatment of the unpredictable "many-standards" control and the predictable "cascade" control by lemniscal and nonlemniscal IC neurons that is not present in the auditory thalamus or cortex. Furthermore, we found that frequency response areas of nonlemniscal IC neurons reflect their role in subcortical predictive processing, distinguishing three hierarchical levels: (1) nonlemniscal neurons with sharply tuned receptive fields exhibit mild repetition suppression without signaling PEs, thereby constituting the input level of the local predictive processing circuitry. (2) Neurons with broadly tuned receptive fields form the main, "spectral" PE signaling system, which provides dynamic gain compensation to near-threshold unexpected sounds. This early enhancement of saliency reliant on spectral features was not observed in the auditory thalamus or cortex. (3) Untuned neurons form an accessory, "nonspectral" PE signaling system, which reports all surprising auditory deviances in a robust and consistent manner, resembling nonlemniscal neurons in the auditory cortex. These nonlemniscal IC neurons show unstructured and unstable receptive fields that could result from inhibitory input controlled by corticofugal projections conveying top-down predictions.

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Depression is a major health problem in Chile. Evidence suggests that physical symptoms of depression (PSD) negatively impact self-perceived health and life satisfaction. The aim of this study was to determine the between-person and within-person associations of PSD with self-perceived health and life satisfaction in Chilean adults. The sample consisted of 1424 participants (64.54% female; Mage = 46.77, SD = 14.88) with data in five waves of the Social Longitudinal Study of Chile. Variables were measured through self-report questionnaires. Hypotheses were tested using multilevel analysis. At the within-person level, physical slowing, fatigue, and sleep problems were associated with poorer self-perceived health and lower life satisfaction. At the between-person level, physical slowing and fatigue were associated with poorer perceived health and lower life satisfaction. PSD are associated with self-perceived health and life satisfaction in Chilean adults longitudinally. The study highlights the importance of monitoring PSD changes in Chilean adults.

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Environmental concerns about residues and the traditional disposal methods are driving the search for more environmentally conscious processes, such as pyrolysis and gasification. Their main final product is synthesis gas (syngas) composed of CO, CO2, H2, and methane. Syngas can be converted into various products using CO-tolerant microorganisms. Among them, Rhodospirillum rubrum is highlighted for its biotechnological potential. However, the extent to which high doses of CO affect its physiology is still opaque. For this reason, we have studied R. rubrum behavior under high levels of this gas (up to 2.5 bar), revealing a profound dependence on the presence or absence of light. In darkness, the key variable affected was the lag phase, where the highest levels of CO retarded growth to more than 20 days. Under light, R. rubrum ability to convert CO into CO2 and H2 depended on the presence of an additional carbon source, such as acetate. In those conditions where CO was completely exhausted, CO2 fixation was unblocked, leading to a diauxic growth. To enhance R. rubrum tolerance to CO in darkness, a UV-accelerated adaptive laboratory evolution (UVa-ALE) trial was conducted to isolate clones with shorter lag phases, resulting in the isolation of clones 1.4-2B and 1.7-2A. The adaptation of 1.4-2B was mainly based on mutated enzymes with a metabolic function, while 1.7-3A was mostly affected at regulatory genes, including the anti-repressor PpaA/AerR. Despite these mutations having slight effects on biomass and pigment levels, they successfully provoked a significant reduction in the lag phase (-50%). KEYPOINTS: • CO affects principally R. rubrum lag phase (darkness) and growth rate (light) • CO is converted to CO2/H2 during acetate uptake and inhibits CO2 fixation (light) • UVa-ALE clones showed a 50% reduction in the lag phase (darkness).

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Immune cells at the feto-maternal interface play an important role in pregnancy; starting at implantation, maintenance of pregnancy, and parturition. The role of decidual immune cells in induction of labor still needs to be understood. Published reports on this topic show heterogeneity in methods of cell isolation, assay, analysis and cellular characterization making it difficult to collate available information in order to understand the contribution of immune cells at term leading to parturition. In the present study, available literature was reviewed to study the differences in immune cells between the decidua basalis and decidua parietalis, as well as between immune cells in term and preterm labor. Additionally, immune cells at the decidua parietalis were isolated from term not in labor (TNL) or term in labor (TL) samples and characterized via flow cytometry using a comprehensive, high-dimensional antibody panel. This allowed a full view of immune cell differences without combining multiple studies, which must include variation in isolation and analysis methods, for more conclusive data. The ratio of cells found in decidua parietalis in this study generally matched those reported in the literature, although we report a lower percentage of natural killer (NK) cells at term. We report that CD4 expression on CD8- NK cells decreased in term labor compared to not in labor samples, suggesting that natural killer cells may be migrating to other sites during labor. Also, we report a decrease in CD38 expression on CD8+ CD57+ T cells in labor, indicative of cytotoxic T cell senescence. Our study provides a comprehensive status of immune cells at the decidua-chorion interface at term.

