Search

Loss and functional failure of pancreatic β-cells results in disruption of glucose homeostasis and progression of diabetes. Although whole pancreas or pancreatic islet transplantation serves as a promising approach for β-cell replenishment and diabetes therapy, the severe scarcity of donor islets makes it unattainable for most diabetic patients. Stem cells, particularly induced pluripotent stem cells (iPSCs), are promising for the treatment of diabetes owing to their self-renewal capacity and ability to differentiate into functional β-cells. In this review, we first introduce the development of functional β-cells and their heterogeneity and then turn to highlight recent advances in the generation of β-cells from stem cells and their potential applications in disease modeling, drug discovery and clinical therapy. Finally, we have discussed the current challenges in developing stem cell-based therapeutic strategies for improving the treatment of diabetes. Although some significant technical hurdles remain, stem cells offer great hope for patients with diabetes and will certainly transform future clinical practice., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict interest. Ethical approval: This article does not contain any studies with human participants or animals performed by any of the authors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Stroke, a major cause of death and disability worldwide, can be haemorrhagic or ischaemic depending on the type of bleeding in the brain. Rapid and accurate identification of stroke type and lesion segmentation is critical for timely and effective treatment. However, existing research primarily focuses on segmenting a single stroke type, potentially limiting their clinical applicability. This study addresses this gap by exploring multi-type stroke lesion segmentation using deep learning methods. Specifically, we investigate two distinct approaches: a single-stage approach that directly segments all tissue types in one model and a hierarchical approach that first classifies stroke types and then utilises specialised segmentation models for each subtype. Recognising the importance of accurate stroke classification for the hierarchical approach, we evaluate ResNet, ResNeXt and ViT networks, incorporating focal loss and oversampling techniques to mitigate the impact of class imbalance. We further explore the performance of U-Net, U-Net++ and DeepLabV3 models for segmentation within each approach. We use a comprehensive dataset of 6650 images provided by the Ministry of Health of the Republic of Türkiye. This dataset includes 1130 ischaemic strokes, 1093 haemorrhagic strokes and 4427 non-stroke cases. In our comparative experiments, we achieve an AUC score of 0.996 when classifying stroke and non-stroke slices. For lesion segmentation task, while the performance of different architectures is comparable, the hierarchical training approach outperforms the single-stage approach in terms of intersection over union (IoU). The performance of the U-Net model increased significantly from an IoU of 0.788 to 0.875 when the hierarchical approach is used. This comparative analysis aims to identify the most effective approach and deep learning model for multi-type stroke lesion segmentation in brain CT scans, potentially leading to improved clinical decision-making, treatment efficiency and outcomes., Competing Interests: Declarations Conflict of Interest The author declares no competing interests., (© 2024. International Federation for Medical and Biological Engineering.)

Mesenchymal stem cells (MSCs) are extensively researched for therapeutic applications in tissue engineering and show significant potential for clinical use. Intrinsic or extrinsic factors causing senescence may lead to reduced proliferation, aberrant differentiation, weakened immunoregulation, and increased inflammation, ultimately limiting the potential of MSCs. It is crucial to comprehend the molecular pathways and internal processes responsible for the decline in MSC function due to senescence in order to devise innovative approaches for rejuvenating senescent MSCs and enhancing MSC treatment. We investigate the main molecular processes involved in senescence, aiming to provide a thorough understanding of senescence-related issues in MSCs. Additionally, we analyze the most recent advancements in cutting-edge approaches to combat MSC senescence based on current research. We are curious whether the aging process of stem cells results in a permanent "memory" and if cellular reprogramming may potentially revert the aging epigenome to a more youthful state., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Integrin β6 (ITGB6), a member of the integrin family of proteins, is only present in epithelial tissues and frequently associates with integrin subunit αv to form transmembrane heterodimers named integrin αvβ6. Importantly, ITGB6 determines αvβ6 expression and availability. In addition to being engaged in organ fibrosis, ITGB6 is also directly linked to the emergence of cancer, periodontitis, and several potential genetic diseases. Therefore, it is of great significance to study the molecular-biological mechanism of ITGB6, which could provide novel insights for future clinical diagnosis and therapy. This review introduces the structure, distribution, and biological function of ITGB6. This review also expounds on ITGB6-related diseases, detailing the known biological effects of ITGB6., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Phage libraries are now amongst the most prominent approaches for the identification of high-affinity antibodies/peptides from billions of displayed phages in a specific library through the biopanning process. Due to its ability to discover potential therapeutic candidates that bind specifically to targets, phage display has gained considerable attention in targeted therapy. Using this approach, peptides with high-affinity and specificity can be identified for potential therapeutic or diagnostic use. Furthermore, phage libraries can be used to rapidly screen and identify novel antibodies to develop immunotherapeutics. The Food and Drug Administration (FDA) has approved several phage display-derived peptides and antibodies for the treatment of different diseases. In the current review, we provided a comprehensive insight into the role of phage display-derived peptides and antibodies in the treatment of different diseases including cancers, infectious diseases and neurological disorders. We also explored the applications of phage display in targeted drug delivery, gene therapy, and CAR T-cell., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

At present, ulcerative colitis (UC) has become a global disease due to its high incidence. Hyperoside (HYP) is a naturally occurring flavonoid compound with many pharmacological effects. This study aimed to develop HYP-loaded mixed micelles (HYP-M) to improve oral bioavailability of HYP and to evaluate its therapeutic effect on UC. The prepared HYP-M exhibited stable physical and chemical properties, smaller particle size (PS) (21.48 ± 1.37 nm), good polydispersity index (PDI = 0.178 ± 0.013), negative Zeta potential (ZP) (- 20.00 ± 0.48 mV) and high entrapment rate (EE) (89.59 ± 2.03%). In vitro release and in vivo pharmacokinetic results showed that HYP-M significantly increased the releasing rate of HYP, wherein its oral bioavailability was 4.15 times higher than that of free HYP. In addition, HYP-M was more effective in the treatment of UC than free HYP. In conclusion, HYP-M could serve as a novel approach to improve bioavailability and increase anti-UC activity of HYP., (© 2023. Controlled Release Society.)

Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths. While polyp detection is important for diagnosing CRC, high miss rates for polyps have been reported during colonoscopy. Most deep learning methods extract features from images using convolutional neural networks (CNNs). In recent years, vision transformer (ViT) models have been employed for image processing and have been successful in image segmentation. It is possible to improve image processing by using transformer models that can extract spatial location information, and CNNs that are capable of aggregating local information. Despite this, recent research shows limited effectiveness in increasing data diversity and generalization accuracy. This paper investigates the generalization proficiency of polyp image segmentation based on transformer architecture and proposes a novel approach using two different ViT architectures. This allows the model to learn representations from different perspectives, which can then be combined to create a richer feature representation. Additionally, a more universal and comprehensive dataset has been derived from the datasets presented in the related research, which can be used for improving generalizations. We first evaluated the generalization of our proposed model using three distinct training-testing scenarios. Our experimental results demonstrate that our ColonGen-V1 outperforms other state-of-the-art methods in all scenarios. As a next step, we used the comprehensive dataset for improving the performance of the model against in- and out-of-domain data. The results show that our ColonGen-V2 outperforms state-of-the-art studies by 5.1%, 1.3%, and 1.1% in ETIS-Larib, Kvasir-Seg, and CVC-ColonDB datasets, respectively. The inclusive dataset and the model introduced in this paper are available to the public through this link: https://github.com/javadmozaffari/Polyp_segmentation ., (© 2024. Australasian College of Physical Scientists and Engineers in Medicine.)

