Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs). PTPRK was found to be increased in steatotic hepatocytes in both humans and mice, and positively correlated with PPAR{gamma}-induced lipogenic signalling. High-fat-fed PTPRK knockout mice displayed reduced weight gain and hepatic fat accumulation. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified fructose-1,6 bisphosphatase-1 and glycolysis as PTPRK targets in metabolic reprogramming. Silencing PTPRK in hepatoma cell lines resulted in reduced colony-forming ability, and PTPRK knockout mice developed smaller tumours after diethylnitrosamine-induced hepatocarcinogenesis. Our study defines a novel role for PTPRK in regulating hepatic glycolysis, lipid metabolism, and tumour development. PTPRK inhibition may provide therapeutic possibilities in obesity-associated liver diseases. less

Oral premalignant lesions (OPLs) with genomic alterations have a heightened risk of evolving into oral squamous cell carcinoma (OSCC). Currently, genomic data are obtained through invasive tissue biopsy. Brush biopsy has been utilized for diagnosing dysplasia but its effectiveness in reflecting the complete genomic landscape of OPLs remains uncertain. This study investigates the potential of brush biopsy samples in accurately reconstructing the genomic profile of OPLs. We analyzed single nucleotide variants (SNVs), copy number aberrations (CNAs), and subclonal structures in paired tissue and brush biopsy samples from a patient with both OPL and OSCC lesions. The results showed that brush biopsy can effectively reflect about 90% of SNVs and similar CNA profiles as those found in tissue biopsies. It was specific, as normal oral epithelium did not share these genomic alterations. Interestingly, brush biopsy revealed shared SNVs and CNAs between the distinct OPL and OSCC lesions, indicating a common ancestral origin. Subclonal reconstruction confirmed this shared ancestry, followed by divergent evolution of the lesions. These findings highlight the potential of brush biopsies in accurately representing the genomic profile of OPL and OSCC, proving useful in understanding tumor evolution. less

Understanding the spatial heterogeneity of tumors and its links to disease is a cornerstone of cancer biology. Emerging spatial technologies offer unprecedented capabilities towards this goal, but several limitations hinder their clinical adoption. To date, histopathology workflows still heavily depend on hematoxylin & eosin (H&E) and serial immunohistochemistry (IHC) staining, a cumbersome and tissue-exhaustive process that yields unaligned tissue images. We propose the VirtualMultiplexer, a generative AI toolkit that translates real H&E images to matching IHC images for several markers based on contrastive learning. The VirtualMultiplexer learns from unpaired H&E and IHC images and introduces a novel multi-scale loss to ensure consistent and biologically reliable stainings. The virtually multiplexed images enabled training a Graph Transformer that simultaneously learns from the joint spatial distribution of several markers to predict clinically relevant endpoints. Our results indicate that the VirtualMultiplexer achieves rapid, robust and precise generation of virtually multiplexed imaging datasets of high staining quality that are indistinguishable from the real ones. We successfully employed transfer learning to generate realistic virtual stainings across tissue scales, patient cohorts, and cancer types with no need for model fine-tuning. Crucially, the generated images are not only realistic but also clinically relevant, as they greatly improved the prediction of different clinical endpoints across patient cohorts and cancer types, speeding up histopathology workflows and accelerating spatial biology. less

The flowering time, which determines when the fruits or seeds can be harvested, is known to be sensitive to plasticity, i.e. the ability of a genotype to display different phenotypes in response to environmental variations. In the context of climate change, strawberry breeding can take advantage of phenotypic plasticity to create high-performing varieties adapted either to local conditions or to a wide range of climates. To decipher how the environment affects the genetic architecture of flowering time in cultivated strawberry (Fragaria x ananassa) and modify its QTL effects, we used a bi-parental segregating population grown for two years at widely divergent latitudes (5 European countries) and combined climatic variables with genomic data (Affymetrix(R) SNP array). We detected 10 unique flowering time QTL and demonstrated that temperature modulates the effect of plasticity-related QTL. We propose candidate genes for the three main plasticity QTL, including FaTFL1 which is the most relevant candidate in the interval of the major temperature-sensitive QTL (6D_M). We further designed and validated a genetic marker for the 6D_M QTL which offers great potential for breeding programs, for example for selecting of early-flowering strawberry varieties well adapted to different environmental conditions. less

