Biological Characteristics Research Articles

Potential Protective or Pathogenic Roles of Parabacteroides distasonis in Diseases: A Narrative Review

Abstract Parabacteroides distasonis is a gram-negative, non-spore-forming, rod-shaped, anaerobic bacterium, and an important gut colonizer first isolated from human feces in 1933. Over more than 90 years of research, P. distasonis has been found to be associated with liver diseases such as liver fibrosis and non-alcoholic fatty liver disease, gastrointestinal diseases such as colitis and colorectal tumors and metabolic diseases such as obesity and diabetes, potentially playing a protective or pathogenic role in the occurrence and progression of these diseases. Herein, we elaborate on the biological characteristics, antibiotic resistance and potential roles of P. distasonis in these diseases, aiming to provide researchers with comprehensive information about P. distasonis and promote in-depth investigations into its safety and protective effects.

Biological and Molecular Characterization of Moroccan Isolates of Spiroplasma citri

Spiroplasma citri, a bacterium from the class Mollicutes, is the causative agent of citrus stubborn disease, a serious threat to Moroccan citrus crops, with yield losses reaching 45%. Despite its long-standing presence since 1949 and regulations mandating disease-free citrus plants, data on S. citri in Morocco remain scarce. This study investigates the pathogenicity and symptom variability of Moroccan S. citri isolates using biological indexing and genetic mapping based on the Spiralin and P58 genes. Biological indexing through reverse inoculation revealed that seven out of ten isolates caused moderate to intense symptoms within 8 to 10 weeks, with symptom severity varying across citrus cultivars and regions. These findings suggest variations in pathogen titer. Molecular analysis showed that Moroccan isolates (27GH, 3GH, 8GH, 56MK, 16MK, 60MK, 2GLK, 13SS, and 30S1) exhibited complete (100%) sequence similarity with each other and the reference strain R2-A8. Furthermore, these isolates displayed a high degree of similarity (99.75%) to a Corsican isolate (U13995) and a 94% similarity to an Iranian isolate (KP666137). Analysis of the P58 gene confirmed a high level of homogeneity with Moroccan reference strain R8-A2, closely aligning (99.75%) with the American BR3-3X strain, and 98% similarity to isolates from Syria and Iran. This study lays a foundational insight into the molecular characterization of S. citri in Morocco and provides a groundwork for future research into managing citrus stubborn disease.

Intratumoral Injection of mRNA-2752 and Pembrolizumab for High-Risk Ductal Carcinoma In Situ

ImportanceIntratumoral immunotherapy that leverages the biological characteristics of high-risk ductal carcinoma in situ (DCIS) may be able to reduce the extent of surgical treatment and provide an alternative approach to improve patient outcomes.ObjectiveTo determine if combination intratumoral immunotherapy can activate immune cells to shrink or eliminate high-risk DCIS.Design, Setting, and ParticipantsThis phase 1 open-label nonrandomized clinical trial at a single academic center tested the safety and efficacy of intratumoral immunotherapy in patients with high-risk DCIS, defined as at least 2 of the following present: younger than 45 years, tumor size greater than 5 cm, high-grade, palpable mass, hormone receptor (HR)–negative, or ERBB2-positive. Patients were enrolled between June 8, 2021, and December 13, 2022.InterventionPembrolizumab (anti–programmed cell death protein 1), dose ranging from 2 mg to 8 mg, and mRNA-2752 (a combination of interleukin [IL]-23, IL-36γ, and OX40L mRNAs), dose ranging from 1 mg to 4 mg, delivered intratumorally, with 2 to 4 doses given 2 to 3 weeks apart.Main Outcomes and MeasuresThe primary objective was to evaluate the safety and tolerability of intratumoral injections of pembrolizumab and mRNA-2752. The secondary objectives were to assess radiologic and pathological responses and immunological and histological differences in the posttreatment tumor microenvironment.ResultsTen female patients with high-risk DCIS (median [range] age, 46 [35-80] years) were enrolled. The median (range) tumor size was 5.3 (1.0-10.0) cm. Five tumors were HR-negative ERBB2-positive; 2 HR-negative ERBB2-negative; 2 HR-positive ERBB2-negative; and 1 HR-positive ERBB2-positive. Of all treated patients, 8 of 10 responded to treatment, and all 8 patients had ERBB2-positive or HR-negative DCIS. Three patients had complete responses. Three patients with negative posttreatment core biopsy results declined surgery and remained disease-free after 1 to 2 years. Multiplex immunofluorescence staining demonstrated that high baseline levels of tumor-infiltrating lymphocytes and programmed cell death ligand 1–positive cells (immune or tumor) were associated with a better treatment response. All patients experienced up to 1 week of fever, malaise, flulike symptoms, axillary adenopathy, erythema, injection site swelling, and swelling in the breast. One patient had intermittent urticaria for 3 months. The dose was serially reduced from 8 mg to 2 mg for pembrolizumab and 4 mg to 1 mg for mRNA-2752 to improve tolerability. The final recommended combination dose is pembrolizumab, 4 mg, with mRNA-2752, 1 mg.Conclusions and RelevanceIn this phase 1 nonrandomized clinical trial, the results suggest that intratumoral injections of pembrolizumab and mRNA-2752 are safe and may induce rapid regression of high-risk DCIS with high immune infiltrates. These findings warrant additional investigation, and studies are ongoing.Trial RegistrationClinicalTrials.gov Identifier: NCT02872025

