Miracle-dz/UniFAR-FTUs huggingface dataset:
The Biologist’s Guide to the Glucocorticoid Receptor’s Structure

The glucocorticoid receptor α (GRα) is a member of the nuclear receptor superfamily and functions as a glucocorticoid (GC)-responsive transcription factor. GR can halt inflammation and kill off cancer cells, thus explaining the widespread use of glucocorticoids in the clinic. However, side effects and therapy resistance limit GR’s therapeutic potential, emphasizing the importance of resolving all of GR’s context-specific action mechanisms. Fortunately, the understanding of GR structure, conformation, and stoichiometry in the different GR-controlled biological pathways is now gradually increasing. This information will be crucial to close knowledge gaps on GR function. In this review, we focus on the various domains and mechanisms of action of GR, all from a structural perspective.
Efficacy of Liver-Directed Combined Radiotherapy in Locally Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis

Simple Summary In this multinational, multi-institutional study, we investigated the efficacy of liver-directed combined radiotherapy compared with sorafenib in hepatocellular carcinoma patients presenting portal vein tumor thrombosis. Propensity score matching was performed to minimize the imbalance between the two groups. The median overall survival was significantly improved in the LD combined RT group, and the conversion rate to curative surgery was also significantly higher in the LD combined RT group. Despite the multimodality of the treatments, toxicity rates of LD combined RT were comparable to those of sorafenib. Abstract Purpose: Although systemic treatment is the mainstay for advanced hepatocellular carcinoma (HCC), numerous studies have highlighted the added value of local treatment. This study aimed to investigate the clinical efficacy of liver-directed combined radiotherapy (LD combined RT) compared with that of sorafenib, a recommended treatment until recently for locally advanced HCC presenting portal vein tumor thrombosis (PVTT), using a multinational patient cohort. Materials and Methods: We identified patients with HCC presenting PVTT treated with either sorafenib or LD combined RT in 10 tertiary hospitals in Asia from 2005 to 2014. Propensity score matching (PSM) was performed to minimize the imbalance between the two groups. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and treatment-related toxicity. Results: A total of 1035 patients (675 in the LD combined RT group and 360 in the sorafenib group) were included in this study. After PSM, 305 patients from each group were included in the analysis. At a median follow-up of 22.5 months, the median OS was 10.6 and 4.2 months for the LD combined RT and sorafenib groups, respectively (p < 0.001). The conversion rate to curative surgery was significantly higher (8.5% vs. 1.0%, p < 0.001), while grade ≥ 3 toxicity was fewer (9.2% vs. 16.1%, p < 0.001) in the LD combined RT group. Conclusions: LD combined RT improved survival outcomes with a higher conversion rate to curative surgery in patients with locally advanced HCC presenting PVTT. Although further prospective studies are warranted, active multimodal local treatment involving radiotherapy is suggested for locally advanced HCC presenting PVTT.
Specific Proteomic Identification of Collagen-Binding Proteins in Escherichia coli O157:H7: Characterisation of OmpA as a Potent Vaccine Antigen

Escherichia coli is a versatile commensal species of the animal gut that can also be a pathogen able to cause intestinal and extraintestinal infections. The plasticity of its genome has led to the evolution of pathogenic strains, which represent a threat to global health. Additionally, E. coli strains are major drivers of antibiotic resistance, highlighting the urgent need for new treatment and prevention measures. The antigenic and structural heterogeneity of enterohaemorrhagic E. coli colonisation factors has limited their use for the development of effective and cross-protective vaccines. However, the emergence of new strains that express virulence factors deriving from different E. coli diarrhoeagenic pathotypes suggests that a vaccine targeting conserved proteins could be a more effective approach. In this study, we conducted proteomics analysis and functional protein characterisation to identify a group of proteins potentially involved in the adhesion of E. coli O157:H7 to the extracellular matrix and intestinal epithelial cells. Among them, OmpA has been identified as a highly conserved and immunogenic antigen, playing a significant role in the adhesion phenotype of E. coli O157:H7 and in bacterial aggregation. Furthermore, antibodies raised against recombinant OmpA effectively reduced the adhesion of E. coli O157:H7 to intestinal epithelial cells. The present work highlights the role of OmpA as a potent antigen for the development of a vaccine against intestinal pathogenic E. coli.
Ethyl Caffeate Can Inhibit Aryl Hydrocarbon Receptor (AhR) Signaling and AhR-Mediated Potentiation of Mast Cell Activation