The kidney is a highly complex organ equipped with a multitude of miniscule filter-tubule units called nephrons. Each nephron can be subdivided into multiple segments, each with its own morphology and physiological function. To date, conventional manual approaches to isolate specific nephron segments are very laborious, time-consuming, often limited to only a specific segment, and typically have low yield. Here, we describe a novel, unconventional method that is superior in many aspects to previous protocols by combining low-cost fluorophore-conjugated lectins or agglutinins (Flaggs) with flow sorting. This allows the simultaneous separation of different nephron segments with preserved 3D morphology from mouse or human samples in under 3 h. Using a 200-µm nozzle and 5 psi, glomeruli, proximal, or distal convoluted tubules are sorted with Cy3-labeled Sambucus Nigra agglutinin (SNA-Cy3), Fluorescein-labeled Lotus Tetragonolobus lectin (LTL-FITC), or Pacific Blue-labeled soybean agglutinin (SBA-PB), respectively. Connecting tubules and collecting ducts are sorted by double-positive SBA-PB and SNA-Cy3 signals, while thick ascending limb segments are characterized by the absence of any Flaggs labeling. From two mouse kidneys, this yields 37-521 ng protein/s or 0.71-16.71 ng RNA/s, depending on the specific nephron segment. The purity of sorted segments, as assessed by mRNA expression level profiling of 15 genes, is very high with a 96.1-fold median enrichment across all genes and sorted segments. In summary, our method represents a simple, straightforward, cost-effective, and widely applicable tool yielding high amounts of pure and morphologically largely intact renal tubule materials with the potential to propel nephron segment-specific research., (© 2023. The Author(s).)

The COP9 signalosome (CSN) is a conserved protein complex found in higher eukaryotes, consisting of eight subunits, and it plays a crucial role in regulating various processes of plant growth and development. Among these subunits, CSN2 is one of the most conserved components within the COP9 signalosome complex. Despite its prior identification in other species, its specific function in Oryza sativa L. (Rice) has remained poorly understood. In this study, we investigated the role of CSN2 in rice using gene editing CRISPR/Cas9 technology and overexpression techniques. We created two types of mutants: the oscsn2 mutant and the OsCSN2-OE mutant, both in the background of rice, and also generated point mutants of OsCSN2 (OsCSN2K64E, OsCSN2K67E, OsCSN2K71E and OsCSN2K104E) to further explore the regulatory function of OsCSN2. Phenotypic observation and gene expression analysis were conducted on plants from the generated mutants, tracking their growth from the seedling to the heading stages. The results showed that the loss and modification of OsCSN2 had limited effects on plant growth and development during the early stages of both the wild-type and mutant plants. However, as the plants grew to 60 days, significant differences emerged. The OsCSN2 point mutants exhibited increased tillering compared to the OsCSN2-OE mutant plants, which were already at the tillering stage. On the other hand, the OsCSN2 point mutant had already progressed to the heading and flowering stages, with the shorter plants. These results, along with functional predictions of the OsCSN2 protein, indicated that changes in the 64th, 67th, 71st, and 104th amino acids of OsCSN2 affected its ubiquitination site, influencing the ubiquitination function of CSN and consequently impacting the degradation of the DELLA protein SLR1. Taken together, it can be speculated that OsCSN2 plays a key role in GA and BR pathways by influencing the functional regulation of the transcription factor SLR1 in CSN, thereby affecting the growth and development of rice and the number of tillers., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Researchers have proposed culture- and religion-based variations in experience and expression of gratitude. Accordingly, the present study developed and validated a Hindu Gratitude Scale (HGS) based on Hindu notion of rnas. The rnas are sacred obligations (duties) that every Hindu is supposed to fulfil during their lifetime. These pious obligations are practised to acknowledge, honour, and appreciate others' contribution in one's life. These five holy duties are Pitṛ-yajna, Bhūta-yajna, Manuṣya-yajna, Deva-yajna, and Brahma-yajna. The study started with rnas-based conceptualisation of gratitude followed by item generation using both inductive and deductive approaches. These statements were subjected to content validity and pretesting, which resulted in nineteen items. The psychometric properties of proposed HGS (with nineteen items) were analysed with the help of three studies. The first study evaluated factorial validity of the proposed HGS using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) using a sample of 1032 respondents. Poor factor loading in EFA suggested removal of three statements. The EFA recommended five dimensions of the HGS-appreciation for family, ancestors, and cultural values (AFF), appreciation for family, ancestors, and cultural values (AFF), appreciation for God, appreciation for knowledge, skills, and talents, and appreciation for ecosystem. Further, CFA also suggested removal of one statement. Lastly, the EFA and CFA result suggested adequate factorial validity of a fifteen-itemed five-factored HGS. The second study examined the reliability and validity of the HGS derived from CFA with the help of a sample of 644 participants. And, in the third study, the test-retest reliability was investigated by collecting the data twice. The results revealed significant positive correlations in two sets of data, thereby concluding test-retest reliability of the HGS. The study offered a novel fifteen-item Hindu Gratitude Scale, which could be used in future studies to explore gratitude level of Hindus., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The intricate neural circuit of retina extracts salient features of the natural world and forms bioelectric impulse as the origin of vision. The early development of retina is a highly complex and coordinated process in morphogenesis and neurogenesis. Increasing evidence indicates that stem cells derived human retinal organoids (hROs) in vitro faithfully recapitulates the embryonic developmental process of human retina no matter in the transcriptome, cellular biology and histomorphology. The emergence of hROs greatly deepens on the understanding of early development of human retina. Here, we reviewed the events of early retinal development both in animal embryos and hROs studies, which mainly comprises the formation of optic vesicle and optic cup shape, differentiation of retinal ganglion cells (RGCs), photoreceptor cells (PRs) and its supportive retinal pigment epithelium cells (RPE). We also discussed the classic and frontier molecular pathways up to date to decipher the underlying mechanisms of early development of human retina and hROs. Finally, we summarized the application prospect, challenges and cutting-edge techniques of hROs for uncovering the principles and mechanisms of retinal development and related developmental disorder. hROs is a priori selection for studying human retinal development and function and may be a fundamental tool for unlocking the unknown insight into retinal development and disease., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Ceramide synthases (CERSes) are also known longevity assurance (LASS) genes. CERSes play important roles in the regulation of cancer progression. The CERS family is expressed in a variety of human tumours and is involved in tumorigenesis. They are closely associated with the progression of liver, breast, cervical, ovarian, colorectal, head and neck squamous cell, gastric, lung, prostate, oesophageal, pancreatic and blood cancers. CERSes play diverse and important roles in the regulation of cell survival, proliferation, apoptosis, migration, invasion, and drug resistance. The differential expression of CERSes in tumour and nontumour cells and survival analysis of cancer patients suggest that some CERSes could be used as potential prognostic markers. They are also important potential targets for cancer therapy., Methods: In this review, we summarize the available evidence on the inhibitory or promotive roles of CERSes in the progression of many cancers. Furthermore, we summarize the identified upstream and downstream molecular mechanisms that may regulate the function of CERSes in cancer settings., (© 2023. Springer Nature Switzerland AG.)

Potassium ion (K + ) plays an important role in the maintenance of cellular biological process for human health. Thus, the detection of K + is very important. Here, based on the interaction between thiamonomethinecyanine dye and G-quadruplex formation sequence (PW17), K + detection spectrum was characterized by UV-Vis spectrometry. The single-stranded sequence of PW17 can fold into G-quadruplex in the presence of K + . PW17 can induce a dimer-to-monomer transition of the absorption spectrum of cyanine dyes. This method shows high specificity against some other alkali cations, even at high concentrations of Na + . Further, this detection strategy can realize the detection of K + in tap water., (© 2023. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)

Autism spectrum disorder (ASD) is a heterogeneous group of early-onset neurodevelopmental disorders known to be highly heritable with a complex genetic architecture. Abnormal brain developmental trajectories that impact synaptic functioning, excitation-inhibition balance and brain connectivity are now understood to play a central role in ASD. Ongoing efforts to identify the genetic underpinnings still prove challenging, in part due to phenotypic and genetic heterogeneity.This review focuses on parent-of-origin effects (POEs), where the phenotypic effect of an allele depends on its parental origin. POEs include genomic imprinting, transgenerational effects, mitochondrial DNA, sex chromosomes and mutational transmission bias. The motivation for investigating these mechanisms in ASD has been driven by their known impacts on early brain development and brain functioning, in particular for the most well-documented POE, genomic imprinting. Moreover, imprinting is implicated in syndromes such as Angelman and Prader-Willi, which frequently share comorbid symptoms with ASD. In addition to other regions in the genome, this comprehensive review highlights the 15q11-q13 and 7q chromosomal regions as well as the mitochondrial DNA as harbouring the majority of currently identified POEs in ASD., (© 2023. The Author(s).)

