Melanoma RBPome identification reveals PDIA6 as an unconventional RNA-binding protein involved in metastasis.

RNA-binding proteins (RBPs) have been relatively overlooked in cancer research despite their contribution to virtually every cancer hallmark. Here, we use RNA interactome capture (RIC) to characterize the melanoma RBPome and uncover novel RBPs involved in melanoma progression. Comparison of RIC profiles of a non-tumoral versus a metastatic cell line revealed prevalent changes in RNA-binding capacities that were not associated with changes in RBP levels. Extensive functional validation of a selected group of 24 RBPs using five different in vitro assays unveiled unanticipated roles of RBPs in melanoma malignancy. As proof-of-principle we focused on PDIA6, an ER-lumen chaperone that displayed a novel RNA-binding activity. We show that PDIA6 is involved in metastatic progression, map its RNA-binding domain, and find that RNA binding is required for PDIA6 tumorigenic properties. These results exemplify how RIC technologies can be harnessed to uncover novel vulnerabilities of cancer cells.

Cold-inducible RNA binding protein promotes breast cancer cell malignancy by regulating Cystatin C levels.

Cold-inducible RNA binding protein (CIRBP) is a stress-responsive protein that promotes cancer development and inflammation. Critical to most CIRBP functions is its capacity to bind and posttranscriptionally modulate mRNA. However, a transcriptome-wide analysis of CIRBP mRNA targets in cancer has not yet been performed. Here, we use an ex vivo breast cancer model to identify CIRBP targets and mechanisms. We find that CIRBP transcript levels correlate with breast cancer subtype and are an indicator of luminal A/B prognosis. Accordingly, overexpression of CIRBP in nontumoral MCF-10A cells promotes cell growth and clonogenicity, while depletion of CIRBP from luminal A MCF-7 cells has opposite effects. We use RNA immunoprecipitation followed by high-throughput sequencing (RIP-seq) to identify a set of 204 high confident CIRBP targets in MCF-7 cells. About 10% of these showed complementary changes after CIRBP manipulation in MCF-10A and MCF-7 cells, and were highly interconnected with known breast cancer genes. To test the potential of CIRBP-mediated regulation of these targets in breast cancer development, we focused on Cystatin C (CST3), one of the most highly interconnected genes, encoding a protein that displays tumor suppressive capacities. CST3 depletion restored the effects of CIRBP depletion in MCF-7 cells, indicating that CIRBP functions, at least in part, by down-regulating CST3 levels. Our data provide a resource of CIRBP targets in breast cancer, and identify CST3 as a novel downstream mediator of CIRBP function.

How a transdiagnostic approach can improve the treatment of emotional disorders: Insights from clinical psychology and neuroimaging.

Multiple psychological treatments for emotional disorders have been developed and implemented, improving the quality of life of individuals. Nevertheless, relapse and poor response to psychotherapy are common. This article argues that a greater understanding of both the psychological and neurobiological mechanisms of change in psychotherapy is essential to improve treatment for emotional disorders. It aims to demonstrate how an understanding of these mechanisms provides a basis for (i) reconceptualizing some mental disorders, (ii) refining and establishing the evidence for existing therapeutic techniques and (iii) designing new techniques that precisely target the processes that maintain these disorders. Possible future directions for researchers and practitioners working at the intersection of neuropsychology and clinical psychology are discussed.

Measuring Interactions in Categorical Datasets Using Multivariate Symmetrical Uncertainty.

Interaction between variables is often found in statistical models, and it is usually expressed in the model as an additional term when the variables are numeric. However, when the variables are categorical (also known as nominal or qualitative) or mixed numerical-categorical, defining, detecting, and measuring interactions is not a simple task. In this work, based on an entropy-based correlation measure for n nominal variables (named as Multivariate Symmetrical Uncertainty (MSU)), we propose a formal and broader definition for the interaction of the variables. Two series of experiments are presented. In the first series, we observe that datasets where some record types or combinations of categories are absent, forming patterns of records, which often display interactions among their attributes. In the second series, the interaction/non-interaction behavior of a regression model (entirely built on continuous variables) gets successfully replicated under a discretized version of the dataset. It is shown that there is an interaction-wise correspondence between the continuous and the discretized versions of the dataset. Hence, we demonstrate that the proposed definition of interaction enabled by the MSU is a valuable tool for detecting and measuring interactions within linear and non-linear models.

