Institute for Biomedical Research and Innovation

To better understand the complexity of biological systems, research has shifted from a reductionist to a holistic approach, expanding the focus from single genes to a genome-scale view of gene activity and regulation. This is known as transcriptomics, a continuously growing field generating gene expression signatures from different technologies. A comparable paradigm shift has occurred in computational systems biology with the implementation of Artificial Intelligence (AI) learning models for gene expression analysis and integration. These models enable transcriptome-based profiling to address challenges of data heterogeneity, integration, and updating, assisting human intelligence and enhancing their ability to retrieve, analyze, integrate, and generate data recursively, thanks to their intrinsic predictive, inferential, reinforcement, and generative capabilities. Additionally, while scientists worldwide are still learning how to leverage AI methods that can maintain the human-in-the-loop, a new fundamental change is emerging: agentic AI, which can autonomously act and employ other AI methods to pursue its objectives. As a futuristic perspective, the proposed data analysis pipeline imagines agentic AI systems allowing the automated retrieval and pre-processing of heterogeneous transcriptomics data, analysis and integration with other omics datasets, performed with an incremental updating and recurrent analysis (IURA) model that could allow the detection of guideline updates (e.g., disease reclassification) and the generation of new hypotheses, such as candidate biomarkers or transcriptome-phenotype correlations. Since personalized medicine could derive profound benefits from its use, this scenario also raises important considerations regarding the advantages and concerns associated with the use of scientific AI agents in research and clinical practice.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is becoming the most common liver disease, affecting between 30 and 40% of the global population. MASLD is a multifaceted disease spectrum that is closely associated with obesity, insulin resistance, type 2 diabetes mellitus and, more broadly, metabolic syndrome. All these conditions increase the risk of liver-related mortality, which explains the intense research efforts in recent years to better elucidate its pathogenesis. The crucial impact of environmental pollutants on the development of MASLD is now well recognized. Polychlorinated biphenyls (PCBs) are environmental contaminants that act as endocrine disruptors. Recently, they have been associated with the development of diabetes, obesity, MASLD, and cancer. The association between liver diseases, namely toxicant-associated steatotic liver disease and steatohepatitis (TASLD and TASH, respectively), and occupational exposure to PCBs and other industrial chemicals has been documented by several lines of evidence, whereas the potential role of low-level environmental pollution in liver disease and in MASLD remains incompletely understood. Previous studies on animal models have shown that PCB exposure is associated with steatosis/steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma (HCC), altered liver enzymes, and mortality in exposed populations. This review investigates the mechanisms underlying hepatic steatogenesis in preclinical and animal models and analyzes the existing literature on the possible role of PCBs, together with the other conventional risk factors, in the development of MASLD in humans.

Abstract Several neurological disorders can be described as alterations of the brain connectome, both anatomic and functional. To model diseases and compare them, it has been proposed the Krankheit -operator ( K -operator), which acts on the weights of the connectome, reproducing the effects of specific disorders. In this article, with algebraic tools, we attempt to provide a more general definition of the operator, that encompasses the previous different definitions provided. We consider a general setting where the linear operator is an endomorphism on the vector space of $$n\times n$$ n × n matrices. We show that the left and right matrix multiplication and a Hadamard multiplications can all be described as a special structured operator.

The endangered anchialine squat lobster Munidopsis polymorpha is restricted to northern Lanzarote. To understand genetic isolation and conservation risks, we genotyped 26 individuals at eight microsatellite loci from four sites in La Corona lava tube and Charcos de Luis. Lava tube sites shared most alleles and were effectively undifferentiated, whereas Charcos de Luis harbored nine private alleles, the highest allelic richness, and clear differentiation from the lava tube complex. We detected no Hardy-Weinberg deviations among testable locus x site combinations and no linkage disequilibrium. These results are consistent with two candidate management units: La Corona lava tube and Charcos de Luis. We outline genomic priorities to guide future conservation plans. To account for our reduced sampling size, we screened for null alleles and repeated the analyses on a reduced set of loci passing conservative quality filters, obtaining congruent patterns of differentiation.

Background: Wild-type transthyretin amyloidosis (ATTRwt) diagnosis remains challenging. Echocardiographic "red flags" play a significant role in raising diagnostic suspicion. Methods: Retrospective study including 33 patients diagnosed with ATTRwt. All patients underwent comprehensive echocardiographic evaluation focusing on the red flags for ATTRwt. Left ventricular hypertrophy (LVH) was defined as interventricular septal wall thickness (IVST) ≥ 12 mm and/or LV mass indexed for body surface area (LVMI) ≥ 115 g/m2 in men and ≥ 95 g/m2 in women. Results: Relative wall thickness > 0.42 and early diastolic myocardial velocity < 7 cm/s were detected in 100% of patients. Severe diastolic dysfunction (grade ≥ 3) (72.7%), apical sparing (36.4%), granular sparkling pattern (30.3%), and pericardial effusion (39.4%) were also observed. Females were younger than males (median age 68 vs. 74.5 years), and IVST ≥ 12 mm was lower in females than in males (64.4% vs. 100%, respectively, p < 0.05). The combined criterion of IVST ≥ 12 mm in men and LVMI ≥ 95 g/m2 in women was encountered in 100% of the global cohort. Conclusions: IVST is a good predictor of LVH in males but shows limited sensitivity for ATTRwt in females; a gender-differenced approach (IVST for men and LVMI for women) might better stratify for ATTRwt suspicion.

