Miracle-dz/UniFAR-FTUs huggingface dataset:
How Can Climate Models Be Used in Paleoelevation Reconstructions?

Paleoelevation reconstructions derived from proxy data such as stable oxygen isotope records in terrestrial archives have been determined for Cenozoic mountain ranges around the world. Recent studies have highlighted that a variety of paleoclimate processes can contribute to the isotopic composition of a measured precipitation (δ18Op) signal used in elevation reconstructions. These processes can include: regional, global, and topographic variations in paleotemperature; environmental conditions of an air mass before orographic ascent; evapotranspiration; water vapor recycling; and changes in the vapor source. In some cases, these processes can overprint the elevation signal sought in proxy data and preclude robust elevation reconstructions. Recent advances in isotope tracking climate models allow us to estimate paleoclimate changes during orogen development and associated changes in paleo δ18Op due to both climate and topographic changes. These models account for adiabatic and non-adiabatic temperature changes, relative humidity variations, changing continental evapotranspiration, vapor recycling, vapor source changes, etc. Modeling strategies using high-resolution isotopes-enabled General Circulation Models (iGCMs) together with time-specific boundary conditions and variable topography provide a powerful tool for enhancing elevation reconstructions from δ18Op proxy data. In this review, we discuss the principles, benefits and caveats of using iGCMs for interpreting isotopic records from natural archives for paleoelevation reconstructions. We also highlight future challenges for the application of iGCMs to paleoaltimetry proxy data that open up new avenues for research on tectonic-climate interactions.
Exploring the Potential of Cytochrome P450 CYP109B1 Catalyzed Regio—and Stereoselective Steroid Hydroxylation

Cytochrome P450 enzyme CYP109B1 is a versatile biocatalyst exhibiting hydroxylation activities toward various substrates. However, the regio- and stereoselective steroid hydroxylation by CYP109B1 is far less explored. In this study, the oxidizing activity of CYP109B1 is reconstituted by coupling redox pairs from different sources, or by fusing it to the reductase domain of two self-sufficient P450 enzymes P450RhF and P450BM3 to generate the fused enzyme. The recombinant Escherichia coli expressing necessary proteins are individually constructed and compared in steroid hydroxylation. The ferredoxin reductase (Fdr_0978) and ferredoxin (Fdx_1499) from Synechococcus elongates is found to be the best redox pair for CYP109B1, which gives above 99% conversion with 73% 15β selectivity for testosterone. By contrast, the rest ones and the fused enzymes show much less or negligible activity. With the aid of redox pair of Fdr_0978/Fdx_1499, CYP109B1 is used for hydroxylating different steroids. The results show that CYP109B1 displayed good to excellent activity and selectivity toward four testosterone derivatives, giving all 15β-hydroxylated steroids as main products except for 9 (10)-dehydronandrolone, for which the selectivity is shifted to 16β. While for substrates bearing bulky substitutions at C17 position, the activity is essentially lost. Finally, the origin of activity and selectivity for CYP109B1 catalyzed steroid hydroxylation is revealed by computational analysis, thus providing theoretical basis for directed evolution to further improve its catalytic properties.
Advances in Human Immune System Mouse Models for Personalized Treg-Based Immunotherapies

Immunodeficient mice engrafted with a functional human immune system [Human immune system (HIS) mice] have paved the way to major advances for personalized medicine and translation of immune-based therapies. One prerequisite for advancing personalized medicine is modeling the immune system of individuals or disease groups in a preclinical setting. HIS mice engrafted with peripheral blood mononuclear cells have provided fundamental insights in underlying mechanisms guiding immune activation vs. regulation in several diseases including cancer. However, the development of Graft-vs.-host disease restrains relevant long-term studies in HIS mice. Alternatively, engraftment with hematopoietic stem cells (HSCs) enables mimicking different disease stages, however, low frequencies of HSCs in peripheral blood of adults impede engraftment efficacy. One possibility to overcome those limitations is the use of patient-derived induced pluripotent stem cells (iPSCs) reprogrammed into HSCs, a challenging process which has recently seen major advances. Personalized HIS mice bridge research in mice and human diseases thereby facilitating the translation of immunomodulatory therapies. Regulatory T cells (Tregs) are important mediators of immune suppression and thereby contribute to tumor immune evasion, which has made them a central target for cancer immunotherapies. Importantly, studying Tregs in the human immune system in vivo in HIS mice will help to determine requirements for efficient Treg-targeting. In this review article, we discuss advances on personalized HIS models using reprogrammed iPSCs and review the use of HIS mice to study requirements for efficient targeting of human Tregs for personalized cancer immunotherapies.
Multiple Myeloma Cells Alter Adipogenesis, Increase Senescence-Related and Inflammatory Gene Transcript Expression, and Alter Metabolism in Preadipocytes