Targeted gene sequencing and bioinformatics analysis of patients with gallbladder neuroendocrine carcinoma: A case report

BACKGROUND Gallbladder neuroendocrine carcinoma (NEC) represents a subtype of gallbladder malignancies characterized by a low incidence, aggressive nature, and poor prognosis. Despite its clinical severity, the genetic alterations, mechanisms, and signaling pathways underlying gallbladder NEC remain unclear. CASE SUMMARY This case study presents a rare instance of primary gallbladder NEC in a 73-year-old female patient, who underwent a radical cholecystectomy with hepatic hilar lymphadenectomy and resection of liver segments IV-B and V. Targeted gene sequencing and bioinformatics analysis tools, including STRING, GeneMANIA, Metascape, TRRUST, Sangerbox, cBioPortal and GSCA, were used to analyze the biological functions and features of mutated genes in gallbladder NEC. Twelve mutations (APC , ARID2 , IFNA6 , KEAP1 , RB1 , SMAD4 , TP53 , BTK , GATA1 , GNAS , and PRDM3 ) were identified, and the tumor mutation burden was determined to be 9.52 muts/Mb via targeted gene sequencing. A protein-protein interaction network showed significant interactions among the twelve mutated genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were used to assess mutation functions and pathways. The results revealed 40 tumor-related pathways. A key regulatory factor for gallbladder NEC-related genes was identified, and its biological functions and features were compared with those of gallbladder carcinoma. CONCLUSION Gallbladder NEC requires standardized treatment. Comparisons with other gallbladder carcinomas revealed clinical phenotypes, molecular alterations, functional characteristics, and enriched pathways.

Unveiling the Emerging Role of Xanthine Oxidase in Acute Pancreatitis: Beyond Reactive Oxygen Species

Acute pancreatitis (AP) is a potentially fatal acute digestive disease that is widespread globally. Although significant progress has been made in the previous decade, the study of mechanisms and therapeutic strategies is still far from being completed. Xanthine oxidase (XO) is an enzyme that catalyzes hypoxanthine and xanthine to produce urate and is accompanied by the generation of reactive oxygen species (ROS) in purine catabolism. Considerable preclinical and clinical studies have been conducted over many decades to investigate the role of XO in the pathogenesis of AP and its potential targeting therapeutic value. There is no doubt that the ROS generated by irreversibly activated XO participates in the local pancreas and multiple organ failure during AP. However, the optimal timing and doses for therapeutic interventions targeting XO in animal studies and the clinic, as well as the additional molecular mechanisms through which XO contributes to disease onset and progression, including metabolic regulation, remain to be elucidated. This review summarized the benefits and contradictions of using XO inhibitors in animal models, offered mechanisms other than ROS, and discussed the difficulties faced in clinical trials. We hope to provide a perspective on the future worthwhile basic and clinical research on XO by analyzing its chemical and biological characteristics, as well as the progress of its regulatory mechanisms in AP.

