Tissue Specificity Research Articles

Genome-wide single-cell and single-molecule footprinting of transcription factors with deaminase

Decades of research have established that mammalian transcription factors (TFs) bind to each gene's regulatory regions and cooperatively control tissue specificity, timing, and intensity of gene transcription. Mapping the combination of TF binding sites genome wide is critically important for understanding functional genomics. Here, we report a technique to measure TFs' binding sites on the human genome with a near single-base resolution by footprinting with deaminase (FOODIE) on a single-molecule and single-cell basis. Single-molecule sequencing reads after enzymatic deamination allow detection of the TF binding fraction on a particular footprint and the binding cooperativity of any two adjacent TFs, which can be either positive or negative. As a newcomer of single-cell genomics, single-cell FOODIE enables the detection of cell-type-specific TF footprints in a pure cell population in a heterogeneous tissue, such as the brain. We found that genes carrying out a certain biological function together in a housing-keeping correlated gene module (CGM) or a tissues-specific CGM are coordinated by shared TFs in the gene's promoters and enhancers, respectively. Scalable and cost-effective, FOODIE allows us to create an open FOODIE database for cell lines, with applicability to human tissues and clinical samples.

Genome-Wide Identification and Evolutionary Analysis of Functional BBM-like Genes in Plant Species

Background/Objectives: BABY BOOM (BBM), a transcription factor from the APETALA2 (AP2) protein family, plays a critical role in somatic embryo induction and apomixis. BBM has now been widely applied to induce apomixis or enhance plant transformation and regeneration efficiency through overexpression or ectopic expression. However, the structural and functional evolutionary history of BBM genes in plants is still not well understood. Methods: The protein sequences of 10 selected plant species were used to locate the branch of BBM-Like by key domain identification and phylogenetic tree construction. The identified BBML genes were used for further conserved motif identification, gene structural analysis, miRNA binding site prediction, cis-acting element prediction, collinear analysis, protein–protein interaction network construction, three-dimensional structure modeling, molecular docking, and expression pattern analysis. Results: A total of 24 BBML proteins were identified from 10 representative plant species. Phylogenetic relationship analysis displayed that BBML proteins from eudicots and monocots were divided into two clusters, with monocots exhibiting a higher number of BBMLs. Gene duplication events indicated that whole genome/segmental duplication were the primary drivers of BBML genes’ evolution in the tested species, with purifying selection playing a key role during evolution processes. Comparative analysis of motif, domains, and gene structures revealed that most BBMLs were highly evolutionarily conserved. The expression patterns of BBML genes revealed significant tissue specificity, particularly in the root and embryo. We also constructed protein–protein interaction networks and molecular docking models to identify functional pathways and key amino acid residues of BBML proteins. The functions of BBMLs may differ between monocots and eudicots, as suggested by the functional enrichment of interacting proteins. Conclusions: Our research delved into the molecular mechanism, evolutionary relationships, functional differentiation, and expression patterns of BBML genes across plants, laying the groundwork for further investigations into the molecular properties and biological roles of BBMLs.

Rarγ-Foxa1 signaling promotes luminal identity in prostate progenitors and is disrupted in prostate cancer.

Retinoic acid (RA) signaling is a master regulator of vertebrate development with crucial roles in body axis orientation and tissue differentiation, including in the reproductive system. However, a mechanistic understanding of how RA signaling governs cell lineage identity is often missing. Here, leveraging prostate organoid technology, we show that RA signaling orchestrates the commitment of adult mouse prostate progenitors to glandular identity, epithelial barrier integrity, and specification of prostatic lumen. RA-dependent RARγ activation promotes the expression of Foxa1, which synergizes with the androgen pathway for luminal expansion, cytoarchitecture and function. FOXA1 mutations are common in prostate and breast cancers, though their pathogenic mechanism is incompletely understood. Combining functional genetics with structural modeling of FOXA1 folding and chromatin binding analyses, we discover that FOXA1F254E255 is a loss-of-function mutation compromising its transcriptional function and luminal fate commitment of prostate progenitors. Overall, we define RA as an instructive signal for glandular identity in adult prostate progenitors. Importantly, we identify cancer-associated FOXA1 indels affecting residue F254 as loss-of-function mutations promoting dedifferentiation of adult prostate progenitors.