Ethyl caffeate (EC) is a natural phenolic compound that is present in several medicinal plants used to treat inflammatory disorders. However, its anti-inflammatory mechanisms are not fully understood. Here, we report that EC inhibits aryl hydrocarbon receptor (AhR) signaling and that this is associated with its anti-allergic activity. EC inhibited AhR activation, induced by the AhR ligands FICZ and DHNA in AhR signaling-reporter cells and mouse bone marrow-derived mast cells (BMMCs), as assessed by AhR target gene expressions such as CYP1A1. EC also inhibited the FICZ-induced downregulation of AhR expression and DHNA-induced IL-6 production in BMMCs. Furthermore, the pretreatment of mice with orally administered EC inhibited DHNA-induced CYP1A1 expression in the intestine. Notably, both EC and CH-223191, a well-established AhR antagonist, inhibited IgE-mediated degranulation in BMMCs grown in a cell culture medium containing significant amounts of AhR ligands. Furthermore, oral administration of EC or CH-223191 to mice inhibited the PCA reaction associated with the suppression of constitutive CYP1A1 expression within the skin. Collectively, EC inhibited AhR signaling and AhR-mediated potentiation of mast cell activation due to the intrinsic AhR activity in both the culture medium and normal mouse skin. Given the AhR control of inflammation, these findings suggest a novel mechanism for the anti-inflammatory activity of EC.
Synaptamide Ameliorates Hippocampal Neurodegeneration and Glial Activation in Mice with Traumatic Brain Injury

Traumatic brain injury (TBI) is a major concern for public health worldwide, affecting 55 million people and being the leading cause of death and disability. To improve the outcomes and effectiveness of treatment for these patients, we conducted a study on the potential therapeutic use of N-docosahexaenoylethanolamine (synaptamide) in mice using the weight-drop injury (WDI) TBI model. Our study focused on exploring synaptamide’s effects on neurodegeneration processes and changes in neuronal and glial plasticity. Our findings showed that synaptamide could prevent TBI-associated working memory decline and neurodegenerative changes in the hippocampus, and it could alleviate decreased adult hippocampal neurogenesis. Furthermore, synaptamide regulated the production of astro- and microglial markers during TBI, promoting the anti-inflammatory transformation of the microglial phenotype. Additional effects of synaptamide in TBI include stimulating antioxidant and antiapoptotic defense, leading to the downregulation of the Bad pro-apoptotic marker. Our data suggest that synaptamide has promising potential as a therapeutic agent to prevent the long-term neurodegenerative consequences of TBI and improve the quality of life.
“Holding in Anger” as a Mediator in the Relationship between Attachment Orientations and Borderline Personality Features

Insecure attachment and difficulties in regulating anger have both been put forward as possible explanations for emotional dysfunction in borderline personality (BP). This study aimed to test a model according to which the influence of attachment on BP features in a subclinical population is mediated by anger regulation. In a sample of 302 participants, BP features were assessed with the Borderline features scale of the Personality Assessment Inventory (PAI-BOR), attachment was measured with the Experiences in Close Relationships-12 (ECR-12), and trait anger and anger regulation were assessed with the State and Trait Anger Expression Inventory-2 (STAXI-2). The results indicated that anger suppression emerged as a significant mediator of the associations between both anxious and avoidant attachment and BP traits, while anger control resulted as a marginal mediator in the association between attachment avoidance and BP. Suppressing anger may reflect different forms of cognitive or behavioural avoidance of anger, which may differ on the basis of attachment orientations. We argue that these results may have important clinical implications: the promotion of anger regulation in BP should be considered a critical treatment goal.
Development Trajectories of Fatigue, Quality of Life, and the Ability to Work among Colorectal Cancer Patients in the First Year after Rehabilitation—First Results of the MIRANDA Study