Pharmacogenomics, biomarker network, and allele frequencies in colorectal cancer.

Colorectal cancer is one of the leading causes of cancer death worldwide. Over the last decades, several studies have shown that tumor-related genomic alterations predict tumor prognosis, drug response, and toxicity. These observations have led to the development of several therapies based on individual genomic profiles. As part of these approaches, pharmacogenomics analyses genomic alterations which may predict an efficient therapeutic response. Studying these mutations as biomarkers for predicting drug response is of a great interest to improve precision medicine. We conduct a comprehensive review of the main pharmacogenomics biomarkers and genomic alterations affecting enzyme activity, transporter capacity, channels, and receptors; and therefore the new advances in CRC precision medicine to select the best therapeutic strategy in populations worldwide, with a focus on Latin America.

A quick guide for using Microsoft OneNote as an electronic laboratory notebook.

Scientific data recording and reporting systems are of a great interest for endorsing reproducibility and transparency practices among the scientific community. Current research generates large datasets that can no longer be documented using paper lab notebooks (PLNs). In this regard, electronic laboratory notebooks (ELNs) could be a promising solution to replace PLNs and promote scientific reproducibility and transparency. We previously analyzed five ELNs and performed two survey-based studies to implement an ELN in a biomedical research institute. Among the ELNs tested, we found that Microsoft OneNote presents numerous features related to ELN best functionalities. In addition, both surveyed groups preferred OneNote over a scientifically designed ELN (PerkinElmer Elements). However, OneNote remains a general note-taking application and has not been designed for scientific purposes. We therefore provide a quick guide to adapt OneNote to an ELN workflow that can also be adjusted to other nonscientific ELNs.

Abuse, invalidation, and lack of early warmth show distinct relationships with self-criticism, self-compassion, and fear of self-compassion in personality disorder.

BACKGROUND: Cultivating self-compassion is increasingly recognized as a powerful method to regulate hyperactive threat processes such as shame and self-criticism, but fear of self-compassion (FSC) can inhibit this. These difficulties are underexplored in personality disorder (PD) despite their prevalence. Furthermore, little evidence exists regarding how these factors relate to adverse childhood experiences (ACEs) and attachment. METHOD: Fifty-three participants with a diagnosis of PD completed measures including childhood abuse/neglect, invalidation, early warmth, self-compassion, shame, self-criticism, FSC, and anxious/avoidant attachment. RESULTS: Self-compassion was predicted uniquely by low early warmth; self-inadequacy by invalidation and abuse; and FSC by multiple ACEs. FSC and self-compassion were significantly correlated with self-criticism and shame, but not with one another. CONCLUSIONS: Low self-compassion and high FSC appear to be distinct problems, substantiating physiological models proposing distinct threat and soothing systems. Results are consistent with theories positing that low self-compassion has distinct origins to shame, self-criticism, and FSC.

Entropy and Contrast Enhancement of Infrared Thermal Images Using the Multiscale Top-Hat Transform.

Discrete entropy is used to measure the content of an image, where a higher value indicates an image with richer details. Infrared images are capable of revealing important hidden targets. The disadvantage of this type of image is that their low contrast and level of detail are not consistent with human visual perception. These problems can be caused by variations of the environment or by limitations of the cameras that capture the images. In this work we propose a method that improves the details of infrared images, increasing their entropy, preserving their natural appearance, and enhancing contrast. The proposed method extracts multiple features of brightness and darkness from the infrared image. This is done by means of the multiscale top-hat transform. To improve the infrared image, multiple scales are added to the bright areas and multiple areas of darkness are subtracted. The method was tested with 450 infrared thermal images from a public database. Evaluation of the experimental results shows that the proposed method improves the details of the image by increasing entropy, also preserving natural appearance and enhancing the contrast of infrared thermal images.

State of Art of Cancer Pharmacogenomics in Latin American Populations.

