Heterogeneous Complex Research Articles

Homebuilt Imaging-Based Spatial Transcriptomics: Tertiary Lymphoid Structures as a Case Example.

Spatial transcriptomics methods provide insight into the cellular heterogeneity and spatial architecture of complex, multicellular systems. Combining molecular and spatial information provides important clues to study tissue architecture in development and disease. Here, we present a comprehensive do-it-yourself (DIY) guide to perform such experiments at reduced costs leveraging open-source approaches. This guide spans the entire life cycle of a project, from its initial definition to experimental choices, wet lab approaches, instrumentation, and analysis. As a concrete example, we focus on tertiary lymphoid structures (TLS), which we use to develop typical questions that can be addressed by these approaches.

The Critical Role of Host and Bacterial Extracellular Vesicles in Endometriosis

Endometriosis is a chronic, inflammatory, oestrogen-dependent disorder that is defined by the presence of endometrium-like tissue in the extra-uterine environment. It is estimated to affect approximately 10% of women of reproductive age, and the cause is still largely unknown. The heterogenous nature and complex pathophysiology of the disease results in diagnostic and therapeutic challenges. This review examines the emerging role of host extracellular vesicles (EVs) in endometriosis development and progression, with a particular focus on bacterial extracellular vesicles (BEVs). EVs are nano-sized membrane-bound particles that can transport bioactive molecules such as nucleic acids, proteins, and lipids, and therefore play an essential role in intercellular communication. Due to their unique cargo composition, EVs can play a dual role, both in the disease pathogenesis and as biomarkers. Both host and bacterial EVs (HEVs and BEVs) have been implicated in endometriosis, by modulating inflammatory responses, angiogenesis, tissue remodelling, and cellular proliferation within the peritoneal microenvironment. Understanding the intricate mechanisms underlying EVs in endometriosis pathophysiology and modulation of the lesion microenvironment may lead to novel diagnostic tools and therapeutic targets. Future research should focus on uncovering the specific cargo, the inter-kingdom cell-to-cell interactions, and the anti-inflammatory and anti-microbial mechanisms of both HEVs and BEVs in endometriosis in the hope of discovering translational findings that could improve the diagnosis and treatment of the disease.

Genomic and transcriptomic landscape of human gastrointestinal stromal tumors

Gastrointestinal stromal tumor (GISTs) are clinically heterogenous exhibiting varying degrees of disease aggressiveness in individual patients. We comprehensively describe the genomic and transcriptomic landscape of a cohort of 117 GISTs including 31 low-risk, 18 intermediate-risk, 29 high-risk, 34 metastatic and 5 neoadjuvant GISTs from 105 patients. GISTs have notably low tumor mutation burden but widespread copy number variations. Aggressive GISTs harbor remarkably more genomic aberrations than low-/intermediate-risk GISTs. Complex genomic alterations, chromothripsis and kataegis, occur selectively in aggressive GISTs. Despite the paucity of mutations, recurrent inactivating YLPM1 mutations are identified (10.3%, 7 of 68 patients), enriched in high-risk/metastatic GIST and functional study further demonstrates YLPM1 inactivation promotes GIST proliferation, growth and oxidative phosphorylation. Spatially and temporally separated GISTs from individual patients demonstrate complex tumor heterogeneity in metastatic GISTs. Finally, four prominent subtypes are proposed with different genomic features, expression profiles, immune characteristics, clinical characteristics and subtype-specific treatment strategies. This large-scale analysis depicts the landscape and provides further insights into GIST pathogenesis and precise treatment.

Generation of Neoproterozoic granites of the Huangling batholith in the northern Yangtze Block, South China: Implications for the evolution of the Precambrian continental crust