Tissue Engineering with Hyaluronic-Acid : Advances Application of Skin Regeneration Bone and Cartilage Repair

One method that has shown promise for healing damaged tissues is tissue engineering. The naturally occurring glycosaminoglycan hyaluronic acid (HA) has drawn interest because of its potential applications in the regeneration of skin, cartilage, and bone. The purpose of this study was to find out how well HA-based scaffolds work to encourage tissue repair and regeneration. We created and examined HA-based hydrogels, assessing their bioactivity, biocompatibility, and mechanical characteristics. Comparing HA-based scaffolds to controls, our findings showed increased tissue development, differentiation, and cell proliferation. HA-based constructions demonstrated noteworthy improvements in bone and cartilage regeneration in vivo, accompanied by notable increases in tissue integration and collagen deposition. These results demonstrate the potential of HA-based tissue engineering for the repair of bone, cartilage, and skin, providing a viable therapeutic approach for a range of dermatological and musculoskeletal applications.

Automatic Tissue Differentiation in Parotidectomy using Hyperspectral Imaging

Abstract In head and neck surgery, continuous intraoperative tissue differentiation is of great importance to avoid injury to sensitive structures such as nerves and vessels. Hyperspectral imaging (HSI) with neural network analysis could support the surgeon in tissue differentiation. A 3D Convolutional Neural Network with hyperspectral data in the range of 400 − 1000 nm is used in this work. The acquisition system consisted of two multispectral snapshot cameras creating a stereo-HSI-system. For the analysis, 27 images with annotations of glandular tissue, nerve, muscle, skin and vein in 18 patients undergoing parotidectomy are included. Three patients are removed for evaluation following the leave-one-subjectout principle. The remaining images are used for training, with the data randomly divided into a training group and a validation group. In the validation, an overall accuracy of 98.7% is achieved, indicating robust training. In the evaluation on the excluded patients, an overall accuracy of 83.4% has been achieved showing good detection and identification abilities. The results clearly show that it is possible to achieve robust intraoperative tissue differentiation using hyperspectral imaging. Especially the high sensitivity in parotid or nerve tissue is of clinical importance. It is interesting to note that vein was often confused with muscle. This requires further analysis and shows that a very good and comprehensive data basis is essential. This is a major challenge, especially in surgery.

Impact of gibberellic acid GA3, quantum dot biochar, and rhizosphere bacteria on fenugreek plant growth and stress responses under lead stress

Lead (Pb) is a stress that can cause problems with several aspects of a plant’s metabolism, potentially impeding the plant’s ability to grow and develop. The use of gibberellic acid (GA3), quantum dot biochar (QDBC), and rhizobacteria (RB) can be effective methods to overcome this problem. Gibberellic acid is a crucial plant hormone that regulates plant growth, cell division, tissue differentiation, flowering, photosynthesis, and transpiration rate. It also significantly impacts crop resilience to stress, affecting plant morphology, enzymatic activity, and physiology. Biochar, a soil supplement, enhances plant development soil health, and reduces stress effects. Due to its large surface area and porosity, it increases soil water-holding capacity, nutrient retention, and microbial activity. Quantum dots, semiconductor nanoparticles, have been proposed as a potential method to alleviate plant stress by acting as antioxidants, reducing oxidative stress, and controlling nutrient and growth regulators. Rhizobacteria, soil bacteria in plant roots, stimulate plant growth, nutrient absorption, and harvesting capacity. They produce phytohormones, increase mineral and nitrogen accessibility, and can induce systemic resistance (ISR), affecting plant defense. This study investigates the effects of combining GA3, QDBC, and RB as amendments to fenugreek, both with 500 Pb stress and without Pb stress. Treatments (control, 0.25 GA3mg/L-QDBC, 0.5 GA3mg/L-QDBC, 0.25 GA3mg/L-QDBC + RB, and 0.5 GA3mg/L-QDBC + RB) were applied in six replications using a completely randomized design. Results demonstrate that the combination of 0.5 GA3mg/L-QDBC + RB with 500 Pb stress led to significant enhancements in fenugreek shoot fresh weight (15.62%), root fresh weight (73.53%), shoot dry weight (24.00%), and root dry weight (36.53%) compared to the control. Additionally, there were notable improvements in chlorophyll a (57.23%), chlorophyll b (19.21%), and total chlorophyll (36.23%) compared to the control under Pb stress, also showing the potential of 0.5 GA3mg/L-QDBC + RB with 500 Pb stress. The study suggests that combining 0.5 GA3mg/L-QDBC + RB with 500 Pb stress can effectively mitigate Pb stress in fenugreek.

