Sexually dimorphic renal expression of Klotho is directed by a kidney-specific distal enhancer responsive to HNF1b.

Transcription enhancers are genomic sequences regulating common and tissue-specific genes and their disruption can contribute to human disease development and progression. Klotho, a sexually dimorphic gene specifically expressed in kidney, is well-linked to kidney dysfunction and its deletion from the mouse genome leads to premature aging and death. However, the sexually dimorphic regulation of Klotho is not understood. Here, we characterize two candidate Klotho enhancers using H3K27ac epigenetic marks and transcription factor binding and investigate their functions, individually and combined, through CRISPR-Cas9 genome engineering. We discovered that only the distal (E1), but not the proximal (E2) candidate region constitutes a functional enhancer, with the double deletion not causing Klotho expression to further decrease. E1 activity is dependent on HNF1b transcription factor binding site within the enhancer. Further, E1 controls the sexual dimorphism of Klotho as evidenced by qPCR and RNA-seq. Despite the sharp reduction of Klotho mRNA, unlike germline Klotho knockouts, mutant mice presented normal phenotype, including weight, lifespan, and serum biochemistry. Lastly, only males lacking E1 display more prominent acute, but not chronic kidney injury responses, indicating a remarkable range of potential adaptation to isolated Klotho loss, especially in female E1 knockouts, retaining renoprotection despite over 80% Klotho reduction.

Awareness of possible complications associated with direct composite restorations: A multinational survey among dentists from 13 countries with meta-analysis.

OBJECTIVES: Resin-based composites (RBCs) evolved into favoured materials for teeth restorations, marking a significant change in dental practice. Despite many advantages, RBCs exhibit various limitations in their physical and chemical properties. Therefore, we assessed the dentists' awareness of possible complications after direct composite restorations and their opinions about this material. METHODS: The online questionnaire was created in English in May 2023. A 16-item survey was dedicated to general dentists and specialists. The first section included four questions related to demographic characteristics. The second section comprised twelve questions and focused on awareness of potential side effects of composite restorations, the most crucial advantages and disadvantages of composite resins, and the frequency of experienced clinical complications after the application of composite materials. RESULTS: A total of 1830 dentists from 13 countries took part in the survey. Dentists most often declared awareness of low adhesion to the dentine (77.5 %) and, most rarely, solubility in oral fluids (42.6 %). Aesthetics was identified as the main advantage of composite fillings (79 %), followed by the possibility of repair (59 %) and adhesion to enamel (57 %). Polymerisation shrinkage was a major disadvantage for most countries (70 % overall). Analysing the declared potential clinical complications for all countries, statistically significant findings were obtained for marginal discolouration (OR=2.982, 95 % CI: 1.321-6.730, p-value=0.009) and borderline significance for secondary caries (OR=1.814, 95 % CI: 0.964-3.415, p-value=0.065). CONCLUSIONS: Dentists value aesthetics and repairability but are aware of shrinkage and experience discolouration. The issue of toxicity and solubility seems to be the least known to dentists. CLINICAL SIGNIFICANCE: Dentists should use RBCs with critical caution due to possible side effects. Despite the undoubted aesthetics of direct composite restorations, it is necessary to remember potential clinical complications such as marginal discolouration or secondary caries.

Potential Immunohistochemical Biomarkers for Grading Oral Dysplasia: A Literature Review.