Granites may contain critical information about composition and reworking of continental crust and are widely used to investigate continental crust evolution. Extensive Neoproterozoic granites in the northern Yangtze Block are significant to the Neoproterozoic continental evolution of the Yangtze Block. We investigated the petrology, mineralogy, whole-rock geochemistry, and zircon U–Pb–Hf isotopes of the Neoproterozoic Wuduhe biotite granites and Xiabaoping K-feldspar granites of the Huangling batholith in the northern Yangtze Block to determine their source characteristics and geological implications for the northern Yangtze Block. The Wuduhe biotite granites yielded zircon U–Pb ages of ca. 818–815 Ma. They displayed high SiO2 contents (70.19–74.23 wt%) and Na2O/K2O ratios (1.38–3.35) but low MgO (0.37–0.90 wt%) and CaO (1.49–2.97 wt%) contents, representing calc-alkaline Na-rich I-type granites. They exhibited enriched whole-rock εNd(t) (−19.8 to − 18.8) and zircon εHf(t) values (−41.3 to − 24.2), and had low CaO/Na2O (0.34–0.63), Al2O3/TiO2 (46.6–89.7), Rb/Ba (0.02–0.08), and Rb/Sr (0.04–0.12) ratios, as well as low zircon saturation temperatures (739 − 770 °C), indicating derivation from Na-rich metabasalts of the Archean Kongling complex. The Xiabaoping K-feldspar granites had zircon U − Pb crystallization ages of ca. 816–812 Ma. They displayed high SiO2 (70.82–74.80 wt%), K2O (4.41–6.35 wt%), and Al2O3 (13.46–16.31 wt%) contents, suggesting A2-type affinities. They showed enriched zircon εHf(t) (−44.3 to − 18.4) and whole-rock εNd(t) values (−23.4 to − 18.4) and high zircon saturation temperatures (869–912 °C), indicating formation by anhydrous melting of K-rich felsic rocks from the Archean Kongling complex. The geochemical diversity of these granites from the Huangling batholith was primarily controlled by source heterogeneity of the Kongling complex and distinct melting temperatures. We infer that the northern Yangtze Block underwent significant remelting of ancient continental crust in a subduction background during the Neoproterozoic, induced by continuous upwelling of mantle-derived mafic magmas.

Keep It Accurate and Robust: An Enhanced Nuclei Analysis Framework

Accurate segmentation and classification of nuclei in histology images is critical but challenging due to nuclei heterogeneity, staining variations, and tissue complexity. Existing methods often struggle with limited dataset variability, with patches extracted from similar whole slide images (WSI), making models prone to falling into local optima. Here we propose a new framework to address this limitation and enable robust nuclear analysis. Our method leverages dual-level ensemble modeling to overcome issues stemming from limited dataset variation. Intra-ensembling applies diverse transformations to individual samples, while inter-ensembling combines networks of different scales. We also introduce enhancements to the HoVer-Net architecture, including updated encoders, nested dense decoding and model regularization strategy. We achieve state-of-the-art results on public benchmarks, including 1st place for nuclear composition prediction and 3rd place for segmentation/classification in the 2022 Colon Nuclei Identification and Counting (CoNIC) Challenge. This success validates our approach for accurate histological nuclei analysis. Extensive experiments and ablation studies provide insights into optimal network design choices and training techniques. In conclusion, this work proposes an improved framework advancing the state-of-the-art in nuclei analysis. We will release our code and models to serve as a toolkit for the community.

Zoon balanitis: not a distinct clinicopathological entity?

Zoon balanitis (ZB) was originally described in the 1950s in patients with clinical features resembling erythroplasia of Queyrat, but with histology that demonstrated a plasma cell infiltrate without evidence of dysplasia. Subsequently, ZB has been extensively reported in the literature, reflecting widespread acknowledgement as an established distinct clinicopathological entity. However, its existence as such has been questioned and there have been suggestions in the literature that ZB represents either a non-specific irritant reaction pattern, or a part of the heterogenous clinicopathological complex of male genital lichen sclerosus (MGLSc). In this study, the entire historical literature of published cases of ZB was subject to review, to determine respectively whether clinical or histological features of MGLSc had been present and been overlooked. One hundred and one papers were reviewed. Seventy-five contained images purporting to be of ZB. Images that were deemed to be of inadequate quality or to present uninformative anatomical views were excluded. The images in 66 manuscripts were amenable to scrutiny; 98.5% of these images demonstrated clinical signs of MGLSc, such as adhesions, effacement of the coronal sulcus and the frenulum, tightening of the prepuce, constrictive posthitis, etiolation of the glans, lichenoid inflammation and sclerosis. These findings strongly suggest that ZB occurs in the vast majority of cases as a manifestation of MGLSc and that its recognition as a distinct clinicopathological entity should be questioned, if not discontinued.