Antibiotic residues in aquatic environments pose a potential hazard, and microbes, which play important roles in aquatic ecosystems, are vulnerable to the impacts of antibiotics. This study aimed to analyze the research progress, trends, and hot topics of the impact of antibiotics on microbial community and biodegradation mechanism using bibliometric analysis. An in-depth analysis of the publication characteristics of 6143 articles published between 1990 and 2021 revealed that the number of articles published increased exponentially. The research sites have been mainly concentrated in the Yamuna River, Pearl River, Lake Taihu, Lake Michigan, Danjiangkou Reservoir, etc., illustrating that research around the world is not even. Antibiotics could change the diversity, structure, and ecological functions of bacterial communities, stimulate a widespread abundance of antibiotic-resistant bacteria and antibiotic-resistant genes, and increase the diversity of eukaryotes, thus triggering the shift of food web structure to predatory and pathogenic. Latent Dirichlet allocation theme model analysis showed three clusters, and the research hotspots mainly included the effect of antibiotics on the denitrification process, microplastics combined with antibiotics, and methods for removing antibiotics. Furthermore, the mechanisms of microbe-mediated antibiotic degradation were unraveled, and importantly, we provided bottlenecks and future research perspectives on antibiotics and microbial diversity research., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Key Message: Our findings indicated that the SlERF.J2-IAA23 module integrates hormonal signals to regulate hypocotyl elongation and plant height in tomato. Light and phytohormones can synergistically regulate photomorphogenesis-related hypocotyl elongation and plant height in tomato. AP2/ERF family genes have been extensively demonstrated to play a role in light signaling and various hormones. In this study, we identified a novel AP2/ERF family gene in tomato, SlERF.J2. Overexpression of SlERF.J2 inhibits hypocotyl elongation and plant height. However, the plant height in the slerf.j2 ko knockout mutant was not significantly changed compared with the WT. we found that hypocotyl cell elongation and plant height were regulated by a network involving light, auxin and gibberellin signaling, which is mediated by regulatory relationship between SlERF.J2 and IAA23. SlERF.J2 protein could bind to IAA23 promoter and inhibit its expression. In addition, light-dark alternation can activate the transcription of SlERF.J2 and promote the function of SlERF.J2 in photomorphogenesis. Our findings indicated that the SlERF.J2-IAA23 module integrates hormonal signals to regulate hypocotyl elongation and plant height in tomato., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Biochar is widely used in agriculture to efficiently solve the problem of sludge. In this study, sludge-based biochar (referred to as BC1, BC2, and BC3) was prepared by mixing sludge with FeCl 3 , Na 2 SiO 3 , and Ca (H 2 PO 4 ) 2 , respectively. Then, it was mixed with fresh soil to plant Brassica chinensis L. The analysis of the effects of the three biochar types showed that all of them were beneficial to the growth of Brassica chinensis L. We added the biochar to the soil and found that the concentration of heavy metals did not exceed the recommended threshold. Additionally, the aboveground part of Brassica chinensis L. met the standard requirement for food safety (GB 2761-2017). Notably, BC3 stood out with the best effect on the growth of Brassica chinensis L. and resulted in the improvement of the physical and chemical properties of soil such as ammonium nitrogen, available phosphorus, and available potassium (BC3 was followed by BC2 and BC1). BC3 could efficiently inhibit the migration of heavy metals, thereby reducing the overall heavy metal pollution level and ameliorating the soil nutrients. BC3 could increase the organic carbon by 258.92%, available phosphorus by 234.45%, and available potassium by 37.12% compared with the CK group. The THQ and TTHQ estimates of Brassica chinensis L. were lower than one, indicating that the health risk of heavy metal intake was not prominent. Additionally, the application of the proposed biochar could reduce the form of F1 (acid extracted state) and increase the form of F4 (residue state) in soil. Overall, we conclude that the application of the proposed biochar can promote the root absorption of heavy metals and inhibit the migration of heavy metals., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

As the labeling cost of object detection for medical images is very high, semi-supervised learning methods for medical images are investigated. In this paper, semi-supervised fine-grained object detection framework with transformer module (SFOD-Trans) is proposed for hepatic portal vein detection. It adopts Sparse R-CNN as the backbone. In detection model, the transformer module is introduced and contrastive loss is added to improve the performance of fine-grained object detection. In order to complete the information transfer both of labeled and unlabeled pictures, a new fusion module named normalized ROI fusion (NRF) is designed based on the characteristics of hepatic portal vein. We run a large number of experiments on a dataset of 1000 real CT scans. The results show that Average Precision (AP) and Average Recall (AR) of the proposed method reach 0.773 and 0.831 respectively with the 300 labeled and 1500 unlabeled samples. An overview of semi-supervised fine-grained object detection framework with transformer module (SFOD-Trans). There are two parallel branches to train supervised loss and semi-supervised loss respectively., (© 2022. International Federation for Medical and Biological Engineering.)

Alzheimer's disease (AD) is an aging-related neurodegenerative disorder. It is characterized clinically by progressive memory loss and impaired cognitive function. Its progression occurs from neuronal synapse loss to amyloid pathology and Tau deposit which eventually leads to the compromised neuronal function. Neurons in central nervous tissue work in a composite and intricate network with the glia and vascular cells. Microglia and astrocytes are becoming the prime focus due to their involvement in various aspects of neurophysiology, such as trophic support to neurons, synaptic modulation, and brain surveillance. AD is also often considered as the sequela of prolonged metabolic dyshomeostasis. The neuron and glia have different metabolic profiles as cytosolic glycolysis and mitochondrial-dependent oxidative phosphorylation (OXPHOS), especially under dyshomeostasis or with aging pertaining to their unique genetic built-up. Various efforts are being put in to decipher the role of mitochondrial dynamics regarding their trafficking, fission/fusion imbalance, and mitophagy spanning over both neurons and glia to improve aging-related brain health. The mitochondrial dysfunction may lead to activation in various signaling mechanisms causing metabolic reprogramming in glia cells, further accelerating AD-related pathogenic events. The glycolytic-dominant astrocytes switch to the neurotoxic phenotype, i.e., disease-associated astrocyte under metabolic stress. The microglia also transform from resting to reactive phenotype, i.e., disease-associated microglia. It may also exist in otherwise a misconception an M1, glycolytic, or M2, an OXPHOS-dependent phenotype. Further, glial transformation plays a vital role in regulating hallmarks of AD pathologies like synapse maintenance, amyloid, and Tau clearance. In this updated review, we have tried to emphasize the metabolic regulation of glial reactivity, mitochondrial quality control mechanisms, and their neuroinflammatory response in Alzheimer's progression., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The antagonistic pleiotropy hypothesis is a well-known evolutionary theory to explain the aging process. It proposes that while a particular gene may possess beneficial effects during development, it can exert deleterious properties in the aging process. The aryl hydrocarbon receptor (AhR) has a significant role during embryogenesis, but later in life, it promotes several age-related degenerative processes. For instance, AhR factor (i) controls the pluripotency of stem cells and the stemness of cancer stem cells, (ii) it enhances the differentiation of embryonal stem cells, especially AhR signaling modulates the differentiation of hematopoietic stem cells and progenitor cells, (iii) it also stimulates the differentiation of immunosuppressive Tregs, Bregs, and M2 macrophages, and finally, (iv) AhR signaling participates in the differentiation of many peripheral tissues. On the other hand, AhR signaling is involved in many processes promoting cellular senescence and pathological processes, e.g., osteoporosis, vascular dysfunction, and the age-related remodeling of the immune system. Moreover, it inhibits autophagy and aggravates extracellular matrix degeneration. AhR signaling also stimulates oxidative stress, promotes excessive sphingolipid synthesis, and disturbs energy metabolism by catabolizing NAD + degradation. The antagonistic pleiotropy of AhR signaling is based on the complex and diverse connections with major signaling pathways in a context-dependent manner. The major regulatory steps include, (i) a specific ligand-dependent activation, (ii) modulation of both genetic and non-genetic responses, (iii) a competition and crosstalk with several transcription factors, such as ARNT, HIF-1α, E2F1, and NF-κB, and (iv) the epigenetic regulation of target genes with binding partners. Thus, not only mTOR signaling but also the AhR factor demonstrates antagonistic pleiotropy in the regulation of the aging process., (© 2022. The Author(s).)