Over the past decades, several studies have shown that tumor-related somatic and germline alterations predicts tumor prognosis, drug response and toxicity. Latin American populations present a vast geno-phenotypic diversity due to the great interethnic and interracial mixing. This genetic flow leads to the appearance of complex characteristics that allow individuals to adapt to endemic environments, such as high altitude or extreme tropical weather. These genetic changes, most of them subtle and unexplored, could establish a mutational profile to develop new pharmacogenomic therapies specific for Latin American populations. In this review, we present the current status of research on somatic and germline alterations in Latin America compared to those found in Caucasian and Asian populations.

APOBEC3G impairs the multimerization of the HIV-1 Vif protein in living cells.

The HIV-1 viral infectivity factor (Vif) is a small basic protein essential for viral fitness and pathogenicity. Vif allows productive infection in nonpermissive cells, including most natural HIV-1 target cells, by counteracting the cellular cytosine deaminases APOBEC3G (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G [A3G]) and A3F. Vif is also associated with the viral assembly complex and packaged into viral particles through interactions with the viral genomic RNA and the nucleocapsid domain of Pr55(Gag). Recently, we showed that oligomerization of Vif into high-molecular-mass complexes induces Vif folding and influences its binding to high-affinity RNA binding sites present in the HIV genomic RNA. To get further insight into the role of Vif multimerization in viral assembly and A3G repression, we used fluorescence lifetime imaging microscopy (FLIM)- and fluorescence resonance energy transfer (FRET)-based assays to investigate Vif-Vif interactions in living cells. By using two N-terminally tagged Vif proteins, we show that Vif-Vif interactions occur in living cells. This oligomerization is strongly reduced when the putative Vif multimerization domain ((161)PPLP(164)) is mutated, indicating that this domain is crucial, but that regions outside this motif also participate in Vif oligomerization. When coexpressed together with Pr55(Gag), Vif is largely relocated to the cell membrane, where Vif oligomerization also occurs. Interestingly, wild-type A3G strongly interferes with Vif multimerization, contrary to an A3G mutant that does not bind to Vif. These findings confirm that Vif oligomerization occurs in living cells partly through its C-terminal motif and suggest that A3G may target and perturb the Vif oligomerization state to limit its functions in the cell.

Characterization of RNA binding and chaperoning activities of HIV-1 Vif protein. Importance of the C-terminal unstructured tail.

The viral infectivity factor (Vif) is essential for the productive infection and dissemination of HIV-1 in non-permissive cells, containing the cellular anti-HIV defense cytosine deaminases APOBEC3 (A3G and A3F). Vif neutralizes the antiviral activities of the APOBEC3G/F by diverse mechanisms including their degradation through the ubiquitin/proteasome pathway and their translational inhibition. In addition, Vif appears to be an active partner of the late steps of viral replication by interacting with Pr55(Gag), reverse transcriptase and genomic RNA. Here, we expressed and purified full-length and truncated Vif proteins, and analyzed their RNA binding and chaperone properties. First, we showed by CD and NMR spectroscopies that the N-terminal domain of Vif is highly structured in solution, whereas the C-terminal domain remains mainly unfolded. Both domains exhibited substantial RNA binding capacities with dissociation constants in the nanomolar range, whereas the basic unfolded C-terminal domain of Vif was responsible in part for its RNA chaperone activity. Second, we showed by NMR chemical shift mapping that Vif and NCp7 share the same binding sites on tRNA(Lys) 3, the primer of HIV-1 reverse transcriptase. Finally, our results indicate that Vif has potent RNA chaperone activity and provide direct evidence for an important role of the unstructured C-terminal domain of Vif in this capacity.

Multidimensional Emotional Disorder Inventory: reliability and validity in a Colombian non-clinical sample.