The primary cilium is characteristic of most of non-immune cells and acts as an environmental signal transduction sensor. The defects in primary cilium have profound consequences on the developmental program, including the maturation of retinal epithelium. The ciliary length is tightly regulated during ciliogenesis. Additionally, many features of ciliogenesis are shared with an immune synapse formation. While the interaction between the cells within an immune synapse is well-characterized, the impact of inflammatory stresses on ciliogenesis in non-immune cells remains elusive. The current study investigates the outcome of inflammatory stimuli for the primary cilium in human retinal epithelial cells. Here, we report that the exposure of retinal epithelium cells to pro-inflammatory cytokine TNF-alpha elongates cilia in a Mixed-Lineage Kinase (MLK) -dependent manner. In contrast, febrile condition-mimicking heat stress dramatically reduced the number of ciliated cells regardless of TNF-alpha exposure, suggesting distinct but rapid effects of inflammatory stresses on ciliogenesis. less

Somatic mitochondrial DNA (mtDNA) mutation accumulation has been observed in individuals with retinal degenerative disorders. To study the effects of aging and mtDNA mutation accumulation in the retina, a Polymerase gamma (POLG) deficiency model, the POLGD257A mutator mice (PolgD257A), was used. POLG is an enzyme responsible for regulating mtDNA replication and repair. Retinas of young and older mice with this mutation were analyzed in vivo and ex vivo to provide new insights into the contribution of age-related mitochondrial dysfunction due to mtDNA damage. Optical coherence tomography (OCT) image analysis revealed a decrease in retinal and photoreceptor thickness starting at 6 months of age in mice with the POLGD257A mutation compared to wild-type (WT) mice. Electroretinography (ERG) testing showed a significant decrease in all recorded responses at 6 months of age. Sections labeled with markers of different types of retinal cells, including cones, rods, and bipolar cells, exhibited decreased labeling starting at 6 months. However, electron microscopy analysis revealed differences in retinal pigment epithelium (RPE) mitochondria morphology beginning at 3 months. Interestingly, there was no increase in oxidative stress observed in the retina or RPE of POLGD257A mice. Additionally, POLGD257A RPE exhibited an accelerated rate of autofluorescence cytoplasmic granule formation and accumulation. Mitochondrial markers displayed decreased abundance in protein lysates obtained from retina and RPE samples. These findings suggest that the accumulation of mitochondrial DNA mutations leads to impaired mitochondrial function and accelerated aging, resulting in retinal degeneration. less

Limited access to low-cost tools to measure, report, and verify (MRV) tree growth with smallholder farmers limits the scaling of tree planting efforts in developing countries. Artificial Intelligence (AI) offers the potential for low-cost, reliable, and accessible measurement and verification tools to be developed for an MRV platform to scale tree planting efforts in developing countries. Here, we present an AI-powered non-contact tree diameter measurement and verification tool. We have developed an AI-powered algorithm that accurately estimates the diameter of a tree from an image of the tree with a reference object. This non-contact measurement method utilizes semantic segmentation and image processing techniques to analyze an image of the tree with the reference object. The performance of the proposed method was evaluated on 142 trees with tape-measured diameters at breast height ranging from 5 to 60 cm. A regression analysis between predicted and measured diameter values had an R2 and an RMSE of 0.97 and 2.23 cm, respectively. Thus, using a smartphone application, the non-contact method developed here can empower anyone to accurately measure and report tree growth by just taking pictures of the trees with the reference object. The images submitted with on-farm measurements serve as data for future verification operations using the AI-powered algorithm. With the reference object serving as a unique tree identifier, a tree\'s survival and diameter measurements can be tracked over time. The MRV system described here, with the developed AI-powered non-contact tree diameter measurement and verification tool, can empower organizations to plant, grow, and monitor trees with anyone, including smallholder farmers. less