Oral cancer is a prevalent global health issue, with significant morbidity and mortality rates. Despite available preventive measures, it remains one of the most common cancers, emphasising the need for improved diagnostic and prognostic tools. This review focuses on oral potentially malignant disorders (OPMDs), precursors to oral cancer, specifically emphasising oral epithelial dysplasia (OED). The World Health Organisation (WHO) provides a three-tier grading system for OED, and recent updates have expanded the criteria to enhance diagnostic precision. In the prognostic evaluation of OED, histological grading is presently regarded as the gold standard; however, its subjectivity and unreliability in anticipating malignant transformation or recurrence pose notable limitations. The primary objective is to investigate whether specific immunohistochemical biomarkers can enhance OED grading assessment according to the WHO classification. Biomarkers exhibit significant potential for comprehensive cancer risk evaluation, early detection, diagnosis, prognosis, and treatment optimisation. Technological advancements, including sequencing and nanotechnology, have expanded detection capabilities. Some analysed biomarkers are most frequently chosen, such as p53, Ki-67, cadherins/catenins, and other proteins used to differentiate OED grades. However, further research is needed to confirm these findings and discover new potential biomarkers for precise dysplasia grading and minimally invasive assessment of the risk of malignant transformation.

Sexually dimorphic renal expression of Klotho is directed by a kidney-specific distal enhancer responsive to HNF1b.

Transcription enhancers are genomic sequences regulating common and tissue-specific genes and their disruption can contribute to human disease development and progression. Klotho, a sexually dimorphic gene specifically expressed in kidney, is well-linked to kidney dysfunction and its deletion from the mouse genome leads to premature aging and death. However, the sexually dimorphic regulation of Klotho is not understood. Here, we characterize two candidate Klotho enhancers using H3K27ac epigenetic marks and transcription factor binding and investigate their functions, individually and combined, through CRISPR-Cas9 genome engineering. We discovered that only the distal (E1), but not the proximal (E2) candidate region constitutes a functional enhancer, with the double deletion not causing Klotho expression to further decrease. E1 activity is dependent on HNF1b transcription factor binding site within the enhancer. Further, E1 controls the sexual dimorphism of Klotho as evidenced by qPCR and RNA-seq. Despite the sharp reduction of Klotho mRNA, unlike germline Klotho knockouts, mutant mice presented normal phenotype, including weight, lifespan, and serum biochemistry. Lastly, only males lacking E1 display more prominent acute, but not chronic kidney injury responses, indicating a remarkable range of potential adaptation to isolated Klotho loss, especially in female E1 knockouts, retaining renoprotection despite over 80% Klotho reduction.

Salivary Biomarkers for Parkinson's Disease: A Systematic Review with Meta-Analysis.

Parkinson's Disease (PD) is a common neurodegenerative disease which manifests with motor features, such as bradykinesia, resting tremor, rigidity, and postural instability. Using the non-invasive technique of saliva collection, we designed a systematic review to answer the question "Are salivary biomarkers reliable for the diagnosis of Parkinson's Disease?". Following inclusion and exclusion criteria, 30 studies were included in this systematic review (according to the PRISMA statement guidelines). Mostly proteins were reported as potential biomarkers in saliva. Based on meta-analysis, in PD patients, salivary levels of total alpha-synuclein were significantly decreased, and those of oligomeric alpha-synuclein were significantly increased. Also, according to pooled AUC, heme oxygenase-1 demonstrated significant predictive value for saliva-based PD diagnosis. In conclusion, some potential biomarkers, especially alpha-synuclein, can be altered in the saliva of PD patients, which could be reliably useful for early diagnosis of this neurodegenerative disease differentiating other synucleopathies.

Salivary Biomarkers for Alzheimer's Disease: A Systematic Review with Meta-Analysis.

Alzheimer's Disease (AD) is the most common neurodegenerative disease which manifests with progressive cognitive impairment, leading to dementia. Considering the noninvasive collection of saliva, we designed the systematic review to answer the question "Are salivary biomarkers reliable for the diagnosis of Alzheimer's Disease?" Following the inclusion and exclusion criteria, 30 studies were included in this systematic review (according to the PRISMA statement guidelines). Potential biomarkers include mainly proteins, metabolites and even miRNAs. Based on meta-analysis, in AD patients, salivary levels of beta-amyloid42 and p-tau levels were significantly increased, and t-tau and lactoferrin were decreased at borderline statistical significance. However, according to pooled AUC, lactoferrin and beta-amyloid42 showed a significant predictive value for salivary-based AD diagnosis. In conclusion, potential markers such as beta-amyloid42, tau and lactoferrin can be detected in the saliva of AD patients, which could reliably support the early diagnosis of this neurodegenerative disease.