N6-methyladenosine (m 6 A) methylation is the most prevalent and abundant internal modification of mRNAs and is catalyzed by the methyltransferase complex. Methyltransferase-like 3 (METTL3), the best-known m 6 A methyltransferase, has been confirmed to function as a multifunctional regulator in the reversible epitranscriptome modulation of m 6 A modification according to follow-up studies. Accumulating evidence in recent years has shown that METTL3 can regulate a variety of functional genes, that aberrant expression of METTL3 is usually associated with many pathological conditions, and that its expression regulatory mechanism is related mainly to its methyltransferase activity or mRNA posttranslational modification. In this review, we discuss the regulatory functions of METTL3 in various diseases, including metabolic diseases, cardiovascular diseases, and cancer. We focus mainly on recent progress in identifying the downstream target genes of METTL3 and its underlying molecular mechanisms and regulators in the above systems. Studies have revealed that the use of METTL3 as a therapeutic target and a new diagnostic biomarker has broad prospects. We hope that this review can serve as a reference for further studies., Competing Interests: Declarations. Conflicts of Interest: The authors declare no competing interests. Ethical approval: Not applicable. Consent to participate: Not applicable. Consent for publication: Not applicable., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Valsartan (VST) is an angiotensin II receptor antagonist with low oral bioavailability. The present study developed a solid self-nanoemulsifying drug delivery system (S-SNEDDS) to enhance the oral absorption and bioavailability of VST. VST-loaded liquid SNEDDS (VST@L-SNEDDS) was prepared by investigating the solubility of VST and constructing the pseudo-ternary phase diagrams. The formulation of VST@S-SNEDDS was obtained by adsorbing VST@L-SNEDDS onto a solid carrier. In vitro studies including drug dissolution, stability, cytotoxicity, and Caco-2 uptake of VST@S-SNEDDS were assessed. An in vivo pharmacokinetic study of VST@S-SNEDDS was employed to evaluate the oral bioavailability of VST. VST@L-SNEDDS, with an average particle size of 19.90 nm and zeta potential of -20.57 mV, consisted of 12.37% VST (drug loading), 21.91% ethyl oleate, 45.50% RH 40, and 20.22% Transcutol HP. VST@S-SNEDDS was prepared using Neusilin® UFL2 as a solid adsorbent, which contained VST@L-SNEDDS at 2.28 ± 0.15 g/g. The in vitro release study demonstrated that VST@S-SNEDDS exhibited rapid release characteristic without affecting by the pH of the media, and dissolution rates exceeded 90% within 60 min in different media. The long-term stability of VST@S-SNEDDS was better than that of VST@L-SNEDDS. These two formulations increased the Caco-2 uptake significantly. The area under the drug concentration-time curve (AUC 0-24h ) and peak drug concentration in plasma (C max ) of VST@S-SNEDDS increased by 2.28-fold and 4.86-fold compared to raw VST, respectively. The proposed VST@S-SNEDDS represents a novel approach to enhance the oral absorption and bioavailability of VST, providing a promising avenue for hypertension treatment., Competing Interests: Declarations. Conflict of Interest: The authors report no declarations of interest., (© 2025. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Key Message: QTL mapping of two RIL populations in multiple environments revealed a consistent QTL for bristle length, and combined with RNA-seq, a potential candidate gene influencing bristle length was identified. Foxtail millet bristles play a vital role in increasing yields and preventing bird damage. However, there is currently limited research on the molecular regulatory mechanisms underlying foxtail millet bristle formation, which constrains the genetic improvement and breeding of new foxtail millet varieties. This study leveraged genetic linkage maps from two populations: the published RYRIL population (Hongjiugu × Yugu 18) with 1420 bins and the newly established YYRIL population (Huangruangu × Yugu 18) with 542 bins. We identified 17 QTLs associated with bristle length, explaining 1.76-47.37% of the phenotypic variation. Among these, 6 were multi-environment QTLs, and 11 were environment-specific QTLs. Notably, qBL-1-1 and qBL-3-2 were detected in both populations, and exhibited epistasis interactions. By analyzing genotypic data from the RYRIL population and its parents, we identified two lines with significant variation in bristle length at the qBL-1-1 locus, designated CM3 (short) and CM4 (long). RNA-seq during the flowering phase identified 1812 differentially expressed genes (DEGs). Thirty-three DEGs were identified within 6 multi-environment QTL regions, and the RNA-seq results were validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Within the qBL-1-1 region, Seita.1G325800 is predicted to be a key candidate gene controlling foxtail millet bristle length. These findings provide preliminary insights into the genetic basis of bristle development and lay a foundation for the genetic improvement of foxtail millet bristle length., Competing Interests: Declarations. Conflict of interest: The authors declare no conflicts of interest. Consent to participate: Not applicable. Consent for publication: Not applicable. Ethical approval: Not applicable., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Eclipta prostrata belongs to the Asteraceae family. The plant contains bioactive compounds like wedelolactone (WDL) and demethylwedelolactone (DW). Its transcriptomic information engaged with secondary metabolite biosynthesis is not available. Based on differential accumulation of WDL and DW in root, shoot of the mature plant, we performed comparative de novo transcriptome of root and shoot tissue in three independent biological replicates and generated 49820 unique transcripts. Annotation resulted in significant matches for 43,015 unigenes. Based on differential gene expression data, we found WDL biosynthesis-related transcripts, which were mainly upregulated in shoot. Finally, 13 selected differentially expressed transcripts related to WDL biosynthesis that were validated by qRT-PCR. Detailed tissue-specific metabolite and transcript profiling revealed that DW highly accumulated in root and WDL accumulation was high in aerial part along with transcripts. For WDL pathway exploration, we did integrated profiling of 08 metabolites and 13 transcripts and witnessed that only naringenin, apigenin, DW, and WDL were detected in different developmental stages. Taking leads from the findings, we postulated that naringenin to apigenin pathway is one potential route for WDL biosynthesis. Moreover, wound stress led to accumulation of DW and WDL and related biosynthetic transcripts. Furthermore, the selected enzymes were subjected to molecular docking and binding studies for the predicted substrates involved in crucial and advance steps of WDL biosynthesis. A comprehensive analysis integrating de novo transcriptomics, metabolomics, and molecular docking of targeted proteins paves the way for the elucidation of the putative wedelolactone biosynthesis pathway from E. prostrata., Competing Interests: Declarations. Competing of interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Initial periods of life, beginning before birth and lasting until weaning are characterised by the greatest neural plasticity. Early postnatal stress causes lasting changes in a variety of behaviours as well as stress reactivity. Cow-calf contact for an extended period is believed to improve the social skills of calves and has also been linked to improved productivity of mothers. This research was carried out to investigate the impact of weaning stress on the growth, behaviour and performance of Sahiwal cows and their calves. For this, 32 healthy cows and their calves were selected from the Sahiwal herd of the Livestock Research Centre, ICAR-National Dairy Research Institute. They were grouped equally into two groups of 16 cow-calf pairs, which became the treatment groups (i.e., 'Fenceline' contact and 'Separated' groups). Calves in the fenceline contact group were allowed to suckle during the morning and evening milking and were housed together with fenceline separation. In the separated group, calves were separated from their mothers immediately after birth and fed colostrum and milk with a bottle throughout the experiment. Each calf was monitored for its growth and behavioural responses while cows were monitored for their production performance and behaviour. The results showed that growth and behaviour responses were better for fenceline calves compared to separated calves and also production performance and behaviour of Sahiwal cows provided with fenceline contact were better when compared to separated cows. From this study, it was concluded that fenceline cow-calf contact improved growth, behavioural response of calves; and production performance and behaviour of cows compared to separated cows and calves., Competing Interests: Declarations. Ethics approval: The experiment was approved and conducted under the established rules of the Institutional animal ethics committee (IAEC), constituted as per form no. 13 of the committee for the purpose of control and supervision of experiments on animals (CPCSEA) rules laid down by the government authority. Consent to participate: All the authors were aware regarding participation and publications. Consent for publication: All the authors were aware regarding participation and publications. Conflict of interest: There is no conflict of interest among authors., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

