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5-Hydroxymethylcytosine (5-hmC) is an important intermediate of DNA demethylation. Hypomethylation of DNA is frequent in cancer, resulting in deregulation of 5-hmC levels in melanoma. However, the interpretation of the intensity and distribution of 5-hmC immunoreactivity is not very standardized, which makes its interpretation difficult. In this study, 5-hmC-stained histological slides of superficial spreading melanomas (SSM) and dysplastic compound nevi (DN) were digitized and analyzed using the digital pathology and image platform QuPath. Receiver operating characteristic/area under the curve (ROCAUC) and t-tests were performed. A p-value of <0.05 was used for statistical significance, and a ROCAUC score of >0.8 was considered a "good" result. In total, 92 5-hmC-stained specimens were analyzed, including 42 SSM (45.7%) and 50 DN (54.3%). The mean of 5-hmC-positive cells/mm2 for the epidermis and dermo-epidermal junction and the entire lesion differed significantly between DN and SSM (p = 0.002 and p = 0.006, respectively) and showed a trend towards higher immunoreactivity in the dermal component (p = 0.069). The ROCAUC of 5-hmC-positive cells of the epidermis and dermo-epidermal junction was 0.79, for the dermis 0.74, and for the entire lesion 0.76. These results show that the assessment of the epidermal with junctional expression of 5-hmC is slightly superior to dermal immunoreactivity in distinguishing between DN and SSM.
The electroencephalography (EEG) signal has a high complexity, and the process of extracting clinically relevant features is achieved by visual analysis of the recordings. The interobserver agreement in EEG interpretation is only moderate. This is partly due to the method of reporting the findings in free-text format. The purpose of our endeavor was to create a computer-based system for EEG assessment and reporting, where the physicians would construct the reports by choosing from predefined elements for each relevant EEG feature, as well as the clinical phenomena (for video-EEG recordings). A working group of EEG experts took part in consensus workshops in Dianalund, Denmark, in 2010 and 2011. The faculty was approved by the Commission on European Affairs of the International League Against Epilepsy (ILAE). The working group produced a consensus proposal that went through a pan-European review process, organized by the European Chapter of the International Federation of Clinical Neurophysiology. The Standardised Computer-based Organised Reporting of EEG (SCORE) software was constructed based on the terms and features of the consensus statement and it was tested in the clinical practice. The main elements of SCORE are the following: personal data of the patient, referral data, recording conditions, modulators, background activity, drowsiness and sleep, interictal findings, "episodes" (clinical or subclinical events), physiologic patterns, patterns of uncertain significance, artifacts, polygraphic channels, and diagnostic significance. The following specific aspects of the neonatal EEGs are scored: alertness, temporal organization, and spatial organization. For each EEG finding, relevant features are scored using predefined terms. Definitions are provided for all EEG terms and features. SCORE can potentially improve the quality of EEG assessment and reporting; it will help incorporate the results of computer-assisted analysis into the report, it will make possible the build-up of a multinational database, and it will help in training young neurophysiologists.
The Ceprano calvarium was discovered in fragments on March 1994 near the town of Ceprano in southern Latium (Italy), embedded in Middle Pleistocene layers. After reconstruction, its morphological features suggests that the specimen belongs to an archaic variant of H. heidelbergensis, representing a proxy for the last common ancestor of the diverging clades that respectively led to H. neanderthalensis and H. sapiens. Unfortunately, the calvarium was taphonomically damaged. The postero-lateral vault, in particular, appears deformed and this postmortem damage may have influenced previous interpretations. Specifically, there is a depression on the fragmented left parietal, while the right cranial wall is warped and angulated. This deformation affected the shape of the occipital squama, producing an inclination of the transverse occipital torus. In this paper, after X-ray microtomography (μCT) of both the calvarium and several additional fragments, we analyze consistency and pattern of the taphonomic deformation that affected the specimen, before the computer-assisted retrodeformation has been performed; this has also provided the opportunity to reappraise early attempts at restoration. As a result, we offer a revised interpretation for the Ceprano calvarium's original shape, now free from the previous uncertainties, along with insight for its complex depositional and taphonomic history.
International challenges have become the standard for validation of biomedical image analysis methods. Given their scientific impact, it is surprising that a critical analysis of common practices related to the organization of challenges has not yet been performed. In this paper, we present a comprehensive analysis of biomedical image analysis challenges conducted up to now. We demonstrate the importance of challenges and show that the lack of quality control has critical consequences. First, reproducibility and interpretation of the results is often hampered as only a fraction of relevant information is typically provided. Second, the rank of an algorithm is generally not robust to a number of variables such as the test data used for validation, the ranking scheme applied and the observers that make the reference annotations. To overcome these problems, we recommend best practice guidelines and define open research questions to be addressed in the future.