BACKGROUND: Contemporary diagnostic frameworks in the realm of mental health have garnered criticism due to their categorical paradigm. Given the propensity of emotional disorders to manifest overlapping features, these frameworks fall short in comprehensively encapsulating their intricate nature. As a strategic response, Brown and Barlow introduced an innovative composite approach, amalgamating dimensions and categorical classifications, to adress this concern. Their strategic implementation hinged on the Multidimensional Emotional Disorder Inventory (MEDI), a transdiagnostic self-report instrument. OBJECTIVE: this study undertakes the task of refining and validating the applicability of the MEDI within a non-clinical sample of Colombian university students (n = 808). METHODS: This study employed Exploratory Structural Equation Modeling (ESEM) to explore the structure of the measure. RESULTS: ESEM suggested that the 8-dimension model with 48 items was the best-fitting solution, aligning with most dimensions identified by the original MEDI validation. Reliability was adequate for almost all dimensions (α: 0.69 - 0.92). An 8-dimension model with 48 items emerged as the most fitting solution, aligning with most dimensions identified by the original MEDI validation. CONCLUSION: The ensuing validation and contextual adaptation of the MEDI for use in the Colombian population augments the transdiagnostic evaluation of emotional disorders, with potential implications for enhanced stratification of targeted therapeutic interventions. By optimizing the assessment of both dimensional and cross-diagnostic paradigms, the MEDI portends a noteworthy impact in realms encompassing both academic inquiry and clinical practice.

Toward Equitable Precision Oncology: Monitoring Racial and Ethnic Inclusion in Genomics and Clinical Trials.

PURPOSE: Ethnic diversity in cancer research is crucial as race/ethnicity influences cancer incidence, survival, drug response, molecular pathways, and epigenetic phenomena. In 2018, we began a project to examine racial/ethnic diversity in cancer research, with a commitment to review these disparities every 4 years. This report is our second assessment, detailing the present state of racial/ethnic diversity in cancer genomics and clinical trials. METHODS: To study racial/ethnic inclusion in cancer genomics, we extracted ethnic records from all data sets available at cBioPortal (n = 125,128 patients) and cancer-related genome-wide association studies (n = 28,011,282 patients) between 2018 and 2022. Concerning clinical trials, we selected studies related to breast cancer (n = 125,518 patients, 181 studies), lung cancer (n = 34,329 patients, 119 studies), and colorectal cancer (n = 40,808 patients, 105 studies). RESULTS: In cancer genomics (N = 28,136,410), 3% of individuals lack racial/ethnic registries; tumor samples were collected predominantly from White patients (89.14%), followed by Asian (7%), African American (0.55%), and Hispanic (0.21%) patients and other populations (0.1%). In clinical trials (N = 200,655), data on race/ethnicity are missing for 60.14% of the participants; for individuals whose race/ethnicity was recorded, most were characterized as White (28.33%), followed by Asian (7.64%), African (1.79), other ethnicities (1.37), and Hispanic (0.73). Racial/ethnic representation significantly deviates from global ethnic proportions (P ≤ .001) across all data sets, with White patients outnumbering other ethnic groups by a factor of approximately 4-6. CONCLUSION: Our second update on racial/ethnic representation in cancer research highlights the persistent overrepresentation of White populations in cancer genomics and a notable absence of racial/ethnic information across clinical trials. To ensure more equitable and effective precision oncology, future efforts should address the reasons behind the insufficient representation of ethnically diverse populations in cancer research.

Data mining identifies novel RNA-binding proteins involved in colon and rectal carcinomas.

Colorectal adenocarcinoma (COREAD) is the second most deadly cancer and third most frequently encountered malignancy worldwide. Despite efforts in molecular subtyping and subsequent personalized COREAD treatments, multidisciplinary evidence suggests separating COREAD into colon cancer (COAD) and rectal cancer (READ). This new perspective could improve diagnosis and treatment of both carcinomas. RNA-binding proteins (RBPs), as critical regulators of every hallmark of cancer, could fulfill the need to identify sensitive biomarkers for COAD and READ separately. To detect new RBPs involved in COAD and READ progression, here we used a multidata integration strategy to prioritize tumorigenic RBPs. We analyzed and integrated 1) RBPs genomic and transcriptomic alterations from 488 COAD and 155 READ patients, 2) ∼ 10,000 raw associations between RBPs and cancer genes, 3) ∼ 15,000 immunostainings, and 4) loss-of-function screens performed in 102 COREAD cell lines. Thus, we unraveled new putative roles of NOP56, RBM12, NAT10, FKBP1A, EMG1, and CSE1L in COAD and READ progression. Interestingly, FKBP1A and EMG1 have never been related with any of these carcinomas but presented tumorigenic features in other cancer types. Subsequent survival analyses highlighted the clinical relevance of FKBP1A, NOP56, and NAT10 mRNA expression to predict poor prognosis in COREAD and COAD patients. Further research should be performed to validate their clinical potential and to elucidate their molecular mechanisms underlying these malignancies.

