Search Results (17,196)

L-arginine and its derivatives L-homoarginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) show distinct (patho-) physiological properties as well as a differential renal handling. L-arginine and L-homoarginine have a lower renal clearance and are largely retained (i.e., reabsorbed) as compared to ADMA and SDMA, which are relatively enriched in the urine and excreted. To obtain a more complete picture of what is known regarding transport proteins involved in renal reabsorption and secretion of these substances, a comprehensive literature review and search of cell-specific gene expression databases were performed. Five transport proteins known to transport L-arginine and its derivatives were included, and the data available regarding their tubular expression pattern and their transport characteristics, as well as experimental and clinical data regarding their possible impact on the renal handling of L-arginine and its derivatives, are presented and discussed in a structured narrative review. Based on their transport properties and links to clinical phenotypes, b^0,+AT-rBAT and y⁺LAT1-4F2hc were identified as the most promising candidates to explain a significant part of the observed differential renal handling. This also makes them promising candidates for further investigations as mediators of possible adverse and beneficial drug effects involving L-arginine, L-homoarginine, ADMA, and SDMA. Full article

Histopathological images play a crucial role in diagnosing skin cancer. However, due to the very large size of digital histopathological images (typically in the order of billion pixels), manual image analysis is tedious and time-consuming. Therefore, there has been significant interest in developing Artificial Intelligence (AI)-enabled computer-aided diagnosis (CAD) techniques for skin cancer detection. Due to the diversity of uncertain cell boundaries, automated nuclei segmentation of histopathological images remains challenging. Automating the identification of abnormal cell nuclei and analyzing their distribution across multiple tissue sections can significantly expedite comprehensive diagnostic assessments. In this paper, a deep neural network (DNN)-based technique is proposed to segment nuclei and detect melanoma in histopathological images. To achieve a robust performance, a test image is first augmented by various geometric operations. The augmented images are then passed through the DNN and the individual outputs are combined to obtain the final nuclei-segmented image. A morphological technique is then applied on the nuclei-segmented image to detect the melanoma region in the image. Experimental results show that the proposed technique can achieve a Dice score of 91.61% and 87.9% for nuclei segmentation and melanoma detection, respectively. Full article

Hederagenin, a pentacyclic triterpenoid saponin from various medicinal plants, shows immense therapeutic potential; however, its inherent low bioavailability severely hinders its clinical translation. This comprehensive review synthesizes recent studies on the health benefits of hederagenin and its glycosides, critically the chemical modification strategies and pharmacological mechanisms aimed at optimizing its bioactivity. Key findings reveal that its broad anticancer and anti-inflammatory activities largely stem from its capacity to modulate crucial cellular signaling pathways, including the NF-κB, PI3K/Akt, and MAPK. Structural modification, particularly intelligent derivatization at the C-28 position, is a central strategy to overcome its pharmacokinetic deficiencies and significantly boost cytotoxicity. Furthermore, its unique pro-oxidant function within cancer cells, achieved by inhibiting the Nrf2-ARE antioxidant pathway, offers a novel approach for selective chemotherapeutics. For the clinical translation of hederagenin, we propose a strategic focus on derivatization through multi-target hybrids and sophisticated delivery systems. This approach is essential for addressing its pharmacokinetic barriers while strategically leveraging its context-dependent pro-oxidant effects. Full article