Within the bone marrow microenvironment, mesenchymal stromal cells (MSCs) are an essential precursor to bone marrow adipocytes and osteoblasts. The balance between this progenitor pool and mature cells (adipocytes and osteoblasts) is often skewed by disease and aging. In multiple myeloma (MM), a cancer of the plasma cell that predominantly grows within the bone marrow, as well as other cancers, MSCs, preadipocytes, and adipocytes have been shown to directly support tumor cell survival and proliferation. Increasing evidence supports the idea that MM-associated MSCs are distinct from healthy MSCs, and their gene expression profiles may be predictive of myeloma patient outcomes. Here we directly investigate how MM cells affect the differentiation capacity and gene expression profiles of preadipocytes and bone marrow MSCs. Our studies reveal that MM.1S cells cause a marked decrease in lipid accumulation in differentiating 3T3-L1 cells. Also, MM.1S cells or MM.1S-conditioned media altered gene expression profiles of both 3T3-L1 and mouse bone marrow MSCs. 3T3-L1 cells exposed to MM.1S cells before adipogenic differentiation displayed gene expression changes leading to significantly altered pathways involved in steroid biosynthesis, the cell cycle, and metabolism (oxidative phosphorylation and glycolysis) after adipogenesis. MM.1S cells induced a marked increase in 3T3-L1 expression of MM-supportive genes including Il-6 and Cxcl12 (SDF1), which was confirmed in mouse MSCs by qRT-PCR, suggesting a forward-feedback mechanism. In vitro experiments revealed that indirect MM exposure prior to differentiation drives a senescent-like phenotype in differentiating MSCs, and this trend was confirmed in MM-associated MSCs compared to MSCs from normal donors. In direct co-culture, human mesenchymal stem cells (hMSCs) exposed to MM.1S, RPMI-8226, and OPM-2 prior to and during differentiation, exhibited different levels of lipid accumulation as well as secreted cytokines. Combined, our results suggest that MM cells can inhibit adipogenic differentiation while stimulating expression of the senescence associated secretory phenotype (SASP) and other pro-myeloma molecules. This study provides insight into a novel way in which MM cells manipulate their microenvironment by altering the expression of supportive cytokines and skewing the cellular diversity of the marrow.
Drawing on Dialogues in Arts-Based Dynamic Interpersonal Therapy (ADIT) for Complex Depression: A Complex Intervention Development Study Using the Medical Research Council (UK) Phased Guidance