Mammography, or breast X-ray imaging, is the most widely used imaging modality to detect cancer and other breast diseases. Recent studies have shown that deep learning-based computer-assisted detection and diagnosis (CADe/x) tools have been developed to support physicians and improve the accuracy of interpreting mammography. A number of large-scale mammography datasets from different populations with various associated annotations and clinical data have been introduced to study the potential of learning-based methods in the field of breast radiology. With the aim to develop more robust and more interpretable support systems in breast imaging, we introduce VinDr-Mammo, a Vietnamese dataset of digital mammography with breast-level assessment and extensive lesion-level annotations, enhancing the diversity of the publicly available mammography data. The dataset consists of 5,000 mammography exams, each of which has four standard views and is double read with disagreement (if any) being resolved by arbitration. The purpose of this dataset is to assess Breast Imaging Reporting and Data System (BI-RADS) and breast density at the individual breast level. In addition, the dataset also provides the category, location, and BI-RADS assessment of non-benign findings. We make VinDr-Mammo publicly available as a new imaging resource to promote advances in developing CADe/x tools for mammography interpretation.
In the past, dentistry heavily relied on manual image analysis and diagnostic procedures, which could be time-consuming and prone to human error. The advent of artificial intelligence (AI) has brought transformative potential to the field, promising enhanced accuracy and efficiency in various dental imaging tasks. This systematic review and meta-analysis aimed to comprehensively evaluate the applications of AI in dental imaging modalities, focusing on in-vitro studies.
Given the high level of expertise required for navigation and interpretation of ultrasound images, computational simulations can facilitate the training of such skills in virtual reality. With ray-tracing based simulations, realistic ultrasound images can be generated. However, due to computational constraints for interactivity, image quality typically needs to be compromised.
Echocardiography is essential to cardiology. However, the need for human interpretation has limited echocardiography's full potential for precision medicine. Deep learning is an emerging tool for analyzing images but has not yet been widely applied to echocardiograms, partly due to their complex multi-view format. The essential first step toward comprehensive computer-assisted echocardiographic interpretation is determining whether computers can learn to recognize these views. We trained a convolutional neural network to simultaneously classify 15 standard views (12 video, 3 still), based on labeled still images and videos from 267 transthoracic echocardiograms that captured a range of real-world clinical variation. Our model classified among 12 video views with 97.8% overall test accuracy without overfitting. Even on single low-resolution images, accuracy among 15 views was 91.7% vs. 70.2-84.0% for board-certified echocardiographers. Data visualization experiments showed that the model recognizes similarities among related views and classifies using clinically relevant image features. Our results provide a foundation for artificial intelligence-assisted echocardiographic interpretation.
Previously, we have shown that human sperm Prohibitin (PHB) expression is significantly negatively correlated with mitochondrial ROS levels but positively correlated with mitochondrial membrane potential and motility. However, the possible role of PHB in mammalian spermatogenesis has not been investigated. Here we document the presence of PHB in spermatocytes and its functional roles in meiosis by generating the first male germ cell-specific Phb-cKO mouse. Loss of PHB in spermatocytes resulted in complete male infertility, associated with not only meiotic pachytene arrest with accompanying apoptosis, but also apoptosis resulting from mitochondrial morphology and function impairment. Our mechanistic studies show that PHB in spermatocytes regulates the expression of STAG3, a key component of the meiotic cohesin complex, via a non-canonical JAK/STAT pathway, and consequently promotes meiotic DSB repair and homologous recombination. Furthermore, the PHB/JAK2 axis was found as a novel mechanism in the maintenance of stabilization of meiotic STAG3 cohesin complex and the modulation of heterochromatin formation in spermatocytes during meiosis. The observed JAK2-mediated epigenetic changes in histone modifications, reflected in a reduction of histone 3 tyrosine 41 phosphorylation (H3Y41ph) and a retention of H3K9me3 at the Stag3 locus, could be responsible for Stag3 dysregulation in spermatocytes with the loss of PHB.