MicroRNAs signatures as potential molecular markers in mild cognitive impairment: a meta-analysis

Mild cognitive impairment (MCI) is characterized by a decline in cognitive functioning without significant interference in daily activities. Its high heterogeneity and elevated conversion rate to dementia pose challenges for accurate diagnosis and monitoring, highlighting the urgent need to identify methodologies focused on the early detection and intervention of MCI. Due to their biological characteristics, microRNAs (miRNAs) are potential candidates as non-invasive molecular markers for the identification and assessment of MCI progression. Therefore, in this study, we conducted a meta-analysis to identify the miRNAs commonly deregulated in MCI, focusing on expression profiles in plasma, serum, and extracellular vesicle samples. Our analysis identified eight upregulated miRNAs, including hsa-miR-149-3p, and four downregulated miRNAs, such as Let-7f-5p. Notably, hsa-miR-149-3p emerged as a central node in interaction networks, suggesting its crucial role in regulating cellular processes relevant to MCI. Additionally, pathway analysis revealed significant enrichment in biological processes associated with transcriptional regulation and neurodegeneration. Our results underscore the potential of circulating miRNAs as non-invasive molecular markers for MCI and open the possibility for new methodologies that enable more accurate diagnosis and monitoring of disease progression. Validating the expression of miRNAs such as hsa-miR-149-3p and Let-7f-5p, along with identifying their functional role in the specific context of MCI, is essential to establish their biological relevance. This work contributes to the understanding of the miRNA profile in mild cognitive impairment using easily accessible samples, which could be useful for the development of various strategies aimed at preventing or delaying MCI in individuals at risk of developing dementia, including Alzheimer’s disease.

Biological characteristics, immune infiltration and drug prediction of PANoptosis related genes and possible regulatory mechanisms in inflammatory bowel disease

PANoptosis is one of several modes of programmed cell death (PCD) and plays an important role in many inflammatory and immune diseases. The role of PANoptosis in inflammatory bowel disease (IBD) is currently unknown. Differentially expressed PANoptosis-related genes (DE-PRGs) were identified, and pathway enrichment analyses were performed. LASSO regression model construction, a nomogram model, calibration curves, ROC and DCA curves were used to evaluate the predictive value of the model. Predicts transcription factors (TFs) and small-molecule drugs of DE-PRGs were analysed. Model genes and immuno-infiltration were analysed. The PANoptosis features of IBD include 12 genes: OGT, TLR2, GZMB, TLR4, PPIF, YBX3, CASP5, BCL2L1, CASP6, MEFV, GSDMB and BAX. The enrichment analysis suggested that these genes were related to TNF signalling, NF-κB, pyroptosis and necroptosis. Machine learning identified three model genes: OGT, GZMB and CASP5. The nomogram model, calibration curves, ROC and DCA curves have strong predictive value. Immuno-infiltration analysis revealed that immune cell infiltration was increased in patients with IBD, and the model genes were closely related to the infiltration of various immune cells. The TFs associated with DE-PRGs were RELA, NFKB1, HIF1A, TP53 and SP1. In addition, the Connectivity Map (CMap) database identified the top 10 small-molecule compounds, including buspirone, chloroquine, spectinomycin and chlortetracycline. This study indicate that DE-PRGs model genes have good predictive ability for IBD. Moreover, PANoptosis may mediate the process of IBD through TNF signalling, NF-κB, pyroptosis, necroptosis and immune mechanisms. These results present a new horizon for the research and treatment of IBD.

Low-intensity pulsed ultrasound enhances the osteogenic potential of PDLSCs-derived extracellular vesicles through COMP/PI3K/AKT.