Network medicine-based epistasis detection in complex diseases: ready for quantum computing.

Most heritable diseases are polygenic. To comprehend the underlying genetic architecture, it is crucial to discover the clinically relevant epistatic interactions (EIs) between genomic single nucleotide polymorphisms (SNPs)1-3. Existing statistical computational methods for EI detection are mostly limited to pairs of SNPs due to the combinatorial explosion of higher-order EIs. With NeEDL (network-based epistasis detection via local search), we leverage network medicine to inform the selection of EIs that are an order of magnitude more statistically significant compared to existing tools and consist, on average, of five SNPs. We further show that this computationally demanding task can be substantially accelerated once quantum computing hardware becomes available. We apply NeEDL to eight different diseases and discover genes (affected by EIs of SNPs) that are partly known to affect the disease, additionally, these results are reproducible across independent cohorts. EIs for these eight diseases can be interactively explored in the Epistasis Disease Atlas (https://epistasis-disease-atlas.com). In summary, NeEDL is the first application that demonstrates the potential of seamlessly integrated quantum computing techniques to accelerate biomedical research. Our network medicine approach detects higher-order EIs with unprecedented statistical and biological evidence, yielding unique insights into polygenic diseases and providing a basis for the development of improved risk scores and combination therapies.

Kleefstra Syndrome-Dental Manifestations and Needs: A Case Report with a Literature Review.

Kleefstra syndrome (KS) is a rare genetic disorder (prevalence < 1/1 000 000) characterised by autistic spectrum disorder (ASD), childhood hypotonia, and seizures. A typical facial appearance includes microcephaly, arched eyebrows, synophrism, hypertelorism, a short nose, midface hypoplasia, prognathism, and tongue protrusion. This case report presents a 19-year-old female with KS from a dentist's perspective. The patient demonstrates limited mouth opening with a slight deviation of the mandible on the left side. The mandibular prognathism and anterior open bite are visible. A generalised inflammatory gingival enlargement is most likely a response to local irritants like plaque and calculus but is enhanced by the patient's mouth breathing habit. Also, the tongue is unusually large-macroglossia. Dental anomalies were diagnosed by digital panoramic radiograph, including dilaceration of the maxillary left second premolar and taurodontism. The patient was qualified to be treated under general anaesthesia with multiple extractions, restorations, hygienisation procedures, and tooth remineralisation. This individual should also be considered for orthodontic treatment and an eventual tongue reduction procedure. In the case of KS, multidisciplinary cooperation as well as frequent dental check-ups with fluoride prophylaxis are recommended. Unfortunately, dental treatment is still not an integral part of taking care of disabled children and youth with rare diseases.

Eating Disorders and Dental Erosion: A Systematic Review.

Both eating disorders and dental erosion are increasingly affecting adolescents and young adults. Thus, our systematic review was designed to answer the question: "Is there a relationship between dental erosion and eating disorders?" Following the inclusion and exclusion criteria, 31 studies were included in this systematic review (according to the PRISMA statement guidelines). Based on the meta-analysis, 54.4% of patients with bulimia nervosa and 26.7% with anorexia nervosa experienced tooth erosion. For the whole group of 1699 patients with eating disorders, erosive lesions were observed in 42.1% of patients. Bulimics were more than 10 times more likely to experience dental erosion compared to healthy individuals (OR = 10.383 [95%CI: 4.882-22.086]). Similarly, more than 16 times increased odds of tooth erosion were found in patients with self-induced vomiting (OR = 16.176 [95%CI: 1.438-181.918]). In conclusion, eating disorders are associated with an increased risk of developing erosive lesions, especially in patients with bulimia nervosa.

Salivary Alterations of Myeloperoxidase in Patients with Systemic Diseases: A Systematic Review.