Resting state functional connectivity holds great potential for diagnostic prediction of neurological and psychiatric illness. This paper introduces a compact and information-rich representation of connectivity that is geared directly towards predictive modeling. Our representation does not require a priori identification of localized regions of interest, yet provides a mechanism for interpretation of classifier weights. Experiments confirm increased accuracy associated with our representation and yield interpretations consistent with known physiology.
The rapid and often uncontrolled rural-urban migration in Sub-Saharan Africa is transforming urban landscapes expected to provide shelter for more than 50% of Africa's population by 2030. Consequently, the burden of malaria is increasingly affecting the urban population, while socio-economic inequalities within the urban settings are intensified. Few studies, relying mostly on moderate to high resolution datasets and standard predictive variables such as building and vegetation density, have tackled the topic of modeling intra-urban malaria at the city extent. In this research, we investigate the contribution of very-high-resolution satellite-derived land-use, land-cover and population information for modeling the spatial distribution of urban malaria prevalence across large spatial extents. As case studies, we apply our methods to two Sub-Saharan African cities, Kampala and Dar es Salaam.
Studies on human brain microcirculation have thus far yielded few quantitative data, preventing the closest possible interpretation of functional imaging methods such as fMRI and PET that necessarily rely on robustly delineated morphology of haemodynamic systems. Inadequate data in this area can lead to severe underestimation of the spatial specificity of the BOLD response. We took thick sections of Indian ink injected human brain and, using confocal laser microscopy and a novel three-dimensional computer-assisted method we extracted and analyzed hundreds of thousands of vascular segments within a large area of cortex. From this database the global densities, the statistical distributions of diameters and lengths were analysed, separating the tree-like and the net-like parts of the microcirculation. Furthermore, our analysis included variations in volume density along the cortical depth and along vectors parallel to the cortical surface. These morphometric parameters are all key requirements for a sound model of cerebral microcirculation.
Microarray analysis was used to investigate the changes of gene expression of ischemic stroke and acupuncture intervention in middle cerebral artery occlusion (MCAo) rat brain. Results showed that acupuncture intervention had a remarkable improvement in neural deficit score, cerebral blood flow, and cerebral infarction volume of MCAo rats. Microarray analysis showed that a total of 627 different expression genes were regulated in ischemic stroke. 417 genes were upregulated and 210 genes were downregulated. A total of 361 different expression genes were regulated after acupuncture intervention. Three genes were upregulated and 358 genes were downregulated. The expression of novel genes after acupuncture intervention, including Tph1 and Olr883, was further analyzed by Real-Time Quantitative Polymerase Chain Reaction (RT-PCR). Upregulation of Tph1 and downregulation of Olr883 indicated that the therapeutic effect of acupuncture for ischemic stroke may be closely related to the suppression of poststroke depression and regulation of olfactory transduction. In conclusion, the present study may enrich our understanding of the multiple pathological process of ischemic brain injury and indicate possible mechanisms of acupuncture on ischemic stroke.
The pancreatic islet is mainly composed of beta-, alpha- and delta-cells with small numbers of pancreatic polypeptide (PP) and epsilon cells. It is known that there is a region in the head of the pancreas that is rich in PP-cells. In the present study, we examined the distribution of PP-cells, and assessed the influence of the PP-cell rich region to quantify the total islet mass. Pancreatic tissues were collected from donors with no history of diabetes or pancreatic diseases (n = 12). A stereological approach with a computer-assisted large-scale analysis of whole pancreatic sections was applied to quantify the entire distribution of endocrine cells within a given section. The initial whole pancreas analysis showed that a PP-cell rich region was largely restricted to the uncinate process with a clear boundary. The distinct distribution of PP-cells includes irregularly shaped clusters composed solely of PP-cells. Furthermore, in the PP-cell rich region, beta- and alpha-cell mass is significantly reduced compared to surrounding PP-cell poor regions. The results suggest that the analysis of the head region should distinguish the PP-cell rich region, which is best examined separately. This study presents an important implication for the regional selection and interpretation of the results.