Investigating the effects of urbanization at the county level on the balance of the carbon budget is essential for progress toward achieving "dual carbon" objectives at the county scale. Based on land use and economic data, this study elucidates the spatiotemporal evolution of urbanization and carbon budget balance ratio in 84 counties in Jiangxi Province from 1980 to 2020. Optimal geographic detectors and geographically weighted random forests were used to explore the impact of urbanization on the carbon budget balance ratio. The results indicate that (1) after 2000, the net carbon emissions of Jiangxi Province increased rapidly from - 0.54 × 10 6 to 217.99 × 10 6 tonnes, with the overall carbon sink area transitioning into a carbon source area; (2) the average carbon budget balance ratio of the counties decreased from 5.45 in 1980 to 0.49 in 2020, and the number of regions with a moderate or higher carbon deficit increased from 8 to 59, primarily concentrated in the Poyang Lake urban agglomeration. Carbon surplus areas decreased from a majority of counties to only 10, now concentrated in less developed areas. (3) The 4 km grid is the optimal spatial scale, and the patch cohesion index, night light index, population density, and civilian vehicle ownership are the main factors affecting the carbon budget balance ratio across different dimensions of urbanization. (4) In terms of spatial relationships, influenced by different stages of urbanization and policy interventions, the nonlinear impact of key urbanization factors across various dimensions on the carbon budget balance ratio is significantly greater than that of the linear model. The effect of the same variable on the carbon budget balance ratio shows significant differences across counties. Therefore, it is essential to comprehensively consider the diverse impacts of urbanization on the carbon budget balance when formulating policies aimed at "carbon reduction and increase.", Competing Interests: Declarations. Ethical approval: All authors have read, understood, and have complied as applicable with the statement on “Ethical responsibilities of Authors” as found in the Instructions for Authors. Consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Extracellular vesicles (EVs) are heterogeneously sized, cell-derived nanoparticles operating as proficient mediators of intercellular communication. They are produced by normal as well as diseased cells and carry a variety of cargo. While the molecular details of EV biology have been worked out over the past two decades, one question that continues to intrigue many is how are EVs able to evade the phagocytic immune cells while also being effectively internalized by the target cell or tissue. While some of the components that facilitate this process have started to be identified, many mechanisms are yet to be dissected. This review summarises some of the key mechanisms that cancer cell-derived and viral infected cell-derived EVs utilize to evade the immune system. It will discuss the diverse cloaking mechanisms, in the form of membrane proteins and cargo content that these EVs utilize to enhance pathogenesis. Further, it will highlight the different strategies that have been used to design EVs to escape the immune system, thereby increasing their circulation time with no major toxic effects in vivo. An understanding of the potential EV components that allow better immune evasion can be used to bioengineer EVs with better circulation times for therapeutic purposes., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: All authors have approved the final manuscript. Competing interests: The authors declare no competing interests., (© 2025. Controlled Release Society.)