Aim: The aim of this paper is to present the development and evaluation of an art psychotherapy brief treatment method for complex depression for patients referred to mental health services. Background: Art Psychotherapy literature describes a range of processes of relational change through the use of arts focused and relationship focused interventions. Complex depression has a prevalence of 3% of the population in the West and it is recorded that in 2016 only 28% of that population were receiving psychological treatment. This study was developed to test the hypothesis of whether an accessible and acceptable approach to the treatment of complex depression could be developed in relation to existing evidence-based practice within mental health services. Method: The United Kingdom Medical Research Council phased guidance for complex intervention development was used (Phases I and II) to develop the intervention. The process included producing a literature overview, systematic description of clinical practice, including a logic model and a clinical protocol. The art psychotherapy protocol described an arts-based dynamic interpersonal therapy approach (ADIT), offered 1:1 over 24 sessions. Further to this the intervention was tested for referrer acceptability. The intervention is in the early stages of evaluation, using changes to the patient's depression and anxiety measured pre- and post-treatment with a follow-up measure at 3 months following completion of treatment. Results: Phase I of the study provided a good basis for developing a logic model and protocol. The authors found that there was good clinical consensus about the use of a structured clinical art psychotherapy method (ADIT) and the literature overview was used to support specific examples of good practice. The verification of clinical coherence was represented by a logic model and clinical protocol for delivering the intervention. The acceptability study demonstrated very high levels of acceptability for referrers reporting that (i) ADIT was acceptable for patients with complex/major depression, (ii) that they were likely to refer to ADIT in the future (iii) that the use of arts was likely to improve accessibility (iv) the use of arts was likely to improve outcomes and (v) that offering ADIT was an effective use of mental health resources. Discussion: Phase I of this intervention development study (following MRC guidance) demonstrated theoretical and practice coherence resulting in a clinical protocol and logic model. Whilst Phase II of this study showed promising results, Phase II would need to be sufficiently scaled up to a full trial to further test the intervention and protocol.
Performance of Interferon-Gamma Release Assays in the Diagnosis of Nontuberculous Mycobacterial Diseases—A Retrospective Survey From 2011 to 2019

There is an urgent need for precise diagnosis to distinguish nontuberculous mycobacterial (NTM) diseases from pulmonary tuberculosis (PTB) and other respiratory diseases. The aim of this study is to evaluate the diagnostic performance of Interferon-gamma (IFN-γ) release assays (IGRAs), including antigen-specific peripheral blood-based quantitative T cell assay (T-SPOT.TB) and QuantiFERON-TB-Gold-Test (QFT-G), in differentiating NTM infections (N = 1,407) from culture-confirmed PTB (N = 1,828) and other respiratory diseases (N = 2,652). At specie level, 2.56%, 10.73%, and 16.49% of NTM-infected patients were infected by Mycobacterium kansasii, M. abscessus, and with M. avmm-intracellulare complex (MAC), respectively. Valid analyses of T-SPOT.TB (ESAT-6, CFP-10) and QFT-G were available for 37.03% and 85.79% in NTM-infected patients, including zero and 100% (36/36) of M. kansasii infection, 21.85% (33/151) and 92.05% (139/151) of M. abscessus infection, and 17.67% (41/232) and 91.24% (211/232) of MAC infection. Based on means comparisons and further ROC analysis, T-SPOT.TB and QFT-G performed moderate accuracy when discriminating NTM from PTB at modified cut-off values (ESAT-6 < 4 SFCs, CFP-10 < 3 SFCs, and QFT-G < 0.667 IU/ml), with corresponding AUC values of 0.7560, 0.7699, and 0.856. At species level of NTM, QFT-G effectively distinguished between MAC (AUC=0.8778), M. kansasii (AUC=0.8834) or M. abscessus (AUC=0.8783) than T-SPOT.TB. No significant differences in discriminatory power of these three IGRA tools were observed when differentiating NTM and Controls. Our results demonstrated that T-SPOT.TB and QFT-G were both efficient methods for differentiating NTM disease from PTB, and QFT-G possessed sufficient discriminatory power to distinguish infections by different NTM species.
Emerging Perspectives on Dipeptide Repeat Proteins in C9ORF72 ALS/FTD

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide expansion in the chromosome 9 open reading frame 72 gene (C9ORF72). This hexanucleotide expansion consists of GGGGCC (G4C2) repeats that have been implicated to lead to three main modes of disease pathology: loss of function of the C9ORF72 protein, the generation of RNA foci, and the production of dipeptide repeat proteins (DPRs) through repeat-associated non-AUG (RAN) translation. Five different DPRs are currently known to be formed: glycine–alanine (GA) and glycine–arginine (GR) from the sense strand, proline–alanine (PA), and proline–arginine (PR) from the antisense strand, and glycine–proline (GP) from both strands. The exact contribution of each DPR to disease pathology is currently under intense scrutiny and is still poorly understood. However, recent advances in both neuropathological and cellular studies have provided us with clues enabling us to better understand the effect of individual DPRs on disease pathogenesis. In this review, we compile the current knowledge of specific DPR involvement on disease development and highlight recent advances, such as the impact of arginine-rich DPRs on nucleolar protein quality control, the correlation of poly-GR with neurodegeneration, and the possible involvement of chimeric DPR species. Further, we discuss recent findings regarding the mechanisms of RAN translation, its modulators, and other promising therapeutic options.
Immunological Impact of Intestinal T Cells on Metabolic Diseases