A novel in-situ fibrillation enhancement strategy to achieve super-elastic green foam with enhanced biodegradation

Driven by concerns about the escalating environmental pollution caused by the widespread use of plastic products, there is considerable interest in developing high-performance biodegradable materials. Poly(butylene adipate-co-terephthalate) (PBAT) foams are recognized as a highly sought-after candidate for alleviating plastic pollution, distinguished by their admirable biodegradability and flexibility. However, the extensive applications of PBAT foam are considerably constrained by inadequate melt strength and inherent shrinkage. Herein, a pioneering and scalable strategy, combining the shear-induced in-situ fibrillation process with microcellular foaming, was devised to achieve lightweight and super-resilient PBAT/poly(tetrafluoroethylene) (PTFE) foams. Thanks to the heterogeneous nucleation effect and complex tangled physical networks induced by in-situ nano-fibrillated PTFE, the crystallization and viscoelasticity of PBAT matrix experienced a dramatic enhancement, further bolstering its foaming capabilities and suppressing the shrinkage process. More importantly, the synergy of reduced foam density and reinforcement effect of PTFE nanofibrils played a crucial role in improving the remarkable compression of PBAT/PTFE foams. These foams showed a maximum increase of 40.2 % in strength and 16.3 % in resilience compared to pure PBAT foams. Moreover, the thermal insulation and soil degradation capability of PBAT/PTFE foams were substantially enhanced, achieving 10.3 % biodegradation after just 2 months. This innovative strategy offers a promising avenue for developing high-performance eco-friendly biocomposites.

The Pyrenean Platform for Observation of the Atmosphere: site, long-term dataset, and science

Abstract. The Pyrenean Platform for Observation of the Atmosphere (P2OA) is a coupled plain–mountain instrumented platform in southwestern France. It is composed of two physical sites: the “Pic du Midi” mountaintop observatory (2877 m a.s.l.) and the “Centre de Recherches Atmosphériques” (600 m a.s.l). Both sites are complementarily instrumented for the monitoring of climate-relevant variables and the study of meteorological processes in a mountainous region. The scientific topics covered by P2OA include surface–atmosphere interactions in heterogeneous landscapes and complex terrain, the physics and chemistry of atmospheric trace species at a large scale, the influence of local- and regional-scale emissions and transport on the atmospheric composition, and transient luminous events above thunderstorms. With a large number of instruments and a high hosting capacity, P2OA contributes to atmospheric sciences through (i) building long-term series of atmospheric observations, (ii) hosting experimental field campaigns and instrumental tests, and (iii) educational training in atmospheric observation techniques. In this context, P2OA is part of the French component of the Aerosol, Clouds and Trace Gases Research Infrastructure (ACTRIS-Fr) and also contributes to the Integrated Carbon Observation System (ICOS) research infrastructure and to several European or international networks. Here, we present the complete instrumentation of P2OA and the associated datasets, give a meteorological characterization of the platform, and illustrate the potential of P2OA and its dataset with past or ongoing studies and projects.

A survey on feature extraction and learning techniques for link prediction in homogeneous and heterogeneous complex networks

Complex networks are commonly observed in several real-world areas, such as social, biological, and technical systems, where they exhibit complicated patterns of connectedness and organised clusters. These networks have intricate topological characteristics that frequently elude conventional characterization. Link prediction in complex networks, like data flow in telecommunications networks, protein interactions in biological systems, and social media interactions on platforms like Facebook, etc., is an essential element of network analytics and presents fresh research challenges. Consequently, there is a growing emphasis in research on creating new link prediction methods for different network applications. This survey investigates several strategies related to link prediction, ranging from feature extraction based to feature learning based techniques, with a specific focus on their utilisation in dynamic and developing network topologies. Furthermore, this paper emphasises on a wide variety of feature learning techniques that go beyond basic feature extraction and matrix factorization. It includes advanced learning-based algorithms and neural network techniques specifically designed for link prediction. The study also presents evaluation results of different link prediction techniques on homogeneous and heterogeneous network datasets, and provides a thorough examination of existing methods and potential areas for further investigation.