The action dynamics of approach-avoidance conflict during decision-making.

Approach-avoidance conflict is observed in the competing motivations towards the benefits and away from the costs of a decision. The current study investigates the action dynamics of response motion during such conflicts in an attempt to characterise their dynamic resolution. An approach-avoidance conflict was generated by varying the appetitive consequences of a decision (i.e., point rewards and shorter participation time) in the presence of simultaneous aversive consequences (i.e., shock probability). Across two experiments, approach-avoidance conflict differentially affected response trajectories. Approach trajectories were less complex than avoidance trajectories and, as approach and avoidance motivations neared equipotentiality, response trajectories were more deflected from the shortest route to the eventual choice. Consistency in the location of approach and avoidance response options reduced variability in performance enabling more sensitive estimates of dynamic conflict. The time course of competing influences on response trajectories including trial-to-trial effects and conflict between approach and avoidance were estimated using regression analyses. We discuss these findings in terms of a dynamic theory of approach-avoidance that we hope will lead to insights of practical relevance in the field of maladaptive avoidance.

Effects of the environmental conditions and seasonality on a population survey of the Andean condor Vultur gryphus in the tropical Andes.

Background: Among the New World vultures, the Andean condor is considered one of the most culturally and ecologically important species. However, their populations are declining over their entire distributional range. In response, conservation strategies have been implemented in many countries to reverse the increasing extinction risk of this species. The initiatives rely on extensive population surveys to gather basic information necessary to implement policies and to intervene efficiently. Still, there is a need to standardize the surveys based on seasonality and suitable environmental conditions throughout the species distribution. Here, we provide the first assessment of how daily temperature, rainfall, and seasonality influence surveys of Andean condors on a communal roost in the central Peruvian Andes. Methods: Using an autoregressive generalized linear model, we associated environmental variables with visual surveys of adult and young condors at three different times of the day and three times a week between June 2014 and March 2015. Results: We found that both adults and young Andean condors showed a threefold reduction in the use of the communal roost after the beginning of the rainy season. Colder and drier days (dry season) are preferable for surveying, as we expect the total number of condors using communal roosts to reduce under rainy (rainfall = -0.53 ± 0.16) and warmer days (temperature = -0.04 ± 0.02) days. Therefore, the significant variation in the use of roosts across seasons and hours should be carefully accounted for in national surveys, at the risk of undermining the full potential of the communal roost surveys. Moreover, we also found a strong bias towards immatures (about 76%) in the adult:immature ratio and a remarkable absence of Andean condors during the wet season. These results suggest that the species might be using other unknown communal roosts hierarchically. Such results provide key information for selecting priority areas for conservation and selecting the best time to survey this species in the tropical Andes. Finally, it may open a fruitful avenue for further research on the protection of the Andean condor.

Integrated multi-omics analysis reveals the molecular interplay between circadian clocks and cancer pathogenesis.

Circadian rhythms (CRs) are fundamental biological processes that significantly impact human well-being. Disruption of these rhythms can trigger insufficient neurocognitive development, insomnia, mental disorders, cardiovascular diseases, metabolic dysfunctions, and cancer. The field of chronobiology has increased our understanding of how rhythm disturbances contribute to cancer pathogenesis, and how circadian timing influences the efficacy of cancer treatments. As the circadian clock steadily gains recognition as an emerging factor in tumorigenesis, a thorough and comprehensive multi-omics analysis of CR genes/proteins has never been performed. To shed light on this, we performed, for the first time, an integrated data analysis encompassing genomic/transcriptomic alterations across 32 cancer types (n = 10,918 tumors) taken from the PanCancer Atlas, unfavorable prognostic protein analysis, protein-protein interactomics, and shortest distance score pathways to cancer hallmark phenotypes. This data mining strategy allowed us to unravel 31 essential CR-related proteins involved in the signaling crossroad between circadian rhythms and cancer. In the context of drugging the clock, we identified pharmacogenomic clinical annotations and drugs currently in late phase clinical trials that could be considered as potential cancer therapeutic strategies. These findings highlight the diverse roles of CR-related genes/proteins in the realm of cancer research and therapy.

