Early Differentiation Research Articles

Imaging breakthroughs in dementia: Pioneering 3D T1-weighted MPRAGE vs. routine spin echo with a focus on Alzheimer's disease

Background. Dementia, a spectrum of neurocognitive disorders, leads to progressive cognitive and functional decline, primarily affecting memory and executive functions. Among the most common causes is Alzheimer's disease (AD), which accounts for 60-80% of dementia cases. Neuroimaging, particularly Magnetic Resonance Imaging (MRI), plays a critical role in diagnosing dementia, helping differentiate between various subtypes such as Alzheimer's disease, vascular dementia (VaD), frontotemporal dementia (FTD), and Lewy body dementia (LBD). This study explores the utility of 3D T1-weighted Magnetization Prepared Rapid Gradient Echo (MPRAGE) and conventional spin echo sequences in distinguishing dementia subtypes, with a focus on Alzheimer's disease. Methods. This cross-sectional study included 40 elderly subjects diagnosed with cognitive impairment or dementia. Participants were assessed using 3D T1 MPRAGE sequences to calculate Medial Temporal Lobe Atrophy (MTA) indices and Entorhinal Cortex and Related Areas (ERICA) scores, alongside conventional spin echo sequences. MRI served as the primary imaging modality to differentiate between Alzheimer's disease, vascular dementia, and other dementia subtypes. Statistical analyses included descriptive statistics, inferential tests, and Receiver Operating Characteristic (ROC) curves to evaluate diagnostic accuracy. Results. The average MTA score for Alzheimer's disease was 3.33, significantly higher than that for vascular dementia (2.73), frontotemporal dementia (2.33), and Lewy body dementia (0.6). The mean ERICA score for Alzheimer's disease was 3.0, higher than FTD (0.83), VaD (0.55), and LBD (0.0). Lewy body dementia exhibited significantly larger hippocampal volumes than other dementia subtypes. The ROC curve for MTA in predicting Alzheimer's disease yielded an area under the curve (AUC) of 0.833, with a sensitivity of 98.7% and an overall diagnostic accuracy of 80%. The ERICA score achieved an AUC of 1.0, demonstrating perfect diagnostic accuracy for Alzheimer's disease. Conclusion. The study underscores the superior diagnostic accuracy of 3D T1 MPRAGE in calculating MTA and ERICA scores, enhancing early detection and differentiation of Alzheimer's disease from other dementia subtypes. The integration of these advanced imaging techniques provides a powerful diagnostic tool, ensuring more reliable and early diagnosis in clinical practice. This research highlights the potential of 3D T1 MPRAGE in revolutionizing dementia diagnostics, paving the way for improved patient outcomes.

Hydroxyurea blunts mitochondrial energy metabolism and osteoblast and osteoclast differentiation exacerbating trabecular bone loss in sickle cell mice

Sickle cell disease (SCD) is a severe hematological disorder characterized by erythrocyte sickling that causes significant morbidity and mortality. Skeletal complications of SCD include a high incidence of bone loss, especially in vertebrae, leading to fragility fractures that contribute to disease burden. Whether hydroxyurea (HU), a front-line therapy for SCD ameliorates bone disease has not been established. To investigate HU action on SCD-related vertebral defects, we used HU-treated “Townes” mice, an SCD animal model and performed high-resolution micro-computed tomography (µCT) imaging to resolve bone volume and micro-architectural structure of cortical and trabecular bone, the two major compartments contributing to bone mass and strength. Our data revealed that cortical bone was significantly diminished in the vertebrae of skeletally mature (representing adults) and immature (representing children) SCD mice, while only mature mice lost trabecular bone mass. Administration of HU ameliorated cortical bone loss in mature SCD mice, but paradoxically promoted trabecular bone decline in both groups. We further investigated the mechanisms of HU action in wild-type C57BL6/J mice. HU caused dose-dependent trabecular bone loss due to diminished osteoclast and osteoblast function, indicative of a low bone turnover state. Mechanistic investigations in vitro revealed that HU impeded osteoblast-progenitor proliferation and early differentiation, and diminished osteoclastogenic cytokine production, blunting osteoclast formation as well as the activity of mature osteoclasts. HU further, suppressed mitochondrial, but not glycolytic energy metabolism in both differentiating osteoblasts and differentiated osteoclasts. Collectively, these findings reveal that despite ameliorating cortical bone loss, HU inhibits trabecular bone formation and resorption, by suppressing mitochondrial energy metabolism and blunting the differentiation and/or activity of osteoblasts and osteoclasts. Together HU drives a low bone turnover state culminating in trabecular bone loss. Further investigation into HU’s impact on bone in SCD patients is warranted for understanding and managing skeletal complications in this population.