Embryotomy for head last retention: A case report from Thiès, Senegal

Introduction: Hydrocephalus is a pathology of heterogeneous nature and complex pathogenesis. It corresponds to an active distension of the ventricular system. Faced with hydrocephalus with retained head in a dead child, embryotomy by craniotomy is indicated. Case Report: We report a case of intrapartum fetal death with head-last retention due to hydrocephalus treated with craniotomy performed at the regional hospital of Thiès (CHRT). This was a 21-year-old primigravida patient seen for premature delivery in a pregnancy of 33 weeks 5 days. The ultrasound concluded that the pregnancy had stopped at 33 weeks 5 days with major hydrocephalus. A craniotomy followed by gradual evacuation of the cerebrospinal fluid allowed easy delivery of a fresh stillborn weighing 1950 grams. The afterbirth was simple. Conclusion: Embryotomy by craniotomy constitutes a good option to complete delivery by natural means in the face of head retention due to hydrocephalus with intrapartum death. It is therefore necessary to master this simple and less morbid technique than a cesarean section in such a situation.

Molecular Modeling and In Vitro Functional Analysis of the RGS12 PDZ Domain Variant Associated with High-Penetrance Familial Bipolar Disorder.

Bipolar disorder's etiology involves genetics, environmental factors, and gene-environment interactions, underlying its heterogeneous nature and treatment complexity. In 2020, Forstner and colleagues catalogued 378 sequence variants co-segregating with familial bipolar disorder. A notable candidate was an R59Q missense mutation in the PDZ (PSD-95/Dlg1/ZO-1) domain of RGS12. We previously demonstrated that RGS12 loss removes negative regulation on the kappa opioid receptor, disrupting basal ganglia dopamine homeostasis and dampening responses to dopamine-eliciting psychostimulants. Here, we investigated the R59Q variation in the context of potential PDZ domain functional alterations. We first validated a new target for the wildtype RGS12 PDZ domain-the SAPAP3 C-terminus-by molecular docking, surface plasmon resonance (SPR), and co-immunoprecipitation. While initial molecular dynamics (MD) studies predicted negligible effects of the R59Q variation on ligand binding, SPR showed a significant reduction in binding affinity for the three peptide targets tested. AlphaFold2-generated models predicted a modest reduction in protein-peptide interactions, which is consistent with the reduced binding affinity observed by SPR, suggesting that the substituted glutamine side chain may weaken the affinity of RGS12 for its in vivo binding targets, likely through allosteric changes. This difference may adversely affect the CNS signaling related to dynorphin and dopamine in individuals with this R59Q variation, potentially impacting bipolar disorder pathophysiology.

Asymptotic synchronisation for coupled heterogeneous complex networks via L' Hoptial' rule

This paper considers the global asymptotic synchronisation (GAS) for the drive-response coupled heterogeneous complex networks (DRCHCNS). By using the different inequality techniques (DIT), L' Hoptial' rule and limit algorithms, three criteria to assure the GAS for the DRCHCNS are derived. Up to now, the results on GAS for DRCHCNS have been obtained usually by applying linear matrix inequality (LMI) and matrix measure approach (MMA). But, in this paper, without applying above approaches, we establish the GAS criteria for the DRCHCNS by using L' Hoptial' rule and limit algorithms. So, our study approach for the complex networks (CNS) extends the study fields of synchronisation of the CNS.

Methods for Quantifying Interactions Between Groundwater and Surface Water

Driven by the need for integrated management of groundwater (GW) and surface water (SW), quantification of GW–SW interactions and associated contaminant transport has become increasingly important. This is due to their substantial impact on water quantity and quality. In this review, we provide an overview of the methods developed over the past several decades to investigate GW–SW interactions. These methods include geophysical, hydrometric, and tracer techniques, as well as various modeling approaches. Different methods reveal valuable information on GW–SW interactions at different scales with their respective advantages and limitations. Interpreting data from these techniques can be challenging due to factors like scale effects, heterogeneous hydrogeological conditions, sediment variability, and complex spatiotemporal connections between GW and SW. To facilitate the selection of appropriate methods for specific sites, we discuss the strengths, weaknesses, and challenges of each technique, and we offer perspectives on knowledge gaps in the current science.