The therapeutic potential of extracellular vesicles (EVs) in bone regeneration is noteworthy; however, their clinical application is impeded by low yield and limited efficacy. This study investigated the effect of low-intensity pulsed ultrasound (LIPUS) on the therapeutic efficacy of EVs derived from periodontal ligament stem cells (PDLSCs) and preliminarily explored its mechanism. PDLSCs were cultured with osteogenic media and stimulated with or without LIPUS, and then EVs and LIPUS-stimulated EVs (L-EVs) were isolated separately. We investigated the biological characteristics and effects of these two EVs on cell proliferation, migration, osteogenic differentiation, and bone regeneration invivo and invitro, and explored the potential mechanism by analyzing protein profiles. LIPUS significantly stimulated the secretion of PDLSCs-EVs, and L-EVs exhibited stronger efficacy in promoting cell proliferation, migration, and osteogenic differentiation, thereby enhancing new bone formation. LIPUS stimulation affected the protein profile of PDLSCs-EVs, and 42 proteins were upregulated and 4 proteins downregulated in L-EVs when compared with EVs. LIPUS significantly upregulated the level of cartilage oligomeric matrix protein (COMP) in EVs, which enhanced EVs' osteogenic ability via the PI3K/AKT pathway. This study proposes that LIPUS has potential as an optimization method for enhancing the therapeutic effects of EVs in tissue regeneration.

Land, Woman and Lord: An Ecofeminist Study of Tehmina Durrani’s Novels My Feudal Lord and Blasphemy

Place and woman have always been considered the utmost important belongings of men since the beginning of life on the earth. Especially in Pakistani rural society patriarchy is more in dominance than in other parts of the country due to the illiteracy and suppression of female rights. Thus, women are treated as entities in the hands of men, just like their places and lands. Female individuality has been marginalized and subjugated ever since. South Asian female writers gave a voice to these voiceless creatures and openly presented their issues in front of the world. With the application of the theory of ecofeminism, this thesis highlights a relative study of particular works of a famous South Asian female author Tehmina Durrani. This thesis will state the ecofeminist stance that women's productive and biological features strongly associate them with land or place owned by men. The study also deals with the effects of patriarchy and the feudal system, which set limitations for women. Ecofeminism, as a tenet of anarcha-feminism, allows women to speak and struggle against the violence they face due to marginalization. Tehmina Durrani has showcased the miseries of women in her books My Feudal Lord and Blasphemy. She has acted as an anarchist who moved a step ahead and crossed the boundaries in which the dominant patriarchy trapped her. Both works will explore the exploitation of women who, like the land, are considered productive and the assets of males. This thesis will propose that females must involve themselves in the struggle to fight for their rights. They must stop the tradition of being treated as puppets in the hands of men. This study will explore Durrani’s struggle as an anarchist and conclude how successful she was in her attempts.

Highly pathogenic bovine viral diarrhea virus BJ-11 unveils genetic evolution related to virulence in calves

Bovine viral diarrhea virus (BVDV) is the causative agent of bovine viral diarrhea, which causes significant economic loss to the global livestock industry. Despite the widespread use of inactivated BVDV vaccines, highly pathogenic strains continue to emerge. In China, regional variations in BVDV subtypes, morbidities, and symptoms, however, only the BVDV 1a subtype vaccine is currently approved. Therefore, this study is to gain insight into the biological characteristics and genetic variation of BVDV strains prevalent in Beijing. Meanwhile, this will provide a theoretical foundation and technical support for the prevention and control of BVDV, as well as raise awareness of the potential for virulence enhancement caused by the unregulated use of BVDV vaccines. In this study, A BVDV strain, BJ-11, was isolated from calves that died of diarrhea and vaccinated of BVDV. To evaluate its virulence, newborn calves were experimentally infected with the BJ-11. Clinical signs included fever, diarrhea, bloody stools, anorexia, and death in some cases. A marked reduction in leukocyte and lymphocyte counts were observed, accompanied by an increase in neutrophil counts. Histopathological changes manifested as severe lung lesions. Phylogenetic analysis indicated that BJ-11 belongs to the BVDV 1b subtype, genetically closest to the JL-1 strain. Analysis of the E2 glycosylation site disappeared (298SYT) in one of the four common glycosylation sites in the BVDV-1, which has been reported to affect the ability of the virus to infect and an additional glycosylation site (122NGS). These results indicate that BJ-11 is a highly pathogenic strain evolved from a low-virulence ancestor and should be served as a challenge strain. Simultaneously, these results contribute to a broader understanding of BVDV and whether imperfect vaccination strategies lead to reversal of immunosuppressive virulence.