Two-transcript signature for differentiation and clinical outcomes in severe fever with thrombocytopenia syndrome (SFTS) patients: a double-blind, multicenter, validation study.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with a high mortality rate that is often underdiagnosed due to the limitations of current laboratory testing. Timely diagnosis and early identification of severe cases are crucial to improving patient outcomes and overall survival rates. This study aimed to evaluate the efficacy of two transcripts, IFI44L and PI3, in the early differentiation between SFTS virus (SFTSV) infection and bacterial sepsis, as well as in the prompt identification of severe cases during epidemic seasons. In a prospective study conducted between 1 May 2021 and 30 September 2022, we enrolled 225 patients who presented with acute fever and thrombocytopenia at four hospitals in Shandong Province, China. The two-transcript signature provided a clear distinction between SFTS and bacterial infection, achieving an area under the receiver operating characteristic curve of 0.961 (95% confidence interval [95% CI] 0.916-0.986), outperforming C-reactive protein (0.810 [95% CI 0.738-0.870]) and procalcitonin (0.764 [95% CI 0.687-0.830]). Importantly, the relative expression of the IFI44L gene was significantly elevated in fatal SFTS cases, with an area under the curve (AUC) of 0.820 (95% CI 0.727-0.914), indicating its potential as an early prognostic marker. Additionally, IFI44L and PI3 were identified as potential biomarkers for distinguishing SFTS patients with and without invasive pulmonary aspergillosis, with AUC values of 0.817 and 0.753, respectively. Our findings demonstrate that the two-transcript signature effectively distinguishes SFTSV infection from bacterial sepsis and helps identify high-risk individuals, guiding appropriate treatment during SFTS outbreak.

Differentiation of Tumors of the Upper Respiratory Tract Using Optical Metabolic Imaging.

With over 184,000 new cases and more than 99,000 deaths per year, malignancies of the larynx are a global health problem. Currently, a dedicated screening method enabling a direct onsite diagnosis is missing. This can lead to delayed diagnosis and worse outcomes of the patients. An endoscopic optical method enabling a direct distinction between healthy tissue, dysplastic tissue and cancerous tissue would be an ideal tool for the detection of tumors of the upper aerodigestive tract (UADT). Healthy and tumor cells differ significantly in their metabolic state due to the different metabolic pathways they use (more oxidative phosphorylation in healthy cells, more glycolysis in tumor cells). Optical metabolic imaging (OMI) measuring relative intracellular concentration of NAD(P)H and FAD redox pairs could be a promising approach for early tumor detection and differentiation of suspicious mucosal lesions. In this study, a specially designed endoscopic two-beam two-photon fluorescence lifetime imaging (FLIM) system was used to perform two-photon two-beam FLIM of NAD(P)H and FAD to image the metabolic state in different tissue samples of the UADT. FLIM data sets of 27 tissue samples from 16 patients were recorded directly after surgery ex vivo in a special tissue culture medium at 37°C on a dedicated microscope using multiphoton excitation. Based on the FLIM measurements of NAD(P)H and FAD, six of the most common indices for the characterization of the cells' metabolism were calculated. Three of them, the ratio of the exponential coefficients (amplitudes) of the short and long lifetime components both for NAD(P)H and FAD (NAD(P)H a1/a2 ratio and FAD a1/a2 ratio) and the fluorescence lifetime redox ratio (FLIRR) enabled differentiation between healthy tissue, benign lesions, dysplastic tissue, and cancer tissue with statistical significance. We showed by measurements on freshly collected tissue samples that mucosal lesions of the UADT can be differentiated using our newly designed endoscopic FLIM device. In vivo measurements in healthy volunteers were also possible. By means of this technology, differentiation of cancerous, pre-cancerous, and healthy tissue in the UADT by OMI could be possible. Of six indices used to characterize cell metabolism we calculated, the FLIRR showed the most significant differences between tissue types.