Doxophylline, a Non-Selective Phosphodiesterase Inhibitor, Protects Against Chronic Fatigue-Induced Neurobehavioral, Biochemical, and Mitochondrial Alterations.

Chronic fatigue stress (CFS) is a multisystem disorder which exhibits multiple signs of neurological complications like brain fog, cognitive deficits and oxidative stress with no specific treatment. Doxophylline, a non-selective phosphodiesterase inhibitor (PDEI), has anti-inflammatory properties with enhanced blood-brain barrier penetration and tissue specificity. We have evaluated the neuroprotective potential of doxophylline in a murine model of forced swim test (FST) induced CFS and in H2O2 (hydrogen peroxide) induced oxidative stress in PC12 cells. An FST model to induce a state of CFS in mice was induced by forcing them to swim daily for 6min for 15 days. The drug was administered daily 30min prior to FST. The immobility period was compared for day 1 and day 15. Animals were sacrificed on day 16 for biochemical, mitochondrial, and histopathological estimations in the brain. Cytotoxicity assay, reactive oxygen species (ROS) and nuclear morphology determination were carried out in PC12 cells. A significant increase in immobility has been observed on the 15th day in CFS-induced mice compared to doxophylline treated group. Neurobehavioral studies revealed hypo locomotion, anxiety, motor incoordination, and memory deficit. Biochemical analysis showed a significant change in oxidative stress markers (superoxide dismutase (SOD), reduced glutathione (GSH), catalase, lipid peroxidation (LPO) and nitrite levels) and acetylcholinesterase enzyme activity (AChE) in brain homogenates. Doxophylline pre-treatment protects against these impairments. In PC12 cell lines, doxophylline exhibits alleviation against H2O2-induced oxidative stress, intracellular ROS generation, and changes in nuclear morphology. Doxophylline could be promising and possess therapeutic potential in CFS treatment. Further research is needed to test if doxophylline can be repurposed for neurological disorders.

Spatiotemporal characterization of cyclooxygenase pathway enzymes during vertebrate embryonic development

Vertebrate development is regulated by several complex well-characterized morphogen signaling pathways, transcription factors, and structural proteins, but less is known about the enzymatic pathways that regulate early development. We have identified that factors from the inflammation-mediating cyclooxygenase (COX) signaling pathway are expressed at early stages of development in avian embryos. Using Gallus gallus (chicken) as a research model, we characterized the spatiotemporal expression of a subset of genes and proteins in the COX pathway during early neural development stages. Specifically, here we show expression patterns of COX-1, COX-2, and microsomal prostaglandin E synthase-2 (mPGES-2) as well as the genes encoding these enzymes (PTGS1, PTGS2, and PTGES-2). Unique expression patterns of individual players within the COX pathway suggest that they may play non-canonical/non-traditional roles in the embryo compared to their roles in the adult. Future work should examine the function of the COX pathway in tissue specification and morphogenesis and determine if these expression patterns are conserved across species.

Spontaneous reversal of small molecule-induced mitochondrial uncoupling: the case of anilinothiophenes.