Synaptic plasticity is the basis for the proper functioning of the central nervous system. Synapses are the contact points between neurons and are crucial for information transmission, the structure and function of synapses change adaptively based on the different activities of neurons, thus affecting processes such as learning, memory, and neural development and repair. Synaptic activity requires a large amount of energy provided by mitochondria. Mitochondrial transport proteins regulate the positioning and movement of mitochondria to maintain normal energy metabolism. Recent studies have shown a close relationship between mitochondrial transport proteins and synaptic plasticity, providing a new direction for the study of adaptive changes in the central nervous system and new targets for the treatment of neurodegenerative diseases., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite years of progress in biotechnology, altering the genetic makeup of many plant species, especially their plastids, remains challenging. The existence of a cell wall poses a significant obstacle to the effectual transportation of biomolecules. Developing efficient methods to introduce genes into plant cells and organelles without causing harm is an ongoing area of research. Traditional approaches like Agrobacterium-mediated transformation, biolistic particle delivery, electroporation and polyethylene glycol (PEG) transformation have shown some success but come with limitations like laborious, time-consuming and causing tissue damage. For instance, the Agrobacterium method can be applied only to the restricted host range, while PEG transformation and biolistic particle delivery are not very efficient. In contrast, nanotechnology made an appearance in the field of genetic engineering. Nanoparticles act as delivery vehicles for many cargos in animals. However, in plants, the application of nanocarriers for the delivery of biomolecules is still in its infant stage. Nonetheless, it holds immense potential for the future of plant biotechnology and genome editing., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Opioids are the primary regimens for perioperative analgesia with controversial effects on oncological survival. The underlying mechanism remains unexplored. This study developed survival-related gene co-expression networks based on RNA-seq and clinical characteristics from TCGA cohort. Two survival-related networks were identified, and drug-induced transcriptional profiles were predicted. Immune cell infiltration algorithm, least absolute shrinkage and selection operator (LASSO) regression, and cox proportional models were executed to explore the correlation between opioid-related drugs and prostate cancer patient prognosis. The opioid receptor agonists, represented by tramadol, were evidenced for anti-survival effects on prostate cancer by facilitating the DNA replication and cell cycle, and immune cell infiltration. Conversely, opioid receptor antagonists showed pro-survival effects. A novel prognostic model containing CNIH2, MCCC1, and Gleason scores was established and validated in two independent cohorts. This study revealed opioids' effect on prostate cancer progression, and provided a novel model to predict these regulations in clinical outcomes., Competing Interests: Declarations. Conflict of interests: There is no competing interest to declare., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Different techniques have been proposed to reduce the incidence of the intraoperative bile duct injury during laparoscopic cholecystectomy (LC). Among these, Near-Infrared Fluorescence Cholangiography (NIFC) with Indocyanine Green (ICG) represents a relatively recent addition. At present, there is considerable variation in the protocols for the administration of ICG., Methods: The aim of this randomized multicenter clinical trial (RCT) is to ascertain whether there are differences between the dosage and administration intervals of ICG, with a view to optimizing a good-quality NIFC during LC. Furthermore, an analysis was conducted to determine the potential impact of different factors on the outcomes of this technique. The trial was approved by the local institutional Ethics Committee., Results: From June 2022 to June 2023, 200 patients were randomized in four arms (G1: 2.5 mg ICG > 3 h prior to surgery, G2: 2.5 mg ICG 15-30 min prior to surgery, G3: 0.05 mg/kg ICG > 3 h prior to surgery and G4: 0.05 mg/kg ICG 15-30 min prior to surgery). We found differences in the DISTURBED score between the groups (p < 0.001), suggesting that ICG administration 15-30 min before surgery was worse than administration > 3 h after LC (p = 0.02). Additionally, it was observed that body mass index (BMI), gender, ASA Classification System, previous liver and biliary disease and the type of surgery had influence on NIFC. Finally, the NIFC had an impact in intraoperative and postoperative complications, operative time and hospital length of stay., Conclusions: The administration of ICG > 3 h improve liver background fluorescence in the NIFC during LC. There are different factors may affect NIFC results (BMI, ASA grade, previous liver disease, presence of gallbladder inflammation and type of surgery). Finally, high-quality NIFC was associated with fewer surgical complications, shorter surgical time and shorter length of hospital stay., Competing Interests: Declarations. Disclosures: Authors Jaime López-Sánchez, Sonsoles Garrosa-Muñoz, Fernando Pardo Aranda, Alba Zarate, Ricardo López Pérez, Patricia Rodríguez Fortúnez, José Manuel Sánchez Santos, Carmen Esteban, José E. Quiñones, Manuel J. Iglesias, Luis M. González Fernández, Jacobo Trébol, Ana B. Sánchez-Casado, A. García-Plaza, J.I. González-Muñoz, Omar Abdel-Lah, Clara Genè Škrabec, Manel Cremades, Francisco Espín, Jordi Navinés, Laura Vidal, Ana Piqueras, Sara Senti, Christian Herrero, Esteban Cugat, Luis Muñoz-Bellvís and Francisco Blanco-Antona have no related conflicts of interest or financial ties to disclose., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Galactosemia is a rare inborn error of galactose metabolism. There are several forms, the most severe being classic galactosemia (CG), which begins in the first few days of life. Nowadays, it is possible to screen CG at birth, averting acute decompensation or death through diet. Although early dietary interventions help manage acute symptoms, long-term complications still occur, particularly primary ovarian insufficiency (POI) in female patients. This systematic review aims to synthesize existing literature on the relationship between galactosemia and POI, exploring the underlying mechanisms of pathophysiology, hormonal balance, metabolic control, fertility, and management., Methods: We performed a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses and PROSPERO. We queried the SCOPUS and PubMed databases using individual keywords and MeSH terms., Results: Despite various proposed mechanisms, such as FSH dysfunction and the accumulation of galactose-1-phosphate, the exact cause of POI remains unclear, with studies showing variable correlations between genotype, galactose levels, and ovarian function. Monitoring AMH in prepubertal galactosemia patients may predict POI. Early estrogen replacement therapy, calcium supplementation, and strategies to improve galactosylation should be considered to enhance bone mineralization, given the impact of hypogonadism and low calcium intake on bone density in these patients. The course of POI in women with CG is unpredictable, with recent studies showing that nearly 30% of those attempting to conceive succeeded within a year, a rate that increases to almost 50% after two years., Conclusion: Despite advancements in understanding and managing CG, POI remains a significant clinical challenge, necessitating ongoing research and a multidisciplinary approach to enhance the long-term health of affected individuals., Competing Interests: Declarations. Financial: The authors have no financial or proprietary interest in any material discussed in this article. Non-financial interests: None., (© 2025. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Large-scale, pan-cancer analysis is enabled by data driven knowledge bases that link tumor molecular profiles with phenotypes. A debilitating cancer-related phenotype is skeletal muscle loss, or cachexia, which occurs partly from tumor products secreted into circulation. Using the LinkedOmicsKB knowledge base assembled from the Clinical Proteomics Tumor Analysis Consortium proteogenomic analysis, along with catalogs of human secretome proteins, ligand-receptor pairs and molecular signatures, we sought to identify candidate pan-cancer proteins secreted to blood that could regulate skeletal muscle phenotypes in multiple solid cancers. Tumor proteins having significant pan-cancer associations with muscle were referenced against secretome proteins secreted to blood from the Human Protein Atlas, then verified as increased in paired tumor vs. normal tissues in pan-cancer manner. This workflow revealed seven secreted proteins from cancers afflicting kidneys, head and neck, lungs and pancreas that classified as protein-binding activity modulator, extracellular matrix protein or intercellular signaling molecule. Concordance of these biomarkers with validated molecular signatures of cachexia and senescence supported relevance to muscle and cachexia disease biology, and high tumor expression of the biomarker set associated with lower overall survival. In this article, we discuss avenues by which skeletal muscle and cachexia may be regulated by these candidate pan-cancer proteins secreted to blood, and conceptualize a strategy that considers them collectively as a biomarker signature with potential for refinement by data analytics and radiogenomics for predictive testing of future risk in a non-invasive, blood-based panel amenable to broad uptake and early management., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Microplastics (MPs) are fragments with a diameter of less than 5 mm that have been directly manufactured or formed by the degradation of plastic waste. MPs are not only prone to bioaccumulation in the environment, but they also lead to the spread of micropollutants in the environment, thereby threatening human health ecological environment. The useful detection method of MPs and understanding their abundance, characteristics and toxicity are great essential for MPs removal and control. This work presented the current methods of MPs' detection, compared the abundance and characteristics of MPs in water, and reviewed MPs' toxicity to organisms. Furthermore, detailed policies intervention for plastics and MPs' mitigation have been focused which delineate for application of science and policy together with scientific evidence. Lastly, this study suggests more attention should be paid to the content of MPs in freshwater and organisms closely related to human life, as well as the toxicological toxicity of MPs in mammals., Competing Interests: Declarations. Ethical responsibilities of authors: All authors have read, understood, and have complied as applicable with the statement on “Ethical responsibilities of Authors” as found in the Instructions for Authors. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Context: Riboflavin (RF), also known as B2 vitamin, is the precursor to flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), two co-enzymes involved in many electron transport processes. Interactions of the isoalloxazine ring, common to all three compounds, are of great interest due to their biological function in flavoproteins and relevance in the transport by the carrier protein leading to development of drug delivery strategies and non-invasive diagnostics techniques. Based on protein crystallographic data, a computational investigation of the interactions in the complexes between lumiflavin, a model compound, and aromatic amino acids, tyrosine and tryptophan, was pursued with the goal of characterizing noncovalent interactions. Density functional theory (DFT) served as the computation framework for all calculations, utilizing long-range corrected hybrid functionals LC-ωPBE and ωB97XD in conjunction with the 6-311+ +g** basis set. The solvation effects were incorporated through the implementation of the polarizable continuum model (PCM) simulating an aqueous solvent environment. The geometries of the five most stable complexes show exclusively p-p interactions among the aromatic moieties in a displaced parallel plane stacking arrangement with interplanar heights and displacements in the range of 3.22-3.62 Å and 0.50-0.63 Å, respectively, at ωB97XD level. The calculated total energies and binding energies indicate two stabilizing p-p interactions: lumiflavin-tyrosine and lumiflavin-tryptophan, with the later stronger for the more stable complexes by 2 kcal mol -1 . The complexes are less entropically favored than the independent molecules as verified by the positive association free Gibbs energies with LC-ωPBE and nearly zero with ωB97XD. Orbital analysis indicates a smaller HOMO-LUMO gap for complexes compared to the individual compounds suggesting a charge transfer component to the interaction. Moreover, the HOMO is localized on tryptophan and HOMO-1 on tyrosine, consistent with the strength of the respective interactions with lumiflavin., Methods: The initial geometry was based on the atom coordinates of the bonding tryptophan-riboflavin-tyrosine region in the protein crystallographic data with the ribityl tail being discarded, leading to a model complex: tryptophan-lumiflavin-tyrosine. The initial conformational search using the Amber force field within the Gabedit led to 30 unique conformations. The subsequent calculations, energy optimization and orbital analysis, were performed in Guassian16 at density functional theory (DFT) level, utilizing long-range corrected hybrid functionals LC-ωPBE and ωB97XD in conjunction with the 6-311+ +g** basis set. The solvent, water, was accounted for using the polarized continuum model (PCM)., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Traumatic brain injury (TBI) is characterized as a heterogeneous and pathological remodeling of brain physiology because of various external mechanisms, including blows, falls, and rapid acceleration and deceleration of the skull. Its pathophysiology consists of two distinct moments, beginning with a primary lesion resulting from the impact that evolves into a secondary lesion as biochemical and molecular mechanisms are activated. The severity and prognosis after TBI vary widely, depending on factors such as the site of the injury, the patient's premorbid history, and the severity of the injury, and can result in long-term sequelae impacting multiple organs and systems, with a reduction in the life expectancy of these individuals. A relevant point to be investigated is the correlation between metabolic syndrome (MS), defined as the combination of glucose intolerance, dyslipidemia, systemic arterial hypertension (SAH), and acute or chronic coronary heart disease, and the prognosis of these individuals after a TBI. Therefore, this review seeks to verify the correlation between the occurrence of MS in patients who have suffered TBI as a pre-existing comorbidity and whether it develops later, looking for evidence in studies based on animal models and cohort follow-ups of individuals who have suffered TBI in the short and long term to assess the prognosis presented., Competing Interests: Declarations. Ethics approval: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Recent research has proven that peripheral (PS) and central sensitization (CS), mental health, and myofascial dysfunction all play a role, alongside nociception, in the genesis and in the perpetuation of endometriosis' symptoms. However, such components of pain are still largely ignored in clinical practice, although not considering such contributors may entail serious consequences on women's health, including the choice of unnecessary surgery and leaving the real causes of pain untreated. At the present time, we are facing a paradox by which 25-40% of women who undergo laparoscopic surgery for pelvic pain do not have an obvious diagnosis, while the percentage of women with endometriosis who have signs of CS, of depressive or anxiety disorders, or who have an increased pelvic muscle tone ammounts to 41-55%, 15-88% and 28-73%, respectively. Moving from the widely-accepted stepwise approach suggested for endometriosis management, which consists in the initial prescription of low-dose combined oral contraceptives (COCs) or of a progestin monotherapy, followed by GnRH analogues and, ultimately, by surgery, when COCs and progestins have proven ineffective or are not tolerated or contraindicated, we propose an integration of such model which takes into account the identification and the simultaneous treatment of all pain contributors. Our objective is to encourage physicians' awareness of the need of a multidisciplinary, multimodal approach to endometriosis-related pain, and ultimately to promote a reduction in the number of unnecessary surgeries., Competing Interests: Declarations. Ethical Approval: Not applicable. Informed Consent: Not applicable. Conflict of Interest: None., (© 2025. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Alzheimer's disease (AD) consists of two main pathologies, which are the deposition of amyloid plaque as well as tau protein aggregation. Evidence suggests that not everyone who carries the AD-causing genes displays AD-related symptoms; they might never acquire AD as well. These individuals are referred to as non-demented individuals with AD neuropathology (NDAN). Despite the presence of extensive AD pathology in their brain, it was found that NDAN had better cognitive function than was expected, suggesting that they were more resilient (better at coping) to AD due to differences in their brains compared to other demented or cognitively impaired patients. Thus, identification of the mechanisms underlying resilience is crucial since it represents a promising therapeutic strategy for AD. In this review, we will explore the molecular mechanisms underpinning the role of genetic and molecular resilience factors in improving resilience to AD. These include protective genes and proteins such as APOE2, BDNF, RAB10, actin network proteins, scaffolding proteins, and the basal forebrain cholinergic system. A thorough understanding of these resilience mechanisms is crucial for not just comprehending the development of AD but may also open new treatment possibilities for AD by enhancing the neuroprotective pathway and targeting the pathogenic process., Competing Interests: Declarations. Ethical approval: This article does not contain any studies with human participants or animals performed by any of the authors. Consent to participate: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Identifying key factors that control the chemical evolution of groundwater along groundwater flow direction is essential in ensuring the safety of groundwater resources in upper watersheds and lower plains. In this study, the ion ratio, multivariate statistics, and inverse geochemical modeling were used to investigate and explore the chemical characteristics of groundwater and factors driving the formation of groundwater components in the plain area of Deyang City, China. The chemical type of groundwater in the area was dominated by the HCO 3 -Ca type, and the variation in groundwater chemical composition was mainly affected by water-rock interaction and human interference. The water-rock interaction process includes carbonate dissolution, oxidation-reduction reactions, and cation exchange. Furthermore, inverse geochemical modeling revealed that the dissolution of evaporite minerals, dissolution/precipitation of carbonate minerals, and weathering of silicate minerals play a key role in the hydrogeochemical evolution of groundwater. Owing to dissimilar geological and hydrological conditions, hydrogeochemical evolution processes differ along different and similar paths. Overall, this study not only provides a conceptual framework for hydrochemical evolution in plains but also has important implications for the sustainable management of groundwater resources in other basins within plains., Competing Interests: Declarations. Ethical approval: This article does not contain any studies with human participants or animals. Competing interests: The authors declare no competing interests. All authors have read, understood, and complied as applicable with the statement on “Ethical responsibilities of Authors” as found in the Instructions for Authors., (© 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Aims: Self-expandable metal stents (SEMS) are effective in alleviating malignant colorectal obstruction. However, bowel perforation following SEMS placement remains a significant concern, as it can adversely affect oncological outcomes. This study aimed to evaluate the recurrence and overall survival rates associated with SEMS-related bowel perforations., Methods: This multicenter, retrospective analysis included patients with obstructive colorectal cancer who underwent SEMS placement as a bridge to surgery. The data collection period spanned from January 2008 to May 2019, with patient matching in a 1:5 ratio based on age, sex, tumor location, pathological stage, and achievement of curative resection., Results: Among the 412 patients who received SEMS placement, 25 (6.1%) patients experienced SEMS-related perforations (perforation group), with 21 instances classified as overt and four as silent perforations. Compared with 125 matched controls (non-perforation group), the perforation group showed elevated rates of emergent surgery, open surgery, and stoma formation, as well as a reduced interval from SEMS placement to surgery. The 5-year recurrence rate was notably higher in the perforation group than in the no-perforation group (47.4% vs. 21.5%, p < 0.001), whereas the 5-year survival rate was not significantly different between groups (63.8% vs. 80.0%, p = 0.330)., Conclusions: SEMS-related perforation led to less favorable surgical outcomes and a higher rate of recurrence, although no notable impact on overall survival was observed. Considering the risk of perforation, these findings support the cautious use of SEMS as a bridge to surgery., Competing Interests: Declarations. Disclosures: Han Hee Lee, Dong Hyun Kim, Hyun Lim, Jung-Wook Kim, Yunho Jung, Hyun-Soo Kim, Hyung-Hoon Oh, Jin Won Kim, Kwang Bum Cho, Young-Eun Joo, and Bo-In Lee have no conflicts of interest or financial ties to disclose., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In humans, glucocorticoid resistance is attributed to mutations in the glucocorticoid receptor (GR). Most of these mutations result in decreased ligand binding, transactivation, and/or translocation, albeit with normal protein abundances. However, there is no clear genotype‒phenotype relationship between the severity or age at disease presentation and the degree of functional loss of the receptor. Previously, we documented that a GR +/- rat line developed clinical features of glucocorticoid resistance, namely, hypercortisolemia, adrenal hyperplasia, and salt-sensitive hypertension. In this study, we analyzed the GR +/em4 rat model heterozygously mutant for the deletion of exon 3, which encompasses the second zinc finger, including the domains of DNA binding, dimerization, and nuclear localization signals. On a standard diet, mutant rats exhibited a trend toward increased corticosterone levels and a normal systolic blood pressure and heart rate but presented with adrenal hyperplasia. They exhibited increased adrenal soluble epoxide hydroxylase (sEH), favoring an increase in less active polyunsaturated fatty acids. Indeed, a significant increase in nonactive omega-3 and omega-6 polyunsaturated fatty acids, such as 5(6)-DiHETrE or 9(10)-DiHOME, was observed with advanced age (10 versus 5 weeks old) and following a switch to a high-salt diet accompanied by salt-sensitive hypertension. In thoracic aortas, a reduced soluble epoxide hydrolase (sEH) protein abundance resulted in altered vascular reactivity upon a standard diet, which was blunted upon a high-salt diet. In conclusion, mutations in the GR affecting the ligand-binding domain as well as the dimerization domain resulted in deregulated GR signaling, favoring salt-sensitive hypertension in the absence of obvious mineralocorticoid excess., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Background: The optimal treatment for resectable Non-Small Cell Lung Cancer (NSCLC) remains under investigation, particularly about its effectiveness across different ethnicities. This meta-analysis aims to investigate the potential benefits of adding PD1/PD-L1 inhibitors for treatment, stratified by ethnicity., Methods: We searched PubMed, Embase, and Cochrane databases for randomized controlled trials (RCTs) that investigated the use of PD1/PD-L1 inhibitors to treat patients with resectable NSCLC. The outcomes evaluated were disease-free survival/event-free survival (DFS/EFS), major pathological response (MPR), and pathological complete response (pCR). Hazard ratios (HRs) or risk ratios (RRs) with 95% confidence intervals (CIs) were computed for all endpoints using DerSimonian and Laird random-effects models. Statistical analyses were performed with R Software, version 4.2.3., Results: A total of six RCTs comprising 3,827 patients with NSCLC were included. In populations of Asian descent, PD1/PD-L1 significantly improved DFS/EFS (HR 0.59; 95% CI 0.44-0.78), MPR (RR 5.76; 95% CI 3.58-9.28), and pCR (RR 25.00; 95% CI 6.17-101.36). Similarly, patients of European ancestry experienced significantly improved DFS/EFS (HR 0.77; 95% CI 0.65-0.90), MPR (RR 2.75; 95% CI 2.00-3.77), and pCR (RR 4.53; 95% CI 2.69-7.6) with PD1/PD-L1 therapy. Notably, patients with mixed ethnicity also demonstrated significant improvement in MPR (RR 4.05; 95% CI 2.60-6.33) and pCR (RR 8.44; 95% CI 3.75-19.00) when receiving PD1/PD-L1 inhibitors., Conclusion: This comprehensive meta-analysis suggests that incorporating PD1/PD-L1 inhibitors into treatments offers a promising benefit for patients with resectable NSCLC, regardless of ethnicity. Future studies with in-depth molecular characterization of patients can further refine these findings and potentially guide the development of personalized treatment strategies based on individual ethnic backgrounds., Competing Interests: Declarations. Informed consent: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Aim: Elevated lactate dehydrogenase (LDH), a marker of tumor aggressiveness and metabolic alterations, may predict treatment response and overall survival across various tumors. This study investigates the correlation between serum LDH levels and clinical outcomes in glioblastoma patients treated with radiotherapy (RT) and temozolomide (TMZ)., Materials and Methods: This retrospective study analysed patients with IDH wild-type glioblastoma (IDH-wt GB) treated at the Radiotherapy Department of Azienda Ospedaliero-Universitaria Senese from 2018 to 2023. Clinical data, including hematologic parameters (e.g., LDH), imaging (MRI), and MGMT promoter methylation status, were collected. All patients received RT and TMZ following the Stupp protocol. Serum LDH levels were measured one week before RT, and Radiological Response (RR) was assessed using RANO criteria. Overall survival (OS), progression-free survival (PFS), and RR were primary endpoints. Statistical analyses included Kaplan-Meier, Cox regression, and decision tree analysis for LDH cut-off determination., Results: In a cohort of 147 IDH wild-type glioblastoma patients treated with the Stupp protocol, the median OS was 14 months and median PFS was 8 months. Elevated baseline LDH levels were associated with significantly poorer outcomes, showing a median OS of 9 months versus 20 months and a median PFS of 6 months versus 13 months for lower LDH levels (p < 0.001 and p = 0.0001, respectively). LDH levels also correlated with RR (p = 0,001), Multivariate analysis confirmed high LDH as an independent predictor of worse OS (HR = 2.31) and PFS (HR = 2.60), suggesting its utility as a prognostic biomarker., Conclusions: Elevated LDH levels before starting the Stupp protocol are clinically significant as they predict poorer overall survival and progression-free survival in glioblastoma patients and worse RR. Incorporating LDH measurements into treatment planning can help identify patients at higher risk of poor outcomes, allowing for more tailored and potentially aggressive treatment strategies to improve management and therapeutic responses in glioblastoma., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Fluorescein angiography (FA) is a diagnostic method for observing the vascular circulation in the eye. However, it poses a risk to patients. Therefore, generative adversarial networks have been used to convert retinal fundus structure images into FA images. Existing high-resolution image generation methods employ complex deep network models that are challenging to optimize, which leads to issues such as blurred lesion boundaries and poor capture of microleakage and microvessels. In this study, we propose a multiple-ResNet generative adversarial network (GAN) to improve model training, thereby enhancing the ability to generate high-resolution FA images. First, the structure of the multiple-ResNet generator is designed to enhance detail generation in high-resolution images. Second, the Gaussian error linear unit (GELU) activation function is used to help the model converge rapidly. The effectiveness of the multiple-ResNet is verified using the publicly available Isfahan MISP dataset. Experimental results show that our method outperforms other methods, achieving better quantitative results with a mean structural similarity of 0.641, peak signal-to-noise ratio of 18.25, and learned perceptual image patch similarity of 0.272. Compared with state-of-the-art methods, the results showed that using the multiple-ResNet framework and GELU activation function can improve the generation of detailed regions in high-resolution FA images., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval: Since this paper is based on a publicly available dataset, no ethical statement is required., (© 2024. International Federation for Medical and Biological Engineering.)