Mixed neuroendocrine non-neuroendocrine tumors: The quest for evidence

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) are rare mixed tumors containing both neuroendocrine and non-neuroendocrine components that occupy at least 30% of the whole tumor. Biologically, both components appear to derive from an identical cellular precursor undergoing early dual differentiation or late transdifferentiation. While our understanding of MiNENs has improved in recent years, many areas of uncertainty remain. In this context, setting diagnostic criteria capable of capturing the continuum of disease biology while providing clinically meaningful information in terms of prognosis and response to treatments appears vital to advance the field and improve patients’ outcomes. Evidence is needed to generate robust classification schemes, and multi-institutional cooperation will likely play a crucial role in building adequately powered cohorts to address some of the most pressing questions discussed in this Editorial. What is the minimum representation for each component needed to define MiNENs? How can the epidemiology of MiNENs change according to different diagnostic definitions? How can we generate the clinical evidence needed to optimize the management of MiNENs?

Retrospective comparative analysis of human fascioliasis versus bacterial liver abscess.

This study aimed to compare the clinical characteristics of human fascioliasis and bacterial liver abscesses to provide a reference for the early and effective differentiation of these 2 diseases to avoid misdiagnosis. We retrospectively compared the epidemiological and clinical characteristics of 95 patients with human fascioliasis and 95 with bacterial liver abscess admitted to the First Affiliated Hospital of Dali University between January 2013 and March 30, 2023. The human fascioliasis group exhibited a higher proportion of female patients and a greater frequency of abdominal pain and lesions affecting both lobes of the liver. Additionally, eosinophil count, percentage of eosinophils, red blood cells, hemoglobin, total protein, albumin, carbohydrate antigen-125 (CA-125), CA-199, and CA-724 levels were elevated compared to the bacterial liver abscess group. Conversely, the proportion of patients with diabetes, duration of hospital stay, and the incidence of lesions affecting the right lobe of the liver, cavity formation, ascites, pleural effusion, white blood cells, total bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase levels were lower in the fascioliasis group compared to the bacterial liver abscess group. Furthermore, higher thrombin time and fibrinogen levels were observed in the fascioliasis group than in the bacterial liver abscess group (P < .05). Human fascioliasis predominantly occurs from August to November, while bacterial liver abscess exhibits a consistent incidence throughout the year. Human fascioliasis predominantly affects young women and demonstrates a seasonal pattern. It is associated with severe abdominal symptoms, widespread lesions, significantly elevated eosinophil levels, and seasonal incidence. Bacterial liver abscess predominantly affects elderly men with diabetes, and it is associated with localized lesions and severe inflammatory manifestations and occurs throughout the year.

Stem Cell-Associated Proteins and Extracellular Matrix Composition of the Human Atrioventricular Junction.

The human heart regenerates slowly through life, but how new cells are generated is mostly unknown. The atrioventricular junction (AVj) has been indicated as a potential stem cell niche region. Little is known about the protein composition of the human AVj. To map the extracellular matrix (ECM) and expression of stem cell-related biomarkers, this study compares protein and gene expression patterns in AVj and Left Ventricular (LV) tissues. Biopsies were collected from 15 human hearts. Global quantitative proteomics and mRNA sequencing were used to identify differentially expressed proteins and altered genes. Of the total 4904 identified proteins, 1138 were differently expressed between the AVj and LV. While the top proteins in LV were involved in cardiac motor function and energy regulation, the AVj displayed proteins associated with early cardiomyocyte development, differentiation, proliferation, migration, and hypoxia. Furthermore, several developmental signalling pathways, including TGF-β, TNF, WNT, Notch, and FGF, were represented. RNA-seq data verified that the expressed genes were involved with differentiation, cell growth, proliferation, or ECM organization. Immunohistochemistry confirmed the expression of the stem cell-related biomarkers NPPA and POSTN in the AVj, further strengthening the hypothesis of the AVj as a specialized microenvironment conducive to stem cell niche activity.