Tissue specificity can render mitochondrial uncouplers more promising asleading compounds for creating drugs against serious diseases. In searchof tissue-specific uncouplers, we address anilinothiophenes as possible glutathione-S-transferase substrates (GST). Earlier, 'cyclic' uncoupling activity was reported for 5-bromo-N-(4-chlorophenyl)-3,4-dinitro-2-thiophenamine (BDCT) in isolated rat liver mitochondria (RLM). The mechanism by which BDCT induced two-phase changes in mitochondrial respiration (stimulation followed by deceleration) was unknown. To clarify this issue, we synthesized BDCT and its two analogues. Among these, 5-bromo-3,4-dinitro-N-(4-nitrophenyl)-2-thiophenamine (BDNT) appeared to be the most effective as a mitochondrial uncoupler, decreasing membrane potential and stimulating respiration at submicromolar concentrations. Importantly, BDNT exerted two-phase changes in both mitochondrial membrane potential and respiration rate of RLM, which were enhanced by the addition of glutathione (GSH) but inhibited by the compounds capable of GSH depleting, such as 1-chloro-2,4-dinitrobenzene (CDNB). By contrast, the phase of recoupling was not observed in rat heart mitochondria (RHM). Remarkably, BDNT elicited mitochondrial depolarization in primary human fibroblasts but not in cultured human liver (HepG2) cells. By detecting proton-selective electrical current through planar bilayer lipid membranes, we demonstrated the ability of BDCT and BDNT to transfer protons across membranes. BDNT proved to be an anionic protonophore with a pKa of 7.38. By using LC-MS and capillary electrophoresis, we directly showed the formation of BDNT conjugates with GSH upon incubation with RLM but not RHM. Therefore, we hypothesize that GST is involved in the disappearance of the anilinothiophene uncoupling activity in RLM, ensuring the tissue-specific behavior of the uncoupler.

Advancing precision in CT-guided bone biopsies: exploring the potential of dual-energy CT imaging.

This study aimed to investigate the integration of dual-energy CT (DECT) into CT-guided bone biopsy procedures, comparing it with conventional CT techniques. The focus was on technical aspects, accuracy and radiation dose exposure. A total of 51 bone biopsies were conducted, with 36 using conventional CT and 15 utilizing DECT. Patient data, lesion characteristics and biopsy techniques were analyzed. Statistical analyses, including Fisher's exact test and independent samples t-test, were performed to compare accuracy and radiation doses between the two methods. DECT-guided biopsies demonstrated a significantly higher accuracy (93.33%) compared to conventional CT biopsies (86.11%). The radiation dose exposure for DECT was comparable to conventional CT. DECT's ability to differentiate tissues, especially in bone marrow edema detection, led to higher precision. Integrating DECT into CT-guided bone biopsies enhances tissue differentiation and accuracy without significantly increasing radiation exposure. This advancement holds promise for improving musculoskeletal interventional radiology, leading to more precise diagnoses, informed treatment decisions and improved patient outcomes.

Automatic discrimination between neuroendocrine carcinomas and grade 3 neuroendocrine tumors by deep learning of H&E images

Neuroendocrine neoplasms (NENs) arise from diffuse neuroendocrine cells and are categorized as either well-differentiated and less proliferative Neuroendocrine Tumors (NETs), divided into low (G1), middle (G2), and high grades (G3), or poorly differentiated, and more proliferative Neuroendocrine Carcinomas (NECs). Low-grade NENs typically necessitate surgical intervention, whereas high-grade ones often require chemotherapy. However, low-grade NENs may exhibit aggressive behavior. Therefore, it is crucial to precisely refine the diagnosis of NENs. This refinement is achievable when differentiation/non-differentiation is evident or when the Ki-67 or mitosis index is low. The challenge arises in cases of morphologically undifferentiated instances with a high Ki-67 percentage and/or high mitotic index. To address this challenge, we developed a Deep Learning (DL) system named NEToC, designed to differentiate between NETs and NECs using exclusively morphological information from immunohistochemistry images, without relying on Ki-67 or mitosis assessments. NEToC was developed using 95 NEN cases from the period 2015 to 2018 at Parc Tauli Hospital in Spain, comprising 588 images. Implemented as a Graphical User Interface (GUI) system, NEToC is intended for deployment in pathological departments of hospitals to perform federated supervision. We tested the performance of NEToC with 119 images that were not used during the Artificial Neural Network (ANN) training phase, and evaluated its robustness across various resolutions: 64 × 64, 128 × 128, 256 × 256, and 512 × 512 pixels. The achieved accuracies for these resolutions were 74 %, 98 %, 98 %, and 100 %, respectively, for an underrepresented NET G3 experiment, and 66 %, 89 %, 95 % and 94 % for a represented NET G3 experiment. Based on several measured performance metrics, the optimal resolution appears to be between 128 × 128 and 256 × 256 pixels, considering computational resources and accuracy requirements. However, we found that the 256 × 256-pixel resolution is more robust to classify underrepresented classes in the learning phase. These results imply that the information to discriminate between NECs and Grade 3 NETs needs to be resolved in regions with a pixel resolution of no more than 4 μm/pixel. Most of the misclassifications were false negatives, where NET G1-type images were erroneously classified as NEC-type. Our results demonstrate that a DL-based diagnostic algorithm provides a more accurate diagnosis in NEN cases where physicians face challenges. NEToC has been initially trained with and used to classify gastrointestinal NENs. Since the NEN morphology does not change among the different organs, the use of NEToC can be extrapolated to NENs from different organs. NEToC facilitates federated supervision, allowing pathologists to collect interchangeable files based on NEToC classification predictions. NEToC is an easy-to-use, adaptable software that integrates multiple ANNs to improve standardization and accuracy NEN diagnosis, opening up possibilities for combining DL and histological diagnosis in federated supervision systems. A future goal is to classify not only NETs, but also the three-tier system (NET G1, NET G2, and NET G3) based solely on tissue differentiation information.