Role of environmental enrichment on social interaction, anxiety, locomotion, and memory in Wistar rats under chronic methylphenidate intake.

Introduction: Chronic use of various compounds can have long-lasting effects on animal behavior, and some of these effects can be influenced by the environment. Many environmental enrichment protocols have the potential to induce behavioral changes. Aim: The aim of the present study was to investigate how environmental enrichment can mitigate the effects of chronic methylphenidate consumption on the behavior of Wistar rats. Methods: The animals were housed for 20 days under either an environmental enrichment protocol (which included tubes of different shapes) or standard housing conditions. After seven days, half of the rats received 13 days of oral administration of methylphenidate (2 mg/kg). After seven days, the rats underwent behavioral tests, including the elevated plus maze (anxiety), open field (locomotion), object-in-place recognition test (spatial memory), and a test for social interaction (social behavior). Results: The results showed that the enriched environmental condition reversed the enhanced time in the open arms of the elevated plus maze induced by methylphenidate (F[1,43] = 4.275, p = 0.045). Methylphenidate also enhanced exploratory rearing in the open field (F[1,43] = 4.663, p = 0.036) and the time spent in the open area of the open field (H[3] = 8.786, p = 0.032). The enriched environment mitigated the inhibition of social interaction with peers induced by methylphenidate (H[3] = 16.755, p < 0.001) as well as the preference for single exploratory behavior (H[3] = 9.041, p = 0.029). Discussion: These findings suggest that environmental enrichment can counteract some of the effects of methylphenidate. These results are relevant for the clinical treatment of the long-lasting secondary effects associated with methylphenidate pharmacological treatment.

Integrated In Silico Analyses Identify PUF60 and SF3A3 as New Spliceosome-Related Breast Cancer RNA-Binding Proteins.

More women are diagnosed with breast cancer (BC) than any other type of cancer. Although large-scale efforts have completely redefined cancer, a cure remains unattainable. In that respect, new molecular functions of the cell should be investigated, such as post-transcriptional regulation. RNA-binding proteins (RBPs) are emerging as critical post-transcriptional modulators of tumorigenesis, but only a few have clear roles in BC. To recognize new putative breast cancer RNA-binding proteins, we performed integrated in silico analyses of all human RBPs (n = 1392) in three major cancer databases and identified five putative BC RBPs (PUF60, TFRC, KPNB1, NSF, and SF3A3), which showed robust oncogenic features related to their genomic alterations, immunohistochemical changes, high interconnectivity with cancer driver genes (CDGs), and tumor vulnerabilities. Interestingly, some of these RBPs have never been studied in BC, but their oncogenic functions have been described in other cancer types. Subsequent analyses revealed PUF60 and SF3A3 as central elements of a spliceosome-related cluster involving RBPs and CDGs. Further research should focus on the mechanisms by which these proteins could promote breast tumorigenesis, with the potential to reveal new therapeutic pathways along with novel drug-development strategies.

Identification of Key Proteins from the Alternative Lengthening of Telomeres-Associated Promyelocytic Leukemia Nuclear Bodies Pathway.

Alternative lengthening of telomeres-associated promyelocytic leukemia nuclear bodies (APBs) are a hallmark of telomere maintenance. In the last few years, APBs have been described as the main place where telomeric extension occurs in ALT-positive cancer cell lines. A different set of proteins have been associated with APBs function, however, the molecular mechanisms behind their assembly, colocalization, and clustering of telomeres, among others, remain unclear. To improve the understanding of APBs in the ALT pathway, we integrated multiomics analyses to evaluate genomic, transcriptomic and proteomic alterations, and functional interactions of 71 APBs-related genes/proteins in 32 Pan-Cancer Atlas studies from The Cancer Genome Atlas Consortium (TCGA). As a result, we identified 13 key proteins which showed distinctive mutations, interactions, and functional enrichment patterns across all the cancer types and proposed this set of proteins as candidates for future ex vivo and in vivo analyses that will validate these proteins to improve the understanding of the ALT pathway, fill the current research gap about APBs function and their role in ALT, and be considered as potential therapeutic targets for the diagnosis and treatment of ALT-positive cancers in the future.