The role of deep learning in diagnostic imaging of spondyloarthropathies: a systematic review.

Diagnostic imaging is an integral part of identifying spondyloarthropathies (SpA), yet the interpretation of these images can be challenging. This review evaluated the use of deep learning models to enhance the diagnostic accuracy of SpA imaging. Following PRISMA guidelines, we systematically searched major databases up to February 2024, focusing on studies that applied deep learning to SpA imaging. Performance metrics, model types, and diagnostic tasks were extracted and analyzed. Study quality was assessed using QUADAS-2. We analyzed 21 studies employing deep learning in SpA imaging diagnosis across MRI, CT, and X-ray modalities. These models, particularly advanced CNNs and U-Nets, demonstrated high accuracy in diagnosing SpA, differentiating arthritis forms, and assessing disease progression. Performance metrics frequently surpassed traditional methods, with some models achieving AUCs up to 0.98 and matching expert radiologist performance. This systematic review underscores the effectiveness of deep learning in SpA imaging diagnostics across MRI, CT, and X-ray modalities. The studies reviewed demonstrated high diagnostic accuracy. However, the presence of small sample sizes in some studies highlights the need for more extensive datasets and further prospective and external validation to enhance the generalizability of these AI models. Question How can deep learning models improve diagnostic accuracy in imaging for spondyloarthropathies (SpA), addressing challenges in early detection and differentiation from other forms of arthritis? Findings Deep learning models, especially CNNs and U-Nets, showed high accuracy in SpA imaging across MRI, CT, and X-ray, often matching or surpassing expert radiologists. Clinical relevance Deep learning models can enhance diagnostic precision in SpA imaging, potentially reducing diagnostic delays and improving treatment decisions, but further validation on larger datasets is required for clinical integration.

Factors associated with the number of CD34-positive hematopoietic progenitor cells in the leukocyte concentrate in patients with lymphomas and acute T-lymphoblastic leukemia

Background. Autologous hematopoietic stem cell transplantation remains in demand for patients with hematological malignancies. The pool of hematopoietic stem cells is known to be heterogeneous. e studied various factors associated with previous treatment, patient and disease characteristics, as well as the composition of the C34+ pool in peripheral blood (), associated with the number of C34+ cells in the first leukocyte concentrate (LC).Aim. To determine the factors associated with C34+ , C34+ C143+ , C34+ C38– HLA-DR+/– and C34+ C38+/– HLA-DR– cells count in the first LC of patients with hematological malignancies.Materials and methods. Subpopulations of hematopoietic stem cells in the and first LC were studied in 80 patients with hematological malignancies (male to female ratio 1:1, median age 51 years). The control group included 24 healthy donors. Flow cytometry was used to determine the number of C34+, C34+ C38– HLA-DR+/–, C34+ C38+/– HLA-DR– and C34+ C143+ cells. Immunophenotyping was performed on samples of patients before mobilization and on the 1st day of leukapheresis, as well as on first LC samples on the 1st day of hematopoietic stem cells collection.Results. It was shown that the presence of early progenitor cells with C34+ C38– HLA-DR+/– immunophenotype in the before mobilization is associated with a higher first LC C34+ cells number (p = 0.003). In the presence of C34+ C38– HLA-DR+/– cells in the before mobilization, the median number of C34+ cells in the first LC was 2.6 %, and in their absence – 0.71 %. hen using granulocyte colonystimulating factor as monotherapy, the C34+ C143+ cells number in the first LC was significantly lower than when using chemotherapy and granulocyte colonystimulating factor (p = 0.03). However, the majority (9 of 16) of patients in the granulocyte colonystimulating factor monotherapy group had renal failure before mobilization. No factors associated with the number of C34+ C38– HLA-DR+/– cells in the first LC were found. In patients &gt;60 years old, the number of C34+ C38+/– HLA-DR– cells in the first LC was lower than in patients ˂ 60 years old, the number of C34+ C38+/– HLA-DR– cells in the first LC was lower than in patients ˂ 60 years old (p = 0.043). In patients with infectious complications during hematopoietic stem cell mobilization, the number of C34+ C38+/– HLA-DR– cells in the first LC was lower than in patients without them (p = 0.019).Conclusion. The first LC number of C34+ cells is associated with number of C34+ C38– HLA-DR+/– cells, i. e. cells of the early differentiation stage with a high proliferation potential. A relationship was established between C34+ C143+ cells number before mobilization and first LC C34+ cells count: in the paired model – within the borderline values (p = 0.05), and in the multifactorial covariance model – with high significance (p = 0.0033). It has been proven that with increasing patient age and in the presence of infectious complications, the number of longterm repopulating C34+ C38+/– HLA-DR– cells decreases.