SLC5A8 is a protein coded by the SLC5A8 gene, and has been proposed as a tumor suppressor and iodide transporter. Its expression is reduced in papillary thyroid carcinoma (PTC), yet the mechanisms underlying this phenomenon are largely unknown. We hypothesized that SLC5A8 expression in PTC is reduced by microRNAs and can be modulated by their inhibition. We used real-time PCR to analyze the expression of SLC5A8 and the microRNAs of interest in a set of 49 PTC/normal tissue pairs. We used an in silico approach to identify microRNAs upregulated in PTC and putatively binding to the SLC5A8 transcript. Luciferase assays were performed to confirm the direct binding of synthetic microRNAs to the 3′UTR of SLC5A8. Subsequently, using mir-expressing plasmids and microRNA sponges, including a microRNA sponge designed to simultaneously inhibit three selected microRNAs, we checked the impact of the modulation of microRNAs on endogenous SLC5A8. Finally, we investigated if modulation of SLC5A8 induces changes in transcriptomes. We confirmed the downregulation of SLC5A8 in PTC. In silico analysis revealed microRNAs potentially targeting SLC5A8. Luciferase assay confirmed direct binding between the 3′UTR of SLC5A8 and miR-181a-5p, miR-182-5p, and miR-494-3p. MiR-181a-5p and miR-182-5p were upregulated in PTC. In HEK293 cell lines, transfection with mir-181a- and mir-182-expressing plasmids decreased endogenous SLC5A8 mRNA, while silencing of miR-181a-5p, miR-182-5p, miR-494-3p, and all three microRNAs simultaneously increased SLC5A8 expression; however, only simultaneous inhibition was able to induce changes visible for SLC5A8 protein. Changes in SLC5A8 expression did not alter the whole transcriptome significantly. This study shows microRNA-dependent regulation of SLC5A8 expression and underlines the potential effectiveness of simultaneous inhibition of a few microRNAs to derepress their common target. Full article

(1) Background: Bispecific antibodies (BsAbs) for the treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) can be delivered in ambulatory healthcare settings; however, the safe and effective management of potential side effects, such as cytokine release syndrome (CRS), requires protocolized monitoring and management. (2) Methods: An Expert Working Group (EWG) of nine hematologists from across Canada, with experience in leading BsAb program implementation, combined a review of published literature, a comparison of national/provincial/regional guidance documents and protocols, and their professional experiences to produce an informed framework for BsAb program implementation in various healthcare settings. (3) Results: The EWG supports and recommends the progression of BsAb provision from predominantly inpatient hospital settings to community/ambulatory care settings closer to the patient’s home. A seven-step implementation process is outlined to support the safe and effective establishment of such programs, from establishing leadership, through customization of protocols, to education and execution. Strategies and considerations are offered to overcome potential barriers and empower healthcare professionals who are working to establish or improve BsAb programs across Canada. (4) Conclusions: For patients with R/R DLBCL, the safe and effective provision of BsAbs closer to home is both feasible and preferred. This guidance is intended to support the efficient and effective setup or enhancement of BsAb programs in lymphoma. Full article

This article reviews and synthesizes highlights of the history of neural models of rate-based and spiking neural networks. It explains that theoretical and experimental results about how all rate-based neural network models, whose cells obey the membrane equations of neurophysiology, also called shunting laws, can be converted into spiking neural network models without any loss of explanatory power, and often with gains in explanatory power. These results are relevant to all the main brain processes, including individual neurons and networks for perception, learning, cognition, and navigation. The results build upon the hypothesis that the functional units of brain processes are spatial patterns of cell activities, or short-term-memory (STM) traces, and spatial patterns of learned adaptive weights, or long-term-memory (LTM) patterns. It is also shown how spatial patterns that are learned by spiking neurons during childhood can be preserved even as the child’s brain grows and deforms while it develops towards adulthood. Indeed, this property of spatiotemporal self-similarity may be one of the most powerful properties that individual spiking neurons contribute to the development of large-scale neural networks and architectures throughout life. Full article