Background: Currently, most inherited retinal diseases lack curative interventions, and available treatment modalities are constrained to symptomatic approaches. Retinal organoid technology has emerged as a method for treating inherited retinal diseases, with growing academic interest in recent years. The purpose of this review was to systematically organize the current protocols for generating retinal organoids using induced pluripotent stem cells from patients with inherited retinal disease and to investigate the application of retinal organoids in inherited retinal disease research., Methods: Data were collected from the PubMed, Scopus, and Web of Science databases using a keyword search. The main search term used was "retinal organoid," accompanied by secondary keywords such as "optic cup," "three-dimensional," and "self-organizing." The final search was conducted on October 2, 2024., Results: Of the 2,129 studies retrieved, 130 were included in the qualitative synthesis. The protocols for the generation of retinal organoids in inherited retinal disease research use five major approaches, categorized into 3D and a combination of 2D/3D approaches, implemented with modifications. Disease phenotypes have been successfully reproduced via the generation of retinal organoids from the induced pluripotent stem cells of individuals with inherited retinal diseases, facilitating the progression of research into novel therapeutic developments. Cells have been obtained from retinal organoids for cell therapy, and progress toward their potential integration into clinical practice is underway. Considering their potential applications, retinal organoid technology has shown promise across various domains., Conclusion: In this systematic review, we organized protocols for generating retinal organoids using induced pluripotent stem cells from patients with inherited retinal diseases. Retinal organoid technology has various applications including disease modeling, screening for novel therapies, and cell replacement therapy. Further advancements would make this technology a clinically significant tool for patients with inherited retinal diseases., Competing Interests: Declarations. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Conflicts of Interest/Competing Interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Previous 3D encoder-decoder segmentation architectures struggled with fine-grained feature decomposition, resulting in unclear feature hierarchies when fused across layers. Furthermore, the blurred nature of contour boundaries in medical imaging limits the focus on high-frequency contour features. To address these challenges, we propose a Multi-oriented Hierarchical Extraction and Dual-frequency Decoupling Network (HEDN), which consists of three modules: Encoder-Decoder Module (E-DM), Multi-oriented Hierarchical Extraction Module (Multi-HEM), and Dual-frequency Decoupling Module (Dual-DM). The E-DM performs the basic encoding and decoding tasks, while Multi-HEM decomposes and fuses spatial and slice-level features in 3D, enriching the feature hierarchy by weighting them through 3D fusion. Dual-DM separates high-frequency features from the reconstructed network using self-supervision. Finally, the self-supervised high-frequency features separated by Dual-DM are inserted into the process following Multi-HEM, enhancing interactions and complementarities between contour features and hierarchical features, thereby mutually reinforcing both aspects. On the Synapse dataset, HEDN outperforms existing methods, boosting Dice Similarity Score (DSC) by 1.38% and decreasing 95% Hausdorff Distance (HD95) by 1.03 mm. Likewise, on the Automatic Cardiac Diagnosis Challenge (ACDC) dataset, HEDN achieves  0.5% performance gains across all categories., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethics approval and consent to participate: We propose a noval deep learning solution for the 3D medical image segmentation. The medical images used in this study are from the publicly available Synapse and ACDC dataset. Therefore, ethics approval and consent to participate were not required. Consent for publication: Confirm that all participants have consented to the submission of the study to the journal., (© 2024. International Federation for Medical and Biological Engineering.)

Conventional approaches like Agrobacterium-mediated transformation, viral transduction, biolistic particle bombardment, and polyethylene glycol (PEG)-facilitated delivery methods have been optimized for transporting specific genes to various plant cells. These conventional approaches in genetically modified crops are dependent on several factors like plant types, cell types, and genotype requirements, as well as numerous disadvantages such as time-consuming, untargeted distribution of genes, and high cost of cultivation. Therefore, it is suggested to develop novel techniques for the transportation of genes in crop plants using tailored nanoparticles (NPs) of manipulative and controlled high-performance features synthesized using green and chemical routes. It is observed that site-specific delivery of genes exhibits high efficacy in species-independent circumstances which leads to an increased level of productivity. Therefore, to achieve these outcomes, NPs can be utilized as gene nano-carriers for excellent delivery inside crops (i.e., cotton, tobacco, rice, wheat, okra, and maize) for desired genetic engineering modifications. As outcomes, this review provides an outline of the conventional techniques and current application of numerous nano-enabled gene delivery needed for crop gene manipulation, the benefits, and drawbacks associated with state-of-the-art techniques, which serve as a roadmap for the possible applicability of nanomaterials in plant genomic engineering as well as crop improvement in the future., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)