Implementation and validation of a very-high-energy electron model in the matRad treatment planning system.

While electron beams of up to 20 MeV are commonly used in radiotherapy, the use of very-high-energy electrons (VHEEs) in the range of 100-200 MeV is now becoming a realistic option thanks to the recent advancements in accelerator technology. Indeed, VHEE offers several clinically attractive features and can be delivered using various conformation methods (including scanning, collimation, and focussing) at ultra-high dose rates. To date, there is a lack of research tools for fast simulation of treatment plans using VHEE beams. This work aims to implement and validate a simple and fast dose calculation algorithm based on the Fermi-Eyges theory of multiple Coulomb scattering for VHEE radiation therapy, with energies up to 200 MeV. A treatment planning system (TPS) toolkit with VHEE modality would indeed allow for further preclinical investigations, including treatment plan optimization and evaluation, and thus contribute to the gradual introduction of VHEE radiotherapy in clinical practice. A VHEE pencil beam scanning double Gaussian model was introduced into the open-source TPS matRad environment along with new functions and options dedicated to VHEE dose calculations. Various geometries and field configurations were then calculated in matRad (up to 200 MeV and 15×15 cm2, with complex bone or lung heterogeneities) and the results were compared to Monte Carlo simulations in the TOPAS/Geant4 toolkit. Two types of beam model (divergent or focused) were also tested. Examples of clinical treatment plans were computed, and the results were compared between the two codes. VHEE modality was fully implemented in matRad with GUI capabilities while preserving all original TPS features. New relevant options such as the importation of specific spot-lists or adjustment of the lateral dose calculation cutoff to optimize the calculation speed were validated. Single spot and square field dose distributions were validated in water alone as well as in clinically relevant inhomogeneities. Dose maps from the VHEE model in matRad were in good agreement with TOPAS (2D gamma index [2%/1mm] with passing rates superior to 90%, <6% mean dose differences), except for large interface heterogeneities. This work describes the implementation of a simple but efficient VHEE simulation model in matRad. A few configurations were studied in order to validate the model against accurate Monte Carlo simulations, demonstrating its usefulness for carrying out preliminary studies involving VHEE radiotherapy.

Expanding the genetic spectrum of hereditary motor sensory neuropathies in Pakistan

BackgroundHereditary motor and sensory neuropathy (HMSN) refers to a group of inherited progressive peripheral neuropathies characterized by reduced nerve conduction velocity with chronic segmental demyelination and/or axonal degeneration. HMSN is highly clinically and genetically heterogeneous with multiple inheritance patterns and phenotypic overlap with other inherited neuropathies and neurodegenerative diseases. Due to this high complexity and genetic heterogeneity, this study aimed to elucidate the genetic causes of HMSN in Pakistani families using Whole Exome Sequencing (WES) for variant identification and Sanger sequencing for validation and segregation analysis, facilitating accurate clinical diagnosis.MethodsFamilies from Khyber Pakhtunkhwa with at least two members showing HMSN symptoms, who had not previously undergone genetic analysis, were included. Referrals for genetic investigations were based on clinical features suggestive of HMSN by local neurologists. WES was performed on affected individuals from each family, with Sanger sequencing used to validate and analyze the segregation of identified variants among family members. Clinical data including age of onset were assessed for variability among affected individuals, and the success rate of genetic diagnosis was compared with existing literature using proportional differences and Cohen’s h.ResultsWES identified homozygous pathogenic variants in GDAP1 (c.310 + 4 A > G, p.?), SETX (c.5948_5949del, p.(Asn1984Profs*30), IGHMBP2 (c.1591 C > A, p.(Pro531Thr) and NARS1 (c.1633 C > T, p.(Arg545Cys) as causative for HMSN in five out of nine families, consistent with an autosomal recessive inheritance pattern. Additionally, in families with HMSN, a SETX variant was found to cause cerebellar ataxia, while a NARS1 variant was linked to intellectual disability. Based on American College of Medical Genetics and Genomics criteria, the GDAP1 variant is classified as a variant of uncertain significance, while variants in SETX and IGHMBP2 are classified as pathogenic, and the NARS1 variant is classified as likely pathogenic. The age of onset ranged from 1 to 15 years (Mean = 5.13, SD = 3.61), and a genetic diagnosis was achieved in 55.56% of families with HMSN, with small effect sizes compared to previous studies.ConclusionsThis study expands the molecular genetic spectrum of HMSN and HMSN plus type neuropathies in Pakistan and facilitates accurate diagnosis, genetic counseling, and clinical management for affected families.