A new scoring in differential diagnosis: multisystem inflammatory syndrome or adenovirus infection?

Differentiating multisystem inflammatory syndrome in children (MIS-C) from adenovirus infection (AI) can be challenging due to similar clinical and laboratory findings. This study aimed to identify distinguishing characteristics and develop a scoring system to facilitate accurate diagnosis. A comprehensive review of medical records was undertaken for 108 MIS-C patients and 259 patients with confirmed AI. A comparison of laboratory data and clinical findings was conducted across the patient groups using appropriate statistical tests. The MIS-C patients were significantly older than the AI patients (p < 0.001). Diarrhea, rash, abdominal pain, vomiting, nonexudative conjunctivitis, lymphadenopathy tachycardia, bradycardia, hypotension, hypoxia seizures, agitation, headache, and altered consciousness symptoms were more frequently associated with MIS-C (p < 0.001), while cough and runny nose were significantly more common in AI (p < 0.001). Lymphopenia and thrombocytopenia were more prevalent in the MIS-C patients (p < 0.001). AI and MIS-C were scored by giving one point each to the parameters that created the difference. For AI, being ≤60 months of age, the presence of cough, runny nose and absence of diarrhea, rash, abdominal pain, vomiting, nonexudative conjunctivitis, lymphadenopathy, tachycardia, bradycardia, hypotension, hypoxia seizures, agitation, headache, and altered consciousness, lymphopenia, thrombocytopenia, and C-reactive protein value <124.5 mg/L were determined as each parameter plus one point. A total score above 14 could predict AI with a high degree of accuracy, with sensitivity at around 97.5% and specificity at 92.6%. The proposed inpatient scoring system, when used in conjunction with polymerase chain reaction testing, may improve the early differentiation of AI and MIS-C. This approach could help reduce unnecessary testing and optimize resource allocation. Further research with larger samples should investigate this novel scoring system to establish its reliability and generalizability.

Differentiating Cystic Lesions in the Sellar Region of the Brain Using Artificial Intelligence and Machine Learning for Early Diagnosis: A Prospective Review of the Novel Diagnostic Modalities.

This paper investigates the potential of artificial intelligence (AI) and machine learning (ML) to enhance the differentiation of cystic lesions in the sellar region, such as pituitary adenomas, Rathke cleft cysts (RCCs) and craniopharyngiomas (CP), through the use of advanced neuroimaging techniques, particularly magnetic resonance imaging (MRI). The goal is to explore how AI-driven models, including convolutional neural networks (CNNs), deep learning, and ensemble methods, can overcome the limitations of traditional diagnostic approaches, providing more accurate and early differentiation of these lesions. The review incorporates findings from critical studies, such as using the Open Access Series of Imaging Studies (OASIS) dataset (Kaggle, San Francisco, USA)for MRI-based brain research, highlighting the significance of statistical rigor and automated segmentation in developing reliable AI models. By drawing on these insights and addressing the challenges posed by small, single-institutional datasets, the paper aims to demonstrate how AI applications can improve diagnostic precision, enhance clinical decision-making, and ultimately lead to better patient outcomes in managing sellar region cystic lesions.