A Logistic Regression Model for the Prediction of Vegetation Recruitment in the Kinu River, Japan

ABSTRACTVegetation overgrowth in rivers worldwide is a considerable problem because it can potentially reduce the flood‐flowing capacity and cause biodiversity loss. In this study, we developed a model to predict vegetation recruitment during the initial stages of secondary succession, which leads to vegetation overgrowth. This study chose a logistic regression model to predict vegetation recruitment because of its simplicity and lower computational load than machine learning. The model was designed for the Kinu River in Japan which is associated with extensive vegetation overgrowth. Data for the model development were obtained from unmanned aerial vehicle (UAV) aerial surveys and public databases. To ensure the model's applicability beyond the training rivers, we trained the logistic regression model across different river flows and geomorphic characteristics, including normal and flood times and gravel and sand beds. The results indicated that the logistic regression model with three explanatory variables, namely distance from the river stream, relative height, and vegetation existence history, was optimal for all rivers, with F‐measures in the range of 0.79‐0.85. In addition, using UAV imagery allows for high‐spatial resolution in predicting vegetation recruitment. The best model prediction map of vegetation recruitment demonstrated that it could accurately predict the vegetation distribution along the main river channel for gravel and sand beds. The simplicity of the present model would be advantageous when applied to other rivers with similar topographic and biological characteristics within the same river segment without hydrodynamic calculations.

Biological Characteristics and Whole-Genome Analysis of a Porcine E. coli Phage

(1) Background: In recent years, the increasing emergence of multidrug-resistant pathogens in pig farms has begun to pose a severe threat to animal welfare and, by extension, public health. In this study, we aimed to explore the biological characteristics and genomic features of bacteriophages that are capable of lysing porcine multidrug-resistant E. coli, which was isolated from sewage. In doing so, we provided a reference for phage therapies that can be used to treat multidrug-resistant strains. (2) Method: Using the multidrug-resistant E. coli isolate sq-1 as the host bacterium, bacteriophages were isolated and purified from fecal samples using a double-layer agar plate method. The morphology was observed using a transmission electron microscope, and its host range, optimal multiplicity of infection (MOI), one-step growth curve, thermal stability, acid–base tolerance, and in vitro antibacterial ability were tested. Genomic features were analyzed using whole-genome sequencing. (3) Results: A lytic phage named vB_EcoS_Psq-1 (abbreviated as Psq-1) was successfully isolated. Electron microscopy revealed that Psq-1 belongs to the family of long-tailed phages, possessing clear and transparent plaques of approximately 1 mm in diameter. Psq-1 only lyses the host bacterium and does not affect other E. coli strains or other species of bacteria. The optimal MOI for phage Psq-1 was 0.1, with a latent period of 25 min, an exponential growth period of 25 min, and a lysis yield of 44.21 PFU/cell. Its activity remains stable at temperatures between 40 °C and 60 °C and from pH 4.0 to pH 13.0. Psq-1 exhibited a significant inhibitory effect on E. coli in liquid culture medium. The nucleic acid type of phage Psq-1 was dsDNA, with a total genome length of 44,183 bp and a GC content of 52.16%. No known resistance, lysogenic, or virulence-related genes were detected. The whole genome contains 55 open reading frames (ORFs). (4) Conclusions: This study isolated a bacteriophage that is capable of lysing multidrug-resistant E. coli. Characterized by a narrow E. coli lysis range, a long latent period, limited lytic ability, and stable biological properties, this bacteriophage can serve as a reference isolate for E. coli phages and can provide biological materials and data to support research on bacteriophages that are effective against multidrug-resistant porcine E. coli.