Type 1 diabetes (T1D) is a serious disease which affects millions of people worldwide and is a major factor for vascular contributions to cognitive impairment and dementia (VCID). In this study, we first characterized cognitive and memory impairments, then evaluated their underlying molecular mechanisms, and finally determined sex-dependent effects in male and female mice with streptozotocin (STZ)-induced T1D. Our findings indicated that significant cognitive impairment, memory loss, and vascular dementia occurred in male and female T1D mice. Cerebral artery (CA) blood flow was greatly reduced in the various brain regions tested. ROS generation in isolated cells, mitochondria, and mitochondrial complex III from CA smooth muscle cells (CASMCs) were all increased in T1D. DNA damage and Tau phosphorylation in CASMCs were largely increased. Linear regression analysis revealed that T1D-induced increased blood glucose was highly correlated with increased ROS production and increased VCID. Taken together, we conclude that T1D causes increased mitochondrial complex III ROS production, DNA damage, and Chk2 phosphorylation in CASMC, thereby leading to vascular dementia in both male and female mice; our results further demonstrate that mitochondrial complex III ROS-mediated DNA damage is more significant in male than female mice, which contributes to more serious vascular dementia in the former than the latter. Full article

Gonadal development and spermatogenesis critically influence fish reproductive performance. Neomales (genetically female but functionally male) are indispensable for generating all-female populations, yet their spermatogenesis remains understudied. In the present study, we systematically investigated gonadal maturation in neomales of the large yellow croaker (Larimichthys crocea), an economically important marine species exhibiting sexually dimorphic growth. We examined the growth performance and gonadal development throughout the maturation process in neomales and control males. Results showed comparable growth performance but a temporal divergence in gonadal development: the gonadosomatic index (GSI) of neomales was significantly higher than control males at 400 and 430 days post-hatching (dph), but not at 460 dph during the reproductive period. Histological, ultrastructural (TEM), and immunofluorescence analyses collectively demonstrated that neomale testes contained all major spermatogenic cell types. Their morphological characteristics and expression patterns of key markers—germ cells (vasa), Sertoli cells (sox9a), and meiotic recombination (dmc1)—were similar to control males. These findings enhance understanding of gonadal development and spermatogenesis in neomales, providing a theoretical and technical foundation for large-scale production of all-female large yellow croaker. Full article

Peach (Prunus persica (L.)) fruits are abundant in nutrients, with fruit shape and sugar content serving as critical indicators of fruit quality. Melatonin plays a pivotal role in peach fruit development; however, the mechanisms by which it regulates fruit shape development, sugar metabolism, and secondary metabolites remain largely unknown. In this study, peach trees were sprayed with 150 µM melatonin 20 days after pollination. Traditional methods were used to investigate fruit morphology, total soluble solids (TSSs), and titratable acidity content (TAC), while liquid chromatography–mass spectrometry (LC-MS) was employed to analyze sugar metabolites during fruit development. The results indicated that melatonin treatment augmented the transverse and longitudinal diameters of peach fruits by 12% and 6%, respectively, and elevated the contents of soluble solids and titratable acid by 7% and 6%, respectively. The single fruit weight experienced a significant increase of 29.4%, whereas fruit firmness at maturity remained unchanged. Metabolite analysis demonstrated that melatonin decreased the levels of sucrose and D-sorbitol in mature fruits but enhanced the accumulation of D-fructose, L-rhamnose, and xylose. Significantly, melatonin expedited the degradation of galactose, D-mannose, and methyl-D-pyranogalactoside prior to maturity (all three substances naturally decline with fruit ripening), highlighting its role in promoting fruit ripening. In conclusion, exogenous melatonin improves the internal nutrition and flavor quality of fruit by regulating the accumulation of primary and secondary metabolites during fruit ripening. Specifically, the increase in D-fructose (a major contributor to sweetness) and L-rhamnose (a potential precursor for aroma compounds) enhances fruit flavor profile. The accelerated degradation of galactose, D-mannose, and methyl-D-pyranogalactoside (components of cell wall polysaccharides) prior to maturity, alongside the metabolic shift favoring fructose accumulation over sucrose, highlights melatonin’s role in promoting fruit ripening and softening processes. It also promotes fruit enlargement and single fruit weight without affecting fruit firmness. This study establishes a theoretical basis for the further investigation of the molecular mechanisms underlying melatonin’s role in peach fruits and for enhancing quality-focused breeding practices. Full article