GRAF1 deficiency leads to defective brown adipose tissue differentiation and thermogenic response.

Adipose tissue, which is crucial for the regulation of energy within the body, contains both white and brown adipocytes. White adipose tissue (WAT) primarily stores energy, while brown adipose tissue (BAT) plays a critical role in energy dissipation as heat, offering potential for therapies aimed at enhancing metabolic health. Regulation of the RhoA/ROCK pathway is crucial for appropriate specification, differentiation and maturation of both white and brown adipocytes. However, our knowledge of how this pathway is controlled within specific adipose depots remains unclear, and to date a RhoA regulator that selectively controls adipocyte browning has not been identified. Our study shows that GRAF1, a RhoGAP, is highly expressed in metabolically active tissues, and closely correlates with brown adipocyte differentiation in culture and in vivo. Mice with either global or adipocyte-specific GRAF1 deficiency exhibit impaired BAT maturation and compromised cold-induced thermogenesis. Moreover, defects in differentiation of human GRAF1-deficient brown preadipocytes can be rescued by treatment with a Rho kinase inhibitor. Collectively, these studies indicate that GRAF1 can selectively induce brown adipocyte differentiation and suggest that manipulating GRAF1 activity may hold promise for the future treatment of diseases related to metabolic dysfunction.

The E3 ubiquitin ligase COP1 and transcription factors HY5 and RHD6 integrate light signaling and root hair development.

Light signaling plays a substantial role in regulating plant development, including the differentiation and elongation of single-celled tissue. However, the identity of the regulatory machine that affects light signaling on root hair cell (RHC) development remains unclear. Here, we investigated how darkness inhibits differentiation and elongation of RHC in Arabidopsis (Arabidopsis thaliana). We found that light promotes the growth and development of RHC. RNA-seq analysis showed that light signaling regulates the differentiation of RHC by promoting the expression of specific genes in the root epidermis associated with cell wall remodeling, JA, auxin, and ethylene signaling pathways. Together, these genes integrate light and phytohormone signals with root hair development. Our investigation also revealed that the core light signal factor ELONGATED HYPOCOTYL 5 (HY5) directly interacts with the key root hair development factor ROOT HAIR DEFECTIVE6 (RHD6), which promotes the transcription of RSL4. However, CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) repressed RHD6 function through the COP1-HY5 complex. Our genetic studies confirm associations between RHD6, HY5, and COP1, indicating that RHD6 largely depends on HY5 for root hair development. Ultimately, our work suggests a central COP1-HY5-RHD6 regulatory module that integrates light signaling and root hair development with several downstream pathways, offering perspectives to decipher single-celled root hair development.

Noncanonical transcription initiation is primarily tissue specific and epigenetically tuned in paleopolyploid plants.

Alternative transcription initiation (ATI) appears to be a ubiquitous regulatory mechanism of gene expression in eukaryotes. However, the extent to which it affects the products of gene expression and how it evolves and is regulated remain unknown. Here, we report genome-wide identification and analysis of transcription start sites (TSSs) in various soybean (Glycine max) tissues using a survey of transcription initiation at promoter elements with high-throughput sequencing (STRIPE-seq). We defined 193,579 TSS clusters/regions (TSRs) in 37,911 annotated genes, with 56.5% located in canonical regulatory regions and 43.5% from start codons to 3' untranslated regions, which were responsible for changes in open reading frames of 24,131 genes. Strikingly, 6,845 genes underwent ATI within coding sequences (CDSs). These CDS-TSRs were tissue-specific, did not have TATA-boxes typical of canonical promoters, and were embedded in nucleosome-free regions flanked by nucleosomes with enhanced levels of histone marks potentially associated with intragenic transcriptional initiation, suggesting that ATI within CDSs was epigenetically tuned and associated with tissue-specific functions. Overall, duplicated genes possessed more TSRs, exhibited lower degrees of tissue specificity, and underwent stronger purifying selection than singletons. This study highlights the significance of ATI and the genomic and epigenomic factors shaping the distribution of ATI in CDSs in a paleopolyploid eukaryote.