Venoms and Extracellular Vesicles: A New Frontier in Venom Biology

Extracellular vesicles (EVs) are nanoparticle-sized vesicles secreted by nearly all cell types under normal physiological conditions. In toxicological research, EVs have emerged as a crucial link between public health and multi-omics approaches, offering insights into cellular responses to disease-causing injury agents such as environmental and biological toxins, contaminants, and drugs. Notably, EVs present a unique opportunity to deepen our understanding of the pathophysiology of envenomation by natural toxins. Recent advancements in isolating and purifying EV cargo, mass spectrometry techniques, and bioinformatics have positioned EVs as potential biomarkers that could elucidate biological signaling pathways and provide valuable information on the relationship between venomous toxins, their mechanisms of action, and the effectiveness of antivenoms. Additionally, EVs hold promise as proxies for various aspects of envenomation, including the toxin dosage, biological characterization, injury progression, and prognosis during therapeutic interventions. These aspects can be explored through multi-omics technology applied to EV contents from the plasma, saliva, or urine samples of envenomated individuals, offering a comprehensive integrative approach to understanding and managing envenomation cases.

Are Suggested Hiking Times Accurate? A Validation of Hiking Time Estimations for Preventive Measures in Mountains

Background and Objectives: Accurate hiking time estimate is crucial for outdoor activity planning, especially in mountainous terrains. Traditional mountain signage and online platforms provide generalized hiking time recommendations, often lacking personalization. This study aims to evaluate the variability in hiking time estimates from different methods and assess the potential of a novel algorithm, MOVE, to enhance accuracy and safety. Materials and Methods: A cross-sectional analysis was conducted using data from 25 Italian loop trails selected via the Wikiloc platform, considering user-uploaded GPS data from at least 20 users per trail. Real-world hiking times were compared with estimations from Komoot, Outdooractive, mountain signage, and the MOVE algorithm, which incorporates individualized biological and trail characteristics. Results: Significant discrepancies were observed between actual hiking times and estimates from Komoot (ΔWK: −48.92 ± 57.16 min), Outdooractive (ΔWO: −69.13 ± 58.23 min), and mountain signage (ΔWS: −29.59 ± 59.90 min; all p < 0.001). In contrast, MOVE showed no statistically significant difference (ΔWM: −0.27 ± 65.72 min; p = 0.278), providing the most accurate predictions. Conclusions: Current hiking time estimation methods show substantial variability and inaccuracy, which may pose safety risks. MOVE demonstrated superior accuracy, offering personalized hiking time predictions based on user-specific data and trail characteristics. Integrating such advanced tools into outdoor activity planning could enhance safety and accessibility, particularly for individuals with chronic conditions. Further studies should explore integrating real-time health data to refine these tools.

Acaricidal and insecticidal activities of entomopathogenic nematodes combined with rosemary essential oil and bacterium-synthesized silver nanoparticles against camel tick, Hyalomma dromedarii and wax moth, Galleria mellonella