Emerging evidence accumulated over the past several years has uncovered intestinal CD4+ T cells as an essential mediator in modulating intestinal immunity in health and diseases. It has also been increasingly recognized that dietary and microbiota-derived factors play key roles in shaping the intestinal CD4+ T-cell compartment. This review aims to discuss the current understanding on how the intestinal T cell immune responses are disturbed by obesity and metabolic stress. In addition, we review how these changes influence systemic metabolic homeostasis and the T-cell-mediated crosstalk between gut and liver or brain in the progression of obesity and its related diseases. Lastly, we highlight the potential roles of some drugs that target intestinal T cells as a therapeutic treatment for metabolic diseases. A better understanding of the interaction among metabolites, bacterial signals, and T cell immune responses in the gut and their roles in systemic inflammation in metabolic tissues should shed new light on the development of effective treatment of obesity and related disorders.
Galaxy and MEAN Stack to Create a User-Friendly Workflow for the Rational Optimization of Cancer Chemotherapy

One aspect of personalized medicine is aiming at identifying specific targets for therapy considering the gene expression profile of each patient individually. The real-world implementation of this approach is better achieved by user-friendly bioinformatics systems for healthcare professionals. In this report, we present an online platform that endows users with an interface designed using MEAN stack supported by a Galaxy pipeline. This pipeline targets connection hubs in the subnetworks formed by the interactions between the proteins of genes that are up-regulated in tumors. This strategy has been proved to be suitable for the inhibition of tumor growth and metastasis in vitro. Therefore, Perl and Python scripts were enclosed in Galaxy for translating RNA-seq data into protein targets suitable for the chemotherapy of solid tumors. Consequently, we validated the process of target diagnosis by (i) reference to subnetwork entropy, (ii) the critical value of density probability of differential gene expression, and (iii) the inhibition of the most relevant targets according to TCGA and GDC data. Finally, the most relevant targets identified by the pipeline are stored in MongoDB and can be accessed through the aforementioned internet portal designed to be compatible with mobile or small devices through Angular libraries.
The Impact of Neonatal Methamphetamine on Spatial Learning and Memory in Adult Female Rats

The present study was aimed at evaluating cognitive changes following neonatal methamphetamine exposure in combination with repeated treatment in adulthood of female Wistar rats. Pregnant dams and their pups were used in this study. One half of the offspring were treated indirectly via the breast milk of injected mothers, and the other half of pups were treated directly by methamphetamine injection. In the group with indirect exposure, mothers received methamphetamine (5 mg/ml/kg) or saline (1 ml/kg) between postnatal days (PD) 1–11. In the group with direct exposure, none of the mothers were treated. Instead, progeny were either: (1) treated with injected methamphetamine (5 mg/ml/kg); or (2) served as controls and received sham injections (no saline, just a needle stick) on PD 1–11. Learning ability and memory consolidation were tested on PD 70–90 in the Morris Water Maze (MWM) using three tests: Place Navigation Test, Probe Test, and Memory Recall Test. Adult female progeny were injected daily, after completion of the last trial of MWM tests, with saline or methamphetamine (1 mg/ml/kg). The effects of indirect/direct neonatal methamphetamine exposure combined with acute adult methamphetamine treatment on cognitive functions in female rats were compared. Statistical analyses showed that neonatal drug exposure worsened spatial learning and the ability to remember the position of a hidden platform. The study also demonstrated that direct methamphetamine exposure has a more significant impact on learning and memory than indirect exposure. The acute dose of the drug did not produce any changes in cognitive ability. Analyses of search strategies (thigmotaxis, scanning) used by females during the Place Navigation Test and Memory Recall Test confirmed all these results. Results from the present study suggested extensive deficits in learning skills and memory of female rats that may be linked to the negative impact of neonatal methamphetamine exposure.
Home Numeracy and Preschool Children’s Mathematical Development: Expanding Home Numeracy Models to Include Parental Attitudes and Emotions