MiRNATissueAtlas 2025: an update to the uniformly processed and annotated human and mouse non-coding RNA tissue atlas.

MiRNAs represent a non-coding RNA class that regulate gene expression and pathways. While miRNAs are evolutionary conserved most data stems from Homo sapiens and Mus musculus. As miRNA expression is highly tissue specific, we developed miRNATissueAtlas to comprehensively explore this landscape in H. sapiens. We expanded the H. sapiens tissue repertoire and included M. musculus. In past years, the number of public miRNA expression datasets has grown substantially. Our previous releases of the miRNATissueAtlas represent a great framework for a uniformly pre-processed and label-harmonized resource containing information on these datasets. We incorporate the respective data in the newest release, miRNATissueAtlas 2025, which contains expressions from 9 classes of ncRNA from 799 billion reads across 61 593 samples for H. sapiens and M. musculus. The number of organs and tissues has increased from 28 and 54 to 74 and 373, respectively. This number includes physiological tissues, cell lines and extracellular vesicles. New tissue specificity index calculations build atop the knowledge of previous iterations. Calculations from cell lines enable comparison with physiological tissues, providing a valuable resource for translational research. Finally, between H. sapiens and M. musculus, 35 organs overlap, allowing cross-species comparisons. The updated miRNATissueAtlas 2025 is available at https://www.ccb.uni-saarland.de/tissueatlas2025.

Single-point mutated lanmodulin as a high-performance MRI contrast agent for vascular and kidney imaging

Magnetic resonance imaging contrast agents can enhance diagnostic precision but often face limitations such as short imaging windows, low tissue specificity, suboptimal contrast enhancement, or potential toxicity, which affect resolution and long-term monitoring. Here, we present a protein contrast agent based on lanmodulin, engineered with a single-point mutation at position 108 from N to D to yield maximum gadolinium binding sites. After loading with Gd3+ ions, the resulting protein complex, LanND-Gd, exhibits efficient renal clearance, high relaxivity, and prolonged renal retention compared to commercial agents. LanND-Gd enables high-performance visualization of whole-body structures and brain vasculature in male mice at a resolution finer than one hundred micrometers. In male ischemia mouse models, LanND-Gd also improves kidney dysfunction monitoring while minimizing risks of neural toxicity or immunogenic reactions. This protein-based contrast agent offers superior image quality, improved biocompatibility, and extended imaging timeframes, promising significant advancements in magnetic resonance-based diagnostics and patient outcomes.

Single-cell transcriptomics reveals the molecular basis of human iPS cell differentiation into ectodermal ocular lineages

The generation of a self-formed, ectodermal, autonomous multi-zone (SEAM) from human induced pluripotent stem cells (hiPSCs) offers a unique perspective to study the dynamics of ocular cell differentiation over time. Here, by utilising single-cell transcriptomics, we have (i) identified, (ii) molecularly characterised and (iii) ascertained the developmental trajectories of ectodermally-derived ocular cell populations which emerge within SEAMs as they form. Our analysis reveals interdependency between tissues of the early eye and delineates the sequential formation and maturation of distinct cell types over a 12-week period. We demonstrate a progression from pluripotency through to tissue specification and differentiation which encompasses both surface ectodermal and neuroectodermal ocular lineages and the generation of iPSC-derived components of the developing cornea, conjunctiva, lens, and retina. Our findings not only advance the understanding of ocular development in a stem cell-based system of human origin, but also establish a robust methodological paradigm for exploring cellular and molecular dynamics during SEAM formation at single-cell resolution and highlight the potential of hiPSC-derived systems as powerful platforms for modelling human eye development and disease.

Abstract 4137457: Cross-sectional Investigation of Proteomic Signatures of Blood Pressure Traits.