Exploring the In Vitro Effects of Zingerone on Differentiation and Signalling Pathways in Bone Cell Lines.

Ensuring adequate bone health is crucial for preventing conditions such as osteoporosis and fractures. Zingerone, a phytonutrient isolated from cooked ginger, has gained attention for its potential benefits in bone health. This study evaluated the osteoprotective potential of zingerone and its effects on differentiation and signalling pathways in vitro using SAOS-2 osteosarcoma and RAW264.7 macrophage cell lines, aiming to elucidate its mechanism of action in bone remodelling. SAOS-2 osteosarcoma and RAW264.7 macrophage cells were treated with zingerone at concentrations of 200 µM. Osteoblast differentiation was assessed by alkaline phosphatase (ALP) activity, bone mineralisation via Alizarin Red S stain, and gene expression markers (ALP, runt-related transcription factor 2 (Runx2), and osteocalcin) via quantitative polymerase chain reaction (q-PCR). Osteoclast differentiation was evaluated by tartrate-resistant acid phosphatase (TRAP) staining, TRAP activity, and mitogen-activated protein kinase (MAPK) pathways. Treatment with zingerone was non-toxic at 200 µM. Zingerone (200 µM) significantly stimulated the gene expression of ALP and Runx2 in SAOS-2 cells (p < 0.05) without statistically significantly enhancing SAOS-2 mineralisation via calcium deposits. Moreover, zingerone significantly inhibited osteoclast differentiation in RAW264.7 cells as evidenced by reduced TRAP staining and activity (p < 0.05). Zingerone shows promise in reducing osteoclast activity and supporting early osteoblast differentiation, suggesting its potential as a dietary supplement for bone health. Further in vivo and clinical studies are needed to confirm its role in managing osteoporosis.

Modulation of Biomaterial-Associated Fibrosis by Means of Combined Physicochemical Material Properties.

Biomaterial-associated fibrosis remains a significant challenge in medical implants. To optimize implant design, understanding the interplay between biomaterials and host cells during the foreign body response (FBR) is crucial. Material properties are known to influence cellular behavior and can be used to manipulate cell responses, but predicting the right combination for the desired outcomes is challenging. This study exploreshow combined physicochemical material properties impact early myofibroblast differentiation using the Biomaterial Advanced Cell Screening (BiomACS) technology, which assesseshundreds of combinations of surface topography, stiffness, and wettability in a single experiment. Normal human dermal fibroblasts (NHDFs) are screened for cell density, area, and myofibroblast markers α-smooth muscle actin (α-SMA) and Collagen type I (COL1) after 24hand 7 days of culture, with or without transforming growth factor-beta (TGF-β). Results demonstrated that material properties influence fibroblast behavior after 7 days with TGF-β stimulation, with wettability emerging as the predominant factor, followed by stiffness. The study identified regions with increased cell adhesion while minimizing myofibroblast differentiation, offering the potential for implant surface optimization to prevent fibrosis. This research provides a powerful tool for cell-material studies andrepresents a critical step toward enhancing implant properties and reducing complications, ultimately improving patient outcomes.

Pregametogenesis: The Earliest Stages of Gonad and Germline Differentiation in Anuran Amphibians.

The gonads of amphibians, like other vertebrates, consist of somatic tissues, which create a specific environment essential for the differentiation of germline cells. The earliest stages of gametogenesis still remain underexplored in anuran amphibians. We propose to introduce the term "pregametogenesis" for a specific period of gonocyte proliferation and differentiation that occurs exclusively during the early stages of gonadal development. This review shows the key steps of early gonad differentiation in anuran amphibians and further compares chromatin reorganization in gonocytes of mammals and hybridogenetic water frogs. In mammals, this phase involves resetting genomic imprinting, which is crucial for determining gene expression in offspring. In hybridogenetic Pelophylax water frogs, we highlight the unique phenomenon of genome elimination, where one parental subgenome is eliminated while the other is replicated. This process, occurring at the same developmental phase as imprinting in mammals, underscores the evolutionary importance of pregametogenesis. The study of amphibian gonocytes provides valuable insights into chromatin reorganization and genome plasticity, offering new perspectives on reproductive biology.