ABSTRACT This article reframes Gestalt psychotherapy as intrinsically relational: experience and self‐emerge from contact at the organism–environment boundary and from the field/situation. We revisit ambiguities in the Perls/Goodman model against a brief historical background and articulate a pragmatic stance grounded in the id of the situation and esthetic relational knowledge (ARK). A brief clinical vignette illustrates how attending to the field's esthetic qualities and to embodied resonance guides participation, timing, and dosage.

Over the years, attentional characteristics such as reduced attention to faces or eye contact have been considered impairments and in need of correction in people with autism. This work proposes a reinterpretation of visual attention in people with autism, going beyond the traditional deficit-based approach. It proposes a shift in perspective by examining the characteristics of visual attention in people with autism as a resource for personal orientation strategies in complex and challenging environments. To better study and observe these mechanisms, the use of digital technologies such as mobile eye trackers, virtual reality, and other digital technologies can offer valuable support for better delineating the different strengths of this type of attentional modality, which deviates from the “norm.” Therefore, rather than focusing on correction, the shift in perspective should focus much more on the understanding, well-being, and autonomy of people with autism. Viewing autistic attention not as a problem, but as a resource to be valued, is the first step towards building a truly inclusive society.

Hypoxia is a common feature of inflamed and ischemic tissues and represents an important regulatory signal for innate immune cells. The master regulator of this response is hypoxia-inducible factor-1α (HIF-1α), a transcription factor whose stabilization and activity are tightly regulated by the presence of oxygen, inflammatory signaling, and cellular metabolism. Monocytes, key players in innate immunity, rapidly sense oxygen deprivation and display specific responses during acute hypoxia, primarily aimed at adapting and maintaining cellular homeostasis. Unlike macrophages, in which HIF-1α activity is known, the mechanisms regulating HIF-1α stabilization, subcellular localization, and transcriptional activity in circulating monocytes remain incompletely elucidated. Recent studies indicate that acute hypoxia primarily triggers post-translational stabilization of HIF-1α, calcium- and PKC-dependent signaling, metabolic reprogramming, and early inflammatory responses, while transcriptional activation of HIF-1α may require additional inflammatory or stress-related signals. Furthermore, extensive crosstalk between HIF-1α and NF-κB integrates hypoxic and inflammatory signals, modulating cytokine production, cell migration, and survival. Epigenetic regulators can also modulate these responses and contribute to hypoxia-induced trained immunity. In this review, we summarize current knowledge of the mechanisms controlling the stabilization, localization, and function of HIF-1α in human monocytes and monocyte-macrophages during acute hypoxia, highlighting the key differences between these cell types and discussing their implications for inflammation, tissue homeostasis, and disease.

The aim of the present study was to assess the cost-effectiveness of bariatric surgery, non-surgical weight loss and pharmacological non-surgical weight loss (BS-WL, NS-WL, PNS-WL) to avoid or delay total knee arthroplasty (TKA) in subjects with end-stage knee osteoarthritis and obesity. The quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were computed using a Markov State Model simulating outcomes and costs in 4000 potential subjects followed for 25 years. Model inputs were derived from the literature and internet sources. Deterministic and probabilistic sensitivity analyses were performed to assess the robustness of the model assumptions. BS-WL and PNS-WL increased QALYs from 7.70 (TKA-only group) to 8.96 and 8.41, respectively, while NS-WL marginally increased QALY to 7.86. The BS-WL and PNS-WL ICERs were $27,127 and $33,461, respectively, far below the willingness-to-pay threshold of $50,000. However, the NS-WL ICER was $57,843. The percentage of subjects needing first revision was greater after TKA-only (26.4%) and lower with the other strategies (12.9% with BS-WL, 23.5% with NS-WL and 20.1% with PNS-WL). The most sensitive parameter was BS-WL success in weight loss; 20% of the key input parameter variations produced BS-WL ICERs that were always below the threshold, as for the PNS-WL strategy. Bariatric surgery is effective and cost-effective in delaying or preventing TKA in patients with severe obesity and reducing the need for primary and secondary surgical revision. Despite current limitations on the long-term effects of available antiobesity medications, semaglutide appears to also be cost-effective, while non-surgical weight loss is the least effective strategy. Clinicians and policy makers should consider the cost-effectiveness of losing weight prior to total knee replacement in patients with obesity.