The human brain has inherent limitations in consciously processing visual information. When individuals monitor a rapid sequence of images for detecting two targets, they often miss the second target (T2) if it appears within a short time frame of 200-500ms after the first target (T1), a phenomenon known as the attentional blink (AB). The neural mechanism behind AB remains unclear, largely due to the use of simplistic visual items such as letters and digits in conventional AB experiments, which differ significantly from naturalistic vision. This study employed advanced multivariate pattern analysis (MVPA) of human EEG data to explore the neural representations associated with target processing within a naturalistic paradigm under conditions where AB does or does not occur. Our MVPA analysis successfully decoded the identity of target images from EEG data. Moreover, in the AB condition, characterized by a limited time between targets, T1 processing coincided with T2 processing, resulting in the suppression of late representational markers of both T1 and T2. Conversely, in the condition with longer inter-target interval, neural representations endured for a longer duration. These findings suggest that the attentional blink can be attributed to the suppression of neural representations in the later stages of target processing. less

Chronic pain is a hallmark of joint diseases and is often accompanied by negative affective symptoms such as low mood, anxiety and memory dysfunction. Whether these may be the results of the more obvious sensory and functional symptoms of joint pain is poorly understood and this likely contributes to the difficulty in adequately managing this condition. Here, we have used two mouse models to address this lack of knowledge. Using a model of ankle inflammation and a model of knee osteoarthritis, we found that these models of joint pain induced weight bearing deficits of different magnitude but relatively similar mechanical allodynia that lasted at least 3 months. However, the models were accompanied by very different affective outcomes, as only the model of knee osteoarthritis, that led to significant early changes in activity and sleep patterns, was accompanied by an increase in negative affective behaviors, including cognitive impairments and depressive-like behavior. The models also had different molecular profiles at both spinal and hippocampal levels. Importantly, the functional outcomes measured in the early stages of the disease stage strongly correlated with sensory and emotional profiles at 3 months, suggesting that early functional measures may be used as predictors of the long-term symptoms associated with persistent joint pain. In conclusion, the predictive value of early measures of functional impact of joint disease could prove useful in the clinics for adapted therapeutic approaches for the prevention of emotional comorbidities and better pain management for patients with joint pain. less

Background & aims: Lymphocytes that produce IL-17 can confer protective immunity during infections by pathogens, yet their involvement in inflammatory diseases is a subject of debate. Although these cells may perpetuate inflammation, resulting in tissue damage, they are also capable of contributing directly or indirectly to tissue repair, thus necessitating more detailed investigation. Mucosal-Associated-Invariant-T (MAIT) cells are innate-like T cells, acquiring a type III phenotype in the thymus. Here, we dissected the role of MAIT cells in vivo using a spontaneous colitis model in a genetically diverse mouse strain. Methods: Multiparameter spectral flow cytometry and scRNAseq were used to characterize MAIT and immune cell dynamics and transcriptomic signatures respectively, in the collaborative-cross strain, CC011/Unc and CC011/Unc-Traj33-/-. Results: In contrast to many conventional mouse laboratory strains, the CC011 strain harbors a high baseline population of MAIT cells. We observed an age-related increase in colonic MAIT cells, Th17 cells, regulatory T cells, and neutrophils, which paralleled the development of spontaneous colitis. This progression manifested histological traits reminiscent of human IBD. The transcriptomic analysis of colonic MAIT cells from CC011 revealed an activation profile consistent with an inflammatory milieu, marked by an enhanced type-III response. Notably, IL-17A was abundantly secreted by MAIT cells in the colons of afflicted mice. Conversely, in the MAIT cell-deficient CC011-Traj33-/- mice, there was a notable absence of significant colonic histopathology. Furthermore, myeloperoxidase staining indicated a substantial decrease in colonic neutrophils. Conclusions: Our findings suggest that MAIT cells play a pivotal role in modulating the severity of intestinal pathology, potentially orchestrating the inflammatory process by driving the accumulation of neutrophils within the colonic environment. less