Heparan sulfate regulates the fate decisions of human pluripotent stem cells.

Heparan sulfate (HS) is an anionic polysaccharide generated by all animal cells, but our understanding of its roles in human pluripotent stem cell (hPSC) self-renewal and differentiation is limited. We derived HS-deficient hPSCs by disrupting the EXT1 glycosyltransferase. These EXT1-/- hPSCs maintain self-renewal and pluripotency under standard culture conditions that contain high levels of basic fibroblast growth factor(bFGF), a requirement for sufficient bFGF signaling in the engineered cells. Intriguingly, Activin/Nodal signaling is also compromised in EXT1-/- hPSCs, highlighting HS's previously unexplored involvement in this pathway. As a result, EXT1-/- hPSCs fail to differentiate into mesoderm or endoderm lineages. Unexpectedly, HS is dispensable for early ectodermal differentiation of hPSCs but still critical in generating motor neurons. Those derived from HS-deficient hPSCs lack proper neuronal projections and show alterations in axonogenesis gene expression. Thus, our study uncovers expected and unexpected mechanistic roles of HS in hPSC fate decisions.

Inflammatory choroidal neovascularization: An evidence-based update.

Inflammatory choroidal neovascularization (iCNV) significantly contributes to vision impairment and ranks as the third primary cause of CNV. Arising from both infectious and noninfectious uveitis, iCNV's pathogenesis involves Bruch membrane rupture, local inflammation, and choriocapillaris ischemia. The diagnosis of iCNV is challenging due to its symptomatic overlap with other uveitis-related conditions. We emphasize the importance of advanced multimodal imaging techniques, particularly optical coherence tomography (OCT) and OCT angiography (OCTA), for early detection and differentiation of iCNV from other types of CNV. Although anti-vascular endothelial growth factor agents have shown high efficacy in treatment, the integration of these treatments with anti-inflammatory therapies remains a critical area of active research. The diversity of uveitis presentations and the rarity of iCNV have resulted in a scarcity of randomized clinical trials, leading to reliance on fragmented data from case reports and series. We consolidate the most recent studies to provide a comprehensive, updated overview of the epidemiology, risk factors, pathogenesis, imaging techniques, and treatment modalities for iCNV, aiming to support clinical decision-making. The absence of standardized guidelines highlights the need for further research to establish best practices for managing iCNV effectively.

Borderline Lepromatous Leprosy With Type 1 Reaction: A Challenging Diagnostic Case.

Borderline lepromatous leprosy with Type 1 reaction poses significant diagnostic challenges due to overlapping clinical features. Early recognition and differentiation are crucial, especially in endemic regions like Mexico, to ensure prompt, appropriate management and prevent complications. Accurate diagnosis requires a multidisciplinary approach integrating clinical, histopathological, and microbiological data.

Preferred Orientation of Hydroxyapatite Ceramics Along the c-Axis Promotes Osteoblast Differentiation.

Hydroxyapatite (HAp) is similar to the main inorganic components of bone and tooth enamel. Furthermore, it possesses biocompatibility, making it suitable for clinical use in artificial bones. This study aimed to verify whether the preferred orientation of HAp influences osteogenesis. Using the templated grain growth method, we successfully fabricated HAp ceramics with a preferred orientation to m (a)-planes (aHAp) and examined the effects of this orientation on bone differentiation. Osteosarcoma-derived osteoblasts (MG-63) were cultured on aHAp and HAp ceramics made from commercially available powder (iHAp). Electron backscatter diffraction analysis revealed the crystal orientation distribution of HAp ceramics and the numerous exposed a-planes of aHAp. The MG-63 cultured on aHAp exhibited significantly higher alkaline phosphatase activity, a marker of early bone differentiation, compared to iHAp. Furthermore, the two-dimensional electrophoresis results indicated that the expressed proteins differed between aHAp and iHAp. These results indicate that controlling HAp's crystal structure may promote the osteogenic potential of osteoblasts. In this study, we propose that the a-plane of HAp promotes bone differentiation during the early stages, presenting a promising approach for novel biomaterials, such as high-performance artificial bones.