An innovative approach to ticks and insect pests management is necessary to mitigate the challenges posed by the indiscriminate use of chemical pesticides, which can lead to resistance development and environmental pollution. Despite their great potential, biological control agents have significant manufacturing, application, and stability limitations. Currently, using phytochemicals, biosynthesized nanoparticles, and bioagents to get rid of arthropods might be a good alternative that would make farmers less worried about residues and resistance. The present investigation was carried out to determine for the first time the in vitro acaricidal and insecticidal efficacies of endogenous two entomopathogenic nematodes (EPNs), Heterorhabditis indica and Steinernema sp. combined with either Proteus mirabilis-synthesized silver nanoparticles or Rosmarinus officinalis essential oil against the camel tick, Hyalomma dromedarii larvae and females, and greater wax moth, Galleria mellonella larvae as well. We also determined the potential effects of these treatments on the biological characteristics of H. dromedarii’s engorged females. We further investigated R. officinalis essential oil (EO) profiling and nanoparticle (AgNPs) characterization. All the evaluated combinations demonstrated synergistic effects on the larvae of G. mellonella and H. dromedarii, as well as on engorged females. When H. indica was mixed with EO or AgNPs, it worked well than when Steinernema sp. was mixed with EO or AgNPs. This was shown by the highest number of tick and insect mortalities and the lowest lethal concentration (LC50) values. One day after G. mellonella was exposed to H. indica (1,000 infective juveniles (IJs)) together with EO at 60 or 40 mg/mL, all tested individuals died. We obtained the same results when H. dromedarii females exposed to the same level of EPN with 60 mg/mL EO, and when H. dromedarii larvae treated with H. indica at 500 IJs + EO at 25 mg/mL. Treatments altered all biological parameters of engorged females, revealing extremely noticeable differences between the treated and untreated groups. Gas chromatography–mass spectrometry (GC-MS) analysis identified a total of 28 compounds in the R. officinalis EO. Visual observation showed a color change from yellow to dark brown for AgNPs biosynthesized from P. mirabilis; the transmission electron microscopy (TEM) image and ultraviolet–visible (UV-Vis) spectrum showed well-dispersed particles with a diameter of 5–45 nm; and the greatest surface plasmon peaked at 320 nm. The results demonstrated the high efficacy of combining EPN, H. indica, with EO to control tick and insect pests. This is due to its acaricidal activity on different stages of H. dromedarii, including larvae and engorged females, and its larvicidal effect on G. mellonella.

An Overview of the Therapeutic Potential of Dimeric Flavonoids for Targeting Cancer Hallmarks

Evidence found in the literature indicates that dimeric flavonoids constitute important therapeutic options against cancer. Using these molecules to prevent cancer progression might be a novel and promising therapeutic approach with advantages like fewer side effects, easy access in nature, overall health benefits and overcoming drug resistance. Cancer is a complex disease and still not understood, but there are some common mechanisms and biological characteristics underlying tumor progression that have been scrutinized over the years. This information was summarized in a conceptual framework designated as hallmarks of cancer. Dimeric flavonoids exert biological effects in several pathways involved in cancer hallmarks including cell growth, cell cycle, apoptosis, metastasis and metabolism.

A strategy for controlling Hypervirulent Klebsiella pneumoniae: inhibition of ClpV expression

The emergence and prevalence of hypervirulent Klebsiella pneumoniae (hvKP) have proposed a great challenge to control this infection. Therefore, exploring some new drugs or strategies for treating hvKP infection is an urgent issue for scientific researchers. In the present study, the clpV gene deletion strain of hvKP (ΔclpV-hvKP) was constructed using CRISPR-Cas9 technology, and the biological characteristics of ΔclpV-hvKP were investigated to explore the new targets for controlling this pathogen. The results showed that clpV gene deletion did not affect the growth ability of hvKP. However, knocking out the clpV gene markedly decreased the mucoid phenotype and the biofilm formation ability of hvKP. It reduced the interspecific competition of hvKP with Escherichia coli, Salmonella, Pseudomonas aeruginosa, and Staphylococcus aureus. The clpV deletion significantly changed the transcriptome profile of hvKP, inhibited the expression of virulence factors, and decreased the lethality of hvKP against Galleria mellonella larvae. In vitro experiments showed that lithocholic acid could inhibit the expression of the clpV gene and reduce the virulence of hvKP. Our data suggested that the clpV gene may be a potential target for decreasing hvKP infection risk.