Simple Summary Colorectal cancer (CRC) patients often experience fatigue, poor ability to work, and low quality of life (QoL) after therapy. We conducted a prospective study of 147 CRC patients who underwent a three-week in-patient rehabilitation clinic visit in Germany. Patients completed questionnaires at the start of rehabilitation and at regular 3-month intervals for up to a year. We found a strong correlation between fatigue and QoL, and moderate correlations between fatigue and the ability to work, as well as between QoL and the ability to work. Fatigue, QoL, and ability to work improved significantly from the start of rehabilitation to the three-month follow-up, and there was little change afterward in the first year after rehabilitation. In summary, fatigue, QoL, and the ability to work were highly interconnected in CRC patients, and all of them improved from the start of rehabilitation to the 3-month follow-up. Abstract Cancer-related fatigue, low quality of life (QoL), and low ability to work are highly prevalent among colorectal cancer (CRC) patients after tumor surgery. We aimed to analyze their intercorrelations and trajectories in the first year after in-patient rehabilitation in the German multicenter MIRANDA cohort study. Recruitment is ongoing, and we included the first 147 CRC patients in this analysis. Participants filled out questionnaires at the beginning of in-patient rehabilitation (baseline) and at 3, 6, 9, and 12 months after the baseline. The EORTC-QLQ-C30-General-Health-Status (GHS)/QoL, the FACIT-F-Fatigue Scale, and the FACIT-F-FWB-ability-to-work items were used to evaluate QoL, fatigue, and ability to work, respectively. The fatigue and QoL scales were highly correlated (r = 0.606). A moderate correlation was observed between the fatigue and ability to work scales (r = 0.487) and between the QoL and ability to work scales (r = 0.455). Compared to the baseline, a statistically significant improvement in the QoL, ability to work, and fatigue scales were observed at the 3-month follow-up (Wilcoxson signed rank test, all p < 0.0001). The three scales plateaued afterward until the 12-month follow-up. In conclusion, fatigue, QoL, and ability to work were highly interrelated, improved quickly during/after in-patient rehabilitation, and did not change much afterward in German CRC patients.
Impact of Shape Irregularity in Medial Sphenoid Wing Meningiomas on Postoperative Cranial Nerve Functioning, Proliferation, and Progression-Free Survival

Simple Summary The shape of meningiomas has been suggested as a potential indicator of the WHO grade. Medial sphenoid wing meningiomas are surgically challenging skull base tumors regarding the preservation of cranial nerve functioning. The present study investigates the impact of tumor shape on neuropathology, progression-free survival, and cranial nerve functioning. The present investigation shows that irregular shape is significantly associated with new postoperative cranial nerve deficits and a shorter time to tumor progression. From a pathological point of view, irregular shapes may result from areas with increased proliferative activity. A systematic review and pooled data analysis that included the present study revealed that an irregular shape is associated with a higher MIB-1 labeling index. Tumor shape should be considered in the preoperative surgical planning regarding the preservation of cranial nerve functioning. Further research is required to examine the molecular basis of irregular meningioma shape. Abstract Medial sphenoid wing meningiomas (MSWM) are surgically challenging skull base tumors. Irregular tumor shapes are thought to be linked to histopathology. The present study aims to investigate the impact of tumor shape on postoperative functioning, progression-free survival, and neuropathology. This monocentric study included 74 patients who underwent surgery for primary sporadic MSWM (WHO grades 1 and 2) between 2010 and 2021. Furthermore, a systematic review of the literature regarding meningioma shape and the MIB-1 index was performed. Irregular MSWM shapes were identified in 31 patients (41.9%). Multivariable analysis revealed that irregular shape was associated with postoperative cranial nerve deficits (OR: 5.75, 95% CI: 1.15–28.63, p = 0.033). In multivariable Cox regression analysis, irregular MSWM shape was independently associated with tumor progression (HR:8.0, 95% CI: 1.04–62.10, p = 0.046). Multivariable regression analysis showed that irregular shape is independently associated with an increased MIB-1 index (OR: 7.59, 95% CI: 2.04–28.25, p = 0.003). A systematic review of the literature and pooled data analysis, including the present study, showed that irregularly shaped meningiomas had an increase of 1.98 (95% CI: 1.38–2.59, p < 0.001) in the MIB-1 index. Irregular MSWM shape is independently associated with an increased risk of postoperative cranial nerve deficits and a shortened time to tumor progression. Irregular MSWM shapes might be caused by highly proliferative tumors.
In Vitro and In Vivo Efficacy of a Stroma-Targeted, Tumor Microenvironment Responsive Oncolytic Adenovirus in Different Preclinical Models of Cancer