Salivary myeloperoxidase (MPO) is a key mediator of the oral immune system, acting as an enzyme that utilises H2O2 to generate molecules with high bactericidal activity. While MPO determination in plasma is quite common, the use of saliva is still rare. Our systematic review was designed to answer the question "Are salivary levels of myeloperoxidase altered in patients with systemic diseases?". Following the inclusion and exclusion criteria, we included twenty-six studies. Altered MPO levels in saliva were most commonly found in patients with cardiovascular and gastrointestinal diseases. Most studies concerned unstimulated whole saliva, and only a few of them stimulated, mainly by chewing paraffin. Enzyme-linked immunosorbent assay (ELISA) was the most common method for determination of MPO concentrations in saliva. Increased salivary MPO levels were more often observed for inflammatory diseases, except patients with inflammatory bowel diseases who were eligible for biologic therapy. In conclusion, MPO could be altered in the saliva of patients with systematic diseases, especially cardiovascular or gastrointestinal diseases. However, further investigations are recommended to validate these outcomes.

circRNA-sponging: a pipeline for extensive analysis of circRNA expression and their role in miRNA sponging.

Motivation: Circular RNAs (circRNAs) are long noncoding RNAs (lncRNAs) often associated with diseases and considered potential biomarkers for diagnosis and treatment. Among other functions, circRNAs have been shown to act as microRNA (miRNA) sponges, preventing the role of miRNAs that repress their targets. However, there is no pipeline to systematically assess the sponging potential of circRNAs. Results: We developed circRNA-sponging, a nextflow pipeline that (i) identifies circRNAs via backsplicing junctions detected in RNA-seq data, (ii) quantifies their expression values in relation to their linear counterparts spliced from the same gene, (iii) performs differential expression analysis, (iv) identifies and quantifies miRNA expression from miRNA-sequencing (miRNA-seq) data, (v) predicts miRNA binding sites on circRNAs, (vi) systematically investigates potential circRNA-miRNA sponging events, (vii) creates a network of competing endogenous RNAs and (viii) identifies potential circRNA biomarkers. We showed the functionality of the circRNA-sponging pipeline using RNA sequencing data from brain tissues, where we identified two distinct types of circRNAs characterized by a specific ratio of the number of the binding site to the length of the transcript. The circRNA-sponging pipeline is the first end-to-end pipeline to identify circRNAs and their sponging systematically with raw total RNA-seq and miRNA-seq files, allowing us to better indicate the functional impact of circRNAs as a routine aspect in transcriptomic research. Availability and implementation: https://github.com/biomedbigdata/circRNA-sponging. Supplementary information: Supplementary data are available at Bioinformatics Advances online.

Glomangioma in the hand: diagnosis, treatment, and challenges.

INTRODUCTION: In this paper, we have analysed all hand glomangioma cases referred to our clinic in the context of symptoms, time to diagnosis, and the role of surgical resection of the lesion. MATERIAL AND METHODS: We have collected the following data: the presence of risk factors, manifestation, time to diagnosis, the treatment applied, and follow-up of patients. RESULTS: We have collected medical records from six patients, three males and three females. The median age was 45 (IQR: 29.5-65.75). The main symptom in all patients was severe pain and tenderness. The first-choice physician(s) were: general practitioners, general surgeons, and neurologists. The median time to diagnosis was 7 (IQR: 5-10) years. The main complaint of our patients was severe pain - 9 (IQR: 9-10) on the VAS scale, which was significantly alleviated after surgical treatment - 0 (IQR: 0-0; p = 0.043). CONCLUSIONS: Extremely long times to final diagnosis, and excellent outcomes of surgical treatment, highlight the necessity of raising awareness of glomangiomas among clinicians.

The Role of Cellular Metabolism in Maintaining the Function of the Dentine-Pulp Complex: A Narrative Review.