Background: Hypertension is a major risk factor for cardiovascular disease affecting one third of the adult population worldwide. Over 90% cases of hypertension are without a distinct etiology. Identification of protein biomarkers of hypertension may provide insight into disease pathophysiology and highlight novel therapeutic targets. Methods: We conducted association analyses between 2922 plasma proteins (exposure) and blood pressure (BP) traits (outcome) in 45,926 UK Biobank participants (aged 57 ± 8 years; 54% women). We employed linear mixed models to study protein associations with systolic and diastolic BP and logistic mixed models to test abundance of proteins in hypertensive vs. normal individuals. The associations were adjusted for age, sex, body mass index, estimated glomerular filtration rate, smoking and alcohol drinking status, and batch effects. Hypertension was defined as systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) or current use of anti-hypertensive medication. Sensitivity analysis excluded individuals taking BP medication (n=10,229). Functional enrichment analysis was performed to elucidate biological functions and tissue specificity of significant protein signatures ( P < 0.00017). We further performed Mendelian randomization (MR) to infer causal relations of protein biomarkers and BP. Results: We identified 1469 proteins associated with systolic BP and 1638 with diastolic BP. The corresponding numbers were 1410 and 1566 after excluding treated individuals. Plasma levels of 1215 proteins (1105 upregulated, 110 downregulated) differed in individuals with hypertension (N=24,724) compared to normal (N= 21,202). Most of these proteins were specific to liver, adipose tissue, renal cortex and coronary artery. Protein signatures of hypertension showed enrichment in pathways involved in inflammatory response, cholesterol homeostasis, complement and coagulation cascades, and hemostasis. Putatively causal associations were observed for 141 proteins with SBP and 142 with DBP. Discussion: This study elucidates protein signatures associated with BP and hypertension. Systemic inflammation and cholesterol homeostasis play important roles in the pathophysiology of hypertension.

Phosphorylated protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) expression in breast cancer is correlated with malignant proliferation and histological grading.

This study aims to detect the expression of phosphorylated PERK in breast cancer using immunohistochemistry and explore its significance. We examined 134 cases of formalin-fixed and paraffin-embedded breast cancer tissues. It was found that the expression of phosphorylated PERK in ductal carcinoma was higher than that in lobular carcinoma, and the difference between them was statistically significant, suggesting that phosphorylated PERK played different roles in the occurrence and development of different types of breast cancer. Compared with Ki-67-negative breast cancer tissues, phosphorylated PERK has higher expression in Ki-67-positive tissues and is positively correlated with Ki67 expression, indicating that phosphorylated PERK plays an important role in breast cancer's malignant proliferation and progression. We also found a positive correlation between phosphorylated PERK expression and the histological grading of invasive ductal carcinoma, indicating that phosphorylated PERK plays an important role in the differentiation of invasive ductal carcinoma. Our study revealed the differential expression of phosphorylated PERK in subtypes of breast cancer. It contributed to the malignant proliferation of breast cancer and tissue differentiation of invasive ductal carcinoma of the breast.

Abraded optical fibre-based dynamic range force sensor for tissue palpation.

Tactile information acquired through palpation plays a crucial role in relation to surface characterisation and tissue differentiation - an essential clinical requirement during surgery. In the case of Minimally Invasive Surgery, access is restricted, and tactile feedback available to surgeons is therefore reduced. This paper presents a novel stiffness controllable, dynamic force range sensor that can provide remote haptic feedback. The sensor has an abraded optical fibre integrated into a silicone dome. Forces applied to the dome change the curvature of the optical fibres, resulting in light attenuation. By changing the pressure within the dome and thereby adjusting the sensor's stiffness, we are able to modify the force measurement range. Results from our experimental study demonstrate that increasing the pressure inside the dome increases the force range whilst decreasing force sensitivity. We show that the maximum force measured by our sensor prototype at 20 mm/min was 5.02 N, 6.70 N and 8.83 N for the applied pressures of 0 psi (0 kPa), 0.5 psi (3.45 kPa) and 1 psi (6.9 kPa), respectively. The sensor has also been tested to estimate the stiffness of 13 phantoms of different elastic moduli. Results show the elastic modulus sensing range of the proposed sensor to be from 8.58 to 165.32 kPa.