More than one million women are diagnosed annually worldwide with a gynecological cancer. Most gynecological cancers are diagnosed at a late stage, either because a lack of symptoms, such as in ovarian cancer or limited accessibility to primary prevention in low-resource countries, such as in cervical cancer. Here, we extend the studies of AR2011, a stroma-targeted and tumor microenvironment responsive oncolytic adenovirus (OAdV), whose replication is driven by a triple hybrid promoter. We show that AR2011 was able to replicate and lyse in vitro fresh explants obtained from human ovarian cancer, uterine cancer, and cervical cancer. AR2011 was also able to strongly inhibit the in vitro growth of ovarian malignant cells obtained from human ascites fluid. The virus could synergize in vitro with cisplatin even on ascites-derived cells obtained from patients heavily pretreated with neoadjuvant chemotherapy. AR2011(h404), a dual transcriptionally targeted derived virus armed with hCD40L and h41BBL under the regulation of the hTERT promoter, showed a strong efficacy in vivo both on subcutaneous and intraperitoneally established human ovarian cancer in nude mice. Preliminary studies in an immunocompetent murine tumor model showed that AR2011(m404) expressing the murine cytokines was able to induce an abscopal effect. The present studies suggest that AR2011(h404) is a likely candidate as a novel medicine for intraperitoneal disseminated ovarian cancer.
Health Workers’ Burnout and COVID-19 Pandemic: 1-Year after—Results from a Repeated Cross-Sectional Survey

(1) Background: This study evaluates, one year later, the levels of burnout, anxious–depressive, and post-traumatic symptoms and the general health status in the Health Workers (HWs) involved in the SARS-COVID-19 pandemic in the Novara area. (2) Methods: The survey was sent via a link in an email to doctors, nurses, and other operators during the period between June and August 2021. The survey collected socio-demographic data and contained some self-administered questionnaires. (3) Results: A total of 688 HWs completed the survey, 53% were aged 30–49 years, 68% were female, 76% were cohabiting, 55% had children, 86% reported family habit changes, and 20% had non-COVID related health problems. Only a few of the respondents had a follow-up by a specialist (12%), of which there were even less in recent times (6%). It was observed that the respondents had undergone burnout; a poor state of general mental health (62%); depressive symptoms (70%); post-traumatic symptoms (29%); and less frequently, anxious symptoms (16%). The data of this study are in line with other studies in the literature. (4) Conclusions: The data indicate that psychological-based suffering was no longer markedly concentrated in some specific bands of HWs. In conclusion, it would be essential to enhance HW support strategies.
Peptide- and Metabolite-Based Hydrogels: Minimalistic Approach for the Identification and Characterization of Gelating Building Blocks

Minimalistic peptide- and metabolite-based supramolecular hydrogels have great potential relative to traditional polymeric hydrogels in various biomedical and technological applications. Advantages such as remarkable biodegradability, high water content, favorable mechanical properties, biocompatibility, self-healing, synthetic feasibility, low cost, easy design, biological function, remarkable injectability, and multi-responsiveness to external stimuli make supramolecular hydrogels promising candidates for drug delivery, tissue engineering, tissue regeneration, and wound healing. Non-covalent interactions such as hydrogen bonding, hydrophobic interactions, electrostatic interactions, and π–π stacking interactions play key roles in the formation of peptide- and metabolite-containing low-molecular-weight hydrogels. Peptide- and metabolite-based hydrogels display shear-thinning and immediate recovery behavior due to the involvement of weak non-covalent interactions, making them supreme models for the delivery of drug molecules. In the areas of regenerative medicine, tissue engineering, pre-clinical evaluation, and numerous other biomedical applications, peptide- and metabolite-based hydrogelators with rationally designed architectures have intriguing uses. In this review, we summarize the recent advancements in the field of peptide- and metabolite-based hydrogels, including their modifications using a minimalistic building-blocks approach for various applications.
Conflict Experience Regulates the Neural Encoding of Cognitive Conflict