The cellular metabolic processes ensure the physiological integrity of the dentine-pulp complex. Odontoblasts and odontoblast-like cells are responsible for the defence mechanisms in the form of tertiary dentine formation. In turn, the main defence reaction of the pulp is the development of inflammation, during which the metabolic and signalling pathways of the cells are significantly altered. The selected dental procedures, such as orthodontic treatment, resin infiltration, resin restorations or dental bleaching, can impact the cellular metabolism in the dental pulp. Among systemic metabolic diseases, diabetes mellitus causes the most consequences for the cellular metabolism of the dentine-pulp complex. Similarly, ageing processes present a proven effect on the metabolic functioning of the odontoblasts and the pulp cells. In the literature, several potential metabolic mediators demonstrating anti-inflammatory properties on inflamed dental pulp are mentioned. Moreover, the pulp stem cells exhibit the regenerative potential essential for maintaining the function of the dentine-pulp complex.

circRNA-sponging: a pipeline for extensive analysis of circRNA expression and their role in miRNA sponging.

MOTIVATION: Circular RNAs (circRNAs) are long non-coding RNAs (lncRNAs) often associated with diseases and considered potential biomarkers for diagnosis and treatment. Among other functions, circRNAs have been shown to act as microRNA (miRNA) sponges, preventing the role of miRNAs that repress their targets. However, there is no pipeline to systematically assess the sponging potential of circRNAs. RESULTS: We developed circRNA-sponging, a nextflow pipeline that (1) identifies circRNAs via backsplicing junctions detected in RNA-seq data, (2) quantifies their expression values in relation to their linear counterparts spliced from the same gene, (3) performs differential expression analysis, (4) identifies and quantifies miRNA expression from miRNA-sequencing (miRNA-seq) data, (5) predicts miRNA binding sites on circRNAs, (6) systematically investigates potential circRNA-miRNA sponging events, (7) creates a network of competing endogenous RNAs, and (8) identifies potential circRNA biomarkers. We showed the functionality of the circRNA-sponging pipeline using RNA sequencing data from brain tissues, where we identified two distinct types of circRNAs characterized by a specific ratio of the number of the binding site to the length of the transcript. The circRNA-sponging pipeline is the first end-to-end pipeline to identify circRNAs and their sponging systematically with raw total RNA-seq and miRNA-seq files, allowing us to better indicate the functional impact of circRNAs as a routine aspect in transcriptomic research. AVAILABILITY: https://github.com/biomedbigdata/circRNA-sponging Contact: markus.daniel.hoffmann@tum.de; markus.list@tum.de Supplementary Material: Supplementary data are available at Bioinformatic Advances online.

Intramedullary Spinal Cord Abscess with Concomitant Spinal Degenerative Diseases: A Case Report and Systematic Literature Review.

Intramedullary spinal cord abscess (ISCA) is a rare clinical pathology of the central nervous system that usually accompanies other underlying comorbidities. Traditionally it has been associated with significant mortality and neurological morbidities because it is often difficult to diagnose promptly, owing to its nonspecific clinical and neuroimaging features. The mortality rate and the outcome of these infections have been improved by the introduction into clinical practice of antibiotics, advanced neuroimaging modalities, and immediate surgery. We report the case of a 65-year-old male patient who presented with a progressive spastic gait and lumbar pain, predominantly in the left leg. An MRI image revealed an expansile intramedullary cystic mass in the thoracic spinal cord, which was initially diagnosed as a spinal tumor. He underwent laminectomy and myelotomy, and eventually the pus was drained from the abscess. The follow-up MRI showed improvement, but the patient's paraplegia persisted. In light of his persistent hypoesthesia and paraplegic gait with developing neuropathic pain, he was readmitted, and an MRI of his lumbar spine revealed multilevel degenerative disease and tethered spinal cord syndrome with compression of the medulla at the L2-L3 level. The patient underwent central flavectomy with bilateral foraminotomy at the L2-L3 level, and the medulla was decompressed. Postoperatively, his neurological symptoms were significantly improved, and he was discharged from hospital on the third day after admission. In support of our case, we systematically reviewed the recent literature and analyzed cases published between 1949 and May 2022, including clinical features, mechanisms of infection, predisposing factors, radiological investigations, microbial etiologies, therapies and their duration, follow-ups, and outcomes. Initial clinical presentation can be misleading, and the diagnosis can be challenging, because this condition is rare and coexists with other spinal diseases. Hence, a high index of suspicion for making an accurate diagnosis and timely intervention is required to preclude mortality and unfavorable outcomes. Our case is a clear example thereof. Long-term follow-up is also essential to monitor for abscess recurrences.