While the pathophysiology of transient global amnesia (TGA) is not understood, due to the specific nature of the clinical deficits, transient dysfunction in the medial temporal lobe, especially in the hippocampus, is assumed; however, concomitant disturbances in other brain regions and in executive function have been postulated. In this study, a cohort of 16 patients was prospectively recruited from the emergency department for resting-state functional MRI (fMRI) during the acute stage of TGA, as confirmed by a standardized neuropsychological assessment. Twenty age- and sex-matched controls, as well as twenty patients with a history of TGA, were recruited for comparison. Functional data were processed using independent component analysis (ICA), allowing the complete automatic (data-driven) identification of spontaneous network dynamics. We documented a severe disturbance in anterograde episodic long-term memory in all patients. Group-based ICA of resting-state data in acute TGA patients versus that of controls and patients with a past TGA episode demonstrated reduced FC mainly of structures belonging to the executive network (EN), but also the hippocampus, confirming its pathophysiological involvement in the disorder, as well as areas belonging to the salience network and other subcortical regions. No significant differences were found when comparing connectivity in patients with a history of TGA and controls. Our findings strengthen previous empirical and theoretical accounts of hippocampal and executive dysfunction in TGA. The disruption of frontal, parietal and insular control regions, together with disruption in the hippocampus, provides a new interpretation for the pathophysiology and neuropsychological profile of this neurological disorder on a large-scale network level.
Myelin protein 0‑like 1 (MPZL1) has been reported to have a role in hepatocellular carcinoma. However, to the best of our knowledge, there have been no studies on the function and molecular mechanism of MPZL1 gene in gallbladder carcinoma. The present study confirmed that MPZL1 was upregulated in four gallbladder carcinoma tissues according to the mRNA microarray analysis. The results of the immunohistochemical analysis of tissues from 82 patients with gallbladder carcinoma demonstrated that patients with advanced tumor stages (both T and N stage) had higher positive expression of MPZL1. Moreover, a total of 20 cases of gallbladder carcinoma and matched paired paracarcinoma tissues along with 20 samples of healthy gallbladder tissue from patients with cholecystitis were analyzed using reverse transcription‑quantitative PCR and western blotting. The results demonstrated that the expression of MPZL1 in gallbladder carcinoma tissues was significantly higher than that of paired paracarcinoma tissues and randomly matched normal gallbladder epithelial tissues. According to the Tumor‑Node‑Metastasis classification, the expression level of MPZL1 protein in stage IV gallbladder carcinoma was significantly higher than that in stage III gallbladder carcinoma. The enhanced expression of MPZL1 gene appeared to improve the migration ability of GBC‑SD cells. Conversely, GBC‑SD cells that transfected with MPZL1 siRNA exhibited decreased migration ability. The results of proliferation experiments showed that the knockdown of MPZL1 siRNA caused impairments in GBC‑SD cell proliferation. On the contrary, the overexpression of MPZL1 increased the proliferation ability of GBC‑SD cells. The results of flow cytometry analyses indicated that the upregulation of MPZL1 had an anti‑apoptotic effect on GBC‑SD cells. In conclusion, the present study showed that the expression and protein levels of MPZL1 were significantly higher in gallbladder carcinoma tissues, especially in patients diagnosed with advanced tumor stages. Overexpression of MPZL1 may have promoted the invasion, metastasis, proliferation and survival of GBC‑SD cells.
Human amnion epithelial cells (hAECs) exert potent antifibrotic and anti-inflammatory effects when transplanted into preclinical models of tissue fibrosis. These effects are mediated in part via the secretion of soluble factors by hAECs which modulate signaling pathways and affect cell types involved in inflammation and fibrosis. Based on these reports, we hypothesized that these soluble factors may also support liver regeneration during chronic liver injury. To test this, we characterized the effect of both hAECs and hAEC-conditioned medium (CM) on liver repair in a mouse model of carbon tetrachloride (CCl4)-induced fibrosis. Liver repair was assessed by liver fibrosis, hepatocyte proliferation, and the liver progenitor cell (LPC) response. We found that the administration of hAECs or hAEC-CM reduced liver injury and fibrosis, sustained hepatocyte proliferation, and reduced LPC numbers during chronic liver injury. Additionally, we undertook in vitro studies to document both the cell-cell and paracrine-mediated effects of hAECs on LPCs by investigating the effects of co-culturing the LPCs and hAECs and hAEC-CM on LPCs. We found little change in LPCs co-cultured with hAECs. In contrast, hAEC-CM enhances LPC proliferation and differentiation. These findings suggest that paracrine factors secreted by hAECs enhance liver repair by reducing fibrosis while promoting regeneration during chronic liver injury.
Tumor necrosis factor-like weak inducer of apoptosis (Tnfsf12; TWEAK) and its receptor Fibroblast growth factor-inducible 14 (Tnfrsf12a; Fn14) participate in the inflammatory response associated with vascular remodeling. However, the functional effect of TWEAK on vascular smooth muscle cells (VSMCs) is not completely elucidated.
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