The systemic evolutionary theory of the origin of cancer (SETOC): an update

The Systemic Evolutionary Theory of the Origin of Cancer (SETOC) is a recently proposed theory founded on two primary principles: the cooperative and endosymbiotic process of cell evolution as described by Lynn Margulis, and the integration of complex systems operating in eukaryotic cells, which is a core concept in systems biology. The SETOC proposes that malignant transformation occurs when cells undergo a continuous adaptation process in response to long-term injuries, leading to tissue remodeling, chronic inflammation, fibrosis, and ultimately cancer. This process involves a maladaptive response, wherein the 'endosymbiotic contract’ between the nuclear-cytoplasmic system (derived from the primordial archaeal cell) and the mitochondrial system (derived from the primordial α-proteobacterium) gradually breaks down. This ultimately leads to uncoordinated behaviors and functions in transformed cells. The decoupling of the two cellular subsystems causes transformed cells to acquire phenotypic characteristics analogous to those of unicellular organisms, as well as certain biological features of embryonic development that are normally suppressed. These adaptive changes enable cancer cells to survive in the harsh tumor microenvironment characterized by low oxygen concentrations, inadequate nutrients, increased catabolic waste, and increased acidity. De-endosymbiosis reprograms the sequential metabolic functions of glycolysis, the TCA cycle, and oxidative phosphorylation (OxPhos). This leads to increased lactate fermentation (Warburg effect), respiratory chain dysfunction, and TCA cycle reversal. Here, we present an updated version of the SETOC that incorporates the fundamental principles outlined by this theory and integrates the epistemological approach used to develop it.

Prognostic, biological, and structural implications of FLT3-JMD point mutations in acute myeloid leukemia: an analysis of Alliance studies.

The FLT3 gene frequently undergoes mutations in acute myeloid leukemia (AML), with internal tandem duplications (ITD) and tyrosine kinase domain (TKD) point mutations (PMs) being most common. Recently, PMs and deletions in the FLT3 juxtamembrane domain (JMD) have been identified, but their biological and clinical significance remains poorly understood. We analyzed 1660 patients with de novo AML and found FLT3-JMD mutations, mostly PMs, in 2% of the patients. Patients with FLT3-JMD mutations had a higher relapse rate and shorter disease-free survival than those with FLT3-TKD, whereas their relapse rate, disease-free and overall survival were not significantly different from those of FLT3-ITD-positive patients. In vitro experiments showed that FLT3-JMD PMs transformed hematopoietic cells and responded well to type I and II FLT3 inhibitors. Molecular dynamics simulations were used to explore the conformational changes of JMD PMs relative to wild-type FLT3. These mutations exhibited constrained domain motions with wider gate openings, potentially enhancing drug binding. Altered residue interactions and structural changes shed light on their unique functional mechanisms, with increased allosteric pathways suggesting reduced interactions with other residues. We conclude that patients with FLT3-JMD PMs represent uncommon but important subset with distinct molecular and biological features, and may benefit from FLT3 inhibitors.

Population dynamics and seasonal variation in biological characteristics of black sea bream (Acanthopagrus schlegelii) in Zhanjiang coastal waters, China

This study examined the population dynamics and seasonal variation (winter-summer) in the biological characteristics of black sea bream (Acanthopagrus schlegelii) in Zhanjiang coastal waters, China. Key growth parameters were estimated using the von Bertalanffy growth model, revealing an asymptotic length (L∞) of 505.05 mm and a growth coefficient (K) of 0.26 year-¹, with an estimated longevity of 11.24 years. Mortality analysis showed a total mortality rate (Z) of 0.35 year-¹, primarily driven by natural causes (M = 0.33 year-¹) with minimal fishing impact (F = 0.02 year-¹), resulting in a low exploitation rate (E) of 0.05. Length-weight relationship (LWR) analysis indicated positive allometric growth in females and nearly isometric growth in males, with significant seasonal variations in condition factors (K). Yield Per Recruit (YPR) analysis identified a maximum sustainable exploitation rate (Emax) of 0.421, with a conservative management approach suggested at E0.1 = 0.355. Seasonal variations in reproductive indices, with higher Gonadosomatic Index (GSI) and Hepatosomatic Index (HSI) in winter, highlight the species’ reproductive cycle. The findings suggest that Acanthopagrus schlegelii is stable, with low fishing pressure. Seasonal GSI and HSI variations suggest fisheries management should time fishing to reduce impacts on reproductive success. Maintaining exploitation rates below Emax is essential for sustainable management, contributing valuable insights for fisheries conservation in coastal China.