What Is Currently Known about Intramedullary Spinal Cord Abscess among Children? A Concise Review.

Intramedullary spinal cord abscesses (ISCA) are rare. Typical symptoms include signs of infection and neurological deficits. Symptoms among (younger) children can be highly uncharacteristic. Therefore, prompt and proper diagnoses may be difficult. Typical therapeutic options include antibiotics and neurosurgical exploration and drainage. In this review, we analyze published cases of ISCA among children. Most pediatric cases were found to be under the age of 6 years. The typical symptoms included motor deficits in 89.06%, infection signs in 85.94%, and sensory deficits in 39.06%. Urinary dysfunction was observed in 43.75%, and bowel dysfunction in 17.19%. The predisposing factors included dermal sinuses, (epi)dermoid cysts, prior infection, iatrogenic disorder, and trauma. The most common pathogens were: Staphylococcus aureus, Mycobacterium tuberculosis, Escherichia coli, and Proteus mirabilis. The pediatric population has good outcomes as 45.93% of patients had complete neurological recovery and only 26.56% had residual neurological deficits. Fifteen (23.44%) had persistent neurological deficits. Only one (1.56%) patient died with an ISCA. In two (3.13%) cases, there were no details about follow-up examinations.

Cervical Paraspinal Chordoma: A Literature Review with a Novel Case Report.

Chordomas are rare malignant neoplasms, accounting for 1-4% of all primary bone tumors. Most spinal chordomas occur in the sacrococcygeal region and the base of the skull; however, 6% of chordomas are observed in the cervical spine. In these cases, the lesion is mainly located in the midline. These tumors slowly grow before becoming symptomatic and encase the surrounding vascular and nerve structures. Patients with advanced chordoma have a poor prognosis due to local recurrence with infiltration and destruction of adjacent bone and tissues. Systemic chemotherapy options have not been fully effective in these tumors, especially for recurrent chordomas. Thus, new combinations of currently available targeted molecular and biological therapies with radiotherapy have been proposed as potential treatment modalities. Here, the present paper describes the case of a 41-year-old male with a C2-C4 chordoma located paravertebrally, who underwent surgical resection with a debulking procedure for a cervical chordoma. Computed tomography angiography revealed a paraspinal mass with bone remodeling and the MRI showed a paravertebral mass penetrating to the spinal canal with a widening of the intervertebral C2-C3 foramen. Initially, the tumor was diagnosed as schwannoma based on its localization and imaging features; however, the histopathology specimen confirmed the diagnosis of chordoma. This case study highlights the effectivity of radical surgical resection as a mainstay treatment for chordomas, discusses neuroimaging, diagnosis, and the use of currently available targeted therapies and forthcoming treatment strategies, as alternative treatment options for chordoma.

The Comparison of InSb-Based Thin Films and Graphene on SiC for Magnetic Diagnostics under Extreme Conditions.