Synovial sarcoma- A potential diagnostic pitfall on FNAC

Synovial sarcoma is a malignant mesenchymal tumour with an uncertain origin. It is most commonly seen in the extremities, particularly lower extremities. The diagnosis of synovial sarcoma can be challenging due to its morphological diversity. Histologically, it can be of three subtypes: Monophasic, Biphasic and Poorly differentiated. The transcriptional corepressor, Transducin-Like Enhancer 1(TLE1) is a sensitive and specific marker for synovial sarcoma which helps in distinguishing it from histologic mimics. This case report presents a 48 year old female with swelling over right forearm since 1 year which was misdiagnosed on FNAC as Benign spindle cell lesion, probably Schwannoma. Surgery was done and on histopathological examination, it was diagnosed as Biphasic synovial sarcoma. It was confirmed by TLE1 immunohistochemistry which showed diffuse strong nuclear positivity. FNAC can sometimes fails to sample the epithelial component in biphasic synovial sarcoma, which complicates accurate diagnosis. The exact subtyping of spindle cell tumours is difficult on cytology owing to their complex heterogeneity. Though, Synovial sarcoma is an aggressive tumour, it responds well to treatment including surgery and chemotherapy. Therefore, correct and early diagnosis of synovial sarcoma is vital.

Influences of Variability in Attenuation Compensation on the Estimation of Backscatter Coefficient of Median Nerves in Vivo.

Peripheral nerves remain a challenging target for medical imaging, given their size, anatomical complexity, and structural heterogeneity. Quantitative ultrasound (QUS) applies a set of techniques to estimate tissue acoustic parameters independent of the imaging platform. Many useful medical and laboratory applications for QUS have been reported, but challenges remain for deployment in vivo, especially for heterogeneous tissues. Several phenomena introduce variability in attenuation estimates, which may influence the estimation of other QUS parameters. For example, estimating the backscatter coefficient (BSC) requires compensation for the attenuation of overlying tissues between the transducer and the underlying tissue of interest. The purpose of this study is to extend prior studies by investigating the efficacy of several analytical methods of estimating attenuation compensation on QUS outcomes in the human median nerve. Median nerves were imaged at the volar wrist in vivo and beam-formed radiofrequency (RF) data were acquired. Six analytical approaches for attenuation compensation were compared: 1-2) attenuation estimated by applying spectral difference method (SDM) and spectral log difference method (SLDM) independently to regions of interest (ROIs) overlying the nerve and to the nerve ROI itself; 3-4) attenuation estimation by applying SDM and SLDM to ROIs overlying the nerve, and transferring these properties to the nerve ROI; and 5-6) methods that apply previously published values of tissue attenuation to the measured thickness of each overlying tissue. Mean between-subject estimates of BSC-related outcomes as well as within-subject variability of these outcomes were compared among the 6 methods. Compensating for attenuation using SLDM and values from the literature reduced variability in BSC-based outcomes, compared to SDM. Variability in attenuation coefficients contributes substantially to variability in backscatter measurements. This work has implications for the application of QUS to in vivo diagnostic assessments in peripheral nerves and possibly other heterogeneous tissues.

Exploring the heterogeneity of hepatic and pancreatic fat deposition in obesity: implications for metabolic health.