In this study, alkali-treated wood flour/dynamic polyurethane composites were successfully prepared through a solvent-free one-pot method and in situ polymerization. The effects of the alkaline treatment process, changes in the flexible long-chain content in the dynamic polyurethane system, and the wood flour filling amount on the interface’s bonding, mechanical, and reprocessing properties were investigated. Partial removal of lignin and hemicellulose from the alkali-treated wood flour enhanced rigidity and improved interface bonding and mechanical strength when combined with dynamic polyurethane. The tensile strength was improved from 5.65–11.00 MPa to 13.08–23.53 MPa. As the composite matrix, dynamic polyurethane could not easily infiltrate all wood flour particles when its content was low or its fluidity was poor. Conversely, excessive content or overly high fluidity led to leakage and the formation of large pores, affecting the mechanical strength. As the polyol content increased, the matrix exhibited greater fluidity, which enabled it to accommodate more wood flour and penetrate the cell cavity or even the cell wall. This improved infiltration enhanced the interface bonding performance of the composites and made their mechanical properties sensitive to changes in wood flour content. The reprocessing ability of the prepared composites decreased with the increase in wood flour content, and the interface bonding was enhanced after reprocessing. The tensile strength retention rate of the composites prepared with alkali-treated wood flour was lower. This study provides a theoretical basis for optimizing the performance of wood fiber/dynamic polyurethane composites and an exploration path for developing self-healing and recyclable wood–plastic composites, which can be applied to building materials, automotive interiors, furniture manufacturing, and other fields. Full article

Systemic light-chain (AL) amyloidosis is a challenging, complex and heterogeneous disease. AL amyloidosis is classified under the category of plasma cell neoplasms and other diseases with paraproteins in the fifth edition of the World Health Organization classification of lymphoid tumors. Epidemiological information is limited, largely due to its low incidence and the lack of a global network of population-based specific registries. Despite recent advances, AL amyloidosis is still considered an incurable disease. The presence of a precursor disease, particularly monoclonal gammopathy of uncertain significance, is the main consolidated risk factor. Limited knowledge about other risk factors precludes the possibility of establishing preventive measures. A relevant percentage of AL amyloidosis patients fulfill the current diagnostic criteria of multiple myeloma. Incidence should be evaluated in the setting of population-based studies. On the one hand, incidence shows a slightly increasing pattern. On the other hand, survival is progressively increasing. Consequently, prevalence is also rising. Early mortality, commonly associated with advanced heart involvement, remains a serious drawback to improve the outcome. Epidemiology represents the first level of heterogeneity in AL amyloidosis. Both genomic and clinical epidemiological research in systemic AL amyloidosis have a crucial role in the global strategy to combat this multifaceted disease. Full article

Improving the restoration of skin defects of various etiologies continues to be an important medical challenge globally. This primarily applies to the treatment of chronic wounds and major burns, which create particularly complex and socially significant problems for surgery. In recent decades the progress in these fields has largely been associated with techniques for regenerative medicine, specifically, techniques based on the use of tissue-engineered constructs. Before their use in clinical practice, all such newly developed constructs require preclinical studies to confirm their safety and effectiveness in animal models. This paper presents the results of preclinical studies of the effectiveness of restoration of full-layer degloving wounds in pigs using grafts of either an original biopolymer hydrogel scaffold or a skin equivalent based on it, but seeded with autologous skin cells (ASCs). It is demonstrated that the scaffold itself integrates into the wound bed tissues, facilitating cell recruitment and the accumulation and early maturation of granulation tissue. Then, at later stages of regeneration, the scaffold accelerates the maturation of connective tissue and promotes the formation of tissues similar to those of healthy skin in terms of thickness and structure. Owing to the ASCs present in it, the skin equivalent demonstrates greater effectiveness than the scaffold alone, in particular, due to overall faster remodeling of the graft connective tissue. Therefore, the scaffold we have developed and the skin equivalent based on it have much potential as products for the repair of skin wounds. Full article