Cognitive control is adaptive in that it rapidly adjusts attention in response to changing contexts and shifting goals. Research provides evidence that cognitive control can rapidly adjust attention to focus on task-relevant information based on prior conflict experience. Neural encoding of goal-related information is critical for goal-directed behaviour; however, the empirical evidence on how conflict experience affects the encoding of cognitive conflict in the brain is rather weak. In the present fMRI study, a Stroop task with different proportions of incongruent trial was used to investigate the neural encoding of cognitive conflict in the environment with changing conflict experience. The results showed that the anterior cingulate cortex, dorsolateral prefrontal cortex, and intraparietal sulcus played a pivotal role in the neural encoding of cognitive conflict. The classification in anterior cingulate cortex was significantly above chance in the high-proportion, moderate-proportion, and low-proportion conflict conditions conducted separately, suggesting that neural encoding of cognitive conflict in this region was not altered based on proportion of conflict. The dorsolateral prefrontal cortex and intraparietal sulcus showed significant above-chance classification in the moderate-proportion and low-proportion conflict conditions, but not in the high-proportion conflict condition. These findings provide direct evidence that conflict experience modulates the neural encoding of cognitive conflict.
Expression of Cell-Adhesion Molecules in E. coli: A High Throughput Screening to Identify Paracellular Modulators

Cell-adhesion molecules (CAMs) are responsible for cell–cell, cell–extracellular matrix, and cell–pathogen interactions. Claudins (CLDNs), occludin (OCLN), and junctional adhesion molecules (JAMs) are CAMs’ components of the tight junction (TJ), the single protein structure tasked with safeguarding the paracellular space. The TJ is responsible for controlling paracellular permeability according to size and charge. Currently, there are no therapeutic solutions to modulate the TJ. Here, we describe the expression of CLDN proteins in the outer membrane of E. coli and report its consequences. When the expression is induced, the unicellular behavior of E. coli is replaced with multicellular aggregations that can be quantified using Flow Cytometry (FC). Our method, called iCLASP (inspection of cell-adhesion molecules aggregation through FC protocols), allows high-throughput screening (HTS) of small-molecules for interactions with CAMs. Here, we focused on using iCLASP to identify paracellular modulators for CLDN2. Furthermore, we validated those compounds in the mammalian cell line A549 as a proof-of-concept for the iCLASP method.
Bibliometric Analysis: Six Decades of Scientific Production from a Nationwide Institution: Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE) from Mexico

Background: This study employed bibliometric analysis to ascertain the research focus areas among a group of Mexican physicians affiliated with the Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE). ISSSTE, a healthcare institution catering to a diverse range of diseases, offers a distinctive perspective on the investigated specialties within the realm of health. The primary objective was to identify knowledge gaps in medical care disciplines through a comprehensive examination of scholarly publications. Methods: We retrieved Scopus papers affiliated with “ISSSTE” and saved them as . CSV files. Subsequently, we employed VOSviewer, biblioshiny, and bibliometrix for bibliometric analysis. This enabled us to identify prominent institutions, prolific authors, highly cited researchers, and their respective affiliations. Results: Our analysis identified 2063 publications; the specialty internal medicine accounted for the greatest proportion with 831 publications. Original papers accounted for 82% of the total, with 52% of them being written in Spanish. The majority of scientific output, 92%, originated from Mexico City. The annual production has steadily increased since 2010, peaking in 2021 with over 200 publications. However, papers on prevalent conditions, such as metabolic syndrome, received limited citations, and the L0 index (percentage of uncited items) for all papers is close to 60%. Scopus mislabeled one affiliation, and some cases show a low paper-to-author ratio of 0.5 Discussion: Additional concerns, such as honorary authorship due to excessive authors per paper, and the underlying causes of low citation rates in Mexican publications, warrant further examination. Moreover, our research emphasizes the urgency of bolstering research and development funding, which was consistently below 0.5% of GDP for the past four decades, falling short of legal mandates and international benchmarks. We endorse the establishment of robust research collectives in Latin America to address these challenges, foster regional scientific output, and transition from knowledge consumers to knowledge producers, thereby reducing dependence on foreign technology.