This retrospective observational study investigates the heterogeneity of hepatic and pancreatic fat deposition and its implications for metabolic health in individuals with obesity. A total of 706 patients with obesity underwent an MRI to quantify liver and pancreatic fat. Patients were classified into four groups based on fat deposition: no fat (None), fatty pancreas only (NAFPD), fatty liver only (NAFLD), and both conditions (NAFLD+NAFPD). Biochemical profiles, insulin resistance (Homeostatic Model Assessment for Insulin Resistance, HOMA-IR), and β-cell function were analyzed. A series of multiple linear regressions were used to investigate the independent effects of characteristics on glucose, insulin, and C-peptide at 0h. Another multiple linear regression was performed to evaluate the effects of basic characteristics on average liver fat, mean pancreatic fat, and visceral fat. The majority (76.63%) exhibited both NAFLD and NAFPD, highlighting the heterogeneity of fat deposition among individuals with obesity. Groups with fatty liver displayed significantly higher fasting glucose, insulin, C-peptide, and HOMA-IR levels than those without fatty liver (P < 0.01). Fatty pancreas alone did not significantly influence these metabolic parameters (P > 0.05). This underscores the greater metabolic impact of hepatic fat compared to pancreatic fat. The study confirms the complex heterogeneity of fat deposition in obesity, with the fatty liver being a more influential factor in metabolic disturbances than the fatty pancreas. The prevalent co-occurrence of NAFLD and NAFPD in this population underscores the need for targeted management strategies focusing on hepatic fat reduction to mitigate metabolic risk.

EZH2 functional dichotomy in reactive oxygen species-stratified glioblastoma.

EZH2, well-known for its canonical methyltransferase activity in transcriptional repression in many cancers including glioblastoma (GBM), has an understudied non-canonical function critical for sustained tumor growth. Recent GBM consortial efforts reveal complex molecular heterogeneity for which therapeutic vulnerabilities correlated with subtype stratification remain relatively unexplored. Current enzymatic EZH2 inhibitors (EZH2inh) targeting its canonical SET domain show limited efficacy and lack durable response, suggesting that underlying differences in the non-canonical pathway may yield new knowledge. Here, we unveiled dual roles of the EZH2 CXC domain in therapeutically-distinct, reactive oxygen species (ROS)-stratified tumors. We analyzed differentially expressed genes between ROS classes by examining cis-regulatory elements as well as clustering of activities and pathways to identify EZH2 as the key mediator in ROS-stratified cohorts. Pull-down assays and CRISPR knockout of EZH2 domains were used to dissect the distinct functions of EZH2 in ROS-stratified GBM cells. The efficacy of NF-κB-inducing kinase inhibitor (NIKinh) and standard-of-care temozolomide was evaluated using orthotopic patient-derived GBM xenografts. In ROS(+) tumors, CXC-mediated co-interaction with RelB drives constitutive activation of non-canonical NF-κB2 signaling, sustaining the ROS(+) chemoresistant phenotype. In contrast, in ROS(-) subtypes, PRC2 methyltransferase activity represses canonical NF-κB. Addressing the lack of EZH2inh targeting its non-methyltransferase roles, we utilized a brain-penetrant NIKinh that disrupts EZH2-RelB binding, consequently prolonging survival in orthotopic ROS(+)-implanted mice. Our findings highlight the functional dichotomy of the EZH2 CXC domain in governing ROS-stratified therapeutic resistance, thereby advocating for the development of therapeutic approaches targeting its non-canonical activities and underscoring the significance of patient stratification methodologies.

The Role of SIRT1 in Leukemia.

Leukemia is a type of hematological malignancy (HM) caused by uncontrolled proliferation, apoptosis, and differentiation of hematopoietic stem cells (HSCs). Leukemia cells proliferate greatly in the bone marrow (BM), infiltrate other tissues and organs, and affect the normal hematopoietic function. Although the emergence of new targeted agents and immune agents has improved the prognosis of patients, due to the complex pathogenic factors and heterogeneity of leukemia, there are still some patients with poor prognosis. Recent studies have shown that silent information regulator 1 (SIRT1) is involved in the proliferation, apoptosis, metabolism, and senescence of leukemia cells. As a double-edged sword in leukemia cells, SIRT1 can both promote and inhibit the growth of leukemia cells. Since its mechanism of action has not been elucidated, it is urgent to explore the regulatory mechanism of SIRT1 in leukemia. In this review, we discussed the mechanisms of SIRT1 in different aspects of leukemia, providing a theoretical basis for the treatment of patients with leukemia.