Most studies suggest that home numeracy is correlated with preschool children’s current mathematical performance, and also predicts their mathematical performance longitudinally. However, this finding is not universal, and some studies do not suggest a close relationship between home numeracy and preschoolers’ mathematical development. There are several possible reasons for the discrepant findings, including the exact nature of numeracy activities provided, and possible unreliability of parental reports of home numeracy. However, parental attitudes might also lead to differing results: because attitudes might influence actual home numeracy provision or the ways in which it is reported; because parental attitudes and beliefs might be transmitted intergenerationally; and because parental mathematics anxiety may interact with home numeracy activities to create early negative emotional associations about mathematics, as some research suggests to be the case with regard to school-age children. There has been a significant amount of research in the first two of these areas, but very little in the third area with regard to preschoolers. It should be seen as an important area for further research.
ICD-11 Personality Disorder: The Indispensable Turn to Narrative Identity

The field of personality disorders (PD) is taking an important step away from a categorical approach by inviting a dimensional understanding of conceptualizing and diagnosing manifestations of personality pathology (1). This means that, in the long awaited 11th revision of the International Classification of Diseases (ICD-11), the core of PD is considered on a spectrum of intraand interpersonal dysfunctions (2). Let me begin this paper by declaring my sympathy for the dimensional model. I do, however, encourage this shift to incorporate an aspect of (maladaptive) personality that is gaining momentum in PD research—a person’s narrative identity. In the following, I illustrate why narrative identity contributes with an indispensable aspect to ICD-11’s self-function that revolves around “stability and coherence of one’s sense of identity” (1). For additional and more thorough arguments on this matter see also Lind, Dunlop and Sharp (under review).
Cognitive Biases Questionnaire for Psychosis (CBQp): Spanish Validation and Relationship With Cognitive Insight in Psychotic Patients

Introduction: Cognitive biases are key factors in the development and persistence of delusions in psychosis. The Cognitive Biases Questionnaire for Psychosis (CBQp) is a new self-reported questionnaire of 30 relevant situations to evaluate five types of cognitive biases in psychosis. In the context of the validation of the Spanish version of the CBQp, our objectives were to (1) analyze the factorial structure of the questionnaire with a confirmatory factor analysis (CFA), (2) relate cognitive biases with a widely used scale in the field of delusion cognitive therapies for assessing metacognition, specifically, Beck's Cognitive Insight Scale (BCIS) (1), and, finally, (3) associate cognitive biases with delusional experiences, evaluated with the Peters Delusions Inventory (PDI) (2). Materials and Methods: An authorized Spanish version of the CBQp, by a translation and back-translation procedure, was obtained. A sample of 171 patients with different diagnoses of psychoses was included. A CFA was used to test three different construct models. Associations between CBQp biases, the BCIS, and the PDI were made by correlation and mean differences. Comparisons of the CBQp scores between a control group and patients with psychosis were analyzed. Results: The CFA showed comparative fit index (CFI) values of 0.94 and 0.95 for the models with one, two, and five factors, with root mean square error of approximation values of 0.031 and 0.029. The CBQp reliability was 0.87. Associations between cognitive biases, self-certainty, and cognitive insight subscales of the BCIS were found. Similarly, associations between total punctuation, conviction, distress, and concern subscales of the PDI were also found. When compared with the group of healthy subjects, patients with psychoses scored significantly higher in several cognitive biases. Conclusion: Given the correlation between biases, a one-factor model might be more appropriate to explain the scale's underlying construct. Biases were associated with a greater frequency of delusions, distress, conviction, and concern as well as worse cognitive insight in patients with psychosis.