Organoid generation from trophoblast stem cells highlights distinct roles for cytotrophoblasts and stem cells in organoid formation and expansion.

BackgroundOrganoids are stem-cell derived, self-organised, three-dimensional cultures that improve in vitro recapitulation of tissue structure. The generation of trophoblast organoids using primary placental villous digests (containing cytotrophoblasts and trophoblast stem cells (TSC)) improved high-throughput assessment of early trophoblast differentiation. However, the relative contributions of cytotrophoblasts and TSCs to trophoblast organoid growth and differentiation remain unclear, with implications for model interpretation. Here we sought to generate organoids from side-population trophoblasts (SpTSCs) to better understand the contribution of TSC to trophoblast organoid formation. MethodsMethods were adapted from Haider et al., 2018 to generate organoids from Okae TSCs (OkTSCs) or SpTSCs. Organoid growth was compared with primary villous trophoblast organoids and cellular composition interrogated by immunohistochemistry. ResultsOrganoids can be derived from first-trimester SpTSCs that exhibit similar architecture to those from primary villous trophoblast. However, organoids established from pure TSC populations (OkTSC or SpTSC) have different growth dynamics to primary placental villous digest-derived organoids – with OkTSCs developing faster and spontaneously generating migratory cells, whilst SpTSC organoids grow more slowly. Importantly, depletion of SpTSC from first-trimester villous digests ablates organoid formation. Finally, the capacity of the side-population technique to isolate late-gestation TSC enabled the generation of trophoblast organoids from term placentae, although these were significantly smaller than their first-trimester SpTSC counterparts. DiscussionTogether, this work highlights the requirement of TSC for organoid formation, and the functional distinction between TSC and cytotrophoblasts. Proof-of-principle data demonstrating organoid generation from late gestation TSC isolated directly from the placenta lays the groundwork for future disease models.

Polycomb protein Bmi1 promotes odontoblast differentiation by accelerating Wnt and BMP signaling pathways.

Bmi1 is a polycomb protein localized in stem cells and maintains their stemness. This protein is also reported to regulate the expression of various differentiation genes. In this study, to analyze the role of Bmi1 during dentinogenesis, we examined the immunohistochemical localization of Bmi1 during rat tooth development as well as after cavity preparation. Bmi1 localization was hardly detected in the dental mesenchyme at the bud and cap stages. After the bell stage, however, this protein became detectable in preodontoblasts and early odontoblasts just beginning dentin matrix secretion. As dentin formation progressed, Bmi1 immunoreactivity in the odontoblasts decreased in intensity. After cavity preparation, cells lining the dentin and some pulp cells under the cavity were immunopositive for Bmi1 at 4days. Odontoblast-like cells forming reparative dentin were immunopositive for Bmi1 at 1week, whereas their immunoreactivity was not detected after 8weeks. We further analyzed the function of Bmi1 using KN-3 cells, a dental mesenchymal cell line. Overexpression of Bmi1 in KN-3 cells promoted mineralized tissue formation. In contrast, siRNA knockdown of Bmi1 in KN-3 cells reduced alkaline phosphatase activity and the expression of odontoblast differentiation marker genes such as Runx2, osterix, and osteocalcin. Additionally, KN-3 cells transfected with siRNA against Bmi1 showed reduced nuclear transition of β-catenin and expression of phosphorylated-Smad1/5/8. Taken together, these findings suggest that Bmi1 was localized in the odontoblast-lineage cells in their early differentiation stages. Bmi1 might positively regulate their differentiation by accelerating Wnt and BMP signaling pathways.