CD20-negative aggressive B-cell lymphomas are a rare and heterogeneous group of lymphomas representing a diagnostic challenge for pathologists and a therapeutic issue for clinicians, because the outcome of these patients is poor with the current therapeutic approaches. CD20-negative aggressive lymphomas include plasmablastic lymphoma, primary effusion lymphoma, ALK-positive large B-cell lymphoma and HHV8-positive diffuse large B-cell lymphoma. Conditions of immunosuppression and viral infections, such as Epstein–Barr virus and Human Herpes virus 8, are associated with all of these lymphomas with the exclusion of ALK-positive large B-cell lymphoma, which occurs in immunocompetent hosts and is not associated with viral infections. Common features of these aggressive tumors are high-grade histology with immunoblastic or plasmablastic differentiation, the absence or weak expression of mature B-cell markers such as CD20 and the frequent expression of plasma cell-associated markers. The aim of this review is to highlight the diagnostic challenges associated with the group of CD20-negative aggressive B-cell lymphomas, emphasizing key morphologic and molecular features, which are critical in the diagnosis of the different entities belonging to this rare group of diseases. Full article

Background and Objectives: Hemoglobinopathies are genetic disorders of hemoglobin and are among the most common inherited diseases. The prevalence rates of sickle cell disease and thalassemia in Saudi Arabia are higher than those in other countries in the Middle East. Saudi Arabia has launched many prevention programs such as a premarital screening program, genetic counseling programs, and neonatal screening in order to reduce the incidence of genetic diseases. The former program includes the most common genetic diseases: sickle cell disease and thalassemia. Many studies conducted since the premarital program started have reported a decrease in the prevalence of sickle cell disease and thalassemia. However, all studies focus on large cities, including their subdivisions, but there is a lack of studies on subdivisions specifically. Materials and Methods: The aim of this study was to assess the prevalence, 5-year time trend, and distribution of β-thalassemia and sickle cell traits in Al-Kharj province using the data of the PMSGC program during the period from January 2017 to February 2021. Results: A total of 21,150 individuals were screened, and 508 were diagnosed with sickle cell disease and thalassemia. Also, we showed that thalassemia was more prevalent than sickle cell disease (66% and 34%, respectively), and there was an increase in β-thalassemia and α-thalassemia. Conclusions: Riyadh city’s prevalence rate of β-thalassemia was reported as 7 per 1000, while the current study found a prevalence rate of 5.6 per 1000 in Al-Kharj, which suggests a possible increase as a result of population growth in Al-Kharj province as part of Riyadh city. This study recommends further improvement in preventive measures in high-risk regions, as well as enhanced community awareness, to provide the highest rate of reduction for disorders. Full article

Neuroendocrine neoplasms (NENs) of the lung are a biologically and clinically diverse group of tumors that includes well-differentiated typical and atypical carcinoids (LNETs), as well as poorly differentiated large-cell neuroendocrine carcinoma and small-cell lung cancer. Despite their relative rarity, the incidence of LNETs is increasing, primarily due to advancements in diagnostic techniques and heightened clinical awareness. While the current World Health Organization (WHO) classification offers a morphological basis for diagnosis and prognosis, particularly for extrapulmonary neuroendocrine neoplasms (ep-NENs), it has limitations in predicting the clinical behavior of pulmonary carcinoids. Recent evidence highlights the inadequacy of traditional criteria in fully capturing the biological complexity and clinical heterogeneity of these tumors. This review explores the evolving landscape of LNETs, focusing on well-differentiated forms and analyzing current classification systems, clinicopathological features, and the emerging role of novel prognostic and predictive biomarkers. Advances in histopathology and molecular profiling have begun to elucidate distinct molecular subsets within carcinoids, offering potential avenues for improved risk stratification and therapeutic decision-making. Although there are limited treatment options for advanced disease, new insights into tumor biology could facilitate the development of personalized therapeutic strategies and pave the way for future innovations in LNET management. Full article