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The posttranslational modification of proteins critically influences many biological processes and is a key mechanism that regulates the function of the RNA-binding protein Hu antigen R (HuR), a hub in liver cancer. Here, we show that HuR is SUMOylated in the tumor sections of patients with hepatocellular carcinoma in contrast to the surrounding tissue, as well as in human cell line and mouse models of the disease. SUMOylation of HuR promotes major cancer hallmarks, namely proliferation and invasion, whereas the absence of HuR SUMOylation results in a senescent phenotype with dysfunctional mitochondria and endoplasmic reticulum. Mechanistically, SUMOylation induces a structural rearrangement of the RNA recognition motifs that modulates HuR binding affinity to its target RNAs, further modifying the transcriptomic profile toward hepatic tumor progression. Overall, SUMOylation constitutes a mechanism of HuR regulation that could be potentially exploited as a therapeutic strategy for liver cancer.

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The effects of endocrine-disrupting compounds (EDCs) on the placenta, a critical gestational organ for xenobiotic protection, are well reported; however, models to determine the role of EDCs in placental disruption are limited. An advanced 2nd-trimester human placenta organ-on-chip model (2TPLA-OOC) was developed and validated, with six representative cells of the maternal and the fetal interface interconnected with microchannels. Various EDCs (150 ng mL-1 each of bisphenol A, bisphenol S, and polybrominated diphenyl ethers-47 and -99) were gradually propagated across the chip for 72 hours, and their various effects were determined. Cigarette smoke extract (CSE), an environmental risk factor, was used as a positive control. EDCs produced overall oxidative stress in the placental/decidual cells, induced cell-specific endocrine effects, caused limited (<10%) apoptosis/necrosis in trophoblasts and mesenchymal cells, induced localized inflammation but an overall anti-inflammatory shift, did not change immune cell migration from stroma to decidua, and did not affect placental nutrient transport. Overall, (1) the humanized 2TPLA-OOC recreated the placental organ and generated data distinct from the trophoblast and other cells studied in isolation, and (2) at doses associated with adverse pregnancies, EDCs produced limited and localized insults, and the whole organ compensated for the exposure.

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The neural mechanisms underlying novelty detection are not well understood, especially in relation to behavior. Here, we present single-unit responses from the primary auditory cortex (A1) from two monkeys trained to detect deviant tones amid repetitive ones. Results show that monkeys can detect deviant sounds, and there is a strong correlation between late neuronal responses (250-350 ms after deviant onset) and the monkeys' perceptual decisions. The magnitude and timing of both neuronal and behavioral responses are increased by larger frequency differences between the deviant and standard tones and by increasing the number of standard tones preceding the deviant. This suggests that A1 neurons encode novelty detection in behaving monkeys, influenced by stimulus relevance and expectations. This study provides evidence supporting aspects of predictive coding in the sensory cortex.

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Exposure to brief, intense sound can produce profound changes in the auditory system, from the internal structure of inner hair cells to reduced synaptic connections between the auditory nerves and the inner hair cells. Moreover, noisy environments can also lead to alterations in the auditory nerve or to processing changes in the auditory midbrain, all without affecting hearing thresholds. This so-called hidden hearing loss (HHL) has been shown in tinnitus patients and has been posited to account for hearing difficulties in noisy environments. However, much of the neuronal research thus far has investigated how HHL affects the response characteristics of individual fibres in the auditory nerve, as opposed to higher stations in the auditory pathway. Human models show that the auditory nerve encodes sound stochastically. Therefore, a sufficient reduction in nerve fibres could result in lowering the sampling of the acoustic scene below the minimum rate necessary to fully encode the scene, thus reducing the efficacy of sound encoding. Here, we examine how HHL affects the responses to frequency and intensity of neurons in the inferior colliculus of rats, and the duration and firing rate of those responses. Finally, we examined how shorter stimuli are encoded less effectively by the auditory midbrain than longer stimuli, and how this could lead to a clinical test for HHL.

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Research on the biology of fetal-maternal barriers has been limited by access to physiologically relevant cells, including trophoblast cells. In this study, we describe the development of a human term placenta-derived cytotrophoblast immortalized cell line (hPTCCTB) derived from the basal plate. Human-term placenta-derived cytotrophoblast immortalized cell line cells are comparable to their primary cells of origin in terms of morphology, marker expression, and functional responses. We demonstrate that these can transform into syncytiotrophoblast and extravillous trophoblasts. We also compared the hPTCCTB cells to immortalized chorionic trophoblasts (hFM-CTC), trophoblasts of the chorionic plate, and BeWo cells, choriocarcinoma cell lines of conventional use. Human-term placenta-derived cytotrophoblast immortalized cell line and hFM-CTCs displayed more similarity to each other than to BeWos, but these differ in syncytialization ability. Overall, this study (1) demonstrates that the immortalized hPTCCTB generated are cells of higher physiological relevance and (2) provides a look into the distinction between the spatially distinct placental and fetal barrier trophoblasts cells, hPTCCTB and hFM-CTC, respectively.

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