The ability to precisely measure magnetic fields under extreme operating conditions is becoming increasingly important as a result of the advent of modern diagnostics for future magnetic-confinement fusion devices. These conditions are recognized as strong neutron radiation and high temperatures (up to 350 °C). We report on the first experimental comparison of the impact of neutron radiation on graphene and indium antimonide thin films. For this purpose, a 2D-material-based structure was fabricated in the form of hydrogen-intercalated quasi-free-standing graphene on semi-insulating high-purity on-axis 4H-SiC(0001), passivated with an Al2O3 layer. InSb-based thin films, donor doped to varying degrees, were deposited on a monocrystalline gallium arsenide or a polycrystalline ceramic substrate. The thin films were covered with a SiO2 insulating layer. All samples were exposed to a fast-neutron fluence of ≈7×1017 cm-2. The results have shown that the graphene sheet is only moderately affected by neutron radiation compared to the InSb-based structures. The low structural damage allowed the graphene/SiC system to retain its electrical properties and excellent sensitivity to magnetic fields. However, InSb-based structures proved to have significantly more post-irradiation self-healing capabilities when subject to proper temperature treatment. This property has been tested depending on the doping level and type of the substrate.

The Underlying Pathogenesis of Neurovascular Compression Syndromes: A Systematic Review.

Neurovascular compression syndromes (NVC) are challenging disorders resulting from the compression of cranial nerves at the root entry/exit zone. Clinically, we can distinguish the following NVC conditions: trigeminal neuralgia, hemifacial spasm, and glossopharyngeal neuralgia. Also, rare cases of geniculate neuralgia and superior laryngeal neuralgia are reported. Other syndromes, e.g., disabling positional vertigo, arterial hypertension in the course of NVC at the CN IX-X REZ and torticollis, have insufficient clinical evidence for microvascular decompression. The exact pathomechanism leading to characteristic NVC-related symptoms remains unclear. Proposed etiologies have limited explanatory scope. Therefore, we have examined the underlying pathomechanisms stated in the medical literature. To achieve our goal, we systematically reviewed original English language papers available in Pubmed and Web of Science databases before 2 October 2021. We obtained 1694 papers after eliminating duplicates. Only 357 original papers potentially pertaining to the pathogenesis of NVC were enrolled in full-text assessment for eligibility. Of these, 63 were included in the final analysis. The systematic review suggests that the anatomical and/or hemodynamical changes described are insufficient to account for NVC-related symptoms by themselves. They must coexist with additional changes such as factors associated with the affected nerve (e.g., demyelination, REZ modeling, vasculature pathology), nucleus hyperexcitability, white and/or gray matter changes in the brain, or disturbances in ion channels. Moreover, the effects of inflammatory background, altered proteome, and biochemical parameters on symptomatic NVC cannot be ignored. Further studies are needed to gain better insight into NVC pathophysiology.

TF-Prioritizer: a Java pipeline to prioritize condition-specific transcription factors.

BACKGROUND: Eukaryotic gene expression is controlled by cis-regulatory elements (CREs), including promoters and enhancers, which are bound by transcription factors (TFs). Differential expression of TFs and their binding affinity at putative CREs determine tissue- and developmental-specific transcriptional activity. Consolidating genomic datasets can offer further insights into the accessibility of CREs, TF activity, and, thus, gene regulation. However, the integration and analysis of multimodal datasets are hampered by considerable technical challenges. While methods for highlighting differential TF activity from combined chromatin state data (e.g., chromatin immunoprecipitation [ChIP], ATAC, or DNase sequencing) and RNA sequencing data exist, they do not offer convenient usability, have limited support for large-scale data processing, and provide only minimal functionality for visually interpreting results. RESULTS: We developed TF-Prioritizer, an automated pipeline that prioritizes condition-specific TFs from multimodal data and generates an interactive web report. We demonstrated its potential by identifying known TFs along with their target genes, as well as previously unreported TFs active in lactating mouse mammary glands. Additionally, we studied a variety of ENCODE datasets for cell lines K562 and MCF-7, including 12 histone modification ChIP sequencing as well as ATAC and DNase sequencing datasets, where we observe and discuss assay-specific differences. CONCLUSION: TF-Prioritizer accepts ATAC, DNase, or ChIP sequencing and RNA sequencing data as input and identifies TFs with differential activity, thus offering an understanding of genome-wide gene regulation, potential pathogenesis, and therapeutic targets in biomedical research.